1. Gestational Diabetes Review & Advances in Treatment Virginia Underwood, Capt, USAF, MC Family Practice Resident David Grant Medical Center

2. Overview Definition Definition Screening Screening Conventional Treatments Conventional Treatments New Treatments New Treatments Goals Goals Postpartum Screening Postpartum Screening

3. Questions  Does screening for and treating GDM affect infant or maternal morbidity or mortality? Does antepartum fetal testing prevent stillbirth or infant morbidity? Does antepartum fetal testing prevent stillbirth or infant morbidity? Does postpartum glucose tolerance testing have an appreciable long term impact on women with a history of GDM? Does postpartum glucose tolerance testing have an appreciable long term impact on women with a history of GDM?

4. Epidemiology 3-7% of pregnant women in the U.S. 3-7% of pregnant women in the U.S. Increasing prevalence Increasing prevalence Risk factors: Risk factors: >25 yrs >25 yrs Hispanic, Native American, South or East Asian, Pacific Islands, African American Hispanic, Native American, South or East Asian, Pacific Islands, African American BMI >25 BMI >25 Previous history glucose intolerance Previous history glucose intolerance History obstetric outcomes associated with GDM History obstetric outcomes associated with GDM History diabetes in a first degree relative History diabetes in a first degree relative

5. Question #1 Does screening for and treating GDM affect infant or maternal morbidity or mortality?

6. GDM Criteria National Diabetes Data Group* American Diabetes Association* World health Organization World health Organization † Carpenter and Coustan* Fasting10595 ≥ 126 95 1 hour 190180-180 2 hours 165155 ≥ 140 155 3 hours 145140-140 *2 or more criteria met = positive diagnosis (cutoff points in mg/dl) † 1 or more criteria met = positive diagnosis

7. Screening & Diagnosis Screen: 50g glucose 1 hour glucose challenge Screen: 50g glucose 1 hour glucose challenge non-fasting state (higher or similar values with fast) non-fasting state (higher or similar values with fast) Diagnosis: 100g, 3 hour glucose tolerance test Diagnosis: 100g, 3 hour glucose tolerance test Positive test = 2 or more thresholds met/exceeded Positive test = 2 or more thresholds met/exceeded No smoking prior No smoking prior Unrestricted diet: at least 150g carbohydrates/d for at least 3 days prior (to avoid spurious high values) Unrestricted diet: at least 150g carbohydrates/d for at least 3 days prior (to avoid spurious high values) One abnormal value with increased risk for macrosomic infants & associated morbidities One abnormal value with increased risk for macrosomic infants & associated morbidities

8. When to Screen? 24-28 weeks gestation 24-28 weeks gestation Early screening: Early screening: marked obesity marked obesity personal history of GDM (33-50% likelihood recurrence) personal history of GDM (33-50% likelihood recurrence) glycosuria glycosuria strong family history of diabetes strong family history of diabetes

9. Maternal glucose intolerance Adverse pregnancy outcomes

10. Recommendations USPSTF: “evidence is insufficient to recommend for or against routine screeening.” (did find fair - good evidence that screening for GDM and treatment of hyperglycemia could reduce the frequency of fetal macrosomia) USPSTF: “evidence is insufficient to recommend for or against routine screeening.” (did find fair - good evidence that screening for GDM and treatment of hyperglycemia could reduce the frequency of fetal macrosomia) ADA: officially recommends screening for GDM, but may omit low risk women ADA: officially recommends screening for GDM, but may omit low risk women ACOG: universal screening is the most sensitive approach; screening may be omitted in low risk women, but universal screening as more practical approach ACOG: universal screening is the most sensitive approach; screening may be omitted in low risk women, but universal screening as more practical approach

11. Treatment Questions Does GDM pose serious risks to offspring? Does GDM pose serious risks to offspring? Does treatment reduce those risks? Does treatment reduce those risks? Does treatment reduce other risks associated with GDM (obesity/diabetes in offspring)? Does treatment reduce other risks associated with GDM (obesity/diabetes in offspring)? Does reducing glycemia reduce risks? (macrosomia & cesarean delivery) Does reducing glycemia reduce risks? (macrosomia & cesarean delivery)

12. Potential risks Macrosomia Macrosomia Brachial plexus injury Brachial plexus injury Fracture with delivery Fracture with delivery Fetal hypoglycemia Fetal hypoglycemia Fetal hyperbilirubinemia Fetal hyperbilirubinemia Fetal hypocalcemia Fetal hypocalcemia Childhood obesity Childhood obesity Neuropsychological outcomes Neuropsychological outcomes Development of diabetes Development of diabetes Perinatal mortality 3 rd /4 th degree lacerations Instrument deliveries Cesarean delivery Preeclampsia Future diabetes mellitus

13. Confounding Factors Fetal size: maternal glucose levels, maternal BMI, pregnancy weight gain, parity Fetal size: maternal glucose levels, maternal BMI, pregnancy weight gain, parity Spectrum of sugars of normal to diabetic patients (single abnormal value of 3hGTT  large for gestational infants) Spectrum of sugars of normal to diabetic patients (single abnormal value of 3hGTT  large for gestational infants) Normal pregnancies with very narrow glucose range (euglycemia difficult to achieve) Normal pregnancies with very narrow glucose range (euglycemia difficult to achieve) Alerting physicians to increased risk Alerting physicians to increased risk

14. Confounding Factors Large number of subjects needed Large number of subjects needed 450 infants undergoing cesarean delivery to prevent one permanent brachial plexus injury 450 infants undergoing cesarean delivery to prevent one permanent brachial plexus injury Lowered cesarean delivery threshold: resulting morbidity and costs outweigh benefits? Lowered cesarean delivery threshold: resulting morbidity and costs outweigh benefits?

15. Research-Crowther et al. Multicenter, 1000 women Multicenter, 1000 women 75g oral glucose tolerance test between 24-32 weeks gestation 75g oral glucose tolerance test between 24-32 weeks gestation Subjects: below 140 fasting, and between 140-198 at 2 hours after glucose challenge Subjects: below 140 fasting, and between 140-198 at 2 hours after glucose challenge Intervention: glucose monitoring, dietary counseling/insulin to maintain sugars Intervention: glucose monitoring, dietary counseling/insulin to maintain sugars Goals: premeal/fasting <99 and 2h postprandial <126 Goals: premeal/fasting <99 and 2h postprandial <126 Control: routine care where GDM screening not standard Control: routine care where GDM screening not standard

16. Crowther et al. Results Intervention group with reduced: Intervention group with reduced: Perinatal death (5 v. 0) Perinatal death (5 v. 0) Shoulder dystocia Shoulder dystocia Bone fracture Bone fracture Nerve palsy Nerve palsy Macrosomia (≥4kg: 21% v. 10%) Macrosomia (≥4kg: 21% v. 10%) Postpartum depression (health status) Postpartum depression (health status)

17. Crowther et al. Results Cesarean delivery rates similar between groups Cesarean delivery rates similar between groups Control group with reduced: Control group with reduced: Inductions of labor Inductions of labor Admissions to neonatal intensive care unit Admissions to neonatal intensive care unit

18. Research- Langer et al. 555 gestational diabetics diagnosed after 37 weeks v. 1110 subjects treated for gestational diabetes mellitus and 1110 nondiabetic subjects 555 gestational diabetics diagnosed after 37 weeks v. 1110 subjects treated for gestational diabetes mellitus and 1110 nondiabetic subjects Adverse outcomes: 59% for untreated, 18% for treated, and 11% for nondiabetic Adverse outcomes: 59% for untreated, 18% for treated, and 11% for nondiabetic 2- to 4-fold increase in metabolic complications and macrosomia/LGA in the untreated group & no difference between nondiabetic and treated 2- to 4-fold increase in metabolic complications and macrosomia/LGA in the untreated group & no difference between nondiabetic and treated Increasing evidence that identifying women with GDM is important because appropriate therapy can decrease fetal and maternal morbidity, particularly macrosomia

19. Upcoming studies Maternal-Fetal Medicine Network multicenter trial of treatment of mild GDM Maternal-Fetal Medicine Network multicenter trial of treatment of mild GDM HAPO- Hyperglycemia and Adverse Pregnancy Outcome study HAPO- Hyperglycemia and Adverse Pregnancy Outcome study

20. Treatment Recommendations American Diabetes Association: American Diabetes Association: Nutrition counseling Nutrition counseling Carbohydrates: 35-40% of daily calories Carbohydrates: 35-40% of daily calories (caution for ketosis  IQ/psychomotor development) (caution for ketosis  IQ/psychomotor development) BMI >30kg/m 2 : lowering daily calories by 30% (goal 25kcal/kg actual weight per day) BMI >30kg/m 2 : lowering daily calories by 30% (goal 25kcal/kg actual weight per day)

21. Treatment Recommendations Trial 2 weeks (if initial fasting <95) Trial 2 weeks (if initial fasting <95) Initial fasting >95 unlikely to be controlled Initial fasting >95 unlikely to be controlled Exercise: Exercise: Weight reduction and improve glucose metabolism Weight reduction and improve glucose metabolism Effects on fasting glucose/tolerance & macrosomia Effects on fasting glucose/tolerance & macrosomia

22. Glucose goals Fasting <90-105 Fasting <90-105 1h <130-140 1h <130-140 2h <120 2h <120 38% with initial fasting glucose <95 required insulin for optimal control 38% with initial fasting glucose <95 required insulin for optimal control 70% with initial fasting glucose 95-104 70% with initial fasting glucose 95-104

23. Monitoring Frequency not established Frequency not established Reduces?: Reduces?: Perinatal mortality/hypoglycemia/shoulder dystocia Perinatal mortality/hypoglycemia/shoulder dystocia Macrosomia Macrosomia Timing: Timing: Fasting v. postprandial (nadirs v. glucose excesses) Fasting v. postprandial (nadirs v. glucose excesses) 1h v. 2h postprandial 1h v. 2h postprandial Severe/preexistent v. mild  frequency Severe/preexistent v. mild  frequency

24. Insulin When: When: > 95 or 105 fasting > 95 or 105 fasting >120 2 h postprandial >120 2 h postprandial Initial dose: 0.7U/kg/day Initial dose: 0.7U/kg/day AM 2/3  2/3 NPH, 1/3 Reg AM 2/3  2/3 NPH, 1/3 Reg PM 1/3  1/2 NPH, 1/2 Reg PM 1/3  1/2 NPH, 1/2 Reg *once daily ultralente with very short acting lispro insulin *once daily ultralente with very short acting lispro insulin

25. Oral hypoglycemics Previous concerns: (Diabinese & Orinase) Previous concerns: (Diabinese & Orinase) 1 st generation sulfonylureas 1 st generation sulfonylureas Potential teratogenicity Potential teratogenicity Transport across placenta (hypoglycemia) Transport across placenta (hypoglycemia) Glyburide: Glyburide: 2 nd generation sulfonylurea 2 nd generation sulfonylurea Does not enter fetal circulation (in vitro/vivo) Does not enter fetal circulation (in vitro/vivo) Comparable maternal/neonatal outcomes Comparable maternal/neonatal outcomes Less maternal hypoglycemia Less maternal hypoglycemia Metformin (PCOS, gestational diabetes, first trimester miscarriage rates) Metformin (PCOS, gestational diabetes, first trimester miscarriage rates)

26. Glyburide Start: 2.5 mg once or twice daily Start: 2.5 mg once or twice daily Increase: by 2.5 mg to 5 mg at weekly intervals as needed until maximum dose of 20 mg daily Increase: by 2.5 mg to 5 mg at weekly intervals as needed until maximum dose of 20 mg daily Peak plasma level of glyburide: 2–4 hours after administration Peak plasma level of glyburide: 2–4 hours after administration Timing administration with hyperglycemia (daytime/fasting) Timing administration with hyperglycemia (daytime/fasting) Fasting hyperglycemia on diet: higher dose/bid Fasting hyperglycemia on diet: higher dose/bid 5-20% conversion to insulin 5-20% conversion to insulin *fasting plasma glucose <110 & no sulfa allergy

27. Question #2 Does antepartum fetal testing prevent stillbirth or infant morbidity?

28. Antepartum Fetal Testing Purpose: identify patients at risk for stillbirth Purpose: identify patients at risk for stillbirth Stillbirth rare occurrence Stillbirth rare occurrence Practice patterns: starting at 32-40 weeks gestation Practice patterns: starting at 32-40 weeks gestation ACOG: ACOG: Glucose not well controlled Glucose not well controlled Requiring insulin Requiring insulin Concomitant hypertension Concomitant hypertension NST/AFI, full biophysical profile NST/AFI, full biophysical profile No evidence regarding fetal ultrasound  macrosomia No evidence regarding fetal ultrasound  macrosomia Insufficient evidence regarding impact of antenatal fetal testing on stillbirth rate, and neonatal morbidity

29. Question #3 Does postpartum glucose tolerance testing have an appreciable long term impact on women with a history of GDM?

30. Postpartum screening 50% women with GDM developing diabetes mellitus in a 28yr study (v. 7% of controls) 50% women with GDM developing diabetes mellitus in a 28yr study (v. 7% of controls) Possible preexistent diabetes Possible preexistent diabetes 6-8wks postpartum 6-8wks postpartum 2h OGTT (75g) 2h OGTT (75g) Impaired: 140-199 (100-125) Impaired: 140-199 (100-125) DM: ≥ 200 (≥ 126) DM: ≥ 200 (≥ 126) Diet, exercise, weight reduction counseling Diet, exercise, weight reduction counseling No long-term follow-up studies that verify the benefit of postpartum diagnostic testing

31. Summary Definition Definition Screening Screening Conventional Treatments Conventional Treatments New Treatments New Treatments Goals Goals Postpartum Screening Postpartum Screening

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33. Questions? Sugar-free chocolate mousse cake