Evidence Report/Technology Assessment Number 210 Screening and Diagnosing Gestational Diabetes Mellitus Evidence-Based Practice Evidence Report/Technology Assessment Number 210 Screening and Diagnosing Gestational Diabetes Mellitus Prepared for: Agency for Healthcare Research and Quality U.S. Department of Health and Human Services 540 Gaither Road Rockville, MD 20850 www.ahrq.gov Contract No. 290-2007-10021-I Prepared by: University of Alberta Evidence-based Practice Center Edmonton, Alberta, Canada Investigators: Research Team: Lisa Hartling, Ph.D. Donna M. Dryden, Ph.D. Alyssa Guthrie, M.S.Sc. Melanie Muise, M.A. Ben Vandermeer, M.Sc. Walie M. Aktary, B.Sc., B.Ed. Dion Pasichnyk, B.Sc. Jennifer C. Seida, M.P.H. Clinical Investigator: Lois Donovan, M.D., FRCPC AHRQ Publication No. 12(13)-E021-EF October 2012 This report is based on research conducted by the University of Alberta Evidence-based Practice Center under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No. 290-2007-10021-I). The findings and conclusions in this document are those of the authors, who are responsible for its contents; the findings and conclusions do not necessarily represent the views of AHRQ. No statement in this report should be construed as an official position of AHRQ or of the U.S. Department of Health and Human Services. The information in this report is intended to help health care decisionmakers—patients and clinicians, health system leaders, and policymakers, among others—make well-informed decisions and thereby improve the quality of health care services. This report is not intended to be a substitute for the application of clinical judgment. Anyone who makes decisions concerning the provision of clinical care should consider this report in the same way as any medical reference and in conjunction with all other pertinent information, i.e., in the context of available resources and circumstances presented by individual patients. This report may be used, in whole or in part, as the basis for development of clinical practice guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied. This document is in the public domain and may be used and reprinted without permission except those copyrighted materials that are clearly noted in the document. Further reproduction of those copyrighted materials is prohibited without the specific permission of copyright holders. Persons using assistive technology may not be able to fully access information in this report. For assistance contact EffectiveHealthCare@ahrq.hhs.gov. None of the investigators have any affiliations or financial involvement that conflicts with the material presented in this report. Suggested citation: Hartling L, Dryden DM, Guthrie A, Muise M, Vandermeer B, Aktary WM, Pasichnyk D, Seida JC, Donovan L. Screening and Diagnosing Gestational Diabetes Mellitus. Evidence Report/Technology Assessment No. 210. (Prepared by the University of Alberta Evidence-based Practice Center under Contract No. 290-2007-10021-I.) AHRQ Publication No. 12(13)-E021-EF. Rockville, MD: Agency for Healthcare Research and Quality. October 2012. www.effectivehealthcare.ahrq.gov/reports/final.cfm. ii Preface The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-based Practice Centers (EPCs), sponsors the development of evidence reports and technology assessments to assist public- and private-sector organizations in their efforts to improve the quality of health care in the United States. The reports and assessments provide organizations with comprehensive, science-based information on common, costly medical conditions, and new health care technologies and strategies. The EPCs systematically review the relevant scientific literature on topics assigned to them by AHRQ and conduct additional analyses when appropriate prior to developing their reports and assessments. To bring the broadest range of experts into the development of evidence reports and health technology assessments, AHRQ encourages the EPCs to form partnerships and enter into collaborations with other medical and research organizations. The EPCs work with these partner organizations to ensure that the evidence reports and technology assessments they produce will become building blocks for health care quality improvement projects throughout the Nation. The reports undergo peer review and public comment prior to their release as a final report. AHRQ expects that the EPC evidence reports and technology assessments will inform individual health plans, providers, and purchasers as well as the health care system as a whole by providing important information to help improve health care quality. We welcome comments on this evidence report. Comments may be sent by mail to the Task Order Officer named in this report to: Agency for Healthcare Research and Quality, 540 Gaither Road, Rockville, MD 20850, or by email to epc@ahrq.hhs.gov. Carolyn M. Clancy, M.D. Director Agency for Healthcare Research and Quality Jean Slutsky, P.A., M.S.P.H. Director, Center for Outcomes and Evidence Agency for Healthcare Research and Quality Stephanie Chang, M.D., M.P.H. Director Evidence-based Practice Program Center for Outcomes and Evidence Agency for Healthcare Research and Quality Suchitra Iyer, Ph.D. Task Order Officer Center for Outcomes and Evidence Agency for Healthcare Research and Quality iii Acknowledgments The authors gratefully acknowledge the following individuals for their contributions to this project: Tamara Durec (searching), Andrea Milne (searching, technical support), Teodora Radisic (article retrieval), Jocelyn Shulhan (screening), Annabritt Chisholm (research support, reference management), and Noah Toppings (development of Figure 1). We thank Dr. Alun Edwards for providing clinical input throughout the project. Technical Expert Panel Howard Berger, M.D. Assistant Professor Health Policy, Management, and Evaluation University of Toronto Toronto, ON Wanda K. Nicholson, M.D., M.P.H., M.B.A. Associate Professor Obstetrics and Gynecology University of North Carolina Chapel Hill, NC Siri L. Kjos, M.D., M.S.Ed. Clinical Faculty David Geffen School of Medicine University of California, Los Angeles Torrance, CA Leann Olansky, M.D. Medical Director Lennon Diabetes Center, Huron Hospital Cleveland Clinic East Cleveland, OH Joy Melnikow, M.D., M.P.H Professor Family and Community Medicine University of California, Davis Sacramento, CA iv Peer Reviewers Hélène Long, M.D. Endocrinologist Cité de la Santé de Laval Hospital Laval, QC, Canada Florence Brown, M.D. Assistant Professor, Harvard Medical School Director, Joslin-Beth Israel Deaconess Diabetes and Pregnancy Program Boston, MA Julia Lowe, M.D. Associate Professor, Endocrinology University of Toronto, Sunnybrook Health Sciences Center Toronto, ON, Canada William Callaghan, M.D., M.P.H. Senior Scientist Maternal and Infant Health Branch Division of Reproductive Health National Center for Chronic Disease Prevention and Health Promotion Atlanta, GA James Peter VanDorsten, M.D. Professor Department of Obstetrics and Gynecology Medical University of South Carolina Charleston, SC Robert P. Kauffman, M.D. Professor Department of Obstetrics and Gynecology Texas Tech University Lubbock, TX v Screening and Diagnosing Gestational Diabetes Mellitus Structured Abstract Background. There is uncertainty as to the optimal approach for screening and diagnosis of gestational diabetes mellitus (GDM). Based on systematic reviews published in 2003 and 2008, the U.S. Preventive Services Task Force concluded that there was insufficient evidence upon which to make a recommendation regarding routine screening of all pregnant women. Objectives. (1) Identify properties of screening tests for GDM, (2) evaluate benefits and harms of screening for GDM, (3) assess the effects of different screening and diagnostic thresholds on outcomes for mothers and their offspring, and (4) determine the benefits and harms of treatment for a diagnosis of GDM. Data Sources. We searched 15 electronic databases from 1995 to May 2012, including MEDLINE and Cochrane Central Register of Controlled Trials (which contains the Cochrane Pregnancy and Childbirth Group registry); gray literature; Web sites of relevant organizations; trial registries; and reference lists. Methods. Two reviewers independently conducted study selection and quality assessment. One reviewer extracted data, and a second reviewer verified the data. We included published randomized and nonrandomized controlled trials and prospective and retrospective cohort studies that compared any screening or diagnostic test with any other screening or diagnostic test; any screening with no screening; women who met various thresholds for GDM with those who did not meet various criteria, where women in both groups did not receive treatment; any treatment for GDM with no treatment. We conducted a descriptive analysis for all studies and metaanalyses when appropriate. Key outcomes included preeclampsia, maternal weight gain, birth injury, shoulder dystocia, neonatal hypoglycemia, macrosomia, and long-term metabolic outcomes for the child and mother. Results. The search identified 14,398 citations and included 97 studies (6 randomized controlled trials, 63 prospective cohort studies, and 28 retrospective cohort studies). Prevalence of GDM varied across studies and diagnostic criteria: American Diabetes Association (75 g) 2 to 19 percent; Carpenter and Coustan 3.6 to 38 percent; National Diabetes Data Group 1.4 to 50 percent; and World Health Organization 2 to 24.5 percent. Lack of a gold standard for the diagnosis of GDM and little evidence about the accuracy of screening strategies for GDM remain problematic. The 50 g oral glucose challenge test with a glucose threshold of 130 mg/dL versus 140 mg/dL improves sensitivity and reduces specificity. Both thresholds have high negative predictive values (NPV) but variable positive predictive values (PPVs) across a range of prevalence. There was limited evidence for the screening of GDM diagnosed less than 24 weeks’ gestation (three studies). One study compared the International Association of Diabetes in Pregnancy Study Groups’ (IADPSG) diagnostic criteria with a two-step strategy. Sensitivity was 82 percent, specificity was 94 percent. Only two studies examined the effects on health outcomes from screening for GDM. One retrospective cohort study (n=1,000) showed more cesarean deliveries in the screened group. A survey within a prospective cohort study (n=93) found the same incidence of macrosomia (≥4.3 kg) in screened and unscreened groups (7 percent each group). vi Thirty-eight studies examined health outcomes for women who met different criteria for GDM and did not undergo treatment. Methodologically strong studies showed a continuous positive relationship between increasing glucose levels and the incidence of primary cesarean section and macrosomia. One of these studies also found significantly fewer cases of preeclampsia, cesarean section, shoulder dystocia and/or birth injury, clinical neonatal hypoglycemia, and hyperbilirubinemia for women without GDM compared with those meeting IADPSG criteria. Among the other studies, fewer cases of preeclampsia were observed for women with no GDM and women who were false positive versus those meeting Carpenter and Coustan criteria. For maternal weight gain, few comparisons showed differences. For fetal birth trauma, single studies showed no differences for women with Carpenter and Coustan GDM and World Health Organization impaired glucose tolerance versus women without GDM. Women diagnosed based on National Diabetes Data Group GDM had more fetal birth trauma compared with women without GDM. Fewer cases of macrosomia were seen in the group without GDM compared with Carpenter and Coustan GDM, Carpenter and Coustan 1 abnormal oral glucose tolerance test, National Diabetes Data Group GDM, National Diabetes Data Group false positives, and World Health Organization impaired glucose tolerance. Fewer cases of neonatal hypoglycemia were found among patient groups without GDM compared with those meeting Carpenter and Coustan criteria. There was more childhood obesity for Carpenter and Coustan GDM versus patient groups with no GDM. Eleven studies compared diet modification, glucose monitoring, and insulin as needed with no treatment. Moderate evidence showed fewer cases of preeclampsia in the treated group. The evidence was insufficient for maternal weight gain and birth injury. Moderate evidence found less shoulder dystocia with treatment for GDM. Low evidence showed no difference for neonatal hypoglycemia between treated and untreated GDM. Moderate evidence showed benefits of treatment for reduction of macrosomia (>4,000 g). There was insufficient evidence for long-term metabolic outcomes among offspring. Five studies provided data on harms of treating GDM. No difference was found for cesarean delivery, induction of labor, small for gestational age, or admission to a neonatal intensive care unit. There were significantly more prenatal visits among those treated. Conclusions. While evidence supports a positive association with increasing plasma glucose on a 75 g or 100 g oral glucose tolerance test and macrosomia and primary cesarean section, clear thresholds for increased risk were not found. The 50 g oral glucose challenge test has high NPV but variable PPV. Treatment of GDM results in less preeclampsia and macrosomia. Current evidence does not show that treatment of GDM has an effect on neonatal hypoglycemia or future poor metabolic outcomes. There is little evidence of short-term harm from treating GDM other than an increased demand for services. Research is needed on the long-term metabolic outcome for offspring as a result of GDM and its treatment, and the “real world” effects of GDM treatment on use of care. vii Contents Executive Summary ................................................................................................................ ES-1 Introduction ................................................................................................................................... 1 Gestational Diabetes Mellitus ....................................................................................................1 Risk Factors .........................................................................................................................2 Screening and Diagnostic Strategies ....................................................................................2 Treatment Strategies ............................................................................................................8 Scope and Key Questions ..........................................................................................................8 Scope of the Review ............................................................................................................8 Key Questions ......................................................................................................................9 Methods ........................................................................................................................................ 13 Topic Refinement and Technical Expert Panel .......................................................................13 Literature Search Strategy........................................................................................................13 Inclusion and Exclusion Criteria..............................................................................................14 Study Selection ........................................................................................................................14 Quality Assessment of Individual Studies .........................................................................15 Quality Assessment of Diagnostic Studies ........................................................................15 Quality Assessment of Trials .............................................................................................15 Quality Assessment of Cohort Studies ..............................................................................15 Data Extraction ........................................................................................................................16 Data Synthesis ..........................................................................................................................16 Strength of the Body of Evidence ............................................................................................17 Applicability ............................................................................................................................18 Peer Review and Public Commentary .....................................................................................18 Results .......................................................................................................................................... 19 Results of Literature Searches .................................................................................................19 Description of Included Studies ...............................................................................................21 Methodological Quality of Included Studies ...........................................................................21 Key Question 1. What are the sensitivities, specificities, reliabilities, and yields of current screening tests for GDM? ..................................................................................22 Description of Included Studies .........................................................................................22 Methodological Quality of Included Studies .....................................................................23 Detailed Synthesis ..............................................................................................................25 Key Question 2. What is the direct evidence on the benefits and harms of screening women for GDM to reduce maternal, fetal, and infant morbidity and mortality? .............40 Description of Included Studies .........................................................................................40 Methodological Quality of Included Studies .....................................................................41 Key Points ..........................................................................................................................41 Detailed Synthesis ..............................................................................................................41 Key Question 3. In the absence of treatment, how do health outcomes of mothers who meet various criteria for gdm and their offspring compare to those who do not? ..........................................................................................................42 Description of Included Studies .........................................................................................42 Methodological Quality of Included Studies .....................................................................43 Key Points ..........................................................................................................................43 viii Detailed Synthesis ..............................................................................................................45 Key Question 4. Does treatment modify the health outcomes of mothers who meet various criteria for GDM and offspring?...........................................................72 Description of Included Studies .........................................................................................72 Methodological Quality of Included Studies .....................................................................72 Key Points ..........................................................................................................................72 Detailed Synthesis ..............................................................................................................74 Key Question 5. What are the harms of treating GDM and do they vary by diagnostic approach? ..........................................................................................................90 Description of Included Studies .........................................................................................90 Methodological Quality of Included Studies .....................................................................90 Key Points ..........................................................................................................................90 Detailed Synthesis ..............................................................................................................91 Discussion..................................................................................................................................... 95 Key Findings and Discussion...................................................................................................95 Key Question 1 ..................................................................................................................95 Key Question 2 ..................................................................................................................97 Key Question 3 ..................................................................................................................98 Key Question 4 ................................................................................................................102 Key Question 5 ................................................................................................................104 Findings in Relationship to What Is Already Known ............................................................105 Applicability ..........................................................................................................................106 Limitations of the Evidence Base ..........................................................................................107 Future Research .....................................................................................................................108 Limitations of the Review......................................................................................................109 Conclusions ............................................................................................................................110 References ...................................................................................................................................120 Acronyms and Abbreviations ...................................................................................................130 Tables Table A. Diagnostic criteria and plasma glucose thresholds for GDM .................................... ES-5 Table B. Relationship between predictive values and prevalence for different screening tests ....................................................................................................................ES-14 Table C. Strength of evidence for Key Question 4: maternal and infant outcomes ............... ES-18 Table D. Summary of evidence for all Key Questions ........................................................... ES-26 Table 1. Diagnostic criteria and plasma glucose thresholds for GDM ........................................... 5 Table 2. Eligibility criteria for the review .................................................................................... 14 Table 3. Prevalence and diagnostic test characteristics for 50 g OGCT by CC or ADA (2000–2010) diagnostic criteria .............................................................................................. 28 Table 4. Prevalence and diagnostic test characteristics for 50 g OGCT by NDDG diagnostic criteria .................................................................................................................... 30 Table 5. Prevalence and diagnostic test characteristics for 50 g OGCT (different thresholds) by ADA (2000–2010) 75 g criteria ...................................................... 32 Table 6. Prevalence and diagnostic test characteristics for 50 g OGCT by WHO diagnostic criteria .................................................................................................................... 33 ix Table 7. Prevalence and diagnostic test characteristics for fasting plasma glucose by CC/ADA (2000–2010) diagnostic criteria ......................................................................... 35 Table 8. Prevalence and diagnostic test characteristics for fasting plasma glucose by NDDG-WHO and other diagnostic criteria ....................................................................... 36 Table 9. Prevalence and diagnostic test characteristics for risk factor screening by different diagnostic criteria ................................................................................................ 37 Table 10. Prevalence and characteristics of other screening tests by GDM diagnostic criteria .................................................................................................................... 38 Table 11. Prevalence and characteristics of various screening tests for screening in the first and second trimesters (Maegawa study)................................................................ 39 Table 12. Evidence summary table: maternal outcomes .............................................................. 52 Table 13. Strength of evidence summary table: maternal outcomes ............................................ 55 Table 14. Evidence summary table: fetal/neonatal outcomes ....................................................... 65 Table 15. Strength of evidence summary table: fetal/neonatal outcomes .................................... 70 Table 16. Evidence summary for Key Question 4: maternal outcomes ....................................... 78 Table 17. Evidence summary for Key Question 4: infant outcomes ............................................ 87 Table 18. Strength of evidence for Key Question 4: maternal and infant outcomes .................... 89 Table 19. Evidence summary for Key Question 5 ........................................................................ 94 Table 20. Relationship between predictive values and prevalence for different screening tests ......................................................................................................................... 97 Table 21. Summary of strength of evidence for the association between different glucose levels and maternal outcomes (Key Question 3) ....................................................... 99 Table 22. Summary of strength of evidence for the association between different glucose levels and neonatal/infant outcomes (Key Question 3) ........................................... 101 Table 23. Summary of strength of evidence for benefits of treatment (Key Question 4)........... 104 Table 24. Summary of evidence for all Key Questions .............................................................. 112 Figures Figure 1. Comparison of different diagnostic thresholds for GDM................................................ 4 Figure 2. Analytic framework for screening and diagnosing GDM ............................................. 12 Figure 3. Flow diagram of study retrieval and selection .............................................................. 20 Figure 4. QUADAS-2 assessment of risk of bias by domain ....................................................... 24 Figure 5. QUADAS-2 assessment of applicability by domain ..................................................... 24 Figure 6. Forest plot of sensitivity and specificity: 50 g OGCT by CC or ADA (2000–2010) criteria................................................................................................................ 27 Figure 7. Forest plot of sensitivity and specificity: 50 g OGCT by NDDG criteria ..................... 30 Figure 8. Forest plot of sensitivity and specificity: 50 g OGCT (different thresholds) by ADA (2000–2010) 75 g criteria ......................................................................................... 31 Figure 9. Forest plot of sensitivity and specificity: 50 g OGCT by WHO criteria ....................... 32 Figure 10. Forest plot of sensitivity and specificity: fasting plasma glucose by CC/ADA (2000–2010) criteria ............................................................................................... 34 Figure 11. Forest plot of sensitivity and specificity: Risk factor screening by different diagnostic criteria (CC/ADA, NDDG, WHO) ........................................................................ 36 Figure 12. Forest plot of sensitivity and specificity: 75 g OGTT by 100 g OGTT ...................... 40 Figure 13. CC GDM versus no GDM: preeclampsia.................................................................... 47 Figure 14. CC GDM versus false positive: preeclampsia ............................................................. 47 x Figure 15. NDDG false positive versus no GDM: preeclampsia.................................................. 48 Figure 16. WHO impaired glucose tolerance versus no GDM: preeclampsia .............................. 48 Figure 17. CC GDM versus no GDM: maternal hypertension ..................................................... 48 Figure 18. CC GDM versus false positive: maternal hypertension .............................................. 49 Figure 19. CC 1 abnormal OGTT versus no GDM: maternal hypertension ................................. 49 Figure 20. CC GDM versus no GDM: cesarean delivery ............................................................. 50 Figure 21. CC GDM versus false positive: cesarean delivery ...................................................... 50 Figure 22. CC, 1 abnormal OGTT versus no GDM: cesarean delivery ....................................... 50 Figure 23. CC false positive versus no GDM: cesarean delivery ................................................. 51 Figure 24. NDDG false positive versus no GDM: cesarean delivery ........................................... 51 Figure 25. WHO impaired glucose tolerance versus no GDM: cesarean delivery ....................... 51 Figure 26. CC, 1 abnormal OGTT versus false positive: cesarean delivery................................. 51 Figure 27. CC GDM versus no GDM: macrosomia (>4,000 g) ................................................... 56 Figure 28. CC, 1 abnormal OGTT versus no GDM: macrosomia (>4,000 g) .............................. 57 Figure 29. NDDG false positive versus no GDM: macrosomia (>4,000 g) ................................. 57 Figure 30. CC GDM versus false positive: macrosomia (>4,000 g) ............................................ 57 Figure 31. CC GDM versus 1 abnormal OGTT: macrosomia (>4,000g) ..................................... 57 Figure 32. CC false positives versus no GDM: macrosomia (>4,000 g) ...................................... 58 Figure 33. CC, 1 Abnormal OGTT versus false positives: macrosomia (>4,000 g) .................... 58 Figure 34. IADPSG GDM versus no GDM: macrosomia (>4,000 g) .......................................... 58 Figure 35. CC GDM versus no GDM: macrosomia (>4,500 g) ................................................... 59 Figure 36. CC GDM versus false positive: macrosomia (>4,500 g) ............................................ 59 Figure 37. CC GDM versus no GDM: shoulder dystocia............................................................. 60 Figure 38. CC GDM versus no GDM: hypoglycemia .................................................................. 61 Figure 39. CC, 1 abnormal OGTT versus no GDM: hypoglycemia ............................................. 61 Figure 40. WHO impaired glucose tolerance versus no GDM: hypoglycemia ............................ 61 Figure 41. CC GDM versus no GDM: hyperbilirubinemia .......................................................... 62 Figure 42. WHO impaired glucose tolerance versus no GDM: hyperbilirubinemia .................... 62 Figure 43. CC GDM versus no GDM: morbidity/mortality ......................................................... 63 Figure 44. CC GDM versus false positive: morbidity/mortality .................................................. 63 Figure 45. CC, 1 abnormal OGTT versus no GDM: morbidity/mortality .................................... 63 Figure 46. CC false positive versus no GDM: morbidity/mortality ............................................. 63 Figure 47. NDDG false positive versus no GDM: morbidity/mortality ....................................... 64 Figure 48. WHO IGT versus no GDM: morbidity/mortality........................................................ 64 Figure 49. Effect of treatment on outcomes of women with GDM: cesarean delivery ................ 75 Figure 50. Effect of treatment on outcomes of women with GDM: induction of labor ............... 76 Figure 51. Effect of treatment on outcomes of women with GDM: preeclampsia ....................... 77 Figure 52. Effect of treatment on outcomes of women with GDM: weight gain ......................... 78 Figure 53. Effect of treatment on outcomes for offspring of women with GDM: birthweight >4,000 g ............................................................................................................... 79 Figure 54. Effect of treatment on outcomes for offspring of women with GDM: birthweight (continuous) ......................................................................................................... 80 Figure 55. Effect of treatment on outcomes for offspring of women with GDM: large for gestational age (LGA) .............................................................................................. 80 Figure 56. Effect of treatment on outcomes for offspring of women with GDM: shoulder dystocia .................................................................................................................... 81 xi Figure 57. Effect of treatment on outcomes for offspring of women with GDM: birth trauma ............................................................................................................................. 82 Figure 58. Effect of treatment on outcomes for offspring of women with GDM: hypoglycemia .......................................................................................................................... 83 Figure 59. Effect of treatment on outcomes for offspring of women with GDM: hyperbilirubinemia .................................................................................................................. 83 Figure 60. Effect of treatment on outcomes for offspring of women with GDM: perinatal deaths ....................................................................................................................... 84 Figure 61. Effect of treatment on outcomes for offspring of women with GDM: respiratory complications ........................................................................................................ 85 Figure 62. Effect of treatment on outcomes for offspring of women with GDM: APGAR scores, 5 minutes ...................................................................................................... 85 Figure 63. Effect of treatment on adverse effects for infants of mothers with GDM: Small for gestational age (SGA) ............................................................................................. 91 Figure 64. Effect of treatment on adverse effects for infants of mothers with GDM: NICU admissions .................................................................................................................... 92 Figure 65. Effect of treatment on outcomes of women with GDM: induction of labor ............... 93 Figure 66. Effect of treatment on outcomes of women with GDM: cesarean delivery ................ 94 Appendixes Appendix A. Literature Search Strings Appendix B. Review Forms Appendix C. Methodological Quality of Included Studies Appendix D. Evidence Tables Appendix E. List of Excluded Studies and Unobtained Studies Appendix F. Key Question 1 HSROC Curves Appendix G. Adjusted Analyses for KQ3 xii Executive Summary Introduction Gestational Diabetes Mellitus Gestational diabetes mellitus (GDM) is defined as glucose intolerance first discovered in pregnancy. Pregestational diabetes mellitus refers to any type of diabetes diagnosed before pregnancy. Pregnant women with pregestational diabetes experience an increased risk of poor maternal, fetal, and neonatal outcomes.1 The extent to which GDM predicts adverse outcomes for mother, fetus, and neonate is less clear. Depending on the diagnostic criteria used and the population screened, the prevalence of GDM ranges from 1.1 to 25.5 percent of pregnancies in the United States.2-4 In 2009, the Centers for Disease Control and Prevention reported a prevalence of 4.8 percent of diabetes in pregnancy. An estimated 0.5 percent of these cases likely represented women with pregestational diabetes. Data from the international Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study3 indicate that 6.7 percent of the women met a fasting plasma glucose threshold of 95 mg/dL (5.3 mmol/L), which is in keeping with the Carpenter and Coustan5 (CC) criteria that are in common practice in North America. In contrast, 17.8 percent of women were diagnosed with GDM using the International Association of the Diabetes in Pregnancy Study Groups (IADPSG) criteria in which lower glucose thresholds diagnose GDM. The prevalence of GDM is not only influenced by diagnostic criteria but also by population characteristics. In a recent publication, data from the Hyperglycemia and Adverse Pregnancy Outcome Study (HAPO) demonstrated wide variability in GDM prevalence across a number of study centers, both internationally and within the United States, even when the same diagnostic criteria are applied (i.e., the IADPSG criteria).6 Prevalence in the United States ranged from 15.5 percent in Providence, RI, to 25.5 percent in Bellflower, CA. There are ethnic differences in the prevalence of GDM in the United States. Native Americans, Asians, Hispanics, and AfricanAmerican women are at higher risk than non-Hispanic white women.7 Data from 2000 showed that prevalence was highest among Asian and Hispanic women (~7 to 8 percent), intermediate among African-American women (~6 percent), and lower among non-Hispanic white women (~5 percent) based on CC criteria and/or hospital discharge diagnosis.7 The rate of increase of prevalence over the past 10 years has been highest for Asian and African-American women.7 The incidence of GDM has increased over the past decades in parallel with the increase in rates of obesity and type 2 diabetes mellitus, and this trend is expected to continue.8 It is unclear how much the increase in obesity will affect the proportion of women diagnosed with overt diabetes during pregnancy versus transient pregnancy-induced glucose intolerance. GDM is usually diagnosed after 20 weeks’ gestation when placental hormones that have the opposite effect of insulin on glucose metabolism increase substantially. Women with adequate insulin secreting capacity overcome this insulin resistance of pregnancy by secreting more endogenous insulin to maintain normal blood glucose. Women with less adequate pancreatic reserve are unable to produce sufficient insulin to overcome the increase in insulin resistance, and glucose intolerance results. Glucose abnormalities in women with GDM usually resolve postpartum, but commonly recur in subsequent pregnancies. Women with GDM have an increased risk of future development of overt diabetes. The cumulative incidence of diabetes after a diagnosis of GDM varies widely ES-1 depending on maternal body mass index (BMI), ethnicity, and time since index pregnancy, and it may reach levels as high as 60 percent.9 When glucose abnormalities persist postpartum in a woman with GDM, her diabetes is recategorized as overt diabetes. When this occurs, the likelihood that this woman had pregestational (i.e., overt) diabetes increases, especially if the diagnosis of GDM occurred before 20 weeks’ gestation and glucose levels were markedly elevated in pregnancy. Studies investigating pregnancy outcomes of women with GDM show considerable variability in the proportion of women with suspected pregestational diabetes. This variability contributes to the confusion surrounding the true morbidity of GDM. In an attempt to enable better comparability across future studies and more accurate risk stratification of pregnant women with diabetes, recommendations10 have proposed that women with more severe glucose abnormalities in pregnancy be excluded from the diagnosis of GDM. The expectation is that this would exclude women with overt diabetes from the population of women defined as having GDM. This proposal is in contrast to the older definition of GDM, which includes any degree of glucose intolerance first discovered in pregnancy. Risk Factors Risk factors for GDM include greater maternal age, higher BMI, member of an ethnic group at increased risk for development of type 2 diabetes mellitus (i.e., Hispanic, African, Native American, South or East Asian, or Pacific Islands ancestry), polyhydramnios, past history of GDM, macrosomia in a previous pregnancy, history of unexplained stillbirth, type 2 diabetes mellitus in a first degree relative, polycystic ovary syndrome, and metabolic syndrome.11 Low risk of GDM is usually defined as young (age less than 25 or 30 years), non-Hispanic white, normal BMI (25 kg/m2 or less), no history of previous glucose intolerance or adverse pregnancy outcomes associated with GDM, and no first degree relative with known diabetes.7,12 Women at high risk of GDM are usually defined as having two or more risk factors for GDM. Women at moderate risk of GDM do not satisfy all criteria of women at low risk, but they lack two or more risk factors for GDM. Screening and Diagnostic Strategies The 2008 U.S. Preventive Services Task Force (USPSTF) evidence review on screening for GDM concluded that at that time, “evidence was insufficient to assess the balance of benefits and harms of screening for GDM either before or after 24 weeks’ gestation.”13 The report suggested that “…until there was better evidence, clinicians should discuss screening for GDM with their patient and make case-by-case decisions. Discussions should include information about the uncertainty of benefits and harms as well as the frequency of positive screening test results.” The 2001 practice guidelines of the American College of Obstetricians and Gynecologists (ACOG) endorsed risk factor-based screening for GDM, recognizing that low-risk women may be less likely to benefit from screening with glucose measurements. Women were considered low risk of GDM if they met all the following criteria: (1) younger than 25 years; (2) not a member of an ethnic group at high risk for development of type 2 diabetes mellitus; (3) BMI of 25 kg/m2 or less; (4) no history of previous glucose intolerance or adverse pregnancy outcomes associated with GDM; and (5) no first degree relative with known diabetes. ACOG plans to update its 2001 practice guidelines on GDM based on the proceedings of the 2012 National Institutes of Health consensus conference on GDM diagnosis. Until 2011, the American Diabetes Association (ADA) also endorsed no screening for pregnant woman who met all the criteria ES-2 mentioned above for low risk of GDM. In 2011 the ADA changed their recommendations to endorse glucose testing for GDM in all pregnant women who do not have a diagnosis of pregestational diabetes. Common practices of glucose screening for GDM in North America involve a two-step approach in which patients with abnormal results on a screening test receive a subsequent diagnostic test.14 Typically, a 50 g oral glucose challenge test (OGCT) is initially administered between 24 and 28 weeks’ gestation in a nonfasting state, in women at moderate risk (i.e., women who do not meet all low risk criteria but lack two or more risk factors for GDM). The test is administered earlier in gestation for women at high risk of GDM (i.e., multiple risk factors for GDM) and repeated at 24–28 weeks’ gestation if initial surveillance is normal. Patients who meet or exceed a screening threshold (usually 130 mg/dL or 140 mg/dL) receive a more involved diagnostic test—the oral glucose tolerance test (OGTT), in which a 75 g or 100 g oral glucose load is administered in a fasting state, and plasma glucose levels are evaluated after 1, 2, or 3 hours. A diagnosis of GDM is made in pregnant women when one or more glucose values fall at or above the specified glucose thresholds. Alternatively, a one-step method in which all patients or high-risk patients forego the screening test and proceed directly to the OGTT has been recommended.15 The absence of a universally accepted gold standard for the diagnosis of GDM has resulted in a variety of recommended diagnostic glucose thresholds that have been endorsed by different stakeholders (Table A). These criteria reflect changes that have occurred in laboratory glucose measurements over the years and in new evidence that suggests the ability of different glucose thresholds to predict poor pregnancy outcomes. The different diagnostic criteria and thresholds result in different estimates of the prevalence of GDM. In 2004, a cross-sectional study reported that universal screening was the most common practice in the United States, with 96 percent of obstetricians routinely screening for GDM.16 In contrast, the guidelines of ACOG and the ADA at that time stated that women at low risk for GDM were unlikely to benefit from screening.14,17 Since only 10 percent of pregnant women were categorized as low risk, some argued that selective screening contributed to confusion, with little benefit and potential for harm.18 Of particular concern was the association between risk factor-based screening and high rates of false negative results.19 Others have endorsed alternative risk scoring systems for screening.20 The IADPSG, an international consensus group with representation from multiple obstetrical and diabetes organizations, recently spearheaded a reexamination of the definition of GDM in an attempt to bring uniformity to GDM diagnoses.21 The IADPSG recommended that a one-step 75 g OGTT be given to all pregnant women who do not have a diagnosis of overt diabetes. They also recommended that a single glucose value, rather than at least two abnormal values at or above diagnostic glucose thresholds on the OGTT be accepted as sufficient for a diagnosis of GDM. The diagnostic glucose thresholds recommended by the IADPSG were the maternal glucose values from the HAPO study3 that identified a 1.75-fold increase (adjusted odds ratio relative to the mean cohort glucose values) in large for gestational age, elevated C-peptide, high neonatal body fat, or in a combination of these factors. Since overt diabetes is often asymptomatic, may not have been screened for before conception, has a prevalence that is increasing dramatically in reproductive-age women, and carries a higher risk for poor pregnancy outcomes,22 the IADPSG also recommended that all women, or at least women from high-risk groups for type 2 diabetes mellitus, be screened for overt diabetes at their first prenatal visit and excluded from the diagnosis of GDM using one of the following criteria: fasting plasma glucose ES-3 ≥126 mg/dL (7.0 mmol/L), glycated hemoglobin (HbA1c) ≥6.5 percent (Diabetes Chronic Complications Trial/United Kingdom Prospective Diabetes Study standardized), or a random plasma glucose ≥200 mg/dL (11.1 mmol/L) confirmed by one of the first two measures. Treatment Strategies Initial treatment for GDM involves diet modification, glucose monitoring, and moderate exercise. When dietary management does not achieve desired glucose control, insulin or oral antidiabetic medications may be used.23 Increased prenatal surveillance may also occur as well as changes in delivery management depending on fetal size and the effectiveness of measures to control glucose. Scope of the Review Based on systematic reviews published in 2003 and 2008, the USPSTF concluded that there was insufficient evidence upon which to make a recommendation regarding routine screening of all pregnant women for GDM.13,24 Several key studies have been published since the 2008 USPSTF evidence report.3,8,25 The National Institutes of Health’s Office of Medical Applications of Research (OMAR) commissioned this report (specifically Key Questions 3 to 5, see section below), which the Agency for Healthcare Research and Quality (AHRQ) Evidence-based Practice Center (EPC) Program conducted. OMAR will use the review to inform members of consensus meetings and inform guideline development. The USPSTF joined this effort and will use the review to update its recommendation on screening for GDM (Key Questions 1 and 2). The primary aims of this review were to (1) identify the test properties of screening and diagnostic tests for GDM, (2) evaluate the potential benefits and harms of screening at ≥24 weeks and <24 weeks’ gestation, (3) assess the effects of different screening and diagnostic thresholds on outcomes for mothers and their offspring, and (4) determine the effects of treatment in modifying outcomes for women diagnosed with GDM. The benefits and harms of treatments were considered in this review to determine the downstream effects of screening on health outcomes. The intent of this review was also to assess whether evidence gaps in the previous USPSTF reviews have been filled. These gaps included lack of sufficient evidence to determine whether maternal or fetal complications are reduced by screening; lack of screening studies with adequate power to evaluate health outcomes such as mortality, neonatal intensive care unit (NICU) admissions, hyperbilirubinemia; limited evidence on the accuracy of screening strategies; and insufficient evidence on the benefits of treating GDM in improving health outcomes. ES-4 Table A. Diagnostic criteria and plasma glucose thresholds for gestational diabetes mellitus Year Organization ADA ADA Low risk† excluded IADPSG ADA 1. CC th 2. 4 IWC (same) th 3. 5 IWC (same as th 4 but 75 g accepted with same glucose thresholds) 1999 26 2000-2010 2011 Abnormal Value(s) 50 g OGCT 1 100 g OGTT 2 or more 50 g OGCT 1 0 (h) — 105 mg/dL 5.8 mmol/L — 10,27-36 37 5 1. 1982 38 2. 1998 39 3. 2007 40 NDDG 1979 WHO 1999 WHO 41 consultation WHO Testing Schedule 1985 WHO study group 42 report 100 g or 75 g OGTT after overnight fast ≥8hr Threshold (Equal to or Greater Than) 1 (h) 2 (h) 140 mg/dL — 7.8 mmol/L 190 mg/dL 165 mg/dL 10.5 mmol/L 9.1 mmol/L 130 mg/dL 7.2 mmol/L or — 140 mg/dL 7.8 mmol/L 3 (h) — 145 mg/dL 8.0 mmol/L — 140 mg/dL 7.8 mmol/L (3 hr value only for 100 g test) 2 or more 95 mg/dL 5.3 mmol/L 180 mg/dL 10.0 mmol/L 155 mg/dL 8.6 mmol/L 75 g OGTT 1 or more 92 mg/dL 5.1 mmol/L 153 mg/dL 8.5 mmol/L 50 g OGCT 1 180 mg/dL 10.0 mmol/L 130 mg/dL 7.2 mmol/L 100 g OGTT 2 or more 95 mg/dL 5.3 mmol/L 180 mg/dL 10.0 mmol/L 155 mg/dL 8.6 mmol/L 140 mg/dL 7.8 mmol/L — 105 mg/dL 5.8 mmol/L — 190 mg/dL 10.5 mmol/L — 165 mg/dL 9.1 mmol/L 140 mg/dL 7.8 mmol/L for IGT of pregnancy; 200 mg/dL 11.1 mmol/L for Dx of DM 7.8 mmol/L (140 mg/dL); for IGT of pregnancy; 200 (11.1 mmol/L) for Dx of DM — 145 mg/dL 8.0 mmol/L 50 g OGCT 100 g OGTT 75 g OGTT 75 g OGTT — — 2 or more 1 6.1 mmol/L for IGT of pregnancy; 7.0 mmol/L for Dx of DM — 1 7.8 mmol/L 140 mg/dL for IGT of pregnancy — ES-5 — — — — — Table A. Diagnostic criteria and plasma glucose thresholds for gestational diabetes mellitus (continued) Organization CDA ACOG – risk factor th 4 IWC rd 3 IWC ADIPS Testing Schedule Year 2003, 2008 2001 1991 1998 43,44 Abnormal Value(s) 50 g OGCT 1 75 g 2 or more 50 g 1 100 g CC 2 or more 100 g NDDG 2 or more 100 g OGTT 2 or more 50 g or 75 g nonfasting 1 75 g fasting 1 0 (h) — 95 mg/dL 5.3 mmol/L — 14,45 46 95 mg/dL 5.3 mmol/L 105 mg/dL 5.8 mmol/L 105 mg/dL 5.8 mmol/L — 47 99 mg/dL 5.5 mmol/L ES-6 Threshold (Equal to or Greater Than) 1 (h) 2 (h) 140 mg/dL 7.8 mmol/L or — 186 mg/dL, 10.3 mmol/L Dx GDM 191 mg/dL 160 mg/dL 10.6 mmol/L 8.9 mmol/L 130 mg/dL 7.2 mmol/L or — 140 mg/dL 7.8 mmol/L 180 mg/dL 155 mg/dL 10.0 mmol/L 8.5 mmol/L 190 mg/dL 165 mg/dL 10.5 mmol/L 9.1 mmol/L 190 mg/dL 165 mg/dL 10.5 mmol/L 9.1 mmol/L 140 mg/dL 7.8 mmol/L (50 g) or — 144 mg/dL 8.0 mmol/L (75 g) 144 mg/dL 8.0 mmol/L or — 162 mg/dL 9.0 mmol/L* 3 (h) — — — 140 mg/dL 7.8 mmol/L 145 mg/dL 8.0 mmol/L 145 mg/dL 8.0 mmol/L — — Table A. Diagnostic criteria and plasma glucose thresholds for gestational diabetes mellitus (continued) Threshold (Equal to or Greater Than) 1 (h) 2 (h) 3 (h) 162 mg/dL 48 EASD 1996 75 g 1 — — 9.0 mmol/L 130 mg/dL 7.2 mmol/L Risk assessment or — — 1 — USPSTF (Grade 1 50 g OGCT 2008‡ 140 mg/dL recommendation) 7.8 mmol/L 100 g OGTT 2 or more NR NR NR NR ACOG = American College of Obstetricians and Gynecologists; ADA = American Diabetes Association; ADIPS = Australasian Diabetes in Pregnancy Society; CC = Carpenter, Coustan; CDA = Canadian Diabetes Association; DM = diabetes mellitus; Dx = diagnosis; EASD = European Association for the Study of Diabetes; GDM = gestational diabetes mellitus; IADPSG = International Association of Diabetes in Pregnancy Study Groups; IGT = impaired glucose tolerance; IWC = International Workshop Conference; NDDG = National Diabetes Data Group; NR = not reported; OGCT = oral glucose challenge test; OGTT = oral glucose tolerance test; USPSTF = U.S. Preventive Services Task Force; WHO = World Health Organization †Low risk defined as age <25 yr, normal body weight, no first degree relative with DM, no history of abnormal glucose, no history of poor obstetrical outcomes, not of high risk ethnicity for DM. *in New Zealand. ‡ Screening for GDM: USPSTF recommendation statement Ann Intern Med 2008;148(10):759-65. Organization Year Testing Schedule Abnormal Value(s) 0 (h) 108 mg/dL 6.0 mmol/L ES-7 Key Questions OMAR and USPSTF developed the Key Questions for this evidence synthesis to inform members of consensus meetings and inform guideline development; OMAR specifically developed Key Questions 3 to 5. Investigators from the University of Alberta EPC worked in consultation with representatives from the AHRQ EPC Program, OMAR and the USPSTF, and a panel of Technical Experts to operationalize the Key Questions. The Technical Expert Panel provided content and methodological expertise throughout the development of this evidence synthesis. Participants in this panel are identified in the front matter of this report. The Key Questions are as follows: Key Question 1: What are the sensitivities, specificities, reliabilities, and yields of current screening tests for GDM? (a) After 24 weeks’ gestation? (b) During the first trimester and up to 24 weeks’ gestation? Key Question 2: What is the direct evidence on the benefits and harms of screening women (before and after 24 weeks’ gestation) for GDM to reduce maternal, fetal, and infant morbidity and mortality? Key Question 3: In the absence of treatment, how do health outcomes of mothers who meet various criteria for GDM and their offspring compare to those who do not meet the various criteria? Key Question 4: Does treatment modify the health outcomes of mothers who meet various criteria for GDM and their offspring? Key Question 5: What are the harms of treating GDM and do they vary by diagnostic approach? Methods Literature Search We systematically searched the following bibliographic databases for studies published from 1995 to May 2012: MEDLINE® Ovid, Ovid MEDLINE® In-Process & Other Non-Indexed Citations, Cochrane Central Register of Controlled Trials (contains the Cochrane Pregnancy and Childbirth Group, which hand searches journals pertinent to its content area and adds relevant trials to the registry), Cochrane Database of Systematic Reviews (CDSR), Database of Abstracts of Reviews of Effects (DARE), Global Health, Embase, Pascal CINAHL Plus with Full Text (EBSCO host), BIOSIS Previews® (Web of KnowledgeSM), Science Citation Index Expanded® and Conference Proceedings Citation Index- Science (both via Web of ScienceSM), PubMed®, LILACS (Latin American and Caribbean Health Science Literature), National Library of Medicine (NLM) Gateway, and OCLC ProceedingsFirst and PapersFirst. We searched trial registries, including the WHO International Clinical Trials Registry Platform (ICTRP), ClinicalTrials.gov, and Current Controlled Trials. We limited the search to trials and cohort studies published in English. We searched the Web sites of relevant professional associations and research groups, including the ADA, IADPSG, International Symposium of Diabetes in Pregnancy, and Diabetes ES-8 in Pregnancy Society for conference abstracts and proceedings from the past 3 years. We reviewed the reference lists of relevant reviews (including the 2008 USPSTF review) and studies that were included in this report. Study Selection Two reviewers independently screened the titles and abstracts using broad inclusion criteria. We retrieved the full text of articles classified as “include” or “unclear.” Two reviewers independently assessed each full-text article using a priori inclusion criteria and a standardized form. We resolved disagreements by consensus or third-party adjudication. We included published randomized controlled trials (RCTs), nonrandomized controlled trials (NRCTs), and prospective and retrospective cohort studies. For Key Question 1, we excluded retrospective cohort studies. We included studies of pregnant women ≥24 weeks’ gestation or <24 weeks’ gestation, with no known history of preexisting diabetes. Comparisons of interest varied by Key Question and were as follows: Key Question 1 – any GDM screening or diagnostic test compared with any GDM reference standard or other screening or diagnostic test; Key Question 2 – any GDM screening versus no GDM screening; Key Question 3 – women who met various thresholds for GDM versus those who did not meet various criteria for GDM, where women in both groups did not receive treatment; Key Questions 4 and 5 – any treatment for GDM, including but not limited to dietary advice, blood glucose monitoring, insulin therapy (all preparations), and oral hypoglycemic agents versus no treatment. Studies meeting these eligibility criteria were included if they reported data for at least one outcome specified in the Key Questions. We included studies regardless of setting and duration of followup. Quality Assessment Two reviewers independently assessed the methodological quality of studies and resolved discrepancies by discussion and consensus. For Key Question 1, we used the QUADAS-2 checklist49 to assessthe quality of diagnostic accuracy studies. We assessed the internal validity of RCTs and NRCTs using the Cochrane Collaboration Risk of Bias tool. For cohort studies, we used the Newcastle-Ottawa Scale. For Key Questions 2 to 5, we summarized the quality of individual studies as “good,” “fair,” or “poor” based on criteria specific to each tool. Data Extraction and Synthesis One reviewer extracted data using a standardized form, and a second reviewer checked the data for accuracy and completeness. We extracted information on study characteristics, inclusion and exclusion criteria, participant characteristics, details of the interventions or diagnostic/screening tests (as appropriate), and outcomes. Reviewers resolved discrepancies by consensus or in consultation with a third party. For each Key Question, we presented evidence tables detailing each study and provided a qualitative description of results. For Key Question 1, we constructed 2x2 tables and calculated sensitivity, specificity, positive and negative predictive values, reliability (i.e., accuracy), and yield (i.e., prevalence) of the screening or diagnostic tests. If studies were clinically homogenous, we pooled sensitivities and specificities using a hierarchical summary receiveroperator curve and bivariate analysis of sensitivity and specificity.50 For the other Key Questions, we combined studies in a meta-analysis if the study design, population, comparisons, and outcomes were sufficiently similar. Results were combined using random effects models. ES-9 We quantified statistical heterogeneity using the I-squared (I2) statistic. When I2 was greater than 75 percent, we did not pool results, and we investigated potential sources of heterogeneity. Strength of the Body of Evidence Two independent reviewers graded the strength of the evidence for Key Questions 3 and 4 using the EPC GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach and resolved discrepancies by discussion and consensus. We graded the evidence for the following key outcomes: birth injury, preeclampsia, neonatal hypoglycemia, maternal weight gain, and long-term metabolic outcomes of the child and mother. We made a post hoc decision to grade shoulder dystocia and macrosomia. These were not included in the protocol as outcomes that would be graded but were felt by the clinical investigators to be important to grade during the course of preparing the review. For each outcome, we assessed four major domains: risk of bias (rated as low, moderate, or high), consistency (rated as consistent, inconsistent, or unknown), directness (rated as direct or indirect), and precision (rated as precise or imprecise). The overall strength of evidence was graded as high, moderate, low, or insufficient. Applicability We assessed the applicability of the body of evidence following the PICOTS (population, intervention, comparator, outcomes, timing of outcome measurement, and setting) format used to assess study characteristics. Factors that may potentially limit applicability were discussed. Peer Review and Public Commentary Peer reviewers were invited to provide written comments on the draft report based on their clinical, content, or methodologic expertise. Peer reviewer comments on the draft report were addressed by the EPC in preparation of the final draft of the report. Peer reviewers do not participate in writing or editing of the final report or other products. The synthesis of the scientific literature presented in the final report does not necessarily represent the views of individual reviewers. The dispositions of the peer review comments are documented and will be published 3 months after the publication of the Evidence Report. Potential reviewers must disclose any financial conflicts of interest greater than $10,000 and any other relevant business or professional conflicts of interest. Invited peer reviewers may not have any financial conflict of interest greater than $10,000. Peer reviewers who disclose potential business or professional conflicts of interest may submit comments on draft reports through AHRQ’s public comment mechanism. Results Description of Included Studies The search identified 14,398 citations, and 97 studies were included: 6 RCTs, 63 prospective cohort studies, and 28 retrospective cohort studies. The studies were published between 1995 and 2012 (median 2004). Studies were conducted in the United States (24 percent), Europe (23 percent), Asia (22 percent), the Middle East (20 percent), Australia (4 percent), Central and South America (3 percent), and Canada (4 percent). The number of women enrolled in each study ranged from 32 to 23,316 (median 750). The mean age of study participants was 30 years. ES-10 Forty-eight studies (50 percent) analyzed women tested for GDM between 24 and 28 weeks, with an OGCT taking place first and the OGTT following within 7 days. Thirty-one studies (32 percent) did not specify when screening or diagnostic procedures took place. Eighteen studies (18 percent) screened or tested within unique time ranges. Of these, one study screened participants with an OGCT at 21–23 weeks followed by a diagnostic OGTT at 24–28 weeks; another screened a group of participants after 37 weeks; one study screened before 24 weeks; another screened women at risk between 14 and 16 weeks, with normal women screened at the usual 24–28 weeks; and one study screened between 16 and 20 weeks or between 17 and 21 weeks followed by a diagnostic OGTT at 26–32 weeks. Remaining studies generally provided broader screening times ranging from 21 to 32 weeks’ gestation. Studies employing WHO criteria generally screened further into gestation as only an OGTT was performed: one study screened at 28–32 weeks, and another study screened women at high risk at 18–20 weeks and others at 28–30 weeks. Methodological Quality of Included Studies The methodological quality was assessed using different tools depending on the Key Question and study design: QUADAS-2 was used for Key Question 1; for Key Questions 2 to 5, the Cochrane Risk of Bias tool was used for RCTs and the Newcastle Ottawa Scale was used for cohort studies. The methodological quality of studies is summarized for each Key Question below. Results of Included Studies The results are presented by Key Question in the sections that follow. A summary of the results for all Key Questions is provided in Table D at the end of the Executive Summary. Key Question 1 Fifty-one studies provided data for Key Question 1, which examined the diagnostic test characteristics and prevalence of current screening and diagnostic tests for GDM. Studies were conducted in a range of geographic regions: 11 in North America, 10 in Europe, 12 in Asia, 15 in the Middle East, 2 in South America, and 1 in Australia. Studies reported on findings for a number of screening tests, including the 50 g OGCT, fasting plasma glucose (FPG), and risk factor-based screening, as well as other, less common tests such as HbA1c, serum fructosamine, and adiponectin. GDM was confirmed using criteria developed by different groups, including CC, ADA, National Diabetes Data Group (NDDG), and WHO. The lack of a gold standard to confirm a diagnosis of GDM limits the ability to compare the results of studies that have used different diagnostic criteria. Different criteria result in different rates of prevalence, regardless of similarities across study settings and patient characteristics. A summary of the results is provided in Table D. Methodological quality of the studies was assessed using the QUADAS-2 tool. The domain of patient selection was rated as low risk for 53 percent and unclear risk for 22 percent of the studies. Overall, 55 percent were assessed as having high concerns about applicability for this domain. This was primarily because these studies were conducted in developing countries and used the WHO criteria to diagnose GDM. The domain of the index test was generally rated as low risk of bias (53 percent). Concern about applicability was assessed as low (82 percent). The domain of the reference standard (i.e., the criteria used to confirm a diagnosis of GDM) was rated as high or unclear risk (80 percent). For most studies, the result of the screening test was ES-11 used to determine whether patients underwent further testing for GDM (lack of blinding) or it was unclear. Concern about applicability for this domain was assessed as low (84 percent). The domain of flow and timing was assessed as low risk of bias in 39 percent of studies. However, 35 percent were assessed as unclear risk of bias because not all patients received a confirmatory reference standard if the screening test was below a certain threshold, so there is a risk of diagnostic review bias. Nine studies provided data to estimate sensitivity and specificity of a 50 g OGCT (cutoff ≥140 mg/dL); GDM was confirmed using a 100 g, 3-hour OGTT using CC criteria. Sensitivity and specificity were 85 percent (95% CI, 76 to 90) and 86 percent (95% CI, 80 to 90), respectively. Prevalence ranged from 3.8 to 31.9 percent. When prevalence was less than 10 percent, PPV ranged from 18 to 27 percent; when prevalence was 10 percent or more, PPV ranged from 32 to 83 percent. The median NPV for all studies was 98 percent. Six studies reported results for a 50 g OGCT (cutoff ≥130 mg/dL); GDM was confirmed using the CC criteria. Sensitivity was 99 percent (95% CI, 95 to 100) and specificity was 77 percent (95% CI, 68 to 83). Prevalence ranged from 4.3 to 29.8 percent. When prevalence was less than 10 percent, PPV ranged from 11 to 27 percent; when prevalence was 10 percent or more, PPV ranged from 31 to 62 percent. The median NPV for all studies was 100 percent. One study assessed a 50 g OGCT with a cutoff value of ≥200 mg/dL; GDM was confirmed using the CC criteria. Prevalence was 6.4 percent. Sensitivity, specificity, PPV and NPV were all 100 percent. The evidence showed that the 50 g OGCT with the 130 mg/dL cutpoint had higher sensitivity when compared with the 140 mg/dL cutpoint; however, specificity was lower. Both thresholds have high NPVs, but variable PPVs across a range of GDM prevalence. The Toronto Trihospital study found evidence to support the use of the lower screening cutpoint for higher risk patients, and the higher screening cutpoint for lower risk patients.12 Seven studies assessed a 50 g OGCT (≥140 mg/dL); GDM was confirmed using the NDDG criteria. Sensitivity was 85 percent (95% CI, 73 to 92) and specificity was 83 percent (95% CI, 78 to 87). Prevalence ranged from 1.4 to 45.8 percent. When prevalence was less than 10 percent, PPV ranged from 12 to 39 percent; prevalence was more than 10 percent in one study and PPV was 57 percent. The median NPV for all studies was 99 percent. Three studies that assessed a 50 g OGCT (≥130 mg/dL) using NDDG were not pooled. Prevalence ranged from 16.7 to 35.3 percent. PPV ranged from 20 to 75 percent; NPV ranged from 86 to 95 percent. Three studies assessed a 50 g OGCT (different thresholds); GDM was confirmed using the ADA 2000-2010 75 g, 2 hour criteria. Sensitivity ranged from 86 to 97 percent; specificity ranged from 79 to 87 percent. Prevalence ranged from 1.6 to 4.1 percent. PPV ranged from 7 to 20 percent; NPV ranged from 99 to 100 percent. Three studies assessed a 50 g OGCT (≥140 mg/dL) with GDM confirmed using the WHO 75 g criteria. Sensitivity was 43 to 85 percent and specificity was 73 to 94 percent. Prevalence ranged from 3.7 to 15.7. In two studies with prevalence less than 10 percent, PPV was 18 and 20 percent; in one study in which prevalence was 10 or more, PPV was 58 percent. The median NPV for all studies was 99 percent. Seven studies assessed FPG to screen for GDM; GDM was confirmed using CC criteria. Four FPG thresholds were compared— ≥85 mg/dL: sensitivity was 87 percent (95% CI, 81 to 91) and specificity was 52 percent (95% CI, 50 to 55); ≥90 mg/dL: sensitivity was 77 percent (95% CI, 66 to 85) and specificity was 76 percent (95% CI, 75 to77); ≥92 mg/dL: sensitivity was 76 percent (95% CI, 55 to 91) and specificity 92 percent (95% CI, 86 to 96); ≥95 mg/dL: ES-12 sensitivity was 54 percent (95% CI, 32 to 74) and specificity was 93 percent (95% CI, 90 to 96). While the effect on health outcomes was not part of this Key Question, the Toronto Trihospital and HAPO studies demonstrated the ability of using fasting glucose to predict GDM outcomes. Limited data support the use of HbA1c as a screening test. One study conducted in the United Arab Emirates using an HbA1c value of 5.5 percent or more lacked specificity (21 percent) despite good sensitivity (82 percent). A study conducted in Turkey showed that an HbA1c cutoff of 7.2 percent or more had 64 percent sensitivity and specificity. HbA1c does not perform as well as the 50 g OGCT as a screening test for GDM. However, when HbA1c is markedly elevated, this supports a possible diagnosis of overt diabetes discovered in pregnancy. Since 2011–2012, the ADA has endorsed the use of an HbA1c of 6.5 percent or more as diagnostic of diabetes in nonpregnant women.36 Although eight studies examined risk factors for screening women, our review did not identify compelling evidence for or against risk factor-based screening. Studies used different diagnostic criteria and could not be pooled. Sensitivity and specificity varied widely across studies. Only three studies included women who were in their first trimester of pregnancy, and they used different diagnostic criteria. Therefore, no conclusions can be made about the test characteristics of the screening tests for this group of women. Four studies compared the 75 g and 100 g load tests, but they were conducted in different countries and used different criteria or thresholds. The prevalence of GDM ranged from 1.4 to 50 percent. Sensitivity and specificity varied widely across studies. Limited data are available to draw conclusions about the effectiveness of the different options for diagnostic testing for GDM. However, because both the 75 g and 100 g load tests are positively linked with outcomes3,51 and the 75 g test is less time consuming, the adoption of the 75 g glucose load may be warranted, even if thresholds continue to be debated.3,51 The IADPSG has proposed the elimination of a screening test in favor of proceeding directly to a diagnostic test for GDM. We identified only one study that compared the IADPSG criteria with the Australasian Diabetes in Pregnancy Society (two-step) criteria. The sensitivity was 82 percent (95% CI: 74 to 88) and specificity was 94 percent (95% CI: 93 to 96); the PPV and NPV were 61 percent (95% CI: 53 to 68) and 98 (95% CI: 97 to 99), respectively. Prevalence and Predictive Values The prevalence of GDM varied across studies and the diagnostic criteria used. Factors contributing to the variability included differences in study setting (i.e., country), screening practices (e.g., universal vs. selective), and population characteristics (e.g., race/ethnicity, age, BMI). The predictive value of a screening or diagnostic test is determined by the test’s sensitivity and specificity and by the prevalence of GDM. Table B presents a series of scenarios that demonstrate the changes in PPV and NPV for three levels of prevalence (7 percent, 15 percent, and 25 percent).6 Separate tables are presented for different screening and diagnostic criteria. The higher the prevalence of GDM, the higher the PPV, or the more likely a positive result is able to predict the presence of GDM. When the prevalence of GDM is low, the PPV is also low, even when the test has high sensitivity and specificity. Generally the NPV (negative result rules out GDM) is very high—98 percent or better at a GDM prevalence of 7 percent. ES-13 Table B. Relationship between predictive values and prevalence for different screening tests Screening Test Prevalence Positive Predictive Value Negative Predictive Value 50 g OGCT ≥140 mg/dL by CC/ADA (2000-2010) Sensitivity=85%; Specificity=86% 7% 31% 99% 15% 52% 97% 25% 67% 95% 50 g OGCT ≥130 mg/dL by CC/ADA (2000-2010) Sensitivity=99%; Specificity=77% 7% 24% 100% 15% 43% 100% 25% 59% 100% 7% 27% 99% 15% 47% 97% 25% 63% 94% 7% 16% 99% 15% 31% 97% 25% 46% 94% 7% 29% 99% 15% 49% 98% 25% 65% 95% 7% 24% 98% 15% 42% 95% 25% 58% 92% 7% 12% 98% 15% 24% 96% 25% 38% 92% 50 g OGCT ≥140 mg/dL by NDDG Sensitivity=85%; Specificity=83% 50 g OGCT ≥130 mg/dL by NDDG Sensitivity=88%; Specificity=66% (median) 50 g OGCT ≥140 mg/dL by ADA 75 g Sensitivity=88%; Specificity=84% (median) 50 g OGCT ≥140 mg/dL by WHO Sensitivity=78%; Specificity=81% (median) FPG (≥85 mg/dL) by CC/ADA (2000-2010) Sensitivity = 87%; Specificity = 52% Risk factor screening by 7% 21% 98% various criteria 15% 38% 96% Sensitivity=84%; Specificity=72% 25% 54% 93% (median) ADA = American Diabetes Association; CC = Carpenter-Coustan; FPG = fasting plasma glucose; NDDG = National Diabetes Data Group; OGCT = oral glucose challenge test; WHO =World Health Organization Key Question 2 Only two retrospective cohort studies were relevant to Key Question 2, which asked about the direct benefits and harms of screening for GDM. One retrospective cohort study (n=1,000) conducted in Thailand showed a significantly greater incidence of cesarean deliveries in the screened group. A survey of a subset of participants (n=93) in a large prospective cohort study involving 116,678 nurses age 25–42 years in the United States found the incidence of macrosomia (infant weight ≥ 4.3 kg) was the same in the screened and unscreened groups (7 percent each group). No RCTs were available to answer questions about screening. There is a paucity of evidence on the effect of screening women for GDM on health outcomes. The comparison for this question was women who had and had not undergone screening. Since screening is now ES-14 commonplace it may be unlikely to identify studies or cohorts in which this comparison is feasible. Key Question 3 Thirty-eight studies provided data for Key Question 3, which sought to examine health outcomes for women who met various criteria for GDM and did not receive treatment. A summary of the results is provided in Table D. The majority of data came from cohort studies or the untreated groups from RCTs. Study quality was assessed using the Newcastle-Ottawa Scale with a possible total of nine stars. The median quality score was 9 out of 9 stars. Studies receiving lower scores most often did not control for potential confounding, and/or had an important proportion of patients lost to followup. Overall, the majority of studies were considered good quality (36 of 38, 95 percent). A wide variety of diagnostic criteria and thresholds were compared across the studies. The most common groups reported and compared were GDM diagnosed by CC criteria, no GDM by any criteria (normal), impaired glucose tolerance defined as one abnormal glucose value, and false positive (positive OGCT, negative OGTT). Only single studies contributed data for many of the comparisons and outcomes; therefore, results that showed no statistically significant differences between groups cannot be interpreted as equivalence between groups, and they do not rule out potential differences. Two studies did not group women according to criteria (as above) but examined glucose levels as a continuous outcome and their association with maternal and neonatal outcomes. Both studies were methodologically strong. A continuous positive association was found between maternal glucose and birthweight (both studies), as well as fetal hyperinsulinemia (one study only). There was some evidence of an association between glucose levels and primary cesarean section and neonatal hypoglycemia, although the associations were not consistently significant. No clear glucose thresholds were found that were predictive of poor outcomes. One of these studies also found significantly fewer cases of preeclampsia, cesarean section, shoulder dystocia and/or birth injury, clinical neonatal hypoglycemia, and hyperbilirubinemia for women with no GDM compared with those meeting IADPSG criteria. For maternal outcomes among the studies that compared groups as described above, women without GDM and those testing false positive showed fewer cases of preeclampsia than those meeting CC criteria. No differences in preeclampsia were found for other comparisons, although evidence was based on few studies per comparison. Fewer cases of cesarean section were found among women without GDM compared with women meeting criteria for CC GDM, CC 1 abnormal OGTT, CC false positives, NDDG false positives, NDDG 1 abnormal oral glucose tolerance test, WHO IGT, IADPSG impaired fasting glucose (IFG), and IADPSG impaired glucose tolerance (IGT) IFG. There were fewer cases of cesarean section among false positives compared with women meeting criteria for CC GDM. For 12 other comparisons, there were no differences in rates of cesarean delivery. For maternal hypertension, significant differences were found for 8 of 16 comparisons; many comparisons were based on single studies. No GDM groups showed lower incidence of maternal hypertension when compared with CC GDM, CC 1 abnormal OGTT, IADPSG IFG, IADPSG IGT-2 (double-impaired glucose tolerance), and IADPSG IGT IFG. Other comparisons showing significant differences were CC GDM versus false positives (lower incidence for false positives), IADPSG IGT versus IGT IFG (lower incidence for IGT), and IADPSG IFG versus IGT IFG (lower incidence for IFG). ES-15 Based on single studies, no differences were observed for maternal birth trauma for three comparisons. For maternal weight gain (less weight gain considered beneficial), significant differences were found for 3 of 12 comparisons: IADPSG IGT versus no GDM (favored IGT), IADPSG IFG versus no GDM (favored IFG), IADPSG IGT-2 versus no GDM (favored IGT-2). All comparisons were based on single studies. For maternal mortality/morbidity, single studies contributed to three comparisons, and no differences were found except for fewer cases among patient groups with no GDM compared with IADPSG GDM. No studies provided data on longterm maternal outcomes, such as type 2 diabetes mellitus, obesity, and hypertension. The most commonly reported outcome for the offspring was macrosomia >4,000 g. Six of 11 comparisons showed a significant difference: there were fewer cases in the group without GDM compared with CC GDM, CC 1 abnormal OGTT, NDDG GDM (unrecognized), NDDG false positives, and WHO IGT. Fewer cases were found for women with false-positive results compared with CC GDM. Data for macrosomia >4,500 g were available for four comparisons and showed significant differences in two comparisons: patient groups with no GDM had fewer cases compared with women with CC GDM and with unrecognized NDDG GDM. For shoulder dystocia, significant differences were found for 7 of 17 comparisons; all but one comparison were based on single studies. Patient groups with no GDM showed lower incidence of shoulder dystocia when compared with CC GDM (5 studies), NDDG GDM (unrecognized), NDDG false positive, WHO IGT, IADPSG IFG, and IADPSG IGT IFG. The other significant difference showed lower incidence among the false-positive group compared with CC 1 abnormal OGTT. For fetal birth trauma or injury, four studies compared CC GDM, NDDG GDM, and WHO IGT with patient groups without GDM. No differences were observed except for NDDG GDM, which favored the group with no GDM. Only one difference was found for neonatal hypoglycemia, with fewer cases among patient groups without GDM compared with those meeting CC criteria. There were 16 comparisons for hyperbilirubinemia; the majority were based on single studies. Three comparisons showed significant differences between groups: patient groups with no GDM had fewer cases compared with CC false positive, IADPSG IGT, and IADPSG IGT-2, respectively. No differences were found for fetal morbidity/mortality for any of eight comparisons, which may be attributable to small numbers of events within some comparisons. Moreover, comparisons were based on single studies. Based on a single study, significant differences were found in prevalence of childhood obesity for CC GDM versus patients without GDM (lower prevalence for no GDM) and CC GDM versus false positives (lower prevalence for false positives). This was consistent for both childhood obesity >85th percentile as well as >95th percentile. However, this study was unable to control for maternal weight or BMI, which are established predictors of childhood obesity. No differences, based on the same single study, were found for the other four comparisons within >85th or >95th percentiles. No other studies provided data on long-term outcomes, including type 2 diabetes mellitus and transgenerational GDM. In summary, different thresholds of glucose intolerance affect maternal and neonatal outcomes of varying clinical importance. While many studies have attempted to measure the association between various criteria for GDM and pregnancy outcomes in the absence of treatment, the ability of a study or pooled analysis to find a statistically significant difference in pregnancy outcomes appears more dependent on study design, in particular the size of the study or pooled analysis, rather than the criteria used for diagnosing GDM. This is not surprising given the strong support found for a continuous positive relationship between glucose and a variety of ES-16 pregnancy outcomes. The clinical significance of absolute differences in event rates requires consideration by decisionmakers even though statistical significance was reached at the strictest diagnostic glucose thresholds for some outcomes. This question focused on outcomes for women who did not receive treatment for GDM. While women with untreated GDM have a variety of poorer outcomes than women without GDM, it cannot be assumed that treatment of GDM reverses all the short- and long-term poor outcomes observed in women with untreated GDM. Some of the reasons for the poorer outcomes in women that have untreated GDM may not be modifiable, such as the influences of genetic makeup. The strength of evidence was insufficient for most outcomes and comparisons in this question due to high risk of bias (observational studies), inconsistency across studies, and/or imprecise results. The strength of evidence was low for the following outcomes and comparisons: preeclampsia (CC GDM vs. no GDM, CC GDM vs. false positives), macrosomia >4,000 g (CC GDM vs. no GDM, CC GDM vs. false positives, CC GDM vs. 1 abnormal OGTT, CC false positives vs. no GDM, NDDG false positives vs. no GDM), macrosomia >4,500 g (CC GDM vs. no GDM), and shoulder dystocia (CC GDM vs. no GDM). Key Question 4 Eleven studies provided data for Key Question 4 to assess the effects of treatment for GDM on health outcomes of mothers and offspring. All studies compared diet modification, glucose monitoring, and insulin as needed with standard care. The strength of evidence for key outcomes is summarized in Table C, and a summary of the results is provided in Table D. Among the 11 included studies, 5 were RCTs and 6 were cohort studies. The risk of bias for the RCTs was low for one trial, unclear for three trials, and high for one trial. The trials that were unclear most commonly did not report detailed methods for sequence generation and allocation concealment. The trial assessed as high risk of bias was due to lack of blinding for outcome assessment and incomplete outcome data. The six cohort studies were all considered high quality, with overall scores of 7 to 9 on a 9-point scale. There was moderate evidence showing a significant difference for preeclampsia, with fewer cases in the treated group. There was inconsistency across studies in terms of differences in maternal weight gain, and the strength of evidence was considered insufficient. There were no data on long-term outcomes among women, including type 2 diabetes mellitus, obesity, and hypertension. In terms of infant outcomes, there was insufficient evidence for birth trauma. This was driven by lack of precision in the effect estimates and inconsistency across studies: there was no difference for RCTs, but a significant difference favoring treatment in the one cohort study. The incidence of shoulder dystocia was significantly lower in the treated groups, and this finding was consistent for the three RCTs and four cohort studies. Overall, the evidence for shoulder dystocia was considered moderate, showing a difference in favor of the treated group. For neonatal hypoglycemia, the strength of evidence was low, suggesting no difference between groups. Moderate evidence showed benefits of treatment in terms of macrosomia (>4,000 g). Only one study provided data on long-term metabolic outcomes among the offspring at a 7to 11-year followup. The strength of evidence was insufficient. For both outcomes―impaired glucose tolerance and type 2 diabetes mellitus―no differences were found between groups although the estimates were imprecise. No differences were observed in single studies that assessed BMI >95 (7- to 11-year followup) and BMI >85 percentile (5- to 7-year followup). Overall, pooled results showed no difference in BMI, and the strength of evidence was low. ES-17 In summary, there was moderate evidence showing differences in preeclampsia and shoulder dystocia, with fewer cases among women (and offspring) who were treated compared with those not receiving treatment. There was also moderate evidence showing significantly fewer cases of macrosomia (>4,000 g) among offspring of women who received treatment for GDM. The results were driven by the two largest RCTs, the Maternal Fetal Medicine Unit (MFMU)25 and the Australian Carbohydrate Intolerance in Pregnancy Study (ACHOIS),52 which had unclear and low risk of bias, respectively. There was little evidence showing differences between groups in other key maternal and infant outcomes. One potential explanation is that for the most part, the study populations included women whose glucose intolerance was less marked, as those whose glucose intolerance was more pronounced would not have been entered into a trial in which they may be assigned to a group receiving no treatment. For outcomes where results were inconsistent between studies, different study glucose threshold entry criteria did not explain the variation. For some outcomes, particularly the long-term outcomes, the strength of evidence was insufficient or low, suggesting that further research may change the results and increase our confidence in them. Moreover, for some outcomes events were rare, and the studies may not have had the power to detect clinically important differences between groups; therefore, findings of no significant difference should not be interpreted as equivalence between groups. Table C. Strength of evidence for Key Question 4: maternal and infant outcomes Outcome Preeclampsia Maternal weight gain Birth injury Shoulder dystocia Neonatal hypoglycemia Macrosomia (>4,000 g) # Studies (# Patients) 3 RCTs (2,014) 1 cohort (258) 4 RCTs (2,530) 2 cohorts (515) 2 RCTs (1,230) 1 cohort (389) 3 RCTs (2,044) 4 cohorts (3,054) 4 RCTs (2,367) 2 cohorts (2,054) 5 RCTs (2,643) 6 cohorts (3,426) Overall Strength of Evidence moderate (favors treatment) insufficient insufficient Comment The evidence provides moderate confidence that the estimate reflects the true effect in favor of the treatment group. There is insufficient evidence to draw conclusions for this outcome due to inconsistency across studies and imprecise effect estimates. insufficient low (no difference) There is insufficient evidence to make a conclusion for this outcome. There is a difference in findings for the RCTs and cohort studies; the number of events and participants across all studies does not allow for a conclusion. insufficient moderate (favors treatment) low (favors treatment) low (no difference) insufficient moderate (favors treatment) low (favors treatment) The evidence provides moderate confidence that the estimate reflects the true effect in favor of the treatment group. The evidence provides low confidence that there is no difference between groups. The evidence provides moderate confidence that the estimate reflects the true effect in favor of the treatment group. ES-18 Table C. Strength of evidence for Key Question 4: maternal and infant outcomes (continued) Outcome # Studies (# Patients) Overall Strength of Evidence Long-term metabolic outcomes: impaired 1 RCT (89) insufficient glucose tolerance Long-term metabolic 1 RCT (89) insufficient outcomes: type 2 diabetes mellitus Long-term metabolic low (no outcomes: BMI 2 RCTs th difference) (assessed as >85 and (284) th >95 percentile) BMI = body mass index; RCT = randomized controlled trial Comment There is insufficient evidence to draw conclusions for this outcome. There is insufficient evidence to draw conclusions for this outcome. The evidence provides low confidence that there is no difference between groups. Key Question 5 Five studies (four RCTs and one cohort study) provided data for Key Question 5 on the harms associated with treatment of GDM. Among the four RCTs, one had low and three had unclear risk of bias. The cohort study was high quality (7/9 points); the primary limitation was not controlling for potential confounders. Four of the studies provided data on the incidence of infants that were small for gestational age and showed no significant difference between groups. This finding may have resulted from inadequate power to detect differences due to a small number of events; therefore, the finding of no significant difference should not be interpreted as equivalence between groups. Four of the studies provided data on admission to the NICU and showed no significant differences overall. One study was an outlier because it showed a significant difference favoring the no treatment group. This difference may be attributable to site-specific policies and procedures or lack of blinding of investigators to treatment arms. Two studies reported on the number of prenatal visits and generally found significantly more visits between the treatment groups. Two of the RCTs showed no significant difference overall in the rate of induction of labor, although there was important statistical heterogeneity between studies. One RCT showed significantly more inductions of labor in the treatment group,52 while the other study did not.25 Different study protocols may account for the heterogeneity of results between studies. In the first study that showed more inductions of labor in the treatment group, no recommendations were provided regarding obstetrical care. In the second study, antenatal surveillance was reserved for standard obstetrical indications. Based on the studies included in Key Question 4 (five RCTs and six cohort studies), there was no difference in rates of cesarean section between treatment and nontreatment groups. A single study assessed depression and anxiety at 6 weeks after study entry and 3 months postpartum using the Spielberger State-Trait Anxiety Inventory and the Edinburgh Postnatal Depression Score, respectively. There was no significant difference in anxiety between the groups at either time point, although there were significantly lower rates of depression in the treatment group at 3 months postpartum. These results should be interpreted cautiously because the assessment of depression and anxiety was conducted in a subgroup of the study population. There was no evidence for some of the outcomes stipulated in the protocol, including costs and resource allocation. ES-19 Findings in Relationship to What Is Already Known This review provides evidence that treating GDM reduces some poor maternal and neonatal outcomes. The recent MFMU trial25 published in 2009 reinforces the findings of the earlier ACHOIS trial that was published in 200552 and included in an earlier version of this review.24 Both trials showed that treating GDM to targets of 5.3 or 5.5 mmol/L fasting and 6.7 or 7.0 mmol/L 2 hours postmeal reduced neonatal birthweight, large for gestational age, macrosomia, shoulder dystocia, and preeclampsia, without a reduction in neonatal hypoglycemia or hyperbilirubinemia/jaundice requiring phototherapy, or an increase in small for gestational age. In contrast to the ACHOIS trial, MFMU demonstrated a reduced cesarean section rate in the GDM treatment group. The failure of ACHOIS to find a lower cesarean section rate despite reduced neonatal birthweight and macrosomia may have been the result of differing obstetrical practices or the different populations studied (e.g., the inclusion of some women with more marked glucose intolerance in ACHOIS, as reflected by the increased prevalence of insulin use; more black and Hispanic women in the MFMU study). Differences may have also resulted due to study design: in the ACHOIS trial, participants did not receive specific recommendations regarding obstetrical care, thus treatment was left to the discretion of the delivering health care provider. In the MFMU study, antenatal surveillance was reserved for standard obstetrical indications. Our findings of the effect of treatment of GDM is similar to a systematic review and meta-analysis published in 2010 by Horvath and colleagues.53 This review included two older RCTs of GDM that were not included in our analysis because we restricted our inclusion criteria to studies published after 1995. The HAPO Study Cooperative Research Group3 used a simpler 75 g OGTT in a large international sample of women and confirmed findings of the earlier Toronto Trihospital study51 that there is a continuous positive association between maternal glucose and increased birthweight, as well as fetal hyperinsulinemia (HAPO only), at levels below diagnostic thresholds for GDM that existed at the time of the study. However, no clear glucose thresholds were found for fetal overgrowth or a variety of other maternal and neonatal outcomes. Subsequently, the IADPSG developed diagnostic thresholds for GDM based on a consensus of expert opinion of what was considered to be the most important outcomes and the degree of acceptable risk for these outcomes. The thresholds chosen by the IADPSG were derived from the HAPO data to identify women with a higher risk (adjusted odds ratio 1.75) of large for gestational age, elevated c-peptide, and high neonatal body fat compared with the mean maternal glucose values of the HAPO study. The glucose threshold chosen by the IADPSG represents differing levels of risk for other outcomes. Specifically, their thresholds represent a 1.4 (1.26– 1.56) risk for pregnancy-induced hypertension and a 1.3 (1.07–1.58) risk for shoulder dystocia. A dichotomous view of GDM may no longer be appropriate, given evidence of a continuous relationship between maternal blood glucose and pregnancy outcomes. An alternative approach may be to define different glucose thresholds based on maternal risk for poor pregnancy outcomes. This approach has been used in the context of lipid levels and risk of adverse cardiovascular outcomes. Neither recent RCT was designed to determine diagnostic thresholds for GDM or therapeutic glucose targets. However, it is noteworthy that therapeutic glucose targets for both ACHOIS and MFMU were above the proposed diagnostic criteria of the IADPSG (fasting 5.5 mmol/L [99 mg/dL] and 5.3 mmol/L [95 mg/dL] and 2 hour postmeal of 7.0 mmol/L [126 mg/dL and 6.7 mmol/L 120 mg/dL], respectively). A change in diagnostic criteria without addressing management thresholds could contribute to clinical confusion. If diagnostic thresholds for GDM ES-20 below the treatment targets of the large RCTs are endorsed, this could ethically obstruct the possibility of future RCTs to compare different treatment targets above such diagnostic thresholds. It has been hypothesized that treatment of GDM may reduce future poor metabolic outcomes for children born to mothers with GDM. If true, the potential for long-term gain is important from a clinical and public health perspective and may justify the “costs” of screening and treating women for GDM. However, the followup of offspring from two RCTs52,54 and a HAPO cohort in Belfast 55 currently fail to support this hypothesis. This may be explained in part due to insufficient length of followup or inadequate numbers of events. The HAPO study showed that maternal weight and glucose predict large for gestational age. However, BMI was the better predictor of large for gestational age than glucose until glucose thresholds higher than the diagnostic thresholds set by the IADPSG were reached.56,57 Most cases of large for gestational age occur in neonates of mothers with normal glycemia. A large observational study found that the upper quartile of maternal BMI accounted for 23 percent of macrosomia, while GDM was responsible for only 3.8 percent.58 The ongoing obesity epidemic in the United States warrants careful consideration of a diagnostic approach for GDM that incorporates maternal BMI. This would require the development and validation of a risk model that incorporates maternal BMI as well as other modifiable risk factors. Such a model could facilitate the identification of women at high risk of adverse pregnancy outcomes and minimize exposure of lower risk women to unnecessary interventions. Applicability Several issues may limit the applicability of the evidence presented in this review to the U.S. population. All of the Key Questions asked about the effects of screening and treatment before and after 24 weeks’ gestation. The vast majority of included studies screened women after 24 weeks’ gestation; therefore, the results are not applicable to screening and treatment earlier in gestation. For Key Question 1 on the test properties of screening and diagnostic tests, comparisons involving the WHO criteria are less applicable to the U.S. setting because these criteria are not used in North America. There were insufficient data from the included studies to assess the performance of screening or diagnostic tests for specific patient characteristics (e.g., BMI, race/ethnicity). Therefore it is unclear whether the evidence applies to specific subpopulations of women. For Key Question 2, limited evidence was identified because the comparison of interest was women who had not undergone screening. Because screening is routine in prenatal care in the United States, the evidence (or limited evidence) is likely not helpful for U.S. decisionmaking, and a refinement of this question may be appropriate to reflect current practices and outstanding questions. With respect to Key Question 3, all studies or groups included for analysis involved women who had not received treatment for GDM. It cannot be assumed that the same associations and outcomes would be observed in clinical practice in which standard care is to screen for and treat GDM. The untreated women may differ from the general population in ways that are related to the reasons for which they did not seek or receive early prenatal care (e.g., socioeconomic status). That is, the reasons they did not receive treatment for GDM are varied; some reasons, such as late presentation for obstetrical care, may confound the observed association with health ES-21 outcomes. Attempts were made to control for these factors in some studies (e.g., Langer and colleagues59) by including a group of women without GDM with similar known confounders or by adjusting for known confounders in the analysis. The adjusted estimates did not change the overall pooled results in the majority of cases and did not change the overall conclusions. The majority of the studies for Key Questions 4 and 5 pertaining to the benefits and harms of treatment for GDM were conducted in North America or Australia. Most of the North American studies were inclusive of mixed racial populations and are likely applicable to the general U.S. population. Even though the Australian RCT52 population had more white women with a lower BMI than the U.S. RCT (MFMU25), this should not affect applicability of most of their findings because these patient characteristics would be factors associated with lower risk of poor outcomes. Differences in physician or hospital billing structures between the United States and Australia may have accounted for the discrepant findings with respect to NICU admissions and, as a result, may limit the applicability of this finding in the United States. Among the studies included in Key Questions 4 and 5, a variety of glucose threshold criteria were used for inclusion, varying from 50 g screen positive with nondiagnostic OGTTs, to women who met NDDG criteria for a diagnosis of GDM. The two large RCTs25,52 used different glucose thresholds for entry in their trials: WHO and CC criteria with a fasting glucose <95 mg/dL (5.3 mmol/L), respectively. The mean glucose levels at study entry were similar between these two RCTs, which may reflect a reluctance to assign women with more marked glucose intolerance to a group receiving no treatment. The results may not be applicable to women with higher levels of glucose intolerance. Limitations of the Evidence Base There is sparse evidence to clarify issues regarding the timing of screening and treatment for GDM (i.e., before and after 24 weeks’ gestation). Earlier screening will help identify overt type 2 diabetes mellitus and distinguish this from GDM. This has important implications for clinical management and ongoing followup beyond pregnancy. Previously unrecognized type 2 diabetes mellitus diagnosed in pregnancy should be excluded from the diagnosis of GDM because this condition has the highest perinatal mortality rate of all classes of glucose intolerance in pregnancy.60 This distinction within research studies will provide more targeted evidence to help obstetrical care providers to risk stratify obstetrical care and glycemic management of patients with overt type 2 diabetes mellitus diagnosed in pregnancy and those with less pronounced pregnancy-induced glucose intolerance. This will also facilitate better comparability across future studies. Few data were available on long-term outcomes. Furthermore, the studies included in this review do not provide evidence of a direct link between short-term and longterm outcomes (e.g., macrosomia and childhood obesity). Care provider knowledge of the glucose screening and diagnostic results may have introduced a bias if their subsequent treatment of women differed depending on the results. This was of particular concern for Key Question 3, which assessed how the various criteria for GDM influenced pregnancy outcomes. For Key Question 3, many of the statistically significant differences seemed to be driven by the size of the study or pooled analysis (i.e., statistically significant differences could be found if the sample were sufficiently large). However, these differences may not be clinically important. The absolute differences in event rates between different glucose thresholds need careful consideration by decisionmakers, even though statistically significant differences were found. Another key limitation with the evidence for Key Question 3 is that the studies included were cohort studies, many of which did not control for ES-22 potential confounders. Therefore, any associations between glucose thresholds and outcomes should be interpreted with caution. Given that the large landmark studies51,61 show a continuous relationship between glucose and maternal and neonatal outcomes, the lack of clear thresholds contributes to the uncertainty regarding a diagnostic threshold for GDM. While there is controversy about where to set lower limits for diagnostic criteria, the identification of overt diabetes in pregnancy is imperative if this diagnosis has not occurred before pregnancy. Overt diabetes first identified in pregnancy should be distinguished from GDM to gain a better understanding of the true risk of GDM to pregnancy outcomes. Unfortunately there is no literature to guide diagnostic criteria for a diagnosis of overt diabetes in pregnancy. There were several methodological concerns for this evidence base. For example, risk of spectrum bias and partial verification bias (Key Question 1); different definitions or methods of assessing key outcomes (e.g., clinical vs. biochemical neonatal hypoglycemia and hyperbilirubinemia) (Key Questions 3 and 4); and lack of blinding of treatment arms in some studies (Key Questions 4 and 5). Future Research Several important gaps in the current literature exist: • The adoption of a consistent comparator for diagnosis of GDM, such as the 75 g OGTT, would facilitate comparisons across studies even if different diagnostic thresholds are used. • Further analysis of the HAPO data could help answer some outstanding questions. For example, further analysis could better define absolute differences in rare event rates. This evidence could be used to inform discussions about the clinical importance of absolute differences in event rates at thresholds other than those of the IADPSG. Such analyses should include adjustment for important confounders such as maternal BMI. • Further analysis of the HAPO data, examining center-to-center differences in glucose outcome relationships would be helpful in determining the usefulness of FPG as a screening test for GDM. • Research is needed to clarify issues regarding earlier screening and treatment, particularly as they relate to the diagnosis, treatment, and long-term outcomes of pregestational (overt) diabetes. • Further research of FPG, a screening test, is needed, given that the reproducibility of fasting glucose measurement is superior to postglucose load measurements.62 • Further study of the long-term metabolic outcomes in offspring whose mothers have been treated for GDM is warranted. In addition, data on the influences of GDM treatment on long-term breastfeeding success have not been studied. The association of breastfeeding with reduced poor metabolic outcomes in offspring of GDM has been found to have a dose-dependent response with duration of breastfeeding.63 • Implementation of well-conducted prospective cohort studies of the “real world” effects of GDM treatment on use of care is needed. • Research on outcomes is needed to help determine the glucose thresholds and treatment targets at which GDM treatment benefits outweigh the risks of treatment and no treatment. This will best be achieved through well-conducted, large RCTs that randomize women with GDM to different glucose treatment targets. ES-23 • • • • • • While this review did not identify evidence of substantial harms to treatment, the populations considered were mostly women whose GDM was controlled without medication. There is a risk for more precautionary management of women diagnosed with GDM, who are perceived by clinicians to be at greater risk, such as those managed with insulin, which may result in unnecessary interventions (e.g., cesarean section).64 Therefore, RCTs investigating the care of women diagnosed with GDM, including fetal surveillance protocols, are needed to guide obstetrical investigations and management of GDM. Further, RCTs comparing delivery management for GDM with and without insulin or medical management are needed to provide clinicians guidance on appropriate timing and management of delivery in women with GDM to avoid unnecessary intervention in “the real world” driven by health care provider apprehension. The development of long-term studies that evaluate the potential increased or decreased resource use associated with the implementation of diabetes prevention strategies after a diagnosis of GDM is required. Studies to assess the long-term results that a label of GDM may have for future pregnancy planning, future pregnancy management, and future insurability are required. The increased prevalence of type 2 diabetes mellitus in women of reproductive age merits consideration of preconception screening for overt diabetes in women at risk of type 2 diabetes. In addition to poor maternal and neonatal outcomes associated with overt diabetes in pregnancy, there is potential for benefit of preconception care. Long-term benefits and harms need to be evaluated among different treatment modalities for GDM (e.g., diet, exercise, insulin, oral glucose-lowering medications, and/or combinations of these). Since 2011–2012, the American Diabetes Association has endorsed the use of an HbA1c of 6.5 percent or more as a diagnostic of diabetes in nonpregnant women.36 Studies of HbA1c with trimester-specific cutoffs to determine the value at which overt diabetes should be diagnosed in pregnancy are needed. Limitations of the Review This review followed rigorous methodological standards, which were detailed a priori. The limitations of the review to fully answer the Key Questions are largely due to the nature and limitations of the existing evidence. Several limitations need to be discussed regarding systematic reviews in general. First, there is a possibility of publication bias. The effects of publication bias on the results of diagnostic test accuracy reviews (Key Question 1) is not well understood, and the tools to investigate publication bias in these reviews have not been developed. For the remaining Key Questions, we may be missing unpublished and/or negative therapy studies and may be overestimating the benefits of certain approaches. However, we conducted a comprehensive and systematic search of the published literature for potentially relevant studies. Search strategies included combinations of subject headings and free text words. These searches were supplemented by handsearching for gray literature (i.e., unpublished or difficult-to-find studies). Despite these efforts, we recognize that we may have missed some studies. There is also a possibility of study selection bias. However, we employed at least two independent reviewers and feel confident that the studies excluded from this report were done so for consistent and appropriate reasons. Our search was comprehensive, so it is unlikely that many studies in press or publication were missed. ES-24 Cost analysis of different screening and diagnostic approaches was not addressed in this review. Conclusions There was limited evidence regarding the test characteristics of current screening and diagnostic strategies for GDM. Lack of an agreed-upon gold standard for diagnosing GDM creates challenges for assessing the accuracy of tests and comparing across studies. The 50 g OGCT with a glucose threshold of 130 mg/dL versus 140 mg/dL improves sensitivity and reduces specificity (10 studies). Both thresholds have high negative predictive value, but variable positive predictive value across a range of GDM prevalence. There was limited evidence for the screening of GDM diagnosed less than 24 weeks’ gestation (3 studies). Single studies compared the diagnostic characteristics of different pairs of diagnostic criteria in the same population. The use of fasting glucose (≥85 mg/dL) as a screen for GDM may be a practical alternative because of similar test characteristics to the OGCT, particularly in women who cannot tolerate any form of oral glucose load. Evidence supports benefits of treating GDM, with little evidence of short-term harm. Specifically, treatment of GDM results in lower incidence of preeclampsia, macrosomia, and large for gestational age infants. Current research does not demonstrate a treatment effect of GDM on clinical neonatal hypoglycemia or future poor metabolic outcomes of the offspring. RCTs of GDM treatment show limited harm related to treating GDM, other than an increased demand for services. There is a risk for more precautionary management of women diagnosed with GDM, who are perceived by clinicians to be at greater risk, such as those managed with insulin, which may result in unnecessary interventions (e.g., cesarean section); however, this review found limited data for these outcomes, and further research on the care of women diagnosed with GDM (e.g., fetal surveillance protocols) is warranted. What remains less clear is what the lower limit diagnostic thresholds for GDM should be. Given the continuous association between glucose and a variety of outcomes, decisions should be made in light of what outcomes altered by treatment are the most important and what level of increased risk is acceptable. A dichotomous view of GDM may no longer be appropriate, given evidence of a continuous relationship between maternal blood glucose and pregnancy outcomes. An alternative approach would be to define different glucose thresholds based on maternal risk for poor pregnancy outcomes. Further study is needed regarding the long-term metabolic outcomes on offspring of mothers receiving GDM treatment; the “real world” impact of GDM treatment on use of care outside of structured research trials; and the results of the timing of screening for GDM, particularly before 24 weeks’ gestation and in the first trimester of pregnancy. Early screening could help identify pregestational (i.e., overt) diabetes. Research is urgently required to determine the best way to diagnose and manage overt diabetes in pregnancy, particularly in an era of increasing rates of obesity and diabetes in the U.S. population. ES-25 Table D. Summary of evidence for all Key Questions Key Question Number and Quality of Studies Limitations/ Consistency Applicability • • KQ1. What are the sensitivities, specificities, reliabilities, and yields of current screening tests for GDM? (a) After 24 weeks’ gestation? (b) During the first trimester and up to 24 weeks’ gestation? Limitations: Lack of an agreed upon gold standard for diagnosis of GDM creates challenges for assessing the accuracy of tests and comparing across studies. GDM was confirmed using criteria developed by CC, ADA, NDDG, and WHO. (a) After 24 wk gestation 51 prospective studies Fair to good quality There were sparse data comparing overall approaches for diagnosis and screening, e.g., one-step vs. two-step, selective vs. universal. Consistency: Across studies numerous tests and thresholds were examined. Screening tests included the 50 g OGCT, FPG, risk factorbased screening, and other less common tests such as HbA1c, serum fructosamine. • Prevalence of GDM varied across studies and diagnostic criteria used. Results need to be interpreted in the context of prevalence. Comparisons involving WHO criteria are less applicable to the North American setting because these criteria are not used in North America. ES-26 • • • • Summary of Findings Prevalence varied across studies and diagnostic criteria: ADA 2000-2010 (75 g) 2.0 to 19% (range), CC 3.6 to 38%, NDDG 1.4 to 50%, WHO 2 to 24.5%. 9 studies examined a 50 g OGCT with a cutoff value of ≥140 mg/dL; GDM was confirmed using CC criteria. Results: sensitivity 85%, specificity 86%, prevalence 3.8 to 31.9%, PPV 18 to 27% (prevalence <10), PPV 32 to 83% (prevalence ≥10), NPV median 98%. 6 studies examined a 50 g OGCT (≥130 mg/dL); GDM was confirmed using CC criteria. Results: sensitivity 99%, specificity 77%, prevalence 4.3 to 29.5%, PPV 11 to 31% (prevalence <10), PPV 31 to 62% (prevalence ≥10), NPV median 100%. 1 study examined a 50 g OGCT (≥200 mg/dL); GDM was confirmed using CC criteria. Sensitivity, specificity, PPV, and NPV were all 100%. Prevalence was 6.4%. 7 studies examined a 50 g OGCT (≥140 mg/dL); GDM was confirmed using NDDG criteria. Results: sensitivity 85%, specificity 83%, prevalence 1.4 to 45.8%, PPV 12 to 39% (prevalence <10), PPV 57% (prevalence ≥10), NPV median 99%. 3 studies examined a 50 g OGCT (≥130 mg/dL); GDM was confirmed using NDDG criteria. Results: sensitivity 67 to 90% (range), specificity 47 to 84%; prevalence 16.7 to 35.3%, PPV 20 to 75%, NPV 86 to 95%. 3 studies examined a 50 g OGCT (different thresholds); GDM was confirmed using ADA 2000-2010 (75 g) criteria. Prevalence was 1.6 to 4.1% (range). Results: sensitivity 86 to 97% (range), specificity 79 to 87%; PPV 7 to 20%, NPV 99 to 100%. Table D. Summary of evidence for all Key Questions (continued) Key Question Number and Quality of Studies Limitations/ Consistency Applicability • • KQ1. What are the sensitivities, specificities, reliabilities, and yields of current screening tests for GDM? (a) After 24 weeks’ gestation? (b) During the first trimester and up to 24 weeks’ gestation? (a) After 24 wk gestation 51 prospective studies Fair to good quality • (a) After 24 wk gestation 51 prospective studies Fair to good quality (continued) • (continued) • ES-27 Summary of Findings 3 studies examined a 50 g OGCT (≥140 mg/dL); GDM was confirmed using WHO criteria. Results: sensitivity 43 to 85%, specificity 73 to 94%, prevalence 3.7 to 15.7%, PPV 18 to 20% (prevalence <10), PPV 58% (prevalence ≥10), NPV median 99%. 7 studies examined FPG at different thresholds; GDM was confirmed using CC criteria. Results: at ≥85 mg/dL sensitivity 87%, specificity 52%; at ≥90 mg/dL sensitivity 77%, specificity 76%; at ≥92 mg/dL sensitivity 76%, specificity 92%; at ≥95 mg/dL sensitivity 54%, specificity 93%. At ≥85 mg/dL prevalence 1.4 to 34.53 (range). PPV 10% (prevalence <10) and 23 to 59% (prevalence ≥10). Median NPV 93%. 8 studies examined risk factor-based screening but were not pooled. Studies used different criteria to confirm GDM. Results: sensitivity 48 to 95% (range), specificity 22 to 94%, prevalence 1.7 to 16.9%, PPV 5 to 19% (prevalence <10), PPV 20% (prevalence ≥10), NPV median 99%. 1 study compared IADPSG vs. ADIPS 2 step (reference) to diagnose GDM. Results: sensitivity 82%, specificity 94%, prevalence 13.0%, PPV 61%, NPV 98%. 4 studies compared 75 g and 100 g load tests to diagnose GDM. Prevalence ranged from 1.4 to 50%. Results were not pooled: sensitivity 18 to 100%, specificity 86 to 100%, PPV 12 to 100%, NPV 62 to 100%. Table D. Summary of evidence for all Key Questions (continued) Key Question KQ1. What are the sensitivities, specificities, reliabilities, and yields of current screening tests for GDM? (a) After 24 weeks’ gestation? (b) During the first trimester and up to 24 weeks’ gestation? Number and Quality of Studies (b) During the first trimester and up to 24 wk gestation 3 prospective cohort studies Limitations/ Consistency Applicability Limitations: Only 3 studies of women before 24 wks gestation; therefore, no conclusions can be made for test characteristics in early pregnancy. • Evidence too limited to judge applicability. Consistency: Not applicable (not enough studies addressing the same question to judge consistency). (continued) KQ2: What is the direct evidence on the benefits and harms of screening women (before and after 24 weeks’ gestation) for GDM to reduce maternal, fetal, and infant morbidity and mortality? Limitations: No RCTs available to answer this question. 2 retrospective cohort studies Fair and good quality Consistency: Not applicable (not enough studies addressing the same question to judge consistency). • The comparison for this question was women who had and had not undergone screening. Since screening is now commonplace, it may be unlikely to identify studies or cohorts where this comparison is feasible. ES-28 • Summary of Findings 1 study examined the 50 g OGCT at 10 wks and confirmed GDM using JSOG criteria (75 g). Results: sensitivity 88%, specificity 79%, prevalence 1.6%, PPV 7%, NPV 100%. 1 study examined 50 g OGCT at 20 wks and confirmed GDM using ADA (2000-2010) 100 g criteria. Results: sensitivity 56%, specificity 94%, prevalence 3.6%, PPV 24%, NPV 98%. st nd 1 study compared 1 and 2 trimester results using 3 screening tests (OGCT at ≥130 mg/dL, FPG, HbA1c); GDM confirmed using JSOG st criteria. Results (OGCT) 1 trimester: prevalence 1.9%, sensitivity 93%, specificity nd 77%, PPV 7.1, NPV 99%; 2 trimester: prevalence 2.9%, sensitivity 100%, specificity 85%, PPV 17%, NPV 100%. 1 study (n=1,000) showed more cesarean deliveries in the screened group. A second study (n=93) found the incidence of macrosomia (≥4.3 kg) was the same in screened and unscreened groups (7% each group). Based on the small number of studies and sample sizes, the effect of screening women for GDM on health outcomes is inconclusive. Table D. Summary of evidence for all Key Questions (continued) Key Question KQ3: In the absence of treatment, how do health outcomes of mothers who meet various criteria for GDM and their offspring compare to those who do not meet the various criteria? Number and Quality of Studies 38 prospective or retrospective cohort studies; 2 studies were long-term followup from RCTs; however, only data from the untreated patients were included. Fair to good quality Limitations/ Consistency Applicability Limitations: Strength of evidence was low to insufficient for all graded outcomes due to risk of bias (all observational studies), inconsistency, and/or imprecision. For many comparisons, the numbers of studies, participants, and/or events was low; therefore, findings of no statistically significant differences between groups do not imply equivalence or rule out potential differences. Consistency: A wide variety of diagnostic criteria and thresholds were compared across studies. There were often few studies with similar comparison groups. Differences in defining and assessing outcomes may have contributed to heterogeneity in results across studies (e.g., biochemical vs. clinical assessment of neonatal hypoglycemia). All studies or groups included for analysis involved women who had not received treatment for GDM. These women may differ from the general population in other ways that are related to the reasons why they did not seek or receive early prenatal care (e.g., socioeconomic status). ES-29 Summary of Findings Maternal outcomes: • A methodologically strong study showed a continuous positive relationship between increasing glucose levels and the incidence of primary cesarean section. This study also found significantly fewer cases of preeclampsia and cesarean section for women with no GDM vs. IADPSG. • For preeclampsia, significant differences were found for CC vs. patients with no GDM (3 studies), with fewer cases among the patients with no GDM, and for CC vs. false-positive groups (2 studies), with fewer cases among the false positives. The strength of evidence was low. No differences were found for NDDG false positive (2 studies), NDDG 1 abnormal OGTT vs. no GDM (1 study), or IGT WHO vs. no GDM (3 studies); the strength of evidence was insufficient. • For maternal weight gain, significant differences were found for 3 of 12 comparisons: IADPSG IGT vs. no GDM (favored IGT), IADPSG IFG vs. no GDM (favored IFG), IADPSG IGT-2 vs. no GDM (favored IGT-2). All comparisons were based on single studies (strength of evidence insufficient). Fetal/neonatal/child outcomes: • 2 methodologically strong studies showed a continuous positive relationship between increasing glucose levels and the incidence of macrosomia. 1 of these studies also showed significantly fewer cases of shoulder dystocia and/or birth injury, clinical neonatal hypoglycemia, and hyperbilirubinemia for women with no GDM vs. IADPSG. Table D. Summary of evidence for all Key Questions (continued) Key Question KQ3: In the absence of treatment, how do health outcomes of mothers who meet various criteria for GDM and their offspring compare to those who do not meet the various criteria? Number and Quality of Studies Limitations/ Consistency Applicability 38 prospective or retrospective cohort studies; 2 studies were long-term followup from RCTs; however, only data from the untreated patients were included. Fair to good quality • • (continued) (continued) ES-30 Summary of Findings For macrosomia >4,000 g, 6 of 11 comparisons showed a significant difference: patient groups with no GDM had fewer cases compared with CC GDM (10 studies), CC 1 abnormal OGTT (7 studies), NDDG GDM (unrecognized) (1 study), NDDG false positives (4 studies), and WHO IGT (1 study). Fewer cases were found for women with false-positive results compared with CC GDM (5 studies). Data for macrosomia >4,500 g were available for 4 comparisons and showed significant differences in 2 cases: patient groups with no GDM had fewer cases compared with CC GDM (3 studies) and unrecognized NDDG GDM (1 study). The strength of evidence for macrosomia was low to insufficient. For shoulder dystocia, significant differences were found for 7 of 17 comparisons; all comparisons but 1 were based on single studies (insufficient strength of evidence). Patient groups with no GDM showed lower incidence of shoulder dystocia when compared with CC GDM (5 studies, low strength of evidence), NDDG GDM (unrecognized), NDDG false positive, WHO IGT, IADPSG IFG, and IADPSG IGT IFG. The other significant difference showed lower incidence among the falsepositive group compared with CC 1 abnormal OGTT. Table D. Summary of evidence for all Key Questions (continued) Key Question KQ3: In the absence of treatment, how do health outcomes of mothers who meet various criteria for GDM and their offspring compare to those who do not meet the various criteria? Number and Quality of Studies Limitations/ Consistency Applicability 38 prospective or retrospective cohort studies; 2 studies were long-term followup from RCTs; however, only data from the untreated patients were included. Fair to good quality (continued) (continued) KQ4: Does treatment modify the health outcomes of mothers who meet various criteria for GDM and offspring? 5 RCTs and 6 retrospective cohort studies. Poor to good quality Limitations: For some outcomes, particularly the long-term outcomes, the strength of evidence was insufficient or low. Moreover, for some outcomes events were rare, and the studies may not have had the power to detect clinically important differences between groups; therefore, findings of no significant difference should not be interpreted as equivalence between groups. For the most part, study populations included women whose glucose intolerance was less marked, as those whose glucose intolerance was more pronounced would not be entered into a trial in which they may be assigned to a group receiving no treatment. The majority of studies were conducted in North America or Australia, with 2 from Italy. Most of the North American studies were inclusive of mixed racial populations and are likely applicable to the general U.S. population. ES-31 • Summary of Findings For fetal birth trauma/injury, single studies compared CC GDM and WHO IGT with no GDM and showed no differences. Two studies showed fewer cases for no GDM compared with NDDG GDM. Strength of evidence was insufficient for all comparisons. • No differences were found for neonatal hypoglycemia for any comparison, including CC GDM vs. no GDM (3 studies), CC GDM vs. 1 abnormal OGTT (1 study), CC 1 abnormal OGTT vs. no GDM (4 studies), NDDG GDM vs. no GDM (1 study), NDDG false positive vs. no GDM (1 study), and WHO IGT vs. no GDM (3 studies). Strength of evidence was insufficient for all comparisons. Maternal outcomes: • Moderate evidence from 3 RCTs showed a significant difference for preeclampsia, with fewer cases in the treated group. • There was inconsistency across studies in terms of maternal weight gain (4 RCTs and 2 cohort studies); the strength of evidence was insufficient due to inconsistency and imprecision in effect estimates. Offspring outcomes: • There was insufficient evidence to make a conclusion for birth injury. There was inconsistency across studies, with the 2 RCTs showing no difference and the 1 cohort study showing a difference in favor of the treated group. The low number of events and participants across all studies resulted in imprecise estimates. • Moderate evidence showed significantly lower incidence of shoulder dystocia in the treated groups, and this finding was consistent for the 3 RCTs and 4 cohort studies. Table D. Summary of evidence for all Key Questions (continued) Key Question KQ4: Does treatment modify the health outcomes of mothers who meet various criteria for GDM and offspring? (continued) Number and Quality of Studies 5 RCTs and 6 retrospective cohort studies. Poor to good quality (continued) Limitations/ Consistency Consistency: Some inconsistency occurred at 2 levels. First, there were inconsistencies for some outcomes between RCTs and observational studies, which may be attributable to confounding and methods of selecting study groups (e.g., historical control groups). Second, in some instances there were inconsistencies across studies within designs, that were often attributable to the manner in which outcomes were defined or assessed (e.g., clinical vs. biochemical assessment of neonatal hypoglycemia). Applicability Summary of Findings • Even though the Australian RCT population had more white women with a lower BMI than the U.S. RCTs; this should not affect applicability of most of their findings for the U.S. women because these subject characteristics would be factors associated with lower risk of poor outcomes. ES-32 • • • There was low evidence of no difference between groups for neonatal hypoglycemia based on 4 RCTs and 2 cohort studies. For outcomes related to birthweight (including macrosomia >4,000 g, macrosomia >4,500 g, actual birthweight, and large for gestational age), differences were often observed favoring the treated groups. Strength of evidence was moderate for macrosomia >4,000 g. 1 RCT followed patients for 7 to 11 years and found no differences for impaired glucose tolerance or type 2 DM, although the strength of evidence was considered insufficient. No differences were observed in single studies that assessed BMI >95 (7-11 yr followup) and BMI >85 percentile (5-7 yr followup). Overall, pooled results showed no difference in BMI, and the strength of evidence was considered low. Table D. Summary of evidence for all Key Questions (continued) Key Question Number and Quality of Studies Limitations/ Consistency Applicability • Summary of Findings 1 RCT assessed depression and anxiety at 6 weeks after study entry and 3 months postpartum. • There was no significant difference between groups in anxiety at either time point, although there were significantly lower rates of Limitations: No study depression in the treatment group at 3 months evaluated costs and resource postpartum. As above for KQ4. In allocation. Limited evidence • 4 RCTs reported small for gestational age and addition, differences in on harms. Limited evidence found no significant difference. billing structures between for number of prenatal visits • 3 RCTs and 1 cohort study provided data on the United States and and NICU admissions. admission to NICU and showed no significant KQ5: What are the Australia may have Findings of no significant 4 RCTs and 1 differences overall. One trial was an outlier harms of treating accounted for the differences may be retrospective cohort because it showed a significant difference GDM and do they discrepant findings with attributable to low power and study. favoring the no treatment group. This difference vary by diagnostic respect to NICU should not be interpreted as Fair to good quality may be attributable to site-specific policies and approach? admissions between equivalence. procedures. these studies and as a • 2 RCTs reported on the number of prenatal result limit the visits and generally found more visits among the Consistency: Not applicable applicability of this finding treatment groups. (not enough studies in the United States. • 2 RCTs reporting on induction of labor showed addressing the same different results, with 1 showing a significant question to judge). difference with more cases in the treatment group and the other showing no difference. • Based on studies included in KQ4, no differences between groups were found for cesarean section (5 RCTs, 6 cohorts) or unplanned cesarean section (1 RCT, 1 cohort). ADA = American Diabetes Association; ADIPS = Australasian Diabetes in Pregnancy Society; BMI = body mass index; CC = Carpenter and Coustan; DM = type 2 diabetes mellitus; FPG = fasting plasma glucose; GDM = gestational diabetes mellitus; HbA1c = glycated hemoglobin; IADPSG = International Association of Diabetes in Pregnancy Study Groups; IFG = impaired fasting glucose; IGT = impaired glucose tolerance; IGT-2 = double impaired glucose tolerance; JSOG = Japan Society of Obstetrics and Gynecology; NDDG = National Diabetes Data Group; NPV = negative predictive value; NICU = neonatal intensive care unit; OGCT = oral glucose challenge test; OGTT = oral glucose tolerance test; PPV = positive predictive value; RCT = randomized controlled trial; wk(s) = week(s); WHO = World Health Organization ES-33 References 1. Balsells M, Garcia-Patterson A, Gich I, et al. Maternal and fetal outcome in women with type 2 versus type 1 diabetes mellitus: a systematic review and metaanalysis. J Clin Endocrinol Metab. 2009;94(11):4284-91. PMID: 19808847. 2. National Diabetes Data Group. Diabetes in America, 2nd ed. Bethesda, MD: National Institutes of Health; 1995. 3. HAPO Study Cooperative Research Group, Metzger B, Lowe L, et al. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med. 2008;358(19):1991-2002. PMID: 18463375. 4. 5. 6. 7. 8. 9. 10. American Diabetes Association. Position statement: standards of medical care in diabetes - 2012. Diabetes Care. 2012;35(Suppl 1):S11-S63. PMID: 22187469. Carpenter MW, Coustan DR. Criteria for screening tests for gestational diabetes. Am J Obstet Gynecol. 1982;144(7):768-73. PMID: 7148898. Sacks DA, Hadden DR, Maresh M, et al. Frequency of gestational diabetes mellitus at collaborating centers based on IADPSG consensus panel-recommended criteria: the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. Diabetes Care. 2012;35(3):526-8. PMID: 22355019. Ferrara A. Increasing prevalence of gestational diabetes mellitus: a public health perspective. Diabetes Care. 2007;30(Suppl 2):S141-S146. PMID: 17596462. Gillman MW, Oakey H, Baghurst PA, et al. Effect of treatment of gestational diabetes mellitus on obesity in the next generation. Diabetes Care. 2010;33(5):964-8. PMID: 20150300. Kaufmann RC, Schleyhahn FT, Huffman DG, et al. Gestational diabetes diagnostic criteria: long-term maternal follow-up. Am J Obstet Gynecol. 1995;172(2 Pt 1):621-5. PMID: 7856695. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2006;29(Suppl 1):S43-S48. PMID: 16373932. ES-34 11. Berger H, Crane J, Farine D, et al. Screening for gestational diabetes mellitus. J Obstet Gynaecol Can. 2002;24(11):894-912. PMID: 12417905. 12. Naylor CD, Sermer M, Chen E, et al. Selective screening for gestational diabetes mellitus. Toronto Trihospital Gestational Diabetes Project Investigators. N Engl J Med. 1997;337(22):1591-6. PMID: 9371855. 13. Hillier T, Vesco K, Pedula K, et al. Screening for gestational diabetes mellitus: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2008;148:766-75. PMID: 18490689. 14. American College of Obstetricians and Gynecologists Committee on Practice Bulletins. ACOG Practice Bulletin. Clinical management guidelines for obstetriciangynecologists. Number 30, September 2001. Gestational Diabetes. Obstet Gynecol. 2001;98(3):525-38. PMID: 1154779. 15. Meltzer SJ, Snyder J, Penrod JR, et al. Gestational diabetes mellitus screening and diagnosis: a prospective randomised controlled trial comparing costs of one-step and two-step methods. BJOG. 2010;117(4):407-15. PMID: 20105163. 16. Gabbe S, Gregory R, Power M, et al. Management of diabetes mellitus by obstetrician-gynecologists. Obstet Gynecol. 2004;103(6):1229-34. PMID: 15172857. 17. American Diabetes Association. Position Statement: Diabetes mellitus. Diabetes Care. 2004;27(Suppl 1):S11-S14. PMID: 14693922. 18. Moses RG, Cheung NW. Point: universal screening for gestational diabetes mellitus. Diabetes Care. 2009;32(7):1349-51. PMID: 19564479. 19. Danilenko-Dixon DR, Van Winter JT, Nelson RL, et al. Universal versus selective gestational diabetes screening: application of 1997 American Diabetes Association recommendations. Am J Obstet Gynecol. 1999;181(4):798-802. PMID: 10521732. 20. Berger H, Sermer M. Counterpoint: selective screening for gestational diabetes mellitus. Diabetes Care. 2009;32(7):1352-4. PMID: 19564480. 31. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2004 Jan;27(Suppl 1):S5S10. PMID: 14693921. 21. Metzger B, Gabbe S, Persson B, et al. International Association of Diabetes and Pregnancy Study Groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care. 2010;33(3):676-82. PMID: 20190296. 32. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2005;28(Suppl 1):S37-S42. PMID: 15618111. 33. American Diabetes Association. Diagnosis and classification of diabetes mellitus.Diabetes Care. 2007 Jan;30(Suppl 1):S42-S7. PMID: 17192378. 34. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2008;31(Suppl 1):S55-S60. PMID: 18165338. 35. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2009;32(Suppl 1):S62-S67. PMID: 19118289. 36. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2010;33(Suppl 1):S62-S69. PMID: 20042775. 37. International association of diabetes and pregnancy study groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care. 2010;33(3):676-82. PMID: 20190296. 38. Jovanovic L. American Diabetes Association's Fourth International Workshop-Conference on Gestational Diabetes Mellitus: summary and discussion. Therapeutic interventions. Diabetes Care. 1998;21(Suppl 2):B131-37. PMID: 9704240. 39. Metzger BE, Oats JN, Kjos SL, et al. Summary and Recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care. 2007;30(Suppl 2):S251-S260. PMID: 17596481. 40. Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. National Diabetes Data Group. Diabetes. 1979;28(12):1039-57. PMID: 510803. 41. World Health Organization. Definition, diagnosis and classification of diabetes mellitus and its complications. Report of a WHO Consultation. Part 1: Diagnosis and classification of diabetes mellitus. 1999. 22. Lipscombe LL, Hux JE. Trends in diabetes prevalence, incidence, and mortality in Ontario, Canada 1995-2005: a populationbased study. Lancet. 2007;369(9563):750-6. PMID: 17336651. 23. American Diabetes Association. Position statement: gestational diabetes mellitus. Diabetes Care. 2003;26(Suppl 1):S103S105. PMID: 12502631. 24. U.S.Preventive Services Task Force. Screening for gestational diabetes mellitus: recommendations and rationale. Obstet Gynecol. 2003;101(393):395. PMID: 12576265. 25. Landon MB, Spong CY, Thom E, et al. A multicenter, randomized trial of treatment for mild gestational diabetes. N Engl J Med. 2009;361(14):1339-48. PMID: 19797280. 26. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 1999;22(Suppl 1):S5-S19. 27. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 2000;23(Suppl 1):S4-S19. PMID: 12017675. 28. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 2001;24(Suppl 1):S5-S20. 29. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 2002;25(Suppl 1):S5-S20. 30. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 2003;26(Suppl 1):S5-S20. PMID: 12502614. ES-35 42. World Health Organization. Report of a WHO study Group (Technical Report Series No.727). Report of a WHO study group (Technical Report Series No. 727). 1985. 43. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Canadian Diabetes Association 2003 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes. 2003;27(Suppl 2), S1-S152. 44. 45. 46. 47. Canadian Diabetes Association 2008 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada [corrected] [published erratum appears in Can J Diabetes 2009 Mar;33(1):46]. Can J Diabetes. 2008;32:iv. Sempowski IP, Houlden RL. Managing diabetes during pregnancy. Guide for family physicians. Canadian Family Physician Médecin De Famille Canadien. 2003;49:761-7. PMID: 12836864. Metzger BE. Summary and recommendations of the Third International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes. 1991;40(Suppl 2):197-201. PMID: 1748259. Hoffman L, Nolan C, Wilson JD, et al. Gestational diabetes mellitus--management guidelines. The Australasian Diabetes in Pregnancy Society. The Medical Journal Of Australia. 1998;169(2):93-7. PMID: 9700346. 51. Sermer M, Naylor CD, Gare DJ, et al. Impact of increasing carbohydrate intolerance on maternal-fetal outcomes in 3637 women without gestational diabetes. The Toronto Tri-Hospital Gestational Diabetes Project. Am J Obstet Gynecol. 1995;173(1):146-56. PMID: 7631672. 52. Crowther CA, Hiller JE, Moss JR, et al. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med. 2005;352(24):2477-86. PMID: 15951574. 53. Horvath K, Koch K, Jeitler K, et al. Effects of treatment in women with gestational diabetes mellitus: systematic review and meta-analysis. BMJ: British Medical Journal (International Edition). 2010;340:c1395. PMID: 20360215. 54. Malcolm JC, Lawson ML, Gaboury I, et al. Glucose tolerance of offspring of mother with gestational diabetes mellitus in a lowrisk population. Diabetic Med. 2006;23(5):565-70. PMID: 16681566. 55. Pettitt DJ, McKenna S, McLaughlin C, et al. Maternal glucose at 28 weeks of gestation is not associated with obesity in 2-year-old offspring: The Belfast Hyperglycemia and Adverse Pregnancy Outcome (HAPO) family study. Diabetes Care. 2010;33(6):1219-23. PMID: 20215449. 56. Ryan EA. Diagnosing gestational diabetes. Diabetologia. 2011;54(3):480-6. PMID: 21203743. 48. Brown CJ, Dawson A, Dodds R, et al. Report of the Pregnancy and Neonatal Care Group. Diabetic Medicine: A Journal Of The British Diabetic Association. 1996;13(9 Suppl 4):S43-S53. PMID: 8894455. 57. HAPO Study Cooperative Research Group. Hyperglycaemia and Adverse Pregnancy Outcome (HAPO) Study: associations with maternal body mass index. BJOG. 2010;117(5):575-84. PMID: 20089115. 49. Whiting PF, Rutjes AW, Westwood ME, et al. QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med. 2011;155(8):52936. PMID: 22007046. 58. Ricart W, Lopez J, Mozas J, et al. Body mass index has a greater impact on pregnancy outcomes than gestational hyperglycaemia. Diabetologia. 2005;48(9):1736-42. PMID: 16052327. 50. Reitsma JB, Glas AS, Rutjes AW, et al. Bivariate analysis of sensitivity and specificity produces informative summary measures in diagnostic reviews. J Clin Epidemiol. 2005;58(10):982-90. PMID: 16168343. 59. Langer O, Yogev Y, Most O, et al. Gestational diabetes: the consequences of not treating. Am J Obstet Gynecol. 2005;192(4):989-97. PMID: 15846171. 60. Cundy T, Gamble G, Townend K, et al. Perinatal mortality in Type 2 diabetes mellitus. Diabet Med. 2000;17(1):33-9. PMID: 10691157. ES-36 61. Sacks DA, Greenspoon JS, bu-Fadil S, et al. Toward universal criteria for gestational diabetes: The 75-gram glucose tolerance test in pregnancy. Am J Obstet Gynecol. 1995;172(2 I):607-14. PMID: 7856693. 62. Rasmussen SS, Glumer C, Sandbaek A, et al. Short-term reproducibility of impaired fasting glycaemia, impaired glucose tolerance and diabetes The ADDITION study, DK. Diabetes Res Clin Pract. 2008;80(1):146-52. PMID: 18082284. ES-37 63. Schaefer-Graf UM, Hartmann R, Pawliczak J, et al. Association of breast-feeding and early childhood overweight in children from mothers with gestational diabetes mellitus. Diabetes Care. 2006;29(5):1105-7. PMID: 16644645. 64. Buchanan TA, Kjos SL, Montoro MN, et al. Use of fetal ultrasound to select metabolic therapy for pregnancies complicated by mild gestational diabetes. Diabetes Care. 1994;17(4):275-83. PMID: 8026282. Introduction Gestational Diabetes Mellitus Gestational diabetes mellitus (GDM) is defined as glucose intolerance first discovered in pregnancy. Pregestational diabetes refers to any type of diabetes diagnosed before pregnancy. Pregnant women with pregestational diabetes experience an increased risk of poor maternal, fetal and neonatal outcomes.1 The extent to which GDM predicts adverse outcomes for mother, fetus and neonate is less clear. Depending on the diagnostic criteria used and the population screened, the prevalence of GDM ranges from 1.1 to 25.5 percent of pregnancies in the United States.2-4 In 2009 the Centers for Disease Control and Prevention reported a prevalence of 4.8 percent of diabetes in pregnancy. An estimated 0.5 percent of these cases likely represented women with pregestational diabetes. Data from the international Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study3 indicate that 6.7 percent of the women met a fasting plasma glucose threshold of 95 mg/dL (5.3 mmol/L), which is in keeping with the Carpenter and Coustan5 (CC) criteria that are in common practice in North America. In contrast, 17.8 percent of women were diagnosed with GDM using the International Association of Diabetes in Pregnancy Study Groups (IADPSG) criteria in which lower glucose thresholds are proposed to diagnose GDM. The prevalence of GDM is not only influenced by diagnostic criteria but also by population characteristics. In a recent publication, data from the HAPO study demonstrate wide variability in GDM prevalence across a variety of study centers internationally and within the United States, even when the same diagnostic criteria are applied (i.e., IADPSG).6 Prevalence in the United States ranged from 15.5 percent in Providence, RI, to 25.5 percent in Bellflower, CA. There are ethnic differences in the prevalence of GDM in the United States. Native American, Asian, Hispanic, and African-American women are at higher risk than non-Hispanic white women based on CC criteria and/or hospital discharge diagnosis.7 Data from 2000 showed that prevalence was highest among Asian and Hispanic women (~7 to 8 percent), intermediate among African-American women (~6 percent), and lower among non-Hispanic white women (~5 percent). The rate of increase of prevalence over the past 10 years has been highest for Asian and African-American women. A report from Montana demonstrated that the prevalence of GDM increased by approximately 10 percent among white women and by approximately 21 percent among Native American women from 2000 to 2003.7 The incidence of GDM has increased over the past decades in parallel with the increase in rates of obesity and type 2 diabetes mellitus, and this trend is expected to continue. In 2001 in the United States, the prevalence of obesity (body mass index [BMI] ≥30) was 20.9 percent and the prevalence of diabetes was 7.9 percent.8 It is unclear how much the increase in obesity will impact the proportion of women diagnosed with overt diabetes during pregnancy versus transient pregnancy induced glucose intolerance.9 GDM is usually diagnosed after 20 weeks’ gestation when placental hormones that have the opposite effect of insulin on glucose metabolism increase substantially. Women with adequate insulin secreting capacity overcome this insulin resistance of pregnancy by secreting more endogenous insulin in order to maintain normal blood glucose. Women with less adequate pancreatic reserve are unable to produce adequate insulin to overcome the increase in insulin resistance, and glucose intolerance results. 1 Glucose abnormalities in women with GDM usually resolve postpartum, but commonly recur in subsequent pregnancies. Women with GDM have an increased risk of future development of overt diabetes. The cumulative incidence of diabetes after a diagnosis of GDM varies widely depending on maternal BMI, ethnicity, and time since index pregnancy, and may reach levels as high as 60 percent.10 When glucose abnormalities persist postpartum in a woman with GDM, her diabetes is recategorized as overt diabetes. When this occurs, the possibility that this woman had pregestational (i.e., overt) diabetes increases, especially if the diagnosis of GDM occurred prior to 20 weeks’ gestation and glucose levels were markedly elevated in pregnancy. The increased rates of obesity and type 2 diabetes mellitus, particularly among young females, makes it increasingly important to distinguish the effect of obesity and pregestational diabetes from GDM.11,12 There is considerable variability in the proportion of women with suspected pregestational diabetes among studies that investigate pregnancy outcomes of women with GDM. This contributes to the confusion surrounding the true morbidity of GDM. In an attempt to enable better comparability across future studies and more accurate risk stratification of pregnant women with diabetes, recommendations13 have proposed the exclusion of women with more severe glucose abnormalities in pregnancy from the diagnosis of GDM in an attempt to exclude women with pregestational (i.e., overt diabetes) from the population of women defined as having GDM. This proposal is in contrast to the older definition of GDM as any degree of glucose intolerance first discovered in pregnancy. Risk Factors Risk factors for GDM include greater maternal age, higher BMI, member of an ethnic group at increased risk for development of type 2 diabetes mellitus (i.e., Hispanic, African, Native American, South or East Asian, or Pacific Inlands ancestry), polyhydramnios, past history of GDM, macrosomia in a previous pregnancy, history of unexplained stillbirth, type 2 diabetes mellitus in a first degree relative, polycystic ovary syndrome, and metabolic syndrome.14 Low risk of GDM is usually defined as young (age less than 25 or 30 years), non-Hispanic white, normal BMI (25 kg/m2 or less), no history of previous glucose intolerance or adverse pregnancy outcomes associated with GDM, and no first degree relative with known diabetes.7,15 Women at high risk of GDM are usually defined as having multiple risk factors for GDM. Women at moderate risk of GDM do not satisfy all criteria of women at low risk, but they lack two or more risks for GDM. Screening and Diagnostic Strategies The 2008 U.S. Preventive Services Task Force (USPSTF) evidence review on screening for GDM concluded that, at that time, “evidence was insufficient to assess the balance of benefits and harms of screening for gestational diabetes mellitus either before or after 24 weeks’ gestation.”16 The report suggested that “…until there was better evidence clinicians should discuss screening for GDM with their patient and make case-by-case decisions. Discussions should include information about the uncertainty of benefits and harm as well as the frequency of positive screening test results.” The 2001 practice guidelines of the American College of Obstetricians and Gynecologists (ACOG) endorsed risk factor-based screening for GDM, recognizing that low risk women may be less likely to benefit from screening with glucose measurements. Women were considered low risk of GDM if they met all the following criteria: (1) younger than 25 years; (2) not a member of an ethnic group at high risk for development of type 2 diabetes mellitus; (3) BMI of 2 25 kg/m2 or less; (4) no history of previous glucose intolerance or adverse pregnancy outcomes associated with GDM; and (5) no first degree relative with known diabetes. AGOG will update their 2001 practice guidelines on GDM based on the proceedings of the 2012 National Institutes of Health consensus conference on GDM diagnosis. Until 2011 the American Diabetes Association (ADA) also endorsed no screening for pregnant woman who met all the criteria mentioned above for low risk of GDM. In 2011 the ADA changed their recommendations to endorse glucose testing for GDM in all pregnant women who do not have a diagnosis of pregestational diabetes. Common practices of glucose screening for GDM in North America involve a two-step approach in which patients with abnormal results on a screening test receive a subsequent diagnostic test.17 Typically, a 50 g oral glucose challenge test (OGCT) is initially administered between 24 and 28 weeks’ gestation in a nonfasting state, in women at moderate risk (i.e., women who do not meet all low risk criteria but lack two or more risk factors for GDM). The test is administered earlier in gestation for women at high risk of GDM (i.e., multiple risk factors for GDM) and repeated at 24-28 weeks’ gestation if initial surveillance is normal. Patients who meet or exceed a screening threshold (usually 130 mg/dL or 140 mg/dL) receive a more involved diagnostic test, the oral glucose tolerance test (OGTT) in which a 75 g or 100 g oral glucose load is administered in a fasting state, and plasma glucose levels are evaluated after 1, 2, or 3 hours. A diagnosis of GDM is made in pregnant women when one or more glucose values fall at or above the specified glucose thresholds. Alternatively, a one-step method in which all patients or high risk patients forego the screening test and proceed directly to the OGTT has been recommended.18 Interest has grown in assessing the usefulness of fasting plasma glucose as an alternative to the OGCT for screening for GDM for a number of reasons. First, the IADPG has proposed the use of a high threshold fasting plasma glucose 126 mg/dL (7.0 mmol/L) as soon as pregnancy is confirmed in women at high risk of type 2 diabetes mellitus as a means of identifying women with overt diabetes that likely predates their pregnancy. It is hypothesized that lesser degrees of fasting glucose elevation could be used to screen for GDM if this test is already being done to rule out overt diabetes. However, fasting glucose in early pregnancy is not well studied. Second, the reproducibility of fasting glucose measurement is superior to post glucose load measurements.149 Third, some women do not tolerate the oral glucose drinks. The absence of a universally accepted “gold standard” for the diagnosis of GDM has resulted in a variety of recommended diagnostic glucose thresholds that have been endorsed by different stakeholders (Table 1; Figure 1). These criteria reflect changes that have occurred in laboratory glucose measurements over the years, and new evidence that suggests the ability of different glucose thresholds to predict poor pregnancy outcomes. The different diagnostic criteria and thresholds result in different estimates of prevalence of GDM. In 2004, a cross-sectional study reported that universal screening was the most common practice in the United States with 96 percent of obstetricians routinely screening for GDM.19 In contrast, the guidelines of ACOG and the ADA at that time stated that women at low risk for GDM were unlikely to benefit from screening.17,20 Since only 10 percent of pregnant women were categorized as low risk, some argued that selective screening contributed to confusion with little benefit and potential for harm.21 Of particular concern was the association between risk factor-based screening and high rates of false negative results.22 Others have endorsed alternative risk scoring systems for screening.23 The IADPSG, an international consensus group with representation from multiple obstetrical and diabetes organizations, recently spearheaded a re-examination of the definition of GDM in 3 an attempt to bring uniformity to GDM diagnoses.24 The IADPSG recommended that a one-step 75 g OGTT be given to all pregnant women who do not have a diagnosis of overt diabetes. They also recommended that a single glucose value, rather than at least two abnormal values at or above diagnostic glucose thresholds on the OGTT be accepted as sufficient for a diagnosis of GDM. The diagnostic glucose thresholds recommended by the IADPSG were the maternal glucose values from the HAPO study3 that identified a 1.75-fold increase (adjusted odds ratio relative to the mean cohort glucose values) in large for gestational age, elevated C-peptide, high neonatal body fat, or a combination of these factors. Since overt diabetes is often asymptomatic, may not have been screened for prior to conception, has a prevalence that is increasing dramatically in reproductive age women, and carries a higher risk for poor pregnancy outcomes, the IADPSG also recommended that all or at least women from high risk groups for type 2 diabetes mellitus be screened for overt diabetes at their first prenatal visit and excluded from the diagnosis of GDM using one of the following criteria: fasting plasma glucose ≥126 mg/dL (7.0 mmol/L), glycated hemoglobin (HbA1c) ≥6.5 percent (Diabetes Chronic Complications Trial/United Kingdom Prospective Diabetes Study standardized), or a random plasma glucose ≥200 mg/dL (11.1 mmol/L) confirmed by one of the first two measures.25 Figure 1. Comparison of different diagnostic thresholds for GDM ADA = American Diabetes Association, CC = Carpenter-Coustan, CDA = Canadian Diabetes Association, dL= deciliter, g = grams, IADPSG = International Association of Diabetes in Pregnancy Study Groups, L= liter; mg = milligrams, mmol = millimoles; NDDG = National Diabetes Data Group, WHO = World Health Organization Note: This figure presents the various diagnostic criteria for GDM. The top bar compares fasting glucose diagnostic thresholds. The bottom bar compares post glucose load diagnostic thresholds. The criteria are arranged from left (green) to right (red) from the lowest diagnostic glucose thresholds to the highest. The post glucose load bar is not entirely comparable because different glucose loads were used as indicated. The bottom part of each box shows which diagnostic thresholds were accepted by various organizations over the years including any modifications to the criteria. For example, ADA 2000 to 2010 endorsed the CC diagnostic thresholds on a 75g or 100g OGTT. 4 Table 1. Diagnostic criteria and plasma glucose thresholds for GDM Year Organization ADA ADA Low risk† excluded IADPSG ADA 1. CC th 2. 4 IWC (same) th 3. 5 IWC (same as th 4 but 75 g accepted with same glucose thresholds) 1999 26 2000-2010 2011-2012 50 g OGCT 1 100 g OGTT 2 or more 50 g OGCT 1 100 g or 75 g OGTT after overnight fast ≥8 hr 2 or more 0 (h) — 105 mg/dL 5.8 mmol/L — 13,27-36 37 5 1. 1982 38 2. 1998 39 3. 2007 40 NDDG 1979 WHO 1999 WHO 41 consultation WHO Abnormal Value(s) Testing Schedule 1985 WHO study group 42 report 75 g OGTT 1 or more 50 g OGCT 1 100 g OGTT 2 or more 50 g OGCT 100 g OGTT 75 g OGTT 75 g OGTT 95 mg/dL 5.3 mmol/L 92 mg/dL 5.1 mmol/L — — 2 or more Threshold (Equal to or Greater Than) 1 (h) 2 (h) 3 (h) 140 mg/dL — — 7.8 mmol/L 190 mg/dL 165 mg/dL 145 mg/dL 10.5 mmol/L 9.1 mmol/L 8.0 mmol/L 130 mg/dL 7.2 mmol/L or — — 140 mg/dL 7.8 mmol/L 140 mg/dL 7.8 mmol/L 180 mg/dL 155 mg/dL 10.0 mmol/L 8.6 mmol/L (3 hr value only for 100-g test) 180 mg/dL 153 mg/dL — 10.0 mmol/L 8.5 mmol/L 130 mg/dL — — 7.2 mmol/L 95 mg/dL 5.3 mmol/L 180 mg/dL 10.0 mmol/L 155 mg/dL 8.6 mmol/L 140 mg/dL 7.8 mmol/L — 105 mg/dL 5.8 mmol/L — 190 mg/dL 10.5 mmol/L — 165 mg/dL 9.1 mmol/L 140 mg/dL 7.8 mmol/L for IGT of pregnancy; 200 mg/dL 11.1 mmol/L for Dx of DM 7.8 mmol/L (140 mg/dL); for IGT of pregnancy; 200 (11.1 mmol/L) for Dx of DM — 145 mg/dL 8.0 mmol/L 1 6.1 mmol/L for IGT of pregnancy; 7.0 mmol/L for Dx of DM — 1 7.8 mmol/L 140 mg/dL for IGT of pregnancy — 5 — — Table 1. Diagnostic criteria and plasma glucose thresholds for GDM (continued) Organization CDA ACOG – risk factor th 4 IWC rd 3 IWC ADIPS Testing Schedule Year 2003, 2008 2001 1991 1998 43,44 Abnormal Value(s) 50 g OGCT 1 75 g 2 or more 50 g 1 100 g CC 2 or more 100 g NDDG 2 or more 100 g OGTT 2 or more 50 g or 75 g nonfasting 1 75 g fasting 1 0 (h) — 95 mg/dL 5.3 mmol/L — 17,45 46 95 mg/dL 5.3 mmol/L 105 mg/dL 5.8 mmol/L 105 mg/dL 5.8 mmol/L — 47 99 mg/dL 5.5 mmol/L 6 Threshold (Equal to or Greater Than) 1 (h) 2 (h) 140 mg/dL 7.8 mmol/L or — 186 mg/dL, 10.3 mmol/L Dx GDM 191 mg/dL 160 mg/dL 10.6 mmol/L 8.9 mmol/L 130 mg/dL 7.2 mmol/L or — 140 mg/dL 7.8 mmol/L 180 mg/dL 155 mg/dL 10.0 mmol/L 8.5 mmol/L 190 mg/dL 165 mg/dL 10.5 mmol/L 9.1 mmol/L 190 mg/dL 165 mg/dL 10.5 mmol/L 9.1 mmol/L 140 mg/dL 7.8 mmol/L (50 g) or — 144 mg/dL 8.0 mmol/L (75 g) 144 mg/dL 8.0 mmol/L or 1 — 62 mg/dL 9.0 mmol/L* 3 (h) — — — 140 mg/dL 7.8 mmol/L 145 mg/dL 8.0 mmol/L 145 mg/dL 8.0 mmol/L — — Table 1. Diagnostic criteria and plasma glucose thresholds for GDM (continued) Threshold (Equal to or Greater Than) 1 (h) 2 (h) 3 (h) 162 mg/dL 48 EASD 1996 75 g 1 — — 9.0 mmol/L 130 mg/dL 7.2 mmol/L Risk Assessment or — — 1 — USPSTF (Grade 1 50 g OGCT 2008‡ 140 mg/dL recommendation) 7.8 mmol/L 100 g OGTT 2 or more NR NR NR NR ACOG = American College of Obstetricians and Gynecologists, ADA = American Diabetes Association, ADIPS = Australasian Diabetes in Pregnancy Society, CC = Carpenter, Coustan, CDA = Canadian Diabetes Association, DM = diabetes mellitus, Dx = diagnosis, EASD = European Association for the Study of Diabetes, h = hours; IADPSG = International Association of Diabetes in Pregnancy Study Groups, IGT = impaired glucose tolerance, IWC = International Workshop Conference, NDDG = National Diabetes Data Group, NR = not reported, OGCT = oral glucose challenge test, OGTT = oral glucose tolerance test, USPSTF = U.S. Preventive Services Task Force, WHO = World Health Organization †Low risk defined as: (1) age <25 yr, (2) normal body weight, (3) no first degree relative with DM, (4) no history of abnormal glucose, (5) no history of poor obstetrical outcomes, (6) not of high-risk ethnicity for DM. *In New Zealand. ‡ Screening for gestational diabetes mellitus: U.S. Preventive Services Task Force recommendation statement. Annals of Internal Medicine 2008;148(10):759-65. Organization Year Testing Schedule Abnormal Value(s) 0 (h) 108 mg/dL 6.0 mmol/L 7 Treatment Strategies Initial treatment for GDM involves diet modification, glucose monitoring, and moderate exercise. When dietary management does not achieve desired glucose control, insulin or oral antidiabetic medications may be used.49 Increased prenatal surveillance may also occur as well as changes in delivery management depending on fetal size and the effectiveness of measures to control glucose. The 2008 USPSTF report found that treatment of women with mild GDM (excluding women who met World Health Organization criteria for overt diabetes) diagnosed after 24 weeks’ gestation provided benefits in terms of maternal and neonatal health outcomes.16 Specifically, they found evidence from a high quality trial involving 1,000 women showing a reduction in “any serious perinatal complication” which included death, shoulder dystocia, bone fracture, and nerve palsy.50 The number of events for many of the individual outcomes was extremely small, which did not provide adequate evidence to make conclusions for individual outcomes. The same study showed a reduction in maternal hypertension.50 Further, among a subset of survey respondents, mothers who received treatment were less depressed at 3 months and data showed a trend to better quality of life compared with women who did not receive treatment.50 The USPSTF report found no evidence of harms of treatment, although the available evidence was sparse and the review authors observed that these events may be rare and may not be observed in trials.16 Potential harms of treatment may include small for gestational age neonates, maternal stress, and additional costs including those associated with laboratory testing as well as patient and clinician time.51 Clinician time can include the physician as well as diabetes educators, nutritionists, and other providers of obstetrical care. Healthcare provider anxiety over the diagnosis of GDM is a potential harm that could result in additional, and possibly unnecessary or overly aggressive, fetal, and neonatal surveillance and delivery management. Evidence suggests that the label of GDM, regardless of need, appears to influence the care provided as evidenced by higher neonatal intensive care unit admission rates for the newborn babies of women treated for GDM.52 Scope and Key Questions Scope of the Review Based on systematic reviews published in 2003 and 2008, the USPSTF concluded that there was insufficient evidence upon which to make a recommendation regarding routine screening of all pregnant women for gestational diabetes.16,53 However, several key studies have been published since the 2008 report.3,9,54 The National Institutes of Health Office of Medical Applications of Research (OMAR) commissioned this report (Key Questions 3 to 5, see section below) and it was conducted by the Agency for Healthcare Research and Quality (AHRQ) Evidence-based Practice Center (EPC) Program. OMAR will use the review to inform a consensus meeting and guideline development. The USPSTF joined this effort and will use the review to update its recommendation on screening for GDM (Key Questions 1 and 2 below). The primary aims of this review were to: (1) identify the test properties of screening and diagnostic tests for GDM, (2) evaluate the potential benefits and harms of screening at ≥24 weeks and <24 weeks’ gestation,(3) assess the impact of different screening and diagnostic thresholds on outcomes for mothers and their offspring, and (4) determine the effects of 8 treatment in modifying outcomes for women diagnosed with GDM. The benefits and harms of treatments will be considered in this review in order to determine the downstream effects of screening on health outcomes. The intent of this review was also to assess whether evidence gaps of the previous USPSTF reviews have been filled. These gaps included lack of sufficient evidence to determine whether maternal or fetal complications are reduced by screening; lack of screening studies with adequate power to evaluate health outcomes such as mortality, NICU admissions, hyperbilirubinemia; limited evidence on the accuracy of screening strategies; and insufficient evidence on the benefits of treating GDM in improving health outcomes. Key Questions The Key Questions for this evidence synthesis were developed by OMAR and the USPSTF to inform consensus meetings and guideline development (OMAR specifically developed Key Questions 3 to 5). Investigators from the University of Alberta EPC worked in consultation with representatives from AHRQ, OMAR and the USPSTF, and a panel of technical experts to operationalize the Key Questions. The technical expert panel provided content and methodological expertise throughout the development of this evidence synthesis. Participants of this panel are identified in the front matter of this report. The Key Questions are as follows: Key Question 1: What are the sensitivities, specificities, reliabilities, and yields of current screening tests for GDM? (a) After 24 weeks’ gestation? (b) During the first trimester and up to 24 weeks’ gestation? • Population: Pregnant women (≥24 weeks’ gestation and <24 weeks’ gestation) without known preexisting diabetes mellitus (DM) • Interventions: Any screening or diagnostic test, including one-step, two-step, or other approach • Comparators: Any reference standard • Outcomes: Sensitivity, specificity, positive predictive value, negative predictive value, reliability (i.e., accuracy), and yield (i.e., prevalence) • Timing: Any duration of followup • Settings: All settings Key Question 2: What is the direct evidence on the benefits and harms of screening women (before and after 24 weeks’ gestation) for GDM to reduce maternal, fetal, and infant morbidity and mortality? • Population: Pregnant women (≥24 weeks’ gestation and <24 weeks’ gestation) without known preexisting DM • Interventions: Any screening or diagnostic test, including one-step, two-step, or other approach; if diagnosed with GDM, any treatment • Comparators: No test for GDM • Outcomes: Maternal, fetal, and infant morbidity and mortality • Timing: Any duration of followup • Settings: All settings Key Question 3: In the absence of treatment, how do health outcomes of mothers who meet various criteria for GDM and their offspring compare to those who do not meet the various criteria? 9 • Population: Pregnant women (≥24 weeks’ gestation and <24 weeks’ gestation) without known preexisting DM who meet different test thresholds for GDM • Interventions: None • Comparators: Pregnant women (≥24 weeks’ gestation and <24 weeks’ gestation) without known preexisting DM who do not meet specific test thresholds for GDM • Outcomes: o Maternal − Short-term: preeclampsia/maternal hypertension, cesarean delivery (elective and medically indicated), depression, birth trauma, mortality, weight gain − Long-term: type 2 DM risk, obesity, hypertension o Fetal/neonatal/child − Short-term: macrosomia, shoulder dystocia, clavicular fracture, brachial plexus injury (permanent and transient), birth injury, hypoglycemia, hyperbilirubinemia, mortality − Long-term: obesity, type 2 DM, transgenerational GDM • Timing: Any duration of followup • Settings: All settings Key Question 4: Does treatment modify the health outcomes of mothers who meet various criteria for GDM and offspring? • Population: Pregnant women (≥24 weeks’ gestation and <24 weeks’ gestation) without known preexisting DM who meet any diagnostic threshold for GDM • Interventions: Any treatment for GDM including, but not limited to, dietary advice, blood glucose monitoring, insulin therapy, and oral hypoglycemic agents • Comparators: Placebo or no treatment • Outcomes: o Maternal − Short-term: preeclampsia/maternal hypertension, cesarean delivery (elective and medically indicated), depression, birth trauma, mortality, weight gain − Long-term: type 2 DM risk, obesity, hypertension o Fetal/neonatal/child − Short-term: macrosomia, shoulder dystocia, clavicular fracture, brachial plexus injury (permanent and transient), birth injury, hypoglycemia, hyperbilirubinemia, mortality − Long-term: obesity, type 2 DM, transgenerational GDM • Timing: Any duration of followup • Settings: All settings Key Question 5: What are the harms of treating GDM and do they vary by diagnostic approach? • Population: Pregnant women (≥24 weeks’ gestation and <24 weeks’ gestation) without known preexisting DM who meet any diagnostic threshold for GDM • Interventions: Any treatment for GDM including, but not limited to, dietary advice, blood glucose monitoring, insulin therapy, and oral hypoglycemic agents • Comparators: Placebo or no treatment 10 • Outcomes: Harms, including anxiety, healthcare system issues, burden on practitioner’s office, increased interventions due to treatment bias (e.g., increased cesarean sections resulting from bias of caregivers toward expectation of adverse outcomes), postpartum depression, SGA, costs, and resource allocations • Timing: Any duration of followup • Settings: All settings We developed an analytic framework (Figure 2) to describe the path from screening pregnant women to the potential benefits and harms of treatment. The figure illustrates the clinical concepts and mechanism by which screening and treatment for GDM may result in beneficial or adverse maternal and fetal/neonatal/child outcomes. The figure also indicates the relation between the Key Questions and the specific links along the pathway from screening to final outcome. 11 Figure 2. Analytic framework for screening and diagnosing GDM Note: The circled numbers correspond to the Key Questions. AE = adverse event, GDM = gestational diabetes mellitus 12 Methods The methods of this evidence synthesis are based on the methods outlined in the Agency for Healthcare Research and Quality (AHRQ) Methods Guide for Effectiveness and Comparative Effectiveness Reviews (www.effectivehealthcare.ahrq.gov/methodsguide.cfm) and the U.S. Preventive Services Task Force (USPSTF) Procedure Manual (www.uspreventiveservicestaskforce.org/uspstf08/methods/procmanual.pdf). The main sections in this chapter reflect the elements of the protocol established for the review. The methods and analyses were determined a priori, except where otherwise specified. Topic Refinement and Technical Expert Panel The National Institutes of Health Office of Medical Applications of Research (OMAR) commissioned this report and it was conducted by AHRQ through the Evidence-based Practice Center (EPC) Program. The Key Questions were developed by OMAR (Key Questions 3 to 5) and the USPSTF. OMAR will use the review to inform a consensus meeting and guideline development. The USPSTF joined this effort and will use the review to update its recommendation on screening for gestational diabetes mellitus. Investigators from the University of Alberta EPC worked in consultation with representatives from AHRQ, OMAR and the USPSTF, and a panel of Technical Experts to operationalize the Key Questions. The Technical Expert Panel provided content and methodological expertise throughout the development of this evidence synthesis. Literature Search Strategy Our research librarian systematically searched the following bibliographic databases for studies published from 1995 to May 2012: MEDLINE® Ovid, Ovid MEDLINE® In-Process & Other Non-Indexed Citations, Cochrane Central Register of Controlled Trials (contains the Cochrane Pregnancy and Childbirth Group, which hand searches journals pertinent to its content area and adds relevant trials to the registry), Cochrane Database of Systematic Reviews (CDSR), Database of Abstracts of Reviews of Effects (DARE), Global Health, Embase, Pascal CINAHL Plus with Full Text (EBSCO host), BIOSIS Previews® (Web of KnowledgeSM), Science Citation Index Expanded® and Conference Proceedings Citation Index- Science (both via Web of ScienceSM), PubMed®, LILACS (Latin American and Caribbean Health Science Literature), National Library of Medicine (NLM) Gateway, and OCLC ProceedingsFirst and PapersFirst. We searched trial registries, including the WHO International Clinical Trials Registry Platform (ICTRP), ClinicalTrials.gov, and Current Controlled Trials. We limited the search to trials and cohort studies published in English. For the search strategies, the research librarian developed a combination of subject headings and keywords for each electronic resource (see Appendix A for the detailed search strategies). The search strategies were not peer reviewed. We searched the Web sites of relevant professional associations and research groups, including the American Diabetes Association, International Association of the Diabetes in Pregnancy Study Groups, International Symposium on Diabetes in Pregnancy, and Australasian Diabetes in Pregnancy Society for conference abstracts and proceedings from the past 3 years. We reviewed the reference lists of relevant reviews (including the 2008 USPSTF review) and included studies to identify additional studies. 13 We used Reference Manager® for Windows version 11.0 (2004–2005 Thomson ResearchSoft) bibliographic database to manage the results of our literature searches. Inclusion and Exclusion Criteria The research team developed the review eligibility criteria in consultation with the technical expert panel. The inclusion and exclusion criteria are presented in Table 2. We included studies only when less than 20 percent of enrolled women had a known history of pre-existing diabetes or separate data were provided for women with no pre-existing diabetes. We limited our eligibility criteria to studies published in English due to lack of translation resources. This decision was made in consultation with the technical expert panel, which expressed no concerns that limiting the search to English language would forfeit important studies. We included studies that were published since 1995 in order to capture several key studies that were published in the late 1990s. Randomized controlled trials (RCTs), nonrandomized controlled trials (NRCTs), and prospective and retrospective cohort studies were eligible for inclusion. Table 2. Eligibility criteria for the review Category Criteria Primary research published in English from 1995 onward. Full text reports available Publication type (abstracts and conference proceedings excluded). Study designs RCTs, NRCTs, PCS, RCS. Pregnant women ≥24 weeks’ gestation or <24 weeks’ gestation, with no known history Population of pre-existing diabetes. KQ1: Any GDM screening or diagnostic test vs. any GDM reference standard or other screening or diagnostic test; KQ2: Any GDM screening test vs. no GDM screening test; KQ3: Women who meet various thresholds for GDM vs. those who do not meet Comparators various criteria for GDM, where women in both groups receive no treatment; KQ4 and 5: Any treatment for GDM, including but not limited to dietary advice, blood glucose monitoring, insulin therapy (all preparations), and oral hypoglycemic agents, vs. placebo or no treatment. KQ1: Sensitivity, specificity, predictive values, accuracy, and yield (i.e., prevalence) KQ2: Maternal, fetal, and infant morbidity and mortality. KQ3 and 4: Maternal outcomes: Short-term: preeclampsia/maternal hypertension, cesarean delivery (elective and medically indicated), depression, birth trauma, mortality, weight gain; Long-term: type 2 DM risk, obesity, hypertension. Fetal, neonatal, and child: Short-term: macrosomia, shoulder dystocia, clavicular Outcomes fracture, brachial plexus injury (permanent and transient), birth injury, hypoglycemia, hyperbilirubinemia, mortality; Long-term: obesity, type 2 DM, transgenerational GDM. KQ5: Harms, including anxiety, healthcare system issues, burden on practitioner’s office, increased interventions due to treatment bias, postpartum depression, SGA, costs, and resource allocations. Timing Any duration of followup. Setting All settings are eligible. DM = diabetes mellitus, GDM = gestational diabetes mellitus, KQ = Key Question, NRCT = nonrandomized controlled trials, PCS = prospective cohort study, RCS = retrospective cohort study, RCT = randomized controlled trial, SGA = small for gestational age Study Selection We assessed the eligibility of articles in two phases. In the first phase, two reviewers used broad criteria to independently screen the titles, keywords, and abstracts (when available) (Appendix B1). They rated each article as “include,” “exclude,” or “unclear.” We retrieved the 14 full text article for any study that was classified as “include” or “unclear” by at least one reviewer. Two reviewers independently assessed each full text article using a detailed form (Appendix B2). We resolved disagreements by discussion and consensus or third-party adjudication. Quality Assessment of Individual Studies Two reviewers independently assessed the methodological quality of the studies and resolved discrepancies by discussion and consensus. We tested each quality assessment tool on a sample of studies and developed guidelines for assessing the remaining studies. In addition, we extracted the source of funding for each study. For studies included in Key Questions 2 to 5, we summarized the quality as “good,” “fair,” or “poor” based on assessments from the tools described below. Quality Assessment of Diagnostic Studies We assessed the methodological quality of studies relevant to Key Question 1 using the quality assessment of diagnostic accuracy studies (QUADAS)-2 checklist.55 The tool consists of 14 items addressing important common biases in diagnostic studies such as spectrum, incorporation, verification, disease progression, and information biases. Individual items are rated “yes,” “no,” or “unclear” (Appendix B3a). Quality Assessment of Trials We assessed the internal validity of RCTs and NRCTs using the Cochrane Collaboration Risk of Bias tool (Appendix B3b). This tool consists of seven domains of potential bias (sequence generation, allocation concealment, blinding or participants and personnel, blinding of outcome assessment, incomplete outcome data, selective outcome reporting, and “other” sources of bias) and a categorization of the overall risk of bias. Each domain was rated as having “low,” “unclear,” or “high” risk of bias. We assessed the blinding and incomplete outcome data items separately for subjective outcomes (e.g., depression scale) and objective clinical outcomes (e.g., mortality). We reported any additional sources of bias, such as baseline imbalances or design-specific risks of bias, in the “other” sources of bias domain. The overall risk of bias assessment was based on the responses to individual domains. If one or more of the individual domains had a high risk of bias, we rated the overall score as high risk of bias. We rated the overall risk of bias as low only if all components were assessed as having a low risk of bias. The overall risk of bias was unclear in all other situations. Quality Assessment of Cohort Studies We used the Newcastle-Ottawa Quality Assessment Scale (Appendix B3c) to assess the methodological quality of prospective and retrospective cohort studies. The scale comprises eight items that evaluate three domains of quality: sample selection, comparability of cohorts, and assessment of outcomes. Each item that is adequately addressed is awarded one star, except for the “comparability of cohorts” item, for which a maximum of two stars can be given. The overall score is calculated by tallying the stars. We considered a total score of 7 to 9 stars to indicate high quality, 4 or 6 stars to indicate moderate quality, and 3 or fewer stars to indicate poor quality. 15 Data Extraction We extracted data using a structured, electronic form and imported the data into a Microsoft Excel™ 2007 spreadsheet (Microsoft Corp., Redmond, WA) (Appendix B4). One reviewer extracted data, and a second reviewer checked the data for accuracy and completeness. Reviewers resolved discrepancies by discussion and consensus or in consultation with a third party. We extracted the following data: author identification, year of publication, source of funding, study design, population (e.g., inclusion and exclusion criteria, number of patients enrolled, study withdrawals, duration of followup), patient baseline characteristics (e.g., age, race, ethnicity, weight, body mass index, previous diagnosis of gestational diabetes mellitus (GDM), family history of diabetes, comorbidities, smoking prevalence), details of the screening or diagnostic test and reference standard, glucose threshold for GDM, type of treatment, and outcomes, including adverse events. We reported outcomes only if quantitative data were reported or could be derived from graphs. We did not include outcomes that were described only qualitatively (e.g., if study authors reported that “there was no difference between the groups”) or for which only a p-value was reported. We planned to extract any cost-related data, including costs to patients, insurance, or health care system, that were reported in the included studies. However, we did not search for cost effectiveness studies or conduct cost-effectiveness analyses of different treatment strategies. Studies that reported only costs and provided no other outcome data were not included in the review. When more than one publication reported the results of a single study, we considered the earliest published report of the main outcome data to be the primary publication. We extracted data from the primary publication first and then any additional outcome data reported in the secondary publications. Data Synthesis We made the following assumptions and performed the following imputations to transform reported data into the form required for analysis. We extracted data from graphs using the measurement tool of Adobe Acrobat 9 Pro (Adobe Systems Inc., California, U.S.) when data were not reported in text or tables. As necessary, we approximated means by medians and used 95% confidence intervals (CI), p-values, or inter-quartile ranges to calculate or approximate standard deviations when they were not given. We calculated p-values when they are not reported.56 For Key Question 1, we constructed 2x2 tables and calculated sensitivity, specificity, positive and negative predictive values, accuracy (true positive plus true negative divided by the sum of true positive, true negative, false positive, and false negative) and yield (i.e., prevalence) of the screening or diagnostic tests. If studies were clinically homogenous, we pooled sensitivities and specificities using a hierarchical summary receiver-operator curve and bivariate analysis of sensitivity and specificity.57 We described the results of studies qualitatively and in evidence tables. For Key Questions 3to 5, we performed meta-analysis to synthesize the available data when studies were sufficiently similar in terms of their study design, population, screening or diagnostic test, and outcomes. This was done using the Mantel-Haenszel method for relative risks and the inverse variance 16 method for pooling mean differences. Due to the expected between-study differences, we decided a priori to combine results using the random effects model.58 We measured statistical heterogeneity among studies using the I2 statistic. We considered an 2 I value of 75 percent or greater to represent substantial heterogeneity and did not pool studies indicating substantial heterogeneity. When studies were not pooled due to substantial heterogeneity, we performed subgroup analyses if the number of studies was sufficient to warrant these analyses.59 Factors to be considered for subgroup analyses included glucose thresholds for tests, type of treatment, maternal age, race or ethnicity, and weight or body mass index, previous diagnosis of GDM, family history of diabetes, and comorbidities, which were extracted from each study. We used Review Manager Version 5.0 (The Cochrane Collaboration, Copenhagen, Denmark) to perform meta-analyses. For dichotomous outcomes, we computed relative risks to estimate between-group differences. If no event was reported in one treatment arm, a correction factor of 0.5 was added to each cell of the 2x2 table in order to obtain estimates of the relative risk. For continuous variables, we calculated mean differences for individual studies. We reported all results with 95% CI. Where possible, we assessed publication bias both visually using the funnel plot and quantitatively using Begg’s60 and Egger’s61 tests. Review Manager version 5.0.22 (The Cochrane Collaboration, Copenhagen, Denmark) and Stata version 7.0 (Stata Corp., College Station, TX) were used for all these analyses. In the event that studies could not be pooled, a narrative summary of the results was presented. Strength of the Body of Evidence Two independent reviewers graded the strength of evidence for major outcomes and comparisons for Key Questions 3 and 4 using the EPC GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. We resolved discrepancies by discussion and consensus. We graded the evidence for the following key outcomes: birth injury, preeclampsia, neonatal hypoglycemia, maternal weight gain, and long-term metabolic outcomes of the child and mother. We made a post hoc decision to grade shoulder dystocia and macrosomia. These were not included in the protocol as outcomes that would be graded but were felt by the clinical investigators to be important to grade. For each outcome, we assessed four major domains: risk of bias (rated as low, moderate, or high), consistency (rated as consistent, inconsistent, or unknown), directness (rated as direct or indirect), and precision (rated as precise or imprecise). No additional domains were used. Based on the individual domains, we assigned the following overall evidence grades for each outcome for each comparison of interest: high, moderate, or low confidence that the evidence reflects the true effect. When no studies were available or an outcome or the evidence did not permit estimation of an effect, we rated the strength of evidence as insufficient. To determine the overall strength of evidence score, we first considered the risk of bias domain. RCTs with a low risk of bias were initially considered to have a “high” strength of evidence, whereas RCTs with high risk of bias and well-conducted cohort studies received an initial grade of “moderate” strength of evidence. Low quality cohort studies received an initial grade of “low” strength of evidence. The strength of evidence was then upgraded or downgraded depending on the assessments of that body of evidence on the consistency, directness, and precision domains. 17 Applicability We assessed the applicability of the body of evidence following the PICOTS (population, intervention, comparator, outcomes, timing of outcome measurement, and setting) format used to assess study characteristics. Factors that may potentially weaken the applicability of studies may include study population factors (e.g., race or ethnicity, age, risk level of GDM [i.e., weight, body mass index, previous GDM diagnosis, family history of diabetes], comorbidities), study design (i.e., highly controlled studies [e.g., RCTs] vs. observational studies), setting (e.g., primary vs. tertiary care), and experience of care providers. Peer Review and Public Commentary Peer reviewers were invited to provide written comments on the draft report based on their clinical, content, or methodologic expertise. Peer review comments on the draft report were addressed by the EPC in preparation of the final draft of the report. Peer reviewers did not participate in writing or editing of the final report or other products. The synthesis of the scientific literature presented in the final report does not necessarily represent the views of individual reviewers. The dispositions of the peer review comments are documented and will be published 3 months after the publication of the Evidence Report. Potential reviewers must disclose any financial conflicts of interest greater than $10,000 and any other relevant business or professional conflicts of interest. Invited peer reviewers may not have any financial conflict of interest greater than $10,000. Peer reviewers who disclose potential business or professional conflicts of interest may submit comments on draft reports through AHRQ’s public comment mechanism. The draft report was posted for public commentary. Comments on the draft report were considered by the EPC in preparing the final report. 18 Results This chapter reports on the results of our literature review and synthesis. First, we describe the results of our literature search and selection process. Description of the characteristics and methodological quality of the studies follow. We present our analysis of the study results by Key Question. Metagraphs and tables reporting the strength of evidence for key outcomes are available within each applicable section. Within each metagraph, the studies that provided data are indexed by the name of the first author. A list of abbreviations is provided at the end of the report. Several appendixes provide supporting information to the findings presented in this section. Appendix C provides the quality assessment ratings by domain for each study. Appendix D contains detailed evidence tables describing the study, characteristics of the population, screening criteria or diagnostic tests used, details of treatment (where relevant), and outcomes. A list of citations for the excluded and unobtained studies is available in Appendix E. Appendixes are available at the Agency for Healthcare Research and Quality (AHRQ) Web site www.effectivehealthcare.ahrq.gov/reports/final.cfm. Results of Literature Searches The search strategy identified 14,398 citations from electronic databases. Screening based on titles and abstracts identified 598 potentially relevant studies. We identified 30 additional studies by hand searching the reference lists from included studies. Using the detailed selection criteria, 151 studies met the inclusion criteria and 469 were excluded. Of the 151 studies, 26 were identified as companion publications and 125 were unique studies (Figure 3). Of the 125 unique studies, 28 were further excluded during data extraction due to a lack of comparison or outcome of interest, leaving the total number of included studies at 97. The most frequent reasons for exclusion were: (1) ineligible comparator (studies comparing two or more treatments but lacking a control group; n = 227); (2) ineligible publication type (abstracts, conference proceedings, studies published prior to 1995; n = 106); (3) ineligible study design (studies other than randomized controlled trials [RCTs], nonrandomized controlled trials [NRCTs], prospective cohort studies, and retrospective cohort studies; n = 11); (4) study did not report prespecified outcomes of interest (lacking test properties for Key Question 1, specified outcomes for Key Questions 3,4, and 5 including harms of screening or treatment; n = 34); (5) duplicate publication (n = 10); (6) intervention not of interest (studies without evaluation of screening tests or criteria, or treatments for gestational diabetes mellitus [GDM]; n = 12); and (7) population was not of interest (if >20 percent of pregnant women enrolled in study had known pre-existing diabetes without subgroup analysis; n = 15). In addition, for Key Question 1 only prospective studies were eligible for inclusion; 54 retrospective cohort studies were excluded. A complete list of excluded studies and reasons for exclusion is provided in Appendix E. 19 Figure 3. Flow diagram of study retrieval and selection * Five studies addressed more than one Key Question, therefore the sum of studies addressing the Key Questions exceeds the total number of studies. 20 Description of Included Studies A total of 97 studies met the eligibility criteria for this review, including 6 RCTs, 63 prospective cohort studies, and 28 retrospective cohort studies. The studies were published between 1995 and 2012 (median 2004). Studies were conducted in the United States (24 percent), Europe (23 percent), Asia (22 percent), the Middle East (20 percent), Australia (4 percent), Central and South America (3 percent), and Canada (4 percent). The source of funding for the included studies was academic (23 studies, 24 percent), foundation or organization (17 studies, 18 percent), government (14 studies, 14 percent), “other” (such as the WHO, or nongovernmental organization; 8 studies, 10 percent), and industry (10 studies, 10 percent). Twentytwo studies presented more than one source of funding. Two studies reported no external source of funding (2 percent), and 46 studies (47 percent) did not describe a source of funding. Forty-eight studies (50 percent) analyzed women tested for GDM between 24-28 weeks, with a OGCT taking place first and the OGTT following within 7 days.50,62-108 Thirty-one studies (32 percent) did not specify when screening or diagnostic procedures took place.54,109-137 Of the 31 studies, one scheduled testing between 24 and 28 weeks, with different undefined test points if clinically warranted.138 Eighteen studies (18 percent) screened or tested within unique time ranges.133,139-155 Of these, one study screened participants with a OGCT at 21-23 weeks followed by a diagnostic OGTT at 24-28 weeks;140 another screened a group of participants after 37 weeks;146 one study screened before 24 weeks; 143 and one study screened women at risk between 14-16 weeks with normal women screened at the usual 24-28 weeks.148 Remaining studies generally provided broader screening times ranging from 21-32 weeks gestation.139,142,144,145,150-152 Studies employing WHO criteria generally screened further into gestation as only an OGTT was performed: one study screened at 28-32 weeks,149 one study between 26-30 weeks,155 another between 25-30 weeks,154 and another study screened women at high risk at 18-20 weeks and others at 28-30 weeks.147 One study using WHO criteria did not specify the time of testing.133 The number of women enrolled in each study ranged from 32143 to 23,3163 (median 750). The mean age of study participants was 30 years. The mean age was consistent among most studies, although women of slightly younger mean age (23-28 years) were enrolled studies originating from countries outside North America (India, Turkey, Hong Kong, United Arab Emirates).113,114,144,156 When duration of followup was reported, it was often described as “until birth” or “to delivery.”62,73,84,95,114,120,146,152 One study reported followup extending from the first prenatal visit (<13 weeks) until a OGCT (26-29 weeks),139 one study within the first trimester until 24-28 weeks gestation,101 and another began at first antenatal booking which ranged from first trimester through to the third in women who were present for antenatal care in late gestation.157 One study followed women for 3 months postpartum;83 and two studies provided longer-term followup extending to 5-7 years132 and 7-11 years, respectively.96 Remaining studies did not provide specific details on duration of followup. Methodological Quality of Included Studies The methodological quality of each study was assessed by two independent reviewers. Our approach to assessing study quality is described in the methods section. The consensus ratings for each study and domains are presented in Appendix C, Tables C1, C2, and C3. Studies were assessed using different tools depending on the Key Question and study design: for Key 21 Question 1, QUADAS-2 was used; for Key Questions 2 to 5, the Cochrane Risk of Bias tool was used for RCTs and the Newcastle Ottawa Scale was used for cohort studies. The methodological quality of studies is described in detail within the results section for each Key Question. Key Question 1. What are the sensitivities, specificities, reliabilities, and yields of current screening tests for GDM? GDM is diagnosed by having one or several glucose values at or above set glucose thresholds following an OGTT administered in the fasting state during pregnancy. Variations in glucose dose, time intervals of glucose measurements, and diagnostic glucose threshold values exist (Table 1). The most commonly used screening practice is a 50 g OGCT without regard to timing of last meal; plasma glucose is measured 1-hour after the glucose challenge. This was first proposed by O’Sullivan and Mahan158 and has been modified over the years. There are two different glucose threshold values commonly used for this screen in North America: ≥140 mg/dL (≥7.8 mmol/L) and ≥130 mg/dL (≥7.2 mmol/L). Clinical and historical risk factors and fasting plasma glucose (FPG) are two other screening practices included in this current review. Two related issues make it difficult to organize and analyze the studies that address Key Question 1. First, there are several screening options (e.g., risk factor-based, universal), and several techniques (e.g., glucola-based, fasting, postprandial). In addition, there is no ‘gold standard’ for diagnosing GDM. There are five different, but commonly used, glucose-based diagnostic measures that overlap in the criteria they use. We grouped studies according to the comparator OGTT diagnosis practices that were used, specifically glucose load, time intervals, and threshold values. These groupings include: 3-hour, 100 g OGTT using Carpenter and Coustan (CC) criteria; 3-hour, 100 g OGTT using National Diabetes Data Group (NDDG) criteria; 2-hour, 75 g OGTT using American Diabetes Association (ADA) (2000-2010) criteria, and, 2-hour, 75 g OGTT using WHO criteria (Table 1). We present results of screening tests based on these groupings that included women who underwent the 50 g OGCT screen (further subdivided by screening threshold ≥140 mg/dL and ≥130 mg/dL), fasting plasma glucose (FPG), clinical and historical risk factors, and other screening criteria. This is followed by a section on studies that compared early and late screening practices. The final section summarizes the evidence comparing different glucose loads for the OGTT diagnostic tests. Forest plots present 2x2 data, sensitivity and specificity; summary tables present prevalence, positive and negative predictive values (PPV, NPV), and accuracy for individual studies. Description of Included Studies There were 51 studies (reported in 52 papers) that met the inclusion criteria for Key Question 1. Two papers from the Tri-Hospital group142 are included as they report on results for different screening practices.159,160 Studies were conducted in a wide range of regions: 11 in North America,64,69,72,104,105,121,123,126,127,142,143 10 in Europe,62,65,66,68,108,115,119,125,151,153 12 in Asia,70,73,101,107,111,114,118,128,129,139,140,157 15 in the Middle East,67,71,74-77,99,100,109,110,112,113,117,138,144 2 in South America,63,120 and 1 in Australia.124 All studies were prospective cohort studies. A summary table of the study and patient characteristics of the individual studies can be found in Appendix D. The prevalence of GDM varied across studies. The variability is due to differences in study setting (i.e., country), screening practices (e.g., universal vs. selective), and/or population characteristics (e.g., race/ethnicity, age, body mass index [BMI], parity). The range of GDM 62-77,91,99-101,104,105,107-115,117-121,123-127,129,138-140,142-144,151,153,157 22 prevalence for each diagnostic criteria is as follows: CC/ADA (2000-2010) (100 g) 3.6 to 38.0 percent; National Diabetes Data Group (NDDG) 1.4 to 50.0 percent, ADA (2000-2010) (75 g) from 2.0 to 19.0 percent, and WHO from 1.7 to 24.5 percent. Prevalence results for individual studies are presented in the following sections. Methodological Quality of Included Studies We used the QUADAS-2 tool to assess the quality of the studies included in this review. The tool comprises four key domains that discuss patient selection, index test, reference standard, and flow of patients through the study and the timing of the index tests and reference standard (flow and timing). The first part of QUADAS-2 concerns bias; the second part considers applicability or concerns that the study does not match the review question. Figure 4 summarizes the assessments for risk of bias and Figure 5 summarizes assessments of applicability. Detailed assessments for each study are presented in Appendix C1. The domain of patient selection was rated as low risk that the selection of patients introduced bias for 53 percent of the studies. These studies were prospective cohort studies, most enrolled a consecutive sample of patients, and most avoided inappropriate exclusions. However, 25 percent of studies were rated as unclear due to inadequate description. Overall, 55 percent of studies were assessed as having high concerns about applicability for this domain. This was primarily because these studies were conducted in developing countries and used the WHO criteria to diagnose GDM. The results of these studies may not be directly relevant to the population in the United States. The domain of the index test was generally rated as low risk that the conduct or interpretation of the index test introduced bias (53 percent). For most studies, the screening test (i.e., the index test) was conducted before the reference standard, and the threshold for the screening test was pre-specified. Concern about applicability was assessed as low (82 percent). The domain of the reference standard (i.e., the criteria used to confirm a diagnosis of GDM) was generally rated as unclear risk that the conduct or interpretation of the reference standard introduced bias (63 percent). For most studies the result of the screening test was used to determine whether patients underwent further testing for GDM. Concern about applicability was assessed as low (86 percent). The domain of flow and timing was assessed as low risk of bias for 39 percent of the studies. For most studies, the interval between the index test and reference standard was appropriate according to the criteria used in the study. Most patients received the reference standard, and received the same reference standard. However, in 35 percent of studies not all patients received a confirmatory reference standard if the screening test was below a certain threshold. These were assessed as unclear risk of bias. 23 Figure 4. QUADAS-2 assessment of risk of bias by domain Figure 5. QUADAS-2 assessment of applicability by domain 24 Key Points • • • • • • • • Comparisons between screening tests and diagnostic thresholds were difficult because of the variety of different populations and different tests that were studied. Prevalence of GDM varied across studies and the diagnostic criteria used. The range of prevalence was: CC 3.6 to 38.0 percent; NDDG 1.4 to 50.0 percent; ADA (75 g) 2.0 to 19.0 percent; and WHO 1.7 to 24.5 percent. The 50 g OGCT with the 130 mg/dL cutpoint has higher sensitivity when compared with the 140 mg/dL cutpoint, however, specificity is lower (6 studies). Both thresholds have high NPV but variable PPV across a range of GDM prevalence. The use of a high cutoff for a diagnosis of GDM on an OGCT is supported by one study that assessed a 50 g OGCT (≥200 mg/dL) with GDM confirmed using the CC criteria. Sensitivity, specificity, PPV and NPV were all 100 percent. Fasting plasma glucose at a threshold of ≥85 mg/dL has similar sensitivity to 50 g OGCT; specificity is lower (4 studies). There were sparse data to assess screening and diagnostic tests for GDM less than 24 weeks’ gestation. Four studies compared a 75 g load with a 100 g load (reference standard) to diagnose GDM. The prevalence of GDM ranged from 1.4 to 50 percent. Median sensitivity and PPV were low; median specificity and NPV were high. One study compared the IADPSG criteria with a two-step strategy. Sensitivity was 82 percent and specificity was 94 percent. Prevalence of GDM was 13.0 percent with IADPSG criteria compared with 9.6 percent with the two-step strategy. PPV and NPV were 61 percent and 98, respectively. Detailed Synthesis 50 g OGCT Screening and GDM Diagnosis with 100 g OGTT This section includes studies in which women underwent a 2-step practice that included screening with a 50 g OGCT at 24 to 28 weeks followed by a 100 g OGTT to confirm a diagnosis of GDM. The 50 g OGCT screening test is grouped by the two following diagnostic confirmation criteria: CC and ADA (2000-2010) criteria and the NDDG criteria. Carpenter and Coustan and ADA (2000-2010) Criteria Description of Included Studies Fourteen studies confirmed a diagnosis of GDM with a 100 g, 3-hour OGTT using CC/ADA 2000-2010 criteria (Appendix D).63,64,68,72,75-77,99,104,108,121,140,159,161 Ten studies used a universal screening practice,63,64,68,72,76,77,108,121,159,161 three studies used a selective, risk-based screening practice for an OGCT,75,99,140 and one study only included women with an abnormal OGCT.104 Six studies performed the OGTT on all women regardless of OGCT value,63,68,72,108,140,159 while eight performed an OGTT in patients with a positive OGCT. 64,75-77,99,104,121,161 Studies were conducted in the United States,64,104,121 Canada,15 Iran,71,75-77 Brazil,63 France,108 Mexico,72 Switzerland,68 Thailand,140 and United Arab Emirates.99 The number of patients analyzed ranged from 138 to 11,545. Maternal age was reported in 12 studies and the mean 25 ranged from 23.7 to 32.5 years. Mean BMI was reported in 10 studies and ranged from 23.3 to 29.6 kg/m2. One study included women tested at ≥20 weeks’ gestation. 121 Results Nine studies provided data to estimate the test characteristics of a 50 g OGCT screening tested at the 1-hour interval and cutoff value of ≥140 mg/dL.63,64,68,72,76,99,108,140,159 The accuracy of the OGCT (i.e., the proportion of true positive and true negative results) was generally high (median = 86.5 percent) and ranged from 66 to 94 percent (Table 3). Figure 6 presents the sensitivities and specificities for the individual studies. The joint estimates of sensitivity and specificity were 85 percent (95% CI, 76 to 90) and 86 percent (95% CI, 80 to 90). Hierarchical summary receiver operator characteristic (HSROC) curves comparing the sensitivity and specificity for all studies are presented in Appendix F. The prevalence of GDM ranged from 3.8 to 31.9 (Table 3). The PPV ranged from 18.5 to 83.1 percent; the NPV ranged from 95.1 to 99.0 percent (Table 3). The study by Rust et al. 121 included women ≥20 weeks and reported a sensitivity of 56 percent (95% CI, 30 to 80) and specificity of 94 percent (95% CI, 91 to 96). The prevalence of GDM was 3.6 percent. Six studies used an OGCT cutoff value of ≥130 mg/dL.64,71,75-77,108 The accuracy of the OGCT ranged from 64.5 to 90.4 (median = 78.5 percent) (Table 3). Figure 6 presents the sensitivities and specificities for the individual studies. The joint estimates of sensitivity and specificity were 99 percent (95% CI, 95 to 100) and 77 percent (95% CI, 68 to 83), respectively. The prevalence of GDM ranged from 4.3 to 29.5 (Table 3). The PPV ranged from 10.7 to 62.3 percent; the NPV ranged from 97.3 to 100 percent (Table 3). One study used an OGCT cutoff value of >200 mg/dL.104 The prevalence was 29.4 percent. The sensitivity was 100 (95% CI, 0.87 to 100) and specificity was 100 percent (95% CI, 0.99 to 100). The studies by Agarwal,99 Weerakiet,140 Bobrowski, 104 and Kashi75 are at high risk for selection bias due to the use of selective screening practice. Not all women received a confirmatory OGTT in the studies by Eslamian,71 Gandevani,76 Soheilykhah,77 and Yogev64 are at high risk for partial verification bias. 26 Figure 6. Forest plot of sensitivity and specificity: 50 g OGCT by CC or ADA (2000–2010) criteria ADA = American Diabetes Association; CC = Carpenter-Coustan; FN = false negative; FP = false positive; OGCT = oral glucose challenge test; TN = true negative; TP = true positive 27 Table 3. Prevalence and diagnostic test characteristics for 50 g OGCT by CC or ADA (2000–2010) diagnostic criteria Screening Prevalence PPV NPV Accuracy Practice** (%) (95% CI) (95% CI) (%) 121 Rust, 1998 U.S. 448 Universal 3.6 24 (13-40) 98 (97-99) 92 63 Ayach, 2006 Brazil 341† Universal 3.8 18 (10-31) 99(97-100) 86 108 Chevalier, 2011 France 11,545† Universal 3.9 37 (34-40) 99 (99-100) 94 159 Trihospital, 1998 Canada 3,836† Universal 6.9 23 (20-26) 97 (96-98) 82 64 Yogev 2004 U.S. 1,783 Universal 8.5 27 (24-32) 98 (97-99) 80 ≥140 mg/dL OGCT 68 Perucchini, 1999 Switzerland 520† Universal 10.2 43 (32-54) 95 (93-97) 88 72 De los Monteros, 1999 Mexico 445† Universal 11.7 47 (38-57) 98 (96-99) 87 140 Weerakiet, 2006 Thailand 359† Selective 16.7 32 (25-39) 97 (93-99) 66 76 Gandevani, 2011 Iran 585 Universal 22.2 62 (55-69) 96 (93-97) 85 99 Agarwal 2000 UAE 368 Selective 31.9 83 (80-89) 98 (96-99) 93 108 Chevalier, 2011 France 11,545† Universal 4.3 31 (29-33) 100 (100-100) 90 64 Yogev 2004 U.S. 2,541 Universal 4.4 11 (9-13) 100 (99-100) 65 71 Eslamian, 2008 Iran 138 Universal 8.6 27 (16-42) 99 (95-100) 78 ≥130 mg/dL OGCT 75 Kashi, 2007 Iran 200 Selective 10.0 31 (21-43) 100 (98-100) 78 76 Gandevani, 2011 Iran 585 Universal 22.2 51 (45-57) 100 (99-100) 79 77 Soheilykhah, 2011 Iran 1,502 Universal 29.5 62 (57-67) 97 (95-98) 82 Abnormal 104 ≥200 mg/dL OGCT Bobrowski, 1996 U.S. 422† 6.4 100 (91-100) 100 (100-100) 100 (99-100) screen** CI = confidence interval; NPV = negative predictive value; OGCT = oral glucose challenge test; OGTT = oral glucose tolerance test, PPV = positive predictive value; UAE = United Arab Emirates *Number of women in the analysis. **As reported in the methods of each study; all studies are 2-step screening and diagnosis. †All women received both an OGCT and OGTT. Diagnostic Test Author, Year Country N* 28 NDDG Criteria Description of Included Studies Ten studies used the NDDG criteria to confirm a diagnosis of GDM (Appendix D).66,67,69,72Eight studies used a universal screening practice;66,67,69,72-74,144,159 two included only women with an abnormal OGCT.104 123 Six studies performed the OGTT on all women regardless of OGCT value,63,68,72,108,140,159 while the remaining studies performed an OGTT only in patients with a positive OGCT. Four studies were conducted in North America,69,104,123,159 two in Europe,74,144 and one each in Mexico,72 Saudi Arabia,67 and Thailand,73 and Turkey.66 The number of patients enrolled ranged from 80 to 4,274. Mean maternal age, reported in seven studies, ranged from 25.7 to 32.1 years. Only two studies reported BMI. All studies screened women after 24 weeks’ gestation. 74,104,123,144,159 Results Seven studies provided data to estimate the test characteristics of a 50 g OGCT tested at the 1-hour interval and cutoff value of ≥140 mg/dL.66,69,72-74,144,159 The accuracy of the OGCT was generally high (median = 82 percent) (Table 4). Figure 7 presents the sensitivities and specificities for the individual studies. HSROC curves comparing the sensitivity and specificity for all studies are presented in Appendix F. The joint estimates of sensitivity and specificity were 85 percent (95% CI, 73 to 92) and 83 percent (95% CI, 78 to 87), respectively. The prevalence of GDM ranged from 1.4 to 45.8 (median = 6.2) (Table 4). The PPV ranged from 12.0 to 57.1; the NPV ranged from 70 to 100 (Table 4). Three studies67,74,113 used a cutoff ≥130 mg/dL. The accuracy of the test ranged from 50.0 to 85.5 percent (Table 4). Figure 7 presents the sensitivities and specificities for the individual studies. As there were only three studies, we did not pool the results. The prevalence of GDM ranged from 16.7 to 35.3 (Table 4). The PPV ranged from 20.0 to 75.0; the NPV ranged from 87.5 to 92.9 (Table 4). One study used an OGCT cutoff value of >200 mg/dL. The sensitivity, specificity, PPV and NPV were all 100 percent. The studies by Ardawi,67 Bobrowski,104 Berkus123 Cetin,144 Deerochanawong, 73 Lamar,69 and Uncu,74 are at high or unclear risk for selection bias due to selective or unclear screening practices. Studies by Ardawi,67 De los Monteros,72 and Lamar,69 are at high or unclear risk for partial verification bias as not all women received a confirmatory OGTT. 29 Figure 7. Forest plot of sensitivity and specificity: 50 g OGCT by NDDG criteria NDDG = National Diabetes Data Group; OGCT = oral glucose challenge test Table 4. Prevalence and diagnostic test characteristics for 50 g OGCT by NDDG diagnostic criteria Diagnostic Test Author, Year Country N* Screening Prevalence Practice** (%) PPV (95% CI) NPV (95% CI) Accuracy (%) 100 (9990 100) Canada 3,836† Universal 3.8 15(12-17) 99 (98-99) 82 U.S. 136 NR 3.8 15 (6-33) 99 (95-100) 82 100 (9919 (14Spain 578 Universal 5.8 76 ≥140 mg/dL 26) 100) OGCT 26 (15144 Cetin, 1997 Turkey 274 Universal 6.2 97(95-99) 86 40) De Los Monteros, 39 (30Mexico 445† Universal 9.7 99 (97-99) 86 72 1999 49) 57 (3374 Uncu, 1995 Turkey 24† Universal 45.8 70 (42-81) 63 79) 49 (34123 95 (85-98) 73 U.S. 80† NR 26.3 Berkus, 1995 64) ≥130 mg/dL 74 Uncu, 1995 Turkey 18† Universal 16.7 20 (6-51) 86 (56-96) 50 OGCT Saudi 75 (6767 Ardawi, 2000 818 Universal 35.3 93 (88-96) 86 Arabia 82) ≥200 mg/dL Abnormal 100 (91- 100 (100104 Bobrowski, 1996 U.S. 422† 6.4 100 OGCT screen 100) 100) CI = confidence interval; NDDG = National Diabetes Data Group; NPV = negative predictive value; NR = not reported; OGCT = oral glucose challenge test; OGTT = oral glucose tolerance test; PPV = positive predictive value *Number of women in the analysis. **As reported in the methods of each study; all studies are 2-step screening and diagnosis. †All women received both an OGCT and OGTT. Deerochanawong, 73 1996 159 Trihospital, 1998 69 Lamar,1999 Perea-Carrasco, 66 2002 Thailand 709 Universal 30 1.4 12 (7-21) 50 g OGCT Screening and GDM Diagnosis with 75 g OGTT This section includes studies in which women underwent a 2-step screening and diagnostic practice that included a 50 g OGCT followed by a 75 g OGTT to confirm a diagnosis of GDM. ADA (2000-2010) Criteria Description of Included Studies Three studies101,125,139 used the ADA 75 g, 2-hour criteria after a 50 g, 1-hour OGCT (Appendix D). All but the study by Maegawa et al.101 used a threshold of ≥140 mg/dL for the OGCT. The studies were conducted in Japan,101,139 and Germany.125 One Canadian study105 confirmed diagnosis using the Canadian Diabetes Association 75 g, 2-hour criteria. The number of patients analyzed ranged from 509 to 912. All studies reported maternal age, which ranged from 28.5 to 33.4 years. BMI ranged from 20.0 to 24.8 kg/m2. All studies performed the OGCT screening at 24-28 weeks; two studies also screened women in early pregnancy.101,139 Results The accuracy of the ADA (2000-2010) 75 g ranged from 84 percent to 87 percent (Table 5). Figure 8 presents the sensitivities and specificities for the individual studies. The results were not pooled. The prevalence of GDM ranged from 1.6 to 18.1 (Table 5). The PPV ranged from 7 to 20; the NPV ranged from 99 to 100 (Table 5). The accuracy of the CDA 75 g was 72 percent; PPV was 37 percent and NPV was 94 percent, respectively. The studies by Rey105 and Yachi139 are at high or unclear risk of selection bias due to their screening practices. The study by Buhling,125 is at high risk for partial verification bias as not all women received a confirmatory OGTT. Figure 8. Forest plot of sensitivity and specificity: 50 g OGCT (different thresholds) by ADA (2000– 2010) 75 g criteria ADA = American Diabetes Association; CDA = Canadian Diabetes Association; OGCT = oral glucose challenge test; OGTT = oral glucose tolerance test 31 Table 5. Prevalence and diagnostic test characteristics for 50 g OGCT (different thresholds) by ADA (2000–2010) 75 g criteria Author, Screening Prevalence PPV NPV Accuracy Country N* Year Practice** (%) (95% CI) (95% CI) (%) Yachi, Japan 509 Universal 1.6 7 (4-13) 100 (99-100) 79 139 2011 ADA (2000Maegawa, Japan 749 Universal 2.9 17 (11-25) 99 (98-100) 87 101 2003 2010) Buhling, Germany 912 Universal 4.1 20 (15-27) 100 (99-100) 84 125 2004 Rey, CDA Canada 188† Selective 18.1 37 (25-51) 94 (87-97) 72 105 2004 ADA = American Diabetes Association; CDA = Canadian Diabetes Association; CI = confidence interval; NPV = negative predictive value; OGCT = oral glucose challenge test, OGTT = oral glucose tolerance test; PPV = positive predictive value *Number of women in the analysis. **As reported in the methods of each study; all studies are 2-step screening and diagnosis. †All women received both an OGCT and OGTT. Organization World Health Organization Criteria Description of Included Studies Four studies used the WHO criteria to confirm a diagnosis of GDM (Appendix D).62,70,73,157 The studies were conducted in Netherlands,62 Sri Lanka,70 Malaysia,157 and Thailand.73 The number of patients enrolled ranged from 188 to 1,301. Mean maternal age ranged from 25.7 to 30.8 years. Mean BMI, as reported in two studies, was 22.4 and 24.2. All studies performed the OGCT screening at 24-28 weeks with OGTT performed the following 1 to 2 weeks. Results The accuracy of the test ranged from 73 percent to 88 percent (Table 6). Figure 9 presents the sensitivities and specificities for the individual studies. The results were not pooled. The prevalence of GDM ranged from 3.7 to 15.7 (Table 6). The PPV ranged from 5 to 20; the NPV ranged from 94 to 99 (Table 6). The prevalence of GDM ranged from 3.7 to 50.0 (Table 6). The PPV ranged from 17.8 to 76.2; the NPV ranged from 78.9 to 98.7 Figure 9. Forest plot of sensitivity and specificity: 50 g OGCT by WHO criteria OGCT = oral glucose challenge test; WHO = World Health Organization 32 Table 6. Prevalence and diagnostic test characteristics for 50 g OGCT by WHO diagnostic criteria Diagnostic Test ≥140 mg/dL OGCT Author, Year Country N* Screening Practice** van Leeuwen, Netherlands 1,301 Universal 200762 Siribaddana, Sri Lanka 721 Universal 70 1998 Deerochanawong, Thailand 709 Universal 73 1996 Prevalence (%) PPV (95% CI) NPV (95% CI) Accuracy (%) 3.7 20 (14-26) 99 (98-99) 88 6.5 18 (13-23) 99 (97-99) 73 15.7 58 (47-68) 90 (87-92) 86 ≥130 mg/dL Tan, 2007157 Malaysia 521 Universal 34.6 39 (35-41) 86 (78-91) 48 OGCT CI = confidence interval; NPV = negative predictive value; OGCT = oral glucose challenge test; PPV = positive predictive value; WHO = World Health Organization *Number of women in the analysis. **As reported in the methods of each study; all studies are 2-step screening and diagnosis. Fasting Plasma Glucose Screening and GDM Diagnosis This section includes studies that examined FPG as a screening test. A diagnosis of GDM was confirmed using CC or ADA (2000-2010), WHO, NDDG, and CDA 75 g OGTT criteria. Fasting Plasma Glucose and CC/ADA (2000-2010) Criteria Description of Included Studies Seven studies provided data on FPG at various thresholds as an alternative screening test to glucola-based screening with a diagnosis of GDM using CC and ADA (2000-2010) criteria (Appendix D).65,75,99,108,112,126,127 Three studies used a universal screening practice112 108,127 and the remaining studies used a selective, risk-based screening practice.65,75,99,126 All but one study75 performed the OGTT on all women regardless of OGCT value. Studies took place in the United States,126,127 France,65,108 Iran,75 and the United Arab Emirates.99,112 The number of patients enrolled ranged from 123 to 11,545. Mean maternal age was reported in four studies and ranged from 27.8 to 32.8 years. Mean BMI was reported in three studies and ranged from 22.5 to 29.6. Most studies tested women after 24 weeks’ gestation; one study tested women at 23 weeks.126 Results The studies provided data to estimate the test characteristics of FPG at four common thresholds: ≥85 mg/dL (4.7 mmol/L), ≥90 mg/dL (5.0 mmol/L), ≥92 mg/dL (5.1 mmol/L), and ≥95 mg/dL (5.3 mmol/L). Figure 10 presents the sensitivities and specificities for the individual studies. The joint estimates of sensitivity and specificity, respectively for the different FPG threshold values are: • ≥85 mg/dL: 87 percent (95% CI, 81 to 91) and 52 percent (95% CI, 50 to 55) • ≥90 mg/dL: 77 percent (95% CI, 66 to 85) and 76 percent (95% CI, 75 to77) • ≥92 mg/dL: 76 percent (95% CI, 55 to 91) and 92 percent (95% CI, 86 to 96) (median) • ≥95 mg/dL: 54 percent (95% CI, 32 to 74) and 93 percent (95% CI, 90 to 96) The prevalence of GDM ranged from 1.4 to 33.3 (median = 6.2) (Table 7). The PPV ranged from 12.0 to 45.8; the NPV ranged from 83.3 to 100 (Table 7). 33 Figure 10. Forest plot of sensitivity and specificity: fasting plasma glucose by CC/ADA (2000– 2010) criteria ADA = American Diabetes Association; CC = Carpenter-Coustan; OGCT = oral glucose challenge test 34 Table 7. Prevalence and diagnostic test characteristics for fasting plasma glucose by CC/ADA (2000–2010) diagnostic criteria FPG by CC/ADA FPG (≥85 mg/dL) Author, Year Country Agarwal, 99 2000 UAE FPG (≥90 mg/dL) FPG (≥92 mg/dL) Agarwal, 112 2006 Chastang, 65 2003 Sacks, 126 2003 Chevalier, 108 2011 75 Kashi, 2007 Kauffman, 127 2006 Agarwal, 99 2000 FPG (≥95 mg/dL) 1,276 (RF) 398 (+OGCT) Screening Prevalence PPV NPV Accuracy Practice** (%) (95% CI) (95% CI) (%) Selective 31.8 47 (40-53) 93 (87-96) 64 Selective 31.0 46 (42-49) 91 (88-93) 64 4,609 Universal 13.3 23 (21-24) 97 (96-98) 58 200 Selective 34.5 59 (49-68) 90 (83-94) 75 4,507 Universal 7.2 10 (9-11) 96 (95-97) 50 1,276 (RF) 398 (+GCT) Selective 31.8 59 (51-66) 91 (86-94) 76 UAE Selective 30.9 59 (54-63) 91 (88-92) 77 UAE 4,609 Universal 13.3 35 (32-37) 97 (96-97) 77 France 354 High risk 19.5 43 (34-52) 93 (89-95) 76 U.S. 4,507 Universal 6.7 14 (12-16) 96 (95-96) 75 France 11,454 Universal 23.9 63 (55-71) 81 (78-83) 79 Iran 200 Selective 34.7 85 (74-91) 90 (83-94) 88 U.S. 123 Universal 20.3 66 (47-80) 94 (87-97) 87 Selective 31.8 80 (72-86) 91 (86-93) 87 UAE 1,276 (>1 RF) 398 (+OGCT Selective 26.9 81 (75-85) 89 (87-90) 87 Agarwal, UAE 112 2006 75 Kashi ,2007 Iran Sacks, U.S. 126 2003 Agarwal, 99 2000 N* Agarwal, UAE 4,609 Universal 13.2 51 (48-54) 95 (94-96) 87 112 2006 75 Kashi , 2007 Iran 200 Selective 23.9 73 (63-81) 80 (77-82) 79 Sacks, U.S. 4,507 Universal 6.7 23 (19-27) 95 (94-96) 88 126 2003 ADA = American Diabetes Association; CC = Carpenter-Coustan; CI = confidence interval; FPG = fasting plasma glucose; NPV = negative predictive value; OGCT = oral glucose challenge test; PPV = positive predictive value; RF = risk factor screening; UAE = United Arab Emirates *Number of women in the analysis. **As reported in the methods of each study. Fasting Plasma Glucose and Other Diagnostic Criteria Description of Included Studies Two studies used the WHO criteria to confirm a diagnosis of GDM,111,120 one used the NDDG criteria,127 and one each used the criteria from the national organizations from Canada105 and Japan.101 Different FPG thresholds were used: Maegawa et al.101 and Wijeyaratne et al.111 used ≥ 85 mg/dL, Kauffman et al.127 used ≥ 92 mg/dL, and Reichelt et al.120 used ≥ 89 mg/dL. Results Table 8 summarizes the prevalence and test characteristics of the studies. 35 Table 8. Prevalence and diagnostic test characteristics for fasting plasma glucose by NDDG-WHO and other diagnostic criteria Author, Year, PrevaSn (%) Sp (%) PPV NPV Accuracy N* Country lence (%) (95% CI) (95% CI) (95% CI) (95% CI) (%) Reichelt,1998, 4,977 0.3 88 (62-98) 78 (77-79) 1.3 (0.8-2.1) 100 78 120 Brazil WHO Wjieyaratne, criteria 853 16.9 92 (87-96) 71 (68-75) 40 (35-45) 98 (96-99) 75 2006, Sri 111 Lanka** NDDG Kauffman123 13.0 81 (54-96) 88 (80-93) 50 (32-68) 97 (92-99) 87 127 criteria 2006, U.S. 749 Maegawa, st Other 101 (1 Tri) 1.9 71 (68-79) 83 (78-87) 7 (4-13) 99 (98-100) 82 2003, Japan nd (2 Tri) diagnostic 77 (72-80) 91 (86-94) 20 (13-30) 2.9 99 (98-100) 90 criteria Rey, 2004, 122 17.2 90 (70-99) 46 (36-56) 22 (14-31) 94 (82- 98) 42 105 Canada* CI = confidence interval; NDDG = National Diabetes Data Group; NPV = negative predictive value; PPV = positive predictive value; Sn = sensitivity; Sp = specificity; Tri = trimester; WHO = World Health Organization *Number of women in the analysis. ** Selective screening practice. Criteria Risk Factor-Based Screening and GDM Diagnosis Description of Included Studies Eight studies presented data on risk factor-based screening (Appendix D).63,99,111,114,115,119,151,160 One study was conducted in North America,160 four in Europe,115,119,151,162 two in the Middle East,114 111 and one in South America.63 The number of patients enrolled ranged from 532 to 4,918. Results Figure 11 presents the sensitivities and specificities for the individual studies. The results were not pooled because different diagnostic criteria were used across the studies (Table 9). The prevalence of GDM ranged from 1.7 to 16.9 (Table 9). The PPV ranged from 5 to 20; the NPV ranged from 94 to 99 (Table 9). Figure 11. Forest plot of sensitivity and specificity: risk factor screening by different diagnostic criteria (CC/ADA, NDDG, WHO) ADA = American Diabetes Association; CC = Carpenter-Coustan; NDDG = National Diabetes Data Group; WHO = World Health Organization *author-defined threshold values 36 Table 9. Prevalence and diagnostic test characteristics for risk factor screening by different diagnostic criteria PPV NPV Accuracy (95% CI) (95% CI) (%) 99 (9663 Ayach, 2006 Brazil 341 Universal ≥1 3.8 6 (3-10) 49 100) CC/ADA (20002010) 98 (96114 Hill, 2005 India 830 Universal ≥1 6.2 10 (8-14) 52 99) Trihospital, 99 (98NDDG Canada 3,131 Universal ≥2 4.6 19 (15-24) 83 160 1997 99) Ostlund, 99 (99Sweden 4,918 Universal ≥1 1.7 5 (4-7) 84 119 2003 100) 99 (98115 WHO Jensen, 2003 Denmark 5,235 Universal ≥1 2.4 5 (4-6) 65 100) 94 (89Wijeyaratne, Sri Lanka 853 Universal ≥1 16.9 20 (17-23) 34 111 2006 97) 99 (98Author-defined Poyhonen-Alho, Finland 532 Universal ≥1 3.6 12 (8-19) 79 151 criteria 2005 100) ADA = American Diabetes Association; CC = Carpenter-Coustan; CI = confidence interval; NDDG = National Diabetes Data Group; NPV = negative predictive value; PPV = positive predictive value; RF = risk factor; WHO = World Health Organization *Number of women in the analysis. **As reported in the methods of each study. Criteria Author, Year Country N* Screening Prevalence # RF Practice** (%) Other Screening Tests Other studies examined point of care testing with a glucometer to measure capillary blood glucose,110,111,116,117,128 or other markers such as fasting plasma insulin,127,139 serum fructosamine,74,109 glycated hemoglobin (HbA1c),74,113 adiponectin levels,140 and glycosuria.125 The results are summarized in Table 10. 37 Table 10. Prevalence and characteristics of other screening tests by GDM diagnostic criteria Screening Test HbA1c Author, Year Country 74 Uncu, 1995, Turkey Agarwal, 2005, 113 UAE 100 Agarwal 2001, UAE 107 Rajput, 2011, India Serum fructosamine Fasting plasma insulin Agarwal, 2011, 109 UAE 74 Uncu, 1995, Turkey 100 Agarwal 2001, UAE Kauffman, 2006, 127 U.S. 139 Yachi, 2007, Japan Author defined = (fructosamlne/ Perea-Carrasco, 66 total protein) 2002, Spain (glucose/100) Weerakiet ,2006, Adiponectin 140 Thailand Agarwal, 2008, 110 UAE Capillary blood 128 Balaji 2012, India glucose Wijeyaratne, 2006, 111 Sri Lanka 42 Index Test Threshold 7.2% Reference Standard CC 442 7.5% 430 Prevalence (%) 33.3 Sn (%) (95% CI) 64 (35-87) Sp (%) (95% CI) 64 (44-81) PPV (95% CI) 47 (27-68) NPV (95% CI) 78 (59-87) ADA (75 g) 19.0 82 (72-90) 21 (17-26) 20 (16-24) 83 (75-90) 33 5.0% 5.5% 5.3% CC ADA IADPSG 26.8 7.1 23.7 92 (86-96) 86 (72-95) 12 (7-18) 28 (23-33) 61 (57-65) 97 (95-98) 32 (27-37) 15 (11-19) 57 (39-73) 91 (83-95) 98 (96-99) 78 (74-82) 45 63 77 849 ≥237 µmol/L ADA (75 g) 13.3 86 (78-92) 23 (20-27) 15 (12-18) 92 (87-95) 32 42 430 ≥2.85 mmol/L ≥210 µmol/L CC CC 33.3 26.7 71 (42-92) 92 (86-96) 46 (28-66) 23 (18-28) 40 (23-59) 31 (26-36) 77 (55-86) 89 (81-94) 55 42 123 ≥93 µmol/L NDDG 13.0 56.0 (35-76) 71 (61-80) 33 (21-48) 86 (78-92) 68 509 ≥3.66 mmol/L JSOG (10 wk) 2.0 48 (43-53) 72 (63-80) 86 (80-90) 29 (24-36) 53 578 ≥27.2 IWC, 3 7.0 98 (90-100) 89 (86-91) 44 (35-53) 100 (99-100) 90 359 ≥10 µg/mL ADA 16.7 92 (82-97) 31 (26 to 36) 18 (14-23) 96 (91-98) 40 ADA (FPG) 11.2 84 (78-89) 75 (73-77) 30 (26-34) 98 (96-98) 76 N* 607 1,662 ≥88 mg/dL rd Accuracy (%) 819 ≥140 mg/dL WHO 10.5 80 (70-88) 98 (97-99) 86 (77-92) 98 (96-99) 97 853 ≥130 mg/dL WHO 16.3 63 (54-70) 37 (34-41) 17 (14-20) 83 (79-87) 42 50 g carb ADA 8.6 83 (52-98) 86 (79-91) 36 (20-5) 98 (94-100) breakfast 50 g (28) jelly Glucose source Lamar, 1999, U.S.69 136 NDDG 3.7 40 (5-85) 85 (78-91) 9 (3-28) 97 (93-99) beans 121 Rust,1998, U.S. 448 100 g carb meal ADA (20 wk) 3.6 25 (7-52) 98 (96-99) 40 (17-69) 96 (93-98) ADA = American Diabetes Association; carb = carbohydrate; CC = Carpenter-Coustan; CI = confidence interval; FPG = fasting plasma glucose; GDM = gestational diabetes mellitus; HbA1c = glycated hemoglobin; IADPSG = International Association of Diabetes in Pregnancy Study Groups; IWC = International Workshop Conference; JSOG = Japan Society of Obstetrics and Gynecology; NDDG = National Diabetes Data Group; NPV = negative predictive value; PPV = positive predictive value; Sn = sensitivity; Sp = specificity; UAE = United Arab Emirates; WHO = World Health Organization *Number of women in the analysis Eslamian, 2008, Iran 71 64 138 38 86 83 94 Comparison of Early and Late Screening Tests One study (n = 749) conducted in Japan provided data on screening for GDM in the first and second trimesters.101 The authors used three different screening tests: FPG, HbA1c, and a casual 50 g, 1-hour OGCT. GDM was confirmed with Japan Society of Obstetrics and Gynecology criteria (75 g, 2-hour) 2 to 4 weeks after screening. Prevalence of GDM using a universal screening practice was 1.9 percent in the first trimester and 2.9 percent in the second trimester. Table 11 presents a summary of the test characteristics by screening test and time point. These results should be interpreted cautiously as the women diagnosed with GDM in the first trimester had pre-pregnancy body weight and BMI that were significantly higher than for women who did not have GDM. Table 11. Prevalence and characteristics of various screening tests for screening in the first and second trimesters (Maegawa study) Screening Test FPG (85 mg/dL) 50 g OGCT (threshold 130 mg/dL) Prevalence (%) Sn (%) First trimester 1.9 71.4 83.0 7.4 99.2 Second trimester 2.9 77.0 90.7 20.0 99.3 First trimester 1.9 92.9 77.0 7.1 99.8 2.9 1.9 100.0 71.4 85.4 70.8 17.2 4.4 100 99.2 2.9 36.4 72.9 3.9 97.4 1.9 28.6 100 100 98.7 Trimester Second trimester HbA1c (threshold 4.8%; First trimester 83.5% ULN) Second trimester HbA1c (threshold 5.8%) First trimester Sp (%) PPV (%) NPV (%) Second trimester 2.9 13.6 99.9 75 97.4 FPG = fasting plasma glucose; HbA1c = glycated hemoglobin; NPV = negative predictive value; OGCT = oral glucose challenge test; PPV = positive predictive value; Sn = sensitivity; Sp = specificity; ULN = upper limit of normal Comparison of Different Diagnostic Criteria Seven studies provided data on the comparability of two diagnostic tests in the same group of women. The diagnostic criteria were: 75 g, 2-hour versus 100 g, 3-hour criteria; IADPSG versus the two-step Australasian Diabetes in Pregnancy Society (ADIPS) criteria; FPG versus ADA 100 g, 3-hour criteria; and IADPSG FPG ≥92 mg/dL versus WHO 75 g criteria. Four studies compared 75 g, 2-hour criteria with 100 g, 3-hour criteria as the reference standard; however, different populations were assessed (Figure 12). The study by Brustman (n = 32) was conducted in the United States and compared the results of a 75 g, 3 hour OGTT with a 100 g, 3 hour OGTT.143 Prevalence of GDM was 50 percent with NDDG criteria. The sensitivity was 29 percent (95% CI, 8 to 58) and the specificity was 89 percent (95% CI, 65 to 99); PPV and NPV were 100 (95% CI, 69 to 100) and 62 (95% CI, 43 to 72), respectively. The study by Deerochanawong was conducted in Thailand (n = 709).73 The prevalence of GDM was 1.4 percent with NDDG criteria and with WHO criteria it was 15.7 percent. Sensitivity was 100 percent (95% CI, 69 to 100) and specificity was 90 percent (95% CI, 92 to 96). PPV and NPV were 12 (95% CI, 7 to 21) and 100 (95% CI, 99 to100), respectively. The study by Soonthornpun was also conducted in Thailand (n = 42).118 The prevalence of GDM using the CC criteria was 21 percent. Sensitivity was 33 percent (95% CI, 7 to 70) and specificity was 100 percent (95% CI, 89 to 100). PPV and NPV were 100 (95% CI, 53 to 100) and 85 (95% CI, 71 to 92), respectively. The fourth study by Mello was conducted in Italy and assessed diagnosis of GDM in women during early pregnancy (16 to 21 weeks) (n = 227) and late pregnancy (26 to 31 weeks) (n = 39 484).153 For the early pregnancy group, the prevalence using CC criteria was 18 percent. Sensitivity was 27 percent (95% CI, 14 to 43) and specificity was 98 percent (95% CI, 95 to 99). PPV and NPV were 73 (95% CI, 48 to 89) and 86 (95% CI, 81 to 90), respectively. For the late pregnancy group the prevalence of GDM was 12 percent. Sensitivity was 18 percent (95% CI, 10 to 30) and specificity was 96 percent (95% CI, 94 to 98). PPV and NPV were 42 (95% CI, 25 to 61) and 89 (95% CI, 86 to 92), respectively. Figure 12. Forest plot of sensitivity and specificity: 75 g OGTT by 100 g OGTT OGTT = oral glucose tolerance test An Australian study (n = 1,275) compared the diagnosis of GDM using IADPSG criteria with the ADIPS criteria as the reference standard.124 GDM prevalence was 13.0 percent with IADPSG criteria compared with 9.6 percent with ADIPS. The sensitivity of IADPSG was 82 percent (95% CI, 74 to 88) and specificity was 94 percent (95% CI, 93 to 96); the PPV and NPV were 61 percent (95% CI, 53 to 68) and 98 (95% CI, 97 to 99), respectively. Two studies assessed FPG as a diagnostic test but used different reference standards. A Brazilian study (n = 341) compared FPG with the ADA 100 g, 3-hour criteria.63 The prevalence of GDM was 3.8 percent using ADA (2000-2010) 100 g criteria. The sensitivity was 84 percent (95% CI, 55 to 98) and specificity was 47 percent (95% CI, 42 to 53); PPV and NPV were 6 (95% CI, 3 to10) and 99 (95% CI, 56 to 100), respectively. The second study, conducted in India (n = 1,463), compared IADPSG FPG criteria with the WHO 75 g criteria.107 The prevalence of GDM was 13.4 percent with WHO criteria and 3.2 percent with FPG (≥95 mg/dL). The sensitivity of FPG as a diagnostic test was 29 percent (95% CI, 29 to 36) and specificity was 89 percent (95% CI, 88 to 91); PPV and NPV were 76 (95% CI, 55 to 89) and 79 (95% CI, 58 to 87), respectively. Key Question 2. What is the direct evidence on the benefits and harms of screening women for GDM to reduce maternal, fetal, and infant morbidity and mortality? Description of Included Studies Two studies met the inclusion criteria for Key Question 2.130,131 Both studies compared outcomes for women who underwent screening or diagnostic testing for GDM with women who were not screened or tested. The studies are described in Appendix D. The studies were published in 2004130 and 1996.131 The methods and outcomes differed between the studies, therefore no results were pooled. 40 Methodological Quality of Included Studies The studies were of high and moderate methodological quality with 7 and 6 of a maximum of 9 points, respectively.130,131 The studies scored well for selection of the non-exposed cohort (same as exposed cohort), ascertainment of exposure and outcome, and adequacy of followup in terms of duration and attrition. Neither study controlled for potential confounding variables. Solomon et al., included a select population (i.e., nurses participating in a longitudinal study) that may not be representative of the general target population of this review. Key Points Only two retrospective cohort studies were relevant to Key Question 2. There were no RCTs available to answer questions about screening. Based on the small number of studies and sample sizes, the impact of screening women for GDM on health outcomes is inconclusive. Detailed Synthesis One retrospective cohort study examined 1,000 women receiving antenatal care and delivering at a single center in Thailand between October 2001 and December 2002.130 Women who presented with specific risk factors underwent screening with OGCT (n = 411), and subsequent OGTT if positive on the OGCT (n = 164). Among those screened, 29 cases of GDM were identified (7 percent of the screened group; 3 percent of the total population). Among those who did not undergo screening, 40 women at high risk for GDM were missed (4 percent) and there were two cases of pregestational DM (0.2 percent). High risk was determined based on a list of risk factors, the most commonly observed were age ≥ 30 years (53 percent of the 40 patients) and family history of type 2 diabetes mellitus (43 percent of the 40 patients). Appendix D lists the obstetric complications that were reported in decreasing frequency. Overall there were significantly more complications in the screened group (64/411 versus 63/589). The only individual obstetric complication that was different between groups was pregnancy-induced hypertension with significantly more cases in the screened group. The screened group was significantly older and had a higher average BMI than the group not screened. The pregnancy outcomes are listed in Appendix D. The only significant difference was in the incidence of cesarean deliveries which was greater in the screened group. The authors concluded that selective OGCT screening was highly effective in detecting GDM; however, the impact on outcomes was inconclusive due to small numbers. No information was provided on how women who screened positive were treated. The second study involved a survey of a subset of participants in a large prospective cohort study involving 116,678 nurses age 25-42 years (the Nurses’ Health Study II).131 Surveys were sent to 422 women who reported a first diagnosis of GDM between 1989 and 1991, as well as a sample of 100 women who reported a pregnancy but no diagnosis of GDM. The intent of the study was to determine the frequency of screening for GDM and the extent to which diagnosis is based on NDDG criteria. Only one outcome was reported that was relevant to this Key Question: the incidence of macrosomia (infant weight > = 4.3 kg) was the same in the screened and unscreened groups (7 percent each group). These results pertained to 93 eligible women who reported a pregnancy and no diagnosis of GDM, 77 of whom reported having a 1-h 50-g OGCT. No information was provided on how women who screened positive were treated. No relevant outcomes were reported for the group of women who reported a pregnancy and first diagnosis of GDM. 41 Key Question 3. In the absence of treatment, how do health outcomes of mothers who meet various criteria for GDM and their offspring compare to those who do not? Description of Included Studies Thirty-eight studies met the inclusion criteria for Key Question 3.3,54,67,78-94,102,103,106,132137,142,145-147,149,150,152,154,155 The studies are described in Appendix D. Studies provided data for untreated women who met criteria for GDM, showed differing levels of glucose tolerance, or had no GDM. Most included studies were prospective or retrospective cohort studies published between 1995 and 2011 (median year 2004). Two studies were long-term followup studies of RCTs; however, only data from the untreated patients were included in the results for this Key Question.54,142 These studies had associated publications providing more detailed break-down of groups and outcomes.160,163 Fourteen studies were conducted in the U.S.,54,78,81,8891,132,135,136,146,150,152 10 in Europe,80,86,87,93,102,106,133,145,149,154 2 in Canada,83,142 2 in Australia,3,85 and 11 from other countries67,79,82,84,92,94,103,134,137,147,155 (including Japan, Saudi Arabia, Turkey, Iran, China, and Taiwan). Populations analyzed in North American studies involved diverse ethnicities representative of the respective populations; studies from Europe or elsewhere most often included women of ethnic descent from the country of study origin. In one case, women analyzed were at risk for GDM;149 this study has been noted as potentially unrepresentative of all women eligible for screening. We grouped studies according to the diagnostic criteria used; these included CC, NDDG, WHO, and IADPSG. CC values were endorsed by the ADA 2000-2010 as well as the 4th and 5th IWC on Gestational Diabetes. Most studies employing NDDG criteria provided comparison groups of women diagnosed with CC criteria. In most cases, the NDDG GDM group received treatment for GDM as it is commonly considered unethical in North America to not treat these women; therefore, these groups were not included in the results for this Key Question. One study compared unrecognized cases of NDDG GDM with a patient group with no GDM; the unrecognized cases were sixteen women diagnosed postpartum and therefore did not receive any treatment.152 CC groups were included; therefore, data from studies employing NDDG criteria with CC comparison groups, CC criteria, ADA, or 4th – 5th IWC criteria were included in the results. Table 1 provides an overview of these criteria. Seventeen studies employed NDDG criteria (with treated groups excluded from this analysis), CC criteria, ADA, or 4th-5th IWC criteria with comparable groups. Groups included GDM diagnosed by CC criteria, no GDM by any criteria (normal), impaired glucose tolerance (IGT) defined as one abnormal glucose value (OAV), and false positive (positive OGCT, negative OGTT). Two studies had unique group selections and are described in the text below. Six studies utilized NDDG criteria exclusively. Four of these presented consistent groups for analysis: normal (no GDM by any criteria) and false positive. One study retrospectively identified women with unrecognized GDM by NDDG criteria and compared this group with woman with normal glucose tolerance. Eight studies presented data according to WHO criteria, four of which provided comparable groups. WHO criteria proved a significant challenge due to variability by year, studies providing insufficient groupings for comparison, and treatment of most IGT or OAV groups. One of the two included studies provided data for women diagnosed with IGT at 8.0-8.9 mmol/L (untreated) and the other provided a similar IGT diagnosis at 7.8-8.9 mmol/L, both at two hours post 75 g load. Studies were pooled for analysis as they were deemed to be sufficiently similar. One study 42 compared WHO GDM (untreated) with no GDM, and was included in the analysis for macrosomia.84 Three studies comparing differing levels of WHO criteria were excluded from pooled analysis because they did not have comparable groups with other included studies.134,137,147 Three studies utilized IADPSG criteria for diagnosis and provided comparable groups for pooled analysis.78,79,93 Methodological Quality of Included Studies The methodological quality of the included studies is described in Appendix C3. Quality was analyzed using the Newcastle-Ottawa Scale (NOS) with a possible total of 9 stars. The median quality score was 9 stars, with two studies receiving a score of 6/9, nine studies a score of 7/9, seven studies a score of 8/9, and twenty a score of 9/9. Studies receiving lower scores on the NOS most often did not control for potential confounding (e.g., due to BMI, age, race), and/or had an important proportion of patients lost to followup. Overall, the majority of studies were considered good quality (36 of 38, 95 percent). Key Points • • Thirty-eight studies provided data for this question that sought to examine health outcomes for women who meet various criteria for GDM and do not receive treatment. The majority of data came from cohort studies or the untreated groups from randomized trials. A wide variety of diagnostic criteria and thresholds were compared across the studies. The most common groups reported and compared were GDM diagnosed by CC criteria, no GDM by any criteria (normal), impaired glucose tolerance defined as OAV, and false positive (positive OGCT, negative OGTT). The following criteria were used: CC (19 studies), NDDG (6 studies), WHO (8 studies), and IADPSG (3 studies). Maternal Outcomes • • • A methodologically strong study showed a continuous positive relationship between increasing glucose levels and the incidence of primary cesarean section. This study also found significantly fewer cases of preeclampsia and cesarean section among women without GDM compared with those meeting IADPSG criteria. For preeclampsia, significant differences were found for CC versus patients with no GDM (3 studies) with fewer cases among the patients with no GDM, and for CC GDM versus false-positive groups (2 studies) with fewer cases among the false positives. The strength of evidence for these comparisons was low. No differences were found for NDDG false positive versus no GDM (2 studies), NDDG 1 abnormal OGTT versus no GDM (1 study), and IGT WHO versus no GDM (3 studies); the strength of evidence for these findings was insufficient. For maternal hypertension, significant differences were found for eight of 16 comparisons; five of these comparisons were based on single studies. Patient groups with no GDM showed lower incidence of maternal hypertension when compared with CC GDM, CC false positives, CC 1 abnormal OGTT, IADPSG impaired fasting glucose (IFG), IADPSG double impaired glucose tolerance (IGT-2), and IADPSG IGT IFG. Other comparisons showing significant differences were CC GDM versus false positives 43 • • • • • (lower incidence for false positives), IADPSG IGT versus IGT IFG (lower incidence for IGT), and IADPSG IFG versus IGT IFG (lower incidence for IFG). There were 21 comparisons for cesarean section with nine significant differences. Patient groups with no GDM showed fewer cesarean sections when compared with CC GDM (9 studies), CC 1 abnormal OGTT (4 studies), CC false positives (5 studies), NDDG false positives (4 studies), NDDG 1 abnormal OGTT (1 study), and WHO IGT (4 studies). Four studies compared CC GDM versus false positives and showed lower incidence for the false positives. Single studies compared IADPSG IFG and IADPSG IGT IFG versus no GDM, respectively, and both showed fewer cases for the patient groups with no GDM. Based on single studies, no differences were observed for maternal birth trauma for CC GDM versus no GDM , CC GDM versus false positives, NDDG GDM (unrecognized) versus no GDM. For maternal weight gain, significant differences were found for three of 12 comparisons: IADPSG IGT versus no GDM (favored IGT), IADPSG IFG versus no GDM (favored IFG), IADPSG IGT-2 versus no GDM (favored IGT-2). All comparisons were based on single studies and strength of evidence was considered insufficient. For maternal mortality/morbidity, single studies compared CC GDM versus no GDM, CC 1 abnormal OGTT versus no GDM, IADPSG GDM versus no GDM. No differences were found except for the latter comparison that showed lower mortality/morbidity for the patient groups with no GDM. No studies provided data on long-term maternal outcomes, such as type 2 diabetes mellitus, obesity and hypertension. Fetal/Neonatal/Child Outcomes • • • • Two methodologically strong studies showed a continuous positive relationship between increasing glucose levels and the incidence of macrosomia. One of these studies also showed significantly fewer cases of shoulder dystocia and/or birth injury, clinical neonatal hypoglycemia, and hyperbilirubinemia among women without GDM compared with women meeting IADPSG criteria. The most commonly reported outcome was macrosomia >4,000 g. Eleven comparisons were made of which six showed a significant difference. Fewer cases were observed among patient groups with no GDM compared with CC GDM (10 studies), CC 1 abnormal OGTT (7 studies), NDDG GDM (unrecognized) (1 study), NDDG falsepositives (4 studies), and WHO IGT (1 study). Fewer cases were found for women with false-positive results compared with CC GDM (5 studies). The strength of evidence for these findings was low to insufficient. Data for macrosomia >4,500 g were available for four comparisons and showed significant differences in two cases: patient groups with no GDM had fewer cases compared with women with CC GDM and with unrecognized NDDG GDM. The strength of evidence for these findings was low and was insufficient, respectively. For shoulder dystocia, significant differences were found for 7 of 17 comparisons; all but 1 comparison was based on single studies (insufficient strength of evidence). Patient groups with no GDM showed lower incidence of shoulder dystocia when compared with CC GDM (5 studies; low strength of evidence), NDDG GDM (unrecognized), NDDG false positive, WHO IGT, IADPSG IFG, and IADPSG IGT IFG. The other significant 44 • • • • • difference showed lower incidence among the false-positive group compared with CC 1 abnormal OGTT. For fetal birth trauma/injury, four studies compared CC GDM, NDDG GDM, and WHO IGT with no GDM. No differences were observed except for NDDG GDM which favored the patient group with no GDM. Strength of evidence was insufficient for all comparisons. Only one difference was found for neonatal hypoglycemia with fewer cases among patient groups with no GDM compared with those meeting CC criteria. No differences were found for other comparisons, including CC GDM versus 1 abnormal OGTT (1 study), CC 1 abnormal OGTT versus no GDM (4 studies), NDDG GDM versus no GDM (1 study), NDDG false positive versus no GDM (1 study), NDDG 1 abnormal OGTT versus no GDM (1 study), and WHO IGT versus no GDM (3 studies). Strength of evidence was insufficient for all comparisons. There were 16 comparisons for hyperbilirubinemia; the majority were based on single studies. Three comparisons showed significant differences between groups: patient groups with no GDM had fewer cases compared with CC false positive, IADPSG IGT, and IADPSG IGT-2, respectively. No differences were found for fetal morbidity/mortality for any of 8 comparisons which may be attributable to small numbers of events within some comparisons. Most comparisons were based on few studies, except for CC GDM versus no GDM which showed no difference based on 6 studies. Based on single studies, significant differences were found in prevalence of childhood obesity for CC GDM versus groups with no GDM (lower prevalence for no GDM) and CC GDM versus false positives (lower prevalence for false positives). No differences, based on single studies, were found for CC GDM versus 1 abnormal OGTT, CC false positive versus no GDM, CC false positive versus 1 abnormal OGTT, or CC 1 abnormal OGTT versus no GDM. No other studies provided data on long-term outcomes, including type 2 diabetes mellitus and transgenerational GDM. Detailed Synthesis Overview Detailed results are described by outcome in the sections that follow. We first describe the maternal outcomes, followed by fetal/neonatal/child outcomes. We present meta-graphs when two or more studies were pooled. These are displayed after the description of results for each outcome. A detailed table of results and a table summarizing the strength of evidence are presented at the end of each of the maternal and fetal/neonatal/child sections (Table 12 and Table 13; Table 14 and Table 15, respectively). The results reported below are based on unadjusted data from the relevant studies. We have reported adjusted results, where available from relevant studies, in Appendix G. In the majority of cases, the adjusted results would not have changed the pooled estimates or overall conclusions. Six studies met inclusion criteria and provided relevant outcomes but were not comparable with other studies and are described here.3,91,134,137,147 In 1995, Sacks et al. published a prospective cohort study of 3,505 unselected pregnant women; the authors sought to determine glucose threshold distributions for the 2 hr, 75 g OGTT, and to define the relationship between glucose intolerance values and neonatal macrosomia. The 45 methodological quality of the study was good receiving a score of 8/9 points. Study participants were not analyzed by groups, rather regression analyses were conducted to identify a threshold level that predicted greater risk for macrosomia. The study did not identify a specific threshold for fasting or 1-2 hour levels that could discriminate between women who were more likely to have infants with macrosomia. Moreover, across all thresholds the ability to predict macrosomia was relatively consistent. The HAPO (Hyperglycemia and Adverse Pregnancy Outcomes) study, published in 2008, examined the effect of less severe hyperglycemia on pregnancy outcomes; therefore, all groups fell below the common diagnostic thresholds for GDM. The study involved 23,316 pregnant women from 15 centers in nine countries. The methodological quality was good with a score of 9/9 points. Women were tested employing the 75 g OGTT at 24-32 weeks. Fasting plasma glucose values were divided into seven categories: ≥100 mg/dL (5.6 mmol/L), 95-99 (5.3-5.5), 90-94 (5.0-5.2), 85-89 (4.8-4.9), and <85. The last category (<85 mg/dL) was further subdivided into three levels: <75 mg/dL (4.2 mmol/L), 75-59 (4.2-4.4), and 80-84 (4.5-4.7). The study found a continuous positive association with increasing glucose levels and macrosomia (or birthweight >90th percentile), primary cesarean section, neonatal hypoglycemia, and cord-blood serum cpeptide >90th percentile. The associations were strongest for macrosomia and blood serum cpeptide levels; moreover, associations for neonatal hypoglycemia were not consistently significant. In unadjusted analyses, preeclampsia, cesarean delivery, shoulder dystocia and/or birth injury, clinical neonatal hypoglycemia, and hyperbilirubinemia were statistically significantly less frequent for women without GDM compared with those with GDM based on the IADPSG criteria (data from Appendix, Table B available at care.diabetesjournals.org/cgi/content/full/dc09-1848/DC1). The study did not identify a clear glucose threshold for increased risk in clinically important outcomes.24 Two studies134,147 conducted in China utilized 1980 WHO criteria on a 2 hr OGTT but did not provide similar groups for comparison. One retrospective cohort study published in 2003 involving 2,149 women compared six glucose values: <6.0 mmol/L, 6.0-6.9, 7.0-7.9, 8.0-8.9, 9.0-10.9, and ≥11.0.147 The latter 3 groups were treated for GDM; the former were untreated. There was no significant difference between groups in the incidence of macrosomia (≥4,000 g) or cesarean deliveries. The methodological quality of the study was good with 8/9 points. The second study published in 2001 was prospective and involved 487 women. The study compared a control group, an “at risk” but normal OGTT group, and a treated GDM group.134 There were no significant differences between groups in preeclampsia or birthweight. There were significantly more cesarean deliveries in the normal OGTT compared with the control group although the comparison did not control for age and BMI (women in the normal OGTT group were older and more obese). The methodological quality was fair scoring 6/9 points. One study137 conducted in Malaysia used 1999 WHO criteria on a 2 hr OGTT in conjunction with a 50 g OGCT. As WHO criteria rarely utilize an OGCT, this study did not provide comparable groups for pooled analysis as they were based upon OGCT test results. The study found significantly more cases of cesarean delivery, postpartum hemorrhage, and macrosomia (>4,000 g) among OGCT-positive versus OGCT-negative women. A study conducted in Turkey between 2003 and 2009 employed CC criteria on a 50 g OGCT as well as a 3 hr, 100 g OGTT.94 Groups were determined according to abnormal fasting, 1 hr, 2 hr, and 3 hr glucose values, which did not provide comparison to included studies. The study did not find a significant difference between groups in mean neonatal birthweight. There were 46 significantly more cases of macrosomia (>4,000 g) among women with increased serum glucose at 2 hours. Maternal Outcomes Short Term A summary of the evidence for short-term maternal outcomes is provided in Table 12. A summary of the strength of evidence is in Table 13. The sections that follow describe the results by outcome. Preeclampsia Ten studies presented data on preeclampsia (Table 12).81,82,88-90,103,133,149,155,160 Definitions of preeclampsia were only reported in two of the ten studies, and the definitions differed. Three studies compared women who met CC criteria for GDM with women who had no GDM and found a significant difference with fewer cases among the no GDM group (Figure 13).81,89,160 Two studies compared women who met CC criteria for GDM with women who were false positive and demonstrated a significant difference with fewer cases in the false-positive group (Figure 14).90,160 The strength of evidence for these two comparisons was low. The following three comparisons showed no differences between groups: 1 abnormal OGTT by NDDG versus no GDM (1 study),103 false positive NDDG versus no GDM (2 studies, Figure 15),82,88 and IGT by WHO criteria versus no GDM (3 studies, Figure 16).133,149,155 The strength of evidence for these three comparisons was insufficient. Figure 13. CC GDM versus no GDM: preeclampsia Study or Subgroup Cheng, 2009 Naylor, 1996 Pennison, 2001 Experimental Control Events Total Events Total Weight 17 10 9 Total (95% CI) Risk Ratio M-H, Random, 95% CI 273 115 43 627 13940 144 2940 10 69 52.5% 30.4% 17.2% 1.38 [0.87, 2.21] 1.78 [0.96, 3.28] 1.44 [0.64, 3.27] 431 16949 100.0% 1.50 [1.07, 2.11] Total events 36 781 Heterogeneity: Tau² = 0.00; Chi² = 0.41, df = 2 (P = 0.81); I² = 0% Test for overall effect: Z = 2.37 (P = 0.02) Risk Ratio M-H, Random, 95% CI 0.2 0.5 1 2 5 Favors CC criteria Favors No GDM CC = Carpenter-Coustan; CI = confidence interval; GDM = gestational diabetes mellitus, M-H = Mantel-Haenszel Figure 14. CC GDM versus false positive: preeclampsia Study or Subgroup Berggren, 2011 Naylor, 1996 Total (95% CI) CC criteria False-positive Total Weight Events Total Events 58 10 460 115 575 264 31 Risk Ratio M-H, Random, 95% CI 3117 580 86.8% 13.2% 1.49 [1.14, 1.94] 1.63 [0.82, 3.22] 3697 100.0% 1.51 [1.17, 1.93] 295 68 Total events Heterogeneity: Tau² = 0.00; Chi² = 0.06, df = 1 (P = 0.81); I² = 0% Test for overall effect: Z = 3.23 (P = 0.001) Risk Ratio M-H, Random, 95% CI 0.2 0.5 1 2 5 Favors CC criteria Favors False-positive CC = Carpenter-Coustan; CI = confidence interval; GDM = gestational diabetes mellitus, M-H = Mantel-Haenszel 47 Figure 15. NDDG false positive versus no GDM: preeclampsia Study or Subgroup NDDG False-positive No GDM Events Total Events Total Weight 7 10 Biri, 2009 Stamilio, 2004 326 164 490 Total (95% CI) 21 107 Risk Ratio M-H, Random, 95% CI 1432 1661 35.5% 64.5% 1.46 [0.63, 3.42] 0.95 [0.51, 1.77] 3093 100.0% 1.10 [0.67, 1.83] 128 17 Total events Heterogeneity: Tau² = 0.00; Chi² = 0.66, df = 1 (P = 0.42); I² = 0% Test for overall effect: Z = 0.39 (P = 0.70) Risk Ratio M-H, Random, 95% CI 0.2 0.5 1 2 5 Favors False-positive Favors No GDM CI = confidence interval; GDM = gestational diabetes mellitus, NDDG = National Diabetes Data Group; M-H = MantelHaenszel Figure 16. WHO impaired glucose tolerance versus no GDM: preeclampsia Study or Subgroup Jensen, 2003 Nord, 1995 Yang, 2002 IGT by WHO Events Total No GDM by WHO Total Weight Events 289 223 102 16 13 3 614 Total (95% CI) 158 14 0 Risk Ratio M-H, Random, 95% CI 2596 391 302 50.3% 42.1% 7.6% 0.91 [0.55, 1.50] 1.63 [0.78, 3.40] 20.59 [1.07, 395.30] 3289 100.0% 1.47 [0.62, 3.52] 172 32 Total events Heterogeneity: Tau² = 0.33; Chi² = 5.40, df = 2 (P = 0.07); I² = 63% Test for overall effect: Z = 0.87 (P = 0.38) Risk Ratio M-H, Random, 95% CI 0.2 0.5 1 2 5 Favors IGT by WHO Favors No GDM by WHO CI = confidence interval; GDM = gestational diabetes mellitus, IGT = impaired glucose tolerance; M-H = Mantel-Haenszel; WHO = World Health Organization Maternal Hypertension Nine studies presented data on maternal hypertension (Table 12).78,80,90,92,93,102,106,133,163 Four studies compared women who met CC criteria for GDM with women without GDM and showed significantly fewer cases in the no GDM group (Figure 17).92,93,102,163 Two studies comparing women who met CC criteria for GDM with women who were false positive showed a significant difference with fewer cases in the false-positive group (Figure 18).90,102 Two studies compared one abnormal OGTT by CC criteria with no GDM and showed a significant difference with fewer cases in the group with no GDM (Figure 19).80,106 No differences were found for the following comparisons: CC false positive versus no GDM (1 study),102 WHO IGT versus no GDM (1 study),133 and IADPSG GDM versus no GDM (1 study).93 A single study of IADPSG criteria78 made comparisons across six different groups and found significant differences for: IADPSG IFG versus no GDM, IADPSG double impaired glucose tolerance (IGT-2) versus no GDM, IADPSG IGT IFG versus no GDM (all favoring no GDM); IADPSG IGT versus IGT IFG (favoring IGT); and IADPSG IFG versus IGT IFG (favoring IFG). Figure 17. CC GDM versus no GDM: maternal hypertension Study or Subgroup Chou, 2010 Landon, 2011 Lapolla, 2011 Ricart, 2005 CC criteria No GDM Events Total Events Total Weight 10 62 9 10 489 455 112 263 238 10116 31 423 76 1815 108 6350 Risk Ratio M-H, Random, 95% CI 22.6% 34.1% 21.1% 22.2% 0.87 [0.46, 1.63] 1.86 [1.23, 2.80] 1.92 [0.99, 3.73] 2.24 [1.18, 4.22] 1319 18704 100.0% Total events 91 453 Heterogeneity: Tau² = 0.07; Chi² = 5.49, df = 3 (P = 0.14); I² = 45% Test for overall effect: Z = 2.51 (P = 0.01) 1.64 [1.11, 2.42] Total (95% CI) Risk Ratio M-H, Random, 95% CI 0.2 0.5 1 2 5 Favors CC criteria Favors No GDM CC = Carpenter-Coustan; CI = confidence interval; GDM = gestational diabetes mellitus, M-H = Mantel-Haenszel 48 Figure 18. CC GDM versus false positive: maternal hypertension Study or Subgroup Berggren, 2011 Ricart, 2005 CC criteria False-positive Events Total Events Total Weight 33 10 460 263 150 42 723 Total (95% CI) Risk Ratio M-H, Random, 95% CI 3117 1838 77.6% 22.4% 1.49 [1.04, 2.15] 1.66 [0.85, 3.28] 4955 100.0% 1.53 [1.11, 2.11] 192 Total events 43 Heterogeneity: Tau² = 0.00; Chi² = 0.08, df = 1 (P = 0.78); I² = 0% Test for overall effect: Z = 2.59 (P = 0.010) Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favors CC criteria Favors False-positive CC = Carpenter-Coustan; CI = confidence interval; GDM = gestational diabetes mellitus, M-H = Mantel-Haenszel Figure 19. CC 1 Abnormal OGTT versus no GDM: maternal hypertension Study or Subgroup Corrado, 2009 Vambergue, 2000 Total (95% CI) CC 1 Abnormal OGTT No GDM Total Events Total Weight Events 21 14 152 131 283 27 5 Risk Ratio M-H, Random, 95% CI 76.9% 23.1% 3.19 [1.86, 5.49] 2.31 [0.86, 6.21] 732 100.0% 2.96 [1.84, 4.77] 624 108 32 35 Total events Heterogeneity: Tau² = 0.00; Chi² = 0.33, df = 1 (P = 0.57); I² = 0% Test for overall effect: Z = 4.48 (P < 0.00001) Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favors 1 Abnormal OGTT Favors No GDM CC = Carpenter-Coustan; CI = confidence interval; GDM = gestational diabetes mellitus, M-H = Mantel-Haenszel ; OGTT = oral glucose tolerance test Cesarean Delivery Twenty-six studies presented data for cesarean delivery (Table 12).67,78,80,81,83,8590,92,93,102,103,132,133,135,145,146,149,150,152,154,155,160 Nine studies compared CC GDM with no GDM and found a significant difference with fewer cases for the no GDM group (Figure 20).81,86,89,92,93,102,146,150,160 Four studies compared CC GDM with false-positive results and showed significantly fewer cases in the false-positive group (Figure 21).90,102,150,160 Four studies compared CC 1 abnormal OGTT versus no GDM and found fewer cases in the group with no GDM (Figure 22).80,86,106,135 Five studies compared CC false positives with no GDM and found fewer events among patient groups with no GDM (Figure 23).87,102,145,150,160 One study compared NDDG with 1 abnormal OGTT with women without GDM and found fewer events for the no GDM group.103 Four studies comparing NDDG false positives versus no GDM showed a significant difference with fewer events for the no GDM group (Figure 24).67,88,132,152 Four studies compared WHO impaired glucose tolerance with no GDM, a significant difference was found in favor of the no GDM group (Figure 25).133,149,154,155 One study compared IADPSG IFG versus no GDM, and the same study compared IADPSG IGT IFG versus no GDM with both showing significant differences with fewer cases in the no GDM group.78 There were no differences between groups for the remaining comparisons (Table 12; Figure 26). 49 Figure 20. CC GDM versus no GDM: cesarean delivery Study or Subgroup Cheng, 2009 Chico, 2005 Chou, 2010 Langer, 2005 Lapolla, 2011 Naylor, 1996 Pennison, 2001 Ricart, 2005 Schwartz, 1999 CC No GDM Events Total Events Total Weight 62 122 196 132 49 34 13 59 38 273 422 489 555 112 115 43 263 154 2356 13940 1442 5767 3761 10116 158 1110 564 1815 585 2940 17 69 1219 6350 1110 7207 Risk Ratio M-H, Random, 95% CI 11.7% 14.7% 16.8% 12.3% 11.7% 9.0% 3.2% 11.3% 9.4% Total (95% CI) 2426 49314 100.0% Total events 705 11212 Heterogeneity: Tau² = 0.02; Chi² = 21.49, df = 8 (P = 0.006); I² = 63% Test for overall effect: Z = 4.54 (P < 0.00001) Risk Ratio M-H, Random, 95% CI 1.34 [1.08, 1.68] 1.16 [0.99, 1.35] 1.08 [0.96, 1.20] 1.67 [1.36, 2.06] 1.41 [1.13, 1.76] 1.49 [1.11, 1.99] 1.23 [0.66, 2.27] 1.17 [0.93, 1.47] 1.60 [1.21, 2.12] 1.32 [1.17, 1.48] 0.2 0.5 1 2 5 Favors CC Favors No GDM CC = Carpenter-Coustan; CI = confidence interval; GDM = gestational diabetes mellitus, M-H = Mantel-Haenszel Figure 21. CC GDM versus false positive: cesarean delivery Study or Subgroup Berggren, 2011 Naylor, 1996 Ricart, 2005 Schwartz, 1999 CC False-positive Events Total Events Total Weight 160 34 59 38 Total (95% CI) 460 115 263 154 942 136 393 197 992 Risk Ratio M-H, Random, 95% CI 3117 580 1838 1066 58.8% 10.7% 18.7% 11.8% 1.15 [1.00, 1.32] 1.26 [0.92, 1.73] 1.05 [0.82, 1.34] 1.34 [0.99, 1.81] 6601 100.0% 1.16 [1.05, 1.29] Total events 291 1668 Heterogeneity: Tau² = 0.00; Chi² = 1.77, df = 3 (P = 0.62); I² = 0% Test for overall effect: Z = 2.83 (P = 0.005) Risk Ratio M-H, Random, 95% CI 0.2 0.5 1 2 5 Favors CC Favors False-positi CC = Carpenter-Coustan; CI = confidence interval; GDM = gestational diabetes mellitus, M-H = Mantel-Haenszel Figure 22. CC, 1 abnormal OGTT versus no GDM: cesarean delivery Study or Subgroup Chico, 2005 Corrado, 2009 Rust, 1996 Vambergue, 2000 Total (95% CI) 1 Abnormal OGTT No GDM Total Events Total Weight Events 19 85 14 23 59 152 78 131 420 1442 243 32 11 Risk Ratio M-H, Random, 95% CI 5767 624 205 108 15.5% 73.1% 6.6% 4.8% 1.29 [0.89, 1.87] 1.44 [1.21, 1.71] 1.15 [0.65, 2.04] 1.72 [0.88, 3.37] 6704 100.0% 1.40 [1.21, 1.63] 1728 141 Total events Heterogeneity: Tau² = 0.00; Chi² = 1.10, df = 3 (P = 0.78); I² = 0% Test for overall effect: Z = 4.52 (P < 0.00001) Risk Ratio M-H, Random, 95% CI 0.2 0.5 1 2 5 Favors CC IGT Favors No GDM CC = Carpenter-Coustan; CI = confidence interval; GDM = gestational diabetes mellitus, IGT = impaired glucose tolerance; M-H = Mantel-Haenszel ; OGTT = oral glucose tolerance test 50 Figure 23. CC false positive versus no GDM: cesarean delivery Study or Subgroup Bo, 2004 Lapolla, 2007 Naylor, 1996 Ricart, 2005 Schwartz, 1999 False-positive No GDM Events Total Events Total Weight 103 45 136 393 197 315 128 580 1838 1066 28 100 585 1219 1110 3927 Total (95% CI) Risk Ratio M-H, Random, 95% CI 91 334 2940 6350 7207 4.0% 5.8% 17.8% 46.9% 25.5% 1.06 [0.75, 1.50] 1.17 [0.88, 1.56] 1.18 [1.00, 1.39] 1.11 [1.01, 1.23] 1.20 [1.05, 1.38] 16922 100.0% 1.15 [1.07, 1.23] Total events 874 3042 Heterogeneity: Tau² = 0.00; Chi² = 1.05, df = 4 (P = 0.90); I² = 0% Test for overall effect: Z = 3.91 (P < 0.0001) Risk Ratio M-H, Random, 95% CI 0.5 0.7 1 1.5 2 Favors False-positive Favors No GDM CC = Carpenter-Coustan; CI = confidence interval; GDM = gestational diabetes mellitus, M-H = Mantel-Haenszel Figure 24. NDDG false-positive versus no GDM: cesarean delivery Study or Subgroup Ardawi, 2000 Hillier, 2007 Retnakaran, 2008 Stamilio, 2004 False-positive by NDDG No GDM Total Events Total Weight Events 3.9% 529 67 187 24 785 1432 83.2% 326 208 4.3% 74 23 128 44 8.6% 286 1661 164 39 3696 805 Total (95% CI) 100.0% Risk Ratio M-H, Random, 95% CI Risk Ratio M-H, Random, 95% CI 1.01 [0.66, 1.57] 1.16 [1.06, 1.28] 1.11 [0.73, 1.68] 1.38 [1.03, 1.85] 1.17 [1.08, 1.28] 1161 315 Total events Heterogeneity: Tau² = 0.00; Chi² = 1.73, df = 3 (P = 0.63); I² = 0% Test for overall effect: Z = 3.62 (P = 0.0003) 0.2 0.5 1 2 5 Favors False-positive Favors No GDM CI = confidence interval; GDM = gestational diabetes mellitus, M-H = Mantel-Haenszel; NDDG = National Diabetes Data Group Figure 25. WHO impaired glucose tolerance versus no GDM: cesarean delivery Study or Subgroup Aberg, 2001 Jensen, 2003 Nord, 1995 Yang, 2002 IGT WHO No GDM Events Total Events Total Weight 12 54 38 75 Total (95% CI) 131 289 223 102 249 450 45 199 745 Risk Ratio M-H, Random, 95% CI 4526 2596 391 302 7.0% 26.4% 12.7% 53.9% 1.67 [0.96, 2.89] 1.08 [0.84, 1.39] 1.48 [0.99, 2.21] 1.12 [0.97, 1.29] 7815 100.0% 1.18 [1.01, 1.37] Total events 179 943 Heterogeneity: Tau² = 0.01; Chi² = 3.86, df = 3 (P = 0.28); I² = 22% Test for overall effect: Z = 2.12 (P = 0.03) Risk Ratio M-H, Random, 95% CI 0.2 0.5 1 2 5 Favors IGT WHO Favors No GDM CI = confidence interval; GDM = gestational diabetes mellitus, IGT = impaired glucose tolerance; M-H = Mantel-Haenszel; WHO = World Health Organization Figure 26. CC, 1 abnormal OGTT versus false positive: cesarean delivery Study or Subgroup Kwik, 2007 Lapolla, 2007 1 Abnormal OGTT False-positive Total Total Events Events 46 27 156 48 61 45 Risk Ratio M-H, Random, 95% CI Risk Ratio M-H, Random, 95% CI 0.95 [0.69, 1.31] 1.60 [1.14, 2.25] 197 128 0.2 0.5 1 2 5 Favors 1 Abnormal OGTT Favors False-positive CC = Carpenter-Coustan; CI = confidence interval; M-H = Mantel-Haenszel; OGTT = Oral glucose tolerance test 51 Birth Trauma Three studies presented data for maternal birth trauma (Table 12).81,90,152 Two studies employed CC GDM and compared with no GDM and a false-positive group, respectively.81,90 In both studies birth trauma was defined as third or fourth degree perineal laceration. Neither study found a significant difference between groups. One study compared unrecognized NDDG GDM with no GDM and showed no difference in rectal injury between groups.152 Weight Gain Three studies presented data for maternal weight gain (Table 12).78,135,155 One study compared 1 abnormal glucose tolerance value by CC criteria with no GDM and found no difference between groups.135 One study compared impaired glucose tolerance by WHO criteria with no GDM; no significant difference was found between groups.155 One study compared varying degrees of glucose intolerance by IADPSG criteria.78 Significantly less weight gain was found in the IGT, IFG, and IGT-2 groups in comparison with no GDM. No significant differences were noted between any other IADPSG glucose tolerance groups. Maternal Morbidity/Mortality Two studies presented data for maternal mortality or morbidity (Table 12).93,135 One study compared CC GDM as well as IADPSG GDM with no GDM.93 No significant difference was found between the CC and no GDM groups, while a significant difference favoring no GDM was found in comparison with the IADPSG group. One study compared one abnormal glucose value by CC criteria with no GDM, with no significant difference noted between groups.135 Long Term No studies provided data on long-term maternal outcomes, such as type 2 diabetes mellitus, obesity and hypertension. Table 12. Evidence summary table: maternal outcomes Outcome Preeclampsia Maternal hypertension 17,380 Effect Estimate* 1.50 [1.07, 2.11] 0% No GDM 2 4,272 1.51 [1.17, 1.93] 0% False positive 2 3,583 1.10 [0.67,1.83] 0% - 1 699 1.33 [0.48, 3.65] NA - WHO IGT vs. no GDM 3 3,903 1.47 [0.62, 3.52] CC GDM vs. no GDM 4 20,023 1.64 [1.11, 2.42] 2 5,678 1.53 [1.11, 2.11] 0% False positive 2 1,015 2.96 [1.84, 4.77] 0% No GDM 1 8,188 1.35 [0.94, 1.94] NA - 1 2,885 0.91 [0.55, 1.50] NA - 1 1,927 1.92 [0.99, 3.73] NA - 1 7,411 1.32 [0.96, 1.82] NA - Comparison Studies CC GDM vs. no GDM CC GDM vs. false positive NDDG false positive vs. no GDM NDDG, 1 abnormal OGTT vs. no GDM 3 CC GDM vs. false positive CC 1 abnormal OGTT vs. no GDM CC false positive vs. no GDM IGT WHO vs. no GDM IADPSG GDM vs. no GDM IADPSG IGT vs. no GDM Participants 52 I 2 63 % 45 % Favors ¶ No GDM Table 12. Evidence summary table: maternal outcomes (continued) Outcome Comparison Studies Participants 1 7,906 1 7,103 1 7,351 IADPSG IGT vs. IFG 1 1,277 IADPSG IGT vs. IGT-2 1 474 IADPSG IGT vs. IGT IFG 1 722 IADPSG IFG vs. IGT-2 1 969 1 1,217 1 414 9 51,740 4 7,593 1 481 4 7,124 5 20,849 2 529 1 80 1 699 4 4,501 4 8,560 1 1,927 1 7,411 1 7,906 1 7,103 1 7,351 1 1,277 IADPSG IFG vs. no GDM IADPSG IGT-2 vs. no GDM IADPSG IGT IFG vs. no GDM Maternal Hypertension (continued) IADPSG IFG vs. IGT IFG IADPSG IGT-2 vs. IGT IFG CC GDM vs. no GDM CC GDM vs. false positive CC GDM vs. 1 abnormal OGTT CC 1 abnormal OGTT vs. No GDM CC false positive vs. no GDM CC 1 abnormal OGTT vs. false positive Cesarean delivery NDDG GDM (unrecognized) vs. no GDM NDDG, 1 abnormal OGTT vs. no GDM NDDG false positive vs. no GDM WHO IGT vs. no GDM IADPSG GDM vs. no GDM IADPSG IGT vs. no GDM IADPSG IFG vs. no GDM IADPSG IGT-2 vs. no GDM IADPSG IGT IFG vs. no GDM IADPSG IGT vs. IFG 53 Effect Estimate* 1.46 [1.18, 1.80] 1.90 [1.09, 3.31] 2.03 [1.54, 2.69] 0.91 [0.63, 1.31] 0.69 [0.37, 1.31] 0.65 [0.43, 0.98] 0.77 [0.43, 1.37] 0.72 [0.51, 0.99] 0.93 [0.51, 1.72] 1.34 [1.17, 1.48] 1.16 [1.05, 1.29] 0.90 [0.60, 1.34] 1.40 [1.21, 1.63] 1.15 [1.07, 1.23] Results not pooled due to substantial heterogeneity. 1.60 [0.58, 4.45] 1.69 [1.04,2.75] 1.17 [1.08, 1.28] 1.18 [1.01, 1.37] 1.92 [0.99, 3.73] 1.11 [0.89, 1.39] 1.28 [1.11, 1.47] 1.58 [0.94, 2.64] 1.32 [1.06, 1.63] 0.87 [0.68, 1.12] I 2 Favors NA No GDM NA No GDM NA No GDM NA - NA - NA IGT NA NA NA ¶ IFG - 63% No GDM 0% False positive NA - 0% No GDM 0% No GDM 79% - NA - NA No GDM 0% No GDM 22% No GDM NA - NA - NA NA NA NA No GDM No GDM - Table 12. Evidence summary table: maternal outcomes (continued) Outcome Cesarean delivery (continued) Studies Participants IADPSG IGT vs. IGT-2 1 474 IADPSG IGT vs. IGT IFG 1 722 IADPSG IFG vs. IGT-2 1 969 1 1,217 1 414 1 722 1 969 1 1,217 1 414 1 14,213 1 3,577 1 80 2.00 [0.40, 9.97] 1 283 Not calculated 1 404 1 7,411 1 7,906 1 7,103 1 7,351 IADPSG IGT vs. IFG 1 1,277 IADPSG IGT vs. IGT-2 1 474 IADPSG IGT vs. IGT IFG 1 722 IADPSG IFG vs. IGT-2 1 969 1 1,217 1 414 IADPSG IFG vs. IGT IFG IADPSG IGT-2 vs. IGT IFG IADPSG IGT vs. IGT IFG IADPSG IFG vs. IGT-2 IADPSG IFG vs. IGT IFG IADPSG IGT-2 vs. IGT IFG CC GDM vs. no GDM Maternal birth trauma CC GDM vs. false positive NDDG GDM (unrecognized) vs. No GDM CC 1 abnormal OGTT vs. no GDM WHO IGT vs. no GDM Maternal weight gain Effect Estimate* 0.77 [0.49, 1.21] 0.85 [0.63, 1.14] 0.88 [0.58, 1.34] 0.97 [0.76, 1.24] 1.10 [0.70, 1.72] 0.85 [0.63, 1.14] 0.88 [0.58, 1.34] 0.97 [0.76, 1.24] 1.10 [0.70, 1.72] 1.26 [0.90, 1.76] 0.80 [0.47, 1.39] Comparison IADPSG IGT vs. no GDM IADPSG IFG vs. no GDM IADPSG IGT-2 vs. no GDM IADPSG IGT IFG vs. no GDM IADPSG IFG vs. IGT IFG IADPSG IGT-2 vs. IGT IFG 54 0.00 [-1.41, 1.41] -1.90 [-3.37, ‡ 0.43] -1.20 [ -2.25, ‡ 0.15] -2.60 [-5.12, ‡ 0.08] -1.20 [-2.83, ‡ 0.43] -0.70 [-2.45, ‡ 1.05] 0.70 [-2.18, ‡ 3.58] -0.70 [-2.85, ‡ 1.45] 1.40 [-1.29, ‡ 4.09] 0.00 [-1.88, ‡ 1.88] -1.40 [-4.36, ‡ 1.56] 2 Favors NA - NA - NA - NA - NA - NA - NA - NA - NA - NA - NA - NA - NA - NA - I † NA IGT NA IFG NA IGT-2 NA - NA - NA - NA - NA - NA - NA - ¶ Table 12. Evidence summary table: maternal outcomes (continued) Effect 2 ¶ I Favors Estimate* 1.53 [0.97, CC GDM vs. no GDM 1 1,927 NA 2.42] Maternal CC 1 abnormal OGTT 1.01 [0.37, 1 283 NA mortality/ vs. no GDM 2.74] morbidity IADPSG GDM vs. no 1.43 [1.01, 1 1,927 NA No GDM GDM 2.04] CC = Carpenter-Coustan; GDM = gestational diabetes mellitus; IFG = impaired fasting glucose; IGT = impaired glucose tolerance; IGT-2 = double impaired glucose tolerance; IADPSG = International Association of Diabetes and Pregnancy Study Groups; NA = not applicable; NDDG = National Diabetes Data Group; OGTT = oral glucose tolerance test; WHO = World Health Organization *Effect estimates are risk ratios and 95% confidence intervals, except where indicated. ¶Where the result was statistically significant, we have listed the group that had the better outcome (e.g., lower incidence of preeclampsia). †Study did not report variances but did report no significant difference between groups. ‡Effect estimates are mean differences and 95% confidence intervals. Outcome Comparison Studies Participants Table 13. Strength of evidence summary table: maternal outcomes Outcome Comparison Studies Risk of Bias Consistency Directness Precision CC GDM vs. no GDM 3 High Consistent Direct Precise CC GDM vs. false 2 High Consistent Direct Precise positive NDDG false positive vs. Preeclampsia 2 High Consistent Direct Imprecise no GDM NDDG, 1 abnormal 1 High Unknown Direct Imprecise OGTT vs. no GDM WHO IGT vs. no GDM 3 High Consistent Direct Imprecise CC 1 abnormal OGTT 1 High Unknown Direct Unknown vs. no GDM WHO IGT vs. no GDM 1 High Unknown Direct Unknown IADPSG IGT vs. no 1 High Unknown Direct Precise GDM IADPSG IFG vs. no 1 High Unknown Direct Precise GDM IADPSG IGT-2 vs. no 1 High Unknown Direct Precise GDM IADPSG IGT IFG vs. Maternal weight 1 High Unknown Direct Imprecise no GDM gain IADPSG IGT vs. IFG 1 High Unknown Direct Imprecise IADPSG IGT vs. IGT-2 1 High Unknown Direct Imprecise IADPSG IGT vs. IGT 1 High Unknown Direct Imprecise IFG IADPSG IFG vs. IGT-2 1 High Unknown Direct Imprecise IADPSG IFG vs. IGT 1 High Unknown Direct Imprecise IFG IADPSG IGT-2 vs. 1 High Unknown Direct Imprecise IGT IFG CC = Carpenter-Coustan; GDM = gestational diabetes mellitus; IFG = impaired fasting glucose; IGT = impaired glucose tolerance; IGT-2 = double impaired glucose tolerance; IADPSG = International Association of Diabetes and Pregnancy Study Groups; NDDG = National Diabetes Data Group; OGTT = oral glucose tolerance test; SOE = strength of evidence; WHO = World Health Organization 55 SOE Low Low Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient Fetal/Neonatal/Child Outcomes Short Term A summary of the evidence for short and long term fetal, neonatal, and child outcomes is found in Table 14. The strength of evidence is presented in Table 15. The sections that follow describe the results by outcome. Macrosomia (>4,000 g) Twenty-one studies presented data for macrosomia (over 4,000 g) (Table 14).79,80,84-86,8890,92,93,102,106,132,133,135,136,145,146,150,152,160 There were significantly fewer cases of macrosomia in the patient groups with no GDM compared with CC GDM (10 studies, Figure 27).86,89,92,93,102,132,136,146,150,160 CC 1 abnormal OGTT (7 studies, Figure 28),80,86,106,132,135,136,145 NDDG GDM (1 study),152 NDDG false positives (4 studies, Figure 29),83,86,88,132 and WHO IGT (1 study).133 Significantly fewer cases of macrosomia were observed among women with falsepositive results compared with CC GDM (5 studies, Figure 30).90,102,132,150,160 There was no significant difference in other comparisons involving other CC groups (Figure 31, Figure 32, Figure 33). One study compared WHO GDM with no GDM; no significant difference was observed between groups.84 Two studies compared women who met IADPSG criteria for GDM with a no GDM group; no difference was observed between groups (Figure 34).79,93 The strength of evidence for this outcome was low to insufficient due to risk of bias (all observational studies), inconsistency across studies, and/or imprecision in effect estimates (Table 15). Figure 27. CC GDM versus no GDM: macrosomia (>4,000 g) Study or Subgroup Berkus, 1995 Chico, 2005 Chou, 2010 Hillier, 2007 Langer, 2005 Lapolla, 2011 Naylor, 1996 Pennison, 2001 Ricart, 2005 Schwartz, 1999 Total (95% CI) GDM No GDM Events Total Events Total Weight 7.4% 573 76 72 13 288 5767 10.1% 422 22 236 10116 10.0% 489 22 905 7609 11.8% 173 25 87 1110 15.5% 555 93 7.0% 145 1815 112 12 395 2940 14.3% 115 33 2.2% 69 5 43 6 292 6350 10.0% 263 21 692 4190 11.7% 91 22 2335 40539 100.0% 3121 269 Total events Heterogeneity: Tau² = 0.03; Chi² = 15.55, df = 9 (P = 0.08); I² = 42% Test for overall effect: Z = 5.38 (P < 0.00001) Risk Ratio M-H, Random, 95% CI Risk Ratio M-H, Random, 95% CI 1.36 [0.80, 2.32] 1.04 [0.68, 1.59] 1.93 [1.26, 2.96] 1.21 [0.84, 1.75] 2.14 [1.63, 2.81] 1.34 [0.77, 2.34] 2.14 [1.58, 2.89] 1.93 [0.63, 5.93] 1.74 [1.13, 2.66] 1.46 [1.01, 2.12] 1.61 [1.35, 1.92] 0.1 0.2 0.5 1 2 5 10 Favors GDM Favors No GDM CC = Carpenter-Coustan; CI = confidence interval; GDM = gestational diabetes mellitus; M-H = Mantel-Haenszel 56 Figure 28. CC, 1 abnormal OGTT versus no GDM: macrosomia (>4,000 g) Study or Subgroup Berkus, 1995 Chico, 2005 Corrado, 2009 Hillier, 2007 Lapolla, 2007 Rust, 1996 Vambergue, 2000 1 Abnormal OGTT No GDM Total Events Total Weight Events 573 20.8% 76 87 18 4.4% 288 5767 59 3 624 17.2% 39 152 19 905 7609 39.0% 288 40 3.3% 334 8 48 3 6.7% 205 18 78 6 8.6% 108 8 131 21 15220 843 Total (95% CI) Risk Ratio M-H, Random, 95% CI 100.0% 1342 110 Total events Heterogeneity: Tau² = 0.02; Chi² = 6.99, df = 6 (P = 0.32); I² = 14% Test for overall effect: Z = 2.99 (P = 0.003) Risk Ratio M-H, Random, 95% CI 1.56 [0.98, 2.48] 1.02 [0.34, 3.08] 2.00 [1.19, 3.36] 1.17 [0.87, 1.57] 2.61 [0.72, 9.50] 0.88 [0.36, 2.13] 2.16 [1.00, 4.69] 1.44 [1.13, 1.82] 0.1 0.2 0.5 1 2 5 10 Favors 1 Abnormal OGTT Favors No GDM CC = Carpenter-Coustan; CI = confidence interval; GDM = gestational diabetes mellitus; M-H = Mantel-Haenszel; OGTT = oral glucose tolerance test Figure 29. NDDG false positive versus no GDM: macrosomia (>4,000 g) Study or Subgroup NDDG False-positive No GDM Total Events Total Weight Events 33 83 6 95 187 326 128 164 15 27 18 14 Chico, 2005 Hillier, 2007 Retnakaran, 2008 Stamilio, 2004 805 Total (95% CI) Risk Ratio M-H, Random, 95% CI 529 1432 74 1661 21.6% 42.9% 9.7% 25.8% 1.29 [0.71, 2.31] 1.43 [0.94, 2.17] 1.73 [0.72, 4.18] 1.49 [0.87, 2.56] 3696 100.0% 1.44 [1.10, 1.89] 217 74 Total events Heterogeneity: Tau² = 0.00; Chi² = 0.33, df = 3 (P = 0.95); I² = 0% Test for overall effect: Z = 2.61 (P = 0.009) Risk Ratio M-H, Random, 95% CI 0.2 0.5 1 2 5 Favors False-positive Favors No GDM CI = confidence interval; GDM = gestational diabetes mellitus; NDDG = National Diabetes Data Group; M-H = Mantel-Haenszel Figure 30. CC GDM versus false positive: macrosomia (>4,000 g) Study or Subgroup Berggren, 2011 Hillier, 2007 Naylor, 1996 Ricart, 2005 Schwartz, 1999 CC GDM False-positive Total Weight Events Total Events 3117 30.1% 411 460 78 999 17.3% 122 173 25 580 20.0% 80 115 33 1838 15.2% 131 263 21 605 17.4% 119 91 22 7139 1102 Total (95% CI) 100.0% Risk Ratio M-H, Random, 95% CI Risk Ratio M-H, Random, 95% CI 1.29 [1.03, 1.60] 1.18 [0.79, 1.76] 2.08 [1.46, 2.96] 1.12 [0.72, 1.74] 1.23 [0.83, 1.83] 1.36 [1.10, 1.68] 863 179 Total events Heterogeneity: Tau² = 0.03; Chi² = 7.33, df = 4 (P = 0.12); I² = 45% Test for overall effect: Z = 2.82 (P = 0.005) 0.2 0.5 1 2 5 Favors GDM Favors False-positiv CC = Carpenter-Coustan; CI = confidence interval; GDM = gestational diabetes mellitus; M-H = Mantel-Haenszel Figure 31. CC GDM versus 1 Abnormal OGTT: macrosomia (>4,000 g) Study or Subgroup Berkus, 1995 Chico, 2005 Hillier, 2007 Total (95% CI) GDM 1 Abnormal OGTT Total Weight Events Events Total 13 22 25 72 422 173 667 18 3 40 87 59 288 Risk Ratio M-H, Random, 95% CI 31.1% 9.3% 59.7% 0.87 [0.46, 1.66] 1.03 [0.32, 3.32] 1.04 [0.66, 1.65] 434 100.0% 0.98 [0.69, 1.41] 61 60 Total events Heterogeneity: Tau² = 0.00; Chi² = 0.20, df = 2 (P = 0.91); I² = 0% Test for overall effect: Z = 0.09 (P = 0.93) Risk Ratio M-H, Random, 95% CI 0.2 0.5 1 2 5 Favors GDM Favors 1 Abnormal O CC = Carpenter-Coustan; CI = confidence interval; GDM = gestational diabetes mellitus; M-H = Mantel-Haenszel; OGTT = oral glucose tolerance test 57 Figure 32. CC false positives versus no GDM: macrosomia (>4,000 g) Study or Subgroup Hillier, 2007 Lapolla, 2007 Naylor, 1996 Ricart, 2005 Schwartz, 1999 False-positive No GDM Events Total Events Total Weight 122 8 80 131 2 999 128 580 1838 49 905 8 395 21 12 3594 Total (95% CI) Risk Ratio M-H, Random, 95% CI 7609 334 2940 263 112 43.8% 3.8% 35.9% 14.9% 1.7% 1.03 [0.86, 1.23] 2.61 [1.00, 6.81] 1.03 [0.82, 1.28] 0.89 [0.57, 1.39] 0.38 [0.09, 1.64] 11258 100.0% 1.02 [0.85, 1.24] Total events 343 1341 Heterogeneity: Tau² = 0.01; Chi² = 5.80, df = 4 (P = 0.21); I² = 31% Test for overall effect: Z = 0.25 (P = 0.80) Risk Ratio M-H, Random, 95% CI 0.1 0.2 0.5 1 2 5 10 Favors False-positive Favors No GDM CC = Carpenter-Coustan; CI = confidence interval; GDM = gestational diabetes mellitus; M-H = Mantel-Haenszel Figure 33. CC, 1 Abnormal OGTT versus False positives: macrosomia (>4,000 g) Study or Subgroup Hillier, 2007 Kwik, 2007 Lapolla, 2007 1 Abnormal OGTT False - positive Total Weight Total Events Events 40 42 3 288 213 48 122 19 8 549 Total (95% CI) Risk Ratio M-H, Random, 95% CI 999 197 128 51.7% 37.8% 10.6% 1.14 [0.82, 1.59] 2.04 [1.23, 3.39] 1.00 [0.28, 3.61] 1324 100.0% 1.40 [0.89, 2.20] 149 85 Total events Heterogeneity: Tau² = 0.07; Chi² = 3.82, df = 2 (P = 0.15); I² = 48% Test for overall effect: Z = 1.46 (P = 0.14) Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favors 1 Anormal OGTT Favors False-positive CC = Carpenter-Coustan; CI = confidence interval; GDM = gestational diabetes mellitus; M-H = Mantel-Haenszel Figure 34. IADPSG GDM versus No GDM: macrosomia (>4,000 g) Study or Subgroup Lapolla, 2011 Morikawa, 2010 Total (95% CI) IADPSG GDM No GDM Total Events Total Weight Events 12 1 112 43 155 145 0 Risk Ratio M-H, Random, 95% CI 1815 160 78.8% 21.2% 1.34 [0.77, 2.34] 10.98 [0.46, 264.81] 1975 100.0% 2.09 [0.39, 11.33] 145 13 Total events Heterogeneity: Tau² = 0.86; Chi² = 1.63, df = 1 (P = 0.20); I² = 39% Test for overall effect: Z = 0.86 (P = 0.39) Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favors IADPSG GDM Favors No GDM CI = confidence interval; GDM = gestational diabetes mellitus; IADPSG = International Association of the Diabetes in Pregnancy Study Groups; M-H = Mantel-Haenszel Macrosomia (>4,500 g) Four studies presented data on macrosomia (over 4,500 g) (Table 14).81,150,152,160 Three studies showed a significant difference favoring the group with no GDM compared with CC GDM (Figure 35). The strength of evidence for this finding was low. No significant difference was found for CC GDM compared with false positives (2 studies; Figure 36) and CC false positives versus groups with no GDM (2 studies; Figure 37). One study compared NDDG GDM with a no GDM group, and found a significant difference in favor of the no GDM group.152 The strength of evidence for these three findings was insufficient (Table 15). 58 Figure 35. CC GDM versus no GDM: macrosomia (>4,500 g) Study or Subgroup Cheng, 2009 Naylor, 1996 Schwartz, 1999 CC GDM No GDM Events Total Events Total Weight 11 7 4 Total (95% CI) Risk Ratio M-H, Random, 95% CI 273 115 91 223 13940 56 2940 108 4190 50.7% 30.6% 18.7% 2.52 [1.39, 4.56] 3.20 [1.49, 6.86] 1.71 [0.64, 4.53] 479 21070 100.0% 2.52 [1.65, 3.84] 387 22 Total events Heterogeneity: Tau² = 0.00; Chi² = 1.00, df = 2 (P = 0.61); I² = 0% Test for overall effect: Z = 4.29 (P < 0.0001) Risk Ratio M-H, Random, 95% CI 0.1 0.2 0.5 1 2 5 10 Favors CC GDM Favors No GDM CC = Carpenter-Coustan; CI = confidence interval; GDM = gestational diabetes mellitus; M-H = Mantel-Haenszel Figure 36. CC GDM versus false positive: macrosomia (>4,500 g) Study or Subgroup Naylor, 1996 Schwartz, 1999 Total (95% CI) False-positive CC GDM Total Weight Events Total Events 7 4 115 91 206 12 28 Risk Ratio M-H, Random, 95% CI 580 605 52.2% 47.8% 2.94 [1.18, 7.31] 0.95 [0.34, 2.64] 1185 100.0% 1.71 [0.56, 5.24] 40 11 Total events Heterogeneity: Tau² = 0.41; Chi² = 2.67, df = 1 (P = 0.10); I² = 63% Test for overall effect: Z = 0.94 (P = 0.34) Risk Ratio M-H, Random, 95% CI 0.1 0.2 0.5 1 2 5 10 Favors CC GDM Favors False-positive CC = Carpenter-Coustan; CI = confidence interval; GDM = gestational diabetes mellitus; M-H = Mantel-Haenszel Shoulder Dystocia Twelve studies presented data on shoulder dystocia (Table 14).54,78,81,85,88-90,92,106,133,146,152 Five studies compared women who met CC criteria for GDM with no GDM and found a significant difference in favor of the no GDM group (Figure 37); the strength of evidence was rated low (Table 15).81,89,92,146,163 One study compared CC GDM with a false-positive group, no significant difference was noted.90 One study compared one abnormal OGTT by CC criteria with no GDM and no significant difference was found between groups.106 One study compared women with 1 abnormal OGTT value by CC criteria with a false-positive group with a significant difference noted in favor of the false-positive group.85 One study compared unrecognized GDM by NDDG criteria with a no GDM group;152 another study compared a falsepositive group with no GDM.88 Both studies noted a significant difference in favor of the groups with no GDM. A single study compared IGT by WHO criteria and no GDM; a significant difference was found in favor of group with no GDM.133 One study compared varying degrees of glucose intolerance by IADPSG criteria and no GDM;78 significant differences were observed when no GDM was compared with IFG and IGT and fasting glucose combined. No GDM was favored in both cases. The remaining groups demonstrated no significant differences (Table 14). The strength of evidence for all comparisons based on single studies was rated insufficient (Table 15). 59 Figure 37. CC GDM versus no GDM: shoulder dystocia Study or Subgroup Cheng, 2009 Chou, 2010 Landon, 2011 Langer, 2005 Pennison, 2001 CC GDM No GDM Events Total Events Total Weight 9 2 18 14 1 273 489 455 555 43 237 13940 11 10116 3 423 7 1110 1 69 Risk Ratio M-H, Random, 95% CI 48.4% 9.2% 14.1% 25.6% 2.8% 1.94 [1.01, 3.73] 3.76 [0.84, 16.92] 5.58 [1.65, 18.80] 4.00 [1.62, 9.85] 1.60 [0.10, 24.99] 1815 25658 100.0% Total events 44 259 Heterogeneity: Tau² = 0.00; Chi² = 3.51, df = 4 (P = 0.48); I² = 0% Test for overall effect: Z = 4.52 (P < 0.00001) 2.86 [1.81, 4.51] Total (95% CI) Risk Ratio M-H, Random, 95% CI 0.02 0.1 1 10 50 Favors CC GDM Favors No GDM CC = Carpenter-Coustan; CI = confidence interval; GDM = gestational diabetes mellitus; M-H = Mantel-Haenszel Clavicular Fracture No studies provided comparable data on clavicular fracture. However, this outcome was often a composite outcome within birth injury or fetal birth trauma. Brachial Plexus Injury No studies provided comparable data on brachial plexus injury, also often a composite of birth injury or fetal birth trauma. Fetal Birth Trauma or Birth Injury Four studies presented data for fetal birth trauma or traumatic delivery (Table 14).81,149,152,155 Birth trauma was undefined in two studies,149,155 one comparing WHO IGT with no GDM. Another defined birth trauma as a composite of brachial plexus injury, facial nerve palsy, clavicular fracture, skull fracture, and head laceration; this study compared CC GDM and no GDM.81 No significant difference was observed in any comparison. Brachial plexus injury, cranial nerve palsy, and clavicular facture were also components of birth trauma in one study.152 This study compared women with unrecognized NDDG GDM and no GDM and showed a significant difference in favor of the no GDM group. Strength of evidence for all comparisons was insufficient. Hypoglycemia Twelve studies presented data on neonatal hypoglycemia (Table 14).67,80,86,89,103,106,133,135,146,149,152,155 Two studies did not define hypoglycemia,67,125 while all other studies defined hypoglycemia with varying glucose threshold criteria or by necessity of intravenous glucose. Three studies compared women meeting CC criteria for GDM with groups without GDM. Results were not pooled due to substantial heterogeneity across studies (I2=94%) (Figure 38); however, all three studies individually showed fewer cases of hypoglycemia among the patient groups with no GDM.86,89,146 The difference in results may be explained in part by the methods of assessing for neonatal hypoglycemia (e.g., biochemical vs. clinical). Posthoc analysis showed that the magnitude of association between glucose intolerance and neonatal hypoglycemia was affected by the definition used (i.e., clinical or biochemical). Many of the observational studies included did not routinely apply the same biochemical screening procedure to the non-GDM groups and glucose intolerant women. No significant difference was found for remaining comparisons. One study compared women meeting CC criteria for GDM with women demonstrating one abnormal OGTT value,86 and four studies compared women meeting CC criteria on one abnormal OGTT value with no GDM (Figure 39).80,86,106,135 One study compared 60 women who met NDDG criteria for GDM with no GDM,152 one study compared NDDG false positive with no GDM,67 and another study compared NGGD 1 abnormal OGTT versus no GDM.103 Three studies compared women meeting WHO criteria for IGT with no GDM (Figure 40).133,149 Strength of evidence for all comparisons was insufficient. Figure 38. CC GDM versus no GDM: hypoglycemia Study or Subgroup Chico, 2005 Langer, 2005 Pennison, 2001 CC GDM No GDM Events Total Events Total 23 100 10 422 555 43 202 21 5 Risk Ratio M-H, Random, 95% CI 5767 1110 69 Risk Ratio M-H, Random, 95% CI 1.56 [1.02, 2.37] 9.52 [6.02, 15.08] 3.21 [1.18, 8.76] 0.05 0.2 1 5 20 Favors CC GDM Favors No GDM CC = Carpenter-Coustan; CI = confidence interval; GDM = gestational diabetes mellitus; M-H = Mantel-Haenszel Figure 39. CC, 1 abnormal OGTT versus no GDM: hypoglycemia Study or Subgroup Chico, 2005 Corrado, 2009 Rust, 1996 Vambergue, 2000 CC1 Abnormal OGTT No GDM Total Events Total Weight Events 59 152 78 131 1 9 9 24 420 Total (95% CI) 202 26 20 14 Risk Ratio M-H, Random, 95% CI 5767 624 205 108 4.0% 27.8% 27.4% 40.8% 0.48 [0.07, 3.39] 1.42 [0.68, 2.97] 1.18 [0.56, 2.48] 1.41 [0.77, 2.60] 6704 100.0% 1.29 [0.88, 1.91] 262 43 Total events Heterogeneity: Tau² = 0.00; Chi² = 1.20, df = 3 (P = 0.75); I² = 0% Test for overall effect: Z = 1.29 (P = 0.20) Risk Ratio M-H, Random, 95% CI 0.05 0.2 1 5 20 Favors 1 Abnormal OGTT FavorsNo GDM CC = Carpenter-Coustan; CI = confidence interval; GDM = gestational diabetes mellitus; M-H = Mantel-Haenszel; OGTT = oral glucose tolerance tests Figure 40. WHO impaired glucose tolerance versus no GDM: hypoglycemia Study or Subgroup Jensen, 2003 Nord, 1995 Yang, 2002 Total (95% CI) IGT No GDM Events Total Events Total Weight 6 2 1 Risk Ratio M-H, Random, 95% CI 281 223 102 63 2596 3 391 1 302 76.6% 16.5% 6.9% 0.88 [0.38, 2.01] 1.17 [0.20, 6.94] 2.96 [0.19, 46.91] 606 3289 100.0% 1.00 [0.49, 2.07] 9 67 Total events Heterogeneity: Tau² = 0.00; Chi² = 0.71, df = 2 (P = 0.70); I² = 0% Test for overall effect: Z = 0.01 (P = 0.99) Risk Ratio M-H, Random, 95% CI 0.1 0.2 0.5 1 2 5 10 Favors WHO IGT Favors No GDM CI = confidence interval; GDM = gestational diabetes mellitus; IGT = impaired glucose tolerance; M-H = Mantel-Haenszel; WHO = World Health Organization Hyperbilirubinemia Eight studies presented data for hyperbilirubinemia or neonatal jaundice (Table 14).67,78,86,87,106,133,146,149 Plasma bilirubin values for the diagnosis of hyperbilirubinemia varied amongst studies. Of the seven studies, four studies compared differing CC criterion, including CC GDM with no GDM (Figure 41),86,146 CC GDM and one abnormal OGTT,86 CC 1 abnormal OGTT and no GDM,106 and CC false positive and no GDM.87 Results for CC GDM versus no GDM were not pooled due to substantial statistical heterogeneity (I2=94%). Possible sources of heterogeneity include differences in assessing outcomes across studies and uncontrolled differences between comparison groups. CC false positive versus no GDM showed a significant difference with fewer cases in the group with no GDM. The other comparison involving CC criteria (CC GDM vs. 1 abnormal OGTT) showed no significant difference between groups. One 61 study compared women with a false-positive result by NDDG criteria with no GDM; no significant difference was found.67 Two studies compared women meeting WHO criteria for IGT with no GDM; no significant difference was found (Figure 42).133,149 One study compared various IADPSG thresholds for glucose intolerance.78 A significant difference was present in comparisons of IADPSG isolated (1 value above threshold) IGT and double-isolated (two values above threshold) IGT with no GDM, both favoring the no GDM group. No further differences were observed for any other IADPSG comparisons. Figure 41. CC GDM versus no GDM: hyperbilirubinemia Study or Subgroup Chico, 2005 Langer, 2005 GDM No GDM Events Total Events Total 17 78 422 555 144 23 Risk Ratio M-H, Random, 95% CI 5767 1110 Risk Ratio M-H, Random, 95% CI 1.61 [0.99, 2.64] 6.78 [4.31, 10.68] 0.05 0.2 1 5 20 Favors GDM Favors No GDM CC = Carpenter-Coustan; CI = confidence interval; GDM = gestational diabetes mellitus; M-H = Mantel-Haenszel Figure 42. WHO impaired glucose tolerance versus no GDM: hyperbilirubinemia Study or Subgroup Jensen, 2003 Nord, 1995 Total (95% CI) IGT No GDM Events Total Events Total Weight 6 10 281 223 504 83 28 Risk Ratio M-H, Random, 95% CI 2596 391 42.4% 57.6% 0.67 [0.29, 1.52] 0.63 [0.31, 1.26] 2987 100.0% 0.64 [0.38, 1.10] 111 Total events 16 Heterogeneity: Tau² = 0.00; Chi² = 0.01, df = 1 (P = 0.91); I² = 0% Test for overall effect: Z = 1.62 (P = 0.11) Risk Ratio M-H, Random, 95% CI 0.2 0.5 1 2 5 Favors IGT Favors No GDM CI = confidence interval; GDM = gestational diabetes mellitus; IGT = impaired glucose tolerance; M-H = Mantel-Haenszel; WHO = World Health Organization Morbidity/Mortality Sixteen studies presented data for neonatal mortality or morbidity (Table 14).67,8588,92,93,102,103,106,135,146,149,150,154,155 No studies demonstrated a significant difference between groups which may be due to small numbers of events within some comparisons. Six studies compared women meeting CC criteria for GDM with no GDM (Figure 43),86,92,93,102,146,150 two studies compared CC GDM with false positives (Figure 44),102,150 and one study compared women with CC GDM and those with one abnormal OGTT.86 Three studies compared one abnormal OGTT to no GDM (Figure 45),86,106,135 three studies compared women with false-positive results by CC criteria with no GDM (Figure 46),87,102,150 and one study compared CC false positive with one abnormal OGTT value.85 Two studies compared women with false-positive results by NDDG criteria with no GDM (Figure 47),67,88 one study compared NDDG 1 abnormal OGTT versus no GDM,103 three studies employed WHO criteria for IGT compared with no GDM (Figure 48),149,154,155 and another study followed IADPSG criteria for GDM diagnosis compared with no GDM.93 62 Figure 43. CC GDM versus no GDM: morbidity/mortality Study or Subgroup Chico, 2005 Chou, 2010 Langer, 2005 Lapolla, 2011 Ricart, 2005 Schwartz, 1999 GDM No GDM Events Total Events Total Weight 0 1 0 18 0 1 Total (95% CI) Risk Ratio M-H, Random, 95% CI 422 489 555 112 263 154 29 5767 42 10116 0 1110 132 1815 25 6350 16 7207 10.1% 16.8% 46.6% 10.1% 16.4% 0.23 [0.01, 3.78] 0.49 [0.07, 3.57] Not estimable 2.21 [1.40, 3.48] 0.47 [0.03, 7.73] 2.92 [0.39, 21.92] 1995 32365 100.0% 1.23 [0.46, 3.30] 244 20 Total events Heterogeneity: Tau² = 0.49; Chi² = 6.62, df = 4 (P = 0.16); I² = 40% Test for overall effect: Z = 0.40 (P = 0.69) Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favors GDM Favors No GDM CC = Carpenter-Coustan; CI = confidence interval; GDM = gestational diabetes mellitus; M-H = Mantel-Haenszel Figure 44. CC GDM versus false positive: morbidity/mortality Study or Subgroup Ricart, 2005 Schwartz, 1999 GDM False-positive Events Total Events Total Weight 0 1 Total (95% CI) 263 154 7 1 417 Risk Ratio M-H, Random, 95% CI 1838 1066 49.1% 50.9% 0.46 [0.03, 8.11] 6.92 [0.44, 110.10] 2904 100.0% 1.83 [0.11, 29.41] Total events 1 8 Heterogeneity: Tau² = 1.95; Chi² = 1.95, df = 1 (P = 0.16); I² = 49% Test for overall effect: Z = 0.43 (P = 0.67) Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favors GDM Favors False-positiv CC = Carpenter-Coustan; CI = confidence interval; GDM = gestational diabetes mellitus; M-H = Mantel-Haenszel Figure 45. CC, 1 abnormal OGTT versus no GDM: morbidity/mortality Study or Subgroup Chico, 2005 Rust, 1996 Vambergue, 2000 1 Abnormal OGTT No GDM Total Events Total Weight Events 0 15 1 59 78 131 29 40 0 268 Total (95% CI) Risk Ratio M-H, Random, 95% CI 5767 205 108 3.4% 93.9% 2.6% 1.63 [0.10, 26.36] 0.99 [0.58, 1.68] 2.48 [0.10, 60.20] 6080 100.0% 1.03 [0.61, 1.72] 69 16 Total events Heterogeneity: Tau² = 0.00; Chi² = 0.42, df = 2 (P = 0.81); I² = 0% Test for overall effect: Z = 0.10 (P = 0.92) Risk Ratio M-H, Random, 95% CI 0.1 0.2 0.5 1 2 5 10 Favors 1 Abnormal OGTT Favors No GDM CC = Carpenter-Coustan; CI = confidence interval; GDM = gestational diabetes mellitus; M-H = Mantel-Haenszel; OGTT = oral glucose tolerance test Figure 46. CC false positive versus no GDM: morbidity/mortality Study or Subgroup Bo, 2004 Ricart, 2005 Schwartz, 1999 Total (95% CI) False-positive No GDM Events Total Events Total Weight 4 7 1 315 1838 1066 3219 2 25 16 Risk Ratio M-H, Random, 95% CI 91 6350 7207 17.4% 70.5% 12.1% 0.58 [0.11, 3.10] 0.97 [0.42, 2.23] 0.42 [0.06, 3.18] 13648 100.0% 0.80 [0.40, 1.61] Total events 12 43 Heterogeneity: Tau² = 0.00; Chi² = 0.73, df = 2 (P = 0.69); I² = 0% Test for overall effect: Z = 0.62 (P = 0.53) Risk Ratio M-H, Random, 95% CI 0.1 0.2 0.5 1 2 5 10 Favors False-positive Favors No GDM CC = Carpenter-Coustan; CI = confidence interval; GDM = gestational diabetes mellitus; M-H = Mantel-Haenszel 63 Figure 47. NDDG false positive versus no GDM: morbidity/mortality Study or Subgroup Ardawi, 2000 Stamilio, 2004 False-positive No GDM Events Total Events Total Weight 2 2 187 164 Total (95% CI) 351 4 6 Risk Ratio M-H, Random, 95% CI 529 1661 47.0% 53.0% 1.41 [0.26, 7.66] 3.38 [0.69, 16.59] 2190 100.0% 2.24 [0.70, 7.14] 4 Total events 10 Heterogeneity: Tau² = 0.00; Chi² = 0.56, df = 1 (P = 0.46); I² = 0% Test for overall effect: Z = 1.37 (P = 0.17) Risk Ratio M-H, Random, 95% CI 0.1 0.2 0.5 1 2 5 10 Favors False-positive Favors No GDM CI = confidence interval; GDM = gestational diabetes mellitus; M-H = Mantel-Haenszel; NDDG = National Diabetes Data Group Figure 48. WHO IGT versus no GDM: morbidity/mortality Study or Subgroup Aberg, 2001 Nord, 1995 Yang, 2002 Total (95% CI) IGT No GDM Events Total Events Total Weight 1 3 2 Risk Ratio M-H, Random, 95% CI 126 223 102 13 4515 391 7 302 2 22.9% 52.2% 24.8% 2.76 [0.36, 20.91] 0.75 [0.20, 2.88] 2.96 [0.42, 20.75] 451 5208 100.0% 1.42 [0.54, 3.75] 22 6 Total events Heterogeneity: Tau² = 0.00; Chi² = 1.86, df = 2 (P = 0.39); I² = 0% Test for overall effect: Z = 0.71 (P = 0.48) Risk Ratio M-H, Random, 95% CI 0.01 0.1 1 10 100 Favors IGT Favors No GDM CI = confidence interval; GDM = gestational diabetes mellitus; IGT = impaired glucose tolerance; M-H = Mantel-Haenszel; WHO = World Health Organization Long Term One study presented data on long term health outcomes for infants and children (i.e., prevalence of childhood obesity).132 Prevalence of Childhood Obesity Significant differences were found between women meeting thresholds for CC GDM in comparison with those without GDM, favoring the no GDM group.132 The CC false-positive group was favored compared with women meeting CC GDM criteria (Table 14). These findings should be interpreted cautiously because this study did not adjust for maternal BMI, one of the most important predictors of childhood obesity. No significant differences were found for the remaining comparisons (Table 14). 64 Table 14. Evidence summary table: fetal/neonatal outcomes Outcome Macrosomia >4,000 g Macrosomia >4,500 g Comparison CC GDM vs. no GDM CC GDM vs. false positive CC GDM vs. 1 abnormal OGTT CC 1 abnormal OGTT vs. no GDM CC false positive vs. no GDM CC 1 abnormal OGTT vs. false positive NDDG GDM (unrecognized) vs. no GDM NDDG false positive vs. no GDM WHO GDM vs. no GDM WHO IGT vs. no GDM IADPSG GDM vs. no GDM CC GDM vs. no GDM CC GDM vs. false positive CC false positive vs. no GDM NDDG GDM (unrecognized) vs. no GDM Studies Participants 10 42,874 5 8,241 3 1,101 7 16,063 5 14,852 3 1,873 1 Effect Estimate* 1.61 [1.35, 1.92] 1.36 [1.10, 1.68] 0.98 [0.69, 1.41] 1.44 [1.13, 1.82] 1.02 [0.85, 1.24] I 2 Favors 42% No GDM 45% False positive 0% - 14% No GDM 31% - 1.40 [0.89, 2.20] 48% - 80 5.60 [2.04, 15.35] NA No GDM 4 4,501 1.44 [1.10, 1.89] 0% No GDM 1 542 1 2,885 2 2,130 3 21,549 2 1,391 2 8,315 1 80 3.33 [0.49, 22.70] 1.26 [1.06, 1.50] 2.09 [0.39, 11.33] 2.52 [1.65, 3.84] 1.71 [0.56, 5.24] 1.48 [0.91, 2.39] 26.76 [1.45, 493.62] 65 NA NA 39% 0% No GDM No GDM 63% - 44% - NA No GDM ‡ Table 14. Evidence summary table: fetal/neonatal outcomes (continued) Outcome Shoulder dystocia Comparison CC GDM vs. no GDM CC GDM vs. false positive CC 1 abnormal OGTT vs. no GDM CC 1 abnormal OGTT vs. false positive NDDG GDM (unrecognized) vs. no GDM NDDG false positive vs. no GDM WHO IGT vs. no GDM IADPSG IGT vs. no GDM IADPSG IFG vs. no GDM IADPSG IGT-2 vs. no GDM IADPSG IGT IFG vs. no GDM IADPSG IGT vs. IFG IADPSG IGT vs. IGT-2 IADPSG IGT vs. IGT IFG IADPSG IFG vs. IGT-2 IADPSG IFG vs. IGT IFG IADPSG IGT-2 vs. IGT IFG Effect Estimate* 2.86 [1.81, 4.51] 1.49 [0.97, 2.30] 0.20 [0.02, 1.82] Participants 5 27,473 1 3,577 1 239 1 410 5.09 [1.14, 22.66] NA False positive 1 80 6.00 [1.09, 32.95] NA No GDM 1 1,825 NA No GDM 1 2,885 NA No GDM 1 7,411 1 7,906 1 7,103 1 7,351 1 1,277 1 474 1 722 1 969 1 1,217 1 414 66 2.79 [1.30, 6.01] 2.18 [1.02, 4.67] 1.21 [0.76, 1.92] 1.48 [1.10, 1.98] 1.58 [0.67, 3.72] 1.82 [1.21, 2.75] 0.82 [0.48, 1.38] 0.76 [0.29, 2.00] 0.66 [0.36, 1.21] 0.94 [0.38, 2.28] 0.81 [0.50, 1.31] 0.87 [0.34, 2.21] I 2 Studies 0% Favors No GDM NA - NA - NA NA NA NA No GDM No GDM NA - NA - NA - NA - NA - NA - ‡ Table 14. Evidence summary table: fetal/neonatal outcomes (continued) Outcome Comparison CC GDM vs. no GDM Neonatal hypoglycemia CC GDM vs. 1 abnormal OGTT CC 1 abnormal OGTT vs. no GDM NDDG GDM vs. no GDM NDDG false positive vs. no GDM NDDG, 1 abnormal OGTT vs. no GDM WHO IGT vs. no GDM CC GDM vs. no GDM Hyperbilirubinemia CC GDM vs. 1 abnormal OGTT CC false positive vs. no GDM CC 1 abnormal OGTT vs. no GDM NDDG False positive vs. no GDM WHO IGT vs. no GDM IADPSG IGT vs. no GDM IADPSG IFG vs. no GDM IADPSG IGT-2 vs. no GDM Studies Participants 3 7,966 1 481 4 7,124 1 80 1 716 1 699 3 3,895 2 7,854 1 481 1 406 1 239 1 716 2 3,491 1 7,411 1 7,906 1 7,103 67 Effect Estimate* Results not pooled due to substantial heterogeneit y. 3.22 [0.44, 23.37] 1.29 [0.88, 1.91] Not † Estimable 2.83 [0.58, 13.89] 9.60 [0.86, 106.73] 1.00 [0.49, 2.07] Results not pooled due to substantial heterogeneit y. 2.38 [0.32, 17.53] 3.03 [1.12, 8.23] 4.19 [0.20, 88.20] 1.07 [0.68, 1.70] 0.64 [0.38, 1.10] 1.32 [1.06, 1.64] 1.03 [0.87, 1.23] 1.55 [1.03, 2.35] I 2 Favors 94% - NA - 0% - NA - NA - NA - 0% - 94% - NA - NA No GDM NA - NA - 0% - NA NA NA No GDM No GDM ‡ Table 14. Evidence summary table: fetal/neonatal outcomes (continued) Outcome Hyperbilirubinemia (continued) Fetal birth trauma/injury Fetal morbidity/mortality Comparison Studies Participants IADPSG IGT IFG vs. no GDM 1 7,351 IADPSG IGT vs. IFG 1 1,277 1 474 1 722 1 969 1 1,217 1 414 1 14,213 1 80 2 1,018 6 34,360 2 3,321 1 481 3 6,348 3 16,867 1 410 2 2,541 IADPSG IGT vs. IGT-2 IADPSG IGT vs. IGT IFG IADPSG IFG vs. IGT-2 IADPSG IFG vs. IGT IFG IADPSG IGT-2 vs. IGT IFG CC GDM vs. no GDM NDDG GDM vs. no GDM WHO IGT vs. no GDM CC GDM vs. no GDM CC GDM vs. false positive CC GDM vs. 1 abnormal OGTT CC 1 abnormal OGTT vs. no GDM CC false positive vs. no GDM CC false positive vs. 1 abnormal OGTT NDDG false positive vs. no GDM 68 Effect Estimate* 0.97 [0.74, 1.29] 1.27 [0.98, 1.66] 0.85 [0.54, 1.34] 1.35 [0.96, 1.91] 0.67 [0.43, 1.03] 1.06 [0.78, 1.46] 1.60 [0.98, 2.61] 1.19 [0.68, 2.08] 34.41 [1.95, 608.47] 0.29 [0.04, 2.41] 1.23 [0.46, 3.30] 1.83 [0.11, 29.41] Not † estimable 1.03 [0.61, 1.72] 0.80 [0.40, 1.61] Not † estimable 2.24 [0.70, 7.14] I 2 Favors NA - NA - NA - NA - NA - NA - NA - NA - NA No GDM NA - 40% - 49% - NA - 0% - 0% - NA - 0% - ‡ Table 14. Evidence summary table: fetal/neonatal outcomes (continued) Effect 2 ‡ I Favors Estimate* NDDG 1 abnormal 0.94 [0.04, 1 699 NA OGTT vs. no GDM 19.69] Fetal morbidity/mortality WHO IGT vs. no 1.42 3 5,659 0% (continued) GDM [0.54,3.75] IADPSG GDM vs. 2.21 [1.40, 1 1927 NA no GDM 3.48] CC GDM vs. no 1.48 [1.20, 1 7,782 NA No GDM GDM 1.82] CC GDM vs. false 1.49 False 1 1,172 NA positive [1.18,1.88] positive 1.30 [0.98, CC GDM vs. 1 1 461 NA abnormal OGTT 1.72] Prevalence of childhood obesity CC false positive vs. 0.99 [0.88, 1 8,608 NA no GDM 1.12] CC false positive vs. 0.81 [0.56, 1 1,287 NA 1 abnormal OGTT 1.18] CC 1 abnormal 1.14 [0.94, 1 7,897 NA OGTT vs. no GDM 1.38] CC = Carpenter-Coustan; GDM = gestational diabetes mellitus; IFG = impaired fasting glycemia; IGT = impaired glucose tolerance; IGT-2 = double impaired glucose tolerance; IADPSG = International Association of Diabetes and Pregnancy Study Groups; NDDG = National Diabetes Data Group; NA = not applicable; OGTT = oral glucose tolerance test; WHO = World Health Organization. *Effect estimates are risk ratios with 95% confidence intervals. †Not estimable due to zero events in both groups. ‡Where the result was statistically significant, we have listed the group that had the better outcome (e.g., lower incidence of macrosomia). Outcome Comparison Studies Participants 69 Table 15. Strength of evidence summary table: fetal/neonatal outcomes Outcome Macrosomia >4,000 g Macrosomia >4,500 g Shoulder dystocia 10 5 Risk of Bias High High Consistent Consistent Direct Direct Precise Precise Low Low 3 High Consistent Direct Precise Low 7 High Consistent Direct Precise Low 5 High Consistent Direct Precise Low 3 High Inconsistent Direct Precise Insufficient 1 High Unknown Direct Imprecise Insufficient 4 High Consistent Direct Precise Low 1 1 2 3 2 2 High high High High High High Unknown Unknown Consistent Consistent Inconsistent Consistent Direct Direct Direct Direct Direct Direct Imprecise Precise Imprecise Precise Imprecise Imprecise Insufficient Insufficient Insufficient Low Insufficient Insufficient 1 High Unknown Direct Imprecise Insufficient 5 1 High High Consistent Unknown Direct Direct Precise Imprecise Low Insufficient 1 High Unknown Direct Imprecise Insufficient 1 High Unknown Direct Imprecise Insufficient 1 High Unknown Direct Imprecise Insufficient 1 High Unknown Direct Imprecise Insufficient 1 1 1 1 1 High High High High High Unknown Unknown Unknown Unknown Unknown Direct Direct Direct Direct Direct Imprecise Imprecise Precise Imprecise Precise Insufficient Insufficient Insufficient Insufficient Insufficient Comparison Studies CC GDM vs. no GDM CC GDM vs. false positive CC GDM vs. 1 abnormal OGTT CC 1 abnormal OGTT vs. no GDM CC false positive vs. no GDM CC 1 abnormal OGTT vs. false positive NDDG GDM (unrecognized) vs. no GDM NDDG false positive vs. no GDM WHO GDM vs. no GDM WHO IGT vs. no GDM IADPSG GDM vs. no GDM CC GDM vs. no GDM CC GDM vs. false positive CC false positive vs. no GDM NDDG GDM (unrecognized) vs. no GDM CC GDM vs. no GDM CC GDM vs. false positive CC 1 abnormal OGTT vs. no GDM CC 1 abnormal OGTT vs. false positive NDDG GDM (unrecognized) vs. no GDM NDDG false positive vs. no GDM WHO IGT vs. no GDM IADPSG IGT vs. no GDM IADPSG IFG vs. no GDM IADPSG IGT-2 vs. no GDM IADPSG IGT IFG vs. no GDM 70 Consistency Directness Precision SOE Table 15. Strength of evidence summary table: fetal/neonatal outcomes (continued) Outcome Comparison Studies Risk of Bias High High High High High High High Consistency Directness Precision SOE IADPSG IGT vs. IFG 1 Unknown Direct Imprecise Insufficient IADPSG IGT vs. IGT-2 1 Unknown Direct Imprecise Insufficient IADPSG IGT vs. IGT IFG 1 Unknown Direct Imprecise Insufficient Shoulder dystocia (continued) IADPSG IFG vs. IGT-2 1 Unknown Direct Imprecise Insufficient IADPSG IFG vs. IGT IFG 1 Unknown Direct Imprecise Insufficient IADPSG IGT-2 vs. IGT IFG 1 Unknown Direct Imprecise Insufficient CC GDM vs. no GDM 3 Inconsistent Direct Imprecise Insufficient CC GDM vs. 1 abnormal 1 High Unknown Direct Imprecise Insufficient OGTT CC 1 abnormal OGTT vs. no 4 High Consistent Direct Imprecise Insufficient GDM Neonatal hypoglycemia NDDG GDM vs. no GDM 1 High Unknown Direct NA Insufficient NDDG false positive vs. no 1 High Unknown Direct Imprecise Insufficient GDM NDDG 1 abnormal OGTT vs. 1 High Unknown Direct Imprecise Insufficient no GDM WHO IGT vs. no GDM 3 High Consistent Direct Imprecise Insufficient 1 High Unknown Direct Imprecise Insufficient CC GDM vs. no GDM Fetal birth trauma/injury NDDG GDM vs. no GDM 1 High Unknown Direct Imprecise Insufficient WHO IGT vs. no GDM 2 High Consistent Direct Imprecise Insufficient CC = Carpenter-Coustan; GDM = gestational diabetes mellitus; IGT = impaired glucose tolerance; IGT-2 = double impaired glucose tolerance; IADPSG = International Association of Diabetes and Pregnancy Study Groups; IFG = impaired fasting glucose; NA = not applicable; NDDG = National Diabetes Data Group; OGTT = oral glucose tolerance test; SOE = strength of evidence; WHO = World Health Organization. 71 Key Question 4. Does treatment modify the health outcomes of mothers who meet various criteria for GDM and offspring? Description of Included Studies Eleven studies met the inclusion criteria for Key Question 4.50,54,92,95-98,146,148,152,160 The studies are described in Appendix D. All studies compared diet modification, glucose monitoring and insulin as needed with standard care. Five of the studies were RCTs,50,54,96-98 while six were retrospective cohort studies.92,95,146,148,152,160 The studies were published between 1996 and 2010 (median year 2005). Two studies had two associated publications reporting initial and longer term outcomes.50,54 Five studies were from the United States,54,95,98,146,152 two from Italy,97,148 two from Canada,96,160 and one each from Taiwan92 and Australia.50 The screening test used in most studies was OGCT with a 100 g OGTT assessed using CC criteria, except for the studies from Canada and Australia that used a OGCT with a 75 g OGTT. Diagnostic testing in all studies occurred at or after 24 weeks’ gestation. Among these studies a variety of glucose inclusion criteria were used, varying from 50 g screen positive with nondiagnostic OGTTs to women who met National Diabetes Data Group criteria for a diagnosis of GDM. The two largest RCTs50,163 by Crowther et al. and Landon et al. used different glucose thresholds for entry in their trials: WHO and CC criteria with a fasting glucose <95 mg/dL (5.3 mmol/L), respectively; however, the mean glucose levels of women at study entry were remarkably similar between these two studies. Methodological Quality of Included Studies The methodological quality of the included studies is described in Appendix C3. The risk of bias for the RCTs was low for one trial,50 unclear for three trials,54,97,98 and high for one trial.96 The trials that were unclear most commonly did not report detailed methods for sequence generation and allocation concealment. The trial assessed as high risk of bias was due to lack of blinding for outcome assessment and incomplete outcome data. The six cohort studies were all considered high quality, with overall quality scores of 7 to 9 on a 9-point scale. Three studies received full scores of 9.54,152,160 One study received a score of 8/9 because the study population was a selected (non-representative) group (i.e., participants at a diabetic center).148 Two studies received a score of 7/9. One study obtained this score due to the study population considered only “somewhat” representative (all women were cared for under a single health plan); as well as a lack of control for potential confounders including age, race, BMI, previous GDM, or family history of DM.95 The absence of control for any potential confounders was also the reason for the lower score in the second study. 92 Key Points • • A variety of glucose threshold criteria were used for inclusion across studies. For outcomes where results were inconsistent between studies, different study glucose threshold entry criteria did not explain the variation. Results for some outcomes were driven by the two largest RCTs, the Maternal Fetal Medicine Unit (MFMU)54 and the Australian Carbohydrate Intolerance in Pregnancy Study (ACHOIS),50 which had unclear and low risk of bias, respectively. 72 Maternal Outcomes • • • • • • • There was moderate evidence from 3 RCTs showing a significant difference for preeclampsia with fewer cases in the treated group. There was inconsistency across studies in terms of differences in maternal weight gain (4 RCTs and 2 cohort studies). The strength of evidence was considered insufficient due to inconsistency across studies and imprecision in effect estimates. No differences between groups were found for cesarean section (5 RCTs, 6 cohorts) or unplanned cesarean section (1 RCT, 1 cohort). There was inconsistency across studies in terms of induction of labor with no difference found for the 2 RCTs overall and a significant difference favoring the treatment group among the one cohort study included. Only one RCT reported on BMI at delivery and showed a significant difference with lower BMI in the treated group. Only one cohort study reported maternal birth trauma (i.e., postpartum hemorrhage) and showed no difference between groups. There was no evidence for long-term maternal outcomes such as type 2 diabetes mellitus, obesity, and hypertension. Short-Term Outcomes in the Offspring • • • • • • • There was insufficient evidence for birth injury. There was inconsistency across studies with the 2 RCTs showing no difference and the one cohort study showing a difference in favor of the treated group. The low number of events and participants across all studies resulted in imprecise estimates. The incidence of shoulder dystocia was significantly lower in the treated groups, and this finding was consistent for the 3 RCTs and 4 cohort studies. Overall, the evidence for shoulder dystocia was considered moderate showing a difference in favor of the treated group. For other injury outcomes, including brachial plexus injury (1 RCT, 1 cohort), and clavicular fractures (1 RCT, 1 cohort), the results were inconsistent across designs with the RCTs showing no differences between groups and the cohort study showing a significant difference in favor of the treated group. There was low evidence of no difference between groups for neonatal hypoglycemia based on four RCTs and 2 cohort studies. For outcomes related to birthweight (including macrosomia >4,000 g, macrosomia >4,500 g, actual birthweight, and large for gestational age), differences were often observed favoring the treated groups. The strength of evidence was moderate for macrosomia >4,000 g suggesting a benefit of treatment. There was no difference in hyperbilirubinemia for the 3 RCTs, while the one cohort study showed a significant difference in favor of the treated group. There were no differences observed across studies for perinatal death (3 RCTs, 3 cohorts). Two RCTs showed no difference between groups for respiratory distress syndrome, while one cohort study found a significant difference favoring the treated group for “respiratory complications.” Several studies assessed APGAR scores, and while differences were found in both the RCT and cohort study for APGAR at 1 minute, no differences were found among the 2 RCTs and 1 cohort study at 5 minutes. 73 Long-Term Outcomes in the Offspring • • One RCT followed patients for 7 to 11 years and found no differences for impaired glucose tolerance or type 2 diabetes mellitus, although the strength of evidence was considered insufficient. No differences were observed in single studies that assessed BMI >95 (7-11 year followup) and BMI >85 percentile (5-7 year followup). Overall, pooled results showed no difference in BMI and the strength of evidence was considered low. Detailed Synthesis Detailed results are described by outcome in the sections that follow. We first describe the maternal outcomes, followed by fetal/neonatal/child outcomes. We present meta-graphs when two or more studies were pooled. These are displayed after the description of results for each outcome. A detailed table of results is presented at the end of each of the maternal and fetal/neonatal/child sections (Table 16 and Table 17, respectively). The strength of evidence for key outcomes is presented in Table 18. Maternal Outcomes Short Term Cesarean Delivery All studies provided data on cesarean delivery (Table 16).50,54,92,95-98,146,148,152,160 There was no significant difference in the pooled estimates for the RCTs (risk ratio [RR] 0.90, 95% CI 0.79 to 1.01, n = 2,613) or for the cohort studies (RR 1.09, 95% CI 0.90 to 1.31, n = 3,110; Figure 49). The results were statistically homogeneous across all studies. One RCT50 and one cohort study95 reported emergency cesarean deliveries and found no difference (RCT, RR 0.81, 95% CI 0.62 to 1.05, n = 1,000; cohort, RR 0.83, 95% CI 0.33 to 2.06, n = 126). 74 Figure 49. Effect of treatment on outcomes of women with GDM: cesarean delivery Study or Subgroup 1.1.1 RCT Bevier 1999 Bonomo 2005 Crowther 2005 Garner 1997 Landon 2009 Subtotal (95% CI) Treatment No treatment Total Weight Events Total Events 5 42 152 30 128 35 150 490 149 476 1300 12 44 164 28 154 Risk Ratio M-H, Random, 95% CI 1.6% 48 150 11.3% 510 43.1% 6.7% 150 455 37.3% 1313 100.0% Risk Ratio M-H, Random, 95% CI 0.57 [0.22, 1.47] 0.95 [0.67, 1.36] 0.96 [0.80, 1.16] 1.08 [0.68, 1.71] 0.79 [0.65, 0.97] 0.90 [0.79, 1.01] 402 357 Total events Heterogeneity: Tau² = 0.00; Chi² = 3.68, df = 4 (P = 0.45); I² = 0% Test for overall effect: Z = 1.81 (P = 0.07) 1.1.2 Cohort studies Adams 1998 Bonomo 1997 Chou, 2010 Fassett 2007 Langer 2005 Naylor, 1996 Subtotal (95% CI) 99 7 40 21 258 48 373 26 233 69 1110 143 1954 4 26 32 19 132 34 4.5% 16 6.4% 88 325 15.0% 57 11.5% 555 43.0% 115 19.6% 1156 100.0% 1.06 [0.45, 2.52] 0.91 [0.45, 1.85] 1.74 [1.13, 2.69] 0.91 [0.55, 1.52] 0.98 [0.81, 1.17] 1.14 [0.79, 1.63] 1.09 [0.90, 1.31] 247 473 Total events Heterogeneity: Tau² = 0.01; Chi² = 6.47, df = 5 (P = 0.26); I² = 23% Test for overall effect: Z = 0.88 (P = 0.38) Test for subgroup differences: Chi² = 2.93, df = 1 (P = 0.09), I² = 65.9% 0.2 0.5 1 2 5 Favors treatment Favors no treatment CI = confidence interval; GDM = gestational diabetes mellitus; RCT = randomized controlled trial; M-H = Mantel-Haenszel Induction of Labor Three studies provided data on induction of labor50,54,146 but results differed significantly across the studies (Table 16). Two RCTs showed no significant difference overall (RR 1.16, 95% CI 0.91 to 1.49, n = 1,931), although there was important statistical heterogeneity between studies (I2 = 69%). One RCT showed a significant difference favoring no treatment,50 while the other study showed no difference (Figure 50).54 Different study protocols may account for the heterogeneity of results between studies. In the study that showed more inductions of labor in the treatment group, no recommendations were provided regarding obstetrical care, thus replicating usual clinical care of women with GDM. In the other study, antenatal surveillance was reserved for standard obstetrical indications. In contrast the one cohort study showed a significant difference with fewer inductions in the treatment group (RR 0.63, 95% CI 0.55 to 0.72, n = 1,665).146 Baseline differences in the study populations and regional practices may have accounted for the different results between studies. Further, the comparison group in the cohort study was women who presented late for obstetrical care which confounds the relationship between induction and GDM treatment. Furthermore, the cohort study protocol was to deliver these women within one week of GDM diagnosis so the outcome of induction was substantially confounded by different delivery protocols between treatment and nontreatment groups. 75 Figure 50. Effect of treatment on outcomes of women with GDM: induction of labor Study or Subgroup 1.6.1 RCT Crowther 2005 Landon 2009 Subtotal (95% CI) Treatment No treatment Events Total Events Total Weight 189 130 490 476 966 150 122 Risk Ratio M-H, Random, 95% CI 510 52.8% 455 47.2% 965 100.0% Risk Ratio M-H, Random, 95% CI 1.31 [1.10, 1.56] 1.02 [0.82, 1.26] 1.16 [0.91, 1.49] Total events 319 272 Heterogeneity: Tau² = 0.02; Chi² = 3.27, df = 1 (P = 0.07); I² = 69% Test for overall effect: Z = 1.20 (P = 0.23) 1.6.2 Cohort Studies Langer 2005 Subtotal (95% CI) 303 1110 1110 242 555 100.0% 555 100.0% 0.63 [0.55, 0.72] 0.63 [0.55, 0.72] Total events 303 242 Heterogeneity: Not applicable Test for overall effect: Z = 6.81 (P < 0.00001) Test for subgroup differences: Chi² = 18.61, df = 1 (P < 0.0001), I² = 94.6% 0.5 0.7 1 1.5 2 Favors treatment Favors no treatment CI = confidence interval; GDM = gestational diabetes mellitus; RCT = randomized controlled trial; M-H = Mantel-Haenszel Preeclampsia Three RCTs and one cohort study provided data on preeclampsia (Table 16).50,54,98,160 Pooled estimate for the RCTs showed a significant difference favoring the treated group (RR 0.62; 95% CI, 0.43 to 0.89, n = 2,014) with minimal statistical heterogeneity across studies (I2 = 16%; Figure 51). The strength of evidence was considered moderate (Table 18). One of the studies also reported preeclampsia or gestational hypertension as a combined outcome,54 and also showed a significant difference favoring the treatment group (RR 0.63; 95% CI, 0.44 to 0.92, n = 931). In all three trials, there was no significant difference between groups in gestational age at delivery. 76 Figure 51. Effect of treatment on outcomes of women with GDM: preeclampsia CI = confidence interval; GDM = gestational diabetes mellitus; RCT = randomized controlled trial; M-H = Mantel-Haenszel Birth Trauma One study provided data on maternal birth trauma (postpartum hemorrhage).92 No significant difference was observed between groups (Table 16). Weight Gain Six studies provided data on weight gain (Table 16).50,54,95-97,152 Pooled results for the RCTs are not presented due to substantial heterogeneity (I2=88%). Two RCTs showed no significant difference,96,97 while two large RCTs showed a significant difference with less weight gain in the treatment group (Figure 52).50,54 Given the high BMIs of the women studied in these large RCTs, less gestational weight gain in the treatment group could be interpreted as a beneficial finding. Pooled results for the cohort studies showed no significant difference between groups (mean difference [MD] -1.04; 95% CI, -2.89 to 0.81, n = 515). The strength of evidence was considered insufficient for this outcome (Table 18). 77 Figure 52. Effect of treatment on outcomes of women with GDM: weight gain CI = confidence interval; GDM = gestational diabetes mellitus; IV = inverse variance; RCT = randomized controlled trial; SD = standard deviation BMI at Delivery Only one RCT reported BMI at delivery and showed a significantly lower BMI in the treated group compared with the untreated group (mean BMI 31.3 vs. 32.3; mean difference -1.00; 95% CI, -1.67 to -0.33, n = 931) (Table 16).54 Table 16. Evidence summary for Key Question 4: maternal outcomes Outcome Cesarean section Unplanned cesarean section Induction of labor Preeclampsia Preeclampsia or gestational hypertension Weight gain (kg) 2 RCT Cohort RCT Cohort RCT Cohort RCT Cohort RCT Number of Studies 5 6 1 1 2 1 3 1 1 Number of Participants 2613 3110 1000 126 1931 1665 2014 258 931 0.90 [0.79, 1.01] 1.09 [0.90, 1.31] 0.81 [0.62, 1.05] 0.83 [0.33, 2.06] 1.16 [0.91, 1.49] 0.63 [0.55, 0.72] 0.62 [0.43, 0.89] 0.97 [0.43, 2.15] 0.63 [0.44, 0.92] I (%) 0 23 NA NA 69 NA 16 NA NA Cohort 1 874 0.30 [0.15, 0.62] NA - RCT 4 2530 88 - Source Cohort 2 Maternal birth trauma Cohort 1 BMI at delivery RCT 1 NA = not applicable; RCT = randomized controlled trial *Risk ratios unless otherwise specified. †Mean difference. 515 874 931 78 Effect Estimate* Pooled estimate not reported due to heterogeneity † -1.04 [-2.89, 0.81] 0.95 [0.21, 4.28] † -1.00 [-1.67, -0.33] 8 NA NA Favors Treatment Treatment Treatment Treatment Fetal/Neonatal/Child Outcomes Short Term Birthweight All studies reported birthweights for the infants (Table 17).50,54,92,95-98,146,148,152,160 Pooled estimate for the RCTs showed significantly lower incidence of birthweights >4,000 g among infants in the treated groups (RR 0.50, 95% CI, 0.35 to 0.71; Figure 53); however, there was moderate heterogeneity across studies. Pooled estimates were not reported for the cohort studies because of substantial heterogeneity (I2=86%). Three of the studies96,152,160 also reported the incidence of birthweights >4,500 g and showed no significant differences between groups. In terms of actual birthweight (Figure 54), the five RCTs showed significantly lower mean birthweights among the treated group (MD -120.8; 95% CI, -163.4 to -78.2, n = 2,670). The two cohort studies showed substantial heterogeneity with one study showing a significantly lower mean birthweight in the treated group and the second cohort study showing no difference between groups. Figure 53. Effect of treatment on outcomes for offspring of women with GDM: birthweight >4,000 g Study or Subgroup 2.5.1 RCT Bevier 1999 Bonomo 2005 Crowther 2005 Garner 1997 Landon 2009 Treatment No treatment Total Events Total Events Risk Ratio M-H, Random, 95% CI 1 8 49 24 28 35 150 506 149 477 12 16 110 28 65 48 150 524 150 454 0.11 [0.02, 0.84] 0.50 [0.22, 1.13] 0.46 [0.34, 0.63] 0.86 [0.53, 1.42] 0.41 [0.27, 0.63] 66 0 36 10 78 15 373 26 385 69 1110 143 7 11 22 8 93 33 16 88 489 57 555 115 0.40 [0.22, 0.73] 0.14 [0.01, 2.35] 2.08 [1.24, 3.47] 1.03 [0.44, 2.44] 0.42 [0.32, 0.56] 0.37 [0.21, 0.64] Risk Ratio M-H, Random, 95% CI 2.5.2 Cohort studies Adams 1998 Bonomo 1997 Chou, 2010 Fassett 2007 Langer 2005 Naylor, 1996 0.01 0.1 1 10 100 Favors treatment Favors no treatment CI = confidence interval; GDM = gestational diabetes mellitus; M-H = Mantel-Haenszel; RCT = randomized controlled trial 79 Figure 54. Effect of treatment on outcomes for offspring of women with GDM: birthweight (continuous) Treatment SD Total Mean Study or Subgroup 2.10.1 RCT Bevier 1999 Bonomo 2005 Crowther 2005 Garner 1997 Landon 2009 No treatment SD Total Mean 459 3,311 436 3,365 551 3,335 575 3,437 3,302 502.4 511 3,600 35 462 150 3,436.6 660 3,482 506 601 3,544 149 3,408 589.4 485 528 3,511.2 3,476.7 554.7 713 3,866 373 69 3,389.4 649.8 Mean Difference IV, Random, 95% CI Mean Difference IV, Random, 95% CI 48 -289.00 [-498.81, -79.19] -71.60 [-173.26, 30.06] 150 524 -147.00 [-221.15, -72.85] 150 -107.00 [-240.32, 26.32] 473 -106.00 [-175.43, -36.57] 2.10.2 Cohort studies Adams 1998 Fassett 2007 16 57 -354.80 [-708.25, -1.35] 87.30 [-126.21, 300.81] -500 -250 0 250 500 Favors treatment Favors no treatment CI = confidence interval; GDM = gestational diabetes mellitus; IV = inverse variance; RCT = randomized controlled trial; SD = standard deviation Large for Gestational Age (LGA) There was a significant difference in LGA with the treatment group having fewer cases among both the three RCTs50,54,97 (RR 0.56; 95% CI, 0.45 to 0.69, n = 2,261) and the four cohort studies (RR 0.43; 95% CI, 0.27 to 0.70, n = 2,294) (Table 17).95,148,152,152 The results for the cohort studies showed moderate statistical heterogeneity (I2 = 58%) (Figure 55). One study appeared to be an outlier,95 and when removed from the analysis there was no heterogeneity. Figure 55. Effect of treatment on outcomes for offspring of women with GDM: large for gestational age (LGA) Study or Subgroup 2.13.1 RCT Bonomo 2005 Crowther 2005 Landon 2009 Subtotal (95% CI) Treatment No treatment Total Weight Events Total Events 9 68 34 150 506 477 1133 21 115 66 8.3% 150 524 61.8% 454 29.9% 1128 100.0% Risk Ratio M-H, Random, 95% CI Risk Ratio M-H, Random, 95% CI 0.43 [0.20, 0.90] 0.61 [0.47, 0.81] 0.49 [0.33, 0.73] 0.56 [0.45, 0.69] 202 111 Total events Heterogeneity: Tau² = 0.00; Chi² = 1.34, df = 2 (P = 0.51); I² = 0% Test for overall effect: Z = 5.34 (P < 0.00001) 2.13.2 Cohort studies Adams 1998 Bonomo 1997 Fassett 2007 Langer 2005 Subtotal (95% CI) 50 3 11 119 373 26 69 1110 1578 7 27 8 163 16 26.0% 88 13.1% 57 18.8% 555 42.1% 716 100.0% 0.31 [0.17, 0.57] 0.38 [0.12, 1.14] 1.14 [0.49, 2.63] 0.37 [0.29, 0.45] 0.43 [0.27, 0.70] 205 183 Total events Heterogeneity: Tau² = 0.13; Chi² = 7.18, df = 3 (P = 0.07); I² = 58% Test for overall effect: Z = 3.45 (P = 0.0006) Test for subgroup differences: Chi² = 0.88, df = 1 (P = 0.35), I² = 0% 0.1 0.2 0.5 1 2 5 10 Favors treatment Favors no treatment CI = confidence interval; GDM = gestational diabetes mellitus; M-H = Mantel-Haenszel; RCT = randomized controlled trial 80 Shoulder Dystocia Seven studies provided data on shoulder dystocia (Table 17).50,54,92,95,98,146,152 Pooled estimates from three RCTs50,54,98 showed a significant difference favoring the treated group (RR 0.42; 95% CI, 0.23 to 0.77, n = 2,044; (Figure 56). The four cohort studies92,95,146,152 also showed a significant difference favoring the treated group (RR 0.38; 95% CI, 0.19 to 0.78, n = 3,054). There was no statistical heterogeneity across studies. Overall, the strength of evidence was considered moderate showing a difference in favor of the treated group. Shoulder dystocia was reduced for all studies combined; however, individual studies that included women with milder forms of glucose intolerance (i.e., OGCT screen positive OGTT negative, one RCT 98 and one cohort study95) showed no differences. Figure 56. Effect of treatment on outcomes for offspring of women with GDM: shoulder dystocia Study or Subgroup 2.2.1 RCT Bevier 1999 Crowther 2005 Landon 2009 Subtotal (95% CI) Treatment No treatment Total Weight Events Total Events 1 7 7 35 506 476 1017 2 16 18 6.4% 48 524 45.9% 455 47.7% 1027 100.0% Risk Ratio M-H, Random, 95% CI Risk Ratio M-H, Random, 95% CI 0.69 [0.06, 7.27] 0.45 [0.19, 1.09] 0.37 [0.16, 0.88] 0.42 [0.23, 0.77] 36 15 Total events Heterogeneity: Tau² = 0.00; Chi² = 0.27, df = 2 (P = 0.87); I² = 0% Test for overall effect: Z = 2.83 (P = 0.005) 2.2.2 Cohort studies Adams 1998 Chou, 2010 Fassett 2007 Langer 2005 Subtotal (95% CI) 13 2 2 10 373 385 69 1110 1937 3 2 2 14 16 28.9% 489 11.9% 57 12.2% 555 47.0% 1117 100.0% 0.19 [0.06, 0.59] 1.27 [0.18, 8.98] 0.83 [0.12, 5.68] 0.36 [0.16, 0.80] 0.38 [0.19, 0.78] 21 27 Total events Heterogeneity: Tau² = 0.11; Chi² = 3.75, df = 3 (P = 0.29); I² = 20% Test for overall effect: Z = 2.65 (P = 0.008) Test for subgroup differences: Chi² = 0.05, df = 1 (P = 0.83), I² = 0% 0.05 0.2 1 5 20 Favors treatment Favors no treatment CI = confidence interval; GDM = gestational diabetes mellitus; M-H = Mantel-Haenszel; RCT = randomized controlled trial Brachial Plexus Injury One RCT50 and one cohort study152 provided data for brachial plexus injury (Table 17). The RCT found no significant difference between groups (RR 0.15; 95% CI, 0.01 to 2.87, n = 1,000), while the cohort study showed a significant difference favoring the treated group (RR 0.04; 95% CI, 0 to 0.66, n = 389). Clavicular Fracture The same two studies50,152 reported clavicular fractures with no difference for the RCT 50 (RR 0.35; 95% CI, 0.01 to 8.45, n = 1,030), and a significant difference favoring the treated group in the cohort study152 (RR 0.02; 95% CI, 0 to 0.22, n = 389; Table 17). Birth Trauma Three studies reported birth trauma.54,96,152 Birth trauma was defined as brachial plexus palsy or clavicular, humeral, or skull fracture in one study.54 Brachial plexus injury, cranial nerve palsy, and clavicular facture were components of birth trauma in one study.152 In the third study 81 birth trauma or injury included fractures and neurologic sequelae. One of the RCTs found no incidents in either group;96 the second RCT54 showed no significant difference between groups (RR 0.48; 95% CI, 0.12 to 1.90, n = 1,230; Figure 57). One cohort study showed a significant difference favoring the treated group (RR 0.02; 95% CI, 0.00 to 0.11, n = 389) (Table 17).152 Overall, the strength of evidence was insufficient for this outcome (Table 18). Figure 57. Effect of treatment on outcomes for offspring of women with GDM: birth trauma Study or Subgroup 2.4.1 RCT Garner 1997 Landon 2009 Subtotal (95% CI) Treatment No treatment Events Total Events Total Weight 0 3 149 476 625 Total events 3 Heterogeneity: Not applicable Test for overall effect: Z = 1.05 (P = 0.29) 0 6 Risk Ratio M-H, Random, 95% CI 150 455 100.0% 605 100.0% Not estimable 0.48 [0.12, 1.90] 0.48 [0.12, 1.90] 16 100.0% 16 100.0% 0.02 [0.00, 0.11] 0.02 [0.00, 0.11] Risk Ratio M-H, Random, 95% CI 6 2.4.2 Cohort studies Adams 1998 Subtotal (95% CI) 2 373 373 4 Total events 2 4 Heterogeneity: Not applicable Test for overall effect: Z = 4.64 (P < 0.00001) Test for subgroup differences: Chi² = 8.16, df = 1 (P = 0.004), I² = 87.7% 0.005 0.1 1 10 200 Favors treatment Favors no treatment CI = confidence interval; GDM = gestational diabetes mellitus; M-H = Mantel-Haenszel; RCT = randomized controlled trial Hypoglycemia Six studies provided data on hypoglycemia (Table 14).50,54,96,97,146,152 The pooled results from four RCTs showed no significant difference between groups (RR 1.18; 95% CI, 0.92 to 1.52, n = 2,367) and no statistical heterogeneity (Figure 58). The two cohort studies showed different results: one study showed no significant difference, while the second study showed a significant difference favoring the treated group (overall RR 0.55; 95% CI, 0.10 to 2.97, n = 2,054). The different results may be due in part to different definitions of hypoglycemia used across the studies. Overall, the strength of evidence was low suggesting no difference between groups in the incidence of hypoglycemia (Table 15). 82 Figure 58. Effect of treatment on outcomes for offspring of women with GDM: hypoglycemia Study or Subgroup 2.7.1 RCT Bonomo 2005 Crowther 2005 Garner 1997 Landon 2009 Subtotal (95% CI) Treatment No treatment Total Weight Events Total Events 5 35 21 62 150 506 149 381 1186 6 27 13 55 150 4.5% 524 25.9% 150 14.4% 357 55.3% 1181 100.0% Risk Ratio M-H, Random, 95% CI Risk Ratio M-H, Random, 95% CI 0.83 [0.26, 2.67] 1.34 [0.82, 2.18] 1.63 [0.85, 3.13] 1.06 [0.76, 1.47] 1.18 [0.92, 1.52] 101 123 Total events Heterogeneity: Tau² = 0.00; Chi² = 1.96, df = 3 (P = 0.58); I² = 0% Test for overall effect: Z = 1.33 (P = 0.18) 2.7.2 Cohort studies Adams 1998 Langer 2005 Subtotal (95% CI) 26 67 373 1110 1483 0 100 16 25.2% 555 74.8% 571 100.0% 2.41 [0.15, 37.88] 0.34 [0.25, 0.45] 0.55 [0.10, 2.97] 100 93 Total events Heterogeneity: Tau² = 0.97; Chi² = 1.97, df = 1 (P = 0.16); I² = 49% Test for overall effect: Z = 0.69 (P = 0.49) 0.05 0.2 1 5 20 Favors treatment Favors no treatment Test for subgroup differences: Chi² = 0.77, df = 1 (P = 0.38), I² = 0% CI = confidence interval; GDM = gestational diabetes mellitus; M-H = Mantel-Haenszel; RCT = randomized controlled trial Hyperbilirubinemia Four studies provided data on hyperbilirubinemia (Table 14).54,96,97,146 Three RCTs showed no significant difference between groups54,96,97 (RR 0.79; 95% CI, 0.56 to 1.10, n = 1,467), while one cohort study showed a significant difference favoring the treated group146 (RR 0.26; 95% CI, 0.18 to 0.37, n = 1,665; Figure 59). Figure 59. Effect of treatment on outcomes for offspring of women with GDM: hyperbilirubinemia Study or Subgroup 2.3.1 RCT Bonomo 2005 Garner 1997 Landon 2009 Subtotal (95% CI) Treatment No treatment Total Weight Events Total Events 6 8 43 150 149 450 749 4 10 54 150 7.3% 150 13.9% 418 78.9% 718 100.0% Risk Ratio M-H, Random, 95% CI Risk Ratio M-H, Random, 95% CI 1.50 [0.43, 5.21] 0.81 [0.33, 1.98] 0.74 [0.51, 1.08] 0.79 [0.56, 1.10] 68 Total events 57 Heterogeneity: Tau² = 0.00; Chi² = 1.14, df = 2 (P = 0.57); I² = 0% Test for overall effect: Z = 1.39 (P = 0.16) 2.3.2 Cohort studies Langer 2005 Subtotal (95% CI) 40 1110 1110 78 555 100.0% 555 100.0% 0.26 [0.18, 0.37] 0.26 [0.18, 0.37] 78 40 Total events Heterogeneity: Not applicable Test for overall effect: Z = 7.26 (P < 0.00001) Test for subgroup differences: Chi² = 19.56, df = 1 (P < 0.00001), I² = 94.9% 0.2 0.5 1 2 5 Favors treatment Favors no treatment CI = confidence interval; GDM = gestational diabetes mellitus; M-H = Mantel-Haenszel; RCT = randomized controlled trial 83 Mortality Six studies provided data on perinatal deaths (Table 14).50,54,92,96,146,152 No significant differences were found between groups for the three RCTs50,54,96 (RD 0; 95% CI, -0.01 to 0.01, n = 2,287) or for the three cohort studies92,146,152 (RD 0; 95% CI, -0.01 to 0.01, n = 2,928; Figure 60). There was heterogeneity among the three RCTs with one study showing a significant difference in favor of the treatment group. Figure 60. Effect of treatment on outcomes for offspring of women with GDM: perinatal deaths Study or Subgroup 2.1.1 RCT Crowther 2005 Garner 1997 Landon 2009 Subtotal (95% CI) Treatment No treatment Events Total Events Total Weight 0 0 0 506 149 485 1140 5 0 0 524 31.7% 150 22.7% 473 45.6% 1147 100.0% Risk Difference M-H, Random, 95% CI Risk Difference M-H, Random, 95% CI -0.01 [-0.02, -0.00] 0.00 [-0.01, 0.01] 0.00 [-0.00, 0.00] -0.00 [-0.01, 0.01] Total events 0 5 Heterogeneity: Tau² = 0.00; Chi² = 5.94, df = 2 (P = 0.05); I² = 66% Test for overall effect: Z = 0.71 (P = 0.48) 2.1.2 Cohort studies Adams 1998 Chou, 2010 Langer 2005 Subtotal (95% CI) 1 5 4 373 385 1110 1868 0 4 3 16 0.6% 489 20.4% 555 78.9% 1060 100.0% 0.00 [-0.08, 0.08] 0.00 [-0.01, 0.02] -0.00 [-0.01, 0.01] -0.00 [-0.01, 0.01] Total events 10 7 Heterogeneity: Tau² = 0.00; Chi² = 0.82, df = 2 (P = 0.66); I² = 0% Test for overall effect: Z = 0.13 (P = 0.89) Test for subgroup differences: Chi² = 0.24, df = 1 (P = 0.62), I² = 0% -0.05 -0.025 0 0.025 0.05 Favors treatment Favors no treatment CI = confidence interval; GDM = gestational diabetes mellitus; M-H = Mantel-Haenszel; RCT = randomized controlled trial Respiratory Complications Two RCTs50,54 reported on respiratory distress syndrome and showed no significant difference between groups (RR 1.05; 95% CI, 0.48 to 2.28, n = 1,962; Table 17, Figure 61). One cohort study146 reported respiratory complications and showed a significant difference favoring the treated group (RR 0.16; 95% CI, 0.10 to 0.26, n = 1,665). 84 Figure 61. Effect of treatment on outcomes for offspring of women with GDM: respiratory complications Study or Subgroup 2.14.1 RCT Crowther 2005 Landon 2009 Subtotal (95% CI) Treatment No treatment Events Total Events Total Weight 27 9 506 477 983 19 13 Risk Ratio M-H, Random, 95% CI 524 57.6% 455 42.4% 979 100.0% Risk Ratio M-H, Random, 95% CI 1.47 [0.83, 2.61] 0.66 [0.29, 1.53] 1.05 [0.48, 2.28] 36 Total events 32 Heterogeneity: Tau² = 0.19; Chi² = 2.38, df = 1 (P = 0.12); I² = 58% Test for overall effect: Z = 0.12 (P = 0.91) 2.14.2 Cohort (respiratory complication) Langer 2005 Subtotal (95% CI) 22 1110 1110 67 555 100.0% 555 100.0% 0.16 [0.10, 0.26] 0.16 [0.10, 0.26] 22 67 Total events Heterogeneity: Not applicable Test for overall effect: Z = 7.52 (P < 0.00001) Test for subgroup differences: Chi² = 16.02, df = 1 (P < 0.0001), I² = 93.8% 0.1 0.2 0.5 1 2 5 10 Favors treatment Favors no treatment CI = confidence interval; GDM = gestational diabetes mellitus; M-H = Mantel-Haenszel; RCT = randomized controlled trial APGAR One RCT50 and one cohort study95 compared APGAR scores at 1 minute (Table 17). Both showed a significant difference favoring the treatment group, although the results were more dramatic for the cohort study (RCT MD -0.30; 95% CI, -0.56 to -0.04, n = 83; cohort MD -1.00; 95% CI, -1.54 to -0.46, n = 126; Figure 56). Another cohort study92 reported the number of infants with APGAR scores <7 at 1 minute and showed no difference between groups (RR 0.76, 95% CI, 0.47 to 1.25). Two RCTs97,98 and one cohort study95 compared APGAR scores at 5 minutes and no overall differences were found (Figure 62). There was substantial statistical heterogeneity between the two RCTs with one RCT showing no difference and the second showing a significant difference favoring the untreated group. The cohort study showed no difference (n = 126). One study50 reported APGAR scores <7 at 5 minutes and found no difference between groups (n = 1,030). Figure 62. Effect of treatment on outcomes for offspring of women with GDM: APGAR scores, 5 minutes Study or Subgroup 2.12.1 RCT Bevier 1999 Bonomo 2005 Treatment No treatment Mean SD Total Mean SD Total 9 9.7 0.3 0.5 35 150 9 0.63 69 9 9.5 Mean Difference IV, Random, 95% CI 0.4 0.5 48 150 0.00 [-0.15, 0.15] 0.20 [0.09, 0.31] 9 0.87 57 0.00 [-0.27, 0.27] Mean Difference IV, Random, 95% CI 2.12.2 Cohort studies Fassett 2007 -0.2 -0.1 0 0.1 0.2 Favors treatment Favors no treatment CI = confidence interval; GDM = gestational diabetes mellitus; IV = inverse variance; RCT = randomized controlled trial; SD = standard deviation 85 Other Infant Outcomes Single studies reported on elevated cord blood c-peptide level,54 preterm delivery,54 length,97 ponderal index,97 any serious perinatal complication,50 and abnormal fetal heart rate.98 Significant differences were found for ponderal index (MD -0.09; 95% CI, -0.16 to -0.02, n = 300) and any serious perinatal complication (RR 0.32; 95% CI, 0.14 to 0.73, n = 1,030). Both results favored the treated group (Table 17). Long Term Type 2 Diabetes Mellitus One small study reported 7 to 11 year followup and showed no significant difference in the incidence of type 2 diabetes mellitus among the offspring (RR 1.88; 95% CI, 0.08 to 44.76, n = 89).96 The same study reported impaired glucose tolerance at 7-11 year followup.96 Overall no difference was found (Table 17) (RR 5.63; 95% CI, 0.31 to 101.32, n = 89). The strength of evidence for both type 2 diabetes mellitus and impaired glucose tolerance was considered insufficient (Table 18). BMI One small study reported the incidence of BMI >95 percentile at 7 to 11 year followup and showed no significant difference between groups (RR 1.58; 95% CI, 0.66 to 3.79, n = 85; Table 17).96 The original RCT96 showed no differences in mean birth weight or macrosomia (birthweight >4,000 g and birthweight >4,500 g). A followup study9 reporting outcomes at 4 to 5 years following the initial RCT reported BMI >85 percentile and also found no difference between groups (RR 1.19; 95% CI, 0.78 to 1.82, n = 199), despite a clear difference in macrosomia rates between treatment and control group (5% vs. 22%, respectively). When the two studies were pooled, the results showed no difference (RR 1.26; 95% CI, 0.86, 1.84, n = 284, Table 17) and the strength of evidence was considered low (Table 18). 86 Table 17. Evidence summary for Key Question 4: infant outcomes Outcome Number of Participants 2,643 Cohort 6 3,426 RCT Cohort RCT 1 2 5 299 647 2,670 Cohort 2 515 RCT Cohort RCT Cohort RCT Cohort RCT Cohort RCT Cohort RCT Cohort RCT Cohort RCT Cohort RCT (RDS) Cohort (complications) RCT Cohort 3 4 3 4 1 1 1 1 2 1 4 2 3 1 3 3 2 2,261 2,294 2,044 3,054 1,000 389 1,030 389 1,230 389 2,367 2,054 1,467 1,665 2,287 2,928 1,962 0.50 [0.35, 0.71] Results not pooled due to substantial heterogeneity 1.01 [0.33, 3.05] 0.29 [0.07, 1.25] † -120.81 [-163.40, -78.23] Results not pooled due to substantial heterogeneity 0.56 [0.45, 0.69] 0.43 [0.27, 0.70] 0.42 [0.23, 0.77] 0.38 [0.19, 0.78] 0.15 [0.01, 2.87] 0.04 [0.00, 0.66] 0.35 [0.01, 8.45] 0.02 [0.00, 0.22] 0.48 [0.12, 1.90] 0.02 [0.00, 0.11] 1.18 [0.92, 1.52] 0.55 [0.10, 2.97] 0.79 [0.56, 1.10] 0.26 [0.18, 0.37] ‡ -0.00 [-0.01, 0.01] ‡ -0.00 [-0.01, 0.01] 1.05 [0.48, 2.28] 1 1,665 1 1 83 126 RCT 2 383 Cohort 1 126 RCT Birthweight >4,000 g Birthweight >4,500 g Birthweight Large for gestational age Shoulder dystocia Brachial plexus injury Clavicular fracture Birth trauma Hypoglycemia Hyperbilirubinemia Perinatal deaths Respiratory complications APGAR 1 min APGAR 5 min 2 Number of Studies 5 Source Effect Estimate* I (%) 50 Treatment 86 Treatment NA 69 2 Treatment 77 Favors - 0 58 0 0 NA NA NA NA NA NA 0 49 0 NA 66 0 58 Treatment Treatment Treatment Treatment Treatment Treatment Treatment Treatment - 0.16 [0.10, 0.26] NA Treatment -0.30 [-0.56, -0.04] -1.00 [-1.54, -0.46] Results not pooled due to substantial heterogeneity 0.00 [-0.27, 0.27] NA NA Treatment Treatment 87 77 - NA - Table 17. Evidence summary for Key Question 4: infant outcomes (continued) Outcome Type 2 DM (long-term) Impaired glucose tolerance 2 RCT Number of Studies 1 Number of Participants 89 1.88 [0.08, 44.76] I (%) NA RCT 1 89 5.63 [0.31, 101.32] 44 Source Effect Estimate* Favors - >95 percentile 1 85 1.58 [0.66, 3.79] NA >85 percentile 1 199 1.19 [0.78, 1.82] NA BMI (long-term) Any BMI (2 2 284 1.26 [0.86, 1.84] 0 studies above combined) BMI = body mass index; DM = diabetes mellitus; NA = not applicable; RCT = randomized controlled trial; RDS = respiratory distress syndrome *Risk ratios unless otherwise specified. †Mean difference. ‡Risk difference. 88 Table 18. Strength of evidence for Key Question 4: maternal and infant outcomes Outcome Preeclampsia Maternal weight gain Birth injury Source Risk of Bias Consistency Directness Precision 3 RCTs Low Consistent Direct Imprecise 1 cohort 4 RCTs 2 cohorts 2 RCTs High Medium High Medium Unknown Inconsistent consistent Consistent Direct Direct Direct Direct Imprecise Imprecise Imprecise Imprecise 1 cohort High Unknown Direct Imprecise 3 RCTs Medium Consistent Direct Precise 4 cohorts High Consistent Direct Precise 4 RCTs Medium Consistent Direct Imprecise 2 cohorts High Inconsistent Direct Imprecise 5 RCTs Medium Consistent Direct Precise 6 cohorts High Inconsistent Direct Precise Overall SOE Comment Moderate (favors treatment) Insufficient Insufficient Insufficient Low The evidence provides moderate confidence that the estimate reflects the true effect in favor of the treatment group. There is insufficient evidence to draw conclusions for this outcome There is insufficient evidence to make a conclusion for this outcome. There is a difference in findings for the RCTs and cohort studies; the number of events and participants across all studies does not allow for a conclusion. Insufficient (favors treatment) Moderate (favors treatment) Shoulder dystocia Neonatal hypoglycemia Macrosomia >4,000 g Long-term metabolic outcomes: impaired 1 RCT Medium Unknown Direct glucose tolerance Long-term metabolic outcomes: type 2 1 RCT Medium Unknown Direct diabetes mellitus Long-term metabolic outcomes: BMI 2 RCTs Medium Consistent Direct th (assessed as >85 th and >95 percentile) BMI = body mass index; RCT = randomized controlled trial; SOE = strength of evidence 89 Low (favors treatment) Low (no difference) Insufficient Moderate (favors treatment) Low (favors treatment) The evidence provides moderate confidence that the estimate reflects the true effect in favor of the treatment group. The evidence provides low confidence that there is no difference between groups. The evidence provides moderate confidence that the estimate reflects the true effect in favor of the treatment group. Imprecise Insufficient There is insufficient evidence to draw conclusions for this outcome. Imprecise Insufficient There is insufficient evidence to draw conclusions for this outcome. Imprecise Low (no difference) The evidence provides low confidence that there is no difference between groups. Key Question 5. What are the harms of treating GDM and do they vary by diagnostic approach? Description of Included Studies Five of the studies included in Key Question 4 also provided data for Key Question 5.50,54,95,97,98 The studies are described in Appendix D. All studies compared diet modification, glucose monitoring and insulin as needed with standard care. Four of the studies were randomized controlled trials,50,54,97,98 while one study was a retrospective cohort.95 The studies were published between 1999 and 2009 (median year 2005). Two studies had two associated publications reporting initial and longer term outcomes.163,164 Three studies were from the United States,54,95,98 and one each from Italy97 and Australia.50 The screening test used in most studies was OGCT with a 100 g OGTT assessed using CC criteria, except for the study from Australia that used a OGCT with a 75 g OGTT. Timing of diagnosis of GDM occurred at or after 24 weeks’ gestation. Among these studies a variety of glucose threshold criteria were used for inclusion, varying from 50 g screen positive with nondiagnostic oral glucose tolerance tests to WHO criteria for a diagnosis of GDM. The 2 largest RCTs by Crowther et al. and Landon et al.50,54 used different glucose thresholds for entry in their trials: WHO and CC criteria with a fasting glucose <95 mg/dL (5.3 mmol/L), respectively. The mean fasting glucose levels at study entry were similar between these 2 trials. Methodological Quality of Included Studies Among the four RCTs, one had low50 and three54,97,98 had unclear risk of bias. The trials that were unclear most commonly did not report detailed methods for sequence generation and allocation concealment. Two trials54,97 were unclear with respect to blinding of participants. One trial had incomplete reporting of outcome data.98 The cohort study was high quality (7/9 points);95 the primary limitation was not controlling for potential confounders. Key Points • There was no evidence for some of the outcomes stipulated in the protocol including costs and resource allocation. There was limited evidence for harms and the evidence related to anxiety and depression. There was also limited evidence for number of prenatal visits and admissions to NICU. Results are detailed below. Maternal Outcomes • A single RCT assessed depression and anxiety at 6 weeks after study entry and 3 months postpartum. There was no significant difference between groups in anxiety at either time point, although there were significantly lower rates of depression in the treatment group at 3 months postpartum. Outcomes in the Offspring • Four RCTs reported small for gestational age and found no significant difference. Health System Outcomes • Three RCTs and one cohort study provided data on admission to NICU and showed no significant differences overall. One trial was an outlier as it showed a significant 90 • • • difference favoring the no treatment group. This difference may be attributable to sitespecific policies and procedures. Two RCTs reported on the number of prenatal visits and generally found significantly more visits among the treatment groups. The same two studies showed a lower incidence of patients requiring insulin therapy in the untreated groups. There was inconsistency across studies in terms of induction of labor with no difference found for the 2 RCTs overall and a significant difference favoring the treatment group among the one cohort study included. Among the RCTs, one showed a significant difference with fewer cases in the group receiving no treatment,50 while the other study showed no difference.54 In the RCT that showed more inductions of labor in the treatment group, no recommendations were provided regarding obstetrical care, thus replicating usual clinical care of women with GDM. In the other RCT, antenatal surveillance was reserved for standard obstetrical indications. No differences between groups were found for cesarean section (5 RCTs, 6 cohorts) or unplanned cesarean section (1 RCT, 1 cohort). Detailed Synthesis Maternal Outcomes Depression and Anxiety One RCT assessed depression and anxiety at 6 weeks after study entry and 3 months postpartum.50 Depression was assessed using the Edinburgh Postnatal Depression Score and anxiety was assessed using the Spielberger State-Trait Anxiety Inventory. There was no significant difference between groups in anxiety at either time point, although there were significantly lower rates of depression in the treatment group 3 months postpartum (Table 19). The authors of the primary study note that the findings regarding anxiety and depression should be interpreted cautiously because they were based on a subgroup of the women included in the trial. Fetal/Neonatal/Child Outcomes Small for Gestational Age (SGA) SGA was reported in four RCTs50,54,97,98 and overall no significant difference was found between groups (RR 1.10; 95% CI, 0.81 to 1.48; Table 19, Figure 63). Figure 63. Effect of treatment on adverse effects for infants of mothers with GDM: SGA Study or Subgroup Bevier 1999 Bonomo 2005 Crowther 2005 Landon 2009 Total (95% CI) Treatment No Treatment Total Weight Events Total Events 3 13 33 36 35 150 506 477 1168 2 9 38 29 Risk Ratio M-H, Random, 95% CI 48 150 524 455 3.0% 13.2% 43.9% 39.9% 2.06 [0.36, 11.67] 1.44 [0.64, 3.28] 0.90 [0.57, 1.41] 1.18 [0.74, 1.90] 1177 100.0% 1.10 [0.81, 1.48] 78 85 Total events Heterogeneity: Tau² = 0.00; Chi² = 1.79, df = 3 (P = 0.62); I² = 0% Test for overall effect: Z = 0.60 (P = 0.55) Risk Ratio M-H, Random, 95% CI 0.1 0.2 0.5 1 2 5 10 Favors Treatment Favors No Treatment CI = confidence interval; GDM = gestational diabetes mellitus; M-H = Mantel-Haenszel; SGA = small for gestational age 91 Society/Health Care System Outcomes Admission to NICU Three RCTs50,54,97 and one cohort study95 provided data on admission to the NICU (Table 19). Among the three RCTs there was no significant difference overall (RR 0.96; 95% CI, 0.67 to 1.37, n = 2,262; Table 19, Figure 64), although there was substantial statistical heterogeneity (I2 = 61%). One study was an outlier as it showed a significant effect favoring the untreated group (RR 1.15; 95% CI, 1.05 to 126, n = 1,030). Removing this study from the analysis reduced the heterogeneity to 0% and the result remained non-significant. One cohort study also showed no significant difference in NICU admissions (RR 0.66; 95% CI, 0.19 to 2.35, n = 126).95 Figure 64. Effect of treatment on adverse effects for infants of mothers with GDM: NICU admissions Study or Subgroup 3.3.1 RCT Bonomo 2005 Crowther 2005 Landon 2009 Subtotal (95% CI) Treatment No Treatment Total Weight Events Total Events 5 357 43 150 506 477 1133 7 321 53 Risk Ratio M-H, Random, 95% CI 150 8.6% 524 56.4% 455 35.0% 1129 100.0% Risk Ratio M-H, Random, 95% CI 0.71 [0.23, 2.20] 1.15 [1.05, 1.26] 0.77 [0.53, 1.13] 0.96 [0.67, 1.37] 405 381 Total events Heterogeneity: Tau² = 0.06; Chi² = 5.16, df = 2 (P = 0.08); I² = 61% Test for overall effect: Z = 0.21 (P = 0.83) 3.3.2 Cohort studies Fassett 2007 Subtotal (95% CI) 4 69 69 4 Total events Heterogeneity: Not applicable Test for overall effect: Z = 0.64 (P = 0.52) 5 57 100.0% 57 100.0% 0.66 [0.19, 2.35] 0.66 [0.19, 2.35] 5 Test for subgroup differences: Chi² = 0.31, df = 1 (P = 0.58), I² = 0% 0.2 0.5 1 2 5 Favors Treatment Favors No Treatment CI = confidence interval; GDM = gestational diabetes mellitus; M-H = Mantel-Haenszel; NICU = neonatal intensive care unit; RCT = randomized controlled trial Number of Prenatal Visits Two RCTs reported on the number of prenatal visits.50,54 Landon et al.54 reported an average of seven prenatal visits in the treatment group versus five in the control group (p<0.001). Crowther et al.50 reported the median number of antenatal clinic visits and physician clinical visits after enrolment. The intervention group had fewer antenatal clinic visits (median 5.0 [interquartile range (IQR) 1-7] vs. 5.2 [IQR 3-7], p<0.001); whereas they had more physician clinic visits (median 3 [IQR 1-7] vs. 0 [IQR 0-2]). The intervention group also had significantly more visits with a dietician (92 percent vs. 10 percent, p<0.001) and with a diabetes educator (94 percent vs. 11 percent, p<0.001). Induction of Labor [Note: This outcome was presented under Key Question 4. It is also presented here as it may be considered a harm in terms of more resource use and more invasive management.] Three studies provided data on induction of labor50,54,146 but results differed significantly across the studies (Table 19). Two RCTs showed no significant difference overall (RR 1.16, 95% CI 0.91 to 1.49, n = 1,931), although there was important statistical heterogeneity between studies (I2 = 92 69%). One RCT showed a significant difference favoring no treatment,50 while the other study showed no difference (Figure 65).54 Different study protocols may account for the heterogeneity of results between studies. In the study that showed more inductions of labor in the treatment group, no recommendations were provided regarding obstetrical care, thus replicating usual clinical care of women with GDM. In the other study, antenatal surveillance was reserved for standard obstetrical indications. In contrast the one cohort study showed a significant difference with fewer inductions in the treatment group (RR 0.63, 95% CI 0.55 to 0.72, n = 1,665).146 Baseline differences in the study populations and regional practices may have accounted for the different results between studies. Further, the comparison group in the cohort study was women who presented late for obstetrical care which confounds the relationship between induction and GDM treatment. Furthermore, the cohort study protocol was to deliver these women within one week of GDM diagnosis so the outcome of induction was substantially confounded by different delivery protocols between treatment and nontreatment groups. Figure 65. Effect of treatment on outcomes of women with GDM: induction of labor Study or Subgroup 1.6.1 RCT Crowther 2005 Landon 2009 Subtotal (95% CI) Treatment No treatment Events Total Events Total Weight 189 130 490 476 966 150 122 Risk Ratio M-H, Random, 95% CI 510 52.8% 455 47.2% 965 100.0% Risk Ratio M-H, Random, 95% CI 1.31 [1.10, 1.56] 1.02 [0.82, 1.26] 1.16 [0.91, 1.49] Total events 319 272 Heterogeneity: Tau² = 0.02; Chi² = 3.27, df = 1 (P = 0.07); I² = 69% Test for overall effect: Z = 1.20 (P = 0.23) 1.6.2 Cohort Studies Langer 2005 Subtotal (95% CI) 303 1110 1110 242 555 100.0% 555 100.0% 0.63 [0.55, 0.72] 0.63 [0.55, 0.72] Total events 303 242 Heterogeneity: Not applicable Test for overall effect: Z = 6.81 (P < 0.00001) Test for subgroup differences: Chi² = 18.61, df = 1 (P < 0.0001), I² = 94.6% 0.5 0.7 1 1.5 2 Favors treatment Favors no treatment CI = confidence interval; GDM = gestational diabetes mellitus; M-H = Mantel-Haenszel; RCT = randomized controlled trial Cesarean Delivery [Note: This outcome was presented under Key Question 4. It is also presented here as it may be considered a harm in terms of more resource use and more invasive management.] All studies provided data on cesarean delivery (Table 19).50,54,92,95-98,146,148,152,160 There was no significant difference in the pooled estimates for the RCTs (RR 0.90, 95% CI 0.79 to 1.01, n = 2,613) or for the cohort studies (RR 1.09, 95% CI 0.90 to 1.31, n = 3,110; Figure 66). The results were statistically homogeneous across all studies. One RCT50 and one cohort study95 reported emergency cesarean deliveries and found no difference (RCT, RR 0.81, 95% CI 0.62 to 1.05, n = 1,000; cohort, RR 0.83, 95% CI 0.33 to 2.06, n = 126). 93 Figure 66. Effect of treatment on outcomes of women with GDM: cesarean delivery Study or Subgroup 1.1.1 RCT Bevier 1999 Bonomo 2005 Crowther 2005 Garner 1997 Landon 2009 Subtotal (95% CI) Treatment No treatment Events Total Events Total Weight 5 42 152 30 128 35 150 490 149 476 1300 12 44 164 28 154 Risk Ratio M-H, Random, 95% CI 48 1.6% 150 11.3% 510 43.1% 150 6.7% 455 37.3% 1313 100.0% Risk Ratio M-H, Random, 95% CI 0.57 [0.22, 1.47] 0.95 [0.67, 1.36] 0.96 [0.80, 1.16] 1.08 [0.68, 1.71] 0.79 [0.65, 0.97] 0.90 [0.79, 1.01] Total events 357 402 Heterogeneity: Tau² = 0.00; Chi² = 3.68, df = 4 (P = 0.45); I² = 0% Test for overall effect: Z = 1.81 (P = 0.07) 1.1.2 Cohort studies Adams 1998 Bonomo 1997 Chou, 2010 Fassett 2007 Langer 2005 Naylor, 1996 Subtotal (95% CI) 99 7 40 21 258 48 373 26 233 69 1110 143 1954 4 26 32 19 132 34 16 4.5% 88 6.4% 325 15.0% 57 11.5% 555 43.0% 115 19.6% 1156 100.0% 1.06 [0.45, 2.52] 0.91 [0.45, 1.85] 1.74 [1.13, 2.69] 0.91 [0.55, 1.52] 0.98 [0.81, 1.17] 1.14 [0.79, 1.63] 1.09 [0.90, 1.31] Total events 473 247 Heterogeneity: Tau² = 0.01; Chi² = 6.47, df = 5 (P = 0.26); I² = 23% Test for overall effect: Z = 0.88 (P = 0.38) Test for subgroup differences: Chi² = 2.93, df = 1 (P = 0.09), I² = 65.9% 0.2 0.5 1 2 5 Favors treatment Favors no treatment CI = confidence interval; GDM = gestational diabetes mellitus; M-H = Mantel-Haenszel; RCT = randomized controlled trial Table 19. Evidence summary for Key Question 5 Outcome Number of Studies Number of Participants Small for gestational age 4 2,345 1.10 [0.81, 1.48] (RCTs) Anxiety (6 weeks, RCT) 682 -0.30 [-0.88, 0.28] 1 Anxiety (3 months, RCT) 573 -0.20 [-0.83, 0.43] 1 Depression (3 months, RCT) 568 0.50 [0.31, 0.79] 1 Admission to NICU RCT 3 2,262 0.96 [0.67, 1.37] Cohort 1 126 0.66 [0.19, 2.35] Induction of labor RCT 2 1,931 1.16 [0.91, 1.49] Cohort 1 1,665 0.63 [0.55, 0.72] Cesarean section RCT 5 2,613 0.90 [0.79, 1.01] Cohort 6 3,110 1.09 [0.90, 1.31] Unplanned cesarean section RCT 1 1000 0.81 [0.62, 1.05] Cohort 1 126 0.83 [0.33, 2.06] NA = not applicable; NICU = neonatal intensive care unit; RCT = randomized controlled trial *Risk ratio 94 I2 (%) Effect Estimate* Favors 0 - NA NA NA Treatment 61 NA - 69 NA Treatment 0 23 - NA NA - Discussion Key Findings and Discussion Key findings are presented by Key Question in the sections that follow. A summary of the results for all Key Questions is provided in Table 24 at the end of the Discussion. Key Question 1 Fifty-one studies provided data for Key Question 1 that sought to examine the test characteristics and prevalence of current screening and diagnostic tests for gestational diabetes mellitus (GDM). The lack of a “gold standard” to confirm a diagnosis of GDM limits the ability to compare the results of studies that used different diagnostic criteria. Different criteria result in different rates of prevalence for GDM, regardless of similarities across study settings and patient characteristics. The methodological quality of the studies was assessed using the QUADAS-2 tool. There were several concerns about the quality and applicability of the studies that addressed Key Question 1. First, there is concern about the risk for partial verification bias, which can occur when not all of the patients are verified by the reference standard. In 25 percent of the studies, women who were below the threshold for further screening on the oral glucose challenge test (OGCT) did not undergo an oral glucose tolerance test (OGTT) to confirm a diagnosis of GDM. For 35 percent of studies, it was unclear risk whether all patients underwent both tests. Another concern relates to the risk of diagnostic review bias in which the interpretation of the results of the reference standard may have been influenced by the knowledge of the results of the index test. Eighty percent of studies were assessed as high or unclear risk for this domain. A third concern relates to the domain of patient selection and the possibility of spectrum bias; 82 percent of studies were assessed as having high or unclear concerns for applicability. This was primarily because the studies were conducted in developing countries and used the World Health Organization (WHO) criteria to diagnose GDM. The evidence showed that the 50 g OGCT with the 130 mg/dL cutpoint had higher sensitivity when compared with the 140 mg/dL cutpoint; however, specificity was lower (99 vs. 85 and 77 vs. 86, respectively). Both thresholds have high negative predictive values (NPV), but variable positive predictive values (PPV) across a range of GDM prevalence. When the risk of a missing a diagnosis is considered high, screening tests with high NPV are preferred at the expense of PPV. However, if the harm of an incorrect diagnostic is high, screening tests with high PPV are preferred at the expense of NPV. The Toronto Trihospital study found evidence to support the use of the lower screening cutpoint for higher risk patients, and the higher screening cutpoint for lower risk patients.15 While graded cutpoints for the diagnosis and treatment of dyslipidemia and osteoporosis based on risk factors are used in routine clinical practice, this approach is not widely accepted for the screening of GDM. The large randomized controlled trials (RCTs) that showed some treatment benefits employed a two-step approach to screening and diagnosis for GDM.50,54 The practical efficiency of a two-step approach may be improved by setting a high threshold value on the screening test, above which no further confirmation testing is required for diagnosis. One study provides support for this approach by demonstrating that a threshold of 200 mg/dL on a 50 g OGCT 95 resulted in 100 percent positive and negative predictive values for diagnosing GDM by Carpenter and Coustan (CC) and National Diabetes Data Group (NDDG) criteria.104 Only three studies included women who were in their first trimester of pregnancy and they used different diagnostic criteria. Therefore, no conclusions can be made about the test characteristics of screening tests for this group of women. There are limited data to support the use of glycated hemoglobin (HbA1c) as a screening test. A study conducted in the United Arab Emirates using an HbA1c value of 5.5 percent or more lacked specificity (21 percent) despite good sensitivity (82 percent).113 A study conducted in Turkey showed that an HbA1c cutoff of 7.2 percent or more had 64 percent sensitivity and specificity.74 HbA1c does not perform as well as the 50 g OGCT as a screening test for GDM. However, when HbA1c is markedly elevated this supports a possible diagnosis of overt diabetes discovered in pregnancy. Since 2011-2012 the American Diabetes Association (ADA) has endorsed the use of an HbA1c of 6.5 percent or more as diagnostic of diabetes in nonpregnant women.36 Studies of HbA1c with trimester specific cutoffs to determine the value at which overt diabetes should be diagnosed in pregnancy are needed. The sensitivity for fasting plasma glucose (FPG) of 85 mg/dL as a screening test for GDM is similar to that for the 50 OGCT with a threshold of 140 mg/dL; however, specificity is lower. As the threshold for fasting glucose is increased specificity is gained at the expense of sensitivity. The use of fasting glucose as a screening test for GDM has several clinical advantages over the OGCT when the tests are performed at or after 24 weeks’ gestation. FPG has the advantage of greater reproducibility than post glucose load testing.165 In addition, it is easier to administer to women who cannot tolerate the glucose drink. Furthermore, fasting glucose has been positively associated with clinical outcomes of concern for GDM.142,166 However, a recent report from the Hyperglycemia and Adverse Pregnancy Outcome Study (HAPO) data found that a fasting glucose of 92 mg/dL did not diagnose GDM in women from Hong Kong and Bangkok as frequently as it did in other populations, and the elevated post glucose load glucose measurements were more frequently diagnostic of an International Association of the Diabetes in Pregnancy Study Groups (IADPSG) diagnosis of GDM in women from Hong Kong and Bangkok.6 Our review did not identify compelling evidence for or against risk factor-based screening. Naylor et al. used the Toronto Trihospital study data to develop a risk scoring system for GDM screening using variable glucose thresholds based on age, body mass index (BMI), and race. When applied to a validation group, sensitivity and specificity were similar to universal screening.167 There are limited data to draw conclusions about the effectiveness of the different options for diagnostic testing for GDM. Four studies compared the 75 g and 100 g load tests, but they were conducted in different countries and used different criteria or thresholds. However, because both the 75 g and 100 g load tests are positively linked with outcomes142,166 and the 75 g test is less time consuming, the adoption of the 75 g glucose load may be warranted even if thresholds continue to be debated3,142 The IADPSG has proposed the elimination of a screening test in favor of proceeding directly to a diagnostic test for GDM. We identified only one study124 that compared the IADPSG criteria with the Australasian Diabetes in Pregnancy Society (ADIPS) that used a two-step strategy. Sensitivity was 82 percent (95% CI, 74 to 88) and specificity was 94 percent (95% CI, 93 to 96). 96 Prevalence and Predictive Values The prevalence of GDM varied across studies and the diagnostic criteria used. Factors contributing to the variability included differences in study setting (i.e., country), screening practices (e.g., universal vs. selective), and population characteristics (e.g., race/ethnicity, age, BMI). The predictive value of a screening or diagnostic test is determined by the test’s sensitivity and specificity and by the prevalence of GDM. Table 20 presents a series of scenarios that demonstrate the changes in PPV and NPV for three levels of prevalence (7 percent, 15 percent, and 25 percent).6 Separate tables are presented for different screening and diagnostic criteria. The higher the prevalence of GDM, the higher the PPV, or the more likely a positive result is able to predict the presence of GDM. When the prevalence of GDM is low, the PPV is also low, even when the test has high sensitivity and specificity. Generally the NPV (negative result rules out GDM) is very high—98 percent or better at a GDM prevalence of 7 percent. Table 20. Relationship between predictive values and prevalence for different screening tests Positive Negative Predictive Predictive Value Value 7% 31% 99% 50 g OGCT ≥140 mg/dL by CC/ADA 15% 52% 97% (2000-2010) Sensitivity=85%; Specificity=86% 25% 67% 95% 7% 24% 100% 50 g OGCT ≥130 mg/dL by CC/ADA 15% 43% 100% (2000-2010) Sensitivity=99%; Specificity=77% 25% 59% 100% 7% 27% 99% 50 g OGCT ≥140 mg/dL by NDDG 15% 47% 97% Sensitivity=85%; Specificity=83% 25% 63% 94% 7% 16% 99% 50 g OGCT ≥130 mg/dL by NDDG 15% 31% 97% Sensitivity = 88%; Specificity = 66% (median) 25% 46% 94% 7% 29% 99% 50 g OGCT ≥140 mg/dL by ADA 75 g 15% 49% 98% Sensitivity=88%; Specificity=84% (median) 25% 65% 95% 7% 24% 98% 50 g OGCT ≥140 mg/dL by WHO 15% 42% 95% Sensitivity=78%; Specificity=81% (median) 25% 58% 92% 7% 12% 98% FPG (≥85 mg/dL) by CC/ADA (2000-2010) 15% 24% 96% Sensitivity=87%; Specificity=52% 25% 38% 92% 7% 21% 98% Risk factor screening by various criteria 15% 38% 96% Sensitivity=84%; Specificity=72% (median) 25% 54% 93% TADA = American Diabetes Association; CC = Carpenter-Coustan; FPG = fasting plasma glucose; NDDG = National Diabetes Data Group; OGCT = oral glucose challenge test; WHO =World Health Organization Screening Test Prevalence Key Question 2 Only two retrospective cohort studies were relevant to Key Question 2 which asked about the direct benefits and harms of screening for GDM. One retrospective cohort study (n=1,000) conducted in Thailand showed a significantly greater incidence of cesarean deliveries in the screened group. A survey of a subset of participants (n=93) in a large prospective cohort study involving 116,678 nurses aged 25-42 years in the United States found the incidence of macrosomia (infant weight ≥ 4.3 kg) was the same in the screened and unscreened groups (7 percent each group). 97 There were no RCTs available to answer questions about screening. There is a paucity of evidence on the impact of screening women for GDM on health outcomes. The comparison for this question was women who had and had not undergone screening. Since screening is now commonplace it may be unlikely to identify studies or cohorts where this comparison is feasible. Key Question 3 Thirty-eight studies provided data for Key Question 3 that sought to examine health outcomes for women who meet various criteria for GDM and do not receive treatment. The majority of data came from cohort studies or the untreated groups from RCTs. A wide variety of diagnostic criteria and thresholds were compared across the studies. The most common groups reported and compared were GDM diagnosed by CC criteria, no GDM by any criteria (normal), impaired glucose tolerance defined as one abnormal glucose value (OAV), and false positive (positive OGCT, negative OGTT).). Only single studies contributed data for many of the comparisons and outcomes, which does not allow for definitive conclusions. Further, results that showed no statistically significant differences cannot be interpreted as equivalence between groups nor do they rule out potential differences. A summary of the strength of evidence for key outcomes is provided in Table 21 and Table 22. For maternal outcomes among the studies that compared groups as described above, women without GDM and those testing false positive showed fewer cases of preeclampsia than those meeting CC criteria; the strength of evidence was considered low for these two comparisons. No differences in preeclampsia were found for other comparisons, although evidence was based on few studies per comparison and strength of evidence was rated insufficient. Fewer cases of cesarean section were found among women without GDM compared with women meeting criteria for CC GDM, CC, 1 abnormal OGTT, CC false positives, NDDG false positives, NDDG 1 abnormal oral glucose tolerance test, WHO IGT, IADPSG impaired fasting glucose (IFG), and IADPSG impaired glucose tolerance (IGT) IFG. There were fewer cases of cesarean section among false positives compared with women meeting criteria for CC GDM. For 12 other comparisons, there were no differences in rates of cesarean delivery. For maternal hypertension, significant differences were found for eight of 16 comparisons; many comparisons were based on single studies. No GDM groups showed lower incidence of maternal hypertension when compared with CC GDM, CC, 1 abnormal OGTT, IADPSG IFG, IADPSG double impaired glucose tolerance (IGT-2), and IADPSG IGT IFG. Other comparisons showing significant differences were CC GDM versus false positives (lower incidence for false positives), IADPSG IGT versus IGT IFG (lower incidence for IGT), and IADPSG IFG versus IGT IFG (lower incidence for IFG). Based on single studies, no differences were observed for maternal birth trauma for three comparisons. For maternal weight gain (less weight gain considered beneficial), significant differences were found for three of 12 comparisons: IADPSG IGT versus no GDM (favored IGT), IADPSG IFG versus no GDM (favored IFG), IADPSG IGT-2 versus no GDM (favored IGT-2). All comparisons were based on single studies and the strength of evidence was insufficient. For maternal mortality/morbidity, single studies contributed to three comparisons and no differences were found except for fewer cases among patient groups with no GDM compared with IADPSG GDM. No studies provided data on long-term maternal outcomes, such as type 2 diabetes mellitus, obesity and hypertension. 98 Table 21. Summary of strength of evidence for the association between different glucose levels and maternal outcomes (Key Question 3) Number of Studies Outcome Preeclampsia Strength of Evidence CC GDM vs. no GDM 3 cohorts Low CC GDM vs. false positive 2 cohorts Low Summary Statistically significant difference with fewer cases in the patient groups with no GDM (RR 1.50, 95% CI 1.07, 2.11) Statistically significant difference with fewer cases in the false-positive group (RR 1.51, 95% CI 1.17, 1.93) NDDG false positive 2 cohorts Insufficient vs. no GDM NDDG, 1 abnormal 1 cohort Insufficient OGTT vs. no GDM WHO IGT vs. no GDM 3 cohorts Insufficient CC, 1 abnormal OGTT 1 cohort Insufficient vs. no GDM WHO IGT vs. no GDM 1 cohort Insufficient IADPSG IGT vs. 1 cohort Insufficient no GDM IADPSG IFG vs. 1 cohort Insufficient no GDM IADPSG IGT-2 vs. 1 cohort Insufficient no GDM IADPSG IGT IFG vs. Maternal weight 1 cohort Insufficient no GDM gain IADPSG IGT vs. IFG 1 cohort Insufficient IADPSG IGT vs. IGT-2 1 cohort Insufficient IADPSG IGT vs. 1 cohort Insufficient IGT IFG IADPSG IFG vs. IGT-2 1 cohort Insufficient IADPSG IFG vs. 1 cohort Insufficient IGT IFG IADPSG IGT-2 vs. 1 cohort Insufficient IGT IFG CC = Carpenter-Coustan; CI = confidence interval; GDM = gestational diabetes mellitus; IFG = impaired fasting glucose; IGT = impaired glucose tolerance; IGT-2 = double impaired glucose tolerance; IADPSG = International Association of Diabetes and Pregnancy Study Groups; NDDG = National Diabetes Data Group; OGTT = oral glucose tolerance test; RR = risk ratio; WHO = World Health Organization The most commonly reported outcome for the offspring was macrosomia >4,000 g. Six of 11 comparisons showed a significant difference: there were fewer cases in the group without GDM compared with CC GDM, CC 1 abnormal OGTT, NDDG GDM (unrecognized), NDDG false positives, and WHO IGT. Fewer cases were found for women with false-positive results compared with CC GDM. The strength of evidence for these findings was low to insufficient. Data for macrosomia >4,500 g was available for four comparisons and showed significant differences in two cases: patient groups with no GDM had fewer cases compared with women with CC GDM and with unrecognized NDDG GDM. The strength of evidence was low and insufficient, respectively. For shoulder dystocia, significant differences were found for seven of 17 comparisons; all but one comparison was based on single studies (insufficient strength of evidence). Patient groups with no GDM showed lower incidence of shoulder dystocia when compared with CC GDM (5 studies; low strength of evidence), NDDG GDM (unrecognized), NDDG false positive, WHO IGT, IADPSG IFG, and IADPSG IGT IFG. The other significant difference showed lower incidence among the false-positive group compared with CC 1 abnormal OGTT. For fetal birth 99 trauma or injury, four studies compared CC GDM, NDDG GDM and WHO IGT with patient groups without GDM (insufficient strength of evidence). No differences were observed except for NDDG GDM which favored the group with no GDM. Only one difference was found for neonatal hypoglycemia with fewer cases among patient groups without GDM compared with those meeting CC criteria; strength of evidence was insufficient. There were 16 comparisons for hyperbilirubinemia; the majority were based on single studies. Three comparisons showed significant differences between groups: patient groups with no GDM had fewer cases compared with CC false positive, IADPSG IGT, and IADPSG IGT-2, respectively. No differences were found for fetal morbidity/mortality for any of eight comparisons which may be attributable to small numbers of events within some comparisons. Moreover, comparisons were based on single studies. Based on a single study, significant differences were found in prevalence of childhood obesity for CC GDM versus no GDM (lower prevalence for no GDM) and CC GDM versus false positives (lower prevalence for false positives). This was consistent for both childhood obesity >85th percentile as well as >95th percentile. However, this study was unable to control for maternal weight or BMI which are established predictors of childhood obesity. No differences, based on the same single study, were found for the other four comparisons within >85th or >95th percentiles. No other studies provided data on long-term outcomes, including type 2 diabetes mellitus and transgenerational GDM. In summary, different thresholds of glucose intolerance impact maternal and neonatal outcomes of varying clinical importance. While many studies have attempted to measure the association between various criteria for GDM and pregnancy outcomes in the absence of treatment, the ability of a study or pooled analysis to find a statistically significant difference in pregnancy outcomes appears more dependent on study design, in particular the size of the study or pooled analysis, rather than the criteria used for diagnosing GDM. This is not surprising given the strong support found for a continuous positive relationship between glucose and a variety of pregnancy outcomes. Moreover, two methodologically strong studies met the inclusion criteria for this question but could not be pooled with the other studies because they examined glucose thresholds as a continuous outcome.3,91 These studies demonstrated a continuous positive relationship between increasing glucose levels and the incidence of primary cesarean section, and macrosomia. One of these studies also found significantly fewer cases of preeclampsia, cesarean section, shoulder dystocia and/or birth injury, clinical neonatal hypoglycemia, and hyperbilirubinemia for women with no GDM compared with those meeting IADPSG criteria.3 The clinical significance of absolute differences in event rates requires contemplation by decision makers even though statistical significance was reached at the strictest diagnostic glucose thresholds for some outcomes. This question focused on outcomes for women who did not receive treatment for GDM. While women with untreated GDM have a variety of poorer outcomes than women without GDM, it cannot be assumed that treatment of GDM reverses all the short- and long-term poor outcomes observed in women with untreated GDM. Some of the reasons for the poorer outcomes in women that have untreated GDM may not be modifiable, such as the influences of genetic makeup. The strength of evidence was insufficient for most outcomes and comparisons in this question due to high risk of bias (observational studies), inconsistency across studies, and/or imprecise results. 100 Table 22. Summary of strength of evidence for the association between different glucose levels and neonatal/infant outcomes (Key Question 3) Number of Studies Outcome Strength of Evidence Statistically significant difference with fewer cases in the patient group with no GDM (RR 1.61, 95% CI 1.35, 1.92) Statistically significant difference with fewer cases in the falsepositive group (RR 1.36, 95% CI 1.10, 1.68) No statistically significant difference (RR 0.99, 95% CI 0.92, 1.07) Statistically significant difference with fewer cases in the patient group with no GDM (RR 1.44, 95% CI 1.13, 1.82) No statistically significant difference (RR 1.02, 95% CI 0.85, 1.24) CC GDM vs. no GDM 10 cohorts Low CC GDM vs. false positive 5 cohorts Low CC GDM vs. 1 abnormal OGTT 3 cohorts Low CC 1 abnormal OGTT vs. no GDM 7 cohorts Low CC false positive vs. no GDM 5 cohorts Low 3 cohorts Insufficient - 1 cohort Insufficient - Macrosomia >4,000 g CC 1 abnormal OGTT vs. false positive NDDG GDM (unrecognized) vs. no GDM Macrosomia >4,500 g Summary NDDG false positive vs. no GDM 4 cohorts Low WHO GDM vs. no GDM WHO IGT vs. no GDM IADPSG GDM vs. no GDM 1 cohort 1 cohort 2 cohorts Insufficient Insufficient Insufficient CC GDM vs. no GDM 3 cohorts Low CC GDM vs. false positive CC false positive vs. no GDM NDDG GDM (unrecognized) vs. no GDM 2 cohorts Insufficient Statistically significant difference with fewer cases in the patient group with no GDM (RR 1.44, 95% CI 1.10, 1.89) Statistically significant difference with fewer cases in the patient group with no GDM (RR 2.52, 95% CI 1.65, 3.84) - 2 cohorts Insufficient - 1 cohort Insufficient - 101 Table 22. Summary of strength of evidence for the association between different glucose levels and neonatal/infant outcomes (Key Question 3) (continued) Outcome Comparison CC GDM vs. no GDM Number of Studies 5 cohorts Strength of Evidence Low Summary Statistically significant difference with fewer cases in the patient group with no GDM (RR 2.86, 95% CI 1.81, 4.51) - CC GDM vs. false positive 1 cohort Insufficient CC 1 abnormal OGTT vs. no 1 cohort Insufficient GDM CC 1 abnormal OGTT vs. 1 cohort Insufficient false positive NDDG GDM (unrecognized) 1 cohort Insufficient vs. no GDM NDDG false positive vs. no 1 cohort Insufficient GDM Shoulder Dystocia WHO IGT vs. no GDM 1 cohort Insufficient IADPSG IGT vs. no GDM 1 cohort Insufficient IADPSG IFG vs. no GDM 1 cohort Insufficient IADPSG IGT-2 vs. no GDM 1 cohort Insufficient IADPSG IGT IFG vs. no 1 cohort Insufficient GDM IADPSG IGT vs. IFG 1 cohort Insufficient IADPSG IGT vs. IGT-2 1 cohort Insufficient IADPSG IGT vs. IGT IFG 1 cohort Insufficient IADPSG IFG vs. IGT-2 1 cohort Insufficient IADPSG IFG vs. IGT IFG 1 cohort Insufficient IADPSG IGT-2 vs. IGT IFG 1 cohort Insufficient CC GDM vs. no GDM 3 cohorts Insufficient CC GDM vs. 1 abnormal 1 cohort Insufficient OGTT CC 1 abnormal OGTT vs. no 4 cohorts Insufficient Neonatal GDM Hypoglycemia NDDG GDM vs. no GDM 1 cohort Insufficient NDDG false positive vs. no 1 cohort Insufficient GDM WHO IGT vs. no GDM 3 cohorts Insufficient CC = Carpenter-Coustan; CI = confidence interval; GDM = gestational diabetes mellitus; IFG = impaired fasting glucose; IGT = impaired glucose tolerance; IGT-2 = double impaired glucose tolerance; IADPSG = International Association of Diabetes and Pregnancy Study Groups; NDDG = National Diabetes Data Group; OGTT = oral glucose tolerance test; RR = risk ratio; WHO = World Health Organization Key Question 4 Eleven studies provided data for Key Question 4 to assess the impact of treatment for GDM on health outcomes of mothers and offspring. All studies compared diet modification, glucose monitoring, and insulin as needed with standard care. The strength of evidence for key outcomes is summarized in Table 23. There was moderate evidence showing a significant difference for preeclampsia with fewer cases in the treated group. There was inconsistency across studies in terms of differences in maternal weight gain and the strength of evidence was considered insufficient. There were no data on long-term outcomes among women including type 2 diabetes mellitus, obesity, and hypertension. 102 In terms of infant outcomes, there was insufficient evidence to make a conclusion for birth injury. This was driven by lack of precision in the effect estimates and inconsistency across studies: there was no difference for RCTs but a significant difference favoring treatment in the one cohort study. The incidence of shoulder dystocia was significantly lower in the treated groups, and this finding was consistent for the 3 RCTs and 4 cohort studies. Overall, the evidence for shoulder dystocia was considered moderate showing a difference in favor of the treated group. For neonatal hypoglycemia, the strength of evidence was low suggesting no difference between groups. There was moderate evidence showing significantly lower incidence of macrosomia among the treated groups. Only one study provided data on long-term metabolic outcomes among the offspring at 7 to 11 year followup. The strength of evidence was insufficient to reach a conclusion. For both outcomes―impaired glucose tolerance and type 2 diabetes mellitus―no differences were found between groups although the estimates were imprecise. No differences were observed in single studies that assessed BMI >95 (7-11 year followup) and BMI >85 percentile (5-7 year followup). Overall, pooled results showed no difference in offspring BMI and the strength of evidence was considered low. In summary, there was moderate evidence showing differences in preeclampsia and shoulder dystocia with fewer cases among women (and offspring) who were treated compared with those not receiving treatment. There was also moderate evidence showing significantly fewer cases of macrosomia (>4,000 g) among offspring of women who received treatment for GDM. The results were driven by the two largest RCTs, the Maternal Fetal Medicine Unit (MFMU)54 and the Australian Carbohydrate Intolerance in Pregnancy Study (ACHOIS),50 which had unclear and low risk of bias, respectively. There was little evidence showing differences in other key maternal and infant outcomes between groups. One potential explanation is that for the most part the study populations included women whose glucose intolerance was less marked, as those whose glucose intolerance was more pronounced would not have been entered into a trial where they may be assigned to a group receiving no treatment. For outcomes where results were inconsistent between studies, different study glucose threshold entry criteria did not explain the variation. For some outcomes, particularly the long-term outcomes, the strength of evidence was insufficient or low suggesting that further research may change the results and increase our confidence in the results. Moreover, for some outcomes events were rare and the studies may not have had the power to detect clinically important differences between groups; therefore, findings of no significant difference should not be interpreted as equivalence between groups. 103 Table 23. Summary of strength of evidence for benefits of treatment (Key Question 4) Outcome Number of Studies Strength of Evidence Preeclampsia 3 RCTs, 1 cohort Moderate Maternal weight gain 4 RCTs, 2 cohorts Insufficient Birth injury 2 RCTs, 1 cohort Insufficient Shoulder dystocia 3 RCTs, 4 cohorts Moderate Neonatal hypoglycemia 4 RCTs, 2 cohorts Low Macrosomia (>4,000 g) 5 RCTs, 6 cohorts Moderate 1 RCT Insufficient Maternal outcomes Infant outcomes Long-term metabolic outcomes in offspring Impaired glucose tolerance Type 2 diabetes mellitus Summary Significant difference in favor of treatment for RCTs (RR 0.62, 95% CI 0.43, 0.89). No difference observed for cohort study. Results not pooled for RCTs due to substantial heterogeneity. No difference for cohort studies (MD -1.04, 95% CI -2.89, 0.81). No difference for RCTs (RR 0.48, 95% CI 0.12, 1.90). Significant difference favoring treatment for cohort study (RR 0.02, 95% CI 0.00, 0.22). Significant difference in favor of treatment for RCTs (RR 0.42, 95% CI 0.23, 0.77) and cohort studies (RR 0.38, 95% CI 0.19, 0.78). No difference for RCTs (RR 1.18, 95% CI 0.92, 1.52) or cohort studies (RR 0.55, 95% CI 0.10, 2.97). Significant difference in favor of treatment for RCTs (RR 0.50, 95% CI 0.35, 0.71). Results not pooled for cohort studies due to substantial heterogeneity. No difference between groups (RR 5.63, 95% CI 0.31, 101.32). No difference between groups (RR 1.88, 95% CI 0.08, 44.76). No difference between groups (RR BMI 2 RCTs Low 1.26, 95% CI 0.86, 1.84) BMI = body mass index; CI = confidence interval; MD = mean difference; RCT = randomized controlled trial; RR = risk ratio 1 RCT Insufficient Key Question 5 Five studies provided data for Key Question 5 on the harms associated with treatment of GDM. There was no evidence for some of the outcomes stipulated in the protocol including costs and resource allocation. Four of the studies provided data on the incidence of infants that were small for gestational age and showed no significant difference between groups. This finding may have resulted from inadequate power to detect differences due to a small number of events; therefore, the finding of no significant difference should not be interpreted as equivalence between groups. Four studies provided data on admission to the neonatal intensive care unit (NICU) and showed no significant differences overall. One study was an outlier as it showed significantly fewer NICU admissions in the group receiving no treatment. This difference may be attributable to site-specific policies and procedures. Two studies reported on the number of prenatal visits and generally found significantly more visits among the treatment groups. Two RCTs showed no significant difference overall in the rate of induction of labor, although there was important statistical heterogeneity between studies. One RCT showed significantly more inductions of labor in the treatment group50 while the other study did not.54 Different study protocols may account for the heterogeneity of results between studies. In the 104 first study, that showed more inductions of labor in the treatment group, no recommendations were provided regarding obstetrical care. In the later study, antenatal surveillance was reserved for standard obstetrical indications. Based on the studies included in Key Question 4, there was no difference in Cesarean section between treatment and non treatment GDM (5 RCTs and 6 cohort studies). A single study assessed depression and anxiety at 6 weeks after study entry and 3 months postpartum using the Spielberger State-Trait Anxiety Inventory and the Edinburgh Postnatal Depression Score, respectively. There was no significant difference between groups in anxiety at either time point, although there were significantly lower rates of depression in the treatment group at 3 months postpartum. These results should be interpreted cautiously because the assessment of depression and anxiety was conducted in a subgroup of the larger RCT. Maternal stress in pregnancy has been associated with poor metabolic consequences in offspring.168 Other research found that women with GDM compared with glucose tolerant women had a higher level of anxiety at time of the first assessment; however, before delivery these differences in anxiety scores did not persist.169 Findings in Relationship to What Is Already Known This review provides evidence that treating GDM reduces some poor maternal and neonatal outcomes. The recent randomized trial published in 2009 by the MFMU54 reinforces the findings of the earlier ACHOIS trial which was published in 2005 50 and included in an earlier version of this review.53 Both trials showed that treating GDM to targets of 5.3 or 5.5 mmol/L fasting and 6.7 or 7.0 mmol/L 2 hours post-meal reduced neonatal birthweight, large for gestational age, macrosomia, shoulder dystocia, and preeclampsia without a reduction in neonatal hypoglycemia or hyperbilirubinemia/jaundice requiring phototherapy, or an increase in small for gestational age. In contrast to the ACHOIS trial, MFMU demonstrated a reduced cesarean section rate in the GDM treatment group. The failure of ACHOIS to find a lower cesarean section rate despite reduced neonatal birthweight and macrosomia may have been the result of differing obstetrical practices or the different populations studied (e.g., the inclusion of some women with more marked glucose intolerance in ACHOIS as reflected by the increased prevalence of insulin use; more black and Hispanic women in the MFMU study). Differences may have also resulted due to study design: in ACHOIS, participants did not receive specific recommendations regarding obstetrical care, thus replicating obstetrical care for women with GDM. In the MFMU study, antenatal surveillance was reserved for standard obstetrical indications. Our findings of the effect of treatment of GDM is similar to a systematic review and meta-analysis published in 2010 by Horvath et al.170 that included two older RCTs of GDM that were not included in our analysis because we restricted our inclusion criteria to studies published after 1995. The Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) Study Cooperative Research Group 3 confirmed findings of the earlier Toronto Trihospital study 142 in a large international sample of women with a simpler 75 g OGTT showing a continuous positive association between maternal glucose and increased birthweight, as well as fetal hyperinsulinemia (HAPO only), at levels below diagnostic thresholds for GDM that existed at the time of the study. However, no clear glucose thresholds were found for fetal overgrowth or a variety of other maternal and neonatal outcomes. Subsequently, the IADPSG developed diagnostic thresholds for GDM based on a consensus of expert opinion of what was considered to be the most important outcomes and the degree of acceptable risk for these outcomes. The thresholds chosen by the IADPSG were derived from the HAPO data to identify women with a higher risk (adjusted odds ratio 1.75) of 105 large for gestational age, elevated c-peptide, high neonatal body fat compared with the mean maternal glucose values of the HAPO study. The glucose threshold chosen by the IADPSG represents differing levels of risk for other outcomes. Specifically the IADPSG thresholds represent a 1.4 (1.26-1.56) risk for pregnancy induced hypertension and a 1.3 (1.07,1.58) risk for shoulder dystocia. Neither recent RCT was designed to determine diagnostic thresholds for GDM or therapeutic glucose targets. However, it is noteworthy that therapeutic glucose targets for both ACHOIS and MFMU were above the proposed diagnostic criteria of the IADPSG (fasting 5.5 mmol/L (99 mg/dL) and 5.3 mmol/L (95 mg/dL and 2 hour post-meal of 7.0 mmol/L (126 mg/dL and 6.7 mmol/L 120 mg/dL), respectively). A change in diagnostic criteria without addressing management thresholds could contribute to clinical confusion. If diagnostic thresholds for GDM below the treatment targets of the large RCTs are endorsed, this could ethically obstruct the possibility of future RCTs to compare different treatment targets above such diagnostic thresholds. It has been hypothesized that treatment of GDM may reduce future poor metabolic outcomes for children born to mothers with GDM. If true, the potential for long-term gain is important from a clinical and public health perspective and may justify the “costs” of screening and treating women for GDM. However, the followup of offspring from two RCTs 50,96 and a HAPO cohort in Belfast 171 currently fail to support this hypothesis. This may be explained in part due to insufficient length of followup or inadequate numbers of events. The HAPO study showed that maternal weight and glucose predict large for gestational age. However, body mass index was the better predictor of large for gestational age than glucose until glucose thresholds higher than the diagnostic thresholds set by the IADPSG were reached.172,173 Most cases of large for gestational age occur in neonates of mothers with normal glycemia. A large observational study found that the upper quartile of maternal BMI accounted for 23 percent of macrosomia, while GDM was responsible for only 3.8 percent.174 The ongoing obesity epidemic in the United States warrants careful consideration of a diagnostic approach for GDM that incorporates maternal BMI. This would require the development and validation of a risk model that incorporates maternal BMI as well as other modifiable risk factors. Such a model could facilitate the identification of women at high risk of adverse pregnancy outcomes and minimize exposure of lower risk women to unnecessary interventions. Applicability There are several issues that may limit the applicability of the evidence presented in this review to the U.S. population, and these vary slightly by Key Question. All of the Key Questions asked about the effects of screening and treatment before and after 24 weeks’ gestation. The vast majority of included studies screened women after 24 weeks’ gestation, therefore the results are not applicable to screening and treatment earlier in gestation. For Key Question 1 on the test properties of screening and diagnostic tests, comparisons involving the WHO criteria are less applicable to the U.S. setting as these criteria are not used in North America. There were insufficient data from the included studies to assess the performance of screening or diagnostic tests for specific patient characteristics (e.g., BMI, race/ethnicity). Therefore it is unclear whether the evidence applies to specific subpopulations of women. For Key Question 2, limited evidence was identified because the comparison of interest was women who had not undergone screening. As screening is routine in prenatal care in the United States, the evidence (or limited evidence) is likely not helpful for U.S. decisionmaking and a 106 refinement of this question may be appropriate to reflect current practices and outstanding questions. With respect to Key Question 3, all studies or groups included for analysis involved women who had not received treatment for GDM. It cannot be assumed that the same association and outcomes would be observed in clinical practice where standard care is to screen for and treat GDM. The untreated women may differ from the general population in ways that are related to the reasons for which they did not seek or receive early prenatal care (e.g., socioeconomic status). That is, the reasons that they did not receive treatment for GDM are varied; some reasons such as late presentation for obstetrical care may confound the observed association with health outcomes. Attempts were made to control for these factors in some studies by including a group of women without GDM with similar known confounderse.g.,146 or by adjusting for known confounders in the analysis. The adjusted estimates did not change the overall pooled results in the majority of cases and did not change the overall conclusions. The majority of the studies for Key Questions 4 and 5 pertaining to the benefits and harms of treatment for GDM were conducted in North America or Australia. Most of the North American studies were inclusive of mixed racial populations and are likely applicable to the general U.S. population. Even though the Australian RCT50 population had more white women with a lower BMI than the U.S. RCT (MFMU54), this should not affect applicability of most of their findings because these patient characteristics would be factors associated with lower risk of poor outcomes. Differences in physician or hospital billing structures between the United States and Australia may have accounted for the discrepant findings with respect to NICU admissions and as a result limit the applicability of this finding in the United States. Among the studies included in Key Questions 4 and 5, a variety of glucose threshold criteria were used for inclusion, varying from 50 g screen positive with nondiagnostic oral glucose tolerance tests to women who met National Diabetes Data Group criteria for a diagnosis of GDM. The two large RCTs used different glucose thresholds for entry in their trials: WHO and CC criteria with a fasting glucose <95 mg/dL (5.3 mmol/L), respectively.50,54 The mean glucose levels at study entry were similar between these two RCTs, which may reflect a reluctance to assign women with more marked glucose intolerance to a group receiving no treatment. The results may not be applicable to women with higher levels of glucose intolerance. Limitations of the Evidence Base There is sparse evidence to clarify issues regarding the timing of screening and treatment for GDM (i.e., before and after 24 weeks’ gestation). Earlier screening will help identify overt type 2 diabetes mellitus and distinguish this from GDM. This has important implications for clinical management and ongoing followup beyond pregnancy. Previously unrecognized type 2 diabetes mellitus diagnosed in pregnancy should be excluded from the diagnosis of GDM because this condition has the highest perinatal mortality rate of all classes of glucose intolerance in pregnancy.175 This distinction within research studies will provide more targeted evidence to assist obstetrical care providers to risk stratify obstetrical care and glycemic management of patients with overt type 2 diabetes mellitus diagnosed in pregnancy and those with less pronounced pregnancy-induced glucose intolerance. This will also facilitate better comparability across future studies. There were few data available on long-term outcomes. Furthermore, the studies included in this review do not provide evidence of a direct link between short-term and long-term outcomes (e.g., macrosomia and childhood obesity). 107 Care provider knowledge of the glucose screening and diagnostic results may have introduced a bias if their subsequent treatment of women differed depending on the results. This was of particular concern for Key Question 3. For Key Question 3, which assessed how the various criteria for GDM influenced pregnancy outcomes, many of the statistically significant differences seemed to be driven by the size of the study or pooled analysis, i.e., statistically significant differences could be found if the sample were sufficiently large. However, these differences may not be clinically important. The absolute differences in event rates between different glucose thresholds need careful consideration by decisionmakers even though statistically significant differences were found. Another key limitation with the evidence for Key Question 3 is that the studies included were cohort studies, many of which did not control for potential confounders. Therefore, any associations between glucose thresholds and outcomes should be interpreted with caution. Given that the large landmark studies91,142 show a continuous relationship between glucose and maternal and neonatal outcomes, the lack of clear thresholds contributes to the uncertainty regarding a diagnostic threshold for GDM. While there is controversy about where to set lower limits for diagnostic criteria, the identification of overt diabetes in pregnancy is imperative if this diagnosis has not occurred prior to pregnancy. Overt diabetes first identified in pregnancy should be distinguished from GDM in order to gain a better understanding of the true risk of GDM to pregnancy outcomes. Unfortunately there is no literature to guide diagnostic criteria for a diagnosis of overt diabetes in pregnancy. There were several methodological concerns for this evidence base. For example, risk of spectrum bias and partial verification bias (Key Question 1); different definitions or methods of assessing key outcomes (e.g., clinical vs. biochemical neonatal hypoglycemia and hyperbilirubinemia) (Key Questions 3 and 4); and, lack of blinding of treatment arms in some studies (Key Questions 4 and 5). Future Research Several important gaps in the current literature exist: • The adoption of a consistent comparator for diagnosis of GDM, such as the 75 g OGTT, would facilitate comparisons across studies even if different diagnostic thresholds are used. • Further analysis of the HAPO data could help answer some outstanding questions. For example, further analysis could better define absolute differences in rare event rates. This evidence could be used to inform discussions about the clinical importance of absolute differences in event rates at thresholds other than those of the IADPSG. Such analyses should include adjustment for important confounders such as maternal BMI. • Further analysis of the HAPO data examining center to center differences in glucose outcome relationships would be helpful in determining the usefulness of FPG as a screening test for GDM. • Research is needed to clarify issues regarding earlier screening and treatment, particularly as they relate to the diagnosis, treatment, and long-term outcomes of pregestational (overt) diabetes. • FPG is a screening test that requires further research, given that the reproducibility of fasting glucose measurement is superior to post glucose load measurements.165 • Further study of the long-term metabolic impact on offspring whose mothers have been treated for GDM is warranted. In addition, data on the influences of GDM treatment on 108 • • • • • • • • long-term breastfeeding success have not been studied. The association of breastfeeding with reduced poor metabolic outcomes in offspring of GDM has been found to have a dose dependent response with duration of breastfeeding.176 Well-conducted prospective cohort studies of the “real world” impact of GDM treatment on care utilization are needed. Research is needed to help determine the glucose thresholds and treatment targets at which GDM treatment benefits outweigh the risks of treatment and no treatment. This will best be achieved through well-conducted, large RCTs that randomize women with GDM to different glucose treatment targets. While this review did not identify evidence of substantial harms to treatment, the populations considered were mostly women whose GDM was controlled without medication. There is a risk for more precautionary management of women diagnosed with GDM who are perceived by clinicians to be at greater risk, such as those managed with insulin, which may result in unnecessary interventions (e.g., cesarean section).177 Therefore, RCTs investigating the care of women diagnosed with GDM, including fetal surveillance protocols, are needed to guide obstetrical investigations and management of GDM. Further, RCTs comparing delivery management for GDM with and without insulin or medical management are needed to provide clinicians guidance on appropriate timing and management of delivery in women with GDM to avoid unnecessary intervention in “the real world” driven by health care provider apprehension. Long-term studies that evaluate the potential increased or decreased resource utilization associated with the implementation of diabetes prevention strategies after a diagnosis of GDM are required. Studies to assess the long-term impact that a label of GDM may have for future pregnancy planning, future pregnancy management, and future insurability are required. The increased prevalence of type 2 diabetes mellitus in women of reproductive age merits consideration of preconception screening for overt diabetes in women at risk of type 2 diabetes. In addition to poor maternal and neonatal outcomes associated with overt diabetes in pregnancy, there is potential for benefit of preconception care. Long-term benefits and harms need to be evaluated among different treatment modalities for GDM (e.g., diet, exercise, insulin, oral glucose lowering medications, and/or combinations of these). Since 2011-2012 the ADA has endorsed the use of an HbA1c of 6.5 percent or more as diagnostic of diabetes in nonpregnant women.36 Studies of HbA1c with trimester-specific cutoffs to determine the value at which overt diabetes should be diagnosed in pregnancy are needed. Limitations of the Review This review followed rigorous methodological standards which were detailed a priori. The limitations of the review to fully answer the Key Questions are largely due to the nature and limitations of the existing evidence. There are several limitations that need to be discussed regarding systematic reviews in general. First, there is a possibility of publication bias. The impact of publication bias on the results of diagnostic test accuracy reviews (Key Question 1) is not well understood nor have the tools to investigate publication bias in these reviews been developed. For the remaining Key Questions we may be missing unpublished and/or negative therapy studies, and may be 109 overestimating the benefits of certain approaches. However, we conducted a comprehensive and systematic search of the published literature for potentially relevant studies. Search strategies included combinations of subject headings and free text words. These searches were supplemented by handsearching for gray literature (i.e., unpublished or difficult to find studies). Despite these efforts, we recognize that we may have missed some studies. There is also a possibility of study selection bias. However, we employed at least two independent reviewers and feel confident that the studies that were excluded from this report were done so for consistent and appropriate reasons. Our search was comprehensive, so it is unlikely that there are many studies in press or publication that were missed. Cost analysis of different screening and diagnostic approaches was not addressed in this review. Conclusions There was limited evidence regarding the test characteristics of current screening and diagnostic strategies for GDM. Lack of an agreed upon gold standard for diagnosis of GDM creates challenges for assessing the accuracy of tests and comparing across studies. The 50 g OGCT with a glucose threshold of 130 mg/dL versus 140 mg/dL improves sensitivity and reduces specificity (10 studies). Both thresholds have high NPV, but variable PPV across a range of GDM prevalence. There was limited evidence for the screening of GDM diagnosed less than 24 weeks’ gestation (3 studies). Single studies compared the diagnostic characteristics of different pairs of diagnostic criteria in the same population. The use of fasting glucose (≥85 mg/dL) as a screen for GDM may be a practical alternative because of similar test characteristics to the OGCT particularly in women who cannot tolerate any form of oral glucose load. Evidence supports benefits of treating GDM with little evidence of short-term harm. Specifically, treatment of GDM results in lower incidence of preeclampsia, macrosomia, and large for gestational age infants. Current research does not demonstrate a treatment effect of GDM on clinical neonatal hypoglycemia or future poor metabolic outcomes of the offspring. RCTs of GDM treatment show limited harm related to treating GDM, other than an increased demand for services. There is a risk for more precautionary management of women diagnosed with GDM who are perceived by clinicians to be at greater risk, such as those managed with insulin, which may result in unnecessary interventions (e.g., cesarean section); however, this review found limited data for these outcomes and further research on the care of women diagnosed with GDM (e.g., fetal surveillance protocols) is warranted. What remains less clear is what the lower limit diagnostic thresholds for GDM should be. Given the continuous association between glucose and a variety of outcomes, decisions should be made in light of what outcomes that are altered by treatment are most important and what level of increased risk is acceptable. A dichotomous view of GDM may no longer be appropriate, given evidence of a continuous relationship between maternal blood glucose and pregnancy outcomes. An alternative approach would be to define different glucose thresholds based on maternal risk for poor pregnancy outcomes. Further study is needed regarding the long-term metabolic impact on offspring of mothers receiving GDM treatment; the “real world” impact of GDM treatment on care utilization outside of structured research trials; and, the impact of the timing of screening for GDM, particularly before 24 weeks’ gestation and in the first trimester of pregnancy. Early screening could help identify pregestational (i.e., overt) diabetes. Research is urgently required to determine the best 110 way to diagnose and manage overt diabetes in pregnancy, particularly in an era of increasing rates of obesity and diabetes in the U.S. population. 111 Table 24. Summary of Evidence for all Key Questions Key Question Number and Quality of Studies Limitations/ Consistency Applicability • • KQ1. What are the sensitivities, specificities, reliabilities, and yields of current screening tests for GDM? (A) After 24 weeks’ gestation? (B) During the first trimester and up to 24 weeks’ gestation? A) After 24 wk gestation 51 prospective studies Fair to good quality Limitations: Lack of an agreed upon gold standard for diagnosis of GDM creates challenges for assessing the accuracy of tests and comparing across studies. GDM was confirmed using criteria developed by CC, ADA, NDDG, and WHO. There were sparse data comparing overall approaches for diagnosis and screening, e.g., one-step vs. two-step, selective vs. universal. Consistency: Across studies, numerous tests and thresholds were examined. Screening tests included the 50 g OGCT, FPG risk factorbased screening, and other less common tests such as HbA1c, serum fructosamine. • Prevalence of GDM varied across studies and diagnostic criteria used. Results need to be interpreted in the context of prevalence. Comparisons involving WHO criteria are less applicable to the North American setting because these criteria are not used in North America. • • • • 112 Summary of Findings Prevalence varied across studies and diagnostic criteria: ADA 2000-2010 (75 g) 2.0 to 19% (range), CC 3.6 to 38%, NDDG 1.4 to 50%, WHO 2 to 24.5%. 9 studies examined a 50 g OGCT with a cutoff value of ≥140 mg/dL; GDM was confirmed using CC criteria. Results: sensitivity 85%, specificity 86%, prevalence 3.8 to 31.9%, PPV 18 to 27% (prevalence <10), PPV 32 to 83% (prevalence ≥10), NPV median 98%. 6 studies examined a 50 g OGCT (≥130 mg/dL); GDM was confirmed using CC criteria. Results: sensitivity 99%, specificity 77%, prevalence 4.3 to 29.5%, PPV 11 to 31% (prevalence <10), PPV 31 to 62% (prevalence ≥10), NPV median 100%. 1 study examined a 50 g OGCT (≥200 mg/dL); GDM was confirmed using CC criteria. Sensitivity, specificity, PPV, and NPV were all 100%. Prevalence was 6.4%. 7 studies examined a 50 g OGCT (≥140 mg/dL); GDM was confirmed using NDDG criteria. Results: sensitivity 85%, specificity 83%, prevalence 1.4 to 45.8%, PPV 12 to 39% (prevalence <10), PPV 57% (prevalence ≥10), NPV median 99%. 3 studies examined a 50 g OGCT (≥130 mg/dL); GDM was confirmed using NDDG criteria. Results: sensitivity 67 to 90% (range), specificity 47 to 84%, prevalence 16.7 to 35.3%, PPV 20 to 75%, NPV 86 to 95%. 3 studies examined a 50 g OGCT (different thresholds); GDM was confirmed using ADA 2000-2010 (75 g) criteria. Prevalence was 1.6 to 4.1 (range). Results: sensitivity 86 to 97% (range), specificity 79 to 87%, PPV 7 to 20%, NPV 99 to 100%. Table 24. Summary of Evidence for all Key Questions (continued) Key Question Number and Quality of Studies Limitations/ Consistency Applicability • • KQ1. What are the sensitivities, specificities, reliabilities, and yields of current screening tests for GDM? (A) After 24 weeks’ gestation? (B) During the first trimester and up to 24 weeks’ gestation? A) After 24 wk gestation 51 prospective studies Fair to good quality • (continued) • (continued) • 113 Summary of Findings 3 studies examined a 50 g OGCT (≥140 mg/dL); GDM was confirmed using WHO criteria. Results: sensitivity 43 to 85%, specificity 73 to 94%, prevalence 3.7 to 15.7%, PPV 18 to 20% (prevalence <10), PPV 58% (prevalence ≥10), NPV median 99%. 7 studies examined FPG at different thresholds; GDM was confirmed using CC criteria. Results: at ≥85 mg/dL sensitivity 87%, specificity 52%; at ≥90 mg/dL sensitivity 77%, specificity 76%; at ≥92 mg/dL sensitivity 76%, specificity 92%; at ≥95 mg/dL sensitivity 54%, specificity 93%. At ≥85 mg/dL prevalence 1.4 to 34.53 (range). PPV 10% (prevalence <10) and 23 to 59% (prevalence ≥10). Median NPV 93%. 8 studies examined risk factor-based screening but were not pooled. Studies used different criteria to confirm GDM. Results: sensitivity 48 to 95% (range), specificity 22 to 94%, prevalence 1.7 to 16.9%, PPV 5 to 19% (prevalence <10), PPV 20% (prevalence ≥10), NPV median 99%. 1 study compared IADPSG vs. ADIPS 2 step (reference) to diagnose GDM. Results: sensitivity 82%, specificity 94%, prevalence 13.0%, PPV 61%, NPV 98%. 4 studies compared 75 g and 100 g load tests to diagnose GDM. Prevalence ranged from 1.4 to 50%. Results were not pooled: sensitivity 18 to 100%, specificity 86 to 100%, PPV 12 to 100%, NPV 62 to 100%. Table 24. Summary of Evidence for all Key Questions (continued) Key Question KQ1. What are the sensitivities, specificities, reliabilities, and yields of current screening tests for GDM? (A) After 24 weeks’ gestation? (B) During the first trimester and up to 24 weeks’ gestation? Number and Quality of Studies (B) During the first trimester and up to 24 wk gestation 3 prospective cohort studies Limitations/ Consistency Limitations: Only 3 studies of women before 24 wks gestation; therefore, no conclusions can be made for test characteristics in early pregnancy. Applicability • • Evidence too limited to judge applicability. • Consistency: Not applicable (not enough studies addressing the same question to judge consistency). (continued) KQ2: What is the direct evidence on the benefits and harms of screening women (before and after 24 weeks’ gestation) for GDM to reduce maternal, fetal, and infant morbidity and mortality? Limitations: No RCTs available to answer this question. 2 retrospective cohort studies Fair and good quality Consistency: Not applicable (not enough studies addressing the same question to judge consistency). The comparison for this question was women who had and had not undergone screening. Since screening is now commonplace it may be unlikely to identify studies or cohorts where this comparison is feasible. 114 • • Summary of Findings 1 study examined the 50 g OGCT at 10 wks and confirmed GDM using JSOG criteria (75 g). Results: sensitivity 88%, specificity 79%, prevalence 1.6%, PPV 7%, NPV 100%. 1 study examined 50 g OGCT at 20 wks and confirmed GDM using ADA (2000-2010) 100 g criteria. Results: sensitivity 56%, specificity 94%, prevalence 3.6%, PPV 24%, NPV 98%. st nd 1 study compared 1 and 2 trimester results using 3 screening tests (OGCT at ≥130 mg/dL, FPG, HbA1c); GDM confirmed using JSOG st criteria. Results (OGCT) 1 trimester: prevalence 1.9%, sensitivity 93%, specificity 77%, PPV 7.1, nd NPV 99%; 2 trimester: prevalence 2.9%, sensitivity 100%, specificity 85%, PPV 17%, NPV 100%. 1 study (n=1,000) showed more cesarean deliveries in the screened group. A second study (n=93) found the incidence of macrosomia ( ≥4.3 kg) was the same in screened and unscreened groups (7% each group). Based on the small number of studies and sample sizes, the effect of screening women for GDM on health outcomes is inconclusive. Table 24. Summary of Evidence for all Key Questions (continued) Key Question Number and Quality of Studies Limitations/ Consistency Applicability Summary of Findings • Maternal outcomes: KQ3: In the absence of treatment, how do health outcomes of mothers who meet various criteria for GDM and their offspring compare to those who do not meet the various criteria? 38 prospective or retrospective cohort studies; 2 studies were long-term followup from RCTs; however, only data from the untreated patients were included. Fair to good quality Limitations: Strength of evidence was low to insufficient for all graded outcomes due to risk of bias (all observational studies), inconsistency, and/or imprecision. For many comparisons, the numbers of studies, participants, and/or events was low; therefore, findings of no statistically significant differences between groups do not imply equivalence or rule out potential differences. Consistency: A wide variety of diagnostic criteria and thresholds were compared across studies. There were often few studies with similar comparison groups. Differences in defining and assessing outcomes may have contributed to heterogeneity in results across studies (e.g., biochemical vs. clinical assessment of neonatal hypoglycemia). • All studies or groups included for analysis involved women who had not received treatment for GDM. These women may differ from the general population in other ways that are related to the reasons that they did not seek or receive early prenatal care (e.g., socioeconomic status). • • 115 A methodologically strong study showed a continuous positive relationship between increasing glucose levels and the incidence of primary cesarean section. This study also found significantly fewer cases of preeclampsia and cesarean section for women with no GDM vs. IADPSG. For preeclampsia, significant differences were found for CC vs. patients with no GDM (3 studies), with fewer cases among the patients with no GDM, and for CC vs. false-positive groups (2 studies), with fewer cases among the false positives. The strength of evidence was low. No differences were found for NDDG false positive (2 studies), NDDG 1 abnormal OGTT vs. no GDM (1 study), or IGT WHO vs. no GDM (3 studies); the strength of evidence was insufficient. For maternal weight gain, significant differences were found for 3 of 12 comparisons: IADPSG IGT vs. no GDM (favored IGT), IADPSG IFG vs. no GDM (favored IFG), IADPSG IGT-2 vs. no GDM (favored IGT-2). All comparisons were based on single studies (strength of evidence insufficient). Fetal/neonatal/child outcomes: 2 methodologically strong studies showed a continuous positive relationship between increasing glucose levels and the incidence of macrosomia. 1 of these studies also showed significantly fewer cases of shoulder dystocia and/or birth injury, clinical neonatal hypoglycemia, and hyperbilirubinemia for women with no GDM vs. IADPSG. Table 24. Summary of Evidence for all Key Questions (continued) Key Question Number and Quality of Studies Limitations/ Consistency Applicability KQ3: In the absence of treatment, how do health outcomes of mothers who meet various criteria for GDM and their offspring compare to those who do not meet the various criteria? • • (continued) 116 Summary of Findings For macrosomia >4,000 g, 6 of 11 comparisons showed a significant difference: patient groups with no GDM had fewer cases compared with CC GDM (10 studies), CC 1 abnormal OGTT (7 studies), NDDG GDM (unrecognized) (1 study), NDDG false positives (4 studies), and WHO IGT (1 study). Fewer cases were found for women with false-positive results compared with CC GDM (5 studies). Data for macrosomia >4,500 g were available for 4 comparisons and showed significant differences in 2 cases: patient groups with no GDM had fewer cases compared with CC GDM (3 studies) and unrecognized NDDG GDM (1 study). The strength of evidence for macrosomia was low to insufficient. For shoulder dystocia, significant differences were found for 7 of 17 comparisons; all comparisons but 1 were based on single studies (insufficient strength of evidence). Patient groups with no GDM showed lower incidence of shoulder dystocia when compared with CC GDM (5 studies, low strength of evidence), NDDG GDM (unrecognized), NDDG false positive, WHO IGT, IADPSG IFG, and IADPSG IGT IFG. The other significant difference showed lower incidence among the false-positive group compared with CC 1 abnormal OGTT. Table 24. Summary of Evidence for all Key Questions (continued) Key Question Number and Quality of Studies Limitations/ Consistency Applicability KQ3: In the absence of treatment, how do health outcomes of mothers who meet various criteria for GDM and their offspring compare to those who do not meet the various criteria? (continued) KQ4: Does treatment modify the health outcomes of mothers who meet various criteria for GDM and offspring? 5 RCTs and 6 retrospective cohort studies. Poor to good quality Limitations: For some outcomes, particularly the long-term outcomes, the strength of evidence was insufficient or low. Moreover, for some outcomes events were rare and the studies may not have had the power to detect clinically important differences between groups; therefore, findings of no significant difference should not be interpreted as equivalence between groups. For the most part, study populations included women whose glucose intolerance was less marked, as those whose glucose intolerance was more pronounced would not be entered into a trial in which they may be assigned to a group receiving no treatment. The majority of studies were conducted in North America or Australia, with 2 from Italy. Most of the North American studies were inclusive of mixed racial populations and are likely applicable to the general U.S. population. Even though the Australian RCT population had more white women with a lower 117 • Summary of Findings For fetal birth trauma/injury, single studies compared CC GDM and WHO IGT with no GDM and showed no differences. Two studies showed fewer cases for no GDM compared with NDDG GDM. Strength of evidence was insufficient for all comparisons. • No differences were found for neonatal hypoglycemia for any comparison, including CC GDM vs. no GDM (3 studies), CC GDM vs. 1 abnormal OGTT (1 study), CC 1 abnormal OGTT vs. no GDM (4 studies), NDDG GDM vs. no GDM (1 study), NDDG false positive vs. no GDM (1 study), and WHO IGT vs. no GDM (3 studies). Strength of evidence was insufficient for all comparisons. Maternal outcomes: • • Moderate evidence from 3 RCTs showed a significant difference for preeclampsia, with fewer cases in the treated group. There was inconsistency across studies in terms of maternal weight gain (4 RCTs and 2 cohort studies); the strength of evidence was insufficient due to inconsistency and imprecision in effect estimates. Offspring outcomes: • • There was insufficient evidence to make a conclusion for birth injury. There was inconsistency across studies with the 2 RCTs showing no difference and the 1 cohort study showing a difference in favor of the treated group. The low number of events and participants across all studies resulted in imprecise estimates. Moderate evidence showed significantly lower incidence of shoulder dystocia in the treated groups, and this finding was consistent for the 3 RCTs and 4 cohort studies. Table 24. Summary of Evidence for all Key Questions (continued) Key Questions Number and Quality of Studies KQ4: Does treatment modify the health outcomes of mothers who meet various criteria for GDM and offspring? (continued) KQ5: What are the harms of treating GDM and do they vary by diagnostic approach? 4 RCTs and 1 retrospective cohort study. Fair to good quality Limitations/ Consistency Consistency: Some inconsistency occurred at 2 levels. First, there were inconsistencies for some outcomes between RCTs and observational studies which may be attributable to confounding and methods of selecting study groups (e.g.,historical control groups). Second, in some instances there were inconsistencies across studies within designs that were often attributable to the manner in which outcomes were defined or assessed (e.g., clinical vs. biochemical assessment of neonatal hypoglycemia). Limitations: No study evaluated costs and resource allocation. Limited evidence on harms. Limited evidence for number of prenatal visits and NICU admissions. Findings of no significant differences may be attributable to low power and should not be interpreted as equivalence. Consistency: Not applicable (not enough studies addressing the same question to judge). Applicability BMI than the U.S. RCT; this should not affect applicability of most of their findings for the U.S. women because these subject characteristics would be factors associated with lower risk of poor outcomes. Summary of Findings • • • • • As above for KQ4. In addition, differences in billing structures between the United States and Australia may have accounted for the discrepant findings with respect to NICU admissions between these studies and as a result limit the applicability of this finding in the United States. 118 • • There was low evidence of no difference between groups for neonatal hypoglycemia based on 4 RCTs and 2 cohort studies. For outcomes related to birthweight (including macrosomia >4,000 g, macrosomia >4,500 g, actual birthweight, and large for gestational age), differences were often observed favoring the treated groups. Strength of evidence was moderate for macrosomia >4,000 g. 1 RCT followed patients for 7 to 11 years and found no differences for impaired glucose tolerance or type 2 DM, although the strength of evidence was considered insufficient. No differences were observed in single studies that assessed BMI >95 (7-11 year followup) and BMI >85 percentile (5-7 year followup). Overall, pooled results showed no difference in BMI, and the strength of evidence was considered low 1 RCT assessed depression and anxiety at 6 weeks after study entry and 3 months postpartum. There was no significant difference between groups in anxiety at either time point, although there were significantly lower rates of depression in the treatment group at 3 months postpartum. 4 RCTs reported small for gestational age and found no significant difference. 3 RCTs and 1 cohort study provided data on admission to NICU and showed no significant differences overall. One trial was an outlier because it showed a significant difference favoring the no treatment group. This difference may be attributable to site-specific policies and procedures. Table 24. Summary of Evidence for all Key Questions (continued) Key Questions Number and Quality of Studies Limitations/ Consistency Applicability • Summary of Findings 2 RCTs reported on the number of prenatal visits and generally found more visits among the treatment groups. KQ5: What are the harms of treating • 2 RCTs reporting on induction of labor showed GDM and do they different results, with 1 showing a significant vary by diagnostic difference with more cases in the treatment approach? group and the other showing no difference. • Based on studies included in KQ4, no (continued) differences between groups were found for cesarean section (5 RCTs, 6 cohorts) or unplanned cesarean section (1 RCT, 1 cohort). ADA = American Diabetes Association; ADIPS = Australasian Diabetes in Pregnancy Society; BMI = body mass index; CC = Carpenter-Coustan; DM = diabetes mellitus; FPG = fasting plasma glucose; GDM = gestational diabetes mellitus; HbA1c = glycated hemoglobin; IADPSG = International Association of Diabetes in Pregnancy Study Groups; IFG = impaired fasting glucose; IGT = impaired glucose tolerance; IGT-2 = double impaired glucose intolerance; JSOG = Japan Society of Obstetrics and Gynecology; KQ = Key Question; NDDG = National Diabetes Data Group; NPV = negative predictive value; NICU = neonatal intensive care unit; OGCT = oral glucose challenge test; OGTT = oral glucose tolerance test; PPV = positive predictive value; RCT = randomized controlled trial; wk(s) = week(s); WHO = World Health Organization 119 References 1. Balsells M, Garcia-Patterson A, Gich I, et al. Maternal and fetal outcome in women with type 2 versus type 1 diabetes mellitus: a systematic review and metaanalysis. J Clin Endocrinol Metab. 2009;94(11):4284-91. PMID: 19808847. 2. National Diabetes Data Group. Diabetes in America, 2nd ed. Bethesda, MD: National Institutes of Health; 1995. 3. HAPO Study Cooperative Research Group, Metzger B, Lowe L, et al. Hyperglycemia and Adverse Pregnancy Outcomes. N Engl J Med. 2008;358(19):1991-2002. PMID: 18463375. 4. 5. 6. American Diabetes Association. Position statement: standards of medical care in diabetes - 2012. Diabetes Care. 2012;35(Suppl 1):S11-S63. PMID: 22187469. Carpenter MW, Coustan DR. Criteria for screening tests for gestational diabetes. Am J Obstet Gynecol. 1982;144(7):768-73. PMID: 7148898. Sacks DA, Hadden DR, Maresh M, et al. Frequency of gestational diabetes mellitus at collaborating centers based on IADPSG consensus panel-recommended criteria: the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. Diabetes Care. 2012;35(3):526-8. PMID: 22355019. 7. Ferrara A. Increasing prevalence of gestational diabetes mellitus: a public health perspective. Diabetes Care. 2007;30 Suppl 2:S141-S146. PMID: 17596462. 8. Mokdad AH, Ford ES, Bowman BA, et al. Prevalence of obesity, diabetes, and obesityrelated health risk factors, 2001. JAMA. 2003;289(1):76-9. PMID: 12503980. 9. Gillman MW, Oakey H, Baghurst PA, et al. Effect of treatment of gestational diabetes mellitus on obesity in the next generation. Diabetes Care. 2010;33(5):964-8. PMID: 20150300. 10. Kaufmann RC, Schleyhahn FT, Huffman DG, et al. Gestational diabetes diagnostic criteria: long-term maternal follow-up. Am J Obstet Gynecol. 1995;172(2 Pt 1):621-5. PMID: 7856695. 120 11. Mokdad AH, Ford ES, Bowman BA, et al. Diabetes trends in the U.S.: 1990-1998. Diabetes Care. 2000;23(9):1278-83. PMID: 10977060. 12. Mokdad AH, Serdula MK, Dietz WH, et al. The spread of the obesity epidemic in the United States, 1991-1998. JAMA. 1999;282(16):1519-22. PMID: 10546690. 13. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2006;29(Suppl 1):S43-S48. PMID: 16373932. 14. Berger H, Crane J, Farine D, et al. Screening for gestational diabetes mellitus. J Obstet Gynaecol Can. 2002;24(11):894-912. PMID: 12417905. 15. Naylor CD, Sermer M, Chen E, et al. Selective screening for gestational diabetes mellitus. Toronto Trihospital Gestational Diabetes Project Investigators. N Engl J Med. 1997;337(22):1591-6. PMID: 9371855. 16. Hillier T, Vesco K, Pedula K, et al. Screening for gestational diabetes mellitus: A systematic review for the U.S. preventive services task force. Ann Intern Med. 2008;148:766-75. PMID: 18490689 17. American College of Obstetricians and Gynecologists Committee on Practice Bulletins. ACOG Practice Bulletin. Clinical management guidelines for obstetriciangynecologists. Number 30, September 2001. Gestational Diabetes. Obstet Gynecol. 2001;98(3):525-38. PMID: 11547793. 18. Meltzer SJ, Snyder J, Penrod JR, et al. Gestational diabetes mellitus screening and diagnosis: a prospective randomised controlled trial comparing costs of one-step and two-step methods. BJOG. 2010;117(4):407-15. PMID: 20105163. 19. Gabbe S, Gregory R, Power M, et al. Management of diabetes mellitus by obstetrician-gynecologists. Obstet Gynecol. 2004;103(6):1229-34. PMID: 15172857. 20. American Diabetes Association. Position Statement: Diabetes mellitus. Diabetes Care. 2004;27(Suppl 1):S11-S14. PMID: 14693922. 21. Moses RG, Cheung NW. Point: Universal screening for gestational diabetes mellitus. Diabetes Care. 2009;32(7):1349-51. PMID: 19564479. 32. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2005;28(Suppl 1):S37-S42. PMID: 15618111. 22. Danilenko-Dixon DR, Van Winter JT, Nelson RL, et al. Universal versus selective gestational diabetes screening: application of 1997 American Diabetes Association recommendations. Am J Obstet Gynecol. 1999;181(4):798-802. PMID: 10521732. 33. American Diabetes Association. Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 2007;30(Suppl 1):S42-S7. PMID: 17192378. 34. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2008;31:S55-S60. PMID: 18165338. 35. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2009;32:S62-S67. PMID: 19118289. 36. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2010;33:S62-S69. PMID: 20042775. 37. International association of diabetes and pregnancy study groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care. 2010;33(3):676-82. PMID: 20190296. 38. Jovanovic L. American Diabetes Association's Fourth International Workshop-Conference on Gestational Diabetes Mellitus: summary and discussion. Therapeutic interventions. Diabetes Care. 1998;21 Suppl 2:B131-B137. PMID: 9704240. 39. Metzger BE, Oats JN, Kjos SL, et al. Summary and Recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care. 2007;30(Suppl 2):s251-s260. PMID: 17596481. 40. Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. National Diabetes Data Group. Diabetes. 1979;28(12):1039-57. PMID: 510803. 41. World Health Organization. Definition, diagnosis and classification of diabetes mellitus and its complications. Report of a WHO Consultation. Part 1: Diagnosis and classification of diabetes mellitus. 1999. 42. World Health Organization. Report of a WHO study Group (Technical Report Series No.727). Report of a WHO study Group (Technical Report Series No.727). 1985. 23. 24. 25. Berger H, Sermer M. Counterpoint: Selective screening for gestational diabetes mellitus. Diabetes Care. 2009;32(7):1352-4. PMID: 19564480. Metzger B, Gabbe S, Persson B, et al. International association of diabetes and pregnancy study groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care. 2010;33(3):676-82. PMID: 20190296. Lipscombe LL, Hux JE. Trends in diabetes prevalence, incidence, and mortality in Ontario, Canada 1995-2005: a populationbased study. Lancet. 2007;369(9563):750-6. PMID: 17336651. 26. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 1999;22(Suppl 1):S5-S19. 27. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 2000;23(Suppl 1):S4-S19. PMID: 12017675. 28. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care. 2001;24(Suppl.1):S5-S20. 29. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 2002;25:S5. 30. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 2003;26:S5-20. PMID: 12502614. 31. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2004;27(Suppl 1):S5-S10. PMID: 14693921. 121 43. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Canadian Diabetes Association 2003 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes. 2003;27(suppl 2), S1-S152. 44. Canadian Diabetes Association 2008 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada [corrected] [published erratum appears in CAN J DIABETES 2009 Mar;33(1):46]. Canadian Journal of Diabetes. 2008;32:iv. 45. 46. Sempowski IP, Houlden RL. Managing diabetes during pregnancy. Guide for family physicians. Canadian Family Physician Médecin De Famille Canadien. 2003;49:761-7. PMID: 12836864. Metzger BE. Summary and recommendations of the Third International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes. 1991;40 Suppl 2:197-201. PMID: 1748259. 47. Hoffman L, Nolan C, Wilson JD, et al. Gestational diabetes mellitus--management guidelines. The Australasian Diabetes in Pregnancy Society. The Medical Journal Of Australia. 1998;169(2):93-7. PMID: 9700346. 48. Brown CJ, Dawson A, Dodds R, et al. Report of the Pregnancy and Neonatal Care Group. Diabetic Medicine: A Journal Of The British Diabetic Association. 1996;13(9 Suppl 4):S43-S53. PMID: 8894455. 49. 50. 51. American Diabetes Association. Position statement: Gestational diabetes mellitus. Diabetes Care. 2003;26(Suppl 1):S103S105. PMID: 12502631. Crowther CA, Hiller JE, Moss JR, et al. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med. 2005;352(24):2477-86. PMID: 15951574. Langer O, Levy J, Brustman L, et al. Glycemic control in gestational diabetes mellitus--how tight is tight enough: small for gestational age versus large for gestational age? Am J Obstet Gynecol. 1989;161(3):646-53. PMID: 2782347. 122 52. Cheung NW, Oats JJ, McIntyre HD. Australian carbohydrate intolerance study in pregnant women: implications for the management of gestational diabetes. Aust N Z J Obstet Gynaecol. 2005;45(6):484-5. PMID: 16401212. 53. U.S.Preventive Services Task Force. Screening for gestational diabetes mellitus: recommendations and rationale. Obstet Gynecol. 2003;101(2):393-395. PMID: 12576265. 54. Landon MB, Spong CY, Thom E, et al. A multicenter, randomized trial of treatment for mild gestational diabetes. N Engl J Med. 2009;361(14):1339-48. PMID: 19797280. 55. Whiting PF, Rutjes AW, Westwood ME, et al. QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med. 2011;155(8):52936. PMID: 22007046. 56. Rutter C, Gastonis C. A hierarchical regression approach to meta-analysis of diagnostic test accuracy evaluations. Stat Med. 2001;20:2865-84. PMID: 11568945. 57. Reitsma JB, Glas AS, Rutjes AW, et al. Bivariate analysis of sensitivity and specificity produces informative summary measures in diagnostic reviews. J Clin Epidemiol. 2005;58(10):982-90. PMID: 16168343. 58. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177-88. PMID: 3802833. 59. Borenstein M, Hedges L, Higgins J, et al. Introduction to meta-analysis. West Sussex, UK: John Wiley & Sons; 2009. 60. Begg C, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50:1088101. PMID: 7786990. 61. Egger M, Smith G, Schneider M, et al. Bias in meta-analysis detected by a single graphical test. Br Med J. 1997;315(629):634. PMID: 9310563. 62. van LM, Zweers EJ, Opmeer BC, et al. Comparison of accuracy measures of two screening tests for gestational diabetes mellitus. Diabetes Care. 2007;30(11):277984. PMID: 17698616. 63. Ayach W, Costa RA, Calderon IM, et al. Comparison between 100-g glucose tolerance test and two other screening tests for gestational diabetes: combined fasting glucose with risk factors and 50-g glucose tolerance test. Rev Paul Med. 2006;124(1):4-9. PMID: 16612455. 64. Yogev Y, Langer O, Xenakis EM, et al. Glucose screening in Mexican-American women. Obstet Gynecol. 2004;103(6):12415. PMID: 15172859. 65. 66. 67. 68. 69. 70. 71. 72. Espinosa De Los MA, Parra A, Hidalgo R, et al. The after breakfast 50-g, 1-hour glucose challenge test in urban Mexican pregnant women: Its sensitivity and specificity evaluated by three diagnostic criteria for gestational diabetes mellitus. Acta Obstet Gynecol Scand. 1999;78(4):294-8. PMID: 10203295. 73. Deerochanawong C, Putiyanun C, Wongsuryrat M, et al. Comparison of National Diabetes Data Group and World Health Organization criteria for detecting gestational diabetes mellitus. Diabetologia. 1996;39(9):1070-3. PMID: 8877291. 74. Perea-Carrasco R, Perez-Coronel R, busacAguilar R, et al. A simple index for detection of gestational diabetes mellitus. J R Soc Med. 2002;95(9):435-9. PMID: 12205206. Uncu G, Ozan H, Cengiz C. The comparison of 50 grams glucose challenge test, HbA(1c) and fructosamine levels in diagnosis of gestational diabetes mellitus. Clin Exp Obstet Gynecol. 1995;22(3):230-4. PMID: 7554262. 75. Ardawi MS, Nasrat HA, Jamal HS, et al. Screening for gestational diabetes mellitus in pregnant females. Saudi Med J. 2000;21(2):155-60. PMID: 11533772. Kashi Z, Borzouei SH, Akha O, et al. Diagnostic value of fasting plasma glucose in screening of gestational diabetes mellitus. Int J Endocrinol Metab. 2007;5(1):1-4. 76. Gandevani SB, Garshasbi A, Dibaj S. Cutoff value of 1-h, 50-g glucose challenge test for screening of gestational diabetes mellitus in an Iranian population. J Obstet Gynaecol Res. 2011;37(6):534-7. PMID: 21375670. 77. Soheilykhah S, Rashidi M, Mojibian M, et al. An appropriate test for diagnosis of gestational diabetes mellitus. Gynecol Endocrinol. 2011;27(10):785-8. PMID: 21250875. 78. Black MH, Sacks DA, Xiang AH, et al. Clinical outcomes of pregnancies complicated by mild gestational diabetes mellitus differ by combinations of abnormal oral glucose tolerance test values. Diabetes Care. 2010;33(12):2524-30. PMID: 20843973. 79. Morikawa M, Yamada T, Yamada T, et al. Change in the number of patients after the adoption of IADPSG criteria for hyperglycemia during pregnancy in Japanese women. Diabetes Res Clin Pract. 2010;90(3):339-42. PMID: 20870307. Chastang N, Hartemann-Heurtier A, Sachon C, et al. Comparison of two diagnostic tests for gestational diabetes in predicting macrosomia. Diabetes Metab. 2003;29(2 Pt 1):139-44. PMID: 12746634. Perucchini D, Fischer U, Spinas GA, et al. Using fasting plasma glucose concentrations to screen for gestational diabetes mellitus: prospective population based study. BMJ: British Medical Journal (International Edition). 1999;319(7213):812-5. PMID: 10496823. Lamar ME, Kuehl TJ, Cooney AT, et al. Jelly beans as an alternative to a fifty-gram glucose beverage for gestational diabetes screening. Am J Obstet Gynecol 1999;181(5 Pt 1):1154-7. PMID: 10561636. Siribaddana SH, Deshabandu R, Rajapakse D, et al. The prevalence of gestational diabetes in a Sri Lankan antenatal clinic. Ceylon Med J. 1998;43(2):88-91. PMID: 9704548. Eslamian L, Ramezani Z. Evaluation of a breakfast as screening test for the detection of gestational diabetes. Acta Medica Iranica. 2008;46(1):43-6. 123 80. Corrado F, Benedetto AD, Cannata ML, et al. A single abnormal value of the glucose tolerance test is related to increased adverse perinatal outcome. J Matern Fetal Neonatal Med. 2009;22(7):597-601. PMID: 19488948. 81. Cheng YW, Block-Kurbisch I, Caughey AB. Carpenter-Coustan criteria compared with the national diabetes data group thresholds for gestational diabetes mellitus. Obstet Gynecol. 2009;114(2:Pt 1):326-32. PMID: 19622994. 82. Biri A, Korucuoglu U, Ozcan P, et al. Effect of different degrees of glucose intolerance on maternal and perinatal outcomes. J Matern Fetal Neonatal Med. 2009;22(6):473-8. PMID: 19479645. 83. Retnakaran R, Qi Y, Sermer M, et al. Glucose intolerance in pregnancy and future risk of pre-diabetes or diabetes. Diabetes Care. 2008;31(10):2026-31. PMID: 18628572. 84. Shirazian N, Mahboubi M, Emdadi R, et al. Comparison of different diagnostic criteria for gestational diabetes mellitus based on the 75-g oral glucose tolerance test: a cohort study. Endocrine Pract. 2008;14(3):312-7. PMID: 18463038. 85. Kwik M, Seeho SK, Smith C, et al. Outcomes of pregnancies affected by impaired glucose tolerance. Diabetes Res Clin Pract. 2007;77(2):263-8. PMID: 17275121. 86. Chico A, Lopez-Rodo V, Rodriguez-Vaca D, et al. Features and outcome of pregnancies complicated by impaired glucose tolerance and gestational diabetes diagnosed using different criteria in a Spanish population. Diabetes Res Clin Pract. 2005;68(2):141-6. PMID: 15860242. 87. Bo S, Menato G, Gallo ML, et al. Mild gestational hyperglycemia, the metabolic syndrome and adverse neonatal outcomes. Acta Obstet Gynecol Scand. 2004;83(4):335-40. PMID: 15005779. 88. Stamilio DM, Olsen T, Ratcliffe S, et al. False-positive 1-hour glucose challenge test and adverse perinatal outcomes. Obstet Gynecol. 2004;103(1):148-56. PMID: 14704259. 124 89. Pennison EH, Egerman RS. Perinatal outcomes in gestational diabetes: a comparison of criteria for diagnosis. Am J Obstet Gynecol. 2001;184(6):1118-21. PMID: 11349174. 90. Berggren EK, Boggess KA, Stuebe AM, et al. National Diabetes Data Group vs. Carpenter-Coustan criteria to diagnose gestational diabetes. Am J Obstet Gynecol. 2011;205(3):253-e1-7. PMID: 22071053. 91. Sacks DA, Greenspoon JS, bu-Fadil S, et al. Toward universal criteria for gestational diabetes: The 75-gram glucose tolerance test in pregnancy. Am J Obstet Gynecol. 1995;172(2 I):607-14. PMID: 7856693. 92. Chou C, Lin C, Yang C, et al. Pregnancy outcomes of Taiwanese women with gestational diabetes mellitus: a comparison of Carpenter-Coustan and National Diabetes Data Group criteria. J Womens Health. 2010;19(5):935-8. PMID: 20370431. 93. Lapolla A, Dalfra MG, Ragazzi E, et al. New International Association of the Diabetes and Pregnancy Study Groups (IADPSG) recommendations for diagnosing gestational diabetes compared with former criteria: a retrospective study on pregnancy outcome. Diabetic Med. 2011;28(9):1074-7. PMID: 21658125. 94. Cok T, Tarim E, Bagis T. Isolated abnormal value during the 3-hour glucose tolerance test: which value is associated with macrosomia? J Matern Fetal Neonatal Med. 2011;24(8):1039-41. PMID: 21247232. 95. Fassett MJ, Dhillon SH, Williams TR. Effects on perinatal outcome of treating women with 1 elevated glucose tolerance test value. Am J Obstet Gynecol. 2007;196(6):597.e1-4. PMID: 17547912. 96. Malcolm JC, Lawson ML, Gaboury I, et al. Glucose tolerance of offspring of mother with gestational diabetes mellitus in a lowrisk population. Diabetic Med. 2006;23(5):565-70. PMID: 16681566. 97. Bonomo M, Corica D, Mion E, et al. Evaluating the therapeutic approach in pregnancies complicated by borderline glucose intolerance: a randomized clinical trial. Diabetic Med. 2005;22(11):1536-41. PMID: 16241919. 98. Bevier WC, Fischer R, Jovanovic L. Treatment of women with an abnormal glucose challenge test (but a normal oral glucose tolerance test) decreases the prevalence of macrosomia. Am J Perinatol. 1999;16(6):269-75. PMID: 10586979. 99. Agarwal MM, Hughes PF, Punnose J, et al. Fasting plasma glucose as a screening test for gestational diabetes in a multi-ethnic, high-risk population. Diabet Med. 2000;17(10):720-6. PMID: 11110505. 100. 101. Agarwal MM, Hughes PF, Punnose J, et al. Gestational diabetes screening of a multiethnic, high-risk population using glycated proteins. Diabetes Research and Clinical Practice. 2001;51(1):67-73. PMID: 11137184. Maegawa Y, Sugiyama T, Kusaka H, et al. Screening tests for gestational diabetes in Japan in the 1st and 2nd trimester of pregnancy. Diabetes Research and Clinical Practice. 2003;62(1):47-53. PMID: 14581157. 102. Ricart W, Lopez J, Mozas J, et al. Potential impact of American Diabetes Association (2000) criteria for diagnosis of gestational diabetes mellitus in Spain. Diabetologia. 2005;48(6):1135-41. PMID: 15889233. 103. Kim HS, Chang KH, Yang JI, et al. Clinical outcomes of pregnancy with one elevated glucose tolerance test value. Int J Gynaecol Obstet. 2002;78(2):131-8. PMID: 12175714. 104. Bobrowski RA, Bottoms SF, Micallef JA, et al. Is the 50-gram glucose screening test ever diagnostic? J Matern Fetal Med. 1996;5(6):317-20. PMID: 8972407. 105. Rey E, Hudon L, Michon N, et al. Fasting plasma glucose versus glucose challenge test: screening for gestational diabetes and cost effectiveness. Clin Biochem. 2004;37(9):780-4. PMID: 15329316. 106. 107. Vambergue A, Nuttens MC, Verier-Mine O, et al. Is mild gestational hyperglycaemia associated with maternal and neonatal complications? The Diagest Study. Diabet Med. 2000;17(3):203-8. PMID: 10784224. Rajput R, Yogeshyadav, Rajput M, et al. Utility of HbA(1c) for diagnosis of gestational diabetes mellitus. Diabetes Res Clin Pract. 2012. PMID: 22456454. 125 108. Chevalier N, Fenichel P, Giaume V, et al. Universal two-step screening strategy for gestational diabetes has weak relevance in French Mediterranean women: should we simplify the screening strategy for gestational diabetes in France? Diabetes Metab. 2011;37(5):419-25. PMID: 21489844. 109. Agarwal MM, Dhatt GS, Othman Y, et al. Gestational diabetes: an evaluation of serum fructosamine as a screening test in a highrisk population. Gynecol Obstet Invest. 2011;71(3):207-12. PMID: 21160150. 110. Agarwal MM, Dhatt GS, Safraou MF. Gestational diabetes: using a portable glucometer to simplify the approach to screening. Gynecol Obstet Invest. 2008;66(3):178-83. PMID: 18562798. 111. Wijeyaratne CN, Ginige S, Arasalingam A, et al. Screening for gestational diabetes mellitus: the Sri Lankan experience. Ceylon Med J. 2006;51(2):53-8. PMID: 17180809. 112. Agarwal MM, Dhatt GS, Punnose J. Gestational diabetes: utility of fasting plasma glucose as a screening test depends on the diagnostic criteria. Diabetic Med. 2006;23(12):1319-26. PMID: 17116182. 113. Agarwal MM, Dhatt GS, Punnose J, et al. Gestational diabetes: a reappraisal of HBA1c as a screening test. Acta Obstet Gynecol Scand. 2005;84(12):1159-63. PMID: 16305701. 114. Hill JC, Krishnaveni GV, Annamma I, et al. Glucose tolerance in pregnancy in South India: relationships to neonatal anthropometry. Acta Obstet Gynecol Scand. 2005;84(2):159-65. PMID: 15683377. 115. Jensen DM, Molsted-Pedersen L, BeckNielsen H, et al. Screening for gestational diabetes mellitus by a model based on risk indicators: a prospective study. Am J Obstet Gynecol. 2003;189(5):1383-8. PMID: 14634573. 116. Buhling KJ, Henrich W, Kjos SL, et al. Comparison of point-of-care-testing glucose meters with standard laboratory measurement of the 50g-glucose-challenge test (GCT) during pregnancy. Clin Biochem. 2003;36(5):333-7. PMID: 12849863. 117. Jakobi P, Weissman A, Egozi J, et al. Perinatal significance of diagnosing glucose intolerance during pregnancy with portable glucose meter. J Perinat Med. 2003;31(2):140-5. PMID: 12747230. 126. Sacks DA, Chen W, Wolde-Tsadik G, et al. Fasting plasma glucose test at the first prenatal visit as a screen for gestational diabetes. Obstet Gynecol. 2003;101(6):1197-203. PMID: 12798525. 118. Soonthornpun S, Soonthornpun K, Aksonteing J, et al. A comparison between a 75-g and 100-g oral glucose tolerance test in pregnant women. Int J Gynaecol Obstet. 2003;81(2):169-73. PMID: 12706274. 127. Kauffman RP, Castracane VD, Peghee D, et al. Detection of gestational diabetes mellitus by homeostatic indices of insulin sensitivity: A preliminary study. Am J Obstet Gynecol. 2006;194(6):1576-82. PMID: 16638603. 119. Ostlund I, Hanson U. Occurrence of gestational diabetes mellitus and the value of different screening indicators for the oral glucose tolerance test. Acta Obstet Gynecol Scand. 2003;82(2):103-8. PMID: 12648169. 128. 120. Reichelt AJ, Spichler ER, Branchtein L, et al. Fasting plasma glucose is a useful test for the detection of gestational diabetes. Brazilian Study of Gestational Diabetes (EBDG) Working Group. Diabetes Care. 1998;21(8):1246-9. PMID: 9702428. Balaji V, Madhuri BS, Paneerselvam A, et al. Comparison of Venous Plasma Glucose and Capillary Whole Blood Glucose in the Diagnosis of Gestational Diabetes Mellitus: A Community-Based Study. Diabetes Technol Ther. 2011;14(2):131-4. PMID: 21992269. 129. Balaji V, Balaji M, Anjalakshi C, et al. Inadequacy of fasting plasma glucose to diagnose gestational diabetes mellitus in Asian Indian women. Diabetes Res Clin Pract. 2011;94(1):e21-e23. PMID: 21831468. 130. Chanprapaph P, Sutjarit C. Prevalence of gestational diabetes mellitus (GDM) in women screened by glucose challenge test (GCT) at Maharaj Nakorn Chiang Mai Hospital. J Med Assoc Thai. 2004;87(10):1141-6. PMID: 15560687. 131. Solomon CG, Willett WC, Rich-Edwards J, et al. Variability in diagnostic evaluation and criteria for gestational diabetes. Diabetes Care. 1996;19(1):12-6. PMID: 8720526. 132. Hillier TA, Pedula KL, Schmidt MM, et al. Childhood obesity and metabolic imprinting: the ongoing effects of maternal hyperglycemia. Diabetes Care. 2007;30(9):2287-92. PMID: 17519427. 133. Jensen DM, Damm P, Sorensen B, et al. Proposed diagnostic thresholds for gestational diabetes mellitus according to a 75-g oral glucose tolerance test. Maternal and perinatal outcomes in 3260 Danish women. Diabetic Med. 2003;20(1):51-7. PMID: 12519320. 134. Lao TT, Tam KF. Gestational diabetes diagnosed in third trimester pregnancy and pregnancy outcome. Acta Obstet Gynecol Scand. 2001;80(11):1003-8. PMID: 11703196. 121. 122. 123. 124. 125. Rust O, Bofill JA, Carroll SC, et al. Twohour postprandial test versus one-hour, fiftygram glucola test as screening tools for gestational diabetes: a critical analysis. J Perinatol. 1998;18(1):49-54. PMID: 9527945. Fung HY, Wong SP, Rogers M. The influence of glucose tolerance tests on subsequent carbohydrate metabolism in pregnancy. Acta Obstet Gynecol Scand. 1996;75(4):347-51. PMID: 8638454. Berkus MD, Langer O. Glucose tolerance test periodicity: the effect of glucose loading. Obstet Gynecol. 1995;85(3):423-7. PMID: 7862384. Moses RG, Morris GJ, Petocz P, et al. The impact of potential new diagnostic criteria on the prevalence of gestational diabetes mellitus in Australia. The Medical Journal Of Australia. 2011;194(7):338-40. PMID: 21470082. Buhling KJ, Elze L, Henrich W, et al. The usefulness of glycosuria and the influence of maternal blood pressure in screening for gestational diabetes. Eur J Obstet Gynecol Reprod Biol. 2004;113(2):145-8. PMID: 15063950. 126 135. Rust OA, Bofill JA, Andrew ME, et al. Lowering the threshold for the diagnosis of gestational diabetes. Am J Obstet Gynecol. 1996;175(4 Pt 1):961-5. PMID: 8885755. 144. Cetin M, Cetin A. Time-dependent gestational diabetes screening values. Int J Gynecol Obstet. 1997;56(3):257-61. PMID: 9127158. 136. Berkus MD, Langer O, Piper JM, et al. Efficiency of lower threshold criteria for the diagnosis of gestational diabetes. Obstet Gynecol. 1995;86(6):892-6. PMID: 7501334. 145. Lapolla A, Dalfra MG, Bonomo M, et al. Can plasma glucose and HbA1c predict fetal growth in mothers with different glucose tolerance levels? Diabetes Res Clin Pract. 2007;77(3):465-70. PMID: 17350135. 137. Tan PC, Ling LP, Omar SZ. The 50-g glucose challenge test and pregnancy outcome in a multiethnic Asian population at high risk for gestational diabetes. Int J Gynaecol Obstet. 2009;105(1):50-5. PMID: 19154997. 146. Langer O, Yogev Y, Most O, et al. Gestational diabetes: the consequences of not treating. Am J Obstet Gynecol. 2005;192(4):989-97. PMID: 15846171. 147. Lao TT, Ho LF. Does maternal glucose intolerance affect the length of gestation in singleton pregnancies? J Soc Gynecol Investig. 2003;10(6):366-71. PMID: 12969780. 148. Bonomo M, Gandini ML, Farina A, et al. Should we treat minor degrees of glucose intolerance in pregnancy? Ann Ist Super Sanita. 1997;33(3):393-7. PMID: 9542269. 149. Nord E, Hanson U, Persson B. Blood glucose limits in the diagnosis of impaired glucose tolerance during pregnancy. Relation to morbidity. Acta Obstet Gynecol Scand. 1995;74(8):589-93. PMID: 7660761. 150. Schwartz ML, Ray WN, Lubarsky SL, et al. The diagnosis and classification of gestational diabetes mellitus: Is it time to change our tune? Am J Obstet Gynecol. 1999;180(6 I):1560-71. PMID: 10368504. 151. Poyhonen-Alho MK, Teramo KA, Kaaja RJ, et al. 50gram oral glucose challenge test combined with risk factor-based screening for gestational diabetes. Eur J Obstet Gynecol Reprod Biol. 2005;121(1):34-7. PMID: 15989983. 152. Adams KM, Li H, Nelson RL, et al. Sequelae of unrecognized gestational diabetes. Am J Obstet Gynecol. 1998;178(6):1321-32. PMID: 9662318. 153. Mello G, Elena P, Ognibene A, et al. Lack of concordance between the 75-g and 100-g glucose load tests for the diagnosis of gestational diabetes mellitus. Clin Chem. 2006;52(9):1679-84. PMID: 16873295. 138. 139. Agarwal MM, Dhatt GS, Punnose J, et al. Gestational diabetes in a high-risk population: using the fasting plasma glucose to simplify the diagnostic algorithm. Eur J Obstet Gynecol Reprod Biol. 2005;120(1):39-44. PMID: 15866084. Yachi Y, Tanaka Y, Anasako Y, et al. Contribution of first trimester fasting plasma insulin levels to the incidence of glucose intolerance in later pregnancy: Tanaka women's clinic study. Diabetes Res Clin Pract. 2011;92(2):293-8. PMID: 21396732. 140. Weerakiet S, Lertnarkorn K, Panburana P, et al. Can adiponectin predict gestational diabetes? Gynecol Endocrinol. 2006;22(7):362-8. PMID: 16864145. 141. Bito T, Nyari T, Kovacs L, et al. Oral glucose tolerance testing at gestational weeks < or =16 could predict or exclude subsequent gestational diabetes mellitus during the current pregnancy in high risk group. Eur J Obstet Gynecol Reprod Biol. 2005;121(1):51-5. PMID: 15989984. 142. 143. Sermer M, Naylor CD, Gare DJ, et al. Impact of increasing carbohydrate intolerance on maternal-fetal outcomes in 3637 women without gestational diabetes. The Toronto Tri-Hospital Gestational Diabetes Project. Am J Obstet Gynecol. 1995;173(1):146-56. PMID: 7631672. Brustman LE, Gela BD, Moore M, et al. Variations in oral glucose tolerance tests: the 100- versus 75-g controversy. J Assoc Acad Minor Phys. 1995;6(2):70-2. PMID: 7772935. 127 154. Aberg A, Rydhstroem H, Frid A. Impaired glucose tolerance associated with adverse pregnancy outcome: a population-based study in southern Sweden. Am J Obstet Gynecol. 2001;184(2):77-83. PMID: 11174484. 155. Yang X, Hsu-Hage B, Zhang H, et al. Women with impaired glucose tolerance during pregnancy have significantly poor pregnancy outcomes. Diabetes Care. 2002;25(9):1619-24. PMID: 12196437. 156. Sun B, Wang X, Song Q, et al. Prospective studies on the relationship between the 50 g glucose challenge test and pregnant outcome. Chin Med J. 1995;108(12):910-3. PMID: 8728943. 157. Tan PC, Ling LP, Omar SZ. Screening for gestational diabetes at antenatal booking in a Malaysian university hospital: the role of risk factors and threshold value for the 50-g glucose challenge test. Aust N Z J Obstet Gynaecol. 2007;47(3):191-7. PMID: 17550485. 158. O'Sullivan JB, Mahan CM. Criteria for the oral glucose tolerance test in pregnancy. Diabetes. 1964;13:278-85. PMID: 14166677. 159. Sermer M, Naylor CD, Farine D, et al. The Toronto Tri-Hospital Gestational Diabetes Project. A preliminary review. Diabetes Care. 1998;21(Suppl 2):B33-B42. PMID: 9704225. 160. Naylor CD, Sermer M, Chen E, et al. Cesarean delivery in relation to birth weight and gestational glucose tolerance: pathophysiology or practice style? Toronto Trihospital Gestational Diabetes Investigators. JAMA. 1996;275(15):116570. PMID: 8609683. 161. Eslamian L, Ramezani Z. Breakfast as a screening test for gestational diabetes. Int J Gynaecol Obstet. 2007;96(1):34-5. PMID: 17188692. 162. van LM, Opmeer BC, Zweers EJ, et al. Estimating the risk of gestational diabetes mellitus: a clinical prediction model based on patient characteristics and medical history. BJOG. 2010;117(1):69-75. PMID: 20002371. 128 163. Landon MB, Mele L, Spong CY, et al. The relationship between maternal glycemia and perinatal outcome. Obstet Gynecol. 2011;117(2 Pt 1):218-24. PMID: 21309194. 164. Pirc LK, Owens JA, Crowther CA, et al. Mild gestational diabetes in pregnancy and the adipoinsular axis in babies born to mothers in the ACHOIS randomised controlled trial. BMC Pediatr. 2007;7:18. PMID: 17430602. 165. Rasmussen SS, Glumer C, Sandbaek A, et al. Short-term reproducibility of impaired fasting glycaemia, impaired glucose tolerance and diabetes The ADDITION study, DK. Diabetes Res Clin Pract. 2008;80(1):146-52. PMID: 18082284. 166. Hyperglycemia and adverse pregnency outcome (HAPO) study Cooperative Research Group. Hyperglycemia and adverse pregnancy outcomes. The New England Journal of Medicine. 2008;358(19):1991-2002. PMID: 18463375. 167. Naylor CD, Sermer M, Chen EL, et al. Selective screening for gestational diabetes mellitus. N Engl J Med. 1997;337(22):15916. PMID: 9371855. 168. Phillips DI. Programming of the stress response: a fundamental mechanism underlying the long-term effects of the fetal environment? J Intern Med. 2007;261(5):453-60. PMID: 17444884. 169. Daniells S, Grenyer BFS, Davis WS, et al. Gestational diabetes mellitus: Is a diagnosis associated with an increase in maternal anxiety and stress in the short and intermediate term? Diabetes Care. 2003;26(2):385-9. PMID: 12547867. 170. Horvath K, Koch K, Jeitler K, et al. Effects of treatment in women with gestational diabetes mellitus: systematic review and meta-analysis. BMJ: British Medical Journal (International Edition). 2010;340:c1395. PMID: 20360215. 171. Pettitt DJ, McKenna S, McLaughlin C, et al. Maternal glucose at 28 weeks of gestation is not associated with obesity in 2-year-old offspring: The Belfast Hyperglycemia and Adverse Pregnancy Outcome (HAPO) family study. Diabetes Care. 2010;33(6):1219-23. PMID: 20215449. 172. Ryan EA. Diagnosing gestational diabetes. Diabetologia 2011;54(3):480-6. PMID: 21203743. 173. HAPO Study Cooperative Research Group. Hyperglycaemia and Adverse Pregnancy Outcome (HAPO) Study: associations with maternal body mass index. BJOG. 2010;117(5):575-84. PMID: 20089115. 174. Ricart W, Lopez J, Mozas J, et al. Body mass index has a greater impact on pregnancy outcomes than gestational hyperglycaemia. Diabetologia. 2005;48(9):1736-42. PMID: 16052327. 129 175. Cundy T, Gamble G, Townend K, et al. Perinatal mortality in Type 2 diabetes mellitus. Diabet Med. 2000;17(1):33-9. PMID: 10691157. 176. Schaefer-Graf UM, Hartmann R, Pawliczak J, et al. Association of breast-feeding and early childhood overweight in children from mothers with gestational diabetes mellitus. Diabetes Care. 2006;29(5):1105-7. PMID: 16644645. 177. Buchanan TA, Kjos SL, Montoro MN, et al. Use of fetal ultrasound to select metabolic therapy for pregnancies complicated by mild gestational diabetes. Diabetes Care. 1994;17(4):275-83. PMID: 8026282. Acronyms and Abbreviations ACHOIS ACOG ADA ADIPS BMI CC CI D dL DM Dx EASD FPG GCT/OGCT GDM g(s) h(s) HSROC HAPO HbA1c IFG IGT IGT-2 IADPSG IQR IWC JSOG kg LGA L m MD µmol mg mmol mo(s) NDDG NICU NOS NR N or n Australian Carbohydrate Intolerance in Pregnant Women Study American Congress of Obstetricians and Gynecologists American Diabetes Association Australasian Diabetes in Pregnancy Society Body-mass index Carpenter and Coustan Confidence interval Day(s) Deciliter Diabetes mellitus Diagnosis/diagnostic European Association for the Study of Diabetes Fasting plasma glucose Glucose tolerance test and oral glucose tolerance test are synonymous Gestational diabetes mellitus Gram(s) Hour(s) Hierarchical summary receiver operator characteristic Hyperglycemia and Adverse Pregnancy Outcomes Study Glycated Hemoglobin, Hemoglobin A1c Impaired fasting glucose Impaired glucose tolerance Double impaired glucose tolerance International Association of the Diabetes in Pregnancy Study Groups Inter-quartile range International Workshop Conference Japan Society of Obstetrics and Gynecology kilogram Large for gestational age Liter Meter Mean difference Micromole Milligrams Millimole Month(s) National Diabetes Data Group Neonatal Intensive Care Unit Newcastle-Ottawa Quality Assessment Scale Not reported Number 130 NPV OGCT OGTT PCS PPV QUADAS RCS RCT(s) RDS RR Sn Sp SD SGA WHO wk(s) yr(s) Negative predictive value Oral glucose challenge text Oral glucose tolerance test Prospective cohort study Positive predictive value Quality assessment of diagnostic accuracy studies Retrospective cohort study Randomized controlled trial(s) Respiratory distress syndrome Risk ratio (or relative risk) Sensitivity Specificity Standard deviation Small for gestational age World Health Organization Week(s) Year(s) 131 Appendix A. Literature Search Strings Table A1. Table A2. Table A3. Table A4. Table A5. Table A6. Table A7. Table A8. Table A9. Table A10. Table A11. Table A12. Table A13. Table A14. MEDLINE Embase EBM Reviews Global Health PASCAL Medline® In Process CINAHL Plus with Full Text Biosis Previews ® Science Citation Index Expanded ® Conference Proceedings Citation Index—Science LILACs (Latin American and Caribbean Health Science Literature) OCLC ProceedingsFirst and PapersFirst PubMed ClinicalTrials.gov and WHO A-1 Table A1. Medline Database: Medline via Ovid <1948 to September Week 4 2011> Search Date: 9 October 2011 Results: 8,234 1. Diabetes, Gestational/ 2. Fetal Macrosomia/ 3. Pregnancy Complications/ 4. GDM.tw. 5. (gestation$ adj2 (diabet$ or DM or glucose intoleran$ or insulin resistan$)).mp. 6. (pregnan$ adj3 (diabet$ or DM or glucose intoleran$ or insulin resistan$)).mp. 7. (maternal adj2 (diabet$ or DM or glyc?emia or hyperglyc?emia)).tw. 8. (hyperglyc?emia adj2 pregnan$).tw. 9. macrosomia.tw. 10. or/1-9 11. mass screening/ 12. prenatal diagnosis/ 13. screen$.tw. 14. ((prenatal or early) adj2 diagnosis).tw. 15. Glucose Tolerance Test/ 16. Glucose Intolerance/ 17. Blood Glucose/ 18. Risk Factors/ 19. (glucose adj (tolerance or intolerance or challenge)).tw. 20. OGTT.tw. 21. GCT.tw. 22. (fasting adj2 glucose).tw. 23. or/11-22 24. "Sensitivity and Specificity"/ 25. "Predictive Value of Tests"/ 26. ROC Curve/ 27. specific$.tw. 28. sensitiv$.tw. 29. predictive value.tw. 30. accurac$.tw. 31. diagnostic errors/ 32. diagnostic error?.tw. 33. false negative reactions/ 34. false positive reactions/ 35. (false adj (negative or positive)).tw. 36. "reproducibility of results"/ 37. reference values/ 38. reference standards/ 39. or/24-38 40. and/10,23,39 41. intervention?.mp. 42. (treating or treatment? or therapy or therapies).mp. 43. manage$.mp. 44. monitor$.mp. 45. exp sulfonylurea compounds/ 46. Gliclazide/ 47. Glyburide/ 48. Tolbutamide/ 49. sulfonylurea?.tw. 50. gliclazid$.tw. 51. glimepirid$.tw. 52. glipizid$.tw. 53. glyburid$.tw. 54. tolbutamid$.tw. 55. (antidiabet$ or anti-diabet$).tw. 56. insulin?.mp. 57. glibenclamid$.mp. 58. acarbos$.mp. A-2 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 99. 100. 101. 102. 103. 104. 105. 106. 107. 108. 109. 110. 111. 112. 113. 114. 115. 116. 117. 118. 119. 120. exp Diet Therapy/ (diet adj2 (therap$ or restrict$ or advice)).tw. medical nutrition$ therapy.tw. MNT.tw. exp Life Style/ (lifestyle$ or life-style$).mp. Blood Glucose Self-Monitoring/ (blood glucose adj (self monitor$ or self-monitor$)).tw. ((self monitor$ or self-monitor$) adj blood glucose).tw. SMBG.tw. Counseling/ counsel$.tw. Labor, Induced/ (induc$ adj2 labo?r).tw. exp Cesarean Section/ c?esarean.tw. exp Pregnancy Outcome/ pregnanc$ outcome?.tw. or/41-76 and/10,77 or/40,78 clinical trial.pt. randomized controlled trial.pt. randomi?ed.ti,ab. placebo.ti,ab. dt.fs. randomly.ti,ab. trial.ti,ab. groups.ti,ab. or/80-87 animals/ humans/ 89 not (89 and 90) 88 not 91 cohort studies/ follow-up studies/ longitudinal studies/ prospective studies/ retrospective studies/ ((cohort? or follow-up or followup or longitud$ or prospectiv$ or retrospectiv$) adj (study or studies or trial?)).tw. or/93-98 99 not 91 exp Guideline/ Health Planning Guidelines/ (clinical adj2 guideline?).tw. CPG?.tw. ((practice or consensus or position) adj2 (guideline? or recommendation? or statement?)).tw. standard?.tw. protocol?.tw. or/101-107 meta analysis.mp,pt. review.pt. search:.tw. or/109-111 [Reviews balanced - HIRU] and/79,92 [Clinical trials & RCTs] and/79,100 [Observational studies] and/79,108 [Guidelines] and/79,112 [SRs MAs] or/113-116 limit 117 to (english language and yr="2000 -Current") limit 117 to (english language and yr="2000 -2005") limit 117 to (english language and yr="2006 -Current") A-3 121. 122. 123. 124. 125. 126. 127. 128. 129. 130. 131. 132. 133. 134. 135. 136. 137. 138. remove duplicates from 119 remove duplicates from 120 or/121-122 113 or 114 or 115 113 or 114 or 115 limit 125 to (english language and yr="2000 -Current") limit 125 to (english language and yr="2000 -2005") remove duplicates from 127 limit 125 to (english language and yr="2006 -Current") remove duplicates from 129 128 or 130 113 or 114 limit 132 to (english language and yr="2000 -Current") limit 132 to (english language and yr="2000 -2005") remove duplicates from 134 limit 132 to (english language and yr="2006 -Current") remove duplicates from 136 135 or 137 Table A2. Embase Database: Embase via Ovid <1996 to 2011 Week 40> Search Date: 10 October 2011 Results: 5,188 1. pregnancy diabetes mellitus/ 2. maternal diabetes mellitus/ 3. pregnancy complication/ 4. macrosomia/ 5. GDM.tw. 6. (gestation$ adj2 (diabet$ or DM or glucose intoleran$ or insulin resistan$)).mp. 7. (pregnan$ adj3 (diabet$ or DM or glucose intoleran$ or insulin resistan$)).mp. 8. (maternal adj2 (diabet$ or DM or glyc?emia or hyperglyc?emia)).mp. 9. (hyperglyc?emia adj2 pregnan$).tw. 10. macrosomia.tw. 11. or/1-10 12. prenatal screening/ 13. early diagnosis/ 14. screen$.tw. 15. ((prenatal or early) adj2 diagnosis).tw. 16. exp glucose tolerance test/ 17. glucose intolerance/ 18. glucose blood level/ 19. risk factor/ 20. (glucose adj (tolerance or intolerance or challenge)).tw. 21. OGTT.tw. 22. GCT.tw. 23. (fasting adj2 glucose).tw. 24. or/12-23 25. "sensitivity and specificity"/ 26. predictive value/ 27. receiver operating characteristic/ 28. specific$.tw. 29. sensitiv$.tw. 30. predictive value.tw. 31. accurac$.tw. 32. diagnostic error/ 33. diagnostic accuracy/ 34. diagnostic error?.tw. 35. false negative result/ 36. false positive result/ 37. (false adj (negative or positive)).tw. 38. reproducibility/ A-4 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 99. 100. reference value/ standard/ or/25-40 and/11,24,41 intervention?.mp. (treating or treatment? or therapy or therapies).mp. manage$.mp. monitor$.mp. sulfonylurea derivative/ gliclazide/ glibenclamide/ glimepiride/ glipizide/ tolbutamide/ sulfonylurea?.tw. gliclazid$.tw. glimepirid$.tw. glipizid$.tw. glyburid$.tw. tolbutamid$.tw. (antidiabet$ or anti-diabet$).tw. insulin?.mp. glibenclamid$.mp. acarbos$.mp. exp diet therapy/ (diet adj2 (therap$ or restrict$ or advice)).tw. medical nutrition$ therapy.tw. MNT.tw. exp lifestyle/ (lifestyle$ or life-style$).mp. blood glucose monitoring/ (blood glucose adj (self monitor$ or self-monitor$)).tw. ((self monitior$ or self-monitor$) adj blood glucose).tw. SMBG.tw. counseling/ nutritional counseling/ counsel$.tw. labor induction/ (induc$ adj2 labo?r).tw. cesarean section/ c?esarean.tw. pregnancy outcome/ pregnanc$ outcome?.tw. or/43-81 and/11,82 or/42,83 clinical trial/ randomized controlled trial/ randomization/ single blind procedure/ double blind procedure/ crossover procedure/ placebo/ randomi?ed controlled trial?.tw. RCT.tw. random allocation.tw. randomly allocated.tw. allocated randomly.tw. (allocated adj2 random).tw. single blind$.tw. double blind$.tw. ((treble or triple) adj blind$).tw. A-5 101. placebo$.tw. 102. prospective study/ 103. or/85-102 104. case study/ 105. case report.tw. 106. abstract report/ or letter/ 107. or/104-106 108. 103 not 107 [SIGN Embase RCT filter] 109. animal/ 110. human/ 111. 109 not (109 and 110) 112. 108 not 111 113. cohort analysis/ 114. follow up/ 115. longitudinal study/ 116. prospective study/ 117. retrospective study/ 118. ((cohort? or follow-up or followup or longitud$ or prospectiv$ or retrospectiv$) adj (study or studies or trial?)).tw. 119. or/113-118 120. 119 not 111 121. exp practice guideline/ 122. (clinical adj2 guideline?).tw. 123. CPG?.tw. 124. ((practice or consensus or position) adj2 (guideline? or recommendation? or statement?)).tw. 125. standard?.tw. 126. protocol?.tw. 127. or/121-126 [Guidelines] 128. and/84,112 [RCTs] 129. and/84,120 [Observational studies] 130. and/84,127 [Guidelines] 131. or/128-130 132. limit 131 to (english language and yr="2000 -2005") 133. remove duplicates from 132 134. limit 131 to (english language and yr="2006 -Current") 135. remove duplicates from 134 133 or 135 Table A3. EMB Reviews Databases: Cochrane Central Register of Controlled Trials (CCTR) via Ovid <3rd Quarter 2011> Cochrane Database of Systematic Reviews (CDSR) via Ovid <2005 to September 2011> Database of Abstracts of Reviews of Effects (DARE) via Ovid <3rd Quarter 2011> Search Date: 9 October 2011 Results: CCTR: 23; CDSR: 79; DARE: 23 1. GDM.tw. 2. (gestation$ adj2 (diabet$ or DM or glucose intoleran$ or insulin resistan$)).mp. 3. (pregnan$ adj3 (diabet$ or DM or glucose intoleran$ or insulin resistan$)).mp. 4. (maternal adj2 (diabet$ or DM or glyc?emia or hyperglyc?emia)).tw. 5. (hyperglyc?emia adj2 pregnan$).tw. 6. macrosomia.tw. 7. or/1-6 8. screen$.tw. 9. ((prenatal or early) adj2 diagnosis).tw. 10. blood glucose.tw. 11. risk factor?.tw. 12. (glucose adj (tolerance or intolerance or challenge)).tw. 13. OGTT.tw. 14. GCT.tw. 15. (fasting adj2 glucose).tw. 16. or/8-15 17. specific$.tw. A-6 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. sensitiv$.tw. predictive value.tw. (ROC or "receiver operating characteristic?").tw. accurac$.tw. diagnostic error?.tw. (false adj (negative or positive)).tw. "reproducibility of results".tw. (reference adj2 (standard? or value?)).tw. or/17-25 and/7,16,26 intervention?.mp. (treating or treatment? or therapy or therapies).mp. manage$.mp. monitor$.mp. sulfonylurea?.tw. gliclazid$.tw. glimepirid$.tw. glipizid$.tw. glyburid$.tw. tolbutamid$.tw. (antidiabet$ or anti-diabet$).tw. insulin?.mp. glibenclamid$.mp. acarbos$.mp. (diet adj2 (therap$ or restrict$ or advice)).tw. medical nutrition$ therapy.tw. MNT.tw. (lifestyle$ or life-style$).mp. (blood glucose adj (self monitor$ or self-monitor$)).tw. ((self monitior$ or self-monitor$) adj blood glucose).tw. SMBG.tw. counsel$.tw. (induc$ adj2 labo?r).tw. c?esarean.tw. pregnanc$ outcome?.tw. or/28-52 and/7,53 or/27,54 clinical trial.pt. randomized controlled trial.pt. randomi?ed.ti,ab. placebo.ti,ab. dt.fs. randomly.ti,ab. trial.ti,ab. groups.ti,ab. or/56-63 (animal? not (animal? and human?)).mp. 64 not 65 ((cohort? or follow-up or followup or longitud$ or prospectiv$ or retrospectiv$) adj (study or studies or trial?)).tw. 67 not 66 (clinical adj2 guideline?).tw. CPG?.tw. ((practice or consensus or position) adj2 (guideline? or recommendation? or statement?)).tw. standard?.tw. protocol?.tw. or/69-73 and/55,66 [Clinical trials & RCTs] and/55,68 [Observational studies] and/55,74 [Guidelines] or/75-77 limit 78 to (english language and yr="2000-Current") A-7 80. remove duplicates from 79 Table A4. Global Health Database: Global Health via Ovid <1973 to September 2011> Search Date: 9 October 2011 Results: 361 1. GDM.tw. 2. (gestation$ adj2 (diabet$ or DM or glucose intoleran$ or insulin resistan$)).mp. 3. (pregnan$ adj3 (diabet$ or DM or glucose intoleran$ or insulin resistan$)).mp. 4. (maternal adj2 (diabet$ or DM or glyc?emia or hyperglyc?emia)).tw. 5. (hyperglyc?emia adj2 pregnan$).tw. 6. macrosomia.tw. 7. or/1-6 8. screen$.tw. 9. ((prenatal or early) adj2 diagnosis).tw. 10. blood glucose.tw. 11. risk factor?.tw. 12. (glucose adj (tolerance or intolerance or challenge)).tw. 13. OGTT.tw. 14. GCT.tw. 15. (fasting adj2 glucose).tw. 16. or/8-15 17. specific$.tw. 18. sensitiv$.tw. 19. predictive value.tw. 20. (ROC or "receiver operating characteristic?").tw. 21. accurac$.tw. 22. diagnostic error?.tw. 23. (false adj (negative or positive)).tw. 24. "reproducibility of results".tw. 25. (reference adj2 (standard? or value?)).tw. 26. or/17-25 27. and/7,16,26 28. intervention?.mp. 29. (treating or treatment? or therapy or therapies).mp. 30. manage$.mp. 31. monitor$.mp. 32. sulfonylurea?.tw. 33. gliclazid$.tw. 34. glimepirid$.tw. 35. glipizid$.tw. 36. glyburid$.tw. 37. tolbutamid$.tw. 38. (antidiabet$ or anti-diabet$).tw. 39. insulin?.mp. 40. glibenclamid$.mp. 41. acarbos$.mp. 42. (diet adj2 (therap$ or restrict$ or advice)).tw. 43. medical nutrition$ therapy.tw. 44. MNT.tw. 45. (lifestyle$ or life-style$).mp. 46. (blood glucose adj (self monitor$ or self-monitor$)).tw. 47. ((self monitior$ or self-monitor$) adj blood glucose).tw. 48. SMBG.tw. 49. counsel$.tw. 50. (induc$ adj2 labo?r).tw. 51. c?esarean.tw. 52. pregnanc$ outcome?.tw. 53. or/28-52 54. and/7,53 55. or/27,54 A-8 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. clinical trial.pt. randomized controlled trial.pt. randomi?ed.ti,ab. placebo.ti,ab. dt.fs. randomly.ti,ab. trial.ti,ab. groups.ti,ab. or/56-63 (animal? not (animal? and human?)).mp. 64 not 65 ((cohort? or follow-up or followup or longitud$ or prospectiv$ or retrospectiv$) adj (study or studies or trial?)).tw. 67 not 66 (clinical adj2 guideline?).tw. CPG?.tw. ((practice or consensus or position) adj2 (guideline? or recommendation? or statement?)).tw. standard?.tw. protocol?.tw. or/69-73 and/55,66 [Clinical trials & RCTs] and/55,68 [Observational studies] and/55,74 [Guidelines] or/75-77 limit 78 to (english language and yr="2000-Current") remove duplicates from 79 Table A5. PASCAL Database: PASCAL via Ovid <1984 to 2011 Week 39> Search Date: 9 October 2011 Results: 498 1. GDM.tw. 2. (gestation$ adj2 (diabet$ or DM or glucose intoleran$ or insulin resistan$)).mp. 3. (pregnan$ adj3 (diabet$ or DM or glucose intoleran$ or insulin resistan$)).mp. 4. (maternal adj2 (diabet$ or DM or glyc?emia or hyperglyc?emia)).tw. 5. (hyperglyc?emia adj2 pregnan$).tw. 6. macrosomia.tw. 7. or/1-6 8. screen$.tw. 9. ((prenatal or early) adj2 diagnosis).tw. 10. blood glucose.tw. 11. risk factor?.tw. 12. (glucose adj (tolerance or intolerance or challenge)).tw. 13. OGTT.tw. 14. GCT.tw. 15. (fasting adj2 glucose).tw. 16. or/8-15 17. specific$.tw. 18. sensitiv$.tw. 19. predictive value.tw. 20. (ROC or "receiver operating characteristic?").tw. 21. accurac$.tw. 22. diagnostic error?.tw. 23. (false adj (negative or positive)).tw. 24. "reproducibility of results".tw. 25. (reference adj2 (standard? or value?)).tw. 26. or/17-25 27. and/7,16,26 28. intervention?.mp. 29. (treating or treatment? or therapy or therapies).mp. 30. manage$.mp. 31. monitor$.mp. A-9 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. sulfonylurea?.tw. gliclazid$.tw. glimepirid$.tw. glipizid$.tw. glyburid$.tw. tolbutamid$.tw. (antidiabet$ or anti-diabet$).tw. insulin?.mp. glibenclamid$.mp. acarbos$.mp. (diet adj2 (therap$ or restrict$ or advice)).tw. medical nutrition$ therapy.tw. MNT.tw. (lifestyle$ or life-style$).mp. (blood glucose adj (self monitor$ or self-monitor$)).tw. ((self monitior$ or self-monitor$) adj blood glucose).tw. SMBG.tw. counsel$.tw. (induc$ adj2 labo?r).tw. c?esarean.tw. pregnanc$ outcome?.tw. or/28-52 and/7,53 or/27,54 clinical trial.pt. randomized controlled trial.pt. randomi?ed.ti,ab. placebo.ti,ab. dt.fs. randomly.ti,ab. trial.ti,ab. groups.ti,ab. or/56-63 (animal? not (animal? and human?)).mp. 64 not 65 ((cohort? or follow-up or followup or longitud$ or prospectiv$ or retrospectiv$) adj (study or studies or trial?)).tw. 67 not 66 (clinical adj2 guideline?).tw. CPG?.tw. ((practice or consensus or position) adj2 (guideline? or recommendation? or statement?)).tw. standard?.tw. protocol?.tw. or/69-73 and/55,66 [Clinical trials & RCTs] and/55,68 [Observational studies] and/55,74 [Guidelines] or/75-77 limit 78 to (english language and yr="2000-Current") remove duplicates from 79 Table A6. Medline In-Process & Other Non-Indexed Citations Database: Medline In-Process & Other Non-Indexed Citations <October 7, 2011> Search Date: 7 October 2011 Results: 98 1. GDM.tw. 2. (gestation$ adj2 (diabet$ or DM or glucose intoleran$ or insulin resistan$)).mp. 3. (pregnan$ adj3 (diabet$ or DM or glucose intoleran$ or insulin resistan$)).mp. 4. (maternal adj2 (diabet$ or DM or glyc?emia or hyperglyc?emia)).tw. 5. (hyperglyc?emia adj2 pregnan$).tw. 6. macrosomia.tw. 7. or/1-6 8. screen$.tw. A-10 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. ((prenatal or early) adj2 diagnosis).tw. blood glucose.tw. risk factor?.tw. (glucose adj (tolerance or intolerance or challenge)).tw. OGTT.tw. GCT.tw. (fasting adj2 glucose).tw. or/8-15 specific$.tw. sensitiv$.tw. predictive value.tw. (ROC or "receiver operating characteristic?").tw. accurac$.tw. diagnostic error?.tw. (false adj (negative or positive)).tw. "reproducibility of results".tw. (reference adj2 (standard? or value?)).tw. or/17-25 and/7,16,26 intervention?.mp. (treating or treatment? or therapy or therapies).mp. manage$.mp. monitor$.mp. sulfonylurea?.tw. gliclazid$.tw. glimepirid$.tw. glipizid$.tw. glyburid$.tw. tolbutamid$.tw. (antidiabet$ or anti-diabet$).tw. insulin?.mp. glibenclamid$.mp. acarbos$.mp. (diet adj2 (therap$ or restrict$ or advice)).tw. medical nutrition$ therapy.tw. MNT.tw. (lifestyle$ or life-style$).mp. (blood glucose adj (self monitor$ or self-monitor$)).tw. ((self monitior$ or self-monitor$) adj blood glucose).tw. SMBG.tw. counsel$.tw. (induc$ adj2 labo?r).tw. c?esarean.tw. pregnanc$ outcome?.tw. or/28-52 and/7,53 or/27,54 clinical trial.pt. randomized controlled trial.pt. randomi?ed.ti,ab. placebo.ti,ab. dt.fs. randomly.ti,ab. trial.ti,ab. groups.ti,ab. or/56-63 (animal? not (animal? and human?)).mp. 64 not 65 ((cohort? or follow-up or followup or longitud$ or prospectiv$ or retrospectiv$) adj (study or studies or trial?)).tw. 67 not 66 (clinical adj2 guideline?).tw. CPG?.tw. A-11 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. ((practice or consensus or position) adj2 (guideline? or recommendation? or statement?)).tw. standard?.tw. protocol?.tw. or/69-73 and/55,66 [Clinical trials & RCTs] and/55,68 [Observational studies] and/55,74 [Guidelines] or/75-77 limit 78 to (english language and yr="2000-Current") remove duplicates from 79 A7. CINAHL Plus with Full Text Database: CINAHL Plus with Full Text via EBSCO <1937–current> Search Date: 10 October 2011 Results: 275 S39= S35 or S37 or S38 S38= S25 and S33 Limiters - English Language; Published Date from: 20000101-20121231; Exclude MEDLINE records S37= S25 and S32 Limiters - English Language; Published Date from: 20000101-20121231; Exclude MEDLINE records S36= S25 and S32 S35= S25 and S31 Limiters - English Language; Published Date from: 20000101-20121231; Exclude MEDLINE records S34= S25 and S31 S33=( CPG? or "best practice?" or "professional standard?" or "standard of care" ) OR ( practice W2 guideline* or practice W2 recommendation* or practice W2 statement or position W2 guideline* or position W2 recommendation* or position W2 statement or consensus W2 guideline* or consensus W2 recommendation* or consensus W2 statement ) S32=( (MH "Prospective Studies+") OR (MH "Retrospective Design") ) OR TI ( cohort* or follow-up or followup or longitud* or prospectiv* or retrospective* ) OR AB ( cohort* or follow-up or followup or longitud* or prospectiv* or retrospective* ) S31= S26 or S27 or S28 or S29 or S30 S30=(MH "Placebos") OR TX placebo* OR (MH "Quantitative Studies") S29= TX randomi* control* trial* OR (MH "Random Assignment") OR TX random* allocat* OR TX allocat* random* S28= TX clinic* n1 trial* OR ( TX ( (singl* n1 blind*) or (singl* n1 mask*) ) or TX ( (doubl* n1 blind*) or (doubl* n1 mask*) ) or TX ( (tripl* n1 blind*) or (tripl* n1 mask*) ) or TX ( (trebl* n1 blind*) or (trebl* n1 mask*) ) ) S27= PT Clinical trial S26=(MH "Clinical Trials+") S25= S14 or S24 S24= S5 and S23 S23= S15 or S16 or S17 or S18 or S19 or S20 or S21 or S22 S22=( (MH "Labor, Induced") OR (MH "Cesarean Section+") OR (MH "Pregnancy Outcomes") ) OR ( induc* n2 labo#r or cesarean or caesarean or pregnan* n1 outcome* ) S21=( (MH "Counseling") OR (MH "Nutritional Counseling") ) OR counsel* S20=(MH "Blood Glucose Self-Monitoring") OR ( "blood glucose" w1 "self monitor*" or "blood glucose" w1 "self-monitor*" ) OR SMBG S19=(MH "Life Style Changes") OR ( lifestyle* or life-style* ) S18=(MH "Diet Therapy") OR ( diet w2 therap* or diet w2 restrict* or diet w2 advice ) OR ( "medical nutrition therapy" or MNT ) S17=( sulfonyurea? or gliclazid* or glimepirid* or glipizid* or glyburid* or tolbutamid* ) OR ( antidiabet* or anti-diabet* ) OR ( insulin* or glibenclamid* or acarbos* ) S16=(MH "Sulfonylurea Compounds+") S15= intervention* or treating or treatment* or therapy or therapies or manage* or monitor* S14= S5 and S10 and S13 S13= S11 or S12 S12=( specific* or sensitiv* or predictive w1 value* or accurac* or diagnostic w1 error* ) OR ( false w1 negative or false w1 positive ) S11=(MH "Diagnostic Errors") OR (MH "Reproducibility of Results") OR (MH "False Negative Results") OR (MH "False Positive Results") OR (MH "Predictive Value of Tests") OR (MH "Sensitivity and Specificity") OR (MH "ROC Curve") OR (MH "Reference Values") S10= S6 or S7 or S8 or S9 S9=( glucose n1 tolerance or glucose n1 intolerance or glucose n1 challenge ) OR ( OGTT or GCT ) OR fasting w2 glucose S8=(MH "Glucose Tolerance Test") OR (MH "Blood Glucose Monitoring") OR (MH "Glucose Intolerance") OR (MH "Blood Glucose") OR (MH "Risk Assessment") S7= screen* OR ( prenatal n2 diagnosis or early n2 diagnosis ) S6=(MH "Neonatal Assessment") OR (MH "Health Screening+") OR (MH "Prenatal Diagnosis+") A-12 S5= S1 or S2 or S3 or S4 S4= hyperglyc#emia n2 pregnan* OR macrosomia S3=( gestation* n2 diabet* or gestation* n2 DM or gestation* n2 glucose intoleran* or gestation* n2 insulin resistan* ) OR ( pregnan* n2 diabet* or pregnan* n2 DM or pregnan* n2 glucose intoleran* or pregnan* n2 insulin resistan* ) OR ( maternal n2 diabet* or maternal n2 DM or maternal n2 glucose intoleran* or maternal n2 insulin resistan* ) S2=( (MM "Diabetes Mellitus, Gestational") OR (MH "Pregnancy Complications") OR (MH "Fetal Macrosomia") ) OR GDM S1=(MM "Diabetes Mellitus, Gestational") OR (MH "Pregnancy Complications") OR (MH "Fetal Macrosomia") Table A8. BIOSIS Preview® Database: Biosis Previews ® via Web of KnowledgeSM <1926–present> Search Date: 9 October 2011 Results: 34 # 17 (#16 OR #15 OR #14) AND Language=(English) # 16 (#9) AND Language=(English) AND Document Types=(Meeting OR Meeting Paper) AND Literature Type=(Meeting Abstract OR Meeting Address OR Meeting Paper OR Meeting Poster OR Meeting Report OR Meeting Slide OR Meeting Summary) # 15 (#13 AND #9) AND Language=(English # 14 (#12 AND #9) AND Language=(English # 13 (TS=( CPG* OR "best practice*" OR "professional standard*" OR "standard of care" OR (practice NEAR/2 guideline*) OR (practice NEAR/2 recommendation*) OR (practice NEAR/2 statement) OR (position NEAR/2 guideline*) OR (position NEAR/2 recommendation*) OR (position NEAR/2 statement) OR (consensus NEAR/2 guideline*) OR (consensus NEAR/2 recommendation*) OR (consensus NEAR/2 statement))) AND Language=(English) # 12 (#10 NOT #11) AND Language=(English) # 11 (TS=(animal* OR rat OR rats OR mouse OR mice OR rodent* OR rabbit OR rabbits OR horse OR horses OR equine OR veterinar* OR bovine OR cow OR cows OR pig OR pigs OR porcine)) AND Language=(English) # 10 ((TS=(randomized controlled trial* OR controlled clinical trial* OR research design OR placebo* OR random*) OR TS=(cohort* OR longitude* OR prospectiv* OR retrospectiv* OR long term OR long-term OR longterm OR followup OR "follow up" OR follow-up) AND TS=(study OR studies OR trial))) AND Language=(English) #9 (#8 OR #4) AND Language=(English) #8 (#7 AND #1) AND Language=(English) #7 (#6 OR #5) AND Language=(English) #6 TS= ((diet NEAR/2 therap*) OR (diet NEAR/2 restrict*) OR (diet NEAR/2 advice) OR "medical nutrition* therapy" OR MNT OR lifestyle* OR life-style* OR ("blood glucose" NEAR self-monitor*) OR ("blood glucose" NEAR "self monitor*") OR SMBG OR counsel* OR (induc* NEAR labour) OR (induc* NEAR labor) OR cesarean OR caesarean OR (pregnan* NEAR outcome*))) AND Language=(English) #5 TS= (intervention* OR treat* OR therap* OR sulfonylurea* OR antidiabet* OR anti-diabet* OR gliclazid* OR glimepirid* OR glipizid* OR glyburid* OR tolbutamid* OR antidiabet* OR anti-diabet* OR insulin* OR glibenclamid* OR acarbos*)) AND Language=(English) #4 #3 AND #2 AND #1 #3 TS=("sensitivity and specificity" OR sensitiv* OR specific* OR "predictive value" OR (diagnos* NEAR error*) OR "false negative" OR "false positive" OR accurac*)) AND Language=(English) #2 TS=( "prenatal screen*" OR (glucose NEAR/3 tolerance) OR (glucose NEAR/3 intoleran*) OR (glucose NEAR/3 challenge*) OR OGTT OR GCT OR "fasting glucose" OR "risk factor* ")) AND Language=(English) #1 TS= ((gestation* NEAR/2 diabet*) OR (gestation* NEAR/2 "glucose intoleran*") OR (gestation* NEAR/2 "insulin resist*") OR (pregnan* NEAR/2 diabet*) OR (pregnan* NEAR/2 "glucose intoleran*") OR (pregnan* NEAR/2 "insulin resist*") OR (maternal NEAR/2 diabet*) OR (maternal NEAR/2 "glucose intoleran*") OR (maternal NEAR/2 "insulin resist*") OR (hyperglycemia NEAR/2 pregnan*) OR (hyperglycaemia NEAR/2 pregnan*) OR macrosomia OR GDM)) AND Language=(English) Table A9. Science Citation Index Expanded® Database: Science Citation Index Expanded (SCI-EXPANDED) via Web of KnowledgeSM <1899–present> Search Date: 9 October 2011 Results: 2,308 # 17 (#16 OR #15 OR #14) AND Language=(English) # 16 (#9) AND Language=(English) AND Document Types=(Meeting OR Meeting Paper) AND Literature Type=(Meeting Abstract OR Meeting Address OR Meeting Paper OR Meeting Poster OR Meeting Report OR Meeting Slide OR Meeting Summary) # 15 (#13 AND #9) AND Language=(English # 14 (#12 AND #9) AND Language=(English # 13 (TS=( CPG* OR "best practice*" OR "professional standard*" OR "standard of care" OR (practice NEAR/2 guideline*) OR (practice NEAR/2 recommendation*) OR (practice NEAR/2 statement) OR (position NEAR/2 guideline*) OR A-13 (position NEAR/2 recommendation*) OR (position NEAR/2 statement) OR (consensus NEAR/2 guideline*) OR (consensus NEAR/2 recommendation*) OR (consensus NEAR/2 statement))) AND Language=(English) # 12 (#10 NOT #11) AND Language=(English) # 11 (TS=(animal* OR rat OR rats OR mouse OR mice OR rodent* OR rabbit OR rabbits OR horse OR horses OR equine OR veterinar* OR bovine OR cow OR cows OR pig OR pigs OR porcine)) AND Language=(English) # 10 ((TS=(randomized controlled trial* OR controlled clinical trial* OR research design OR placebo* OR random*) OR TS=(cohort* OR longitude* OR prospectiv* OR retrospectiv* OR long term OR long-term OR longterm OR followup OR "follow up" OR follow-up) AND TS=(study OR studies OR trial))) AND Language=(English) #9 (#8 OR #4) AND Language=(English) #8 (#7 AND #1) AND Language=(English) #7 (#6 OR #5) AND Language=(English) #6 TS= ((diet NEAR/2 therap*) OR (diet NEAR/2 restrict*) OR (diet NEAR/2 advice) OR "medical nutrition* therapy" OR MNT OR lifestyle* OR life-style* OR ("blood glucose" NEAR self-monitor*) OR ("blood glucose" NEAR "self monitor*") OR SMBG OR counsel* OR (induc* NEAR labour) OR (induc* NEAR labor) OR cesarean OR caesarean OR (pregnan* NEAR outcome*))) AND Language=(English) #5 TS= (intervention* OR treat* OR therap* OR sulfonylurea* OR antidiabet* OR anti-diabet* OR gliclazid* OR glimepirid* OR glipizid* OR glyburid* OR tolbutamid* OR antidiabet* OR anti-diabet* OR insulin* OR glibenclamid* OR acarbos*)) AND Language=(English) #4 #3 AND #2 AND #1 #3 TS=("sensitivity and specificity" OR sensitiv* OR specific* OR "predictive value" OR (diagnos* NEAR error*) OR "false negative" OR "false positive" OR accurac*)) AND Language=(English) #2 TS=( "prenatal screen*" OR (glucose NEAR/3 tolerance) OR (glucose NEAR/3 intoleran*) OR (glucose NEAR/3 challenge*) OR OGTT OR GCT OR "fasting glucose" OR "risk factor* ")) AND Language=(English) #1 TS= ((gestation* NEAR/2 diabet*) OR (gestation* NEAR/2 "glucose intoleran*") OR (gestation* NEAR/2 "insulin resist*") OR (pregnan* NEAR/2 diabet*) OR (pregnan* NEAR/2 "glucose intoleran*") OR (pregnan* NEAR/2 "insulin resist*") OR (maternal NEAR/2 diabet*) OR (maternal NEAR/2 "glucose intoleran*") OR (maternal NEAR/2 "insulin resist*") OR (hyperglycemia NEAR/2 pregnan*) OR (hyperglycaemia NEAR/2 pregnan*) OR macrosomia OR GDM)) AND Language=(English) Table A10. Conference Proceedings Citation Index–Science Database: Conference Proceedings Citation Index- Science [CPCI-S] via Web of ScienceSM <1990–present> Search Date: 9 October 2011 Results: 562 # 17 (#16 OR #15 OR #14) AND Language=(English) # 16 (#9) AND Language=(English) AND Document Types=(Meeting OR Meeting Paper) AND Literature Type=(Meeting Abstract OR Meeting Address OR Meeting Paper OR Meeting Poster OR Meeting Report OR Meeting Slide OR Meeting Summary) # 15 (#13 AND #9) AND Language=(English # 14 (#12 AND #9) AND Language=(English # 13 (TS=( CPG* OR "best practice*" OR "professional standard*" OR "standard of care" OR (practice NEAR/2 guideline*) OR (practice NEAR/2 recommendation*) OR (practice NEAR/2 statement) OR (position NEAR/2 guideline*) OR (position NEAR/2 recommendation*) OR (position NEAR/2 statement) OR (consensus NEAR/2 guideline*) OR (consensus NEAR/2 recommendation*) OR (consensus NEAR/2 statement))) AND Language=(English) # 12 (#10 NOT #11) AND Language=(English) # 11 (TS=(animal* OR rat OR rats OR mouse OR mice OR rodent* OR rabbit OR rabbits OR horse OR horses OR equine OR veterinar* OR bovine OR cow OR cows OR pig OR pigs OR porcine)) AND Language=(English) # 10 ((TS=(randomized controlled trial* OR controlled clinical trial* OR research design OR placebo* OR random*) OR TS=(cohort* OR longitude* OR prospectiv* OR retrospectiv* OR long term OR long-term OR longterm OR followup OR "follow up" OR follow-up) AND TS=(study OR studies OR trial))) AND Language=(English) #9 (#8 OR #4) AND Language=(English) #8 (#7 AND #1) AND Language=(English) #7 (#6 OR #5) AND Language=(English) #6 TS= ((diet NEAR/2 therap*) OR (diet NEAR/2 restrict*) OR (diet NEAR/2 advice) OR "medical nutrition* therapy" OR MNT OR lifestyle* OR life-style* OR ("blood glucose" NEAR self-monitor*) OR ("blood glucose" NEAR "self monitor*") OR SMBG OR counsel* OR (induc* NEAR labour) OR (induc* NEAR labor) OR cesarean OR caesarean OR (pregnan* NEAR outcome*))) AND Language=(English) #5 TS= (intervention* OR treat* OR therap* OR sulfonylurea* OR antidiabet* OR anti-diabet* OR gliclazid* OR glimepirid* OR glipizid* OR glyburid* OR tolbutamid* OR antidiabet* OR anti-diabet* OR insulin* OR glibenclamid* OR acarbos*)) AND Language=(English) #4 #3 AND #2 AND #1 #3 TS=("sensitivity and specificity" OR sensitiv* OR specific* OR "predictive value" OR (diagnos* NEAR error*) OR "false negative" OR "false positive" OR accurac*)) AND Language=(English) A-14 #2 TS=( "prenatal screen*" OR (glucose NEAR/3 tolerance) OR (glucose NEAR/3 intoleran*) OR (glucose NEAR/3 challenge*) OR OGTT OR GCT OR "fasting glucose" OR "risk factor* ")) AND Language=(English) #1 TS= ((gestation* NEAR/2 diabet*) OR (gestation* NEAR/2 "glucose intoleran*") OR (gestation* NEAR/2 "insulin resist*") OR (pregnan* NEAR/2 diabet*) OR (pregnan* NEAR/2 "glucose intoleran*") OR (pregnan* NEAR/2 "insulin resist*") OR (maternal NEAR/2 diabet*) OR (maternal NEAR/2 "glucose intoleran*") OR (maternal NEAR/2 "insulin resist*") OR (hyperglycemia NEAR/2 pregnan*) OR (hyperglycaemia NEAR/2 pregnan*) OR macrosomia OR GDM)) AND Language=(English) Table A11. LILACS (Latin American and Caribbean Health Science Literature) Database: LILACS (Latin American and Caribbean Health Science Literature) <1982–current> Search Date: 14 October 2011 Results: 236 1. gestational diabet$ AND (screening OR diagnos$) 2. maternal diabet$ AND (screening OR diagnos$) 3. gestational diabet$ AND (treating or treatment$ or therapy or therapies) 4. maternal diabet$ AND (treating or treatment$ or therapy or therapies) Table A12. OCLC PapersFirst and PapersFirst Databases: ProceedingsFirst PapersFirst Search Date: 16 October 2011 Results: ProceedingsFirst: 138; PapersFirst: 102 (kw: gestation* w2 diabet* OR kw: gestation* w2 glucose w intoleran* OR kw: gestation* w2 insulin w resist* OR kw: pregnan* w2 diabet* OR kw: pregnan* w2 glucose w intoleran* OR kw: pregnan* w2 insulin w resist* OR kw: maternal w2 diabet* OR kw: maternal w2 glucose w intoleran* OR kw: maternal w2 insulin w resist* OR kw: hyperglycemia w2 pregnan* OR kw: hyperglycaemia w2 pregnan* OR kw: macrosomia OR kw: GDM) and ((kw: prenatal w screen* OR kw: glucose w3 tolerance OR kw: glucose w3 intoleran* OR kw: glucose w3 challenge* OR kw: OGTT OR kw: GCT OR kw: fasting w glucose OR kw: risk w factor*) or ((kw: intervention* OR kw: treat* OR kw: therap* OR kw: sulfonylurea* OR kw: antidiabet* OR kw: anti-diabet* OR kw: gliclazid* OR kw: glimepirid* OR kw: glipizid* OR kw: glyburid* OR kw: tolbutamid* OR kw: antidiabet* OR kw: anti-diabet* OR kw: insulin* OR kw: glibenclamid* OR kw: acarbos*) or (kw: diet w2 therap* OR kw: diet w2 restrict* OR kw: diet w2 advice OR kw: medical w nutrition* w therapy OR kw: MNT OR kw: lifestyle* OR kw: life-style* OR kw: blood w glucose w self-monitor* OR kw: blood w glucose w self w monitor* OR kw: SMBG OR kw: counsel* OR kw: induc* w labour OR kw: induc* w labor OR kw: cesarean OR kw: caesarean OR kw: pregnan* w outcome*))) Table A13. PubMed Database: PubMed via NLM <last 180 days from 9 October 2011> Search Date: 9 October 2011 Results: 377 #46 #39 NOT #45 #45 animal[TI] OR rat[TI] OR rats[TI] OR mouse [TI] OR mice[TI] OR rodent*[TI] OR rabbit*[TI] OR horse*[TI] OR horses[TI] veterinar*[TI] OR cattle[TI] OR bovine[TI] OR cow[TI] OR cows[TI] OR swine[TI] OR pig[TI] OR pigs[TI] OR porcine[TI] #39 #21 OR #37 Limits: English, published in the last 180 days #38 #21 OR #37 #37 #7 and #36 #36 #22 OR #23 OR #25 OR #28 OR #30 OR #31 OR #32 OR #33 OR #34 OR #34 #35 pregnanc* outcome* #34 cesarean OR caesarean #33 ((induc* AND labour) OR (induc* AND labor)) #32 counsel* #31 SMBG #30 ((self monitor* OR self-monitor*) AND blood glucose) #28 (blood glucose AND (self monitor* OR self-monitor*)) #25 lifestyle OR life-style #24 diet therap* OR diet* restrict* OR diet* advice OR medical nutrition therapy OR MNT #23 sulfonylurea* OR gliclazid* OR glimepirid* OR glipizid* OR glyburid* OR tolbutamid* OR antidiabet* OR anti-diabet* OR insulin* OR glibenclamid* OR acarbos* #22 intervention* OR treating OR treatment? OR therapy OR therapies OR manage* OR monitor* A-15 #21 #7 AND #16 AND #20 #20 #17 OR #18 OR #19 #19 reference standard* OR reference value* #18 ROC OR "receiver operating characteristic" #17 specific* OR sensitiv* OR predictive value OR accurac* OR diagnostic error* #16 #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 #15 fasting glucose #14 OGTT OR GCT #13 (glucose AND (tolerance OR intolerance OR challenge)) #12 risk factor* #11 blood glucose #10 ((prenatal OR early) AND diagnosis) #9 screen* #8 mass screening[MeSH Terms] #7 #1 OR #2 OR #3 OR #4 OR #5 OR #6 #6 macrosomia #5 ((hyperglycaemia OR hyperglycemia) AND pregnan*) #4 (maternal AND (diabetic* OR diabete* OR DM OR glucose intoleran* OR insulin resistan*)) #3 (pregnan* AND (diabetic* OR diabete* OR DM OR glucose intoleran* OR insulin resistan*)) #2 (gestation* AND (diabetic* OR diabete* OR DM OR glucose intoleran* OR insulin resistan*)) #1 GDM Table A14. Clinical Trials.gov and WHO Databases: ClinicalTrials.gov <1987 to February week 3 2012> WHO International Clinical Trials Registry Search Date: 23 February 2012 Results: 200 ((asperger) OR (autistic disorder) OR autism OR schizophrenia OR (bipolar disorder) OR (depression) OR (bipolar disorder) OR (obsessive-compulsive) OR (post-traumatic) OR (anorexia nervosa) OR anorexia) AND (antipsychotics) AND (child OR adolescent OR pediatric OR infant) AND PDN(>1/1/1987) AND PDN(<12/31/2010) A-16 Appendix B. Review Forms B1. Screening Criteria for Key Questions 1-5 B2. Eligibility Criteria for Key Questions 1-5 B3. Methodological Quality Assessment by Study Design a. Diagnostic studies – QUADAS-2 Tool b. Randomized controlled trials – Cochrane Collaboration’s tool for assessing risk of bias c. Cohort studies – Newcastle-Ottawa Quality Assessment Scale B4. Data Extraction Forms a. b. c. d. Screening and diagnosing gestational diabetes – key question 1 Screening and diagnosing gestational diabetes – key question 2 Screening and diagnosing gestational diabetes – key question 3 Screening and diagnosing gestational diabetes – key question 4 and 5 B-1 B1. Screening Criteria for Key Questions 1-5 1. Primary Research Yes No Unclear 2. Published in English language Yes No Unclear 3. Published from 1995 onward Yes No Unclear 4. Must have a comparison group (i.e., RCT, NRCT, R or P cohort, case control) Yes No Unclear 5. Population: Pregnant women Yes No Unclear 6. Intervention: Using any GDM screening or diagnostic approach, (e.g., 1-step, 2-step, or other); and/or Any treatment for GDM (e.g., dietary advice, blood glucose monitoring, insulin therapy) Yes No Unclear Notes for screeners: 1. Mark each study as “no” [exclude], “unclear” or “yes” [retrieve full text] based on the criteria above. 2. FLAG any relevant systematic reviews or meta-analyses using the code “sr”. 3. FLAG any studies that may be useful for background information with the code “bkg”. Key words have been colour-coded and will appear in a different font. Here is an index of the colouring: Green  population (e.g., gestational diabetes, pregnancy) Purple  treatments (e.g., diet, insulin, blood glucose monitoring, antidiabetic) Aqua  screening-related terms (e.g., screening, diagnosis, sensitivity, specificity, positive predictive value, negative predictive value) Orange  specific tests (e.g., glucose tolerance test, glucose challenge test, glucose screening test, diagnostic threshold) Blue  study designs (e.g., randomized, controlled trial, cohort, case control) B-2 B2. Eligibility Criteria for Key Questions 1-5 INCLUSION / EXCLUSION FORM Reviewer: Ref ID: CRITERIA Yes No Unclear 1. PUBLICATION TYPE a) Report of primary research b) Full report available (Exclude abstracts and conference proceedings) c) English language d) Published in 1995 onward 2. STUDY DESIGN a) Comparative study design (2 or more groups); one of: i. RCT ii. NRCT iii. Prospective or retrospective cohort studies (with concurrent or nonconcurrent/historical control groups) 3. POPULATION a) Pregnant women (any duration of gestation); Exclude if >20% of enrolled women had known pre-existing diabetes and no subgroup analysis 4. INTERVENTION a) Evaluating any GDM screening or diagnostic approach, (KQ1 & 2) or screening / diagnostic threshold (KQ3) and/or b) Evaluating any treatment for GDM (KQ4 & 5) 5. COMPARATORS One or more of the following: a) Any reference standard, other screening / diagnostic test, or criteria (KQ1) [note: can also be a risk-factor if used for screening]; b) No screening / diagnostic test for GDM (KQ2); c) Patients meeting different screening / diagnostic threshold for GDM (e.g., GDM vs. no GDM) (KQ3); d) Placebo or no treatment (KQ4 & 5) Exclude studies that compare 2 or more treatment, but have no placebo, standard care or no treatment group 6. OUTCOME Any one or more of the following: a) Test properties (i.e., sensitivity, specificity, predictive values, accuracy; not yield only); b) Maternal outcomes: i. Short-term: preeclampsia/maternal hypertension, cesarean delivery, depression, birth trauma, mortality, weight gain, other morbidity ii. Long-term: Type 2 DM risk, obesity, hypertension c) Fetal/neonatal/child outcomes: i. Short-term: macrosomia, shoulder dystocia, clavicular fracture, brachial plexus injury, birth injury, hypoglycemia, hyperbilirubinemia, mortality, other morbidity ii. Long-term: obesity, type 2 DM, transgenerational GDM d) Any adverse events or harms of screening or treatment (e.g., anxiety, healthcare system issues, burden on practitioner’s office, increased interventions, postpartum depression, small for gestational age, costs, resource allocations) Comments: REVIEWER’S DECISION : Include Exclude Unsure RELEVANT TO QUESTION(S): KQ1 KQ2 KQ3 B-3 KQ4 KQ5 B3. Methodological Quality a. QUADAS-2 Checklist (Diagnostic Studies) Item Assessment 1. Patient Selection a. Was a consecutive or random sample of patients enrolled? Support for judgment b. Did the study avoid inappropriate exclusions? Support for judgment c. Was the study a low risk of bias? d. Is the study applicable to the review? Support for judgment 2. Index Test a. Were the index test results interpreted without knowledge of the results of the reference standard? Support for judgment b. If a threshold was used, was it pre-specified? Support for judgment c. Was the study a low risk of bias? d. Is the study applicable to the review? Support for judgment 3. Reference Standard a. Is the reference standard likely to correctly classify the target audience? Support for judgment b. Were the reference standard results interpreted without knowledge of the results of the index test? Support for judgment c. Was the study a low risk of bias? d. Is the study applicable to the review? Support for judgment 4. Flow and Timing a. Was there an appropriate interval between the index test and reference standard? Support for judgment b. Did all patients receive the same reference standard? Support for judgment c. Were all patients included in the analysis? Support for judgment d. Was the study a low risk of bias? B-4 b. The Cochrane Collaboration’s tool for assessing risk of bias (randomized controlled trials) Domain Description Review authors’ judgment Random sequence generation Was the allocation sequence adequately generated? Allocation concealment Was allocation adequately concealed? Blinding of participants and personnel Subjective outcomes Was knowledge of the allocated intervention adequately prevented during the study? Subjective: Objective: Objective outcomes Blinding of outcome assessment Subjective outcomes Was knowledge of the allocated intervention adequately prevented during the study? Subjective: Objective: Objective outcomes Incomplete outcome data, Outcome: Subjective outcomes Were incomplete outcome data adequately addressed? Subjective: Objective outcomes Objective: Selective outcome reporting Are reports of the study free of suggestion of selective outcome reporting? Other sources of bias Was the study apparently free of other problems that could put it at a high risk of bias? Overall risk of bias Subjective outcomes Objective outcomes B-5 c. Newcastle-Ottawa Quality Assessment Scale (Cohort Studies) Selection 1) Representativeness of the exposed cohort (i.e., glucose intolerant or GDM patients) a) truly representative of the average patient with glucose intolerance in the community * b) somewhat representative of the average glucose intolerance in the community * c) selected group of users eg nurses, volunteers d) no description of the derivation of the cohort 2) Selection of the non-exposed cohort (i.e., normal or minimal glucose intolerant patients) a) drawn from the same community as the exposed cohort * b) drawn from a different source c) no description of the derivation of the non exposed cohort 3) Ascertainment of exposure a) secure record (eg surgical records) * b) structured interview * c) written self report d) no description 4) Demonstration that outcome of interest was not present at start of study a) yes * b) no Comparability 1) Comparability of cohorts on the basis of the design or analysis a) study controls for age, race/ethnicity, weight/BMI, previous GDM, or family history of diabetes ** b) study controls for any additional factor * Outcome 1) Assessment of outcome a) independent blind assessment * b) record linkage * c) self report d) no description 2) Was follow-up long enough for outcomes to occur a) yes (follows patients at least until birth) * b) no 3) Adequacy of follow up of cohorts a) complete follow up - all subjects accounted for * b) subjects lost to follow up unlikely to introduce bias: small number lost (>90% follow up), or description provided of those lost * c) follow up rate <75% and no description of those lost d) no statement TOTAL STARS (0-9) Note: A study can be awarded a maximum of one star for each numbered item within the Selection and Outcome categories. A maximum of two stars can be given for Comparability B4. Data Extraction B-6 a. Screening and Diagnosing Gestational Diabetes – Key Question 1 I. Coder Information RefID: First Author: DE initials: DV initials: Year: Other KQs: 2; 3; 4; 5 II. Study Characteristics Country: Publication type: Centers: Recruitment start date (e.g., Jan 1998): Funding: Industry; Government; Study design: Recruitment end date (e.g., Feb 2000): Foundation; No funding; Other; ND Academic; If industry, specify firm*: Blinding to test result: * Use “NR” if not reported III. Selection Criteria and Testing Conditions Inclusion criteria: If “other,” specify*: Duration of followup: Exclusion criteria: Exclude pre-pregnancy (type 1, 2)? Exclude overt diabetes diagnosed during pregnancy? Did patients routinely undergo early testing for overt diabetes during pregnancy? Patients Enrolled Consecutively: Comparisons Done: Matched Study (all comparator tests performed in all patients) Random (comparator tests done in different patients) Yes No ND Non-Random (comparator tests in different patients, select gp) Reference standard reported? If so, specify: B-7 IV. Screening and Diagnostic Tests GCT/GST? OGTT? Index test? : Pre-test protocol (fast/diet): Index test? : Pre-test protocol (fast/diet): Test Intervals: Fasting; 1 hr; 2 hr; 3 hr Glucose load: Time of test (wks): Criteria: ADA, year: CC, year: NDDG, year: WHO, year: Other1: , year: Other2: , year: NR Brand of beverage*: Amount of liquid*: Brand of Glucose meter: Manufacturing company: Plasma glucose estimation method: Manufacturing company: Central lab? Test Intervals: Fasting; 1 hr; hr Glucose load: Time of test (wks): Criteria: ADA, year: CC, year: NDDG, year: WHO, year: Other1: , year: Other2: , year: NR Brand of beverage*: Amount of liquid*: 2 hr; Other test 1? Specify: Index test? : Pre-test protocol (fast/diet): 3 Other test 2? Specify: Index test? : Pre-test protocol (fast/diet): Test Intervals: Test Intervals: Fasting; 1 hr; 2 hr; 3 Fasting; 1 hr; hr hr Glucose load: Glucose load: Time of test (wks): Time of test (wks): Criteria: Criteria: ADA, year: ADA, year: CC, year: CC, year: NDDG, year: NDDG, year: WHO, year: WHO, year: Other1: , year: Other1: , year: Other2: , year: Other2: , year: NR NR Brand of beverage*: Brand of beverage*: Amount of liquid*: Amount of liquid*: Measurements performed by trained staff? Notes: *If not reported, use NR B-8 2 hr; 3 V. Study Arms Group 1 Group 2 Group label GCT: Fasting ± ± GCT: 1hr ± ± GCT: 2hr ± ± GCT:3hr ± ± OGTT: Fasting ± ± OGTT: 1hr ± ± OGTT: 2hr ± ± OGTT: 3hr ± ± Treatment status Glucose levels reported in the following units: mg/dL; mmol/L Are groups mutually exclusive? Baseline Characteristics Group 1 Group 2 Pts enrolled, n Pts analyzed, n Withdrawals, n Age (yr), ± ± mean ± SD median ± IQR Prepregn. weight, ± ± lb; kg mean ± SD median ± IQR BMI, ± ± mean±SD median ± IQR SBP (mmHg), ± ± mean ± SD median ± IQR Group 1 Group 2 White, n Black, n Hispanic, n Asian, n Other, n Gestation at time ± ± of test (wk) mean ± SD median ± IQR Smoking, n Alcohol use, n Family history of Group 3 Group 4 TOTAL ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± Glucose levels reported as: median ± IQR mean ± SD; I. Group 3 Group 4 TOTAL ± ± ± ± ± ± ± ± ± ± ± ± Group 3 Group 4 TOTAL ± ± ± B-9 diabetes, n History of GDM, n Parity, n Parity mean ± SD median ± IQR Comorbidities, n 0 1 ≥2 0 1 ≥2 ± 0 1 ≥2 ± 0 1 ≥2 ± Comments II. Conclusions Briefly paraphrase the author conclusions: REFERENCES TO BE CHECKED: ASSOCIATED PUBLICATIONS (list all separated by semi-colons): B-10 0 1 ≥2 ± ± b. Screening and Diagnosing Gestational Diabetes – Key Question 2 IV. Coder Information RefID: First Author: DE initials: DV initials: Year: Other KQs: 1; 3; 4; V. Study Characteristics Country: Publication type: Centers: Recruitment start date (e.g., Jan 1998): Funding: Industry; Government; Study design: Recruitment end date (e.g., Feb 2000): Foundation; No funding; Other; ND Academic; If industry, specify firm*: Blinding to test result: * Use “NR” if not reported VI. Study Eligibility Criteria Inclusion criteria: 5 If “other,” specify*: Duration of followup: Exclusion criteria: Exclude pre-pregnancy (type 1, 2)? Exclude overt diabetes diagnosed during pregnancy? Did patients routinely undergo early testing for overt diabetes during pregnancy? VII. Screening and Diagnostic Tests GCT/GST? OGTT? Test intervals: Test intervals: Fasting; 1 hr; 2 hr; Fasting; 1 hr; 3 hr 3 hr Glucose load: Glucose load: Time of test (wks): Time of test (wks): Criteria: Criteria: ADA, year: ADA, year: CC, year: CC, year: NDDG, year: NDDG, year: WHO, year: WHO, year: Other1: , year: Other1: , year: Other2: , year: Other2: , year: NR NR Central lab? Notes: B-11 2 hr; Specify: Other test? Test intervals: Fasting; 1 hr; 2 hr; 3 hr Glucose load: Time of test (wks): Criteria: ADA, year: CC, year: NDDG, year: WHO, year: Other1: , year: Other2: , year: NR VIII. Study Arms Group 1 Group 2 Group label GCT: Fasting ± ± GCT: 1 hr ± ± GCT: 2 hr ± ± GCT: 3 hr ± ± OGTT: Fasting ± ± OGTT: 1 hr ± ± OGTT: 2 hr ± ± OGTT: 3 hr ± ± Treatment status Glucose levels reported in the following units: Are groups mutually exclusive? Baseline Characteristics Group 1 Pts enrolled, n Pts analyzed, n Withdrawals, n Age (yr), ± mean ± SD median ± IQR Prepregn. weight, ± lb; kg mean ± SD median ± IQR BMI, ± mean±SD median ± IQR SBP (mmHg), ± mean ± SD median ± IQR Group 1 Group 3 Group 4 Group 5 Group 6 Group 7 TOTAL ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± mean ± SD; median ± IQR mg/dL; mmol/L Glucose levels reported as: IX. Group 2 Group 3 Group 4 Group 5 Group 6 Group 7 TOTAL ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± Group 2 Group 3 Group 4 Group 5 Group 6 Group 7 TOTAL B-12 White, n Black, n Hispanic, n Asian, n Other, n Gestation at time of test (wk) mean ± SD median ± IQR Smoking, n Alcohol use, n Family history of diabetes, n History of GDM, n Parity, n Parity mean ± SD median ± IQR Comorbidities, n ± 0 1 ≥2 ± 0 1 ≥2 ± ± 0 1 ≥2 ± ± 0 1 ≥2 ± ± 0 1 ≥2 ± Comments B-13 ± 0 1 ≥2 ± ± 0 1 ≥2 ± ± 0 1 ≥2 ± ± X. Conclusions Briefly paraphrase the author conclusions: REFERENCES TO BE CHECKED: ASSOCIATED PUBLICATIONS (list all separated by semi-colons): B-14 c. Screening and Diagnosing Gestational Diabetes – Key Question 3 I. Coder Information RefID: First Author: DE initials: DV initials: Year: Other KQs: 1; 2; 4; II. Study Characteristics Country: Publication type: Centers: Recruitment start date (e.g., Jan 1998): Funding: Industry; Government; Study design: Recruitment end date (e.g., Feb 2000): Foundation; No funding; Other; ND Academic; If industry, specify firm*: Blinding to test result: * Use “NR” if not reported III. Study Eligibility Criteria Inclusion criteria: 5 If “other,” specify*: Duration of followup: Exclusion criteria: Exclude pre-pregnancy (type 1, 2)? Exclude overt diabetes diagnosed during pregnancy? Did patients routinely undergo early testing for overt diabetes during pregnancy? IV. Screening and Diagnostic Tests GCT/GST? OGTT? Test intervals: Test intervals: Fasting; 1 hr; 2 hr; Fasting; 1 hr; 3 hr 3 hr Glucose load: Glucose load: Time of test (wks): Time of test (wks): Criteria: Criteria: ADA, year: ADA, year: CC, year: CC, year: NDDG, year: NDDG, year: WHO, year: WHO, year: Other1: , year: Other1: , year: Other2: , year: Other2: , year: NR NR Central lab? Notes: B-15 2 hr; Specify: Other test? Test intervals: Fasting; 1 hr; 2 hr; 3 hr Glucose load: Time of test (wks): Criteria: ADA, year: CC, year: NDDG, year: WHO, year: Other1: , year: Other2: , year: NR V. Study Arms Group 1 Group 2 Group label GCT: Fasting ± ± GCT: 1 hr ± ± GCT: 2 hr ± ± GCT: 3 hr ± ± OGTT: Fasting ± ± OGTT: 1 hr ± ± OGTT: 2 hr ± ± OGTT: 3 hr ± ± Treatment status Glucose levels reported in the following units: Are groups mutually exclusive? Baseline Characteristics Group 1 Pts enrolled, n Pts analyzed, n Withdrawals, n Age (yr), ± mean ± SD median ± IQR Prepregn. weight, ± lb; kg mean ± SD median ± IQR BMI, ± mean±SD median ± IQR SBP (mmHg), ± mean ± SD median ± IQR Group 1 Group 3 Group 4 Group 5 Group 6 Group 7 TOTAL ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± mean ± SD; median ± IQR mg/dL; mmol/L Glucose levels reported as: VI. Group 2 Group 3 Group 4 Group 5 Group 6 Group 7 TOTAL ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± Group 2 Group 3 Group 4 Group 5 Group 6 Group 7 TOTAL B-16 White, n Black, n Hispanic, n Asian, n Other, n Gestation at time of test (wk) mean ± SD median ± IQR Smoking, n Alcohol use, n Family history of diabetes, n History of GDM, n Parity, n Parity mean ± SD median ± IQR Comorbidities, n ± 0 1 ≥2 ± 0 1 ≥2 ± ± 0 1 ≥2 ± ± 0 1 ≥2 ± ± 0 1 ≥2 ± Comments B-17 ± 0 1 ≥2 ± ± 0 1 ≥2 ± ± 0 1 ≥2 ± ± VII. Conclusions Briefly paraphrase the author conclusions: REFERENCES TO BE CHECKED: ASSOCIATED PUBLICATIONS (list all separated by semi-colons): B-18 d. Screening and Diagnosing Gestational Diabetes Mellitus – Key Question 4 and 5 I. Ref ID: Coder Information First Author: DE Initials: DE Reviewer Initials: II. Study Characteristics Country: Centers: Funding: Year of Publication: Industry; Government; Other KQs: 1; 3 Publication Type: Study Design: Recruitment start date (e.g. Jan. 2001): Recruitment end date (e.g. Feb. 2000): Academic; Foundation; No funding; If Industry, specify firm:* If "Other", specify*: Blinding to test result: Duration of followup: *use NR if not reported III. Study Eligibility Criteria Inclusion Criteria: 2; Other; ND Exclusion Criteria: Exclude pre-pregnancy diabetes (type 1, 2)? Exclude overt diabetes diagnosed during pregnancy? Did patients routinely undergo early testing for overt diabetes during pregnancy? IV. Screening and Diagnostic Tests GCT/GST? OGTT? Test intervals: Test intervals: Fasting; 1 hr; 2 hr; Fasting; 1 hr; 3 hr 3 hr Glucose load: Glucose load: Time of test (wks): Time of test (wks): Criteria: Criteria: ADA, year: ADA, year: CC, year: CC, year: NDDG, year: NDDG, year: WHO, year: WHO, year: Other1: , year: Other1: , year: Other2: , year: Other2: , year: NR NR Central lab? Notes: B-19 2 hr; Specify: Other test? Test intervals: Fasting; 1 hr; 2 hr; 3 hr Glucose load: Time of test (wks): Criteria: ADA, year: CC, year: NDDG, year: WHO, year: Other1: , year: Other2: , year: NR V. Study Arms Group 1 Group 2 Group label GCT: Fasting ± ± GCT: 1hr ± ± GCT: 2hr ± ± GCT:3hr ± ± OGTT: Fasting ± ± OGTT: 1hr ± ± OGTT: 2hr ± ± OGTT: 3hr ± ± Treatment status Glucose levels reported in the following units: mg/dL; mmol/L Are groups mutually exclusive? VI. Intervention Group 1 Study arm label Brief description of intervention Care provider(s) BG target: FGB BG target: 1 hr Dietary counseling/ advice? Formal diet plan? If formal diet, describe: Involve dietician/ nutritionist? BG monitoring? Frequency of BG monitoring BGM device Insulin? Oral medications? Drug name BG values for prescription: Dosing Daily dosage Other tx Rules for tx/dose adjustment Group 3 Group 4 TOTAL ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± Glucose levels reported as: median ± IQR Group 2 Group 3 mean ± SD; Group 4 Units: Units: Units: Units: Units: Units: Units: Units: x per x per x per x per ≥ Units: Time: ≥ Units: Time: ≥ Units: Time: ≥ Units: Time: Units: Units: Units: Units: B-20 Comments VII. Baseline Characteristics Group 1 Pts enrolled, n Pts analyzed, n Withdrawals, n Age (yr) ± mean ± SD median ± IQR Prepregn. weight, ± lb; kg mean ± SD median ± IQR BMI, ± mean±SD median ± IQR SBP (mmHg), ± mean ± SD median ± IQR White, n Black, n Hispanic, n Asian, n Other, n Gestation at time ± of test (wk) mean ± SD median ± IQR Smoking, n Alcohol use, n Family history of diabetes, n History of GDM, n Parity, n 0 1 ≥2 Parity ± mean ± SD median ± IQR Overt diabetes, n Comorbidities, n Group 2 Group 3 Group 4 TOTAL ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 0 1 ≥2 0 1 ≥2 ± 0 1 ≥2 ± B-21 0 1 ≥2 ± ± Comments VIII. Conclusions Briefly paraphrase author conclusions: REFERENCES TO BE CHECKED: ASSOCIATED PUBLICATIONS (list all separated by semi-colons): B-22 Appendix C. Methodological Quality of Included Studies Table C1. Methodological quality of diagnostic studies using QUADAS-2 for Key Question 1 Table C2. Methodological quality of randomized controlled trials (RCTs) using the Cochrane Collaboration’s tool for assessing risk of bias for Key Questions 2 to 5 Table C3. Methodological quality of prospective cohort studies (PCS) and retrospective cohort studies (RCS) using Newcastle-Ottawa Quality Assessment Scale, by Key Question and design C-1 Table C1. Methodological quality of diagnostic studies using QUADAS-2 for Key Question 1 d. applicable a. likely to classify b. index results not known c. low risk of bias d. applicable a. interval b. same standard c. all included in analysis d. low risk of bias Flow and Timing* c. low risk of bias 4. b. threshold Reference Standard* a. reference results not known 3. d. applicable Index Test* c. low risk of bias Agarwal, 2000 PCS Agarwal, 2001 PCS (34426) Agarwal, 2005a PCS Agarwal, 2005b PCS Agarwal, 2006 PCS Agarwal, 2008 PCS Agarwal, 2011 PCS Ardawi, 2000 PCS Ayach, 2006 PCS Balaji(1), 2011 PCS Balaji(2), 2011 PCS Berkus, 1995 PCS Bobrowski, 1996 PCS Brustman, 1995 PCS 2. b. exclusion Author, Year Study design Patient Selection* a. sample 1. No Yes No No U U U Yes Yes U U Yes U Yes Yes U No Yes No No U Yes U Yes Yes U U Yes U Yes Yes U Yes U U No U Yes U Yes Yes U U Yes U Yes Yes U Yes Yes Yes No U Yes U Yes Yes U U Yes U Yes Yes U Yes Yes Yes No U U U Yes Yes U U Yes U Yes Yes U Yes No U No U Yes U Yes Yes U U Yes Yes Yes Yes Yes Yes Yes Yes No U U U U Yes U U Yes Yes Yes Yes Yes Yes U U No Yes Yes Yes Yes Yes No No Yes Yes Yes U U Yes No No No Yes Yes Yes Yes Yes U U Yes Yes Yes U U Yes Yes Yes No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No U Yes U Yes U Yes U Yes Yes Yes U U No Yes No Yes U Yes U Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes No Yes U Yes U Yes Yes U U Yes U Yes Yes U No Yes No Yes U Yes U Yes Yes Yes Yes Yes Yes Yes Yes Yes C-2 d. applicable a. likely to classify b. index results not known c. low risk of bias d. applicable a. interval b. same standard c. all included in analysis d. low risk of bias Flow and Timing* c. low risk of bias 4. b. threshold Reference Standard* a. reference results not known Chevalier, 2011 PCS De los Monteros, 1999 PCS Deerochanawong, 1996 PCS Eslamian, 2008 PCS Gandevani, 2011 PCS Hill, 2005 PCS Jakobi, 2003 PCS Jensen, 2004 PCS Kashi, 2007 PCS Kauffman, 2006 PCS Lamar, 1999 PCS 3. d. applicable Chastang, 2003 PCS Index Test* c. low risk of bias Buhling, 2004 PCS Cetin, 1996 PCS 2. b. exclusion Author, Year Study design Patient Selection* a. sample 1. Yes Yes Yes U Yes U U U U No U U Yes Yes No No U Yes U No Yes Yes Yes Yes Yes U U Yes Yes Yes Yes Yes No No No U No Yes No Yes Yes No No Yes Yes Yes Yes Yes Yes Yes Yes U Yes Yes Yes Yes Yes U U Yes Yes No Yes No Yes Yes Yes U Yes Yes Yes Yes Yes U U Yes Yes Yes No No U Yes U No Yes Yes Yes Yes U U U Yes Yes No Yes No Yes Yes Yes No Yes Yes Yes Yes Yes Yes No U Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes Yes Yes No No U Yes No Yes Yes Yes No No No U Yes U Yes Yes U U Yes Yes Yes No No U No No No U No U Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes U Yes Yes Yes U Yes Yes Yes Yes U Yes U U No No No No Yes Yes Yes U Yes No No Yes U Yes No No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes U U Yes Yes Yes Yes Yes Yes U U Yes Yes Yes No No C-3 d. applicable a. likely to classify b. index results not known c. low risk of bias d. applicable a. interval b. same standard c. all included in analysis d. low risk of bias Flow and Timing* c. low risk of bias 4. b. threshold Reference Standard* a. reference results not known 3. d. applicable Index Test* c. low risk of bias Maegawa, 2003 PCS Mello, 2006 PCS Moses, 2011 PCS Ostlund, 2003 PCS Perea-Carrasco, 2002 PCS Perucchini, 1999 PCS Poyhonen-Alho, 2004 PCS Rajput, 2012 PCS Reichelt, 1998 PCS Rey, 2004 PCS Rust, 1998 PCS Sacks, 2003 PCS Siribaddana, 2003 PCS Soheilykhah, 2011 PCS 2. b. exclusion Author, Year Study design Patient Selection* a. sample 1. Yes Yes Yes U Yes Yes Yes Yes Yes U U U Yes No Yes No Yes Yes Yes U Yes Yes Yes Yes Yes No No Yes Yes No Yes No Yes Yes Yes U Yes Yes Yes Yes U Yes U U Yes Yes Yes Yes Yes Yes Yes U Yes Yes Yes Yes Yes No No Yes U Yes U No Yes Yes Yes U U Yes U Yes Yes U U Yes U Yes Yes U Yes Yes Yes U Yes Yes Yes U Yes U U Yes Yes Yes U Yes Yes Yes Yes U Yes Yes Yes Yes U No Yes U Yes No U U Yes Yes Yes No No No No Yes Yes U U Yes Yes Yes Yes Yes Yes U U No U No U U Yes U U Yes U Yes U U Yes U U Yes Yes Yes Yes Yes Yes U U Yes U Yes Yes U Yes Yes Yes Yes Yes Yes Yes Yes Yes U U Yes Yes No Yes Yes Yes U U Yes Yes Yes Yes Yes Yes U U Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No No Yes No Yes U No No Yes U Yes U U C-4 d. applicable a. likely to classify b. index results not known c. low risk of bias d. applicable a. interval b. same standard c. all included in analysis d. low risk of bias Flow and Timing* c. low risk of bias 4. b. threshold Reference Standard* a. reference results not known 3. d. applicable Index Test* c. low risk of bias Soonthornpun, 2003 PCS Tan, 2007 PCS Trihospital 1998 PCS (Naylor) Uncu, 1995 PCS van Leeuwen 2007 PCS Weerakiet, 2006 PCS Wijeyaratne, 2006 PCS Yachi, 2011 PCS Yogev, 2004 PCS 2. b. exclusion Author, Year Study design Patient Selection* a. sample 1. No U No No U Yes U Yes Yes U U Yes Yes Yes Yes Yes Yes Yes Yes No U Yes U Yes Yes U U Yes Yes No Yes No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes U U U No Yes Yes U Yes Yes U U Yes Yes Yes Yes Yes Yes Yes Yes U Yes Yes Yes Yes Yes No No Yes Yes U Yes U Yes Yes Yes No U No No U Yes U U Yes Yes Yes Yes Yes Yes U U No Yes U U U Yes Yes Yes Yes Yes U Yes U U Yes U U Yes Yes Yes U Yes U U U No No Yes Yes U Yes U Yes Yes Yes Yes Yes Yes No U Yes Yes U Yes U *QUADAS domain descriptions: 1.a. Random or consecutive sample; 1.b. Did the study avoid inappropriate exclusions?; 1.c. Was the study a low risk of bias?; 1.d.Is the study applicable?; 2.a. Reference standard results not known; 2.b. Pre specified threshold; 2.c. Was the study a low risk of bias?; 2.d. Is the study applicable?; 3.a. Likely to classify target patients; 3.b. Index test results not known; 3.c. Was the study a low risk of bias?; 3.d. Is the study applicable?; 4.a. Interval between tests; 4.b. Same standard for all patients; 4.c. All patients included in analysis; 4.d. Was the study a low risk of bias? U = unclear C-5 Table C2. Methodological quality of randomized controlled trials (RCTs) using the Cochrane Collaboration’s tool for assessing risk of bias for Key Questions 2 to 5 Blinding Author Year Bevier, 1999 Bonomo, 2005 Crowther, 2005 Garner, 1997 Landon, 2009 Sequence generation Allocation concealment Unclear Incomplete outcome data* Selective outcome reporting Other Participants* Outcome assessment* Unclear Unclear Low Unclear Low Low Low Unclear Unclear Low Low Low Low Low Low Low Low Low Low Low Unclear Unclear Unclear High High Low Low Unclear Unclear Low Low Low Low Low * Domains for which assessments are made by outcome were assessed for objective outcomes † Quality rating based on EPC Methods Guide (good, fair, poor) C-6 Overall Risk of Bias* † (quality rating) Unclear (fair) Unclear (fair) Low (good) High (poor) Unclear (fair) Table C3. Methodological quality of prospective cohort studies (PCS) and retrospective cohort studies (RCS) using Newcastle-Ottawa Quality Assessment Scale, by Key Question and design Selection of non-exposed cohort Ascertainment of exposure Outcome of interest not present at start of study known factors* additional factor Assessment of outcome Follow up long enough for outcomes to occur Adequacy of cohort follow up Total stars † (quality rating) KQ2 - PCS Solomon, 1996 Representativeness of exposed cohort Author, Year Comparability of cohorts (Study controls) Selected group of users Same community as exposed cohort Structured interview Yes No No Record linkage Yes Subjects lost unlikely to introduce bias 6 (fair) Truly representative Same community as exposed cohort Secure record Yes No No Record linkage Yes Complete follow up 7 (good) Secure record Yes No No Record linkage Yes Secure record Yes No No No description Yes Secure record Yes Yes Yes No description Yes Secure record Yes Yes Yes Independent blind assessment Yes Secure record Yes Yes Yes No description Yes Secure record Yes Yes Yes No description Yes Secure record Yes Yes Yes Record linkage Yes KQ2 - RCS Chanprapaph, 2004 KQ3 – PCS Ardawi, 2000 Truly representative Lao, 2001 Somewhat representative Lapolla, 2007 Truly representative Metzger/ HAPO, 2008 Truly representative Retnakaran, 2008 Somewhat representative Sacks, 1995 Somewhat representative Sermer, 1995 RCT Somewhat representative Same community as exposed cohort Same community as exposed cohort Same community as exposed cohort Same community as exposed cohort Same community as exposed cohort Same community as exposed cohort Same community as exposed cohort C-7 Subjects lost unlikely to introduce bias Subjects lost unlikely to introduce bias Complete follow up Subjects lost unlikely to introduce bias Subjects lost unlikely to introduce bias Subjects lost unlikely to introduce bias Subjects lost unlikely to introduce bias 7 (good) 6 (fair) 8 (good) 9 (good) 8 (good) 8 (good) 9 (good) known factors* additional factor Assessment of outcome Follow up long enough for outcomes to occur Adequacy of cohort follow up Total stars † (quality rating) No description Yes Subjects lost unlikely to introduce bias 8 (good) Secure record Yes Yes Yes Record linkage Yes Complete follow up 9 (good) Secure record Yes Yes Yes Record linkage Yes Complete follow up 9 (good) Secure record Yes Yes Yes Record linkage Yes Subjects lost unlikely to introduce bias 9 (good) Secure record Yes No No Record linkage Yes Complete follow up 7 (good) Secure record Yes No No Record linkage Yes Complete follow up 7 (good) Secure record Yes Yes Yes Record linkage Yes Complete follow up 9 (good) Secure record Yes Yes Yes Record linkage Yes Complete follow up 9 (good) Secure record Yes Yes Yes Record linkage Yes Complete follow up 9 (good) Secure record Yes No No Record linkage Yes Complete follow up 7 (good) Secure record Yes No No Record linkage Yes Complete follow up 7 (good) Outcome of interest not present at start of study Yes Ascertainment of exposure Yes Selection of non-exposed cohort Shirazian, 2008 Representativeness of exposed cohort Author, Year Comparability of cohorts (Study controls) Somewhat representative Same community as exposed cohort Secure record Yes KQ3 - RCS Aberg, 2001 Adams, 1998 Berggren, 2011 Truly representative Truly representative Truly representative Berkus, 1995 Somewhat representative Biri, 2009 Truly representative Black, 2010 Truly representative Bo, 2004 Somewhat representative Cheng, 2009 Truly representative Chico, 2005 Somewhat representative Chou, 2010 Somewhat representative Same community as exposed cohort Same community as exposed cohort Same community as exposed cohort Same community as exposed cohort Same community as exposed cohort Same community as exposed cohort Same community as exposed cohort Same community as exposed cohort Same community as exposed cohort Same community as C-8 Ascertainment of exposure Outcome of interest not present at start of study known factors* additional factor Assessment of outcome Follow up long enough for outcomes to occur Adequacy of cohort follow up Total stars † (quality rating) Selection of non-exposed cohort Representativeness of exposed cohort Author, Year Comparability of cohorts (Study controls) Secure record Yes No No Record linkage Yes Complete follow up 7 (good) Secure record Yes Yes Yes Record linkage Yes Secure record Yes Yes Yes Independent blind assessment Yes Secure record Yes Yes Yes Record linkage Yes Secure record Yes Yes Yes Record linkage Yes Secure record Yes No No Record linkage Yes Subjects lost unlikely to introduce bias 7 (good) Secure record Yes Yes Yes Record linkage Yes Complete follow up 9 (good) Secure record Yes Yes No Record linkage Yes Subjects lost unlikely to introduce bias 8 (good) Secure record Yes Yes Yes Record linkage Yes Complete follow up 9 (good) Secure record Yes No No Record linkage Yes Complete follow up 7 (good) exposed cohort Cok, 2011 Corrado, 2009 Somewhat representative Somewhat representative Hillier, 2007 Truly representative Jensen, 2002 Somewhat representative Kim, 2002 Somewhat representative Kwik, 2007 Truly representative Langer, 2005 Somewhat representative Lao, 2003 Somewhat representative Lapolla, 2011 Somewhat representative Morikawa, 2010 Somewhat representative Same community as exposed cohort Same community as exposed cohort Same community as exposed cohort Same community as exposed cohort Same community as exposed cohort Same community as exposed cohort cohort Same community as exposed cohort Same community as exposed cohort Same community as exposed cohort Same community as exposed cohort C-9 Subjects lost unlikely to introduce bias Subjects lost unlikely to introduce bias Subjects lost unlikely to introduce bias Subjects lost unlikely to introduce bias 9 (good) 9 (good) 9 (good) 8 (good) Somewhat representative Vambergue, 2000 Truly representative Yang, 2002 Somewhat representative Selection of non-exposed cohort Total stars † (quality rating) Tan, 2008 Same community as exposed cohort Same community as exposed cohort Same community as exposed cohort Same community as exposed cohort Adequacy of cohort follow up Somewhat representative Follow up long enough for outcomes to occur Stamilio, 2004 Truly representative Assessment of outcome Schwartz, 1999 Somewhat representative additional factor Rust, 1996 Truly representative known factors* Ricart, 2005 Truly representative Same community as exposed cohort Same community as exposed cohort Same community as exposed cohort Same community as exposed cohort Same community as exposed cohort Outcome of interest not present at start of study Pennison, 2001 Somewhat representative Ascertainment of exposure Nord, 1995 Representativeness of exposed cohort Author, Year Comparability of cohorts (Study controls) Secure record Yes No No Record linkage Yes Subjects lost unlikely to introduce bias 7 (good) Secure record Yes Yes Yes Record linkage Yes Complete follow up 9 (good) Secure record Yes No No Record linkage Yes Complete follow up 7 (good) Secure record Yes Yes Yes Record linkage Yes Secure record Yes No No Record linkage Yes Secure record Yes Yes Yes Record linkage Yes Complete follow up 9 (good) Secure record Yes Yes Yes Record linkage Yes Complete follow up 9 (good) Secure record Yes Yes Yes Record linkage Yes Complete follow up 9 (good) Secure record Yes Yes Yes Record linkage Yes Complete follow up 9 (good) No Record linkage Yes Follow up rate <75% and no description of those lost 6 (fair) Subjects lost unlikely to introduce bias Follow up rate <75% and no description of those lost 9 (good) 6 (fair) KQ4/5 - PCS Malcolm, 2006 Somewhat representative Same community as exposed cohort Secure record Yes C-10 No Ascertainment of exposure Outcome of interest not present at start of study known factors* additional factor Assessment of outcome Follow up long enough for outcomes to occur Adequacy of cohort follow up Total stars † (quality rating) Selection of non-exposed cohort Representativeness of exposed cohort Author, Year Comparability of cohorts (Study controls) Secure record Yes Yes Yes Record linkage Yes Subjects lost unlikely to introduce bias 9 (good) Secure record Yes Yes Yes Record linkage Yes Complete follow up 8 (good) Secure record Yes No No Record linkage Yes Complete follow up 7 (good) Secure record Yes Yes Yes Record linkage Yes Complete follow up 9 (good) KQ4/5 – RCS Adams, 1998 Truly representative Bonomo, 1997 Selected group of users Fassett, 2007 Somewhat representative Langer, 2005 Truly representative Same community as exposed cohort Same community as exposed cohort Same community as exposed cohort Same community as exposed cohort * Controls for known factors: age, race, BMI, history of GDM, family history of DM † Quality rating based on EPC Methods Guide (good, fair, poor): total scores of 7-9 were considered good, 4-6 fair, and 0-3 poor. BMI = body mass index; GDM = gestational diabetes mellitus; DM = diabetes mellitus; PCS = prospective cohort study; RCS = retrospective cohort study C-11 Appendix D. Evidence Tables Table D1. Characteristics of studies examining properties of current screening and diagnostic tests for GDM, Key Question 1 Table D2. Characteristics of studies comparing outcomes for women who were and were not screened for GDM, Key Question 2 Table D3. Characteristics of studies examining outcomes of mothers and offspring in the absence of treatment, Key Question 3 Table D4. Characteristics of studies examining treatment outcomes of mothers and offspring, Key Questions 4 and 5 D-1 Table D1. Characteristics of studies examining properties of current screening and diagnostic tests for GDM, Key Question 1 Author, year Dates of study Country Agarwal, 2000 June 1998 to Apr 2000 United Arab Emirates Agarwal, 2001 Dec 1997 to May 1998 Women Analyzed, n Screening Practice^ Inclusion/Exclusion Criteria Maternal Age, mean ± SD/median ± IQR (yr) BMI, mean ± SD 2 (kg/m ) 1644 (+hx = 1276, +GCT 398) 29.8±5.87 (+hx) 30.2±5.62 (+GCT) NR 430 (HbA1c) 426 (cFruc) Exclusion: prescreened by other methods Inclusion: attending antenatal clinic; referred for OGTT NR Selective, 2-step CC, 513/1644 (31.2%) +hx, 396/1276 (31.0%) +GCT, 117/368 (31.8%) NR Time of GDM Confirmation FPG, various thresholds (taken same time as OGTT) 28.1 wks (+hx) 28.7 wks (+GCT) CC, 1991 100g, 3 h 1-2 wks after OGCT Risk factor: anytime during pregnancy OGCT: 24-28 wks Selective, 2-step Risk factor OGCT HbA1c ≥5.0% cFruc ≥210 µmol/L ADA, 1997/CC, 1991 100g, 3 h ADA, 116/430 (27.0%) 1-2 wks after OGCT/ 2428 wks risk factor screen D-2 Study Purpose Load, Interval Time of Screening Inclusion: attending antenatal clinic; referred for OGTT because of clinical history or +OGCT Reference†*, Date Conclusion(s) Prevalence of GDM Criteria, n (%) Exclusion: NR United Arab Emirates Index†, (Comment) Purpose: Investigate the value of FPG as an alternative screen to OGCT Recommendations: In a high-risk population FPG offers a simple and practical screening test Purpose: Investigate practical alternative screening amongst highrisk population which can be easily performed on a single blood sample Recommendations: Screening high-risk pregnancies with a combination of cFRUC and HbA1c could avoid OGTT in 37.9% women. Author, year Dates of study Country Agarwal, 2005(a) May 2003 to Jul 2003 Women Analyzed, n Maternal Age, mean ± SD/median ± IQR (yr) BMI, mean ± SD 2 (kg/m ) 442 G1: 26.2 ± 5.3 G2: 28.5 ± 5.9 NR United Arab Emirates Agarwal, 2005(b) Jun 2003 to Jan 2004 United Arab Emirates Screening Practice^ Inclusion/Exclusion Criteria 1,685 26.6 ± 5.7 (nonGDM) 29.3 ± 6.4 (GDM) 27.7 ± 8.5 (nonGDM) 28.9 ± 5.6 (GDM) Index†, (Comment) Universal, 1-step ADA, 85 (19%) WHO, 49 (11%) Load, Interval Time of GDM Confirmation HbA1c (cutoff value ≥7.5%; collected at time of OGTT) No screen ADA, 2004 WHO, 1999 Purpose: Is HbA1c is an effective screen for GDM 75 g, 2 h Recommendations: HbA1c is a poor test to screen for GDM 24-28wks Universal, 1-step Study Purpose Conclusion(s) Prevalence of GDM Criteria, n (%) Time of Screening Inclusion: Attended routine antenatal clinics, 24-28 wks gestation, complete OGTT record Exclusion: Delivery in other hospital, failure to undergo OGTT, hepatic, renal or evident DM, diet treatment, previous GDM, any endocrine disorder Inclusion: Attended routine antenatal clinics at hospital, 2428 wks gestation, complete OGTT record Reference†*, Date FPG, <4.7 and >5.6 mmol/L WHO, 1999 WHO, 333 (19.8%) 75 g, 2 h No screen 24 to 28 wks Purpose: evaluate the value of FPG in screening a high-risk population for GDM Recommendations: FPG has the potential to avoid nearly 1/3 of OGTTs at the expense of missing 1/5 of pregnant women with milder GDM Exclusion: Delivery in other hospital, failure to undergo OGTT, hepatic, renal or evident DM, diet treatment, previous GDM, any endocrine D-3 Author, year Dates of study Women Analyzed, n Country Maternal Age, mean ± SD/median ± IQR (yr) Agarwal, 2006 BMI, mean ± SD 2 (kg/m ) 4,602 May 2004 to Sep 2005 28.4 ± 6 Screening Practice^ Inclusion/Exclusion Criteria Inclusion: Routine antenatal clinic attendance at study hospital Exclusion: NR Universal, 2-step Reference†*, Date Load, Interval Time of GDM Confirmation FPG (various cutoff values) ADA, 675 (14.7%) WHO, 979 (21.3%) ADIPS, 1158 (25.2%) EASD, 556 (12.1%) ADA, 2004 WHO, 1999 ADIPS, 1999 EASD, 1998 75 g, 2 h 24-28 wks 24-28 wks Universal, 1-step 28.8 ± 5.9 Inclusion: Routine antenatal clinic attendance NR Exclusion: NR No screen Agarwal, 2011 849 Inclusion: Routine antenatal care Oct 2008 to May 2009 29.4 ± 6.0 Agarwal, 2008 1,662 Nov 2006 to Jun 2007 ADA, 186 (11.2%) FBG (hand-held glucometer; cutoff value ≥4.9 mmol/L) ADA, 2004 75 g, 2 h 24-28 wks United Arab Emirates NR United Arab Emirates Exclusion: Twin pregnancy, pregestational DM, Hx of GDM Universal, 1-step ADA, 113 (13.3%) IADPSG, 279 (32.9%) WHO, 156 (20.3%) ADIPS, 172 (20.3% EASD, 90 (10.6%) 24-28 wks Serum fructosamine (cutoff value ≥237 µmol/L) ADA, 2004 IADPSG, 2010 WHO, 1999 ADIPS, 1999 EASD, 1998 75 g, 2 h 24-28 wks D-4 Study Purpose Conclusion(s) Prevalence of GDM Criteria, n (%) Time of Screening NR United Arab Emirates Index†, (Comment) Purpose: Effect of diagnostic criteria on the usefulness of FPG as a screen for GDM Recommendations: Initial testing by FPG can decrease the number of OGTTs needed to diagnose GDM Purpose: Test the practical value of measuring FBG vs. FPG Recommendations: FBG is a simple, practical, cost-effective and patientfriendly approach to screen for GDM Purpose: Evaluate the value of serum fructosamine to screen for GDM Recommendations: Serum fructosamine is a poor test to screen for GDM Author, year Dates of study Country Ardawi, 2000 Women Analyzed, n Maternal Age, mean ± SD/median ± IQR (yr) BMI, mean ± SD 2 (kg/m ) 818 Jun 1996 to Jun 1998 G1:29.2 ± 4.6 G2:30.7 ± 4.8 G3:32.1 ± 5.1 Saudi Arabia NR Ayach, 2006 341 Jul 1997 to Dec 1999 Brazil Screening Practice^ Inclusion/Exclusion Criteria Age ≥25, n = 54 (15.8%) BMI ≥27, n = 49 (14.4%) Index†, (Comment) Universal, 2-step Load, Interval Time of GDM Confirmation 50 g OGCT (≥7.2 mmol/L) NDDG, 102 (12.5%) NDDG, 1979 100 g, 3 h Exclusion: NR Inclusion: All pregnant women, no Hx of DM, sought care in study st hospital during 1 half of pregnancy 24-28 wks Universal, 2-step ADA, 13 (3.8%) 24-28 wks Exclusion: Failure to perform or finish screening/diagnostic test, withdrawal of consent or premature termination of pregnancy, miscarriage, pseudocyesis, premature birth, fetal death, intolerance to oral glucose test D-5 Study Purpose Conclusion(s) Prevalence of GDM Criteria, n (%) Time of Screening Inclusion: Attended antenatal care clinics at 2 hospitals Reference†*, Date FPG and risk factors (age ≥ 25, BMI before pregnancy ≥ 27 2 kg/m , family or personal history of diabetes, and membership of an ethnic group with high prevalence of GDM) ADA, 2002 Purpose: Evaluate applicability of the 50 g OGCT as a screening test for GDM in relation to pregnancy outcomes Recommendations: 50 g OGT at 24-28 weeks with a cutoff value of 7.8 mmol/L is a reliable screening test for GDM Purpose: Compare FPG + risk factors vs.50 g GTT 100 g, 3 h 24-28 wks Recommendations: FPG + risk factors are more appropriate for screening compared with 50 g OGCT Author, year Dates of study Country Balaji, 2011 Women Analyzed, n Screening Practice^ Inclusion/Exclusion Criteria Maternal Age, mean ± SD/median ± IQR (yr) BMI, mean ± SD 2 (kg/m ) 1,463 23.6 ± 3.3 NR 21.5 ± 4.1 Index†, (Comment) Universal, 1-step Study Purpose Conclusion(s) Prevalence of GDM Criteria, n (%) Load, Interval Time of GDM Confirmation Time of Screening Inclusion: Visiting antenatal clinic for the first time in second or third trimester Reference†*, Date FPG (IADPSG ≥5.1 mmol/L) WHO, 196 (13.4%) WHO, 1999 75 g, 2 h 24-28 wks No screen 24-28 wks Purpose: Ascertain the ability of FPG to diagnose glucose intolerance during pregnancy in Asian Indians India Exclusion: Hx of GDM or DM Balaji, 2012 819 23.8 ± 3.48 NR 21.2 ± 4.87 Inclusion: Pregnant women at 24-28 wks, attending community health center Universal, 1-step WHO, 86 (10.5%) No screen India Exclusion: NR Berkus, 1995 80 NR G1: 28.1 ± 5 G2: 25.7 ± 5 U.S. Inclusion: Nonhypertensive women, recruited from obstetric clinic in Texas, non diabetic CBG (point-ofcare testing with glucometer; 75 g glucose load, 2 h sample, cutoff value of ≥7.8 mmol/L) WHO, 1999 75 g, 2 h 24-28 wks NR, 2-step 50 g OGTT NDDG, 1979 NDDG, 21/40 (26%) WHO, 20/40 (50%) 75 g OGTT, WHO 100g, 3 h G1:28.6 ±4 G2:30.6 ±4 NR Recommendations: FPG is not suitable for diagnosis of GDM in this population Purpose: Compare pointof-care measured CBG with a glucometer and lab-estimated VPG Recommendations: CBG value at a 2 h plasma glucose ≥7.8 mmol/L may be recommended for the diagnosis of GDM Purpose: Determine whether glucose abnormality, as shown by GTT periodicity, is not affected by different glucose loads Exclusion: NR Recommendations: GTT periodicity identifies patients with GDM regardless of GTT load D-6 Author, year Dates of study Country Bobrowski, 1996 Women Analyzed, n Screening Practice^ Inclusion/Exclusion Criteria Maternal Age, mean ± SD/median ± IQR (yr) BMI, mean ± SD 2 (kg/m ) 422 Index†, (Comment) NR (included women with abnormal OGCT) Load, Interval Time of GDM Confirmation 50 g OGTT, ≥135 mg/dL NDDG, 1979 CC,1982 NR Exclusion: no followup OGTT Jul 1992 to Jan 1994 Brustman, 1995 24-28 wks 100 g, 3 h NDDG, 124(29%) CC, 161 (38%) U.S. 32 28 ± 5 NR NR U.S. Inclusion: Women 2626 wks gestation, abnormal glucose screen ≥130 mg/dl after 24 wks gestation NR (included women with abnormal OGCT) 1-2 wks after GCT rd IWC, 3 (75 g, 3-h OGTT) NDDG, 1979 100 g, 3 h NDDG, 16 (50%) IWC, 6 (19%) 26-36 wks Exclusion: NR Buhling, 2004 912 28.5 ± 5 Jun 1997 to Jan 2000 Inclusion: Received prenatal care at clinic, no previous GDM testing Universal, 2-step ADA, 37 (4.1%) Study Purpose Conclusion(s) Prevalence of GDM Criteria, n (%) Time of Screening Inclusion: + OGCT screen Reference†*, Date 50g OGCT (≥140 mg/dL) ADA, 2001 75 g, 2 h Purpose: examine the utility of various 50 g screen cutoff values in establishing the diagnosis of gestational diabetes Recommendations: 50-g glucose screen result ≥220 mg/dL can obviate the need for a 3-h OGTT Purpose: Compare results of a 75 g, 3h OGTT with a 100g OGTT Recommendations: 75 g OGTT using the NDDG criteria, recognizes carbohydrate intolerance in pregnancy Purpose: Evaluate the sensitivity of the glucosesticks for screening for GDM 33.8 ±3 wks 23.6 ± 4.4 Recommendations: Urine glucose dip stick analysis is not useful to detect GDM Exclusion: NR Germany D-7 Author, year Dates of study Country Cetin, 1996 Oct 1994 to Jan 1996 Turkey Chastang, 2003 Women Analyzed, n Maternal Age, mean ± SD/median ± IQR (yr) BMI, mean ± SD 2 (kg/m ) 274 G1:27 (19-37) G2: 28 (18-37) G3: 29 (19-41) G1: 24.8 (17.340.1) G2: 24.5 (17-40) G3: 25 (19.3-39.8) 354 31.4 ± 4.6 Jun 1997 to Jun 1998 France Screening Practice^ Inclusion/Exclusion Criteria 22.5 ± 4.1 Index†, (Comment) Exclusion: Hx of preexisting diabetes, preeclampsia, regular ingestion of any drug, delivery ≤28 wks , premature rupture of membranes Inclusion: Presented at least 1 RF for GDM: >35 years, BMI > 25, family Hx of diabetes, personal Hx of GDM, Hx of macrosomia/ LGA, Hx or preeclampsia, presence of obstetrical event(s) in current pregnancy, excessive weight gain during in current pregnancy Universal, 2-step Load, Interval Time of GDM Confirmation 50g, 1 h OGCT (≥140 mg/dL) NDDG, 17 (6.2%) NDDG, NR 100 g, 3 h 26-28 wks CC, 69 (20%) ≥25 g carbohydrate breakfast 24 to 28 wks FPG Selective, 2-step D-8 Purpose: Examine different cutoff values with regard to the time of patient’s last meal Recommendations: Different cutoff values lead to improved efficiency of the OGCT and decreased frequency of OGTT CNGOF, 1998 (based on CC criteria) Purpose: Validate a diagnostic test for GDM which predicts the risk of macrosomia 100 g, 3 h Recommendations: Standard 50 g carbohydrate breakfast is more sensitive than the 50 g GCT to screen women at risk of macrosomia 24-28 wks Exclusion: NR Study Purpose Conclusion(s) Prevalence of GDM Criteria, n (%) Time of Screening Inclusion: Women > 24 yrs, 24-28 wks gestation, examined by obstetrician before 20 wks, singleton pregnancy Reference†*, Date Author, year Dates of study Country Chevalier, 2011 Jan 2002 to Dec 2006 France De Los Monteros, 1999 Jul 1996 to Dec 1996 Women Analyzed, n Screening Practice^ Inclusion/Exclusion Criteria Maternal Age, mean ± SD/median ± IQR (yr) BMI, mean ± SD 2 (kg/m ) 11,545 32.8 ± 5.5 (GDM) 30.7 ± 5.3 (no GDM) 28.6 ± 5.7 (GDM) 27.8 ± 4.9 (no GDM) 445 >25 (n=359) <25 (n=86) Inclusion: screened between 24-28 at hospital Exclusion: NR Inclusion: 24-28 wks gestation, attending medical centre for routine care 26.9 ± 5.6 NR 22.4 ± 3.8 Exclusion: NR 709 CC (≥130 mg/dL), 344 (4.3%) CC (≥140 mg/dL), 300 (3.9%) Universal, 2-step Time of GDM Confirmation OGCT, ≥130 mg/dL and ≥140 mg/dL Postprandial 50 g OGCT NDDG, 43 (9.7%) CC, 52 (11.7%) Sacks, 62 (13.9%) CNGOF, 1996 (based on CC, 1982) Purpose: Explore GDM screening according to the 1996 French guidelines 100 g, 3 h Recommendations: Twostep screening strategy for GDM was neither relevant nor efficient Purpose: Study sensitivity and specificity of the 50 g, 1 h GCT performed 1 to 2 h after a nonstandardized home breakfast NDDG, 1979 CC, 1982 Sacks, 1989 100 g, 3 h 24-28 wks 1 wk after OGCT Universal, 2-step 50 g OGCT NDDG, 1979 NDDG, 10 (1.4%) WHO, 111 (15.7%) WHO, 1980 (75 g, 2 h OGTT) 100 g, 3 h 24-28 wks Thailand D-9 Study Purpose Load, Interval 24-28 wks Deerochanawong, 1996 Mexico Universal, 2-step Reference†*, Date Conclusion(s) Prevalence of GDM Criteria, n (%) Time of Screening Exclusion: Previous Hx of DM, consent withdrawal during either glucose tolerance test, inability to recall last menstrual period, Hx of regular drug ingestion during pregnancy Inclusion: Attending antenatal clinic, no prepregnancy DM NR Index†, (Comment) Within 7 days Recommendations: Sensitivity after breakfast was similar, based on the NDDG and CC criteria for GDM Purpose: Compare criteria of the NDDG and WHO for pregnancy outcomes Recommendations: WHO criteria resulted in poorer pregnancy outcomes but fewer perinatal complications were missed than with the NDDG criteria Author, year Dates of study Country Eslamian, 2008 Women Analyzed, n Screening Practice^ Inclusion/Exclusion Criteria Maternal Age, mean ± SD/median ± IQR (yr) BMI, mean ± SD 2 (kg/m ) 138 27.5 ± 4.6 Universal, 2-step Exclusion: Pregestational DM, current GDM 24-28 wks Inclusion: Prenatal clinic attendance at study center, referred for 50 g GCT between 24-28 wks Universal, 2-step CC, 12 (8.6%) 24.9 ± 3.1 Gandevani, 2011 1,804 32.5 ± NR 2007 to 2008 23.3 ± 2.4 CC, 130 (7.2%) Time of GDM Confirmation Standard breakfast containing 50 g simple sugar 50 g OGCT (various cutoff values) CC, NR 100 g, 3 h CC, 1982 100 g, 3 h Hill, 2005 830 24 (16-40) Jun 1997 to Aug 1998 India 23.1 (20.7-25.7) Selective, 2-step CC, 49 (6%) NR Exclusion: Prepregnancy DM D-10 Risk Factors (one or more of the following: 2 BMI ≥25 kg/m ; family Hx of DM in a first or second degree relative; poor obstetric Hx; previous baby weighing ≥3800 g; PIH; polyhydramnios Purpose: Compare a standard breakfast with a 50 g glucola-based OGCT Recommendations: Standard breakfast can be used as an alternative method for assessing carbohydrate intolerance Purpose: Investigate cutoff value of GCT in an Iranian population 24-28 wks Recommendations: Best cutoff value is 135 mg/dL to identify GDM CC, 1982 Purpose: Determine the incidence of GDM in one urban maternity unit in South India and examine its effect on the offspring Iran Exclusion: Glucose intolerance before pregnancy, Hx of GDM Inclusion: Planned to deliver at hospital, singleton pregnancy, <32 wks GA determined by LMP or a first trimester ultrasound scan Study Purpose Load, Interval Time of Screening Inclusion: Patients receiving prenatal care Reference†*, Date Conclusion(s) Prevalence of GDM Criteria, n (%) NR Iran Index†, (Comment) 100 g, 3 h 28-32 wks Recommendations: Effect of maternal glucose concentrations on neonatal anthropometry is continuous and extends into those diagnosed as normal Author, year Dates of study Country Jakobi, 2003 Women Analyzed, n Screening Practice^ Inclusion/Exclusion Criteria Maternal Age, mean ± SD/median ± IQR (yr) BMI, mean ± SD 2 (kg/m ) 180 NR 1998 to 1999 NR Index†, (Comment) Abnormal OGCT Load, Interval Time of GDM Confirmation BG/ portable glucose meter rd IWC, 25 (13.9%) IWC, 3 (similar to NDDG) NR 100 g, 3 h Israel Exclusion: NR Jensen, 2003 5,235 1999 to 2000 NR Denmark NR Inclusion: Risk group: women presenting ≥1 RF. Non-risk group: contacted by study midwife at first appointment Study Purpose Conclusion(s) Prevalence of GDM Criteria, n (%) Time of Screening Inclusion: Positive 50 g OGCT (≥7.8 mmol/L), referred to high-risk pregnancy clinic Reference†*, Date Purpose: Evaluate perinatal effects of replacing current methods for 100 g OGTT with portable glucose meters 28-32 wks Universal, 2-step WHO, 124 (2%) NR Exclusion: Preexisting DM, <18 yrs, delivery or migration before 30 wks, first booking later than 30 wks D-11 Risk factors (glucosuria, GDM in a previous pregnancy, prepregnancy 2 BMI ≥27 kg/m , family history of DM, and previous delivery of macrosomic infant) WHO, 1998 75 g, 2 h Recommendations: No difference between the 2 methods Purpose: Evaluate a screening model for GDM using clinical risk indicators 28-32 wks Recommendations: Using risk factor assessment reduces the need for screening and diagnostic testing in 66% pregnant women Author, year Dates of study Country Kashi, 2007 Women Analyzed, n Maternal Age, mean ± SD/median ± IQR (yr) BMI, mean ± SD 2 (kg/m ) 200 27.8 ± 95.2 NR 29.6 ± 4.5 Iran Kauffman, 2006 123 NR NR NR U.S. Screening Practice^ Inclusion/Exclusion Criteria Index†, (Comment) Exclusion: Pregestational overt DM Inclusion: Women attending obstetrical clinic, 24-28 wks gestation with consent to undergo 100 g, 3h OGTT in lieu of 50 g screen Selective, 2-step Load, Interval Time of GDM Confirmation FPG (≥91.5 mg/dL) ADA, 20 (10%) NDDG, 16 (13.0%) CC, 25 (20.3%) homeostatic insulin sensitivity indices (HOMA1, HOMA-2, QUICKI) FPG ≥92 mg/dL FPI ≥93 µmol/L Exclusion: Hx DM or GDM, untreated endocrine disorders, medications with impact on circulating glucose or insulin levels D-12 ADA, 2006 100 g, 3 h 24-28 wks No screen, OGTT in lieu of OGCT Study Purpose Conclusion(s) Prevalence of GDM Criteria, n (%) Time of Screening Inclusion: Referred to prenatal clinic, ≥1 risk factors: >25 years old, Hx of recurrent abortion, previous GDM, preeclampsia, macrosomia, still birth, DM in first degree family or pregestational BMI 2 >25 kg/m Reference†*, Date Purpose: Determine a cutoff point of FPG for screening for GDM 1-2 wks after +OGCT Recommendations: FPG level of 91.5 mmol/dL showed highest sensitivity and specificity NDDG, 1979 CC, 1982 Purpose: investigate homeostatic indices of insulin sensitivity to screen for GDM 100 g, 3 h 24-28 wks Recommendations: FPG and the homeostatic insulin sensitivity indices are sensitive alternatives to OGCT Author, year Dates of study Country Lamar, 1999 Women Analyzed, n Screening Practice^ Inclusion/Exclusion Criteria Maternal Age, mean ± SD/median ± IQR (yr) BMI, mean ± SD 2 (kg/m ) 136 26 ± 5.3 NR NR U.S. NDDG, 5 (3.7%) Index†, (Comment) NR, 2-step NDDG, 5 (3.7%) 24-28 wks Load, Interval Time of GDM Confirmation 50 g OGCT (traditional and alternative sugar source 28 jelly beans consisting of 50 g of simple sugar) Exclusion: NR Maegawa, 2003 Apr 1999 to Sep 2001 Japan 749 28.9±4.1 (normal) 30.7±2.5 (early) 34.1±3.3 (late) Inclusion: Women in st 1 trimester; attending hospital JSOG, 22 (2.9%) Exclusion: Hx of DM 21.0±2.9 (normal) 24.8±6.2 (early) 22.6±2.3 (late) Mello, 2006 227 (16-20 wks) 976 (26-30 wks) Jan 1997 to Dec 1999 Italy NR Inclusion: nonobese; nondiabetic; singleton pregnancy Universal, 1-step Early: CC 41/227 (18.1%) ADA 15/227 (6.75) Exclusion: NR NR ACOG, 1994 (Values same as NDDG) Late: CC 60/484 (12.4%) ADA, 26/484 (4.4%) D-13 GCT*, 130 mg/dL and140 mg/dL FPG* 85 mg/dL HbA1c *4,8% and 5.8% *Taken in both st nd 1 and 2 trimester 75 g, 2 h (ADA) OGTT JSOG, 2002 (Values same as ADA, 75 g) 75 g, 2 h 2-4 wks after nd 2 trimester screen CC, 1982 100 g, 3 h 16-20 wks 26-30 wks Purpose: Determine if a standardized dose of jelly beans is an alternative sugar source to the 50 g glucose beverage to screen for GDM 100 g, 3 h Within 7-10 days of OGCT Universal, 2-step Study Purpose Conclusion(s) Prevalence of GDM Criteria, n (%) Time of Screening Inclusion: Women in general obstetric population at institution ≥18 yrs and between 24-28 wks, no Hx of overt DM Reference†*, Date 1 wk after 75 g Recommendations: Jelly beans provide a “dose” of simple carbohydrate similar to that of the 50 g glucose beverage but with suboptimal sensitivity Purpose Characteristics of various screening procedures for GDM in Japan during the first trimester and between 24 and 28 wks of pregnancy Recommendations: Of 22 with GDM, 14 were diagnosed in the first trimester and 8 in the second trimester. Purpose: Investigate the comparability of the 75 g and the 100 g tests in the diagnosis of GDM Recommendations: There was only weak diagnostic agreement between 75-g and 100-g glucose loads Author, year Dates of study Country Moses, 2011 Jan 2010 to Jun 2010 Women Analyzed, n Screening Practice^ Inclusion/Exclusion Criteria Maternal Age, mean ± SD/median ± IQR (yr) Index†, (Comment) Load, Interval Time of GDM Confirmation Time of Screening Inclusion: NR Univresal, 1-step NR Exclusion: NR ADIPS, 123 (9.6%) IADPSG, 166 (13.0%) IADPSG, 2010 ADIPS, 1991 75 g, 2 h Purpose: Compare the prevalence of GDM using IADPSG criteria vs. ADIP criteria NR NR Australia Ostlund, 2003 4,918 Jul 1994 to Jun 1996 NR Inclusion: Nondiabetic women visiting maternal health care clinics in Sweden NR Sweden Study Purpose Conclusion(s) Prevalence of GDM Criteria, n (%) BMI, mean ± SD 2 (kg/m ) 1 ,275 Reference†*, Date Universal, 2-step WHO, 61 (1.7%) NR Exclusion: Prepregnancy DM D-14 Anamnestic risk factors (Heredity, nonNordic origin, prior macrosomia, prior GDM, multipara, prior macrosomia, and prior GDM) WHO, 1980 75 g, 2 h 28-32 wks Recommendations: IADPSG criteria Increased the prevalence of GDM from 9.6% to 13.0% Purpose: Determine prevalence of GDM and the value of traditional anamnestic risk factors for predicting the outcome of the OGTT Recommendations: Traditional risk factors as an indicator to perform an OGTT gives a low sensitivity to detect GDM Author, year Dates of study Country PereaCarrasco, 2002 NR Women Analyzed, n Maternal Age, mean ± SD/median ± IQR (yr) BMI, mean ± SD 2 (kg/m ) 578 NR NR Index†, (Comment) Universal, 2-step IWC, 46 (7%) 24-28 wks 520 28.4 ± 0.2 1995 to 1997 Inclusion: Singleton pregnancy, attended hospital, delivery >28 wks Time of GDM Confirmation rd Index test (I) = (fructosamine/ total protein) (glucose/100) IWC, 3 (same as NDDG thresholds) I = ≥27.2 100 g, 3 h 24-28 wks Universal, 2-step IWC, 53 (10.2%) FPG (≥4.8 mmol/L, 86 mg/dL) th IWC, 4 (similar to CC/ADA 2000/10) 23.8 ± 0.2 Switzerland PoyhonenAlho, 2004 532 Jan 1996 to Aug 1998 NR NR Exclusion: Preexisting DM, not examined before 24 wks Inclusion: Caucasian, attendance at primary health care units Study Purpose Load, Interval Time of Screening Inclusion: Attended routine antenatal clinic, OGCT and OGTT between 2428 wks Reference†*, Date Conclusion(s) Prevalence of GDM Criteria, n (%) Exclusion: Multiple pregnancies Spain Perucchini, 1999 Screening Practice^ Inclusion/Exclusion Criteria 100 g, 3 h Purpose: Devise an index test to improve screening sensitivity and specificity, offering better screening capability and greater ease of diagnosis Recommendations: Proposed index offers an efficient screening test for GDM, and with more stringent cutoff points may be applicable as a single-step diagnostic procedure Purpose: Evaluate FPG vs. the 1 h 50 g OGCT Recommendations: More women are referred for the OTT using FPG vs. those using the OGCT 24-28wks Universal, 2-step Author defined, 123 (23%) Exclusion: Prepregnancy DM Finland D-15 Risk factor based screening (BMI >27; age >40; previous child >4500 g; previous GDM; glucosuria; or macrosomia in current pregnancy) Author defined 75 g, 2 h Fasting ≥4.8, 1h ≥10.0, 2h ≥8.7 mmol/L 26-28 wks Purpose: Compare whether universal screening by OGCT will identify more women with GDM vs. risk factor based screening Recommendations: 50 g OGCT identified a higher number women with GDM Author, year Dates of study Country Rajput, 2011 NR Women Analyzed, n Maternal Age, mean ± SD/median ± IQR (yr) BMI, mean ± SD 2 (kg/m ) 607 16–20 18%; 21–25 58%; 26–30 20%; >30 4% India <18.5 38%; 18.5– 24.9 54%; ≥25 8% Reichelt, 1998 4,977 27.9 ± 5.5 May 1991 to Aug 1995 Brazil Rey, 2004 Inclusion: all pregnant women 24-28 wks GA; Inclusion: Women ≥20 yrs, 21-28 wks gestation 188 Inclusion: all women between 24 and 28 wks; normal firsttrimester glucose testing; screened according to CDA screening program NR Universal, 1-step ADA, 43 (7.1%) IADPSG, 144 (23.7%) Reference†*, Date Study Purpose Conclusion(s) Prevalence of GDM Criteria, n (%) Load, Interval Time of GDM Confirmation HbA1c , >5.45% and >5.25% (diagnostic) Exclusion: know Dx DM, anemia, chronic renal, pancreatic or other severe illness Exclusion: Prepregnancy DM 9 mo period Index†, (Comment) Time of Screening 26.1 ± 4.1 30.2 ± 5.2 Canada Screening Practice^ Inclusion/Exclusion Criteria ADA, 2010 IADPSG, 2010 Purpose: Evaluate the utility of HbA1c in combination with OGTT for diagnosis of GDM 75 g, 2 h 24-28 wks Universal, 1-step FPG (≥87 mg/dL) WHO, 379 (7.6%) WHO, 1994 75 g, 2 h 24-28 wks st Normal 1 trimester screen CDA, 21 (11.2%) 25.7 ± 1.2 wks Exclusion: NR D-16 Recommendations: HbA1c in combination with OGTT can obviate the need of OGTT in almost two-thirds of women with GDM Purpose: Evaluate FPG as a screening test for GDM GCT, 7.8 mmol/L FPG, 4.5 mmol/L FCG, 4.6 mmol/L Recommendations: FPG is a useful screening test for GDM CDA, 1998 75 g, 2 h 27.2 ± 1.4 wks Purpose: compare the performance in screening of the 1 h, 50 g GCT, FPG and FCG Recommendations: There is not enough benefit to be gained by using the FPG instead of the GCT as the screening test for GDM Author, year Dates of study Country Rust, 1998 Women Analyzed, n Maternal Age, mean ± SD/median ± IQR (yr) BMI, mean ± SD 2 (kg/m ) 448 23.7 ± 6.1 Jul 1994 to Jun 1995 Screening Practice^ Inclusion/Exclusion Criteria Index†, (Comment) 26.8 ± 7.6 Universal, 2-step ADA, 16 (3.6%) ≥20 wks Study Purpose Conclusion(s) Prevalence of GDM Criteria, n (%) Load, Interval Time of GDM Confirmation Time of Screening Inclusion: Women at medical centre obstetric clinics, >20 wks gestation Reference†*, Date Postprandial 50 g GCT (1 and 2 hrs post meal glucose load) ADA, 100 g, 3 h 20 wks Purpose: Compare 2 h postprandial glucose measurements with the 1 h, 50 g glucola screen as a predictor of GDM Exclusion: NR U.S. Sacks, 2003 4,507 NR Feb 1998 to Jul 1999 NR Inclusion: Prenatal visit at medical center, no known diabetic Hx, able to return for lab work and glucose testing Universal, 2-step FPG (≥83 mg/dL) ADA, 2001 ADA, 302 (6.7%) 75 g, 2 h ≥23 wk NR Recommendations: 1 h glucola test is a reliable screening test for GDM whereas the 2 h postprandial test is not Purpose: Determine whether the FPG test administered at the first prenatal visit is an efficient screen for GDM Recommendations: FPG has poor specificity (high false-positive rate) making it an inefficient screening test U.S. Exclusion: Transferred care to other institution, began prenatal care or screened elsewhere, spontaneous abortion after enrollment D-17 Author, year Dates of study Country Siribaddana, 2003 Women Analyzed, n Screening Practice^ Inclusion/Exclusion Criteria Maternal Age, mean ± SD/median ± IQR (yr) BMI, mean ± SD 2 (kg/m ) 721 Time of GDM Confirmation Universal, 2-step 50g OGCT WHO, 1985 NR Inclusion: Attended antenatal clinic hospital WHO, 40 (5.5%) 75 g, 2 h NR Exclusion: Known DM 24-28 wks Traditional risk factors (Age, family Hx, parity, Hx of poor pregnancy outcomes) 1,502 Inclusion: Attended prenatal clinics 27.3 ± 6.1 2007 to 2010 25.7 ± 6.9 Exclusion: Hx hyperglycemia, on medication known to affect glucose metabolism Universal, 2-step Time intervals of 100 g OGTT 1 wk after OGCT ADA, 2009 ADA, 216 (13.1%) 100 g, 3 h 24-28 wks 1-2 wks after +OGCT D-18 Study Purpose Load, Interval Time of Screening Sri Lanka Iran Reference†*, Date Conclusion(s) Prevalence of GDM Criteria, n (%) NR Soheilykhah, 2010 Index†, (Comment) Purpose: Determine the prevalence of GDM in a Sri Lankan population using WHO criteria, and establish the predictive value of a 50g OGCT vs. the OGTT Recommendations: Traditional risk factors did not predict GDM; screening for GDM should be performed in all women with a GCT Purpose: To find an appropriate and simple way to perform screening tests for GDM Recommendations: A positive GCT result (≥130 mg/dL) with subsequent 2 h 100g OGTT (≥150 mg/dL) will diagnose GDM Author, year Dates of study Country Soonthornpun, 2003 Women Analyzed, n Screening Practice^ Inclusion/Exclusion Criteria Maternal Age, mean ± SD/median ± IQR (yr) BMI, mean ± SD 2 (kg/m ) 42 33.6 ± 5.4 NR Inclusion: 50 g OGCT values ≥140 mg/dL at screening between 14-36 wks Study Purpose Load, Interval Time of GDM Confirmation ADA, 2000 (75 g, 2 h GTT) CC, 1982 100 g, 3 h CC, 9 (21.4%) ADA, 3 (7.1%) 28.2 ± 4.2 Purpose: Test the validity of a 75 g, 2 h OGTT using the ADA criteria and reference values for the 100 g, 3 h OGTT Exclusion: NR 521 29.6 ± 4.8 Jan 2006 to Jul 2006 NR (included women with abnormal OGCT) Reference†*, Date Conclusion(s) Prevalence of GDM Criteria, n (%) Time of Screening NR Thailand Tan, 2007 Index†, (Comment) Inclusion: antenatal booking; ≥1 risk factors Universal, 2-step Selective, 2-step WHO, 180 (34.5%) 26.7 ± 4.6 Exclusion: NR 28.8 ± 6.4 wks Malaysia D-19 Clinical risk factors, 1 or more: ≥35 years, Hx macrosomia ≥4 kg; Hx intrauterine death; weight ≥70 kg, BMI ≥30, Hx of GDM, family Hx DM, or glycosuria WHO, 1999 75 g, 1 h Recommendations: The prevalence of GDM was lower using the 75 g OGTT using the criteria and reference values of the 100 g OGTT Purpose: Evaluate the role of risk factors in conjunction with GCT to determine an appropriate threshold for 1 h GCT Recommendations: 2-step screening threshold for a positive GCT should be ≥ 7.6 mmol/L. After a GCT result, clinical risk factors are no longer useful in selecting women. Author, year Dates of study Country Tri-Hospital (2 papers) Sermer, 1998 Naylor, 1997 Women Analyzed, n Screening Practice^ Inclusion/Exclusion Criteria Maternal Age, mean ± SD/median ± IQR (yr) BMI, mean ± SD 2 (kg/m ) 3,836 NR NR Sept 1989 to Mar 1992 Index†, (Comment) Universal, 2-step NDDG, 145 (3.8%) Load, Interval Time of GDM Confirmation 50 g, 2 h OGCT (time of last meal prior to glucose load) 26-28 wks NDDG, 1979 100 g, 3 h Exclusion: NR 42 NR 27.5 ± 4.3 Turkey NR Inclusion: Attending outpatient clinic, OGCT between 2428 wks Universal, 2-step CC, 1988 CC, 14 (33%) Serum fructosamine (≥2.85 mmol/L) 24-28 wks HbA1c (≥7.2%) NR 100 g, 3 h Exclusion: Pregnancies beyond wk 28 previously diagnosed as DM van Leeuwen, 2007 1,301 Inclusion: NR Universal, 2-step 30.8 ± 4.9 Exclusion: Known preexisting diabetes; no prenatal care before 24 wks of gestation WHO, 48 (3.7%) 75 g, 2 h 24-28 wks NR NR 24.2 ± 4.6 Netherlands Purpose: Established more efficient screening strategies for detection of GDM 26-28 wks Canada Uncu, 1995 Study Purpose Conclusion(s) Prevalence of GDM Criteria, n (%) Time of Screening Inclusion: >24 yrs at time of delivery, no Hx of DM examined by physician before 24 wks gestation, delivery >28 wks Reference†*, Date Random 50 g glucose test WHO, NR Recommendations: Increasing maternal carbohydrate intolerance is associated with a graded increase in adverse maternal and fetal outcomes Purpose: Evaluated the sensitivity and specificity of 50 g OGCT, serum fructosamine and HbA1c levels as screening tests for GDM Recommendations: HbA1c and fructosamine levels are reliable methods to 50 g OGCT Purpose: Compare the accuracy measures of the random glucose test and the 50 g GCT as screening tests for GDM Recommendations: The 50 g glucose challenge test is more useful than the random glucose test D-20 Author, year Dates of study Country Weerakiet, 2006 Women Analyzed, n Maternal Age, mean ± SD/median ± IQR (yr) BMI, mean ± SD 2 (kg/m ) 359 31.8 ± 6.1 Jul 2004 to Mar 2005 23.2 ± 4.3 Thailand Wijeyaratne, 2006 Screening Practice^ Inclusion/Exclusion Criteria 853 Inclusion: Singleton pregnancy, presenting ≥1 risk factor for GDM: age >30, obesity, family Hx of DM, prior GDM, glucosuria, signs of hyperglycemia, Hx of poor obstetric outcome Exclusion: Hypertension, known DM, known chronic disease requiring Tx, positive result for syphilis, hepatitis B (HBSAg), HIV Inclusion: Registered for antenatal care NR Selective, 2-step ADA, 66 (16.7%) Risk factor screen recommended by ACOG Time of GDM Confirmation Adiponectin levels (10 µmg/mL) ADA, 2000 50g OGCT (≥140 mg/dL) 24-28 wks 100 g, 3 h FBG (≥4.1 mmol/L) Risk factors proposed by ADA, NR Sri Lanka D-21 WHO, 1999 75 g, 2 h FPG (≥4.7 mmol/L) 24-28 wks Purpose: Evaluate adiponectin as a predictive factor for GDM and appropriate as a screening test for GDM Recommendations: Adiponectin was not as strong a predictor as GCT 21-27 weeks (OGCT) Selective, 2-step Study Purpose Load, Interval WHO, 144 (16.3%) Exclusion: Established glucose intolerance Reference†*, Date Conclusion(s) Prevalence of GDM Criteria, n (%) Time of Screening NR Apr 2003 to Jul 2003 Index†, (Comment) Purpose: Evaluate tests used for screening and confirmation of GDM in Sri Lanka 24-28 wks Recommendations: Urine and FBG are unsuitable for screening Author, year Dates of study Country Yachi, 2011 Women Analyzed, n Maternal Age, mean ± SD/median ± IQR (yr) BMI, mean ± SD 2 (kg/m ) 509 33.4 ± 3.7 Sep 2008 to Jan 2010 20 ± 2.5 Japan Yogev, 2004 1995 to 1999 U.S. Screening Practice^ Inclusion/Exclusion Criteria 2,541 26.1±6.3(>130) 29.2±7.0 (>180) 26.4±3.7 (>130) 27.6±3.1 (>180) Index†, (Comment) Load, Interval Time of GDM Confirmation Time of Screening Universal, 2-step Exclusion: FPG levels ≥2.5 mmol/L; missing or incomplete data 24-29 wks Inclusion: Singleton pregnancies; screened at 24-28 wks Universal, 2-step Exclusion: No Hx of GDM and pregestational DM 24-28 wks JSOG, 8 (2.0%) CC, 469 (6.8%) NDDG, NR (7.3%) Study Purpose Conclusion(s) Prevalence of GDM Criteria, n (%) Inclusion: Visited clinic; ≥13wks gestation Reference†*, Date FPG (≥3.66 mmol/L at 10 wks) JSOG, 1999 FPI (≥36.69 mmol/L at 10 wks) 26-29 wks 50 g OGCT (130, 135, 140 mg/dL) CC, 1982 NDDG, 1979 75 g, 2 h 100 g, 3 h +OGCT only, 1-2 wks OGCT Purpose: Determine early screening tests and risk factors predictive of glucose intolerance in later pregnancy Recommendations: FPG is not an acceptable screening test for glucose intolerance Purpose: Describe the predictive value for GDM using different OGCT thresholds in MexicanAmerican women Recommendations: A threshold of ≥130 mg/dL is recommended Notes: ^ Screening practice described in study;†Index and reference data used in this review. *Complete diagnostic criteria can be found in Table 1. ADA = American Diabetes Association; ADIPS = Australian Diabetes in Pregnancy Society; BMI = body mass index; CBG = capillary blood glucose; CHT = chronic hypertension; d = day; dL = deciliter; DM = diabetes mellitus; Dx = diagnosis/diagnostic; EASD = European Association for the Study of Diabetes FPG = fasting plasma glucose; GA = gestational age; GCI = gestational carbohydrate intolerance; GCT = glucose tolerance test; GDM = gestational diabetes mellitus; GHT = gestational hypertension; HbA1c = glycated hemoglobin; HBSAg = hepatitis B virus surface antigen; HOMA = homeostatic model assessment; h = hour; mg = milligrams; IADPSG = International Association of Diabetes and Pregnancy Study Groups; IWC = International Workshop Conference; JSOG = Japan Society of Obstetrics and Gynecology; CNGOF = National College of French Obstetricians and Gynaecologists; NDDG = National Diabetes Data Group; NR = not reported; OGTT = oral glucose tolerance test; PCS = prospective cohort study; PIH = pregnancy-induced hypertension; PROM = premature rupture of the membrane; QUICKI = Quantitative insulin sensitivity check index ; RCS = retrospective cohort study; RF = risk factors; SD = standard deviation; Tx = treatment; WHO = World Health Organization; wk(s) = week(s); yr(s) = year(s) Table D2. Characteristics of studies comparing outcomes for women who were and were not screened for GDM, Key Question 2 D-22 Author, year Women Enrolled, n Study Design, Duration of Followup Country Chanprapaph, 2004 RCS, Until birth Maternal Age, mean± SD (yr) BMI, mean ± SD s (kg/m ) 1,000 Screened: 31.5 ± 5.5 Not screened: 24.0 ± 3.8 Inclusion/ Exclusion Criteria Inclusion: Pregnant women attending a single antenatal care center; attendance from Oct 2001 to Dec 2002. Exclusion: NR Thailand RCS, Until birth 93 Screened: 30.5 Not screened: 31.1 Screening Test First booking; 24 & 28 wks; 30 & 32 wks Step 1: Risk factors + 50 g OGCT; positive ≥ 140 mg/dL after 1 hour Step 2: 100 g OGTT: 1) fasting glucose value 105 mg/dL 2) 1 hr 190 mg/dL 3) 2 hr 165 mg/dL 4) 3 hr 145 mg/dL -test considered positive if any 2 of non-fasting values greater than normal Screened: 22.5 ± 3.8 Not screened: 20.9 ± 2.9 Solomon, 1996 Gestational Age at Screening Inclusion: Female nurses; 25 to 42 yrs residing in 1 of 14 US states Gestational Age: NR Step 1: 1 h 50 g OGCT Exclusion: NR Outcomes Reported Numbers screened vs. not screened, n (%) Obstetric complications: PROM: 30 (7) vs. 46 (8) PIH: 21 (5) vs. 7 (1) GHT: 4 (1) vs. 4 (1) CHT: 4 (1) vs. 2 (0.3) PPH: 3 (1) vs. 1 (0.2) Chorioamnionitis: 0 (0) vs. 1 (0.2) Polyhydramnios: 1 (0.2) vs. 0 (0) Total obstetric complications: 65 (16) vs. 63 (11) Pregnancy outcomes: Preterm delivery: 42 (10) vs. 50 (8) Birthweight: th >90 percentile: 50 (12) vs. 55 (9) th <10 percentile: 42(10) vs. 58 (10) Fetal anomalies: 3 (2) vs. 1 (1) Cesarean section: 81 (20) vs. 71 (12) Maternal morbidity: NR Fetal morbidity: Macrosomia (7% each group) US Screened: 23.0 Not screened: 23.6 * BMI = body mass index; CHT = chronic hypertension; dl = deciliter; DM = diabetes mellitus; GA = gestational age; OGCT = oral glucose tolerance test; GDM = gestational diabetes mellitus; GHT = gestational hypertension; mg = milligrams; NR = not reported; OGTT = oral glucose tolerance test; PCS = prospective cohort study; PIH = pregnancy – induced hypertension; PROM = premature rupture of the membrane; RCS = retrospective cohort study; SD = standard deviation; wk = weeks; yr = years D-23 Table D3. Characteristics of studies examining outcomes of mothers and offspring in the absence of treatment, Key Question 3 Author, year Study Design (number of centers) Country Dates of study Women Analyzed, n Groups Aberg, 2001 4,657 RCS (4) G1: Sub-GDM Group (no Tx) G2: Control (no Tx) Sweden Maternal Age, mean ± SD/ median ± IQR (yr) BMI, mean ± SD/ Median ± IQR s (kg/m ) NR NR Outcomes Inclusion Criteria Inclusion: Singleton pregnancy, within Lund University hospital register, results matched Diagnostic Test Criteria 2 h, 75 g OGTT WHO, NR RCS (1) US Jan 1986 - Sep 1996 389 G1: GDM Diet (Tx) G2: GDM Insulin (Tx) G3: Unrecognized GDM (no Tx) G4: Control (no Tx) Ardawi, 2000 818 PCS (2) G1: Negative Screenees (no Tx) G2: Positive Screenees (no Tx) G3: GDM by NDDG (Tx) Saudi Arabia Jun 1996 – Jun 1998 G1: 31.4 ± 4.9 G2: 31.5 ± 4.6 G3: 30.2 ± 4.7 G4: 30.2 ± 4.5 Inclusion: Positive OGCT; meets NDDG criteria (2 plasma glucose values on OGTT) for GDM 1 h, 50 g OGCT 3 h, 100 g OGTT G1: 26.1 ± 6.1 G2: 30.3 ± 7.2 G3: 26.6 ± 7.5 G4: 26.3 ± 7.0 Exclusion: Multiple gestation; fetal congenital anomalies; delivery before 34 wks; delivery elsewhere; diet or insulin therapy initiated < 4 wks before delivery NDDG, 1979 G1: 29.2 ± 4.6 G2: 30.7 ± 4.8 G3: 32.1 ± 5.1 G1: 64.3 ± 4.1 G2: 68.6 ± 4.1 G3: 75.2 ± 4.5 Inclusion: NR Exclusion: Hepatic renal disease, DM prior to pregnancy, previous diet therapy, previous GDM, known endocrine disorders D-24 Emergency cesarean delivery, elective cesarean delivery, perinatal mortality rate Other: Gestational duration, birth weight, umbilical artery pH, APGAR score Exclusion: NR Jan 1995 - Dec 1997 Adams,1998 Other Outcomes (Not defined by KQ) 1 h, 50 g OGCT 3 h, 100 g OGTT Cesarean delivery, maternal weight gain, maternal birth trauma (rectal injury), macrosomia (BW >4000 gm, >4500 gm), shoulder dystocia, clavicular fracture, brachial plexus injury (cranial nerve palsy, brachial plexus, permanent & healed), hypoglycemia, hyperbilirubinemia (within neonatal complications composite), mortality (stillbirth) Other: Birthweight, LGA, vacuum & forceps delivery Cesarean delivery, macrosomia, hypoglycemia, hyperbilirubinemia, mortality(stillbirth) NDDG 1979 Other: Fetal length, <25g, head circumference, wk at delivery Author, year Study Design (number of centers) Country Dates of study Women Analyzed, n Groups Berggren, 2001 3,759 RCS (1) G1: CC GDM (no Tx) G2: NDDG GDM (Tx) G3: Control (no Tx) US Maternal Age, mean ± SD/ median ± IQR (yr) BMI, mean ± SD/ Median ± IQR s (kg/m ) NR 833 RCS (NR) G1: GDM by CC (no Tx) G2: GDM by Sacks (no Tx) G3: GDM by Langer (no Tx) G4: Normal (no Tx) US 1987 – 1988 Biri, 2009 2,029 RCS (1) G1: Normal 50 g GLT (no Tx) G2: Abnormal 50 g/ Normal 100 g (no Tx) G3: 1 Abnormal 100 g (no Tx) G4: GDM - 100 g GLT (Tx) G5: GDM – 50 g GLT (no Tx) Turkey Jan 2004 - Dec 2006 Inclusion Criteria Inclusion: Delivery at UNC women’s hospital NR Exclusion: No results available on 1 hr 50 g OGCT, delivery <24 wks, pregestational DM, GDM diagnosed by 50 g OGCT only Apr 1996 – May 2010 Berkus, 1995 Outcomes G1: 29.0 ± 5.0 G2: 30.0 ± 7.0 G3: 29.0 ± 6.0 G4: 26.0 ± 6.0 Inclusion: Nonhypertensive gravidas; singleton pregnancy; underwent 3hour GTT; attended clinics in San Antonio area 1 h, 50 g OGCT 3 h, 100 g OGTT NDDG 1979 CC 1982 No OGCT 3 h, 100 g OGTT Other Outcomes (Not defined by KQ) Preeclampsia, Maternal Hypertension, Cesarean delivery, maternal birth trauma (3rd or 4th degree laceration), macrosomia, shoulder dystocia Other: GA at delivery, mode of delivery other than c-section, HELLP (hemolysis, elevated liver enzymes, low platelet count), birthweight, NICU admission, NICU stay >48 hrs Macrosomia Other: Birthweight Exclusion: Women with 2+ abnormal OGTT values by NDDG criteria Coustan & Lewis, 1978 NDDG, 1979 Langer,1987 Sacks,1989 Inclusion: Singleton pregnancies, screened at study centre 1 h, 50 g OGCT 3 h, 100 g OGTT Preeclampsia, cesarean delivery, macrosomia, hypoglycemia, hyperbilirubinemia Exclusion: Prepregnancy DM, multiple gestations ACOG, 2001 NDDG, 1979 Other: Birthweight, LGA/SGA, APGAR, respiratory complications, polyhydramnios, prematurity NR G1: 29.6 ± 4.6 G2: 30.9 ± 4.9 G3: 32.1 ± 4.6 G4: 33.3 ± 4.8 G5: 32.6 ± 5.0 Diagnostic Test Criteria NR D-25 Author, year Study Design (number of centers) Country Dates of study Women Analyzed, n Groups Black, 2010 8,711 RCS (1) All no Tx G1: No GDM G2: IGT G3: IFG G4: IGT-2 G5: IFG-IGT US Oct 2005 – Mar 2010 Bo, 2004 RCS (1) Italy Apr 1999 - Feb 2001 700 G1: OGCT negative (normal) (no Tx) G2: OGCT positive OGTT negative (no Tx) G3: OGTT1 abnormal value (Tx) G4: GDM positive (Tx) Maternal Age, mean ± SD/ median ± IQR (yr) BMI, mean ± SD/ Median ± IQR s (kg/m ) G1: 28.6 ± 5.9 G2: 32.1 ± 5.4 G3: 30.4 ± 5.6 G4: 32.3 ± 5.2 G5: 32.0 ± 5.1 G1: 26.9 ± 5.8 G2: 28.1 ± 5.6 G3: 30.8 ± 7.1 G4: 27.5 ± 4.7 G5: 31.8 ± 7.0 G1: 30.8 ± 4.2 G2: 31.8 ± 4.3 G3: 32.9 ± 4.7 G4: 32.6 ± 4.9 NR Cheng, 2009 1,469 NR RCS (1) G1: No GDM (no Tx) G2: GDM by CC only (no Tx) G3: GDM NDDG only (Tx) NR US Jan 1988 - Dec 2001 Outcomes Inclusion Criteria Inclusion: Singleton birth >20 wks gestation, received 2 hr 75 g OGTT with no prior 50 g OGCT, available pre-pregnancy and delivery anthropometric data Diagnostic Test Criteria 2 h, 75 g OGTT IADPSG, 2010 Cesarean delivery, maternal weight gain, gestational hypertension, shoulder dystocia/birth injury, hyperbilirubinemia Other: Birthweight, LGA, ponderal index, preterm delivery Exclusion: Any form of treatment Inclusion: Caucasian; attending clinic Other Outcomes (Not defined by KQ) 1 h, 50 g OGCT 3 h, 100 g OGTT Cesarean delivery, macrosomia, hyperbilirubinemia (icterus), mortality (death) Exclusion: Known DM, any disease affecting glucose metabolism CC, 1982 Inclusion: All pregnancies screened and delivered at University of California 1 h, 50 g OGCT 3 h, 100 g OGTT Exclusion: Multifetal pregnancies, vaginal breech deliveries, delivery <24 wks, congenital anomalies, pregestational DM NDDG,1979 CC, 1982 Other: "Metabolic Syndrome in Pregnancy", premature births, birthweight, LGA/SGA, APGAR score, respiratory distress, malformations, neonatal diseases Preeclampsia, cesarean delivery (mode of delivery), maternal birth trauma (3rd or 4th degree laceration), macrosomia, shoulder dystocia, birth trauma composite variable incl. brachial plexus injury, facial nerve palsy, clavicular and skull fracture, head laceration Other: Preterm delivery <37wks, APGAR <7, neonatal acidemia, LGA D-26 Author, year Study Design (number of centers) Country Dates of study Women Analyzed, n Groups Chico, 2005 6,248 RCS (1) G1: Standard criteria (Tx) G2: New criteria (Tx) G3: Subgroup- New IGT criteria (no Tx) G4: Normal tolerance (no Tx) Spain Jan 1999 - Dec 2001 Chou, 2010 10,990 RCS (1) Jan 2001 - Sep 2008 G1: Normal (no Tx) G2: GDM by CC but not NDDG criteria (no Tx) G3: GDM by NDDG criteria (Tx) Cok, 2011 185 RCS(1) G1: 0h OGTT (no Tx) G2: 1 h OGTT (no Tx) G3: 2 h OGTT (no Tx) G4: 3 h OGTT (no Tx) Taiwan Turkey Jan 2003 - Jun 2009 Corrado, 2009 776 RCS (NR) G1: OAV (no Tx) G2: Control (no Tx) Italy Maternal Age, mean ± SD/ median ± IQR (yr) BMI, mean ± SD/ Median ± IQR s (kg/m ) G1: 33.4 ± 4.0 G2: 33.3 ± 4.0 G3: 33.3 ± 4.0 G4: 32.8 ± 4.0 Outcomes Inclusion Criteria Inclusion: All pregnancies handled in 2 yr period Diagnostic Test Criteria 1 h, 50 g OGCT 3 h, 100 g OGTT Exclusion: None NR NDDG, 1979 th 4 IWC/ADA, 2003 th 4 IWC/CC, 1998 1 h, 50 g OGCT 3 h, 100 g OGTT G1: 32.8 ± NR G2: 33.4 ± NR G3: 34.4 ± NR Inclusion: Singleton pregnancies delivered at Cathay General Hospital NR Exclusion: Multiple pregnancies, fetal anomalies diagnosed prenatally CC, 1982 NDDG, 1979 G1: 32.5 ± 4.8 G2: 30.1 ± 4.5 G3: 30.0 ± 5.1 G4: 30.2 ± 4.3 Inclusion: Women presenting to Baskent Unviersity, one abnormal OGTT value 1 h, 50 g OGCT 3 h, 100 g OGTT G1: 33.7 ± 4.5 G2: 30.8 ± 3.8 G3: 29.8 ± 4.3 G4: 30.1 ± 3.2 Exclusion: Multiple gestations or prepregnancy DM, 2 abnormal OGTT values G1: 31.2 ± 5.1 G2: 30.1 ± 4.9 Inclusion: Caucasian, one positive screening test and OGTT 1 h, 50 g OGCT 3 h, 100 g OGTT Exclusion: Multiple gestations, Tx for GDM CC, 1982 Other Outcomes (Not defined by KQ) Cesarean delivery, maternal weight gain, macrosomia (>4000 g), hypoglycemia, hyperbilirubinemia (jaundice), mortality (fetal deaths) Other: Week of delivery, instrumentation, birthweight, LGA/SGA, APGAR, malformations Maternal hypertension, cesarean delivery, maternal birth trauma (postpartum hemorrhage), macrosomia, shoulder dystocia, mortality (intrauterine fetal demise) Other: Preterm labour, APGAR scores Macrosomia Other: LGA, birthweight, birth week CC, 1982 G1: 25.0 ± 5.1 G2: 24.2 ± 4.4 D-27 Preeclampsia/maternal hypertension (hypertensive disorders of pregnancy), cesarean delivery, macrosomia, hypoglycemia Author, year Study Design (number of centers) Country Dates of study Jan 1996 - Dec 2005 Hillier, 2007 RCS (2) US 1995-2000 Jensen, 2002 RCS(4) Denmark Jan 1992 - Dec 1996 Kim, 2002 PCS(1) South Korea NR Women Analyzed, n Groups Maternal Age, mean ± SD/ median ± IQR (yr) BMI, mean ± SD/ Median ± IQR s (kg/m ) Outcomes Inclusion Criteria Diagnostic Test Criteria Other: GA, birthweight, APGAR (insulin/diet) 9,439 NR G1: Normal (no Tx) G2: Positive OGCT normal OGTT (no Tx) G3: Positive OGCT and 1 Abnormal CC or NDDG (no Tx) G4: GDM-CC (no Tx), G5: GDM NDDG (Tx) 3,260 NR G1: Normal WHO (no Tx) G2: Normal DPSG but IGT WHO (no Tx) G3: Abnormal DPSG and IGT WHO (Tx) G4: GDM by both (Tx) 699 NR G1: Normal (no elevated) G2: 1 Elevated (1 h elevated) G3: 2 Elevated (2 h elevated) G4: 3 Elevated (3 h elevated) Inclusion: Data on motherchild pairs 5-7 yrs PP Other Outcomes (Not defined by KQ) 1 h, 50 g OGCT 3 h, 100 g OGTT Macrosomia (maternal glycemic level associated with macrosomia, childhood obesity) NDDG, NR (1979) CC criteria as presented in th 4 IWC, 1998 Other: Prevalence, risk of childhood obesity; association with maternal GDM screening results during pregnancy (hyperglycemia) 2 h, 75 g OGTT Preeclampsia, maternal hypertension, cesarean delivery, maternal weight gain, macrosomia (>4000g), hypoglycemia, hyperbilirubinemia (jaundice) Exclusion: Preexisting DM NR Inclusion: First pregnancy in study period, tested with 75 g OGTT WHO, 1985 DPSG, 1991 Exclusion: Pregestational GDM, multiple pregnancies, chronic disease G1: 30.7 ± 3.9 G2: 29.5 ± 4.4 G3: 30.2 ± 3.3 G4: 32.3 ± 3.8 G1: 21.4 ± 2.9 G2: 21.0 ± 3.0 G3: 20.7 ± 2.6 G4: 21.8 ± 2.8 Inclusion: singleton pregnancy; antenatal care at Ajou University Hospital Department of Obstetrics and Gynecology Exclusion: missing data; confirmed GDM dx D-28 1 h, 50 g OGCT 3 h, 100 g OGTT Other: LGA, respiratory distress, preterm delivery, glucosuria, GA Preeclampsia, cesarean delivery, th birthweight, LGA 90 percentile (macrosomia), hypoglycemia, perinatal death NDDG, NR Other: Gestational age at birth (wks), APGAR, respiratory distress syndrome, poor perinatal outcome Author, year Study Design (number of centers) Country Dates of study Kwik, 2007 RCS(1) Women Analyzed, n Groups 675 G1: Treated G2: Untreated G3: Comparison Australia Feb 2000/Oct 2003 - May 2005 Landon, 2009 (primary) Landon, 2011 RCT(Multicenter, n = NR) US Oct 2002 - Nov 2007 1,841 G1: CC Mild GDM (no Tx) G2: CC False-positive, further divided by normal/ abnormal OGTT value (no Tx, no distinct data) G3: Normal control (no Tx) Maternal Age, mean ± SD/ median ± IQR (yr) BMI, mean ± SD/ Median ± IQR s (kg/m ) G1: 34.5 ± 4.8 G2: 33.3 ± 4.7 G3: 32.8 ± 4.5 G1: 23.8 ± 4.4 G2: 22.9 ± 4.6 G3: 22.6 ± 3.7 G1: 28.9 ± 5.6 G2: 27.4 ± 5.5 G3: 25.1 ± 5.3 G1: 30.2 ± 5.1 G2: 30.1 ± 5.3 G3: 29.9 ± 5.8 Outcomes Inclusion Criteria Inclusion: Singleton pregnancy, 75 g GTT with a fasting value ≤ 5.5 mmol/L and 2-h blood sugar ≥7.8 mmol/L Diagnostic Test Criteria 1 h, 50 g OGCT 2 h, 75 g OGTT ADA, 2000 Exclusion: Confined ≤34 wks gestation Inclusion: Between 24 wks 0 ds and 30 wks 6 ds gestation, 135 and 200 mg/dL 1 hour after a 50 g glucose loading test Exclusion: Preexisting diabetes, abnormal results before 24 wks, prior GDM, Hx of stillbirth, multifetal gestation, asthma, CHT, corticosteriod use, known fetal anomaly, likely preterm delivery D-29 1 h, 50 g OGCT 3 h, 100 g OGTT CC, 1982 th 4 IWC, 1998 Other Outcomes (Not defined by KQ) Preeclampsia, cesarean delivery, macrosomia (BW > 4000 g), shoulder dystocia, clavicular fracture, brachial plexus injury (Erb's Palsy) Other: Mean birthweight, SCN admission, APGAR, premature delivery, GA at delivery Preeclampsia, maternal hypertension, cesarean delivery, maternal weight gain, macrosomia (BW >4000 g), shoulder dystocia, birth injury (trauma), hypoglycemia, hyperbilirubinemia, mortality (stillbirth/neonatal death) Other: GA at birth, elevated c-cord peptide, birthweight, LGA/SGA, Fat mass, Preterm delivery, NICU admission, IV glucose Tx, respiratory distress Author, year Study Design (number of centers) Country Dates of study Women Analyzed, n Groups Langer, 2005 2,775 US(1) G1: GDM (no Tx, Dx after 37 wks) G2: GDM (Tx) G3: Nondiabetic control (no Tx) RCS Maternal Age, mean ± SD/ median ± IQR (yr) BMI, mean ± SD/ Median ± IQR s (kg/m ) G1: 27.6 ± 6.0 G2: 29.1 ± 6.0 G3: 25.0 ± 6.0 NR Jan 1999 - Sept 1999 Lao, 2001 487 PCS(1) NR G1: GDM by WHO (Tx) G2: Normal OGTT only (no Tx) G3: Control (no Tx) Lao, 2003 2,149 RCS(1) 2 h OGTT (mmol/L): G1: <6.0 (no Tx) G2: 6.0 -6.9 (no Tx) G3: 7.0 -7.9 (no Tx) China China 1996 – 1997 G1: 32.1 ± 4.6 G2: 30.4 ± 5.3 G3: 27.7 ± 4.0 G1: 22.6 ± 3.2 G2: 22.0 ± 2.7 G3: 21.1 ± 2.7 G1: 28.6 ± 4.6 G2: 29.6 ± 4.6 G3: 30.8 ± 4.4 G1: 21.5 ± 2.6 G2: 21.7 ± 2.7 G3: 21.8 ± 2.8 Outcomes Inclusion Criteria Inclusion: Singleton pregnancies, FPG<140 mg/dL on OGTT; Casecontrol groups: GDM diagnosed >37 wks, treated GDM and non diabetic matched 2:1 for obesity, parity, ethnicity, GA at delivery (within 5 ds), yr of delivery Exclusion: Pregestational DM, substance abusers, multifetal gestation, fetal anomalies Inclusion: Singleton pregnancies with visits to antenatal care between 2830 wks Exclusion: Preexisting DM, CHT or other medical complication, thalassemia trait Inclusion: Singleton pregnancy, antenatal OGTT, delivery at Queen Mary hospital, no insulin requirements Exclusion: Significant medical complications, taking no medication (ie. corticosteriods) D-30 Diagnostic Test Criteria 1 h, 50 g OGCT 3 h, 100 g OGTT Other Outcomes (Not defined by KQ) Cesarean delivery, macrosomia, shoulder dystocia, hypoglycemia, hyperbilirubinemia, mortality (stillbirth) CC, 1982 Other: Birthweight, LGA, ponderal Index >2.85, arterial cord pH <7.2, erythrocytosis, respiratory complication, induction of labour 2 h, 75 g OGTT WHO, 1980 Preeclampsia, cesarean delivery, maternal birth trauma (antepartum hemorrhage) Other: Preterm labor, prelabor rupture of the membranes, delivery mode, weeks gestation, birthweight, LGA/SGA, APGAR score 1 min., NICU admission Cesarean delivery, macrosomia 2 h, 75 g OGTT WHO, 1980 Other: Birthweight, LGA/SGA, preterm birth Author, year Study Design (number of centers) Country Dates of study Women Analyzed, n Groups Lapolla, 2007 611 PCS(5) G1: Normal Control (no Tx) G2: False Positive (no Tx) G3: 1 Abnormal Glucose Value (OAV) (no Tx) G4: GDM (Tx) 1,927 Italy NR Lapolla, 2011 RCS(1) Italy G1: GDM formerly normal (no Tx) G2: Normal (no Tx) Maternal Age, mean ± SD/ median ± IQR (yr) BMI, mean ± SD/ Median ± IQR s (kg/m ) G1: 30.9 ± 4.7 G2: 31.7 ± 4.9 G3: 32.5 ± 4.4 G4: 33.4 ± 4.4 Outcomes Inclusion Criteria Diagnostic Test Criteria Inclusion: No smoking; no CHT/specific conditions known to affect glucose metabolism 1 h, 50 g OGCT 3 h, 100 g OGTT HbA1c* G1: 22.4 ± 4.2 G2: 22.8 ± 3.9 G3: 23.7 ± 4.7 G4: 24.7 ± 4.8 Exclusion: Those with conditions known to affect glucose metabolism G1: 32.4 ± 4.5 G2: 32.2 ± 4.5 Inclusion: Positive 50 g OGCT (1-h plasma glucose ≥ 7.8mmol/L), 3-h OGTT at 24–28 wks; negative result on OGCT or OGTT formed control group Criteria not defined, values same as CarpenterCoustan 1 h, 50 g OGCT 3 h, 100 g OGTT G1: 23.7 ± 4.3 G2: 23.3 ± 4.2 IADPSG, 2010 th 4 IWC, 1998 1998 - 2008 Other Outcomes (Not defined by KQ) Cesarean delivery, macrosomia Other: LGA, ponderal index Maternal morbidity (eclampsia), maternal hypertension, cesarean delivery, macrosomia, shoulder dystocia (within fetal morbidity, incl. malformations, hypoglycemia,asphyxia,hyperbilir ubinemia, etc.) Exclusion: NR Metzger/ HAPO, 2008 PCS(15) Various Jul 2000 - Apr 2006 23,316 (All no Tx) G1: 100 mg/dL + G2: 95-99 mg/dL G3: 90-94mg/dL G4: 85-89mg/dL G5: <85mg/dL; subdivided into G6: <75mg/dL G7: 75-79 mg/dL Tot: 29.2 ± 5.8 Tot: 27.7 ± 5.1 Inclusion: Pregnant women 2 h, 75 g OGTT Exclusion: <18 years, unknown LMP, no ultrasonographic estimation of GA between 6-24 wks, no OGTT within 32 wks, multiple pregnancies, assisted conception/IVF, glucose testing before recruitment, participation in another study or previous HAPO study, HIV, hepatitis B or C virus; no English language proficiency HAPO Criteria; defined by groups D-31 Other: LGA/SGA, birthweight, ponderal index Preeclampsia, maternal hypertension, cesarean delivery, shoulder dystocia, hypoglycemia, hyperbilirubinemia Other: Cord blood serum Cpeptide, Cord blood PG, CHT, intensive neonatal care, premature delivery, BW >90th percentile Author, year Study Design (number of centers) Country Dates of study Women Analyzed, n Groups Morikawa, 2010 228 RCS(1) G1: JSOG GDM (Tx) G2: JSOG - No GDM (no Tx) G3: IADPSGHyperglycemia (Tx) G4: IADPSG-New Patients (no Tx) G5: IADPSG No GDM (no Tx) 614 Japan Jan 2002- Dec 2006 Nord, 1995 RCS(2) Sweden 1989 -1990 G1: 2-h OGTT 8.08.9mmol/L (no Tx) G2: Controls (no Tx) Maternal Age, mean ± SD/ median ± IQR (yr) BMI, mean ± SD/ Median ± IQR s (kg/m ) NR NR Outcomes Inclusion Criteria Inclusion: Women with both OGCT and OGTT; singleton birth Exclusion: NR G1: 30 ± 1846 G2: 29 ± 1645 G1: 22.3 ± 17.0 -43.3 G2: 21.3 ± 16.0-41.8 Inclusion: Intervention group: Indications to perform OGTT (Hx of DM in first degree relative; obesity (≥120 % or >9 kg); previous LFD-baby (>4.5 kg); IGT in previous pregnancy; accelerated fetal growth or polyhydraminosis; glucosuria; random Bglucose ≥7. mmol/L). Control group: No indication to perform OGTT Exclusion: NR D-32 Diagnostic Test Criteria 1 h, 50 g OGCT 2 h, 75 g OGTT Other Outcomes (Not defined by KQ) Macrosomia Other: BW percentile IADPSG, 2010 JSOG, 2008 2 h, 75 g OGTT WHO, 1980 Preeclampsia, cesarean delivery, macrosomia (LFD - large for date), clavicular facture, brachial plexus injury, birth injury (traumatic delivery), hypoglycemia, hyperbilirubinemia, mortality Other: Premature delivery, respiratory distress syndrome, polycythemia requiring Tx, traumatic delivery Author, year Study Design (number of centers) Country Dates of study Women Analyzed, n Groups Maternal Age, mean ± SD/ median ± IQR (yr) Pennison, 2001 242 BMI, mean ± SD/ Median ± IQR s (kg/m ) NR RCS (1) G1: Control (no Tx) G2: GDM NDDG (Tx) G3: GDM ADA (no Tx) G1: 30.2 ± 1.1 G2: 31.7 ± 1.0 G3: 29.6 ± 1.1 US Outcomes Inclusion Criteria 396 PCS (Multicenter, n = NR) 2003 - Sep 2007 G1: Normal OGCT, NGT (no Tx) G2: Abnormal OGCT, NGT (no Tx) G3: GIGT (no Tx) G4: GDM (Tx) Ricart, 2005 9270 PCS (16) G1: NDDG GDM (Tx), G2: NDDG Negative (No Tx), G3: False-positive ADA (No Tx), G4: ADA GDM (No Tx) Canada Spain 1 h, 50 g OGCT 3 h, 100 g OGTT Preeclampsia, cesarean delivery, macrosomia, shoulder dystocia, hypoglycemia Exclusion: NR ADA, 1998 CC, 1982 NDDG/ACOG, 1994 1 h, 50 g OGCT 3 h, 100 g OGTT 3 mo. PP: 2 h, 75 g OGTT Maternal weight gain 2002 - NR G1: 34.0 ± 4.4 G2: 33.8 ± 4.2 G3: 34.2 ± 4.2 G4: 34.5 ± 4.3 Inclusion: Attending outpatient obstetrics clinics; late second trimester; 50 g OGCT screen G1: 23.0 ± 21.5-26.1 G2: 23.5 ± 21.1-27.5 G3: 23.5 ± 21.8-27.7 G4: 25.0 ± 22.0-30.1 G1: 31.9 ± 4.7 G2: 28.8 ± 5.3 G3: 30.5 ± 4.9 G4: 31.7 ± 4.6 Exclusion: NR G1: 25.9 ± 5.2 G2: 23.5 ± 3.9 G3: 24.5 ± 4.5 G4: 25.2 ± 4.7 Other Outcomes (Not defined by KQ) Inclusion: Delivery at regional medical centre in Memphis; euglycemic or Dx GDM 1995 - 1999 Retnakaran, 2008 Diagnostic Test Criteria Other: 3 mo postpartum: maternal insulin sensitivity, beta-cell function, glycemia NDDG 1979, CDA 2003 Inclusion: Singleton pregnancy, no former Dx of GDM 1 h, 50g OGCT 3 h, 100g OGTT Cesarean delivery, pregnancy induced hypertension, perinatal mortality, macrosomia Exclusion: Women who did not undergo screening, unavailable results ADA, 2000 NDDG, 1979 Other: Preterm birth, LGA/SGA, APGAR score 1 & 5 mins, major malformations D-33 Author, year Study Design (number of centers) Country Dates of study Women Analyzed, n Groups Rust, 1996 664 RCS(1) G1: ≥ 2 of 4 values, abnormal by Sacks criteria G2: ≥ 2 of 4 values, abnormal by CC criteria G3: 1 abnormal by Sacks G4: 1 abnormal by CC G5: No abnormal by Sacks G6: No abnormal by CC US NR - NR Sacks,1995 3,505 PCS(NR) Groups: Women were not grouped; actual glucose levels were used in regression analyses to assess the association with birthweight US Mar 1992 - Mar 1993 Maternal Age, mean ± SD/ median ± IQR (yr) BMI, mean ± SD/ Median ± IQR s (kg/m ) G1: 25.7 ± NR G2: 23.7 ± NR G3: 22.7 ± NR G4: 26.7 ± NR G5: 24.0 ± NR G6: 22.7 ± NR Outcomes Inclusion Criteria Inclusion: Positive GDM screen result; underwent 3 h100 g OGT Exclusion: Delivery outside study hospital G1: 26.6 ± NR G2: 25.5 ± NR G3: 24.8 ± NR G4: 28.1 ± NR G5: 25.7 ± NR G6: 24.6 ± NR Tot: 27.2 ± 5.8 Inclusion: Enrolled in prenatal care Tot: 24.9 ± NR Exclusion: GDM in previous pregnancy, glucocorticoids, diet or insulin Tx, high fasting plasma glucose values, multiple gestations D-34 Diagnostic Test Criteria 1 h, 50 g OGCT 3 h, 100 g OGTT CC,1982 NDDG,1979 O'Sullivan and Mahan,1964 Sacks, 1975 2 h, 75 g OGTT No criteria defined, purpose of study to ID threshold values Other Outcomes (Not defined by KQ) Maternal hypertension,cesarean delivery, birth trauma (obstetric lacerations, hemorrhage) maternal weight gain, macrosomia, shoulder dystocia, birth trauma (dystocia disorders, birth trauma), hypoglycemia, hyperbilirubinemia, mortality (cumulative neonatal morbidity) Other: Intrauterine growth restriction, oligohydramnios, preterm labor, premature or prolonged rupture of the membranes, chorioamnionitis, malpresentation, labour induction, labour augmentation, fetal intolerance of labour, abdominal delivery, operative vaginal delivery Maternal weight gain, macrosomia Author, year Study Design (number of centers) Country Dates of study Schwartz, 1999 RCS(4) US 1995 - 1996 Sermer, 1995 (Primary) Naylor, 1996 RCT(3) Canada Sep 1989 - Mar 1992 Shirazian, 2008 PCS(5) Iran NR - NR Women Analyzed, n Groups 8,711 G1: Normal results, prenatal screen (no Tx) G2: Abnormal (or no) prenatal screen and normal OGTT (no Tx) G3: NDDG GDM (Tx) G4: CC GDM (no Tx) 3,780 G1: Negative screenees (no Tx), G2: False-positive Screenees (no Tx) G3: GDM- Borderline (no Tx) G4: GDM (Tx) Maternal Age, mean ± SD/ median ± IQR (yr) BMI, mean ± SD/ Median ± IQR s (kg/m ) NR Outcomes Inclusion Criteria Inclusion: No previous DM or GDM NR Diagnostic Test Criteria 1 h, 50 g OGCT 3 h, 100 g OGTT Other Outcomes (Not defined by KQ) Cesarean delivery, macrosomia (BW >4000 g , >4500 g), mortality (stillbirth) Exclusion: NR CC, 1982 NDDG, 1979 G1: 30.9 ± 4.1 G2: 31.9 ± 4.3 G3: 32.1 ± 4.4 G4: 32.7 ± 4.3 G1: 22.7 ± 3.8 G2: 23.1 ± 4.5 G3: 24.7 ± 5.8 G4: 24.2 ± 4.8 Inclusion: >24 yrs at delivery; no Hx of preexisting DM; examined by physician before 24 wks gestation 1 h, 50 g OGCT 3 h,100 g OGTT NDDG, 1979 CC, 1982 Exclusion: Delivery <28 wks 612 NR Inclusion: No Hx of DM 2 h, 75 g OGTT G1: No GDM (no Tx) G2: GDM by ADA only (Tx) G3: GDM by WHO only (NR) G4: GDM by ADIPS only (NR) Tot: 24.4 ± 4.6 Exclusion: Pregestational DM, inablity to complete OGTT at 24-48 wks, twin pregnancies, no CHT, chronic renal failure, heart diseases, advanced pulmonary disease, current th smokers, labor before 37 th or after 40 gestational wk, planning to deliver at another hospital ADA, 2008 WHO, 2008 ADIPS, 2008 D-35 Preeclampsia, cesarean delivery, macrosomia, hypoglycemia, hyperbilirubinemia (phototherapy) Other: Fetal trauma, congenital anomalies, respiratory distress syndrome, maternal/fetal length of stay Macrosomia Author, year Study Design (number of centers) Country Dates of study Stamilio, 2004 RCS(1) US Women Analyzed, n Groups 1,825 G1: False-positive OGCT (no Tx) G2: Negative OGCT (no Tx) G3: GDM (Tx) Maternal Age, mean ± SD/ median ± IQR (yr) BMI, mean ± SD/ Median ± IQR s (kg/m ) G1: 28.5 ± NR G2: 25.5 ± NR G1: 28.5 ± NR G2: 25.5 ± NR Tan, 2008 1,200 RCS(1) G1: Negative OGCT (no Tx) G2: False-Positive OGCT (no Tx) G1: 28.9 ± 4.6 G2: 30.3 ± 4.7 G1: 26.5 ±4.4 G2: 27.0 ± 4.4 Vambergue, 2000 239 PCS(15) G1: Mild Gestational Hyperglycemia (MGH) (no Tx) G2: Control (no Tx) Feb 1992 - Sep 1992 Inclusion: Delivery at University of Pennsylvania Medical Center, entry into triple marker screen perinatal database, complete followup Diagnostic Test Criteria 1 h, 50 g OGCT 3 h, 100 g OGTT NDDG modified by O’Sullivan cutoff, NR Inclusion: GCT screen at prenatal booking, GTT test only of GCT was positive, available delivery records 1 h, 50 g OGCT 2 h, 75 g OGTT G1: 28.8 ± 5.8 G2: 27.0 ± 5.2 Inclusion: Attendance at public maternity unit G1: 24.8 ± 4.8 G2: 23.0 ± 3.9 Exclusion: Twin pregnancies, prepregnancy high blood pressure, asthma, haemochromatosis, prepregnancy diabetes or GDM D-36 Other Outcomes (Not defined by KQ) Preeclampsia, maternal hypertension (chronic hypertension), long term hypertension (chronic hypertension), macrosomia, shoulder dystocia, mortality (antenatal death) Other: NICU admission, chorioamionitis, endometritis, birthweight (mean), high 28-week mean arterial pressure (maternal) Cesarean delivery, maternal birth trauma (hemorrhage), macrosomia, SGA, fetal loss WHO, 1999 Other: Preterm birth, induction of labor, APGAR, cord blood ph Exclusion: Women missing GTT despite positive GCT, multiple gestations Jan 2006 - July 2006 France Inclusion Criteria Exclusion: Multiple gestations, anomalous fetuses 1995 -1997 Malaysia Outcomes 1 h, 50 g OGCT 3 h, 100 g OGTT CC, 1982 Pregancy induced hypertension, cesarean delivery, shoulder dystocia, macrosomia, hypoglycemia, hyperbilirubinemia, mortality Other: LGA/SGA, respiratory distress, pathological deliveries, transfer to neonatal care unit, malformations, prematurity, APGAR score, adverse maternal and fetal outcome Author, year Study Design (number of centers) Country Dates of study Women Analyzed, n Groups Yang, 2002 404 PCS(16) G1: Impaired Glucose Tolerance (no Tx) G2: Normal (Normal Glucose Tolerance (no Tx) China Dec 1998 - Dec 1999 Maternal Age, mean ± SD/ median ± IQR (yr) BMI, mean ± SD/ Median ± IQR s (kg/m ) G1: 28.0 ± 3.68 G2: 26.5 ± 2.95 G1: 22.6 ± 3.49 G2: 21.5 ± 2.57 Outcomes Inclusion Criteria Diagnostic Test Criteria Inclusion: NR Exclusion: <18 yrs, multiple pregnancies, maternal-fetal ABO incompatibility, maternal disease incl. prepregnancy diabeetes & those under long term medical treatment that may affect glucose metabolism, delivery outside Tianjin (rural or home delivery) 1 h, 50 g OGCT 2 h, 75 g OGTT WHO, 1998 Other Outcomes (Not defined by KQ) Weight gain in pregnancy, cesarean delivery, birth trauma/dystocia, mild/moderate th preeclampsia, birthweight > 90 percentile (macrosomia), th birthweight > 95 percentile, hypoglycemia, perinatal death Other: PROM, breech presentation, preterm delivery, fetal male gender, low birth weight (< 2500 g), APGAR score < 7 @ 1 min, pneumonia * ACOG = American Congress of Obstetricians and Gynecologists; ADA = American Diabetes Association; ADIPS = Australian Diabetes in Pregnancy Society; BMI = body mass index; CC = Carpenter-Coustan; CHT = chronic hypertension; d(s) = day(s); dL = deciliter; DM = diabetes mellitus; Dx = diagnosis/diagnostic; FPG = fasting plasma glucose; OGCT = oral glucose tolerance test; GDM = gestational diabetes mellitus; GLT = glucose load test; g = grams; HAPO = Hyperglycemia and Adverse Pregnancy Outcomes Study; h = hour; IADPSG = International Association of Diabetes and Pregnancy Study Groups; IFG = impaired fasting glucose; IGT = impaired glucose tolerance; IGT-2 = double impaired glucose tolerance; IQR = inter-quartile range; JSOG = Japan Society of Obstetrics and Gynecology; kg = kilogram; LGA = large for gestational age; m = meter; mg = milligrams; NDDG = National Diabetes Data Group; NR = not reported; OGTT = oral glucose tolerance test; PP= postpartum; PCS = prospective cohort study; PROM = premature rupture of the membranes; RCS = retrospective cohort study; SD = standard deviation; SGA = small for gestational age; Tx = treatment; wk(s) = week(s); WHO = World Health Organization; yr(s) = year(s) Table D4. Characteristics of studies examining treatment outcomes of mothers and offspring, Key Questions 4 and 5 Author, year Study Design Dates of study Women Enrolled, n Maternal Age, mean± SD (yr) BMI, mean ± SD; median IQR s (kg/m ) Screening and Diagnostic Tests Interventions Outcomes Reported Quality Glucose Levels, mean ± SD Country Adams, Inclusion/ Exclusion Criteria Race 389 Inclusion: Positive Screen: 50 g GCT (24–30 D-37 G1: Diet with weekly Weight gain, NOS = 9 Author, year Study Design Dates of study Women Enrolled, n Maternal Age, mean± SD (yr) BMI, mean ± SD; median IQR s (kg/m ) US Interventions Outcomes Reported Quality Race 1998 Jan 1986 to Sep 1996 Screening and Diagnostic Tests Glucose Levels, mean ± SD Country RCS Inclusion/ Exclusion Criteria G1: 31.5 ± 4.6 G2: 31.4 ± 4.9 G3: 30.2 ± 4.7 G1: 30.3 ± 7.2 G2: 26.1 ± 6.1 G3: 26.6 ± 7.5 NR G1: White: 73 G2: White: 277 G3: White: 15 OGCT; meets NDDG criteria (2 plasma glucose values on OGTT) for GDM Exclusion: Multiple gestation; fetal congenital anomalies; delivery before 34 wks; delivery elsewhere; diet or insulin therapy initiated < 4 wks before delivery wks with 1-h cutoff by NDDG criteria, ≥ 140 mg/dL) Diagnostic:100 g OGTT at 24–30 wks (Fasting: 105 mg/dL;1 h 190 mg/dL; 2 h 165 mg/dL; 3 h 145 mg/dL) blood glucose monitoring, daily BG self-monitoring and insulin required (n=76) G2: Diet with weekly blood glucose monitoring (n=297) G3: No treatment (n=16) D-38 shoulder dystocia, hypoglycemia, stillbirth or neonatal death, birth trauma, birth weight, bone fracture/clavicul ar fracture, nerve palsy/brachial plexus injury, LGA, rectal injury, neonatal complications, Horner's syndrome, hemidiaphragm paralysis, unilateral eyelid ptosis from partial cranial nerve palsy (good) Author, year Study Design Dates of study Women Enrolled, n Maternal Age, mean± SD (yr) BMI, mean ± SD; median IQR s (kg/m ) Screening and Diagnostic Tests Interventions Outcomes Reported G1: No diet, random glucose checks, and usual care (n=48) Preeclampsia, shoulder dystocia, birth weight, APGAR, abnormal fetal heart rate, SGA Quality Glucose Levels, mean ± SD Country Bevier, 1999 Inclusion/ Exclusion Criteria Race 83 RCT G1: 26.3 ± 6.0 G2: 27.4 ± 5.4 NR NR US NR G1: White: 2 Black: 1 Hispanic: 45 G2: White: 2 Black: 0 Hispanic: 33 Inclusion: Positive OGCT screen and negative OGTT Exclusion: Hypertension; collagen disease; chronic renal disease; cardiac or pulmonary disease; Rh sensitization; Hx of preterm labor or SGA Screen: 50 g GCT (24–30 wks with 1-h cutoff by NDDG criteria, ≥ 140 mg/dL) Diagnostic: 100 g OGTT (24–30 wks with fasting: 105 mg/dL; 1 h 190 mg/dL; 2 h 165 mg/dL; 3 h 145 mg/dL) HbA1c (28–32 wks) D-39 G2: Standard euglycemic diet, HBGM, random glucose checks HBGM recorded in a diary and reviewed weekly; 3 meals and 3 snacks: 40% carbohydrates, 20% protein, and 40% fat (n=35) RoB = Unclear (fair) Author, year Study Design Dates of study Women Enrolled, n Maternal Age, mean± SD (yr) BMI, mean ± SD; median IQR s (kg/m ) Screening and Diagnostic Tests Inclusion: Screened at diabetic centre; Dx of mild degree of glucose intolerance; OGCT >140 mg/dL and OAV on OGTT Screen: 50 g GCT (14–16 wks for at risk and 24–28 wks for women without risk with 1 h cutoff) by CC and NDDG criteria Outcomes Reported Quality G1: Elevated OGCT and Normal OGTT with no treatment from 1989 to 1993; from 1994 on patients given dietary advice; 25-30 kcal/kg per day diet; biweekly visits, BG monitoring (n=49) Caesarean delivery, birth weight, APGAR, LGA NOS = 8 (good) Race 112 RCS G1: 30.6 ± 3.4 G2: 30.7 ± 4.8 1989 to 1995 G1: 23.12 ± 4.4 G2: 25.0 ± 5.7 Exclusion: NR Italy Interventions Glucose Levels, mean ± SD Country Bonomo, 1997 Inclusion/ Exclusion Criteria NR G1: NR G2: NR Diagnostic: 100 g OGTT (14–16 wks for at risk and 24–28 wks for women without risk with Fasting, 1 h, 2 h, and 3 h intervals) by CC and NDDG criteria D-40 G2: 1 elevated OGTT with no treatment from 1989 to 1993; from 1994 on patients given dietary advice; 25-30 kcal/kg per day diet; biweekly visits, BG monitoring (n=63) Author, year Study Design Dates of study Women Enrolled, n Maternal Age, mean± SD (yr) BMI, mean ± SD; median IQR s (kg/m ) Screening and Diagnostic Tests Interventions Outcomes Reported G1: Diet and regular glucose monitoring; dietary counseling; 24–30 kcal/kg per day formal diet; caloric intake divided into 3 meals and 2–3 snacks; distributed as 50–55% carbohydrates, 25– 30% protein, and 25% fat (n=150) Caesarean delivery, weight gain, hypoglycemia, hyperbilirubine mia, admission to NICU, birth weight, weight, length, APGAR, LGA, ponderal index, SGA Quality Glucose Levels, mean ± SD Country Bonomo, 2005 Inclusion/ Exclusion Criteria Race 300 RCT G1: 31.1 ± 4.7 G2: 30.7 ± 5.1 1997 to 2002 G1: 23.1 ± 4.4 G2: 23.0 ± 4.5 Italy G1: fasting 4.68 ± 0.45 mmol/L G2: fasting 4.77 ± 0.52 mmol/L Inclusion: Caucasian; OGCT >140 mg/dL and normal OGTT; singleton pregnancies Exclusion: Normal GCT; one abnormal OGTT value; GDM under CC criteria Screen: 50 g GCT (24–28 wks with 1 h cutoff by Italian Society of Diabetology criteria, plasma glucose 1 h after challenge ≥ 7.8 mmol/L) Diagnostic:100 g OGTT (within 7 d of GCT) assessed by CC criteria GCT/OGTT repeated at 30– 34 wks for complete diagnosis of Borderline Gestational Glucose Intolerance (BGGI) D-41 G2: No special care, diet or treatment (n=150) RoB = Unclear (fair) Author, year Study Design Dates of study Women Enrolled, n Maternal Age, mean± SD (yr) BMI, mean ± SD; median IQR s (kg/m ) Screening and Diagnostic Tests Interventions Outcomes Reported Quality G1: Consultation with a dietitian; 2 weeks of diet restriction; fasting glucose level >105mg/dL, patient referred to endocrinologist, received glucose monitoring device, and began insulin treatment (n=489) Maternal hypertension, cesarean delivery, maternal birth trauma (postpartum hemorrhage), macrosomia, shoulder dystocia, mortality (intrauterine fetal demise), preterm labour, APGAR scores NOS = 7 (good) Glucose Levels, mean ± SD Country Race Chou, 2010 10,990 RCS (1) G1: 34.4 ± NR G2: 33.4 ± NR Jan 2001 to Sep 2008 Inclusion/ Exclusion Criteria G1: 23.11 ± NR G2: 23.45 ± NR Taiwan NR Inclusion: Singleton pregnancies delivered at Cathay General Hospital Exclusion: Multiple pregnancies, fetal anomalies diagnosed prenatally Screen: 1 h, 50 g OGCT Diagnostic: 3 h, 100 g OGTT (CC, 1982; NDDG, 1979) NR G2: Did not receive further medical control (n=385) D-42 Author, year Study Design Dates of study Women Enrolled, n Maternal Age, mean± SD (yr) BMI, mean ± SD; median IQR s (kg/m ) RCT, multicenter Sept 1993 to June 2003 Australia Screening and Diagnostic Tests Inclusion: Singleton or twin pregnancy; 16–30 wks gestation; prenatal clinic attendance; ≥1 risk factors for GDM on selective screen (WHO) or positive 50 g GCT and 75 g OGTT at 24–34 wks Screen: 50 g GCT (24–34 wks with 1h cutoff by WHO criteria, 1985) From 1998 onward any glucose level above normal classified as GDM (glucose level 1 h after GCT of at least 7.8 mmol/L) Interventions Outcomes Reported G1: Ongoing care; dietary advice; blood glucose monitoring; pre-prandial blood glucose target 5.5 mmol/L; 2 h 7.0 mmol/L; BG target of under 8.0 mmol/l was set at more than 35 weeks of pregnancy (n=490) Induction of labor, caesarean delivery (elective & emergency), shoulder dystocia, hypoglycemia, hyperbilirubine mia, stillbirth or neonatal death, admission to NICU, birth weight, bone fracture/clavicul ar fracture, nerve palsy/brachial plexus injury, “Any serious prenatal complication”, APGAR, LGA + SGA, 6 wk + 3 mo. Postpartum physical functioning, general health, vitality, emotional role, health state utility, anxiety, visits with healthcare professionals Quality Glucose Levels, mean ± SD Country Crowther, 2005 Gillman, 2010 (4-5 year outcomes for children) Moss, 2007 (economic analysis) Inclusion/ Exclusion Criteria Race 1,000 G1: 30.9 ± 5.4 G2: 30.1 ± 5.5 G1: 26.8 (23.3–31.2) G2: 26.0 (22.9–30.9) G1: 4.8 ± 0.7 mmol/L G2: 4.8 ± 0.6 mmol/L G1: White: 356 Asian: 92 Other: 42 G2: White: 396 Asian: 72 Other: 42 Exclusion: More severe glucose impairment; Hx of GDM; active chronic systemic disease Diagnostic: 75 g OGTT (24–34 wks at fasting and 2-h) assessed by WHO criteria, 1985 From 1998 onward any glucose level above normal classified as GDM (venous plasma glucose level less than 6.1 – 7.0 mmol/L after overnight fast and 7.0– 11.0 mmol/L at 2 h) D-43 G2: Replicated routine clinical care where GDM screening not available (n=510) RoB = Low (good) Author, year Study Design Dates of study Women Enrolled, n Maternal Age, mean± SD (yr) BMI, mean ± SD; median IQR s (kg/m ) Cohort (with historical controls) Jan 2001 to June 2006 US Screening and Diagnostic Tests Interventions Outcomes Reported Quality Caesarean delivery, unplanned caesarean delivery, weight gain, shoulder dystocia, admission to NICU, birth weight, neonatal metabolic complications, APGAR NOS = 7 (good) Glucose Levels, mean ± SD Country Fassett, 2007 Inclusion/ Exclusion Criteria Race 126 G1: 28.5 ± 5.8 G2: 29.2 ± 5.0 NR NR G1: White: 23 Black: 2 Hispanic: 39 Asian: 5 Other: 0 G2: White: 14 Black: 1 Hispanic: 35 Asian: 6 Other: 1 Inclusion: Women with ≥1 risk factors: prior GDM; prior macrosomia; firstdegree relative with DM; prior stillbirth; prior malformation; 24–28 wks gestation; GDM Dx with CC criteria but not NDDG Screen: 50 g GCT (24–28 wks with 1 h cutoff) Diagnostic: 100 g OGTT (24–28 wks at Fasting, 1 h, 2 h, and 3 h intervals) assessed by CC criteria G1: Routine medical nutrition therapy by dietitian; formal diet (20–35 kcal/kg of prepregnancy body weight); BG daily self-monitoring, insulin as needed (n=69) G2: Historical controls before institution of routine medical nutrition therapy (n=57) Exclusion: NR D-44 Author, year Study Design Dates of study Women Enrolled, n Maternal Age, mean± SD (yr) BMI, mean ± SD; median IQR s (kg/m ) Interventions Outcomes Reported G1: Strict glycemic control and tertiary level obstetric monitoring; dietary counseling, calorierestricted diet, BG daily self-monitoring, insulin as needed (n=149) Caesarean delivery, weight gain, hypoglycemia, hyperbilirubine mia, birth trauma, birth weight, child outcomes 7-11 yrs Normal 2 h GTT, at risk for overweight Quality Race 300 G1: 30.7 ± 4.8 G2: 30.7 ± 4.6 Inclusion: Women with GDM diagnosed between 24–32 wks gestation; low-risk pregnancy NR RCT Sept 1991 to May 1994 Screening and Diagnostic Tests Glucose Levels, mean ± SD Country Garner, 1997 Malcolm, 2006 (7-11 yr f-up) Inclusion/ Exclusion Criteria G1: 180.0 ± 25.2 (10.0 ± 1.4 mmol/L) G2: 183.6 ± 32.4 mg/dL (10.2 ± 1.8 mmol/L) Canada G1: NR G2: NR Exclusion: Multiple gestation; maternalfetal group incompatibility; known congenital anomaly; prior evidence of placenta previa or abruptio placentae; CHT; connective tissue disease; endocrine disorders; chronic hepatic disease; longterm medical therapy affecting glucose metabolism; imminent delivery Screen: 75 g GCT (24–28 wks with 1 h cutoff by O’Sullivan criteria,1 h level of 144 mg/dL Diagnostic: 75 g OGTT (24–28 wks with Fasting ≥140 mg/dL, ≥11.1; 1 h, 2 h, and 3 h intervals) assessed by Hatem et al. criteria D-45 G2: Routine obstetric care (unrestricted healthy diet) (n=150) RoB = High (poor) Author, year Study Design Dates of study Women Enrolled, n Maternal Age, mean± SD (yr) BMI, mean ± SD; median IQR s (kg/m ) RCT, multicenter Oct 2002 to Nov 2007 US Screening and Diagnostic Tests Interventions Outcomes Reported G1: Nutritional counseling and dietary therapy; daily BG self-monitoring; insulin as needed (n=485) Induction of labor, caesarean delivery, preeclampsia, GHT, BMI at delivery, weight gain, shoulder dystocia, hypoglycemia, hyperbilirubine mia, elevated cord-blood cpeptide level, stillbirth or neonatal death, birth trauma, preterm delivery, admission to NICU, primary perinatal outcome, intravenous glucose Tx, respiratory distress syndrome, LGA, SGA, BMI at delivery Quality Glucose Levels, mean ± SD Country Landon, 2009 Inclusion/ Exclusion Criteria Race 958 G1: 29.2 ± 5.7 G2: 28.9 ± 5.6 G1: 30.1 ± 5.0 G2: 30.2 ± 5.1 G1: fasting 86.6 ± 5.7 mg/dL (4.8 ± 0.3 mmol/L); 1 h 191.8 ± 21.9 mg/dL (10.7 ± 1.2 mmol/L); 2 h 173.7 ± 21.8 mg/dL (9.6 ±1.2 mmol/L); 3 h 137.3 ± 29.0 mg/dL (7.6 ±1.6 mmol/L) G2: fasting 86.3 ± 5.7 mg/dL (4.8 ± 0.3 mmol/L); 1 h 193.4 ± 19.3 mg/dL (10.7 ± 1.1 mmol/L ); 2 h173.3 ± 19.6 mg/dL (9.6 ± 1.1 mmol/L ); 3 h 134.1 ± 31.5 G1:White: 123 Black: 56 Hispanic: 281 Asian: 22 Other: 3 G2: White: 119 Black: 54 Hispanic: 265 Asian: 28 Other: 7 Inclusion: Women between 24 wks 0 days and 30 wks 6 days; OGCT values between 135 and 200 mg/dL or 7.5 and 11.1 mmol/L; OGTT fasting glucose <95 mg/dL and 2-3 timed measurements exceeded above thresholds at 1, 2, and 3 h. Screen: 50 g GCT (1-h cutoff) Diagnostic: 100 g OGTT (Fasting, 1 h, 2 h, and 3 h intervals) assessed by the th 4 IWC criteria (1 h 180 mg/dL; 2 h 155 mg/dL; 3 h 140 mg/dL) Exclusion: Abnormal result before 24 wks of gestation; preexisting diabetes; prior GDM; Hx of stillbirth; multifetal gestation; asthma; CHT; corticosteroid use; known fetal anomaly; likely preterm delivery D-46 G2: Usual perinatal care (n=473) RoB = Unclear (fair) Author, year Study Design Dates of study Women Enrolled, n Maternal Age, mean± SD (yr) BMI, mean ± SD; median IQR s (kg/m ) Screening and Diagnostic Tests Inclusion: Singleton pregnancies; FPG < 140 mg/dL on OGTT; CASE CONTROL: GDM diagnosed > 37 wks; treated GDM and diabetic matched 2:1 obesity, parity, ethnicity, GA at delivery (within 5 days), and yr of delivery Screen: 50 g GCT (1 h >37 wks for G2; G1 underwent universal screening); Plasma glucose < 130 mg/dL Interventions Outcomes Reported Quality G1: Diet alone or insulin and diet; formal diet with caloric restriction: 25 (overweight/obese) to 35 (normal weight) kcal/kg for actual pregnancy weight; 3 meals and 4 snacks; daily BG selfmonitoring, insulin therapy if diet not successful in achieving glycemic control after 2 weeks (n=1,110) Induction of labor, caesarean delivery, shoulder dystocia, hypoglycemia, stillbirth or neonatal death, birth weight, ponderal index, arterial cord <7.0, composite outcome, overall metabolic complications, erythrocytosis, respiratory complication, LGA, SGA NOS = 9 (good) Glucose Levels, mean ± SD Country Langer 2005 Inclusion/ Exclusion Criteria Race 2,775 Cohort G1: 29.1 ± 6 G2: 27.6 ± 6 Jan 1990 to Sept 1999 G1: NR G2: NR US G1: fasting 97 ± 16 mg/dL (5.4 mmol/L); 1 h 199 ± 28 mg/dL (11.1 mmol/L); 2 h 178 ± 30 (9.9 mmol/L); 3 h 136 ± 36 (7.5 mmol/L) G2: fasting 97 ± 15 mg/dL (5.4 mmol/L); 1 hr 199 ± 27 mg/dL (11.1 mmol/L); 2 hr 181 ± 36 mg/dL (10.1 mmol/L); 3 hr 141 ± 32 mg/dL 7.8 mmol/L) Diagnostic: 100 g OGTT (>37 wks for G2; G1 underwent universal screening; Fasting, 1 h, 2 h, and 3 h intervals) assessed by CC criteria Exclusion: Pregestational DM; substance abusers; multifetal gestation; fetal anomalies G2: Standard care until delivery (n=555) G1: White: 144 Black: 56 Hispanic: 910 G2: White: 61 Black: 17 Hispanic: 477 D-47 Author, year Study Design Dates of study Women Enrolled, n Maternal Age, mean± SD (yr) BMI, mean ± SD; median IQR s (kg/m ) Screening and Diagnostic Tests Interventions Outcomes Reported Quality Preeclampsia, cesarean delivery, macrosomia, hypoglycemia, hyperbilirubine mia (phototherapy), fetal trauma, congenital anomalies, respiratory distress syndrome, maternal/fetal length of stay NOS = 9 (good) Glucose Levels, mean ± SD Country Naylor, 1997 Inclusion/ Exclusion Criteria Race 3,778 RCT G1: 32.7(4.3) G2: 32.1 (4.4) Sept 1989 to Mar 1992 G1: 24.2 (4.8) G2: 24.7(5.8) Inclusion: >24 yrs at time of delivery, no Hx of DM examined by physician before 24 wks gestation, delivery >28 wks ; Screen: 50 g GCT (1 h - Plasma glucose < 130 mg/dL G1: Known to have received treatment for GDM (n= 143) Diagnostic: 100 g OGTT assessed by NDDG criteria G2: Usual perinatal care (n= 115) Exclusion: NR Canada NR G1: White: 63 Black: 8 Asian: 27 Other: 45 G2: White: 67 Black: 2 Asian: 17 Other: 29 * ADA = American Diabetes Association; ADIPS = Australian Diabetes in Pregnancy Society; BMI = body mass index; CHT = chronic hypertension; d(s) = day(s); dL = deciliter; DM = diabetes mellitus; Dx = diagnosis/diagnostic; FPG = fasting plasma glucose; GCT = glucose tolerance test; GDM = gestational diabetes mellitus; GLT = glucose load test; g = grams; h = hour; IADPSG = International Association of Diabetes and Pregnancy Study Groups; JSOG = Japan Society of Obstetrics and Gynecology; mg = milligrams; NDDG = National Diabetes Data Group; NR = not reported; NOS = Newcastle-Ottawa Quality Assessment Scale; n = number; OGTT = oral glucose tolerance test; PP= postpartum; PCS = prospective cohort study; RCS = retrospective cohort study; RoB = Collaboration’s tool for assessing risk of bias; SD = standard deviation; tx = treatment; wk(s) = week(s); WHO = World Health Organization; yr(s) = year(s) D-48 Appendix E. List of Excluded Studies and Unobtained Studies Excluded – Comparator (N=227) 11. Reece EA, Hagay Z, Gay LJ, et al. A randomized clinical trial of a fiber-enriched diabetic diet vs. the standard American Diabetes Associationrecommended diet in the management of diabetes mellitus in pregnancy. J Matern Fetal Invest 1995;5(1):8-12. 1. Catalano PM, Avallone DA, Drago NM, et al. Reproducibility of the oral glucose tolerance test in pregnant women. Am J Obstet Gynecol 1993;169(4):874-81. 2. Schrader HM, Jovanovic-Peterson L, Bevier WC, et al. Fasting plasma glucose and glycosylated plasma protein at 24 to 28 weeks of gestation predict macrosomia in the general obstetric population. Am J Perinatol 1995;12(4):247-51. 12. Hughes PF, Agarwal M, Newman P, et al. An evaluation of fructosamine estimation in screening for gestational diabetes mellitus. Diabet Med 1995;12(8):708-12. 3. Moses RG, Griffiths RD. Can a diagnosis of gestational diabetes be an advantage to the outcome of pregnancy? J Soc Gynecol Investig 1995;2(3):523-5. 13. Agardh CD, Aberg A, Norden NE. Glucose levels and insulin secretion during a 75 g glucose challenge test in normal pregnancy. J Intern Med 1996;240(5):303-9. 4. Bassaw B, Ataullah I, Roopnarinesingh S, et al. Diabetes in pregnancy. Int J Gynaecol Obstet 1995;50(1):5-9. 14. Hod M, Rabinerson D, Kaplan B, et al. Perinatal complications following gestational diabetes mellitus how 'sweet' is ill? Acta Obstet Gynecol Scand 1996;75(9):809-15. 5. de VM, Major CA, Morgan MA, et al. Postprandial versus preprandial blood glucose monitoring in women with gestational diabetes mellitus requiring insulin therapy. N Engl J Med 1995;333(19):123741. 15. Nasrat HA, Ardawi MS, Abalkhail BA. The diagnosis of "pathological hyperglycaemia' in gestational diabetes in a high risk obstetric population. Diabetic Med 1996;13(10):861-7. 6. Damm P, Kuhl C, Hornnes P, et al. A longitudinal study of plasma insulin and glucagon in women with previous gestational diabetes. Diabetes Care 1995;18(5):654-65. 16. Di SN, Ronsisvalle E, Fulghesu AM, et al. Insulin plasma levels in pregnant patients with impaired glucose tolerance: relationship with pregnancy outcome. Gynecol Obstet Invest 1996;42(1):16-20. 7. Koukkou E, Taub N, Jackson P, et al. Difference in prevalence of gestational diabetes and perinatal outcome in an innercity multiethnic London population. Eur J Obstet Gynecol Reprod Biol 1995;59(2):153-7. 17. Tranquilli AL, Pizzichini L, Cingolani F, et al. Prediction of the need for insulin therapy in pregnant women with impaired gestational glucose tolerance (IGGT). Clin Exp Obstet Gynecol 1996;23(2):79-82. 8. Gribble RK, Meier PR, Berg RL. Blood glucose limits in the diagnosis of impaired glucose tolerance during pregnancy. Relation to morbidity. Obstet Gynecol 1995;86(3):405-10. 18. Moses RG. The recurrence rate of gestational diabetes in subsequent pregnancies. Diabetes Care 1996;19(12):1348-50. 19. Di CG, Benzi L, Casadidio I, et al. Screening of gestational diabetes in Tuscany: results in 2000 cases. Ann Ist Super Sanita 1997;33(3):389-91. 9. al-Najashi SS. Control of gestational diabetes. Int J Gynaecol Obstet 1995;49(2):131-5. 10. Kjos SL, Peters RK, Xiang A, et al. Predicting future diabetes in Latino women with gestational diabetes. Utility of early postpartum glucose tolerance testing. Diabetes 1995;44(5):586-91. 20. Fedele D, Lapolla A. A protocol of screening of gestational diabetes mellitus. Ann Ist Super Sanita 1997;33(3):383-7. E-1 21. Bienstock JL, Blakemore KJ, Wang E, et al. Managed care does not lower costs but may result in poorer outcomes for patients with gestational diabetes. Am J Obstet Gynecol 1997;177(5):1035-7. controlled gestational diabetes. Obstet Gynecol 1998;91(4):600-4. 34. Lao TT, Lee CP. Gestational 'impaired glucose tolerance': should the cut-off be raised to 9 mmol l(1)? Diabetic Med 1998;15(1):25-9. 22. Helton MR, Arndt J, Kebede M, et al. Do low-risk prenatal patients really need a screening glucose challenge test? J Fam Pract 1997;44(6):556-61. 35. Moses RG, Moses J, Davis WS. Gestational diabetes: Do lean young Caucasian women need to be tested? Diabetes Care 1998;21(11):1803-6. 23. Avery MD, Leon AS, Kopher RA. Effects of a partially home-based exercise program for women with gestational diabetes. Obstet Gynecol 1997;89(1):10-5. 36. Moses RG, Moses M, Russell KG, et al. The 75-g glucose tolerance test in pregnancy - A reference range determined on a low-risk population and related to selected pregnancy outcomes. Diabetes Care 1998;21(11):1807-11. 24. al-Najashi SS. Diagnosis of gestational diabetes mellitus. A study of 315 pregnant women at King Fahd Hospital of the University, Al-Khobar, Saudi Arabia. Bahrain Med Bull 1997;19(4):104-7. 37. Lemen PM, Wigton TR, Miller-McCarthey AJ, et al. Screening for gestational diabetes mellitus in adolescent pregnancies. Am J Obstet Gynecol 1998;178(6):1251-4. 25. Persson B, Edwall L, Hanson U, et al. Insulin sensitivity and insulin response in women with gestational diabetes mellitus. Horm Metab Res 1997;29(8):393-7. 26. Berria R, Murgia C, Serri F, Pilia I. GDM: screening, diagnosis and management. 1997. 38. Lauszus FF, Paludan J, Klebe JG. Birthweight in women with potential gestational diabetes mellitus An effect of obesity rather than glucose intolerance? Acta Obstet Gynecol Scand 1999;78(6):520-5. 27. Casey BM, Lucas MJ, McIntire DD, et al. Pregnancy outcomes in women with gestational diabetes compared with the general obstetric population. Obstet Gynecol 1997;90(6):869-73. 39. Roncaglia N, Bellini P, Arreghini A, et al. Gestational diabetes mellitus: intensive versus mild treatment. Clin Exp Obstet Gynecol 1999;26(2):957. 28. Lurie S, Levy R, Weiss R, et al. Low values on 50 gram glucose challenge test or oral 100 gram glucose tolerance test are associated with good perinatal outcome. J Obstet Gynaecol 1998;18(5):451-4. 40. McFarland MB, Langer O, Conway DL, et al. Dietary therapy for gestational diabetes: how long is long enough? Obstet Gynecol 1999;93(6):978-82. 41. Kvetny J, Poulsen HF, Damgaard DW. Results from screening for gestational diabetes mellitus in a Danish county. Dan Med Bull 1999;46(1):57-9. 29. Ramachandran A, Snehalatha C, Clementina M, et al. Foetal outcome in gestational diabetes in south Indians. Diabetes Res Clin Pract 1998;41(3):185-9. 42. Shivvers SA, Lucas MJ. Gestational diabetes - Is a 50-g screening result >= 200 mg/dL diagnostic? J Reprod Med 1999;44(8):685-8. 30. Whitaker RC, Pepe MS, Seidel KD, et al. Gestational diabetes and the risk of offspring obesity. Pediatrics 1998;101(2):e9. 43. Jovanovic L, Gutierrez M, Peterson CM. Chromium supplementation for women with gestational diabetes mellitus. J Trace Elem Exp Med 1999;12(2):91-7. 31. Kitzmiller JL, Elixhauser A, Carr S, et al. Assessment of costs and benefits of management of gestational diabetes mellitus. Diabetes Care 1998;21(Suppl 2):B123-B130. 44. Vohr BR, McGarvey ST, Tucker R. Effects of maternal gestational diabetes on offspring adiposity at 4-7 years of age. Diabetes Care 1999;22(8):128491. 32. Schafer-Graf UM, Dupak J, Vogel M, et al. Hyperinsulinism, neonatal obesity and placental immaturity in infants born to women with one abnormal glucose tolerance test value. J Perinat Med 1998;26(1):27-36. 45. Mirghani OA, Saeed OK. A simplified management of diabetic pregnant woman. Saudi Med J 2000;21(4):335-9. 33. Major CA, Henry MJ, de VM, et al. The effects of carbohydrate restriction in patients with diet- 46. Rae A, Bond D, Evans S, et al. A randomised controlled trial of dietary energy restriction in the E-2 management of obese women with gestational diabetes. Aust N Z J Obstet Gynaecol 2000;40(4):416-22. 58. MacNeill S, Dodds L, Hamilton DC, et al. Rates and risk factors for recurrence of gestational diabetes. Diabetes Care 2001;24(4):659-62. 47. Langer O, Conway DL, Berkus MD, et al. A comparison of glyburide and insulin in women with gestational diabetes mellitus. N Engl J Med 2000;343(16):1134-8. 59. Ray JG, Vermeulen MJ, Shapiro JL, et al. Maternal and neonatal outcomes in pregestational and gestational diabetes mellitus, and the influence of maternal obesity and weight gain: the DEPOSIT study. Diabetes Endocrine Pregnancy Outcome Study in Toronto. QJM 2001;94(7):347-56. 48. Rudge MV, Calderon IM, Ramos MD, et al. Perinatal outcome of pregnancies complicated by diabetes and by maternal daily hyperglycemia not related to diabetes. A retrospective 10-year analysis. Gynecol Obstet Invest 2000;50(2):108-12. 60. Xiong X, Saunders LD, Wang FL, et al. Gestational diabetes mellitus: prevalence, risk factors, maternal and infant outcomes. Int J Gynaecol Obstet 2001;75(3):221-8. 49. Rigano S, Ferrazzi E, Radaelli T, et al. Sonographic measurements of subcutaneous fetal fat in pregnancies complicated by gestational diabetes and in normal pregnancies. Croat Med J 2000;41(3):240-4. 61. Baliutaviciene D, Petrenko V, Zalinkevicius R. Selective or universal diagnostic testing for gestational diabetes mellitus. Int J Gynaecol Obstet 2002;78(3):207-11. 50. Bancroft K, Tuffnell DJ, Mason GC, et al. A randomised controlled pilot study of the management of gestational impaired glucose tolerance. BJOG 2000;107(8):959-63. 62. Gezer A, Esen F, Mutlu H, et al. Prognosis of patients with positive screening but negative diagnostic test for gestational diabetes. Arch Gynecol Obstet 2002;266(4):201-4. 51. Lao TT, Ho LF. Impaired glucose tolerance and pregnancy outcome in Chinese women with high body mass index. Hum Reprod 2000;15(8):1826-9. 63. Di CG, Volpe L, Casadidio I, et al. Universal screening and intensive metabolic management of gestational diabetes: cost-effectiveness in Italy. Acta Diabetol 2002;39(2):69-73. 52. Simpson RW, Kast SJ. Management of gestational diabetes with a conservative insulin protocol. The Medical Journal Of Australia 2000;172(11):537-40. 64. Homko CJ, Sivan E, Reece EA. The impact of selfmonitoring of blood glucose on self-efficacy and pregnancy outcomes in women with diet-controlled gestational diabetes. Diabetes Educ 2002;28(3):43543. 53. Hearty RT, Traub AI, Hadden DR. Screening for hyperglycaemia in pregnancy: analysis of two screening protocols and review of current methods. Ulster Med J 2000;69(1):35-43. 65. Rumbold AR, Crowther CA. Women's experiences of being screened for gestational diabetes mellitus. Aust N Z J Obstet Gynaecol 2002;42(2):131-7. 54. Crowe SM, Mastrobattista JM, Monga M. Oral glucose tolerance test and the preparatory diet. Am J Obstet Gynecol 2000;182(5):1052-4. 66. Pullen F, Grenfell A. The diagnosis of gestational diabetes in a multiethnic population: Which diagnostic criteria should be used with respect to maternal outcome? Pract Diabetes Int 2002;29(9):279-82. 55. Wong L, Tan AS. The glucose challenge test for screening gestational diabetes in pregnant women with no risk factors. Singapore Med J 2001;42(11):517-21. 67. Pettitt DJ, Ospina P, Jovanovic L. Comparison of an insulin analog, insulin aspart, and regular human insulin with no insulin in gestational diabetes mellitus. Diabetologia 2002;45(Suppl 2):A254A255. 56. Lauszus FF, Rasmussen OW, Henriksen JE, et al. Effect of a high monounsaturated fatty acid diet on blood pressure and glucose metabolism in women with gestational diabetes mellitus. Eur J Clin Nutr 2001;55(6):436-43. 68. Chen R, Yogev Y, Ben-Haroush A, et al. Continuous glucose monitoring for the evaluation and improved control of gestational diabetes mellitus. J Matern Fetal Neonatal Med 2003;14(4):256-60. 57. Jensen DM, Damm P, Sorensen B, et al. Clinical impact of mild carbohydrate intolerance in pregnancy: a study of 2904 nondiabetic Danish women with risk factors for gestational diabetes mellitus. Am J Obstet Gynecol 2001;185(2):413-9. E-3 69. Mecacci F, Carignani L, Cioni R, et al. Maternal metabolic control and perinatal outcome in women with gestational diabetes treated with regular or lispro insulin: comparison with non-diabetic pregnant women. Eur J Obstet Gynecol Reprod Biol 2003;111(1):19-24. 80. Schaefer-Graf UM, Kjos SL, Fauzan OH, et al. A randomized trial evaluating a predominantly fetal growth-based strategy to guide management of gestational diabetes in Caucasian women. Diabetes Care 2004;27(2):297-302. 81. Lauenborg J, Hansen T, Jensen DM, et al. Increasing Incidence of Diabetes after Gestational Diabetes: A long-term follow-up in a Danish population. Diabetes Care 2004;27(5):1194-9. 70. Gruendhammer M, Brezinka C, Lechleitner M. The number of abnormal plasma glucose values in the oral glucose tolerance test and the feto-maternal outcome of pregnancy. Eur J Obstet Gynecol Reprod Biol 2003;108(2):131-6. 82. Kim C, Brawarsky P, Jackson RA, et al. Changes in health status experienced by women with gestational diabetes and pregnancy-induced hypertensive disorders. J Womens Health 2005;14(8):729-36. 71. Kulkarni M, Jones KD, Newbold S. Screening for gestational diabetes: a retrospective audit. J Obstet Gynaecol 2003;23(2):160-2. 72. Daniells S, Grenyer BFS, Davis WS, et al. Gestational diabetes mellitus: Is a diagnosis associated with an increase in maternal anxiety and stress in the short and intermediate term? Diabetes Care 2003;26(2):385-9. 83. Bertini AM, Silva JC, Taborda W, et al. Perinatal outcomes and the use of oral hypoglycemic agents. J Perinat Med 2005;33(6):519-23. 84. Sharpe PB, Chan A, Haan EA, et al. Maternal diabetes and congenital anomalies in South Australia 1986-2000: a population-based cohort study. Birth Defects Res Part A Clin Mol Teratol 2005;73(9):605-11. 73. Saldana TM, Siega-Riz AM, Adair LS, et al. The association between impaired glucose tolerance and birth weight among black and white women in central North Carolina. Diabetes Care 2003;26(3):656-61. 85. Leipold H, Worda C, Gruber CJ, et al. Large-forgestational-age newborns in women with insulintreated gestational diabetes under strict metabolic control. Wien Klin Wochenschr 2005;117(1516):521-5. 74. Sunsaneevithayakul P, Ruangvutilert P, Sutanthavibul A, et al. Effect of 3-day intensive dietary therapy during admission in women after diagnosis of gestational diabetes mellitus. J Med Assoc Thai 2004;87(9):1022-8. 86. Chan BC, Lao TT. Gestational diabetes mellitus in women in the fourth decade--is treatment worthwhile? Gynecol Obstet Invest 2005;60(2):1126. 75. Ertunc D, Tok E, Dilek U, et al. The effect of carbohydrate intolerance on neonatal birth weight in pregnant women without gestational diabetes mellitus. Ann Saudi Med 2004;24(4):280-3. 87. Jacobson GF, Ramos GA, Ching JY, et al. Comparison of glyburide and insulin for the management of gestational diabetes in a large managed care organization. Am J Obstet Gynecol 2005;193(1):118-24. 76. Bonomo M, Cetin I, Pisoni MP, et al. Flexible treatment of gestational diabetes modulated on ultrasound evaluation of intrauterine growth: a controlled randomized clinical trial. Diabetes Metab 2004;30(3):237-44. 88. Barahona MJ, Sucunza N, Garcia-Patterson A, et al. Period of gestational diabetes mellitus diagnosis and maternal and fetal morbidity. Acta Obstet Gynecol Scand 2005;84(7):622-7. 77. Maser RE, Lenhard MJ, Henderson BC, et al. Detection of subsequent episodes of gestational diabetes mellitus: a need for specific guidelines. J Diabetes Complications 2004;18(2):86-90. 89. Yogev Y, Langer O, Xenakis EM, et al. The association between glucose challenge test, obesity and pregnancy outcome in 6390 non-diabetic women. J Matern Fetal Neonatal Med 2005;17(1):29-34. 78. Conway DL, Gonzales O, Skiver D. Use of glyburide for the treatment of gestational diabetes: the San Antonio experience. J Matern Fetal Neonatal Med 2004;15(1):51-5. 90. Weisz B, Shrim A, Homko CJ, et al. One hour versus two hours postprandial glucose measurement in gestational diabetes: a prospective study. J Perinatol 2005;25(4):241-4. 79. Brankston GN, Mitchell BF, Ryan EA, et al. Resistance exercise decreases the need for insulin in overweight women with gestational diabetes mellitus. Am J Obstet Gynecol 2004;190(1):188-93. E-4 91. Ho LF, Benzie IF, Lao TT. Relationship between caloric intake and pregnancy outcome in diettreated gestational diabetes mellitus. Nurs Health Sci 2005;7(1):15-20. 102. Dudhbhai M, Lim L, Bombard A, et al. Characteristics of patients with abnormal glucose challenge test and normal oral glucose tolerance test results: comparison with normal and gestational diabetic patients. Am J Obstet Gynecol 2006;194(5):e42-e45. 92. Langer O, Yogev Y, Xenakis EM, et al. Insulin and glyburide therapy: dosage, severity level of gestational diabetes, and pregnancy outcome. Am J Obstet Gynecol 2005;192(1):134-9. 103. McLaughlin GB, Cheng YW, Caughey AB. Women with one elevated 3-hour glucose tolerance test value: are they at risk for adverse perinatal outcomes? Am J Obstet Gynecol 2006;194(5):e16e19. 93. Keshavarz M, Cheung NW, Babaee GR, et al. Gestational diabetes in Iran: incidence, risk factors and pregnancy outcomes. Diabetes Res Clin Pract 2005;69(3):279-86. 104. Sunsaneevithayakul P, Kanokpongsakdi S, Sutanthavibul A, et al. Result of ambulatory diet therapy in gestational diabetes mellitus. J Med Assoc Thai 2006;89(1):8-12. 94. Ezimokhai M, Joseph A, Bradley-Watson P. Audit of pregnancies complicated by diabetes from one center five years apart with selective versus universal screening. Ann N Y Acad Sci 2006;1084:132-40. 105. D'Anna R, Baviera G, De VA, et al. C-reactive protein as an early predictor of gestational diabetes mellitus. J Reprod Med 2006;51(1):55-8. 95. Li K, Yang HX. Value of fructosamine measurement in pregnant women with abnormal glucose tolerance. Chin Med J 2006;119(22):18615. 106. Nordin NM, Wei JW, Naing NN, et al. Comparison of maternal-fetal outcomes in gestational diabetes and lesser degrees of glucose intolerance. J Obstet Gynaecol Res 2006;32(1):107-14. 96. Thanasuan S, Borriboonhirunsarn D. Incidence of gestational diabetes mellitus among pregnant women with one abnormal value of oral glucose tolerance test. J Med Assoc Thai 2006;89(8):110914. 107. Weijers RN, Bekedam DJ, Goldschmidt HM, et al. The clinical usefulness of glucose tolerance testing in gestational diabetes to predict early postpartum diabetes mellitus. Clin Chem Lab Med 2006;44(1):99-104. 97. Rochon M, Rand L, Roth L, et al. Glyburide for the management of gestational diabetes: risk factors predictive of failure and associated pregnancy outcomes. Am J Obstet Gynecol 2006;195(4):10904. 108. Cosson E, Benchimol M, Carbillon L, et al. Universal rather than selective screening for gestational diabetes mellitus may improve fetal outcomes. Diabetes Metab 2006;32(2):140-6. 98. Reader D, Splett P, Gunderson EP, et al. Impact of gestational diabetes mellitus nutrition practice guidelines implemented by registered dietitians on pregnancy outcomes. J Am Diet Assoc 2006;106(9):1426-33. 109. Moore LE, Briery CM, Clokey D, et al. Metformin and insulin in the management of gestational diabetes mellitus: preliminary results of a comparison. J Reprod Med 2007;52(11):1011-5. 110. Most O, Langer O. GDM women in good glycemic control: which meal-related measure enhances fetal well-being? J Perinat Med 2007;35(6):481-5. 99. Shefali AK, Kavitha M, Deepa R, et al. Pregnancy outcomes in pre-gestational and gestational diabetic women in comparison to non-diabetic women--A prospective study in Asian Indian mothers (CURES-35). J Assoc Physicians India 2006;54:613-8. 111. Cypryk K, Kaminska P, Kosinski M, et al. A comparison of the effectiveness, tolerability and safety of high and low carbohydrate diets in women with gestational diabetes. Endokrynol Pol 2007;58(4):314-9. 100. Chandna A, Zuberi LM, Munim S. Threshold values for the glucose challenge test in pregnancy. Int J Gynaecol Obstet 2006;94(2):119-20. 112. Cheng YW, McLaughlin GB, Esakoff TF, et al. Glucose challenge test: screening threshold for gestational diabetes mellitus and associated outcomes. J Matern Fetal Neonatal Med 2007;20(12):903-8. 101. Kahn BF, Davies JK, Lynch AM, et al. Predictors of glyburide failure in the treatment of gestational diabetes. Obstet Gynecol 2006;107(6):1303-9. E-5 113. Krishnaveni GV, Hill JC, Veena SR, et al. Gestational diabetes and the incidence of diabetes in the 5 years following the index pregnancy in South Indian women. Diabetes Res Clin Pract 2007;78(3):398-404. 124. Ramos GA, Jacobson GF, Kirby RS, et al. Comparison of glyburide and insulin for the management of gestational diabetics with markedly elevated oral glucose challenge test and fasting hyperglycemia. J Perinatol 2007;27(5):262-7. 114. Virally M, Laloi-Michelin M, Meas T, et al. Occurrence of gestational diabetes mellitus, maternal and fetal outcomes beyond the 28th week of gestation in women at high risk of gestational diabetes. A prospective study. Diabetes Metab 2007;33(4):290-5. 125. Simmons D. Relationship between maternal glycaemia and birth weight in glucose-tolerant women from different ethnic groups in New Zealand. Diabetic Med 2007;24(3):240-4. 126. Lee AJ, Hiscock RJ, Wein P, et al. Gestational diabetes mellitus: clinical predictors and long-term risk of developing type 2 diabetes: a retrospective cohort study using survival analysis. Diabetes Care 2007;30(4):878-83. 115. Pettitt DJ, Ospina P, Howard C, et al. Efficacy, safety and lack of immunogenicity of insulin aspart compared with regular human insulin for women with gestational diabetes mellitus. Diabetic Med 2007;24(10):1129-35. 127. Price N, Bartlett C, Gillmer M. Use of insulin glargine during pregnancy: a case-control pilot study. BJOG 2007;114(4):453-7. 116. Yogev Y, Langer O. Spontaneous preterm delivery and gestational diabetes: the impact of glycemic control. Arch Gynecol Obstet 2007;276(4):361-5. 128. Berg M, Adlerberth A, Sultan B, et al. Early random capillary glucose level screening and multidisciplinary antenatal teamwork to improve outcome in gestational diabetes mellitus. Acta Obstet Gynecol Scand 2007;86(3):283-90. 117. Todorova K, Palaveev O, Petkova VB, et al. A pharmacoeconomical model for choice of a treatment for pregnant women with gestational diabetes. Acta Diabetol 2007;44(3):144-8. 129. Sinclair BA, Rowan JA, Hainsworth OT. Macrosomic infants are not all equal. Aust N Z J Obstet Gynaecol 2007;47(2):101-5. 118. Dodd JM, Crowther CA, Antoniou G, et al. Screening for gestational diabetes: the effect of varying blood glucose definitions in the prediction of adverse maternal and infant health outcomes. Aust N Z J Obstet Gynaecol 2007;47(4):307-12. 130. Koklanaris N, Bonnano C, Seubert D, et al. Does raising the glucose challenge test threshold impact birthweight in Asian gravidas? J Perinat Med 2007;35(2):100-3. 119. Rowan JA, MiG I. A trial in progress: gestational diabetes. Treatment with metformin compared with insulin (the Metformin in Gestational Diabetes [MiG] trial).[Erratum appears in Diabetes Care. 2007 Dec;30(12):3154]. Diabetes Care 2007;30(Suppl 2):S214-S219. 131. Anjalakshi C, Balaji V, Balaji MS, et al. A prospective study comparing insulin and glibenclamide in gestational diabetes mellitus in Asian Indian women. Diabetes Res Clin Pract 2007;76(3):474-5. 120. Di CG, Seghieri G, Lencioni C, et al. Normal glucose tolerance and gestational diabetes mellitus: what is in between? Diabetes Care 2007;30(7):1783-8. 132. Jasbinder K, Shivani J, Anju H, et al. Pregnancy outcome in gestational diabetes mellitus: continued risk related to FBS levels. Diabetes Res Clin Pract 2007;78(2):302-3. 121. Homko CJ, Santamore WP, Whiteman V, et al. Use of an internet-based telemedicine system to manage underserved women with gestational diabetes mellitus. Diabetes Technol Ther 2007;9(3):297-306. 133. Anderberg E, Kallen K, Berntorp K, et al. A simplified oral glucose tolerance test in pregnancy: compliance and results. Acta Obstet Gynecol Scand 2007;86(12):1432-6. 122. Artal R, Catanzaro RB, Gavard JA, et al. A lifestyle intervention of weight-gain restriction: diet and exercise in obese women with gestational diabetes mellitus. Appl Physiol Nutr Metab 2007;32(3):596601. 134. Ozcimen EE, Uckuyu A, Ciftci FC, et al. Diagnosis of gestational diabetes mellitus by use of the homeostasis model assessment-insulin resistance index in the first trimester. Gynecol Endocrinol 2008;24(4):224-9. 123. Kestila KK, Ekblad UU, Ronnemaa T. Continuous glucose monitoring versus self-monitoring of blood glucose in the treatment of gestational diabetes mellitus. Diabetes Res Clin Pract 2007;77(2):174-9. 135. Tam WH, Ma RC, Yang X, et al. Glucose intolerance and cardiometabolic risk in children E-6 exposed to maternal gestational diabetes mellitus in utero. Pediatrics 2008;122(6):1229-34. 147. Savona-Ventura C, Chircop M. Significant thresholds for the 75-g oral glucose tolerance test in pregnancy. J Diabetes Complications 2008;22(3):178-80. 136. Akinci B, Celtik A, Yener S, et al. Is fasting glucose level during oral glucose tolerance test an indicator of the insulin need in gestational diabetes? Diabetes Res Clin Pract 2008;82(2):219-25. 148. Lapolla A, Dalfra MG, Mello G, et al. Early detection of insulin sensitivity and beta-cell function with simple tests indicates future derangements in late pregnancy. J Clin Endocrinol Metab 2008;93(3):876-80. 137. Holt RI, Clarke P, Parry EC, et al. The effectiveness of glibenclamide in women with gestational diabetes. Diabetes Obes Metab 2008;10(10):906-11. 149. Hawkins JS, Lo JY, Casey BM, et al. Diet-treated gestational diabetes mellitus: comparison of early vs routine diagnosis. Am J Obstet Gynecol 2008;198(3):287-e1-6. 138. Snapp CA, Donaldson SK. Gestational diabetes mellitus: physical exercise and health outcomes. Biol Res Nurs 2008;10(2):145-55. 150. Keely EJ, Malcolm JC, Hadjiyannakis S, et al. Prevalence of metabolic markers of insulin resistance in offspring of gestational diabetes pregnancies. Pediatr Diabetes 2008;9(1):53-9. 139. Ju H, Rumbold AR, Willson KJ, et al. Borderline gestational diabetes mellitus and pregnancy outcomes. BMC Pregnancy Childbirth 2008;8:31. 140. Suhonen L, Hiilesmaa V, Kaaja R, et al. Detection of pregnancies with high risk of fetal macrosomia among women with gestational diabetes mellitus. Acta Obstet Gynecol Scand 2008;87(9):940-5. 151. Elnour AA, El Mugammar IT, Jaber T, et al. Pharmaceutical care of patients with gestational diabetes mellitus. Journal of Evaluation in Clinical Practice 2008;14(1):131-40. 141. Mendelson SG, Neese-Smith D, Koniak-Griffin D, et al. A community-based parish nurse intervention program for Mexican American women with gestational diabetes. J Obstet Gynecol & Neonatal Nurs 2008;37(4):415-25. 152. Elnour AA, McElnay JC. Antenatal oral glucosetolerance test values and pregnancy outcomes. Int J Pharm Pract 2008;16(3):189-97. 153. Carr DB, Newton KM, Utzschneider KM, et al. Modestly elevated glucose levels during pregnancy are associated with a higher risk of future diabetes among women without gestational diabetes mellitus. Diabetes Care 2008;31(5):1037-9. 142. Gumus II, Turhan NO. Are patients with positive screening but negative diagnostic test for gestational diabetes under risk for adverse pregnancy outcome? J Obstet Gynaecol Res 2008;34(3):359-63. 143. Lee H, Jang HC, Park HK, et al. Prevalence of type 2 diabetes among women with a previous history of gestational diabetes mellitus. Diabetes Res Clin Pract 2008;81(1):124-9. 154. Jensen DM, Korsholm L, Ovesen P, et al. Adverse pregnancy outcome in women with mild glucose intolerance: is there a clinically meaningful threshold value for glucose? Acta Obstet Gynecol Scand 2008;87(1):59-62. 144. Rowan JA, Hague WM, Gao W, et al. Metformin versus insulin for the treatment of gestational diabetes.[Erratum appears in N Engl J Med. 2008 Jul 3;359(1):106]. N Engl J Med 2008;358(19):2003-15. 155. Seshiah V, Balaji V, Balaji MS, et al. Prevalence of gestational diabetes mellitus in South India (Tamil Nadu)--a community based study. J Assoc Physicians India 2008;56:329-33. 156. Rai L, Meenakshi D, Kamath A. Metformin--a convenient alternative to insulin for Indian women with diabetes in pregnancy. Indian J Med Sci 2009;63(11):491-7. 145. Grotegut CA, Tatineni H, Dandolu V, et al. Obstetric outcomes with a false-positive one-hour glucose challenge test by the Carpenter-Coustan criteria. J Matern Fetal Neonatal Med 2008;21(5):315-20. 157. Hebert MF, Ma X, Naraharisetti SB, et al. Are we optimizing gestational diabetes treatment with glyburide? The pharmacologic basis for better clinical practice. Clin Pharmacol Ther 2009;85(6):607-14. 146. Negrato CA, Jovanovic L, Tambascia MA, et al. Mild gestational hyperglycaemia as a risk factor for metabolic syndrome in pregnancy and adverse perinatal outcomes. Diabetes Metab Res Rev 2008;24(4):324-30. 158. Negrato CA, Jovanovic L, Tambascia MA, et al. Association between insulin resistance, glucose E-7 intolerance, and hypertension in pregnancy. Metab Syndr Relat Disord 2009;7(1):53-9. gestational diabetes mellitus. Am J Obstet Gynecol 2009;200(6):672-4. 159. Segregur J, Bukovic D, Milinovic D, et al. Fetal macrosomia in pregnant women with gestational diabetes. Coll Antropol 2009;33(4):1121-7. 170. Moses RG, Barker M, Winter M, et al. Can a lowglycemic index diet reduce the need for insulin in gestational diabetes mellitus? A randomized trial. Diabetes Care 2009;32(6):996-1000. 160. Pedula KL, Hillier TA, Schmidt MM, et al. Ethnic differences in gestational oral glucose screening in a large US population. Ethn Dis 2009;19(4):414-9. 171. Barrett HL, Morris J, McElduff A. Watchful waiting: a management protocol for maternal glycaemia in the peripartum period. Aust N Z J Obstet Gynaecol 2009;49(2):162-7. 161. Persson M, Winkvist A, Mogren I. Surprisingly low compliance to local guidelines for risk factor based screening for gestational diabetes mellitus - A population-based study. BMC Pregnancy Childbirth 2009;9:53. 172. Lain KY, Garabedian MJ, Daftary A, et al. Neonatal adiposity following maternal treatment of gestational diabetes with glyburide compared with insulin. Am J Obstet Gynecol 2009;200(5):501-6. 162. Perichart-Perera O, Balas-Nakash M, ParraCovarrubias A, et al. A medical nutrition therapy program improves perinatal outcomes in Mexican pregnant women with gestational diabetes and type 2 diabetes mellitus. Diabetes Educ 2009;35(6):1004-13. 173. Karmon A, Levy A, Holcberg G, et al. Decreased perinatal mortality among women with dietcontrolled gestational diabetes mellitus. Int J Gynaecol Obstet 2009;104(3):199-202. 174. Most OL, Kim JH, Arslan AA, et al. Maternal and neonatal outcomes in early glucose tolerance testing in an obstetric population in New York city. J Perinat Med 2009;37(2):114-7. 163. Wroblewska-Seniuk K, Wender-Ozegowska E, Szczapa J. Long-term effects of diabetes during pregnancy on the offspring. Pediatr Diabetes2009;10(7):432-40. 175. Kucuk M, Doymaz F. Placental weight and placental weight-to-birth weight ratio are increased in diet- and exercise-treated gestational diabetes mellitus subjects but not in subjects with one abnormal value on 100-g oral glucose tolerance test. J Diabetes Complications 2009;23(1):25-31. 164. Balani J, Hyer SL, Rodin DA, et al. Pregnancy outcomes in women with gestational diabetes treated with metformin or insulin: a case-control study. Diabetic Med 2009;26(8):798-802. 165. Retnakaran R, Shah BR. Abnormal screening glucose challenge test in pregnancy and future risk of diabetes in young women. Diabetic Med 2009;26(5):474-7. 176. Pawelec M, Karmowski A, Krzemieniewska J, et al. The clinical and financial effects of replacing the 1 h 50 g screening test for gestational diabetes mellitus by the stick method. Adv Clin Exp Med 2009;18(6):601-7. 166. Lapolla A, Dalfra MG, Bonomo M, et al. Gestational diabetes mellitus in Italy: a multicenter study. Eur J Obstet Gynecol Reprod Biol 2009;145(2):149-53. 177. Hossein-nezhad A, Mirzaei K, Maghbooli Z, et al. Maternal glycemic status in GDM patients after delivery. Iran J Diabetes Lipid Disord 2009;8(1):95104. 167. Madarasz E, Tamas G, Tabak AG, et al. Carbohydrate metabolism and cardiovascular risk factors 4 years after a pregnancy complicated by gestational diabetes. Diabetes Res Clin Pract 2009;85(2):197-202. 178. Clausen TD, Mathiesen ER, Hansen T, et al. Overweight and the metabolic syndrome in adult offspring of women with diet-treated gestational diabetes mellitus or type 1 diabetes. J Clin Endocrinol Metab 2009;94(7):2464-70. 168. Lin CH, Wen SF, Wu YH, et al. Using the 100-g oral glucose tolerance test to predict fetal and maternal outcomes in women with gestational diabetes mellitus. Chang Gung Medical Journal 2009;32(3):283-9. 179. Riskin-Mashiah S, Younes G, Damti A, et al. FirstTrimester Fasting Hyperglycemia and Adverse Pregnancy Outcomes. Diabetes Care 2009;32(9):1639-43. 169. Esakoff TF, Cheng YW, Sparks TN, et al. The association between birthweight 4000 g or greater and perinatal outcomes in patients with and without 180. Herring SJ, Oken E, Rifas-Shiman SL, et al. Weight gain in pregnancy and risk of maternal E-8 hyperglycemia. Am J Obstet Gynecol 2009;201(1):61-7. 191. Negrato CA, Rafacho A, Negrato G, et al. Glargine vs. NPH insulin therapy in pregnancies complicated by diabetes: an observational cohort study. Diabetes Res Clin Pract 2010;89(1):46-51. 181. Chen YZ, Quick WW, Yang WY, et al. Cost of Gestational Diabetes Mellitus in the United States in 2007. Population Health Management 2009;12(3):165-74. 192. Fadl HE, Ostlund IK, Magnuson AF, et al. Maternal and neonatal outcomes and time trends of gestational diabetes mellitus in Sweden from 1991 to 2003. Diabetic Med 2010;27(4):436-41. 182. Hedderson MM, Darbinian JA, Ferrara A. Disparities in the risk of gestational diabetes by race-ethnicity and country of birth. Paediatr Perinat Epidemiol 2010;24(5):441-8. 193. Flores-Le Roux JA, Chillaron JJ, Goday A, et al. Peripartum metabolic control in gestational diabetes. Am J Obstet Gynecol 2010;202(6):568-e16. 183. de Barros MC, Lopes MA, Francisco RP, et al. Resistance exercise and glycemic control in women with gestational diabetes mellitus. Am J Obstet Gynecol 2010;203(6):556-e1-6. 194. Geifman-Holtzman O, Machtinger R, Spiliopoulos M, et al. The clinical utility of oral glucose tolerance test at term: can it predict fetal macrosomia? Arch Gynecol Obstet 2010;281(5):817-21. 184. Karcaaltincaba D, Yalvac S, Kandemir O, et al. Glycosylated hemoglobin level in the second trimester predicts birth weight and amniotic fluid volume in non-diabetic pregnancies with abnormal screening test. J Matern Fetal Neonatal Med 2010;23(10):1193-9. 195. Buscicchio G, Gentilucci L, Giannubilo SR, et al. Computerized analysis of fetal heart rate in pregnancies complicated by gestational diabetes mellitus. Gynecol Endocrinol 2010;26(4):270-4. 185. Silva JC, Pacheco C, Bizato J, et al. Metformin compared with glyburide for the management of gestational diabetes. Int J Gynaecol Obstet 2010;111(1):37-40. 196. Hamilton JK, Odrobina E, Yin J, et al. Maternal insulin sensitivity during pregnancy predicts infant weight gain and adiposity at 1 year of age. Obesity 2010;18(2):340-6. 186. Anderberg E, Kallen K, Berntorp K. The impact of gestational diabetes mellitus on pregnancy outcome comparing different cut-off criteria for abnormal glucose tolerance. Acta Obstet Gynecol Scand 2010;89(12):1532-7. 197. Rowan JA, Gao W, Hague WM, et al. Glycemia and its relationship to outcomes in the metformin in gestational diabetes trial. Diabetes Care 2010;33(1):9-16. 187. Kvehaugen AS, Andersen LF, Staff AC. Anthropometry and cardiovascular risk factors in women and offspring after pregnancies complicated by preeclampsia or diabetes mellitus. Acta Obstet Gynecol Scand 2010;89(11):1478-85. 198. Moore LE, Clokey D, Rappaport VJ, et al. Metformin compared with glyburide in gestational diabetes: a randomized controlled trial. Obstet Gynecol 2010;115(1):55-9. 199. Chodick G, Elchalal U, Sella T, et al. The risk of overt diabetes mellitus among women with gestational diabetes: A population-based study. Diabetic Med 2010;27(7):779-85. 188. Pugh SK, Poole AT, Hill JB, et al. Abnormal 1 hour glucose challenge test followed by a normal 3 hour glucose tolerance test: does it identify adverse pregnancy outcome? J Miss State Med Assoc 2010;51(1):3-6. 200. Elkind-Hirsch KE, Ogden BW, Darensbourg CJ, et al. Clinical assessment of insulin action during late pregnancy in women at risk for gestational diabetes: Association of maternal glycemia with perinatal outcome. Int J Diabetes Mellitus 2010;2(1):3-9. 189. Balaji V, Balaji MS, Alexander C, et al. Premixed insulin aspart 30 (Biasp 30) vs. premixed human insulin 30 (BHI 30) in gestational diabetes mellitus - a pilot study. J Assoc Physicians India 2010;58:99-101. 201. Perez-Ferre N, Galindo M, Fernandez MD, et al. The outcomes of gestational diabetes mellitus after a telecare approach are not inferior to traditional outpatient clinic visits. Int J Endocrinol 2010;386941. 190. Barakat MN, Youssef RM, Al-Lawati JA. Pregnancy outcomes of diabetic women: charting Oman's progress towards the goals of the Saint Vincent Declaration. Ann Saudi Med 2010;30(4):265-70. 202. Hedderson MM, Gunderson EP, Ferrara A. Gestational weight gain and risk of gestational E-9 diabetes mellitus. Obstet Gynecol 2010;115(3):597604. in women without gestational diabetes mellitus? J Matern Fetal Neonatal Med 2011;24(9):1102-6. 203. O'Sullivan EP, Avalos G, O'Reilly M, et al. Atlantic Diabetes in Pregnancy (DIP): the prevalence and outcomes of gestational diabetes mellitus using new diagnostic criteria. Diabetologia 2011;54(7):1670-5. 215. Kaymak O, Iskender CT, Ustunyurt E, et al. Retrospective evaluation of perinatal outcome in women with mild gestational hyperglycemia. J Obstet Gynaecol 2011;37(8):986-91. 204. Ehrlich SF, Crites YM, Hedderson MM, et al. The risk of large for gestational age across increasing categories of pregnancy glycemia. Am J Obstet Gynecol 2011;204(3):240-e1-6. 216. Jovanovic L, Pettitt D. Frequent monitoring of a1c during pregnancy as a treatment tool to guide therapy. Diabetes Technol Ther 2011;34(1):53-4. 217. Durnwald CP, Mele L, Spong CY, et al. Glycemic characteristics and neonatal outcomes of women treated for mild gestational diabetes. Obstet Gynecol 2011;117(4):819-27. 205. Corrado F, D'Anna R, Di VG, et al. The effect of myoinositol supplementation on insulin resistance in patients with gestational diabetes. Diabetic Med 2011;28(8):972-5. 218. Ijas H, Vaarasmaki M, Morin-Papunen L, et al. Metformin should be considered in the treatment of gestational diabetes: a prospective randomised study. BJOG 2011;118(7):880-5. 206. Yogev Y, Melamed N, Chen R, et al. Glyburide in gestational diabetes--prediction of treatment failure. J Matern Fetal Neonatal Med 2011;24(6):842-6. 207. Ouzounian JG, Rosenheck R, Lee RH, et al. Onehour post-glucola results and pre-pregnancy body mass index are associated with the need for insulin therapy in women with gestational diabetes. J Matern Fetal Neonatal Med 2011;24(5):718-22. 219. Balaji V, Balaji M, Anjalakshi C, et al. Diagnosis of gestational diabetes mellitus in Asian-Indian women. Indian J Endocrinol Metab 2011;15(3):18790. 220. Anderberg E, Landin-Olsson M, Kalen J, et al. Prevalence of impaired glucose tolerance and diabetes after gestational diabetes mellitus comparing different cut-off criteria for abnormal glucose tolerance during pregnancy. Acta Obstet Gynecol Scand 2011;90(11):1252-8. 208. Korpi-Hyovalti EA, Laaksonen DE, Schwab US, et al. Feasibility of a lifestyle intervention in early pregnancy to prevent deterioration of glucose tolerance. BMC Public Health 2011;11:179. 209. Riskin-Mashiah S, Damti A, Younes G, et al. Normal fasting plasma glucose levels during pregnancy: a hospital-based study. J Perinat Med 2011;39(2):209-11. 221. Louie JC, Markovic TP, Perera N, et al. Randomized Controlled Trial Investigating the Effects of a Low-Glycemic Index Diet on Pregnancy Outcomes in Gestational Diabetes Mellitus. Diabetes Care 2011;34(11):2341-6. 210. Kosus A, Kosus N, Turhan NO. Assessment of cardiomyopathy in fetuses of women with false positive oral glucose loading test. Eur J Obstet Gynecol Reprod Biol 2011;154(1):37-9. 222. Saxena P, Tyagi S, Prakash A, et al. Pregnancy outcome of women with gestational diabetes in a tertiary level hospital of north India. Indian J Community Med 2011;36(2):120-3. 211. Grant SM, Wolever TM, O'Connor DL, et al. Effect of a low glycaemic index diet on blood glucose in women with gestational hyperglycaemia. Diabetes Res Clin Pract 2011;91(1):15-22. 223. Gandhi P, Bustani R, Madhuvrata P, et al. Introduction of metformin for gestational diabetes mellitus in clinical practice: has it had an impact? Eur J Obstet Gynecol Reprod Biol 2012;160(2):147-50. 212. Deierlein AL, Siega-Riz AM, Chantala K, et al. The association between maternal glucose concentration and child BMI at age 3 years. Diabetes Care 2011;34(2):480-4. 224. Bahado-Singh RO, Mele L, Landon MB, et al. Fetal male gender and the benefits of treatment of mild gestational diabetes mellitus. Am J Obstet Gynecol 2012;206(5):422-5. 213. Nanda S, Savvidou M, Syngelaki A, et al. Prediction of gestational diabetes mellitus by maternal factors and biomarkers at 11 to 13 weeks. Prenat Diagn 2011;31(2):135-41. 225. Dennedy MC, Avalos G, O'Reilly MW, et al. ATLANTIC-DIP: raised maternal body mass index (BMI) adversely affects maternal and fetal outcomes in glucose-tolerant women according to 214. Yee LM, Cheng YW, Liddell J, et al. 50-Gram glucose challenge test: Is it indicative of outcomes E-10 International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria. J Clin Endocrinol Metab 2012;97(4):E608-E612. 227. O'Dwyer V, Farah N, Hogan J, et al. Timing of screening for gestational diabetes mellitus in women with moderate and severe obesity. Acta Obstet Gynecol Scand 2012;91(4):447-51. 226. Gasim T. Gestational diabetes mellitus: maternal and perinatal outcomes in 220 saudi women. Oman Med J 2012;27(2):140-4. Excluded – Duplicate (N=10) 1. Cabero L, Corcoy R, Cerqueria MJ, Codina M. Treatment and Outcome of 100 Gestational Diabetics. 1989. Human Development Maternal-Fetal Medicine Unit Network randomized clinical trial in progress: standard therapy versus no therapy for mild gestational diabetes. Chicago, IL 2007 p. S194S199. 2. Retnakaran R. lsolated Hyperglycemia at 1 Hour on Oral Glucose Tolerance Test in Pregnancy Resembles Gestational Diabetes Mellitus in Predicting Postpartum Metabolic Dysfunction. Diabetes Care 2008;2008(7):1275-81. 6. Langer O, Yogev Y, Most O. Gestational diabetes mellitus: the consequences of not treating. Am J Obstet Gynecol 2005;192(4):989-997. 3. Landon MB, Thom E, Spong CY, et al. The National Institute of Child Health and Human Development Maternal-Fetal Medicine Unit Network randomized clinical trial in progress: Standard therapy versus no therapy for mild gestational diabetes. Diabetes Care 2007;30(Suppl 2):S194-S199. 7. Reichelt AJ, Spichler ER, Branchtein L, et al. Easting plasma glucose is a useful test for the detection of gestational diabetes. Diabetes Care 1998;21(8):1246-9. 8. Naylor CD, Sermer M, Chen EL, et al. Selective screening for gestational diabetes mellitus. N Engl J Med 1997;337(22):1591-6. 4. Landon MB. The national institute of child health and human development maternal-fetal medicine unit network randomized clinical trial in progress : Standard therapy versus no therapy for mild gestational diabetes. Proceedings of the fifth International Workshop-Conference on Gestational Diabetes Mellitus, 11-13 November 2005, Chicago, Illinois. Diabetes Care 2007;30(Suppl 2):S194S199. 9. Balaji V, Balaji MS, Alexander C, et al. Premixed insulin aspart 30 (biasp 30) vs premixed human insulin 30 (bhi 30) in gestational diabetes mellitus a pilot study. J Assoc Physicians India 2010;58(2):95-7. 10. Retnakaran R. -Cell Function Declines Within the First Year Postpartum in Women With Recent Glucose Intolerance in Pregnancy. Diabetes Care 2010;2010(8):1798-804. 5. Landon MB, Thom E, Spong CY, Carpenter M, et al. The National Institute of Child Health and Excluded – Intervention (N=12) 1. Persily CA. Relationships between the perceived impact of gestational diabetes mellitus and treatment adherence. J Obstet Gynecol Neonatal Nurs 1996;25(7):601-7. postprandial glucose level be monitored? Aust N Z J Obstet Gynaecol 1999;39(4):457-60. 4. Nachum Z, Ben-Shlomo I, Weiner E, et al. Twice daily versus four times daily insulin dose regimens for diabetes in pregnancy: randomised controlled trial. BMJ: British Medical Journal (International Edition) 1999;319(7219):1223-7. 2. Fisher JE, Smith RS, Lagrandeur R, et al. Gestational diabetes mellitus in women receiving beta-adrenergics and corticosteroids for threatened preterm delivery. Obstet Gynecol 1997;90(6):880-3. 5. Holt RI, Goddard JR, Clarke P, et al. A postnatal fasting plasma glucose is useful in determining which women with gestational diabetes should 3. Moses RG, Lucas EM, Knights S. Gestational diabetes mellitus. At what time should the E-11 undergo a postnatal oral glucose tolerance test. Diabetic Med 2003;20(7):594-8. quality of life after delivery? Eur J Obstet Gynecol Reprod Biol 2010;148(1):40-3. 6. Mosca A, Paleari R, Dalfra MG, et al. Reference intervals for hemoglobin A1c in pregnant women: data from an Italian multicenter study. Clin Chem 2006;52(6):1138-43. 10. Karcaaltincaba D, Buyukkaragoz B, Kandemir O, et al. Gestational diabetes and gestational impaired glucose tolerance in 1653 teenage pregnancies: prevalence, risk factors and pregnancy outcomes. J Pediatr Adolesc Gynecol 2011;24(2):62-5. 7. Wong ML, Wong WH, Cheung YF. Fal myocardial performance in pregnancies complicated by gestational impaired glucose toleranceet. Ultrasound Obstet Gynecol 2007;29(4):395-400. 11. Perera NJ, Molyneaux L, Constantino MI, et al. Suboptimal performance of blood glucose meters in an antenatal diabetes clinic. Diabetes Care 2011;34(2):335-7. 8. Kakad R, Anwar A, Dyer P, et al. Fasting plasma glucose is not sufficient to detect ongoing glucose intolerance after pregnancy complicated by gestational diabetes. Exp Clin Endocrinol Diabetes 2010;118(4):234-6. 12. Catalano PM, McIntyre HD, Cruickshank JK, et al. The hyperglycemia and adverse pregnancy outcome study: associations of GDM and obesity with pregnancy outcomes. Diabetes Care 2012;35(4):780-6. 9. Halkoaho A, Kavilo M, Pietila AM, et al. Does gestational diabetes affect women's health-related Excluded – Key Question 1 RCS (N=54) 1. Swinn RA, Wareham NJ, Gregory R, et al. Excessive secretion of insulin precursors characterizes and predicts gestational diabetes. Diabetes 1995;44(8):911-5. 8. Jimenez-Moleon JJ, Bueno-Cavanillas A, Luna-delCastillo JD, et al. Predictive value of a screen for gestational diabetes mellitus: influence of associated risk factors. Acta Obstet Gynecol Scand 2000;79(11):991-8. 2. Hooper DE. Detecting GD and preeclampsia. Effectiveness of routine urine screening for glucose and protein. J Reprod Med 1996;41(12):885-8. 9. Grover J, Beall MH, Ross MG. Intrapartum screen for diabetes in patients without prenatal care: use of labor admission serum glucose. J Matern Fetal Med 2000;9(4):216-8. 3. Landy HJ, Gomez-Marin O, O'Sullivan MJ. Diagnosing gestational diabetes mellitus: use of a glucose screen without administering the glucose tolerance test. Obstet Gynecol 1996;87(3):395-400. 10. Shamsuddin K, Mahdy ZA, Siti R, I, et al. Risk factor screening for abnormal glucose tolerance in pregnancy. Int J Gynaecol Obstet 2001;75(1):27-32. 4. Tan YY, Yeo GS. Impaired glucose tolerance in pregnancy--is it of consequence? Aust N Z J Obstet Gynaecol 1996;36(3):248-55. 11. Kyle CV, Cundy TF. Screening for gestational diabetes mellitus: can we be more efficient? Aust N Z J Obstet Gynaecol 2001;41(3):285-90. 5. Kousta E, Lawrence NJ, Penny A, et al. Implications of new diagnostic criteria for abnormal glucose homeostasis in women with previous gestational diabetes. Diabetes Care 1999;22(6):9337. 12. Chan LY, Wong SF, Ho LC. Diabetic family history is an isolated risk factor for gestational diabetes after 30 years of age. Acta Obstet Gynecol Scand 2002;81(2):115-7. 6. Atilano LC, Lee-Parritz A, Lieberman E, et al. Alternative methods of diagnosing gestational diabetes mellitus. Am J Obstet Gynecol 1999;181(5 Pt 1):1158-61. 13. Larijani B, Hossein-nezhad A, Rizvi SW, et al. Cost analysis of different screening strategies for gestational diabetes mellitus. Endocrine Pract 2003;9(6):504-9. 7. Khine ML, Winklestein A, Copel JA. Selective screening for gestational diabetes mellitus in adolescent pregnancies. Obstet Gynecol 1999;93(5 Pt 1):738-42. 14. Miyakoshi K, Tanaka M, Ueno K, et al. Cutoff value of 1 h, 50 g glucose challenge test for screening of gestational diabetes mellitus in a Japanese population. Diabetes Res Clin Pract 2003;60(1):63-7. E-12 15. De Sereday MS, Damiano MM, Gonzalez CD, et al. Diagnostic criteria for gestational diabetes in relation to pregnancy outcome. J Diabetes Complications 2003;17(3):115-9. 27. Johnston-MacAnanny EB, Ness A, Weinstein L. Diagnosis of gestational diabetes mellitus: is it time for a new critical value? J Reprod Med 2007;52(6):463-6. 16. Schytte T, Jorgensen LG, Brandslund I, et al. The clinical impact of screening for gestational diabetes. Clin Chem Lab Med 2004;42(9):1036-42. 28. Hackmon R, James R, O'Reilly GC, et al. The impact of maternal age, body mass index and maternal weight gain on the glucose challenge test in pregnancy. J Matern Fetal Neonatal Med 2007;20(3):253-7. 17. Jakobi P, Solt I, Weissman A. A 2 hour versus the 3 hour 100 g glucose tolerance test for diagnosing gestational diabetes mellitus. J Perinat Med 2004;32(4):320-2. 29. Khan HA, Sobki SH, Alhomida AS, et al. Indian J Clin Biochem 2007;22(1):65-70. 18. Caliskan E, Kayikcioglu F, Ozturk N, et al. A population-based risk factor scoring will decrease unnecessary testing for the diagnosis of gestational diabetes mellitus. Acta Obstet Gynecol Scand 2004;83(6):524-30. 30. Ogonowski J, Miazgowski T, Homa K, et al. Low predictive value of traditional risk factors in identifying women at risk for gestational diabetes. Acta Obstet Gynecol Scand 2007;86(10):1165-70. 31. Rudge MV, Lima CA, Paulette TA, et al. Influence of lower cutoff values for 100-g oral glucose tolerance test and glycemic profile for identification of pregnant women at excessive fetal growth risk. Endocrine Pract 2008;14(6):678-85. 19. Sun JH, See LC, Chiu TH, et al. An appropriate indicator for diagnosing gestational diabetes. Chang Gung Medical Journal 2005;28(12):824-8. 20. Agarwal MM, Dhatt GS, Punnose J, et al. Gestational diabetes: dilemma caused by multiple international diagnostic criteria. Diabetic Med 2005;22(12):1731-6. 32. Yamasmit W, Chaithongwongwatthana S, Uerpairojkit B. A 50-g glucose challenge test: is there any diagnostic cut-off? J Med Assoc Thai 2008;91(9):1309-12. 21. Esakoff TF, Cheng YW, Caughey AB. Screening for gestational diabetes: different cut-offs for different ethnicities? Am J Obstet Gynecol 2005;193(3 Suppl):1040-4. 33. Punthumapol C, Tekasakul P. 50 grams glucose challenge test for screening of gestational diabetes mellitus in each trimester in potential diabetic pregnancy. J Med Assoc Thai 2008;91(6):787-93. 22. Dabelea D, Snell-Bergeon JK, Hartsfield CL, et al. Increasing prevalence of gestational diabetes mellitus (GDM) over time and by birth cohort: Kaiser Permanente of Colorado GDM Screening Program. Diabetes Care 2005;28(3):579-84. 34. Montagnana M, Lippi G, Targher G, et al. Glucose challenge test does not predict gestational diabetes mellitus. Intern Med 2008;47(13):1171-4. 35. Korucuoglu U, Biri A, Turkyilmaz E, et al. Glycemic levels with glucose loading test during pregnancy and its association with maternal and perinatal outcomes. Diabetes Res Clin Pract 2008;80(1):69-74. 23. Cheng YW, Esakoff TF, Block-Kurbisch I, et al. Screening or diagnostic: markedly elevated glucose loading test and perinatal outcomes. J Matern Fetal Neonatal Med 2006;19(11):729-34. 24. Rodacki M, Lacativa PG, Lima GA, et al. Can we simplify the 100-g oral glucose tolerance test in pregnancy? Diabetes Res Clin Pract 2006;71(3):247-50. 36. Boriboonhirunsarn D, Sunsaneevithayakul P. Abnormal results on a second testing and risk of gestational diabetes in women with normal baseline glucose levels. Int J Gynaecol Obstet 2008;100(2):147-53. 25. Agarwal MM, Dhatt GS, Punnose J. Gestational diabetes: an alternative, patient-friendly approach for using the diagnostic 100-g OGTT in high-risk populations. Arch Gynecol Obstet 2006;273(6):32530. 37. Phaloprakarn C, Tangjitgamol S. Diagnosis of gestational diabetes mellitus using a modified 100 g oral glucose tolerance test. J Perinatol 2008;28(1):711. 26. Fadl H, Ostlund I, Nilsson K, et al. Fasting capillary glucose as a screening test for gestational diabetes mellitus. BJOG 2006;113(9):1067-71. 38. Aldasouqi SA, Solomon DJ, Bokhari SA, et al. Glycohemoglobin A1c: A promising screening tool in gestational diabetes mellitus. Int J Diabetes Dev Ctries 2008;28(4):121-4. E-13 39. Phaloprakarn C, Tangjitgamol S, Manusirivithaya S. A risk score for selective screening for gestational diabetes mellitus. Eur J Obstet Gynecol Reprod Biol 2009;145(1):71-5. diagnosis of gestational diabetes mellitus. J Med Assoc Thai 2011;94(5):540-4. 47. Teh WT, Teede HJ, Paul E, et al. Risk factors for gestational diabetes mellitus: implications for the application of screening guidelines. Aust N Z J Obstet Gynaecol 2011;51(1):26-30. 40. Wong VW, Garden F, Jalaludin B. Hyperglycaemia following glucose challenge test during pregnancy: When can a screening test become diagnostic? Diabetes Res Clin Pract 2009;83(3):394-6. 48. Shah A, Stotland NE, Cheng YW, et al. The association between body mass index and gestational diabetes mellitus varies by race/ethnicity. Am J Perinatol 2011;28(7):515-20. 41. Karcaaltincaba D, Kandemir O, Yalvac S, et al. Prevalence of gestational diabetes mellitus and gestational impaired glucose tolerance in pregnant women evaluated by National Diabetes Data Group and Carpenter and Coustan criteria. Int J Gynaecol Obstet 2009;106(3):246-9. 49. Samuel A, Simhan HN. Clinical indications for abnormal early gestational 50-g glucose tolerance testing. Am J Perinatol 2011;28(6):485-7. 42. Flack JR, Ross GP, Ho S, et al. Recommended changes to diagnostic criteria for gestational diabetes: impact on workload. Aust N Z J Obstet Gynaecol 2010;50(5):439-43. 50. Huynh J, Ratnaike S, Bartalotta C, et al. Challenging the glucose challenge test. Aust N Z J Obstet Gynaecol 2011;51(1):22-5. 51. Church D, Halsall D, Meek C, et al. Random Blood Glucose Measurement at Antenatal Booking to Screen for Overt Diabetes in Pregnancy: A retrospective study. Diabetes Care 2011;34(10):2217-9. 43. Ruangvutilert P, Chaemsaithong P, Ruangrongmorakot K, et al. Development of a modified 100-gram oral glucose tolerance test for diagnosis of gestational diabetes mellitus and its diagnostic accuracy. J Med Assoc Thai 2010;93(10):1121-7. 52. Gandhi P, Farrell T. Gestational diabetes mellitus (GDM) screening in morbidly obese pregnant women. Eur J Obstet Gynecol Reprod Biol 2011;159(2):329-32. 44. Kalamegham R, Nuwayhid BS, Mulla ZD. Prevalence of gestational fasting and postload single dysglycemia in Mexican-American women and their relative significance in identifying carbohydrate intolerance. Am J Perinatol 2010;27(9):697-704. 53. Kosus A, Kosus N, Turhan NO. Gestational diabetes: comparision of the carpenter and the coustan thresholds with the new thresholds of turkish women and implications of variations in diagnostic criteria. J Matern Fetal Neonatal Med 2011. 45. Agarwal MM, Dhatt GS, Shah SM. Gestational Diabetes Mellitus Simplifying the International Association of Diabetes and Pregnancy diagnostic algorithm using fasting plasma glucose. Diabetes Care 2010;33(9):2018-20. 54. Teede HJ, Harrison CL, Teh WT, et al. Gestational diabetes: Development of an early risk prediction tool to facilitate opportunities for prevention. Aust N Z J Obstet Gynaecol 2011;51(6):499-504. 46. Hansarikit J, Manotaya S. Sensitivity and specificity of modified 100-g oral glucose tolerance tests for Excluded – Outcome (N=34) 1. Tan YY, Liauw PC, Yeo GS. Using glucose tolerance test results to predict insulin requirement in women with gestational diabetes. Aust N Z J Obstet Gynaecol 1995;35(3):262-6. 3. Giampietro O, Matteucci E. Gestational diabetes mellitus (GDM) and macrosomia: a controversial story. Ann Ist Super Sanita 1997;33(3):399-402. 4. Kerbel D, Glazier R, Holzapfel S, et al. Adverse effects of screening for gestational diabetes: a prospective cohort study in Toronto, Canada. J Med Screen 1997;4(3):128-32. 2. Phillipov G. Short- and long-term reproducibility of the 1-h 50-g glucose challenge test. Clin Chem 1996;42(2):255-7. 5. Weiss PAM. Toward universal criteria for gestational diabetes : Relationships between E-14 seventy-five and one hundred gram glucose loads and between capillary and venous glucose concentrations. Am J Obstet Gynecol 1998;1998(4):835. 16. Roggenbuck LF, Kleinwechter HJ, Demandt N, et al. Diagnostics of gestational diabetes: which cutoff-values are valid for capillary whole blood? Clin Lab 2004;50(7-8):403-8. 6. Mills JL, Jovanovic L, Knopp R, et al. Physiological reduction in fasting plasma glucose concentration in the first trimester of normal pregnancy: the diabetes in early pregnancy study. Metabolism 1998;47(9):1140-4. 17. Bito T, Foldesi I, Nyari T, et al. Prediction of gestational diabetes mellitus in a high-risk group by insulin measurement in early pregnancy. Diabetic Med 2005;22(10):1434-9. 18. Bito T, Nyari T, Kovacs L, et al. Oral glucose tolerance testing at gestational weeks < or =16 could predict or exclude subsequent gestational diabetes mellitus during the current pregnancy in high risk group. Eur J Obstet Gynecol Reprod Biol 2005;121(1):51-5. 7. Stulberg RA, John SL, Houlden RL. Gestational age at screening, diagnosis and management of gestational diabetes in a Canadian community. Canadian Journal of Diabetes 1999;23(3):27-31. 8. Griffin ME, Coffey M, Johnson H, et al. Universal vs. risk factor-based screening for gestational diabetes mellitus: detection rates, gestation at diagnosis and outcome. Diabetic Med 2000;17(1):26-32. 19. Cypryk K, Pertynska-Marczewska M, Szymczak W, et al. Evaluation of metabolic control in women with gestational diabetes mellitus by the continuous glucose monitoring system: a pilot study. Endocrine Pract 2006;12(3):245-50. 9. Juutinen J, Hartikainen AL, Bloigu R, et al. A retrospective study on 435 women with gestational diabetes: Fasting plasma glucose is not sensitive enough for screening but predicts a need for insulin treatment [7]. Diabetes Care 2000;23(12):1858-9. 20. Thomas B, Ghebremeskel K, Lowy C, et al. Nutrient intake of women with and without gestational diabetes with a specific focus on fatty acids. Nutrition 2006;22(3):230-6. 10. Weiss PA, Haeusler M, Tamussino K, et al. Can glucose tolerance test predict fetal hyperinsulinism? BJOG 2000;107(12):1480-5. 21. Seshiah V, Balaji V, Balaji MS, et al. Glycemic level at the first visit and prediction of GDM. J Assoc Physicians India 2007;55:630-2. 11. Zargar AH, Khan AK, Masoodi SR, et al. Prevalence of type 2 diabetes mellitus and impaired glucose tolerance in the Kashmir Valley of the Indian subcontinent. Diabetes Res Clin Pract 2000;47(2):135-46. 22. van LM, Opmeer BC, Zweers EJ, et al. Estimating the risk of gestational diabetes mellitus: a clinical prediction model based on patient characteristics and medical history. BJOG 2010;117(1):69-75. 23. Zisser HC, Biersmith MA, Jovanovic LB, et al. Fetal risk assessment in pregnancies complicated by diabetes mellitus. J Diabetes Sci Technol 2010;4(6):1368-73. 12. Kirwan JP, Huston-Presley L, Kalhan SC, et al. Clinically useful estimates of insulin sensitivity during pregnancy: validation studies in women with normal glucose tolerance and gestational diabetes mellitus. Diabetes Care 2001;24(9):1602-7. 24. Luo ZC, Delvin E, Fraser WD, et al. Maternal glucose tolerance in pregnancy affects fetal insulin sensitivity. Diabetes Care 2010;33(9):2055-61. 13. Davey RX, Hamblin PS. Selective versus universal screening for gestational diabetes mellitus: an evaluation of predictive risk factors. Med J Aust 2001;174(3):118-21. 25. Akinci B, Celtik A, Yener S, et al. Prediction of developing metabolic syndrome after gestational diabetes mellitus. Fertil Steril 2010;93(4):1248-54. 14. Jimenez-Moleon JJ, Bueno-Cavanillas A, Luna-delCastillo JD, et al. Prevalence of gestational diabetes mellitus: variations related to screening strategy used. Eur J Endocrinol 2002;146(6):831-7. 26. Radaelli T, Farrell KA, Huston-Presley L, et al. Estimates of insulin sensitivity using glucose and CPeptide from the hyperglycemia and adverse pregnancy outcome glucose tolerance test. Diabetes Care 2010;33(3):490-4. 15. Jorgensen LG, Schytte T, Brandslund I, et al. Fasting and post-glucose load--reference limits for peripheral venous plasma glucose concentration in pregnant women. Clin Chem Lab Med 2003;41(2):187-99. 27. Meltzer SJ, Snyder J, Penrod JR, et al. Gestational diabetes mellitus screening and diagnosis: a prospective randomised controlled trial comparing E-15 costs of one-step and two-step methods. BJOG 2010;117(4):407-15. related to perinatal mortality: a cohort study in Brazil. BMC Pregnancy Childbirth 2011;11:92. 28. Das S, Behera MK, Misra S, et al. Beta-cell function and insulin resistance in pregnancy and their relation to fetal development. Metab Syndr Relat Disord 2010;8(1):25-32. 32. Gibson KS, Waters TP, Catalano PM. Maternal weight gain in women who develop gestational diabetes mellitus. Obstet Gynecol 2012;119(3):5605. 29. Lopez Caudana AE, Lopez RR, Gonzalez VC, et al. Prediction of alterations in glucose metabolism by glucose and insulin measurements in early pregnancy. Arch Med Res 2011;42(1):70-6. 33. Verhaeghe J, Van HE, Benhalima K, et al. Glycated hemoglobin in pregnancies at increased risk for gestational diabetes mellitus. Eur J Obstet Gynecol Reprod Biol 2012;161(2):157-62. 30. Perovic M, Garalejic E, Gojnic M, et al. Sensitivity and specificity of ultrasonography as a screening tool for gestational diabetes mellitus. J Matern Fetal Neonatal Med 2011. 34. Werner EF, Pettker CM, Zuckerwise L, et al. Screening for gestational diabetes mellitus: are the criteria proposed by the international association of the Diabetes and Pregnancy Study Groups costeffective? Diabetes Care 2012;35(3):529-35. 31. Wendland EM, Duncan BB, Mengue SS, et al. Lesser than diabetes hyperglycemia in pregnancy is Excluded – Population (N=15) 8. Akhlaghi F, Hamedi AB. Comparison of maternal and fetal/neonatal complications in gestational and pre-gestational diabetes mellitus. Acta Medica Iranica 2005;43(4):263-7. 1. Gribble RK, Fee SC, Berg RL. The value of routine urine dipstick screening for protein at each prenatal visit. Am J Obstet Gynecol 1995;173(1):214-7. 2. Chang CJ, Wu JS, Lu FH, et al. Fasting plasma glucose in screening for diabetes in the Taiwanese population. Diabetes Care 1998;21(11):1856-60. 9. Sandbaek A, Lauritzen T, Borch-Johnsen K, et al. The comparison of venous plasma glucose and whole blood capillary glucose in diagnoses of Type 2 diabetes: a population-based screening study. Diabet Med 2005;22(9):1173-7. 3. Bor MV, Bor P, Cevik C. Serum fructosamine and fructosamine-albumin ratio as screening tests for gestational diabetes mellitus. Arch Gynecol Obstet 1999;262(3-4):105-11. 10. Kraemer J, Klein J, Lubetsky A, et al. Perfusion studies of glyburide transfer across the human placenta: implications for fetal safety. Am J Obstet Gynecol 2006;195(1):270-4. 4. Rich-Edwards JW, Colditz GA, Stampfer MJ, et al. Birthweight and the risk for type 2 diabetes mellitus in adult women. Ann Intern Med 1999;130(4 Pt 1):278-84. 11. Franks PW, Looker HC, Kobes S, et al. Gestational glucose tolerance and risk of type 2 diabetes in young Pima Indian offspring. Diabetes 2006;55(2):460-5. 5. Gray-Donald K, Robinson E, Collier A, et al. Intervening to reduce weight gain in pregnancy and gestational diabetes mellitus in Cree communities: an evaluation. CMAJ (Ottawa) 2000;163(10):124751. 12. Ratner RE, Christophi CA, Metzger BE, et al. Prevention of diabetes in women with a history of gestational diabetes: effects of metformin and lifestyle interventions. J Clin Endocrinol Metab 2008;93(12):4774-9. 6. Ko GT, Chan JC, Tsang LW, et al. Combined use of fasting plasma glucose and HbA1c predicts the progression to diabetes in Chinese subjects. Diabetes Care 2000;23(12):1770-3. 13. Phillips LS, Ziemer DC, Kolm P, et al. Glucose challenge test screening for prediabetes and undiagnosed diabetes. Diabetologia 2009;52(9):1798-807. 7. Agarwal MM, Punnose J, Dhatt GS. Gestational diabetes: Implications of variation in post-partum follow-up criteria. Eur J Obstet Gynecol Reprod Biol 2004;113(2):149-53. 14. Opara PI, Jaja T, Onubogu UC. Morbidity and mortality amongst infants of diabetic mothers E-16 admitted into a special care baby unit in Port Harcourt, Nigeria. Ital J Pediatr 2010;36(1):77. 15. Ohno MS, Sparks TN, Cheng YW, et al. Treating mild gestational diabetes mellitus: a costeffectiveness analysis. Am J Obstet Gynecol 2011;205(3):282-e1-7. Excluded – Publication Type (N=106) 1. Joshi R, Bharadwaj A. Gestational diabetes screening: can hemoglobin A~1~C measurement replace the glucose challenge test? Obstet Gynecol 2002:99(4 Suppl 1):S93. 11. Persson B, Hanson U. Neonatal morbidities in gestational diabetes mellitus. Diabetes Care 1998;21 Suppl 2:B79-B84. 12. Jovanovic L. Optimization of insulin therapy in patients with gestational diabetes. Endocrine Pract 2000;6(1):98-100. 2. Forest JC, Masse J, Garrido-Russo M. Glucose tolerance test during pregnancy: the significance of one abnormal value. Clin Biochem 1994;27(4):299304. 13. Hadden D. Evidence-based screening for gestational diabetes? Diabetic Med 2000;17(5):402-4. 3. JovanovicPeterson L, Bevier W, Peterson CM. A Cost-Effective Program to Normalize Birth-Weight (Bwt) by Screening for and Treatment of GlucoseIntolerance of Pregnancy (Igt). Diabetes 1995;44:A258. 14. Kitzmiller JL. Cost analysis of diagnosis and treatment of gestational diabetes mellitus. Clin Obstet Gynecol 2000;43(1):140-53. 4. Dolci M, Bianchini G, Andreani G, et al. Screening and treatment of gestational diabetes (GDM): The experience of seven years. Diabetologia 1996;39(Suppl 1):769. 15. Souvatzoglou ES, Anastasiou E, Alevizaki M, et al. Is there any cutoff point of HbA1c levels indicative of the need for insulin treatment in women with gestational diabetes? Diabetologia 2001;44(Suppl 1):A42. 5. Pavlic Renar I, Tomic M, Horvat B, Metelko Z. Screening and intervention in gestational diabetes mellitus. Fourth meeting for the implementation of the St. Vincent declaration, Lisbon 1997 p. 55. 16. de Aguiar LG, de Matos HJ, de Brito GM. Could fasting plasma glucose be used for screening highrisk outpatients for gestational diabetes mellitus? Diabetes Care 2001;24(5):954-5. 6. Roncaglia N, Arreghini A, Bellini P, Bertalero C, et al. Gestational diabetes mellitus: is therapy always necessary? Rome, 1997 p. 68. 17. Berger H, Crane J, Farine D, et al. Screening for gestational diabetes mellitus. J Obstet Gynaecol Can 2002;24(11):894-912. 7. Harder T, Plagemann A, Kohlhoff R, Rohde W. Overweight and obesity in children of mothers with long-term insulin-dependent diabetes or gestational diabetes. 1997. 18. McElduff A, Hitchman R. Screening for gestational diabetes: The time of day is important. The Medical Journal Of Australia 2002;176(3):136. 8. Cypryk K, Wilczynski J, Penza G, Krekora M. Early detection of gestational diabetes (GDM) improves pregnancy outcome. 1997. 19. Bustani RJ, Todd DM, Akinsola M, et al. Increased insulin usage and reduced macrosomia in gestational diabetes mellitus managed with postprandial blood glucose targets. Diabetologia 2002;45(Suppl 2):A291. 9. Bancroft K, Tuffnell DJ, Mason GC, et al. A randomized controlled study of the management of impaired glucose intolerance in pregnancy. Br J Obstet Gynaecol 1998;105(Suppl 17):53-4. 20. Jang HC, Park B, Park J, et al. Carbohydrate restricted diet in Korean women with mild gestational diabetes mellitus. Diabetes 2002;51:A615. 10. Pavlic Renar I, Tomic M, Horvat B, Metelko Z. Screening and intervention in gestational diabetes mellitus. 1998. 21. Castracane VD, Myles TD, Driggs SC, White D, et al. Early Detection of Gestational Diabetes is Enhances With Glucose Tolerance Testing in Early Pregnancy Source. Los Angeles, CA 2002 p. 171A. E-17 22. Seshiah V, Balaji V, Balaji MS. Diagnosis and management of diabetes in pregnancy. J Indian Med Assoc 2003;101(12):742. 34. Ramos G, Jacobson G, Kirby R, et al. Comparison of glyburide and insulin for the management of gestational diabetics with greatly elevated oral glucose challenge test and fasting hyperglycemia. Am J Obstet Gynecol 2005;193(6):S93. 23. Giuffrida FM, Castro AA, Atallah AN, et al. Diet plus insulin compared to diet alone in the treatment of gestational diabetes mellitus: a systematic review. Braz J Med Biol Res 2003;36(10):1297300. 35. Barbour LA, Kahn BF, Davies JK, et al. Effectiveness of glyburide as an alternative to treat gestational diabetes. Diabetes 2005;54:A672. 24. McElduff A. Shared care: gestational diabetes. Aust Fam Physician 2003;32(3):113-7. 36. Ross G. Gestational diabetes. Aust Fam Physician 2006;35(6):392-6. 25. Platt J, O'Brien W. Acarbose therapy for gestational diabetes: A retrospective cohort study. Am J Obstet Gynecol 2003;189(6):S107. 37. Seely EW. Does treatment of gestational diabetes mellitus affect pregnancy outcome? Nat Clin Pract Endocrinol Metab 2006;2(2):72-3. 26. Yogev Y, Langer O, Rosenn B, et al. Glucose challenge test as a predictor for gestational diabetes in mexican american women. Am J Obstet Gynecol 2003;189(6 Suppl):S86. 38. Loomis L, Lee J, Tweed E. What is appropriate fetal surveillance for women with diet-controlled gestational diabetes? J Fam Pract 2006;55(3):23840. 27. Senanayake H, Ariyaratne H, Wijeratne S. Is there a place for a single value oral glucose tolerance test for the diagnosis of gestational diabetes mellitus? Ceylon Med J 2004;49(4):136. 39. Chollet MB, Pettitt DJ. Treatment of gestational diabetes mellitus. Clin Diabetes 2006;24(1):35-6. 40. Simmons D, Wolmarans L, Cutchie W, et al. Gestational diabetes mellitus: Time for consensus on screening and diagnosis. N Z Med J 2006;119(1228). 28. Fotinos C, Dodson S. Does tight control of blood glucose in pregnant women with diabetes improve neonatal outcomes? J Fam Pract 2004;53(10):83840. 41. Cortez J, Tarsa M, Agent S, et al. Randomized controlled trial of acarbose vs. placebo in the treatment of gestational diabetes [abstract]. Am J Obstet Gynecol 2006;195(6 Suppl 1):S149. 29. Arnqvist HJ, Hanson U, Nystrom L, et al. A population based study (G-DISS) of diagnosis of gestational diabetes and pregnancy outcome. Importance of fasting blood glucose. Diabetologia 2004;47(Suppl 1):A351. 42. Kwik M, Seeho S, Morris J, et al. ACHOIS confirmed: Adverse perinatal outcomes in pregnancies complicated by mild untreated gestational diabetes. Diabetes 2006;55:A418. 30. Cheung NW, Oats JJ, McIntyre HD. Australian carbohydrate intolerance study in pregnant women: implications for the management of gestational diabetes. Aust N Z J Obstet Gynaecol 2005;45(6):484-5. 43. Parikh RM, Joshi SR, Menon PS, et al. Intensive glycemic control in diabetic pregnancy with intrauterine growth restriction is detrimental to fetus. Med Hypotheses 2007;69(1):203-5. 31. Yang HX, Gao XL, Dong Y, et al. Analysis of oral glucose tolerance test in pregnant women with abnormal glucose metabolism. Chin Med J 2005;118(12):995-9. 44. Moss JR, Crowther CA, Hiller JE, et al. Costs and consequences of treatment of gestational diabetes mellitus - evaluation from the ACHOIS randomised trial. Journal of Paediatr Child Health 2007;43(Suppl 1):A28-A29. 32. Hawkins JS, Lo J, Casey B, et al. Pregnancy outcomes associated with early diagnosis of diettreated gestational diabetes. Am J Obstet Gynecol 2005;193(6):S91. 45. Williams M, Nguyen H, Towner D. Use of the maternal serum screen to predict adverse maternal outcomes among pregnant diabetics. Am J Obstet Gynecol 2007;197(6):S158. 33. Moore L, Clokey D, Robinson A. A randomized trial of metformin compared to glyburide in the treatment of gestational diabetes. Am J Obstet Gynecol 2005;193(6):S92. 46. De Mendonca NIM, Brace-Well-Milnes TJJ, Kaushal R, et al. Gestational diabetes in a multiethnic London population; the demographics, treatment requirements and pregnancy outcomes E-18 and the implications of the ACHOIS trial for them. Diabetologia 2007;50(Suppl 1):S387. 58. Mansell A, Gouveia C, Braggins F, et al. Early screening for gestational diabetes is essential to detect undiagnosed impaired glucose tolerance and Type 2 diabetes in a high risk, ethnically-diverse population. Diabetic Med 2009;26:117-8. 47. Lundberg GD. Metformin Trumps insulin in the treatment of gestational diabetes. Medscape J Med 2008;10(7):179. 59. Fontaine P, Schaller S, Lenne X, et al. Increasing incidence of abnormal glucose tolerance in women with gestational diabetes (GDM) or mild gestational diabetes (MGH) in France: DIAGEST 2 study. Diabetologia 2009;52(Suppl 1):S457. 48. Rowan JA, Hague WM, Gao W, et al. Metformin versus insulin for the treatment of gestational diabetes. Obstet Gynecol Surv 2008;63(10):616-8. 49. Tieu J, Crowther CA, Middleton P, et al. Screening for gestational diabetes mellitus for improving maternal and infant health. Cochrane Database of Systematic Reviews 2008;(3):CD007222. 60. Vambergue A, Schaller S, Lenne X, et al. Anthropometric characteristics at 11 years in children exposed to maternal gestational diabetes mellitus or mild gestational hyperglycaemia in France: DIAGEST 2 study. Diabetologia 2009;52(Suppl 1):S64. 50. Simmons D. Diagnosis of gestational diabetes mellitus - A comparison of two screening tests. Which is the way ahead? Nat Clin Pract Endocrinol Metab 2008;4(2):72-3. 61. Yakubovich N, Qi Y, Sermer M, et al. Screening glucose challenge test in pregnancy: Impact of family history of diabetes on the likelihood of a false-negative result. Canadian Journal of Diabetes 2009;33(3):221. 51. Landon MB. A Prospective Multicenter Randomized Treatment Trial of Mild Gestational Diabetes (Gdm). Am J Obstet Gynecol 2008;199(6):S2. 62. Strevens H, Ursing D, Landin-Olsson M. Safe and efficient reporting of blood glucose values during pregnancy. Int J Gynecol Obstet 2009;107(Suppl 2):S644. 52. Lee S, Pettker C, Funai E, et al. Is Lowering the Diagnostic Threshold for Gestational Diabetes (Gdm) Cost-Effective? Implications from the Hyperglycemia and Adverse Pregnancy Outcomes (Hapo) Trial. Am J Obstet Gynecol 2008;199(6):S199. 63. Divakar H, Kumar N, Manyonda I. Diagnostic criteria influence prevalence rates for gestational diabetes: Implications for interventions in an Indian pregnant population. Int J Gynecol Obstet 2009;107(Suppl 2):S439. 53. Riskin-Mashiah S, Auslander R. First Trimester Fasting Hyperglycemia and Adverse Pregnancy Outcomes. Am J Obstet Gynecol 2008;199(6):S206. 64. Phylos B, Lindow S, Coetzee E. Reproducibility of 75 g oral glucose tolerance test in pregnancy in South African population. Int J Gynecol Obstet 2009;107(Suppl 2):S436-S437. 54. Khurana R, Kozak SE, Thompson DM. Which values of the 3 hour 100g oral glucose tolerance test (OGTT) predict who will require insulin for treatment of gestational diabetes (GDM)? Diabetes 2008;57:A755. 65. Ng JM, Masson EA, Allan BJ, et al. Post-natal follow up of patients with gestational diabetes: One year onward. Pract Diabetes Int 2009;26(3):98. 55. Cheng YW, Block-Kurbisch I, Lydell J, et al. A Different Diagnostic Strategy Using the 100gram, 3-Hour Glucose Tolerance Test for the Diagnosis of Gestational Diabetes Mellitus. Reprod Sci 2008;15(1 Suppl):245A. 66. Durnwald C. Glycemic characteristics of women treated for mild gestational diabetes and perinatal outcomes. Am J Obstet Gynecol 2009;201(6):S107. 67. Al-Haddabi R, Scott H, O'connell C, et al. Screening for gestational diabetes: does a false positive glucose challenge test predict adverse pregnancy outcome? Am J Obstet Gynecol 2009;201(6):S110. 56. Wilson N, Goodwin W, Thomas S, et al. The multidisciplinary diabetes-endocrinology clinic and postprandial blood glucose monitoring in the management of gestational diabetes: Impact on maternal and neonatal outcomes. Diabetic Med 2009;26:181. 68. Yogev Y, Chen R, Hod M, et al. Associations with preeclampsia: lessons from the hyperglycemia and adverse pregnancy outcome (HAPO) study. Am J Obstet Gynecol 2009;201(6):S27. 57. Nayyar V, Tier A, Hooker J, et al. Pregnancy outcomes inpatients with gestational diabetes. Diabetic Med 2009;26:179. E-19 69. Gillman MW, Oakey H, Baghurst P, et al. Effect of Treatment of Gestational Diabetes on Obesity in the Next Generation. Obesity 2009;17:S315. torrecardenas hospital. J Matern Fetal Neonatal Med 2010;23(S1):469. 81. Martinez PS, Abdulhaj MM, Andres NP, et al. A randomized study comparing metformin and insulin in the treatment of gestational diabetes mellitus. interim results. J Matern Fetal Neonatal Med 2010;23(S1):381. 70. Negrato CA, Teixeira MF, Silva CA, et al. Use of Insulin Glargine vs NPH vs Diet in Pregnant Women with Gestational Diabetes. Diabetes 2009;58:A641. 71. Kohzuma T, Koga M. Lucica GA-L glycated albumin assay kit: a new diagnostic test for diabetes mellitus. Mol Diagn Ther 2010;14(1):49-51. 82. Gregorini ME, Pagani G, Moretti P, et al. Treatment and gestational outcome in patients with gestational diabetes mellitus (GDM) in relation to the way of diagnosis. J Matern Fetal Neonatal Med 2010;23(S1):330. 72. Zera CA, Seely EW. Diabetes: Treatment of gestational diabetes reduces obstetric morbidity. Nat Rev Endocrinol 2010;6(2):69-70. 83. Jenum AK, Sletner L, Voldner N, et al. The STORK Groruddalen research programme: a population-based cohort study of gestational diabetes, physical activity, and obesity in pregnancy in a multiethnic population. Rationale, methods, study population, and participation rates. SCAND J PUBLIC HEALTH 2010;38(5 Suppl):60-70. 73. Rowan JA. Gestational diabetes-complications, management, outcomes. Reprod Fertil Dev 2010;22:7. 74. Mahdavian M, Hivert MF, Baillargeon JP, et al. Gestational diabetes mellitus: Simplifying the international association of diabetes and pregnancy diagnostic algorithm using fasting plasma glucose. Diabetes Care 2010;33(11):e145. 84. Comparative evaluation of fasting plasma glucose and one hour 50-g glucose challenge test in screening gestational diabetes mellitus. J Zanjan Univ Med Sci Health Serv 2010;18(71):1-9. 75. Driul L, Londero A, Citossi A, et al. Neonatal and maternal outcomes by gestational diabetes mellitus and impaired glucose tolerance: A retrospective analysis of our 6-years experience. Arch Gynecol Obstet 2010;282(Suppl 1):S73. 85. Gayle C, Germain S, Marsh MS, et al. Comparing pregnancy outcomes for intensive versus routine antenatal treatment of gestational diabetes based on a 75gram oral glucose tolerance test 2-hour blood glucose 7.8-8.9mmol/l. Diabetologia 2010;53(Suppl 1). 76. Azriel S, Garcia BA, Camao I, et al. Relationship between perinatal outcomes and thyroid-peroxidase antibodies (TPO) in a cohort of pregnant women with gestational diabetes (GD). Diabetologia 2010;53:S438. 86. Napoli A, Festa C, Merola G, et al. Low glycaemic index and hypocaloric diet therapy versus conventional approach in gestational diabetes/one abnormal value in pregnancy, after medical nutritional therapy failure. Diabetologia 2010;53(Suppl 1). 77. O'Reilly MW, Avalos G, Dennedy MC, et al. ATLANTIC DIP: Persistent postpartum glucose intolerance in women with previous gestational diabetes along the Irish Atlantic seaboard. Diabetologia 2010;53:S430. 87. Hadden DR, Metzger BE, Lowe LP, et al. Hyperglycaemia and Adverse Pregnancy Outcome (HAPO) Study: Frequency of gestational diabetes mellitus (GDM) at collaborating centers based on IADPSG consensus panel recommended criteria. Diabetologia 2010;53(Suppl 1):S9. 78. Anderberg E, Landin-Olsson M, Kalen J, et al. Prevalence of diabetes mellitus after pregnancy with gestational diabetes mellitus using different cut-off criteria for abnormal glucose tolerance. Diabetologia 2010;53:S153. 88. Metzger BE, Lowe LP, Dyer AR, et al. The Hyperglycemia & Adverse Pregnancy Outcome (HAPO) Study: Associations of Higher Levels of Maternal Glucose and BMI with Macrosomia: An Example of Diabesity. Diabetes 2010;59:A42. 79. Onofriescu M, Nemescu D, Tirnoveanu M, et al. Obstetrical and neonatal outcomes of gestational diabetes mellitus. J Matern Fetal Neonatal Med 2010;23(S1):562. 89. Metzger BE, Lowe LP, Dyer AR, et al. The Hyperglycemia & Adverse Pregnancy Outcome (HAPO) Study: Perinatal Outcome in Pregnancies with GDM and Fasting Plasma Glucose (FPG) <= 4.4 mmol/l. Diabetes 2010;59:A43. 80. Marco P, Pastor M, Snchez EC, et al. Positive predictive value of O'Sullivan test in pregnants women and incidence of gestational diabetes in E-20 90. Maher N, Reidy F, Walsh J, et al. Gestational diabetes-early treatment without rescreening: does this affect the incidence of macrosomia? Ir J Med Sci 2010;179(Suppl 2):S76-S77. diagnostic criteria for gestational diabetes National Diabetes Data Group versus Carpenter-Coustan. Am J Obstet Gynecol 2011;204(1):S224. 99. Zollinger T, Contreras K, Kominiarek M. Large for gestational age infants and the 3-hour oral glucose tolerance test values in gestational diabetes: Is there a relationship? Am J Obstet Gynecol 2011;204(1 Suppl):S111. 91. Trivedi N, Wen E, Aguayo J, et al. Impact of Diagnostic Intervals in Gestational Diabetes on Glycemic Control and Pregnancy Outcomes. Reprod Sci 2010;17(3):208A. 92. Simmons D, McElduff A, McIntyre HD, et al. Gestational Diabetes Mellitus: NICE for the US? A comparison of the American Diabetes Association and the American College of Obstetricians and Gynecologists guidelines with the UK National Institute for Health and Clinical Excellence guidelines. Diabetes Care 2010;33(1):34-7. 100. de VM, Wang J, Ferguson C, et al. How does the degree of hyperglycemia recorded during glucose tolerance testing for gestational diabetes impact perinatal outcome? Am J Obstet Gynecol 2011;204(1 Suppl):S109. 101. Lee EJ, Kim YH, Kwon JY, et al. Obstetric outcomes with a false positive 1-hour glucose challenge test. Am J Obstet Gynecol 2011;204(1 Suppl):S107-S108. 93. Ayach W, Calderon IM, Rudge MV, et al. [Comparison between two gestational diabetes screening tests and the perinatal outcome] [Portuguese]. Rev Bras Ginecol Obstet 2010;32(5):222-8. 102. Wen E, Trivedi N, Aguayo J, et al. Early versus routine diagnosis of gestational diabetes mellitus: Comparison of perinatal outcomes and postpartum screening. Am J Obstet Gynecol 2011;204(1 Suppl):S107. 94. Trivedi N, Aguayo J, Agent S, et al. Gestational diabetes in multiple gestations: incidence and implications of early screening. Reprod Sci 2011;18(Suppl 3):144A. 103. Centre for Reviews and Dissemination. Screening for gestational diabetes mellitus (Structured abstract). Database of Abstracts of Reviews of Effects 2011;4. 95. Ma KK. The obstetrical and neonatal implications of a low value on the glucose screening test. Reprod Sci 2011;18(Suppl 3):142A. 104. Liu Y, Wang J, Du M. Analysis for gestational diabetes screening of 1 676 pregnant women. [Chinese]. Matern Child Health Care China 2011;26(19):-2921. 96. Brass E, Sheeder J, Dugoff.L. Is there a benefit to screening adolescents for gestational diabetes. Reprod Sci 2011;18(Suppl 3):139A. 97. Bertini AM, Silva JC, Narciso DRR, et al. Comparative study between metformin and glibenclamide in the treatment of gestational diabetes mellitus. Diabetes Technol Ther 2011;13(2). 105. Gorriz S, Esteve S, Guerrero A. Usefulness of Screening for Gestational Diabetes. Clin Chem Lab Med 2011;49(Suppl 1):S379. 106. Klebanoff M. Treatment of Gestational Diabetes (Gdm), Weight Gain and Perinatal Outcome Marginal Structural Model (Msm) Analysis. Am J Epidemiol 2011;173(11 Suppl):S41. 98. Berggren EK, Boggess KA, Funk MJ, et al. Perinatal outcomes associated with changing Excluded – Study Design (N=11) 1. Mires GJ, Williams FL, Harper V. Screening practices for gestational diabetes mellitus in UK obstetric units. Diabet Med 1999;16(2):138-41. clinic of the mid-Anatolian region of Turkey. Clin Exp Obstet Gynecol 2005;32(4):241-4. 4. Dunne F. Type 2 diabetes and pregnancy. [Review] [56 refs]. Semin Fetal Neonatal Med 2005;10(4):333-9. 2. Kremer CJ, Duff P. Glyburide for the treatment of gestational diabetes. Am J Obstet Gynecol 2004;190(5):1438-9. 5. Ferrara A, Weiss NS, Hedderson MM, et al. Pregnancy plasma glucose levels exceeding the American Diabetes Association thresholds, but below the National Diabetes Data Group thresholds 3. Tanir HM, Sener T, Gurer H, et al. A ten-year gestational diabetes mellitus cohort at a university E-21 for gestational diabetes mellitus, are related to the risk of neonatal macrosomia, hypoglycaemia and hyperbilirubinaemia. Diabetologia 2007;50(2):298306. diabetes mellitus. Acta Obstet Gynecol Scand 2010;89(5):700-4. 9. Sapienza AD, Francisco RP, Trindade TC, et al. Factors predicting the need for insulin therapy in patients with gestational diabetes mellitus. Diabetes Res Clin Pract 2010;88(1):81-6. 6. Gonzalez-Quintero VH, Istwan NB, Rhea DJ, et al. Antenatal factors predicting subsequent need for insulin treatment in women with gestational diabetes. J Womens Health 2008;17(7):1183-7. 10. Patel S, Fraser A, Davey SG, et al. Associations of gestational diabetes, existing diabetes, and glycosuria with offspring obesity and cardiometabolic outcomes. Diabetes Care 2012;35(1):63-71. 7. Davenport MH, Mottola MF, McManus R, et al. A walking intervention improves capillary glucose control in women with gestational diabetes mellitus: a pilot study. Appl Physiol Nutr Metab 2008;33(3):511-7. 11. Renar IP, Tomic M, Horvat B, Metelko Z. Screening and intervention in getational diabetes mellitus. Diabetologia 1997;40(suppl 1):848. 8. Son GH, Kwon JY, Kim YH, et al. Maternal serum triglycerides as predictive factors for large-forgestational age newborns in women with gestational Excluded – Unobtainable (N=7) 1. Bell AW. Insulin Resistance in Pregnancy: Implications for Gestational Diabetes Source: In: Nutrition Society of Australia; p. 11-19; The Society; 1995 Series: Proceedings – Nutrition Society of Australia. Number: Vol 19 ISSN: 03141004 Language: English. Melbourne, Australia. 7. Cheng YW, Block-Kurbisch I, Lydell J, Caughey AB. 2008. (missing reference data) 8. 2. Mori M, Dolci M, Baccetti F. Evaluation after 1, 2, 3 years to delivery of glucose tolerance in women with gestational diabetes and of sons' development anthropometric. 1997. 3. Meyer WJ, Carbone J, Gauthier DW, et al. Early gestational glucose screening and gestational diabetes. J Reprod Med 1996;41(9):675-9. 4. Gorgojo Martinez JJ, Almodovar Ruiz F, Lopez Hernandez E, et al. Incidence of gestational diabetes mellitus according to different diagnostic criteria in the southeast Madrid area. Influence of diagnosis on materno-fetal parameters. Rev Clin Esp 2002;202(3):136-41. 5. Fan ZT, Yang HX, Gao XL, et al. Pregnancy outcome in gestational diabetes. Int J Gynaecol Obstet 2006;94(1):12-6. 6. Eslamian L, Ramezani Z. Breakfast as a screening test for gestational diabetes. Int J Gynaecol Obstet 2007;96(1):34-5. E-22 Sultan M, Khlaif H. Impact of gestational impaired glucose tolerance test (GIGTT) on pregnancy outcome. Jamahiriya Med J 2010;10(4):268-71. Appendix F. Key Question 1 – HSROC Curves Hierarchical summary receiver-operator curves (HSROC) with the 95 percent confidence ellipse are shown below for two different comparisons. The summary graphic compares the sensitivity and specificity for all studies comparing a particular screening test with GDM diagnostic criteria. All points are clustered in the upper left hand quadrant and there is no overalp between the 95 percent confidence ellipse and the diagonal null line. This indicates that the ability of the screening test to correctly classify patients with GDM is significantly better than random classification. Figure F-1. HSROC curve: 50 g OGCT (≥140 mg/dL and ≥130 mg/dL ) by Carpenter-Coustan criteria F-1 Figure F-2. HSROC curve: 50 g OGCT (≥ 140 mg/dL) by NDDG criteria F-2 Appendix G. Adjusted Analyses for KQ3 Tables G-1 and G-2, on the following pages, provide unadjusted and adjusted results for maternal and offspring outcomes, respectively. The data that contributed to the meta-analysis for each comparison and outcome are provided. The data used in the meta-analyses and reported in the main report were unadjusted data from the relevant studies. We have also included the following for each study: whether the study provided adjusted results; what the adjusted effect estimate was (with its 95% confidence interval); whether the adjusted results were different from the unadjusted results in terms of statistical significance; and the variables that were controlled for in the adjusted analyses. For the overall pooled estimate within each comparison, we have noted whether the estimate would have changed if the adjusted values were used rather than the unadjusted values. For comparisons and outcomes with single studies, we have indicated whether the unadjusted and adjusted estimates differed in terms of statistical significance. G-1 Table G-1. Maternal outcomes: Unadjusted data included in meta-analyses for Key Question 3 and adjusted effect estimates where available from included studies Author, Year n/N* PREECLAMPSIA CC GDM vs. no GDM Cheng, 2009 17/273 n/N* 627/ 13,940 Weight Effect estimate † (95% CI) Were there adjusted results? Adjusted effect estimate (95% CI) Adjusted results different 52.5% 1.38 (0.87, 2.21) yes 1.3 (0.71, 2.38) no yes n/a n/a 1.56 (0.58, 4.22) no Naylor, 1996 Pennison, 2001 10/115 9/43 144/2,940 30.4% 10/69 17.2% 1.78 (0.96, 3.28) 1.44 (0.64, 3.27) Total (95% CI) 431 16,949 1.50 (1.07, 2.11) 100.0% no 264/3,117 86.8% 1.49 (1.14, 1.94) yes 1.47 (1.02, 2.13) no Naylor, 1996 Total (95% CI) 31/580 3,697 1.63 (0.82, 3.22) 1.51 (1.17, 1.93) no n/a 13.2% 100.0% Impact of adjusted results on pooled estimates Parity, maternal age, race or ethnicity, gestational weight gain, gestational age at delivery, year of delivery, epidural anesthesia, induction of labor, (with mode of delivery and episiotomy additionally controlled for perineal laceration, postpartum hemorrhage, shoulder dystocia, and birth trauma) African American race, elevated BMI Adding adjusted values would not change significance CC GDM vs. false-positive Berggren, 2011 58/460 10/115 575 Variables in model Parity, maternal delivery age over 35 years, ethnicity, delivery year; cesarean and operative deliveries were also controlled for prior cesarean. Summary measure is adjusted prevalence ratio n/a Adding adjusted values would not change significance NDDG 1 abnormal OGTT vs. no GDM G-2 Kim, 2002 5/122 18/577 Total (95% CI) 122 577 NDDG false-positive vs. no GDM Biri, 2009 7/326 21/1,432 Stamilio, 2004 10/164 107/1,661 100.0% 100.0% 1.33 (0.48, 3.65) 1.33 (0.48, 3.65) no 35.5% 64.5% 1.46 (0.63, 3.42) 0.95 (0.51, 1.77) no yes Total (95% CI) 100.0% 1.10 (0.67, 1.83) 490 3,093 WHO IGT vs. no GDM Jensen, 2003 16/289 158/2,596 50.3% 0.91 (0.55, 1.50) Nord, 1995 Yang, 2002 Total (95% CI) 14/391 0/302 3,289 42.1% 7.6% 100.0% 13/223 3/102 614 MATERNAL HYPERTENSION CC vs. no GDM Chou, 2010 10/489 238/ 10,116 Landon, 2011 62/455 31/423 n/a n/a No change n/a 0.33 (0.1, 1.11) n/a no Body mass index, parity, gestational age at delivery, chronic hypertension, tobacco use, race, midtrimester serum -fetoprotein and human chorionic gonadotropin levels, maternal age, and history of preeclampsia in a prior pregnancy. Adding adjusted values would not change significance yes 0.9 (0.5,1.8) no 1.63 (0.78, 3.40) no 20.59 (1.07, 395.30) yes 1.47 (0.62, 3.52) n/a 2.1 (0.89, 4.94) n/a yes 22.6% 0.87 (0.46, 1.63) no n/a 34.1% 1.86 (1.23, 2.80) yes 1.94 (1.09, 3.52) no Pre-pregnancy BMI, maternal age,parity, smoking, weight gain during pregnancy, gestational age, anamnestic risk indicators for GDM, ethnic background and clinical centre. Adding adjusted values would not change significance G-3 n/a Maternal age, gestational age at enrollment and at delivery, parity, BMI, and race and ethnicity Lapolla, 2011 Ricart, 2005 9/112 10/263 76/1,815 21.1% 108/6,350 22.2% 1.92 (0.99, 3.73) 2.24 (1.18, 4.22) Total (95% CI) 1,319 18,704 1.64 (1.11, 2.42) 100.0% no yes n/a n/a 2.34 (1.15, 4.77) no Maternal BMI, fetal sex (male), gestational age, maternal age, macrosomia (yes), PIH (yes) Adding adjusted values would not change significance CC vs. false-positive Berggren, 2011 33/460 150/3,117 77.6% 1.49 (1.04, 2.15) yes 1.48 (1.02,2.13) no Ricart, 2005 10/263 42/1,838 22.4% 1.66 (0.85, 3.28) no n/a Total (95% CI) 723 4,955 100.0% 1.53 (1.11, 2.11) 108/6,350 100.0% 1.35 (0.94, 1.94) yes 1.25 (0.83, 1.90) no Maternal BMI, fetal sex (male), gestational age, maternal age, macrosomia (yes), PIH (yes) 76.9% 3.19 (1.86, 5.49) yes 2.3 (1.23,4.6) no Age and BMI (adjusted estimate for “hypertensive disorders) no n/a n/a Parity, maternal delivery age over 35 years, ethnicity, delivery year; cesarean and operative deliveries were also controlled for prior cesarean. Summary measure is adjusted prevalence ratio n/a Adding adjusted values would not change significance CC False-positive vs. no GDM Ricart, 2005 42/ 1,838 CC 1 abnormal vs. no GDM Corrado, 2009 21/152 27/624 Vambergue, 2000 Total (95% CI) 14/131 5/108 23.1% 2.31 (0.86, 6.21) 283 732 100.0% 2.96 (1.84, 4.77) Adding adjusted values would not change significance Adding adjusted values would not change significance IADPSG GDM vs. no GDM G-4 Lapolla, 2011 9/112 76/1815 100.0% IADPSG IGT (1 abnormal OGTT) vs no GDM Black, 2010 36/391 490/7,020 100.0% n/a No change 1.92 (0.99, 3.73) no n/a 1.32 (0.96, 1.82) yes 1.49 (1.03, 2.16) yes Changed to Adjusted for maternal age, race/ethnicity, parity, statistically significant prepregnancy BMI, gestational weight gain, infant sex, and gestational age at OGTT IADPSG IFG vs. no GDM Black, 2010 90/886 490/7,020 100.0% 1.46 (1.18, 1.80) yes 1.29 (1.01, 1.66) no No change Adjusted for maternal age, race/ethnicity, parity, prepregnancy BMI, gestational weight gain, infant sex, and gestational age at OGTT IADPST IGT-2 vs. no GDM Black, 2010 11/83 490/7,020 100.0% 1.90 (1.09, 3.31) yes 2.33 (1.20, 4.51) no No change Adjusted for maternal age, race/ethnicity, parity, prepregnancy BMI, gestational weight gain, infant sex, and gestational age at OGTT IADPSG IGT IFG vs no GDM Black, 2010 47/331 490/7,020 100.0% 2.03 (1.54, 2.69) yes 2.01 (1.42, 2.84) no No change Adjusted for maternal age, race/ethnicity, parity, prepregnancy BMI, gestational weight gain, infant sex, and gestational age at OGTT IADPSG IGT vs IFG Black, 2010 36/391 IADPSG IGT vs. IGT-2 Black, 2010 36/391 IADPSG IGT vs IGT IFG 90/886 100.0% 0.91 (0.63, 1.31) no n/a n/a No change 11/83 100.0% 0.69 (0.37, 1.31) no n/a n/a No change Black, 2010 36/391 IADPSG IFG vs. IGT-2 47/331 100.0% 0.65 (0.43, 0.98) no n/a n/a No change Black, 2010 90/886 IADPSG IFG vs IGT IFG Black, 2010 90/886 IADPSG IGT-2 vs. IGT IFG 11/83 100.0% 0.77 (0.43, 1.37) no n/a n/a No change 47/331 100.0% 0.72 (0.51, 0.99) no n/a n/a No change G-5 Black, 2010 11/83 WHO IGT vs. no GDM Jensen, 2003 16/289 CESAREAN DELIVERY CC GDM vs. no GDM Cheng, 2009 62/ 273 Chico, 2005 0.93 (0.51, 1.72) no n/a n/a No change 158/2,596 158 0.91 (0.55, 1.50) yes 0.9 (0.5,1.8) no No change pre-pregnancy BMI, maternal age, parity, smoking, weight gain during pregnancy, gestational age, anamnestic risk indicators for GDM, ethnic background and clinical centre. 2,356/ 13,940 13.2% 1.34 (1.08, 1.68) yes 1.44 (1.01,2.07) no 47/331 100.0% 1,442/ 16.2% 5,767 3,761/ 18.2% 10,116 158/1,110 13.9% 1.16 (0.99, 1.35) no n/a n/a 1.08 (0.96, 1.20) no n/a n/a 1.67 (1.36, 2.06) no n/a n/a Lapolla, 2011 Naylor, 1996 122/ 422 196/ 489 132/ 555 49/112 34/115 564/1,815 13.3% 585/2,940 10.5% 1.41 (1.13, 1.76) 1.49 (1.11, 1.99) no yes n/a 1.2 (0.7,2.0) n/a yes Pennison, 2001 13/43 17/69 3.9% 1.23 (0.66, 2.27) yes 1.52 (0.54, 4.31) no Ricart, 2005 59/263 1,219/ 6,350 11.3% 1.17 (0.93, 1.47) yes 0.95 (0.67, 1.35) no Ching-Yu, 2010 Langer, 2005 G-6 Parity, maternal age, race or ethnicity, gestational weight gain, gestational age at delivery, year of delivery, epidural anesthesia, induction of labor, (with mode of delivery and episiotomy additionally controlled for perineal laceration, postpartum hemorrhage, shoulder dystocia, and birth trauma) Maternal age. race. parity. BMI, history of preeclampsia, history of cesarean delivery. gestational age. and current preeclampsia African American race, elevated BMI Maternal BMI, fetal sex (male), gestational age, maternal age, macrosomia (yes), PIH (yes) Schwartz, 1999 38/154 Total (95% CI) 2,426 1,110/ 7,207 49,314 10.8% 1.60 (1.21, 2.12) 100.0% 1.32 (1.17, 1.48) no n/a n/a Adding adjusted results would likely reduce lower confidence interval closer to null; not sure whether significance would change CC GDM vs. false-positive Berggren, 2011 160/ 460 942/3,117 72.3% 1.15 (1.00, 1.32) yes 1.16 (1.04, 1.30) yes Naylor, 1996 Ricart, 2005 34/115 59/263 136/580 13.2% 393/1,838 0.187% 1.26 (0.92, 1.73) 1.05 (0.82, 1.34) no no n/a n/a n/a n/a Schwartz, 1999 Total (95% CI) 38/154 992 197/1,066 14.5% 6,601 100.0% 1.34 (0.99, 1.81) 1.16 (1.05, 1.29) no n/a n/a Parity, maternal delivery age over 35 years, ethnicity, delivery year; cesarean and operative deliveries were also controlled for prior cesarean. Adding adjusted values would not change significance CC GDM vs. 1 abnormal OGTT Chico, 2005 122/ 19/59 422 CC 1 abnormal OGTT vs. no GDM 100.0% 0.90 (0.60, 1.34) no n/a n/a Chico, 2005 19/59 15.5% 1.29 (0.89, 1.87) no n/a n/a Corrado, 2009 Rust, 1996 Vambergue, 2000 Total (95% CI) 85/152 14/78 23/131 1,442/ 5,767 243/624 32/205 11/108 73.1% 6.6% 4.8% 1.44 (1.21, 1.71) 1.15 (0.65, 2.04) 1.72 (0.88, 3.37) yes no no 2.2 (1.55, 3.39) n/a n/a no n/a n/a 420 6,704 100.0% 1.40 (1.21, 1.63) No change Age and BMI Adding adjusted values would not G-7 change significance CC false-positive vs. no GDM Bo, 2004 103/ 28/91 4.0% 315 Lapolla, 2007 45/128 100/334 5.8% Naylor, 1996 136/ 585/2,940 17.8% 580 1.06 (0.75, 1.50) no n/a n/a 1.17 (0.88, 1.56) 1.18 (1.00, 1.39) no yes n/a 1.2 (0.9, 1.5) n/a no Ricart, 2005 393/ 1,838 1,219/ 6,350 46.9% 1.11 (1.01, 1.23) yes 1.06 (0.91, 1.23) no Schwartz, 1999 197/ 1,066 3,927 1,110/ 7,207 16,922 25.5% 1.20 (1.05, 1.38) no n/a 100.0% 1.15 (1.07, 1.23) NDDG 1 Abnormal OGTT vs. no GDM Kim, 2002 27/122 83/577 100.0% CC 1 abnormal OGTT vs. false-positive 1.69 (1.04, 2.75) Total (95% CI) Kwik, 2007 46/156 61/197 Lapolla, 2007 27/48 45/128 Total (95% CI) 204 325 NDDG GDM vs no GDM Adams, 1998 4/16 10/64 NDDG false-positive vs. no GDM Ardawi, 2000 24/187 67/529 Hillier, 2007 208/326 785/1,432 Retnakaran, 44/128 23/74 2008 Maternal age. race. parity. BMI, history of preeclampsia, history of cesarean delivery. gestational age. and current preeclampsia Maternal BMI, fetal sex (male), gestational age, maternal age, macrosomia (yes), PIH (yes) n/a Adding adjusted value may lower the lower confidence bound closer to null; not clear whether significance would change no n/a n/a n/a n/a n/a n/a 50.7% 49.3% 100.0% 0.95 (0.69, 1.31) 1.60 (1.14, 2.25) 1.23 (0.73, 2.06) no no 100.0% 1.60 (0.58, 4.45) no n/a n/a 3.9% 83.2% 4.3% 1.01 (0.66, 1.57) 1.16 (1.06, 1.28) 1.11 (0.73, 1.68) no no no n/a n/a n/a n/a n/a n/a No change No change G-8 No change Stamilio, 2004 39/164 286/1,661 8.6% 1.38 (1.03, 1.85) Total (95% CI) 805 3,696 1.17 (1.08, 1.28) 100.0% yes 1.76 (0.99, 3.14) yes Body mass index, parity, gestational age at delivery, chronic hypertension, tobacco use, race, midtrimester serum -fetoprotein and human chorionic gonadotropin levels, maternal age, and history of preeclampsia in a prior pregnancy. Adding adjusted values would not change significance WHO IGT vs no GDM Aberg, 2001 12/131 249/4,526 7.0% 1.67 (0.96, 2.89) no n/a n/a Jensen, 2003 54/289 450/2,596 26.4% 1.08 (0.84, 1.39) yes 1 (0.7, 1.4) no Nord, 1995 Yang, 2002 38/223 75/102 45/391 199/302 12.7% 53.9% 1.48 (0.99, 2.21) 1.12 (0.97, 1.29) no no n/a n/a n/a n/a Total (95% CI) 745 7,815 100.0% 1.18 (1.01, 1.37) Lapolla, 2011 9/112 IADPSG IGT vs no GDM 76/1,815 100.0% 1.92 (0.99, 3.73) no n/a n/a No change Black, 2010 1,112/ 7,020 100.0% 1.11 (0.89, 1.39) yes 1.03 (0.77,1.38) no No change Adjusted for maternal age, race/ethnicity, parity, prepregnancy BMI, gestational weight gain, infant sex, and gestational age at OGTT Pre-pregnancy body mass index (BMI), maternal age,parity, smoking, weight gain during pregnancy, gestational age, anamnestic risk indicators for GDM, ethnic background and clinical centre. Adding adjusted values would not change significance IADPSG GDM vs no GDM 69/391 G-9 IADPSG IFG vs no GDM 1,112/ 7,020 100.0% 1.28 (1.11, 1.47) yes 1.16 (0.95,1.41) yes Changed to not Adjusted for maternal age, race/ethnicity, parity, statistically significant prepregnancy BMI, gestational weight gain, infant sex, and gestational age at OGTT 1,112/ 7,020 100.0% 1.58 (0.94, 2.64) yes 1.39 (0.78, 2.46) no No change Adjusted for maternal age, race/ethnicity, parity, prepregnancy BMI, gestational weight gain, infant sex, and gestational age at OGTT 1,112/ 7,020 100.0% 1.32 (1.06, 1.63) yes 1.36 (1.00,1.85) yes Changed to not Adjusted for maternal age, race/ethnicity, parity, statistically significant prepregnancy BMI, gestational weight gain, infant sex, and gestational age at OGTT Black, 2010 69/391 IADPSG IGT vs. IGT-2 179/886 100.0% 0.87 [0.68, 1.12] no n/a n/a No change. Black, 2010 69/391 IADPSG IGT vs. IGT IFG Black, 2010 69/391 IADPSG IFG vs. IGT-2 19/83 100.0% 0.77 (0.49, 1.21) no n/a n/a No change. 69/331 100.0% 0.85 (0.63, 1.14) no n/a n/a No change. Black, 2010 19/83 100.0% 0.88 (0.58, 1.34) no n/a n/a No change. 69/331 100.0% 0.97 (0.76, 1.24) no n/a n/a No change. Black, 2010 19/83 69/331 MATERNAL BIRTH TRAUMA CC GDM vs no GDM Cheng, 2009 31/273 1,255/ 13,940 100.0% 1.10 (0.70, 1.72) no n/a n/a No change. yes 1.16 (0.73,1.86) no Parity, maternal age, race No change or ethnicity, gestational weight gain, gestational age at delivery, year of Black, 2010 179/ 886 IADPSG IGT-2 vs no GDM Black, 2010 19/83 IADPSG IGT IFG vs. no GDM Black, 2010 69/331 IADPSG IGT vs. IFG 179/886 IADPSG IFG vs. IGT IFG Black, 2010 179/886 IADPSG IGT-2 vs. IGT IFG 100.0% 1.26 (0.90, 1.76) G-10 delivery, epidural anesthesia, induction of labor, (with mode of delivery and episiotomy additionally controlled for perineal laceration, postpartum hemorrhage, shoulder dystocia, and birth trauma) CC GDM vs false-positive Berggren, 2011 14/460 118/3,117 100.0% 0.80 (0.47, 1.39) yes 0.83 (0.48, 1.44) no Parity, maternal delivery age over 35 years, ethnicity, delivery year; cesarean and operative deliveries were also controlled for prior cesarean. NDDG GDM vs no GDM Adams, 1998 2/16 4/64 100.0% 2.00 (0.40, 9.97) no n/a n/a MATERNAL WEIGHT GAIN CC 1 abnormal OGTT vs no GDM Rust, 1996 36/78 38/205 100.0% 2.49 (1.71, 3.62) no n/a n/a WHO IGT vs. No GDM (data presented are mean (SD), n for each group; weight; and mean difference with 95% CI) Yang, 2002 15.4 (6.5), 15.4 (5.6), 100.0% 0.00 (-1.41, 1.41) no n/a n/a 102 302 IADPSG IGT vs. NO GDM (data presented are mean (SD), n for each group; weight; and mean difference with 95% CI) Black, 2010 27.1 (14.5), 29.0 100.0% -1.90 (-3.37, -0.43) no n/a n/a 391 (13.7), 7,020 IADPSG IFG vs NO GDM (data presented are mean (SD), n for each group; weight; and mean difference with 95% CI) Black, 2010 27.8 (15.2), 29.0 100.0% -1.20 (-2.25, -0.15) no n/a n/a 886 (13.7), 7,020 IADPSG IGT-2 vs. NO GDM (data presented are mean (SD), n for each group; weight; and mean difference with 95% CI) Black, 2010 26.4 (11.6), 29.0 100.0% -2.60 (-5.12, -0.08) no n/a n/a 83 (13.7), 7,020 IADPSG IGT IFG vs. NO GDM (data presented are mean (SD), n for each group; weight; and mean difference with 95% CI) Black, 2010 27.8 (14.8), 29.0 100.0% -1.20 (-2.83, 0.43) no n/a n/a 331 (13.7), 7,020 G-11 No change No change No change No change No change No change No change IADPSG IGT vs. IFG (data presented are mean (SD), n for each group; weight; and mean difference with 95% CI) Black, 2010 27.1 (14.5), 27.8 100.0% -0.70 (-2.45, 1.05) no n/a n/a 391 (15.2), 886 IADPSG IGT vs IGT-2 (data presented are mean (SD), n for each group; weight; and mean difference with 95% CI) No change Black, 2010 27.1 (14.5), 26.4 100.0% 0.70 (-2.18, 3.58) no n/a n/a 391 (11.6), 83 IADPSG IGT vs. IGT IFG (data presented are mean (SD), n for each group; weight; and mean difference with 95% CI) Black, 2010 27.1 (14.5), 27.8 100.0% -0.70 (-2.85, 1.45) no n/a n/a 391 (14.8), 331 IADPSG IFT vs. IGT-2 (data presented are mean (SD), n for each group; weight; and mean difference with 95% CI) No change Black, 2010 27.8 (15.2), 26.4 100.0% 1.40 (-1.29, 4.09) no n/a n/a 886 (11.6), 83 IADPSG IFG vs. IGT IFG (data presented are mean (SD), n for each group; weight; and mean difference with 95% CI) No change Black, 2010 27.8 (15.2), 27.8 100.0% 0.00 (-1.88, 1.88) no n/a n/a 886 (14.8), 331 IADPSG IGT-2 vs. IGT IFG (data presented are mean (SD), n for each group; weight; and mean difference with 95% CI) Black, 2010 26.4 (11.6), 27.8 100.0% -1.40 (-4.36, 1.56) no n/a n/a 83 (14.8), 331 MATERNAL MORBIDITY/MORTALITY CC GDM vs no GDM No change Lapolla, 2011 26/112 299/1,815 100.0% CC 1 ABNORMAL OGTT vs NO GDM 1.53 (0.97, 2.42) no n/a n/a No change Rust, 1996 5/78 IADPSG GDM vs no GDM Lapolla, 2011 26/112 100.0% 1.01 (0.37, 2.74) no n/a n/a No change 294/1,815 100.0% 1.43 (1.01, 2.04) no n/a n/a No change 13/205 No change No change * The information presented in these columns is number of patients with the outcome / numbers of patients per group, except where otherwise indicated. † The effect estimates are risk ratios with 95% confidence intervals, unless otherwise indicated. BMI = body mass index; CC = Carpenter-Coustan; CI = confidence interval; GDM = gestational diabetes mellitus; IADPSG = International Association of Diabetes and Pregnancy Study Groups; IFG = impaired fasting glucose; IFT = impaired fasting tolerance; IGT = impaired glucose tolerance; IGT-2 = double impaired glucose tolerance; NDDG = National Diabetes Data Group; n = number of patients with the outcome; N = numbers of patients per group; n/a = not applicable; OGTT = oral glucose tolerance test; PIH = Pregnancy induced hypertension;SD = standard deviation; WHO = World Health Organization G-12 Table G-2. Offspring outcomes: Unadjusted data included in meta-analyses for Key Question 3 and adjusted effect estimates where available from included studies Author, Year n/N* n/N* Weight Effect estimate † (95% CI) Were there adjusted results? Adjusted effect estimate (95% CI) Adjusted results different Variables in model Impact of adjusted results on pooled estimates Macrosomia >4,500 g CC GDM vs. no GDM Cheng, 2009 11/273 223/13,940 50.7% 2.52 (1.39, 4.56) Yes 4.47 (2.26, 8.86) no 56/2,940 108/4,190 21,070 30.6% 18.7% 100.0% 3.20 (1.49, 6.86) 1.71 (0.64, 4.53) 2.52 (1.65, 3.84) no no n/a n/a n/a n/a Naylor, 1996 7/115 12/580 Schwartz, 1999 4/91 28/605 Total (95% CI) 206 1185 CC false positive vs. no GDM Naylor, 1996 12/580 56/2940 Schwartz, 1999 28/605 108/4,190 Total (95% CI) 1,185 7,130 52.2% 47.8% 100.0% 2.94 (1.18, 7.31) 0.95 (0.34, 2.64) 1.71 (0.56, 5.24) no no 39.0% 61.0% 100.0% 1.09 (0.59, 2.01) 1.80 (1.20, 2.70) 1.48 (0.91, 2.39) no no Naylor, 1996 7/115 Schwartz, 1999 4/91 Total (95% CI) 479 Parity, maternal age, race or ethnicity, gestational weight gain, gestational age at delivery, year of delivery, epidural anesthesia, induction of labor, (with mode of delivery and episiotomy additionally controlled for perineal laceration, postpartum hemorrhage, shoulder dystocia, and birth trauma) No difference in significance if adjusted estimate was added; may increase estimate of RR CC vs. false-positive n/a n/a n/a n/a No change n/a n/a n/a n/a No change G-13 NDDG GDM vs no GDM Adams, 1998 3/16 Macrosomia >4,000 g CC GDM vs. no GDM 0/64 100.0% 26.76 (1.45, 493.62) no n/a n/a Berkus, 1995 Chico, 2005 Chou, 2010 Hillier, 2007 Langer, 2005 Lapolla, 2011 Naylor, 1996 13/72 22/422 22/489 25/173 93/555 12/112 33/115 76/573 288/5,767 236/1,0116 905/7,609 87/1,110 145/1,815 395/2,940 7.4% 10.1% 10.0% 11.8% 15.5% 7.0% 14.3% 1.36 (0.80, 2.32) 1.04 (0.68, 1.59) 1.93 (1.26, 2.96) 1.21 (0.84, 1.75) 2.14 (1.63, 2.81) 1.34 (0.77, 2.34) 2.14 (1.58, 2.89) no no no no no no no n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a Pennison, 2001 6/43 5/69 2.2% 1.93 (0.63, 5.93) no Ricart, 2005 21/263 292/6,350 10.0% 1.74 (1.13, 2.66) yes 1.45 (0.83, 2.52) yes Schwartz, 1999 Total (95% CI) 22/91 2335 692/4,190 40,539 11.7% 100.0% 1.46 (1.01, 2.12) 1.61 (1.35, 1.92) no n/a n/a No change Maternal BMI, fetal sex (male), gestational age, maternal age, macrosomia (yes), PIH (yes) Adding adjusted value would not change significance CC GDM vs. false-positive Berggren, 2011 78/460 411/3,117 30.1% 1.29 (1.03, 1.60) yes 1.25 (1.01,1.56) no Hillier, 2007 Naylor, 1996 25/173 33/115 122/999 80/580 17.3% 20.0% 1.18 (0.79, 1.76) 2.08 (1.46, 2.96) no no n/a n/a Ricart, 2005 21/263 131/1,838 15.2% 1.12 (0.72, 1.74) no n/a n/a Schwartz, 1999 Total (95% CI) 22/91 1,102 119/605 7,139 17.4% 100.0% 1.23 (0.83, 1.83) 1.36 (1.10, 1.68) no n/a n/a Parity, maternal delivery age over 35 years, ethnicity, delivery year; cesarean and operative deliveries were also controlled for prior cesarean Adding adjusted value would not change significance G-14 CC GDM vs 1 abnormal OGTT Berkus, 1995 13/72 18/87 Chico, 2005 22/422 3/59 Hillier, 2007 25/173 40/288 Total (95% CI) 667 434 CC 1 abnormal OGTT vs. no GDM Berkus, 1995 18/87 76/573/ Chico, 2005 3/59 288/5,767 Corrado, 2009 19/152 39/624 Hillier, 2007 40/288 905/7,609 Lapolla, 2007 3/48 8/334 Rust, 1996 6/78 18/205 Vambergue, 21/131 8/108 2000 Total (95% CI) 843 15,220 31.1% 9.3% 59.7% 100.0% 0.87 (0.46, 1.66) 1.03 (0.32, 3.32) 1.04 (0.66, 1.65) 0.98 (0.69, 1.41) no no no 20.8% 4.4% 17.2% 39.0% 3.3% 6.7% 8.6% 1.56 (0.98, 2.48) 1.02 (0.34, 3.08) 2.00 (1.19, 3.36) 1.17 (0.87, 1.57) 2.61 (0.72, 9.50) 0.88 (0.36, 2.13) 2.16 (1.00, 4.69) no no yes no no no yes 100.0% 1.44 (1.13, 1.82) n/a n/a n/a n/a n/a n/a No change n/a n/a 2 (1.13, 3.61) n/a n/a n/a n/a no n/a n/a 2.5 (1.16, 5.4) yes Age and BMI Pre-pregnancy, BMI > 27, maternal age >35, multiparity, educational level. Adding adjusted estimates would not change significance of overall result CC false-positive vs. no GDM Hillier, 2007 Lapolla, 2007 Naylor, 1996 Ricart, 2005 122/999 8/128 80/580 131/1838 905/7,609 8/334 395/2,940 21/263 43.8% 3.8% 35.9% 14.9% 1.03 (0.86, 1.23) 2.61 (1.00, 6.81) 1.03 (0.82, 1.28) 0.89 (0.57, 1.39) no no no yes n/a n/a n/a n/a 1.33 (1.04, 1.72) yes Schwartz, 1999 Total (95% CI) 2/49 3,594 12/112 11,258 1.7% 100.0% 0.38 (0.09, 1.64) 1.02 (0.85, 1.24) no n/a n/a 51.7% 37.8% 10.6% 1.14 (0.82, 1.59) 2.04 (1.23, 3.39) 1.00 (0.28, 3.61) no no no Adding adjusted estimates would not change significance of overall result CC 1 abnormal OGTT vs. false-positive Hillier, 2007 Kwik, 2007 Lapolla, 2007 40/288 42/213 3/48 122/999 19/197 8/128 Maternal BMI, fetal sex (male), gestational age, maternal age, macrosomia (yes), PIH (yes) G-15 n/a n/a n/a n/a n/a n/a Total (95% CI) 549 NDDG vs no GDM Adams, 1998 7/16 1,324 100.0% 1.40 (0.89, 2.20) No change 5/64 100.0% 5.60 (2.04, 15.35) no No change NDDG false positive vs no GDM Chico, 2005 Hillier, 2007 Retnakaran, 2008 Stamilio, 2004 15/187 27/326 18/128 33/529 83/1,432 6/74 21.6% 42.9% 9.7% 1.29 (0.71, 2.31) 1.43 (0.94, 2.17) 1.73 (0.72, 4.18) no no no n/a n/a n/a n/a n/a n/a 14/164 95/1,661 25.8% 1.49 (0.87, 2.56) yes 1.79 (0.91, 3.51) no Total (95% CI) 805 3,696 100.0% 1.44 (1.10, 1.89) 16/532 100.0% 3.33 (0.49, 22.70) no 1.34 (0.15, 12) no No change 696/2,596 100.0% 1.26 (1.06, 1.50) yes 1.5 (1.1, 2.2) no Pre-pregnancy BMI, No change maternal age,parity, smoking, weight gain during pregnancy, gestational age, anamnestic risk indicators for GDM, ethnic background and clinical centre. 145/1,815 78.8% 1.34 (0.77, 2.34) no n/a n/a WHO GDM vs no GDM Shirazian, 2008 1/10 BMI, parity, gestational age at delivery, chronic hypertension, tobacco use, race, midtrimester serum Bfetoprotein and human chorionic gonadotropin levels, maternal age, history of preeclampsia in previous pregnancy Adding adjusted estimate would not change significance of overall result WHO IGT vs no GDM Jensen, 2003 98/289 IADPSG GDM vs no GDM Lapolla, 2011 12/112 G-16 Morikawa, 2010 1/43 Total (95% CI) 155 Shoulder dystocia CC GDM vs. no GDM 0/160 1,975 21.2% 100.0% 10.98 (0.46, 264.81) 2.09 (0.39, 11.33) no Cheng, 2009 9/273 237/ 13,940 48.40% 1.94 (1.01, 3.73) yes 2.24 (1.03,4.88) no Chou, 2010 Landon, 2011 2/489 18/455 11/10,116 3/423 9.2% 14.1% 3.76 (0.84, 16.92) 5.58 (1.65, 18.80) no yes n/a 5.44 (1.81, 20.1) n/a no Langer, 2005 Pennison, 2001 Total (95% CI) 14/555 1/43 1,815 7/1,110 1/69 25,658 25.6% 2.8% 100.0% 4.00 (1.62, 9.85) 1.60 (0.10, 24.99) 2.86 (1.81, 4.51) no no n/a n/a n/a n/a 100.0% 1.49 (0.97, 2.30) yes CC GDM vs. false-positive Berggren, 2011 24/460 109/3,117 n/a n/a No change Parity, maternal age, race or ethnicity, gestational weight gain, gestational age at delivery, year of delivery, epidural anesthesia, induction of labor, (with mode of delivery and episiotomy additionally controlled for perineal laceration, postpartum hemorrhage, shoulder dystocia, and birth trauma) Maternal age, gestational age at enrollment and at delivery, parity, BMI, and race and ethnicity Adding adjusted estimate would not change significance of overall result CC 1 abnormal OGTT vs. no GDM G-17 1.41 (0.91,2.18) no Parity, maternal delivery age over 35 years, ethnicity, delivery year; cesarean and operative deliveries were also controlled for prior cesarean No change Vambergue, 1/131 4/108 100.0% 2000 CC 1 abnormal OGTT vs. false-positive Kwik, 2007 11/213 2/197 100.0% NDDG GDM (unrecognized) vs. no GDM Adams, 1998 3/16 2/64 100.0% 0.20 (0.02, 1.82) no n/a n/a No change 5.09 (1.14, 22.66) no n/a n/a No change 6.00 (1.09, 32.95) yes 5.2 (1.1, 30.6) no Maternal BMI, age, parity, weight gain, gestational age No change NDDG false-positive vs. no GDM Stamilio, 2004 8/164 29/1,661 100.0% 2.79 (1.30, 6.01) yes 2.85 (1.25, 6.51) no No change BMI, parity, gestational age at delivery, chronic hypertension, tobacco use, race, midtrimester serum Bfetoprotein and human chorionic gonadotropin levels, maternal age, history of preeclampsia in previous pregnancy WHO IGT vs. no GDM Jensen, 2003 8/289 33/2,596 100.0% 2.18 (1.02, 4.67) yes 1.3 (0.4, 3.9) yes Pre-pregnancy BMI, Adjusted estimate maternal age,parity, not statistically smoking, weight gain significant during pregnancy, gestational age, anamnestic risk indicators for GDM, ethnic background and clinical centre. IADPSG IGT vs. no GDM Black, 2010 18/391 268/7,020 100.0% 1.21 (0.76, 1.92) yes 1.31 (0.80, 2.16) no Adjusted for maternal No change age, race/ethnicity, parity, prepregnancy BMI, gestational weight gain, infant sex, and gestational age at OGTT IADPSG IFG vs. no GDM G-18 268/7,020 100.0% 1.48 (1.10, 1.98) yes 1.45 (1.05, 2.00) no Adjusted for maternal No change age, race/ethnicity, parity, prepregnancy BMI, gestational weight gain, infant sex, and gestational age at OGTT IADPSG IGT-2 vs. no GDM Black, 2010 5/83 268/7,020 100.0% 1.58 (0.67, 3.72) yes 1.72 (0.68, 4.35) no Adjusted for maternal No change age, race/ethnicity, parity, prepregnancy BMI, gestational weight gain, infant sex, and gestational age at OGTT IADPSG IGT IFG vs. no GDM Black, 2010 23/331 268/7,020 100.0% 1.82 (1.21, 2.75) yes 1.87 (1.18, 2.96) no Adjusted for maternal No change age, race/ethnicity, parity, prepregnancy BMI, gestational weight gain, infant sex, and gestational age at OGTT IADPSG IGT vs. IFG Black, 2010 18/391 50/886 100.0% 0.82 (0.48, 1.38) no n/a n/a No change IADPSG IGT vs. IGT-2 Black, 2010 18/391 5/83 100.0% 0.76 (0.29, 2.00) no n/a n/a No change 23/331 100.0% 0.66 (0.36, 1.21) no n/a n/a No change 5/83 100.0% 0.94 (0.38, 2.28) no n/a n/a No change 23/331 100.0% 0.81 (0.50, 1.31) no n/a n/a No change 23/331 100.0% 0.87 (0.34, 2.21) no n/a n/a No change Black, 2010 50/886 IADPSG IGT vs. IGT IFG Black, 2010 18/391 IADPSG IFG vs. IGT-2 Black, 2010 50/886 IADPSG IFT vs. IGT IFG Black, 2010 50/886 IADPSG IGT-2 vs. IGT IFG Black, 2010 5/83 G-19 Fetal birth injury NDDG GDM (unrecognized) vs. no GDM Adams, 1998 4/16 0/64 100.0% No change 34.41 (1.95, 608.47) no n/a n/a 35.1% 34.8% 30.1% 100.0% 1.56 (1.02, 2.37) 9.52 (6.02, 15.08) 3.21 (1.18, 8.76) 3.64 (0.96, 13.76) no no no n/a n/a n/a n/a n/a n/a 100.0% 3.22 (0.44, 23.37) no n/a n/a 4.0% 27.8% 27.4% 40.0% 0.48 (0.07, 3.39) 1.42 (0.68, 2.97) 1.18 (0.56, 2.48) 1.41 (0.77, 2.60) no no no no n/a n/a n/a n/a n/a n/a n/a n/a 100.0% 1.29 (0.88, 1.91) Not estimable n/a n/a n/a n/a No change 100.00% 2.83 (0.58, 13.89) no n/a n/a No change 100.00% 9.60 (0.86, 106.73) no n/a n/a No change WHO IGT vs. WHO no GDM Jensen, 2003 6/281 63/2,596 76.60% 0.88 (0.38, 2.01) yes 0.7 (0.2, 2.2) no Nord, 1995 Yang, 2002 16.50% 6.90% 1.17 (0.20, 6.94) 2.96 (0.19, 46.91) no no n/a n/a n/a n/a Neonatal hypoglycemia CC GDM vs. No GDM Chico, 2005 23/422 202/5,767 Langer, 2005 100/555 21/1,110 Pennison, 2001 10/43 5/69 Total (95% CI) 1,020 6,946 CC GDM vs. 1 abnormal OGTT Chico, 2005 23/422 1/59 CC 1 abnormal OGTT vs. no GDM Chico, 2005 1/59 202/5,767 Corrado, 2009 9/152 26/624 Rust, 1996 9/78 20/205 Vambergue, 24/131 14/108 2000 Total (95% CI) 420 6,704 NDDG GDM vs. No GDM Adams, 1998 0/16 0/64 NDDG false-positive vs. no GDM Ardawi, 2000 3/187 3/529 NDDG 1 abnormal vs. no GDM Kim, 2002 2/122 1/577 2/223 1/102 3/391 1/302 No change No change G-20 Pre-pregnancy BMI, maternal age,parity, smoking, weight gain during pregnancy, gestational age, anamnestic risk indicators for GDM, ethnic background and clinical centre. Total (95% CI) 606 3,289 Hyperbilirubinemia CC GDM vs. No GDM Chico, 2005 17/422 144/5,767 Langer, 2005 78/555 23/1,110 Total (95% CI) 977 6,877 CC GDM vs. 1 abnormal OGTT Chico, 2005 17422/ 1/59 CC false-positive vs. no GDM Bo, 2004 42/315 4/91 CC 1 abnormal OGTT vs. no GDM Vambergue, 2/131 0/108 2000 NDDG false-positive vs. no GDM Ardawi, 2000 22/187 58/529 WHO IGT vs. WHO no GDM Jensen, 2003 6/281 83/2,596 Nord, 1995 10/223 28/391 Total (95% CI) 504 2,987 IADPSG IGT vs. no GDM Black, 2010 72/391 980/7,020 IADPSG IFG vs. no GDM Black, 2010 128/886 980/7,020 100.00% 1.00 (0.49, 2.07) Adding adjusted estimate would not change statistical significance of overall result 49.80% 50.20% 100.00% 1.61 (0.99, 2.64) 6.78 (4.31, 10.68) 3.32 (0.80, 13.74) no no 100.00% 2.38 (0.32, 17.53) no n/a n/a No change 100.00% 3.03 (1.12, 8.23) no n/a n/a No change 100.00% 4.19 (0.20, 88.20) no n/a n/a No change 100.00% 1.07 (0.68, 1.70) no n/a n/a No change 42.40% 57.60% 100.00% 0.67 (0.29, 1.52) 0.63 (0.31, 1.26) 0.64 (0.38, 1.10) no no n/a n/a n/a n/a 100.00% 1.32 (1.06, 1.64) yes 1.33 (1.02, 1.74) no Adjusted for maternal No change age, race/ethnicity, parity, prepregnancy BMI, gestational weight gain, infant sex, and gestational age at OGTT 100.00% 1.03 (0.87, 1.23) yes 1.04 (0.85, 1.27) no Adjusted for maternal No change age, race/ethnicity, parity, prepregnancy BMI, gestational weight gain, infant sex, and gestational age at OGTT n/a n/a n/a n/a No change No change IADPSG IGT-2 vs. no GDM G-21 980/7,020 100.00% 1.55 (1.03, 2.35) yes 1.56 (0.92, 2.65) yes Adjusted for maternal Adjusted result is not statistically age, race/ethnicity, parity, prepregnancy significant BMI, gestational weight gain, infant sex, and gestational age at OGTT IADPSG IGT OFG vs. no GDM Black, 2010 45/331 980/7,020 100.00% 0.97 (0.74, 1.29) yes 0.96 (0.69, 1.33) no Adjusted for maternal No change age, race/ethnicity, parity, prepregnancy BMI, gestational weight gain, infant sex, and gestational age at OGTT IADPSG IGT vs. IFG Black, 2010 72/391 128/886 100.0% 1.27 (0.98, 1.66) no n/a n/a No change 18/83 100.0% 0.85 (0.54, 1.34) no n/a n/a No change 45/331 100.0% 1.35 (0.96, 1.91) no n/a n/a No change 128/ 18/83 886 IADPSG IFG vs. IGT IFG Black, 2010 128/ 45/331 886 IADPSG IGT-2 vs. IGT IFG Black, 2010 18/83 45/331 100.0% 0.67 (0.43, 1.03) no n/a n/a No change 100.0% 1.06 (0.78, 1.46) no n/a n/a No change 100.0% 1.60 (0.98, 2.61) no n/a n/a No change 1.19 (0.68, 2.08) yes 1.26 (0.66, 2.42) no Parity, maternal age, No change race or ethnicity, gestational weight gain, gestational age at delivery, year of delivery, epidural anesthesia, induction Black, 2010 18/83 IADPSG IGT vs. IGT-2 Black, 2010 72/391 IADPSG IGT vs. IGT IFG Black, 2010 72/391 IADPSG IFG vs. IGT-2 Black, 2010 Fetal Birth Trauma/ Injury CC GDM vs. no GDM Cheng, 2009 12/273 516/13,940 100.00% G-22 of labor, (with mode of delivery and episiotomy additionally controlled for perineal laceration, postpartum hemorrhage, shoulder dystocia, and birth trauma) NDDG GDM vs. No GDM Adams, 1998 4/16 WHO IGT vs. no GDM Nord, 1995 1/223 Yang, 2002 0/102 0/64 100.0% 34.41 (1.95, 608.47) no n/a no 6/391 0/302 100.00% 0.00% 0.29 (0.04, 2.41) Not estimable n/a n/a n/a n/a 693 100.00% 0.29 (0.04, 2.41) Fetal Morbidity/Mortality CC GDM vs. no GDM Chico, 2005 0/422 Chou, 2010 1/489 Langer, 2005 0/555 Lapolla, 2011 18/112 Ricart, 2005 0/263 29/5,767 42/10,116 0/1,110 132/1,815 25/6350 10.10% 16.80% 46.80% 10.10% 0.23 (0.01, 3.78) 0.49 (0.07, 3.57) Not estimable 2.21 (1.40, 3.48) 0.47 (0.03, 7.73) no no no no no n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a Schwartz, 1999 Total (95% CI) 16/7,207 32,365 16.40% 100.00% 2.92 (0.39, 21.92) 1.23 (0.46, 3.30) no n/a n/a CC GDM vs. false-positive Ricart, 2005 0/263 7/1,838 49.10% 0.46 (0.03, 8.11) no n/a n/a Schwartz, 1999 Total (95% CI) 50.90% 100.00% 6.92 (0.44, 110.10) no 1.83 (0.11, 29.41) n/a n/a n/a Not estimable no n/a n/a 3.40% 93.90% 2.60% 1.63 (0.10, 26.36) 0.99 (0.58, 1.68) 2.48 (0.10, 60.20) no no no n/a n/a n/a n/a n/a n/a 100.00% 1.03 (0.61, 1.72) Total (95% CI) 325 1/154 1,995 1/154 417 1/1,066 2,904 CC GDM vs. 1 abnormal OGTT Chico, 2005 0/422 0/59 CC 1 abnormal OGTT vs. no GDM Chico, 2005 0/59 29/5,767 Rust, 1996 15/78 40/205 Vambergue, 1/131 0/108 2000 Total (95% CI) 268 6,080 no no No change No change No change No change No change No change CC false-positive vs. no GDM G-23 Bo, 2004 Ricart, 2005 4/315 7/1,838 2/91 25/6,350 17.40% 70.50% 0.58 (0.11, 3.10) 0.97 (0.42, 2.23) no no n/a n/a n/a n/a Schwartz, 1999 Total (95% CI) 1/1,066 3,219 16/7,207 13,648 12.10% 100.00% 0.42 (0.06, 3.18) 0.80 (0.40, 1.61) no n/a n/a No change CC false-positive vs. 1 abnormal OGTT Kwik, 2007 0/197 0/213 n/a NDDG false-positive vs. no GDM Ardawi, 2000 2/187 4/529 47.00% Stamilio, 2004 2/164 6/1,661 53.00% Not estimable no n/a 1.41 (0.26, 7.66) 3.38 (0.69, 16.59) no yes n/a n/a 4.61 (0.77, 27.48) no Total (95% CI) 100.00% 2.24 (0.70, 7.14) NDDG 1 abnormal OGTT vs. no GDM Kim, 2002 0/122 2/577 100.00% 0.94 (0.04, 19.69) no n/a n/a WHO IGT vs. no GDM Aberg, 2001 1/126 13/4,515 22.90% 2.76 (0.36, 20.91) no n/a n/a Nord, 1995 Yang, 2002 3/223 2/102 7/391 2/302 52.20% 24.80% 0.75 (0.20, 2.88) 2.96 (0.42, 20.75) no no n/a n/a n/a n/a Total 451 5,208 100.0% 1.42 (0.54, 3.75) 351 2,190 IADPSG GDM vs. no GDM Lapolla, 2011 18/112 132/1,815 100.00% 2.21 (1.40, 3.48) Prevalence of Childhood Obesity (>85th percentile) CC GDM vs. no GDM Hillier, 2007 60/173 1788/7,609 100.00% 1.48 (1.20, 1.82) No change n/a BMI, parity, gestational age at delivery, chronic hypertension, tobacco use, race, midtrimester serum Bfetoprotein and human chorionic gonadotropin levels, maternal age, history of preeclampsia in previous pregnancy Adding adjusted estimate would not change significance of overall result No change No change no n/a n/a yes 1.89 (1.30, 2.76) no G-24 No change Maternal age, parity, weight gain during pregnancy, ethnicity, macrosomia at birth No change (4,000 g), and sex of child CC GDM vs. false-positive Hillier, 2007 60/173 233/999 100.00% CC GDM vs. 1 abnormal OGTT Hillier, 2007 60/173 77/288 100.00% CC false-positive vs. no GDM Hillier, 2007 233/999 1788/7,609 100.00% CC false-positive vs. 1 abnormal OGTT Hillier, 2007 233/999 77/288 100.00% CC 1 abnormal OGTT vs. no GDM Hillier, 2007 77/288 1788/7,609 100.00% 1.49 (1.18, 1.88) no n/a n/a No change 1.30 (0.98, 1.72) no n/a n/a No change 0.99 (0.88, 1.12) yes 0.98 (0.81, 1.17) no 0.87 (0.70, 1.09) no n/a n/a 1.14 (0.94, 1.38) yes 1.37 (1.01, 1.84) yes (result Maternal age, parity, becomes weight gain during significant) pregnancy, ethnicity, macrosomia at birth (4,000 g), and sex of child Maternal age, parity, weight gain during pregnancy, ethnicity, macrosomia at birth (4,000 g), and sex of child No change No change * The information presented in these columns is number of patients with the outcome / numbers of patients per group. † The effect estimates are risk ratios with 95% confidence intervals. BMI = body mass index; CC = Carpenter-Coustan; CI = confidence interval; GDM = gestational diabetes mellitus; IADPSG = International Association of Diabetes and Pregnancy Study Groups; IFG = impaired fasting glucose; IFT = impaired fasting tolerance; IGT = impaired glucose tolerance; IGT-2 = double impaired glucose tolerance; NDDG = National Diabetes Data Group; n = number of patients with the outcome; N = numbers of patients per group; n/a = not applicable; OGTT = oral glucose tolerance test; PIH = Pregnancy induced hypertension;SD = standard deviation; WHO = World Health Organization G-25