Canadian Diabetes Association Clinical Practice Guidelines Pregnancy Chapter 36 David Thompson, Howard Berger, Denice Feig, Robert Gagnon, Tina Kader, Erin Keely, Sharon Kozak, Edmond Ryan, Mathew Sermer, Christina Vinokuroff

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Diabetes in Pregnancy: 2 Categories Pregestational diabetes Gestational diabetes Pregnancy in pre-existing diabetes Type 1 diabetes Type 2 diabetes Diabetes diagnosed in pregnancy

Diabetes in Pregnancy: Consider Phases Pregestational diabetes Gestational diabetes 1. Preconception counseling 1. Screening 2. Glycemic control during pregnancy 3. Management in labour 4. Postpartum considerations

Diabetes in Pregnancy: Consider Phases Pregestational diabetes Gestational diabetes 1. Preconception counseling 1. Screening 2. Glycemic control during pregnancy 3. Management in labour 4. Postpartum considerations

Dysglycemia in Pregnancy can Result in Adverse Pregnancy Outcome Elevated glucose levels can have adverse effects on the fetus 1st trimester  ↑ fetal malformations 2nd and 3rd trimester: ↑ risk of macrosomia and metabolic complications

Risk of Fetal Anomaly Relative to Periconceptional A1C Glycemic control pre-conception = essential Guerin A et al. Diabetes Care 2007;30:1-6.

Need a Preconception Checklist for Women with Pre-existing Diabetes 2013 1. Attain a preconception A1C of ≤7.0% (if safe) 2. Assess for and manage any complications 3. Switch to insulin if on oral agents 4. Folic Acid 5 mg/d: 3 months pre-conception to 12 weeks post-conception 5. Discontinue potential embryopathic meds: Ace-inhibitors/ARB (prior to or upon detection of pregnancy) Statin therapy Script:

Preconception Counseling for Pregestational Diabetes Advise reproductive age women with diabetes about reliable birth control NOTE: Metformin in PCOS may improve fertility  need to warn about possible pregnancy Metformin safe for ovulation induction in PCOS Achieving a healthy weight is essential – obesity associated with adverse pregnancy outcomes

Screen for Complications: Pre-pregnancy and Intrapartum Screening for: Retinopathy: Need ophthalmological evaluation Nephropathy: Assess creatinine + urine microalbumin / creatinine ratio (ACR) Women with microalbuminuria or overt nephropathy are at ↑ risk for hypertension and preeclampsia

Recommendations 1-2: Preconception Care All women of reproductive age with type 1 or type 2 diabetes should receive advice on reliable birth control, the importance of glycemic control prior to pregnancy, impact of BMI on pregnancy outcomes, need for folic acid and the need to stop potentially embyropathic drugs prior to pregnancy [Grade D, Level 4]. Women with type 2 diabetes and irregular menses/PCOS who are started on metformin or a thiazolidinedione should be advised that fertility may improve and be warned about possible pregnancy [Grade D, Consensus]. 2013

Recommendation 3: Preconception Care 3. Before attempting to become pregnant, women with type 1 or type 2 diabetes should: Receive preconception counseling that includes optimal diabetes management and nutrition, preferably in consultation with an interdisciplinary pregnancy team to optimize maternal and neonatal outcomes [Grade C, Level 3]

Recommendation 3: Preconception Care (continued) Strive to attain a preconception A1C of ≤7.0% (or A1C as close to normal as can safely be achieved) to decrease the risk of: Spontaneous abortion [Grade C, Level 3] Congenital anomalies [Grade C, Level 3] Pre-eclampsia [Grade C, Level 3] Progression of retinopathy in pregnancy [Grade A, level 1 for type 1 diabetes (23); Grade D, Consensus for type 2 diabetes]

Recommendation 3: Preconception Care (continued) Supplement their diet with multivitamins containing 5 mg of folic acid at least 3 months pre-conception and continuing until at least 12 weeks post-conception [Grade D, Level 4]. Supplementation should continue with a multivitamin containing 0.4-1.0 mg of folic acid from 12 weeks postconception through to 6 weeks postpartum or as long as breastfeeding continues [Grade D, Consensus].

Recommendation 3: Preconception Care (continued) Discontinue medications that are potentially embryopathic, including any from the following classes: ACE inhibitors and ARBs prior to conception or upon detection of pregnancy [Grade C, Level 3] Statins [Grade D, Level 4] 2013

Recommendation 4: Preconception Care Women with type 2 diabetes who are planning a pregnancy should switch from non-insulin antihyperglycemic agents to insulin for glycemic control [Grade D, Consensus]. Women with pregestational diabetes who also have PCOS may continue metformin for ovulation induction [Grade D, Consensus].

Recommendations 5 and 6: Preconception and Complications Women should undergo an ophthalmological evaluation by an eye care specialist [Grade A, Level 1, for type 1; Grade D, Level 4 for type 2]. Women should be screened for chronic kidney disease prior to pregnancy [Grade D level 4 for type 1 diabetes Grade D, consensus for type 2 diabetes]. Women with microalbuminuria or overt nephropathy are at increased risk for the development of HTN and preeclampsia [Grade A level 1]; and should be followed closely for these conditions [Grade D, Consensus]

Diabetes in Pregnancy: Consider Phases Pregestational diabetes Gestational diabetes 1. Preconception counseling 1. Screening 2. Glycemic control during pregnancy 3. Management in labour 4. Postpartum considerations

Need Optimal Glycemic Control in Pregnancy for Pre-existing Diabetes Individualized insulin therapy with close monitoring Bolus insulin: May use aspart or lispro instead of regular insulin Basal insulin: May use detemir or glargine as alternative to NPH Encourage patients to SMBG pre- and postprandially Target glucose values Fasting PG <5.3 mmol/L 1h postprandial PG <7.8 mmol/L 2h postprandial PG <6.7 mmol/L Script: Patients need individualized insulin therapy with close monitoring, especially across trimesters as insulin resistance changes. It is essential to avoid hypoglycemia while maintaining euglycemia. For prandial insulin, one can use aspart or lispro instead of regular insulin especially to improve glycemic control and avoid hypoglycemia. For Basal insulin, Detemir or Glargine may be used instead of NPH. Encourage patients SMBG pre- and postprandially to achieve glycemic targets and improve pregnancy outcomes. The target glucose levels in pregnancy: listed above. The limiting factor when seeking euglycemia in women with pregestational diabetes is the increased risk of hypoglycemia during pregnancy, particularly in the first trimester

Diabetes in Pregnancy: Consider Phases Pregestational diabetes Gestational diabetes 1. Preconception counseling 1. Screening 2. Glycemic control during pregnancy 3. Management in labour 4. Postpartum considerations

Glucose Management During Labour and Delivery 2013 Glucose Management During Labour and Delivery Maternal blood glucose levels should be kept between 4.0 -7.0 mmol/L  ↓ neonatal hypoglycemia Women should receive adequate glucose during labour in order to meet the high energy requirements IV Dextrose + IV insulin protocols may be helpful

Postpartum care for pre-existing diabetes Adjust insulin  at risk of hypoglycemia Encourage women to breastfeed Metformin and glyburide may be used during breast-feeding  no long term data but appears safe Screen for postpartum thyroiditis in T1DM  check TSH at 6-8 weeks postpartum Women with pregestational diabetes should be carefully monitored postpartum as they have a high risk of hypoglycemia with loss of placental insulin resistance. All women should be encouraged to breast-feed, since this may reduce offspring obesity, especially in the setting of maternal obesity. Metformin and glyburide may be used during breast-feeding as appears to be safe, but no long-term data available. It’s essential to screen for postpartum thyroiditis – need to check TSH at 6-8 weeks postpartum.

Recommendation 7: Management in Pregnancy for Pregestational Diabetes Pregnant women with type 1 or type 2 diabetes should: Receive an individualized insulin regimen and glycemic targets typically using intensive insulin therapy [Grade A, Level 1B for type 1; Grade A, Level 1 for type 2] b) Strive for target glucose values [Grade D consensus]: Fasting PG below 5.3 mmol/L 1h postprandial below 7.8 mmol/L 2h postprandial below 6.7 mmol/L

Recommendation 7: Management in Pregnancy for Pre-gestational Diabetes (continued) c) Be prepared to raise these targets if need be because of the increased risk of severe hypoglycemia during pregnancy [Grade D, Consensus] d) Perform SMBG, both pre- and postprandially to achieve glycemic targets and improve pregnancy outcomes [Grade C, Level 3] 2013

Recommendations 8-9: Management in Pregnancy for Pre-gestational Diabetes Women with pregestational diabetes may use aspart or lispro in pregnancy instead of regular insulin to improve glycemic control and reduce hypoglycemia [Grade C level 2 for aspart , Grade C, Level 3 for lispro]. Detemir [Grade C, Level 2] or glargine [Grade C, Level 3 ] may be used in women with pregestational diabetes as an alternative to NPH. 2013 2013

Recommendation 10 and 11: Intrapartum Glucose Management Women should be closely monitored during labour and delivery and maternal blood glucose levels should be kept between 4.0 and 7.0 mmol/L in order to minimize the risk of neonatal hypoglycemia [Grade D, Consensus] Women should receive adequate glucose during labour in order to meet the high energy requirements [Grade D, Consensus] 2013 2013

Recommendations 12 and 13: Postpartum Glucose Management Women with pregestational diabetes should be carefully monitored postpartum as they have a high risk of hypoglycemia [Grade D, Consensus]. Metformin and glyburide may be used during breast-feeding [Grade C, Level 3 for metformin; Grade D, Level 4 for glyburide]. 2013 2013

Recommendation 14 and 15: Postpartum Glucose Management Women with type 1 diabetes in pregnancy should be screened for postpartum thyroiditis with a TSH test at 6-8 weeks postpartum [Grade D, Consensus]. All women should be encouraged to breast-feed, since this may reduce offspring obesity, especially in the setting of maternal obesity [Grade C level 3-] Bullet, no number, don’t forget - easier

Diabetes in Pregnancy: Consider Phases Pregestational diabetes Gestational diabetes 1. Preconception counseling 1. Screening & diagnosis 2. Glycemic control during pregnancy 3. Management in labour 4. Postpartum considerations

Gestational Diabetes (GDM) Diagnosis Universal screening for GDM @ 24-28 weeks Gestational Age (GA) Screen earlier if risk factors for GDM: Previous GDM BMI ≥30 kg/m2 Prediabetes Polycystic ovarian syndrome High risk population (Aboriginal, Hispanic, South Asian, Asian, African) Current fetal macrosomia or polyhydramnios Age ≥35 years History of macrosomic infant Corticosteroid use Acanthosis nigricans 2 shorter lists

Why Diagnose and Treat GDM? Macrosomia Shoulder dystocia and nerve injury Neonatal hypoglycemia Preterm delivery Hyperbilirubinemia Caesarian section Offspring obesity (?) Offspring diabetes (?)

HAPO: Incidence of Adverse Outcomes Increases Along Continuum N Engl J Med. 2008 May 8;358(19):1991-2002. doi: 10.1056/NEJMoa0707943. Hyperglycemia and adverse pregnancy outcomes. HAPO Study Cooperative Research Group, Metzger BE, Lowe LP, Dyer AR, Trimble ER, Chaovarindr U, Coustan DR, Hadden DR, McCance DR, Hod M, McIntyre HD, Oats JJ, Persson B, Rogers MS, Sacks DA. Source Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. bem@northwestern.edu Abstract BACKGROUND: It is controversial whether maternal hyperglycemia less severe than that in diabetes mellitus is associated with increased risks of adverse pregnancy outcomes. METHODS: A total of 25,505 pregnant women at 15 centers in nine countries underwent 75-g oral glucose-tolerance testing at 24 to 32 weeks of gestation. Data remained blinded if the fasting plasma glucose level was 105 mg per deciliter (5.8 mmol per liter) or less and the 2-hour plasma glucose level was 200 mg per deciliter (11.1 mmol per liter) or less. Primary outcomes were birth weight above the 90th percentile for gestational age, primary cesarean delivery, clinically diagnosed neonatal hypoglycemia, and cord-blood serum C-peptide level above the 90th percentile. Secondary outcomes were delivery before 37 weeks of gestation, shoulder dystocia or birth injury, need for intensive neonatal care, hyperbilirubinemia, and preeclampsia. RESULTS: For the 23,316 participants with blinded data, we calculated adjusted odds ratios for adverse pregnancy outcomes associated with an increase in the fasting plasma glucose level of 1 SD (6.9 mg per deciliter [0.4 mmol per liter]), an increase in the 1-hour plasma glucose level of 1 SD (30.9 mg per deciliter [1.7 mmol per liter]), and an increase in the 2-hour plasma glucose level of 1 SD (23.5 mg per deciliter [1.3 mmol per liter]). For birth weight above the 90th percentile, the odds ratios were 1.38 (95% confidence interval [CI], 1.32 to 1.44), 1.46 (1.39 to 1.53), and 1.38 (1.32 to 1.44), respectively; for cord-blood serum C-peptide level above the 90th percentile, 1.55 (95% CI, 1.47 to 1.64), 1.46 (1.38 to 1.54), and 1.37 (1.30 to 1.44); for primary cesarean delivery, 1.11 (95% CI, 1.06 to 1.15), 1.10 (1.06 to 1.15), and 1.08 (1.03 to 1.12); and for neonatal hypoglycemia, 1.08 (95% CI, 0.98 to 1.19), 1.13 (1.03 to 1.26), and 1.10 (1.00 to 1.12). There were no obvious thresholds at which risks increased. Significant associations were also observed for secondary outcomes, although these tended to be weaker. CONCLUSIONS: Our results indicate strong, continuous associations of maternal glucose levels below those diagnostic of diabetes with increased birth weight and increased cord-blood serum C-peptide levels. Metzger BE, et al. Hyperglycemia and Adverse Pregnancy Outcomes. NEJM 2008;358(19):1991-2002.

Benefits of Treatment of GDM BMJ. 2010 Apr 1;340:c1395. doi: 10.1136/bmj.c1395. Effects of treatment in women with gestational diabetes mellitus: systematic review and meta-analysis. Horvath K, Koch K, Jeitler K, Matyas E, Bender R, Bastian H, Lange S, Siebenhofer A. Source EBM Review Center, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria. Karl.Horvath@medunigraz.at Abstract OBJECTIVE: To summarise the benefits and harms of treatments for women with gestational diabetes mellitus. DESIGN: Systematic review and meta-analysis of randomised controlled trials. DATA SOURCES: Embase, Medline, AMED, BIOSIS, CCMed, CDMS, CDSR, CENTRAL, CINAHL, DARE, HTA, NHS EED, Heclinet, SciSearch, several publishers' databases, and reference lists of relevant secondary literature up to October 2009. Review methods Included studies were randomised controlled trials of specific treatment for gestational diabetes compared with usual care or "intensified" compared with "less intensified" specific treatment. RESULTS: Five randomised controlled trials matched the inclusion criteria for specific versus usual treatment. All studies used a two step approach with a 50 g glucose challenge test or screening for risk factors, or both, and a subsequent 75 g or 100 g oral glucose tolerance test. Meta-analyses did not show significant differences for most single end points judged to be of direct clinical importance. In women specifically treated for gestational diabetes, shoulder dystocia was significantly less common (odds ratio 0.40, 95% confidence interval 0.21 to 0.75), and one randomised controlled trial reported a significant reduction of pre-eclampsia (2.5 v 5.5%, P=0.02). For the surrogate end point of large for gestational age infants, the odds ratio was 0.48 (0.38 to 0.62). In the 13 randomised controlled trials of different intensities of specific treatments, meta-analysis showed a significant reduction of shoulder dystocia in women with more intensive treatment (0.31, 0.14 to 0.70). CONCLUSIONS: Treatment for gestational diabetes, consisting of treatment to lower blood glucose concentration alone or with special obstetric care, seems to lower the risk for some perinatal complications. Decisions regarding treatment should take into account that the evidence of benefit is derived from trials for which women were selected with a two step strategy (glucose challenge test/screening for risk factors and oral glucose tolerance test).

Benefits of Treatment of GDM BMJ. 2010 Apr 1;340:c1395. doi: 10.1136/bmj.c1395. Effects of treatment in women with gestational diabetes mellitus: systematic review and meta-analysis. Horvath K, Koch K, Jeitler K, Matyas E, Bender R, Bastian H, Lange S, Siebenhofer A. Source EBM Review Center, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria. Karl.Horvath@medunigraz.at Abstract OBJECTIVE: To summarise the benefits and harms of treatments for women with gestational diabetes mellitus. DESIGN: Systematic review and meta-analysis of randomised controlled trials. DATA SOURCES: Embase, Medline, AMED, BIOSIS, CCMed, CDMS, CDSR, CENTRAL, CINAHL, DARE, HTA, NHS EED, Heclinet, SciSearch, several publishers' databases, and reference lists of relevant secondary literature up to October 2009. Review methods Included studies were randomised controlled trials of specific treatment for gestational diabetes compared with usual care or "intensified" compared with "less intensified" specific treatment. RESULTS: Five randomised controlled trials matched the inclusion criteria for specific versus usual treatment. All studies used a two step approach with a 50 g glucose challenge test or screening for risk factors, or both, and a subsequent 75 g or 100 g oral glucose tolerance test. Meta-analyses did not show significant differences for most single end points judged to be of direct clinical importance. In women specifically treated for gestational diabetes, shoulder dystocia was significantly less common (odds ratio 0.40, 95% confidence interval 0.21 to 0.75), and one randomised controlled trial reported a significant reduction of pre-eclampsia (2.5 v 5.5%, P=0.02). For the surrogate end point of large for gestational age infants, the odds ratio was 0.48 (0.38 to 0.62). In the 13 randomised controlled trials of different intensities of specific treatments, meta-analysis showed a significant reduction of shoulder dystocia in women with more intensive treatment (0.31, 0.14 to 0.70). CONCLUSIONS: Treatment for gestational diabetes, consisting of treatment to lower blood glucose concentration alone or with special obstetric care, seems to lower the risk for some perinatal complications. Decisions regarding treatment should take into account that the evidence of benefit is derived from trials for which women were selected with a two step strategy (glucose challenge test/screening for risk factors and oral glucose tolerance test). Horvath K et al. BMJ 2010;340:c1935

Diagnosis of GDM Are there clear threshold glucose levels above which the risk of adverse neonatal or maternal outcomes increases?

IADPSG Diabetes Care 2010;22:676-682 June 2008, the IADPSG sponsored an International Workshop Conference on Gestational Diabetes Diagnosis and Classification in Pasadena, California. More than 225 conferees from 40 countries reviewed published results of the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study, additional unpublished HAPO study findings and results of other work that examined associations of maternal glycemia with perinatal and long-term outcomes in offspring.

HAPO: Incidence of Adverse Outcomes Increases Along Continuum – No Threshold N Engl J Med. 2008 May 8;358(19):1991-2002. doi: 10.1056/NEJMoa0707943. Hyperglycemia and adverse pregnancy outcomes. HAPO Study Cooperative Research Group, Metzger BE, Lowe LP, Dyer AR, Trimble ER, Chaovarindr U, Coustan DR, Hadden DR, McCance DR, Hod M, McIntyre HD, Oats JJ, Persson B, Rogers MS, Sacks DA. Source Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. bem@northwestern.edu Abstract BACKGROUND: It is controversial whether maternal hyperglycemia less severe than that in diabetes mellitus is associated with increased risks of adverse pregnancy outcomes. METHODS: A total of 25,505 pregnant women at 15 centers in nine countries underwent 75-g oral glucose-tolerance testing at 24 to 32 weeks of gestation. Data remained blinded if the fasting plasma glucose level was 105 mg per deciliter (5.8 mmol per liter) or less and the 2-hour plasma glucose level was 200 mg per deciliter (11.1 mmol per liter) or less. Primary outcomes were birth weight above the 90th percentile for gestational age, primary cesarean delivery, clinically diagnosed neonatal hypoglycemia, and cord-blood serum C-peptide level above the 90th percentile. Secondary outcomes were delivery before 37 weeks of gestation, shoulder dystocia or birth injury, need for intensive neonatal care, hyperbilirubinemia, and preeclampsia. RESULTS: For the 23,316 participants with blinded data, we calculated adjusted odds ratios for adverse pregnancy outcomes associated with an increase in the fasting plasma glucose level of 1 SD (6.9 mg per deciliter [0.4 mmol per liter]), an increase in the 1-hour plasma glucose level of 1 SD (30.9 mg per deciliter [1.7 mmol per liter]), and an increase in the 2-hour plasma glucose level of 1 SD (23.5 mg per deciliter [1.3 mmol per liter]). For birth weight above the 90th percentile, the odds ratios were 1.38 (95% confidence interval [CI], 1.32 to 1.44), 1.46 (1.39 to 1.53), and 1.38 (1.32 to 1.44), respectively; for cord-blood serum C-peptide level above the 90th percentile, 1.55 (95% CI, 1.47 to 1.64), 1.46 (1.38 to 1.54), and 1.37 (1.30 to 1.44); for primary cesarean delivery, 1.11 (95% CI, 1.06 to 1.15), 1.10 (1.06 to 1.15), and 1.08 (1.03 to 1.12); and for neonatal hypoglycemia, 1.08 (95% CI, 0.98 to 1.19), 1.13 (1.03 to 1.26), and 1.10 (1.00 to 1.12). There were no obvious thresholds at which risks increased. Significant associations were also observed for secondary outcomes, although these tended to be weaker. CONCLUSIONS: Our results indicate strong, continuous associations of maternal glucose levels below those diagnostic of diabetes with increased birth weight and increased cord-blood serum C-peptide levels. Metzger BE, et al. HAPO. NEJM 2008;358(19):1991-2002.

Are there clear threshold glucose levels above which the risk of adverse neonatal or maternal outcomes increases? NO

IADPSG Consensus Threshold Values for Diagnosis of GDM (≥1 Value is Diagnostic) Glucose measure with a 75 g OGTT Glucose threshold (mmol/L) Proportion of HAPO cohort above threshold (%) Fasting plasma glucose (FPG) 5.1 8.3 1-h plasma glucose 10.0 14.0 2-h plasma glucose 8.5 16.1 Given the lack of a clear threshold, the IADPSG chose an odds ratio of 1.75 for developing the primary outcome of HAPO as their threshold for determining the diagnostic criteria for HAPO. The glucose thresholds as well as proportion of HAPO cohort above threshold are shown here. Based on odds ratio (OR) of 1.75 for primary outcome OGTT = Oral Glucose Tolerance Test HAPO = Hyperglycemia and Adverse Pregnancy Outcomes study IADPSG. Diabetes Care 2010;22:676-682

Odds Ratio (OR) of 1.75 vs. 2.0 for Primary Outcome in HAPO OR 1.75 Threshold glucose levels (mmol/L) after a 75g OGTT OR 1.75 OR 2.0 Fasting plasma glucose 5.1 5.3 1-h plasma glucose 10.0 10.6 2-h plasma glucose 8.5 9.0 % of cohort that met ≥ 1 threshold above 16.1% 8.8% However, since OR 1.75 was an arbitrary selection, here are the thresholds if an OR of 2.0 was selected instead. These values are very similar to the diagnostic criteria that CDA recommended in 2008. OGTT = Oral Glucose Tolerance Test HAPO = Hyperglycemia and Adverse Pregnancy Outcomes study IADPSG. Diabetes Care 2010;22:676-682

HAPO: Incidence of Adverse Outcomes for Glucose Categories (OR 1 HAPO: Incidence of Adverse Outcomes for Glucose Categories (OR 1.75 or 2.0 ) N Engl J Med. 2008 May 8;358(19):1991-2002. doi: 10.1056/NEJMoa0707943. Hyperglycemia and adverse pregnancy outcomes. HAPO Study Cooperative Research Group, Metzger BE, Lowe LP, Dyer AR, Trimble ER, Chaovarindr U, Coustan DR, Hadden DR, McCance DR, Hod M, McIntyre HD, Oats JJ, Persson B, Rogers MS, Sacks DA. Source Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. bem@northwestern.edu Abstract BACKGROUND: It is controversial whether maternal hyperglycemia less severe than that in diabetes mellitus is associated with increased risks of adverse pregnancy outcomes. METHODS: A total of 25,505 pregnant women at 15 centers in nine countries underwent 75-g oral glucose-tolerance testing at 24 to 32 weeks of gestation. Data remained blinded if the fasting plasma glucose level was 105 mg per deciliter (5.8 mmol per liter) or less and the 2-hour plasma glucose level was 200 mg per deciliter (11.1 mmol per liter) or less. Primary outcomes were birth weight above the 90th percentile for gestational age, primary cesarean delivery, clinically diagnosed neonatal hypoglycemia, and cord-blood serum C-peptide level above the 90th percentile. Secondary outcomes were delivery before 37 weeks of gestation, shoulder dystocia or birth injury, need for intensive neonatal care, hyperbilirubinemia, and preeclampsia. RESULTS: For the 23,316 participants with blinded data, we calculated adjusted odds ratios for adverse pregnancy outcomes associated with an increase in the fasting plasma glucose level of 1 SD (6.9 mg per deciliter [0.4 mmol per liter]), an increase in the 1-hour plasma glucose level of 1 SD (30.9 mg per deciliter [1.7 mmol per liter]), and an increase in the 2-hour plasma glucose level of 1 SD (23.5 mg per deciliter [1.3 mmol per liter]). For birth weight above the 90th percentile, the odds ratios were 1.38 (95% confidence interval [CI], 1.32 to 1.44), 1.46 (1.39 to 1.53), and 1.38 (1.32 to 1.44), respectively; for cord-blood serum C-peptide level above the 90th percentile, 1.55 (95% CI, 1.47 to 1.64), 1.46 (1.38 to 1.54), and 1.37 (1.30 to 1.44); for primary cesarean delivery, 1.11 (95% CI, 1.06 to 1.15), 1.10 (1.06 to 1.15), and 1.08 (1.03 to 1.12); and for neonatal hypoglycemia, 1.08 (95% CI, 0.98 to 1.19), 1.13 (1.03 to 1.26), and 1.10 (1.00 to 1.12). There were no obvious thresholds at which risks increased. Significant associations were also observed for secondary outcomes, although these tended to be weaker. CONCLUSIONS: Our results indicate strong, continuous associations of maternal glucose levels below those diagnostic of diabetes with increased birth weight and increased cord-blood serum C-peptide levels. Metzger BE, et al. HAPO. NEJM 2008;358(19):1991-2002.

Remains a Controversial Topic … Obstet Gynecol. 2013 Jan;121(1):177-82. doi: http://10.1097/AOG.0b013e31827711e5. Perspectives on the proposed gestational diabetes mellitus diagnostic criteria. Langer O, Umans JG, Miodovnik M. Source Cookeville Regional Medical Center, Cookeville, Tennessee 38501, USA. odlanger@gmail.com Abstract To date, The International Association of the Diabetes and Pregnancy Study Groups (IADPSG) criteria for the diagnosis of gestational diabetes mellitus (GDM) have not been analyzed systematically for medical, social, and economic ramifications if used in substitution for the current GDM diagnostic criteria. The IADPSG dependence on expert opinion and consensus rather than on rigorously obtained outcome measures is concerning given the dramatic changes in clinical intervention and medical-resource reallocation that would follow their wide adoption. This commentary attempts to highlight needed research as well as the key knowledge gaps that should prevent adoption of the revised criteria until their effect on perinatal outcomes and health care costs is determined. In light of the overall, ethnic, and regional variation in GDM prevalence and the demands of increased GDM diagnosis on clinical resources, it may not be realistic and practical to impose universal strategies and standards for diagnosis. The newly proposed criteria may affect medical care negatively, unnecessarily stigmatize patients with a "sick label," and adversely affect health care costs without ensuring the desired improvements in maternal and neonatal outcomes. This commentary serves as a caution to not promote a new endeavor until it has been compared rigorously with current practice and its implications are understood fully. Diabetologia. 2011 Mar;54(3):480-6. doi: 10.1007/s00125-010-2005-4. Epub 2011 Jan 4. Diagnosing gestational diabetes. Ryan EA. Division of Endocrinology and Metabolism, Department of Medicine, 362 Clinical Wing, Heritage Medical Research Building, Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada. edmond.ryan@ualberta.ca The newly proposed criteria for diagnosing gestational diabetes will result in a gestational diabetes prevalence of 17.8%, doubling the numbers of pregnant women currently diagnosed. These new diagnostic criteria are based primarily on the levels of glucose associated with a 1.75-fold increased risk of giving birth to large-for-gestational age infants (LGA) in the Hyperglycemia Adverse Pregnancy Outcome (HAPO) study; they use a single OGTT. Thus, of 23,316 pregnancies, gestational diabetes would be diagnosed in 4,150 women rather than in 2,448 women if a twofold increased risk of LGA were used. It should be recognised that the majority of women with LGA have normal glucose levels during pregnancy by these proposed criteria and that maternal obesity is a stronger predictor of LGA. The expected benefit of a diagnosis of gestational diabetes in these 1,702 additional women would be the prevention of 140 cases of LGA, 21 cases of shoulder dystocia and 16 cases of birth injury. The reproducibility of an OGTT for diagnosing mild hyperglycaemia is poor. Given that (1) glucose is a weak predictor of LGA, (2) treating these extra numbers has a modest outcome benefit and (3) the diagnosis may be based on a single raised OGTT value, further debate should occur before resources are allocated to implementing this change. Diabet Med. 2012 Feb;29(2):176-80. doi: 10.1111/j.1464-5491.2011.03407.x. Proposed new diagnostic criteria for gestational diabetes--a pause for thought? Cundy T. Department of Medicine, Faculty of Medical & Health Sciences, University of Auckland, Auckland, New Zealand. t.cundy@auckland.ac.nz New criteria for the diagnosis of gestational diabetes promulgated by the International Association of Diabetes and Pregnancy Study Groups (IADSPG) have been adopted by a number of groups, including the American Diabetes Association. These criteria will increase two- to three-fold the number of women diagnosed with gestational diabetes and have enormous resource implications. The recommendations are derived from observations made in the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study, which demonstrated continuous relationships between maternal glucose tolerance and two clinically relevant outcomes of pregnancy (caesarean section rate and neonatal hypoglycaemia) and two surrogate measures (birth weight and cord C-peptide). The recent randomized intervention studies in mild gestational diabetes indicate that the major effects of detecting and treating mild gestational diabetes are a reduction in mean birth weight of 100-140 g, and a reduction in the incidence of shoulder dystocia. However, the women included in these studies were identified using different diagnostic criteria, and it cannot be assumed that women diagnosed by the less stringent IADSPG criteria will have the same benefit. Moreover, as the majority of cases of macrosomia and shoulder dystocia occur in women with normal glucose tolerance, the real impact of diagnosing many more 'cases' of gestational diabetes is likely to be minimal. The concentration on mild degrees of hyperglycaemia may well be misplaced, as most of the outcomes usually attributed to gestational diabetes are more strongly associated with maternal obesity and weight gain in pregnancy. The new testing procedure (with diagnosis based on a single blood glucose measurement) will inevitably be imprecise. Given the many reservations about the new criteria an urgent but dispassionate debate is required on the risks, costs and benefits of their introduction.

Considerations for the CDA Adopting the IADPSG Thresholds How can we select an odds ratio threshold in the absence of a true threshold in the data? What is the impact on the patient and workload of increasing the prevalence of GDM? Do we have sufficient evidence with respect to treatment benefit at the various thresholds to make an informed decision? In the absence of clear benefit, should the diagnostic criteria be changed from 2008?

2013 CDA Diagnostic Criteria for GDM PREFERRED APPROACH (2 steps) 50 gram glucose challenge test 75 gram oral glucose tolerance test Using thresholds of OR 2.0 ALTERNATIVE APPROACH (1 step) 75 gram oral glucose tolerance test Using thresholds of OR 1.75

2013 GDM Diagnosis: Two Approaches

2013 GDM Diagnosis: Preferred Approach

2013 GDM Diagnosis: Preferred Approach

2013 GDM Diagnosis: Preferred Approach

2013 GDM Diagnosis: Preferred Approach

2013 GDM Diagnosis: Preferred Approach

2013 GDM Diagnosis: Preferred Approach

2013 GDM diagnosis: Alternative Approach

2013 GDM diagnosis: Alternative Approach

Recommendations 16-17: Diagnosis of GDM All pregnant women should be screened for GDM at 24-28 weeks of gestation [Grade C, Level 3]. If there is a high risk of GDM based on multiple clinical factors, screening should be offered at any stage in the pregnancy [Grade D, Consensus]. If the initial screening is performed before 24 weeks of gestation and is negative, rescreen between 24-28 weeks of gestation. (see next slide)

Recommendation 17: Risk Factors for GDM (continued) Age ≥35 years Previous GDM Prediabetes High risk population Aboriginal, Hispanic, South Asian, Asian, African BMI ≥30 kg/m2 Polycystic ovarian syndrome Acanthosis nigricans Corticosteroid use History of macrosomic infant Current fetal macrosomia or polyhydramnios [Grade D, Consensus]

Recommendation 18: Diagnosis of GDM The preferred approach for the screening and diagnosis of GDM is the following [Grade D, Consensus]: Screening for GDM should be conducted using the 50 g glucose challenge test (GCT) administered in the non-fasting state with plasma glucose measured one hour later [Grade D, Level 4]. A plasma glucose value ≥7.8 mmol/L at one hour will be considered a positive screen and will be an indication to proceed to the 75 gram OGTT [Grade C, Level 2]. A plasma glucose value >11.1 mmol/L can be considered to be diagnostic of gestational diabetes and does not require a 75 gram OGTT for confirmation [Grade C, Level 3]. 2013

Recommendation 18: Diagnosis of GDM (continued) If the GCT screen is positive, a 75 gram OGTT should be performed as the diagnostic test for GDM using the following criteria: >1 of the following values: Fasting >5.3 mmol/L, 1h >10.6 mmol/L, 2h >9.0 mmol/L [Grade B, Level 1] 2013

Recommendation 19: Diagnosis of GDM An alternative approach that may be used to screen and diagnose GDM is the one-step approach [Grade D, Consensus]: A 75 gram OGTT should be performed (with no prior screening 50g GCT) as the diagnostic test for GDM using the following criteria [Grade D, Consensus]: ≥1 of the following values: Fasting > 5.1 mmol/L, 1h > 10.0 mmol/L, 2h > 8.5 mmol/L [Grade B, Level 1 (4)] 2013

Diabetes in Pregnancy: Consider Phases Pregestational diabetes Gestational diabetes 1. Preconception counseling 1. Screening & diagnosis 2. Glycemic control during pregnancy 3. Management in labour 4. Postpartum considerations

GDM: Glycemic Management During Pregnancy Perform SMBG, both fasting and postprandially Glycemic Targets during pregnancy: Receive nutrition counseling Moderate carbohydrate restriction: 3 meals + 3 snacks Targets not met within 2 weeks start insulin Avoid hypocaloric diet  weight loss + ketosis Target glucose values Fasting PG <5.3 mmol/L 1h postprandial PG <7.8 mmol/L 2h postprandial PG <6.7 mmol/L Perform SMBG, both fasting and postprandially to achieve glycemic targets and improve pregnancy outcomes

IOM Guidelines for Gestational Weight Gain Pre-Pregnancy BMI Recommended range of total weight gain (Kg) Recommended range of total weight gain (lb) BMI <18.5 12.5 – 18.0 28 – 40 BMI 18.5 - 24.9 11.5 – 16.0 25 – 35 BMI 25.0 - 29.9 7.0 – 11.5 15 – 23 BMI > or = 30 5.0 – 9.0 11 – 20 Recommended rate of weight gain and total weight gain for singleton Pregnancies according to pre-pregnancy BMI Institute of Medicine. Weight gain during pregnancy: reexamining the guidelines. Consensus Report. May 2009. The National Academies Press. Washington, DC.

What About Insulin Analogues and Oral Agents Among Patients with GDM? May use rapid-acting analog insulin for postprandial glucose control – no difference in perinatal outcomes May use glyburide or metformin for women who are non-adherent to or who refuse insulin Likely safe BUT it is OFF-Label  no long-term data, need discussion with patient

GDM: Glycemic Management During Labour and Delivery 2013 GDM: Glycemic Management During Labour and Delivery Keep maternal blood glucose l between 4.0 and 7.0 mmol/L  reduce risk of neonatal hypoglycemia Women should receive adequate glucose during labour in order to meet the high energy requirements

Postpartum GDM Management Checklist Encourage Breastfeeding 75g OGTT between 6 weeks - 6 months postpartum to detect prediabetes or diabetes Discuss increased long-term risk of diabetes – Importance of returning to pre-pregnancy weight Script:

Recommendation 20: Management During Pregnancy (GDM) Women with GDM should: Strive for target glucose values: Fasting PG below 5.3 mmol/L [Grade B, Level 2] 1h postprandial below 7.8 mmol/L [Grade B, Level 2] 2h postprandial below 6.7 mmol/L [Grade B, Level 2] Perform SMBG, both fasting and postprandially to achieve glycemic targets and improve pregnancy outcomes [Grade B, Level 2] Avoid ketosis during pregnancy [Grade C, Level 3]

Recommendation 21: Management During Pregnancy (GDM) Receive nutrition counseling from a registered dietitian during pregnancy [Grade C, Level 3] and postpartum [Grade D, Consensus]. Recommendations for weight gain during pregnancy should be based on pregravid BMI [Grade D, Consensus].

Recommendation 22 and 24: Management During Pregnancy (GDM) If women with GDM do not achieve glycemic targets within 2 weeks from nutritional therapy alone, insulin therapy should be initiated [Grade D, Consensus]. Insulin therapy in the form of multiple injections should be used [Grade A, Level 1]. Rapid-acting bolus analog insulin may be used over regular insulin for postprandial glucose control although perinatal outcomes are similar [Grade B, Level 2]. 2013

Recommendation 25: Management During Pregnancy (GDM) For women who are non-adherent to or who refuse insulin, glyburide [Grade B, Level 2] or metformin [Grade B, Level 2] may be used as alternative agents for glycemic control. Use of oral agents in pregnancy is off-label and this should be discussed with the patient [Grade D, Consensus].

Recommendation 26: Intrapartum Management (GDM) Women should be closely monitored during labour and delivery and maternal blood glucose levels should be kept between 4.0 and 7.0 mmol/L in order to minimize the risk of neonatal hypoglycemia. [Grade D, Consensus] Women should receive adequate glucose during labour in order to meet the high energy requirements [Grade D, Consensus]. 2013 2013

Recommendation 28: Postpartum (GDM) Women with GDM should be encouraged to breastfeed immediately after delivery in order to avoid neonatal hypoglycemia [Grade D, Level 4] and to continue for at least three months postpartum in order to prevent childhood obesity [Grade C, Level 3] and reduce risk of maternal hyperglycemia [Grade C, Level 3]. Women should be screened with a 75g OGTT between 6 weeks and 6 months postpartum to detect prediabetes and diabetes [Grade D, Consensus]. 2013

CDA Clinical Practice Guidelines http://guidelines.diabetes.ca – for professionals 1-800-BANTING (226-8464) http://diabetes.ca – for patients