Gestational Gestational DiabetesDiabetes

Review & Advances in Review & Advances in TreatmentTreatment

Virginia Underwood, Capt, Virginia Underwood, Capt, USAF, MCUSAF, MC

Family Practice ResidentFamily Practice Resident

David Grant Medical CenterDavid Grant Medical Center

OverviewOverview

DefinitionDefinition ScreeningScreening Conventional TreatmentsConventional Treatments New TreatmentsNew Treatments GoalsGoals Postpartum ScreeningPostpartum Screening

QuestionsQuestions

Does screening for and treating GDM Does screening for and treating GDM affect infant or maternal morbidity or affect infant or maternal morbidity or mortality? mortality?

Does antepartum fetal testing prevent Does antepartum fetal testing prevent stillbirth or infant morbidity?stillbirth or infant morbidity?

Does postpartum glucose tolerance Does postpartum glucose tolerance testing have an appreciable long term testing have an appreciable long term impact on women with a history of impact on women with a history of GDM?GDM?

EpidemiologyEpidemiology 3-7% of pregnant women in the U.S.3-7% of pregnant women in the U.S. Increasing prevalenceIncreasing prevalence Risk factors:Risk factors:

>25 yrs>25 yrs Hispanic, Native American, South or East Hispanic, Native American, South or East

Asian, Pacific Islands, African AmericanAsian, Pacific Islands, African American BMI >25BMI >25 Previous history glucose intolerancePrevious history glucose intolerance History obstetric outcomes associated with History obstetric outcomes associated with

GDMGDM History diabetes in a first degree relativeHistory diabetes in a first degree relative

Question #1Question #1

Does screening for and Does screening for and treating GDM affect infant or treating GDM affect infant or

maternal morbidity or maternal morbidity or mortality?mortality?

GDM CriteriaGDM CriteriaNational National Diabetes Diabetes

Data Group*Data Group*

American American Diabetes Diabetes

Association*Association*

World World health health

OrganizatioOrganization n †

Carpenter Carpenter and and

Coustan*Coustan*

FastingFasting 105105 9595 ≥ ≥ 126126 9595

1 hour1 hour 190190 180180 -- 180180

2 hours2 hours 165165 155155 ≥ ≥ 140140 155155

3 hours3 hours 145145 140140 -- 140140

*2 or more criteria met = positive diagnosis (cutoff points in mg/dl)

† 1 or more criteria met = positive diagnosis

Screening & DiagnosisScreening & Diagnosis Screen: 50g glucose 1 hour glucose challengeScreen: 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 testDiagnosis: 100g, 3 hour glucose tolerance test

Positive test = 2 or more thresholds met/exceededPositive test = 2 or more thresholds met/exceeded No smoking priorNo smoking prior Unrestricted diet: at least 150g carbohydrates/d for Unrestricted diet: at least 150g carbohydrates/d for

at least 3 days prior (to avoid spurious high values)at least 3 days prior (to avoid spurious high values) One abnormal value with increased risk for One abnormal value with increased risk for

macrosomic infants & associated morbiditiesmacrosomic infants & associated morbidities

When to Screen?When to Screen?

24-28 weeks gestation24-28 weeks gestation Early screening: Early screening:

marked obesitymarked obesity personal history of GDM (33-50% personal history of GDM (33-50%

likelihood recurrence)likelihood recurrence) glycosuriaglycosuria strong family history of diabetes strong family history of diabetes

Maternal glucose intolerance

Adverse pregnancy outcomes

RecommendationsRecommendations USPSTF: “evidence is insufficient to USPSTF: “evidence is insufficient to

recommend for or against routine recommend for or against routine screeening.” (did find fair - good evidence screeening.” (did find fair - good evidence that screening for GDM and treatment of that screening for GDM and treatment of hyperglycemia could reduce the frequency hyperglycemia could reduce the frequency of fetal macrosomia)of fetal macrosomia)

ADA: officially recommends screening for ADA: officially recommends screening for GDM, but may omit low risk womenGDM, but may omit low risk women

ACOG: universal screening is the most ACOG: universal screening is the most sensitive approach; screening may be sensitive approach; screening may be omitted in low risk women, but universal omitted in low risk women, but universal screening as more practical approachscreening as more practical approach

Treatment QuestionsTreatment Questions

Does GDM pose serious risks to Does GDM pose serious risks to offspring?offspring?

Does treatment reduce those risks?Does treatment reduce those risks? Does treatment reduce other risks Does treatment reduce other risks

associated with GDM associated with GDM (obesity/diabetes in offspring)?(obesity/diabetes in offspring)?

Does reducing glycemia reduce risks? Does reducing glycemia reduce risks? (macrosomia & cesarean delivery)(macrosomia & cesarean delivery)

Potential risksPotential risks MacrosomiaMacrosomia Brachial plexus injuryBrachial plexus injury Fracture with deliveryFracture with delivery Fetal hypoglycemiaFetal hypoglycemia Fetal hyperbilirubinemiaFetal hyperbilirubinemia Fetal hypocalcemiaFetal hypocalcemia Childhood obesityChildhood obesity Neuropsychological Neuropsychological

outcomes outcomes Development of diabetesDevelopment of diabetes

Perinatal mortalityPerinatal mortality 33rdrd/4/4thth degree degree

lacerationslacerations Instrument deliveriesInstrument deliveries Cesarean deliveryCesarean delivery PreeclampsiaPreeclampsia Future diabetes Future diabetes

mellitusmellitus

Confounding FactorsConfounding Factors

Fetal size: maternal glucose levels, Fetal size: maternal glucose levels, maternal BMI, pregnancy weight gain, maternal BMI, pregnancy weight gain, parityparity

Spectrum of sugars of normal to diabetic Spectrum of sugars of normal to diabetic patients (single abnormal value of 3hGTT patients (single abnormal value of 3hGTT large for gestational infants) large for gestational infants)

Normal pregnancies with very narrow Normal pregnancies with very narrow glucose range (euglycemia difficult to glucose range (euglycemia difficult to achieve)achieve)

Alerting physicians to increased riskAlerting physicians to increased risk

Confounding FactorsConfounding Factors

Large number of subjects neededLarge number of subjects needed 450 infants undergoing cesarean 450 infants undergoing cesarean

delivery to prevent one permanent delivery to prevent one permanent brachial plexus injurybrachial plexus injury

Lowered cesarean delivery Lowered cesarean delivery threshold: resulting morbidity and threshold: resulting morbidity and costs outweigh benefits?costs outweigh benefits?

Research-Crowther et al.Research-Crowther et al. Multicenter, 1000 womenMulticenter, 1000 women 75g oral glucose tolerance test between 24-75g oral glucose tolerance test between 24-

32 weeks gestation32 weeks gestation Subjects: below 140 fasting, and between Subjects: below 140 fasting, and between

140-198 at 2 hours after glucose challenge140-198 at 2 hours after glucose challenge Intervention: glucose monitoring, dietary Intervention: glucose monitoring, dietary

counseling/insulin to maintain sugarscounseling/insulin to maintain sugars Goals: premeal/fasting <99 and 2h Goals: premeal/fasting <99 and 2h

postprandial <126postprandial <126 Control: routine care where GDM screening Control: routine care where GDM screening

not standardnot standard

Crowther et al. ResultsCrowther et al. Results

Intervention group with reduced:Intervention group with reduced: Perinatal death (5 v. 0)Perinatal death (5 v. 0) Shoulder dystociaShoulder dystocia Bone fractureBone fracture Nerve palsyNerve palsy Macrosomia (≥4kg: 21% v. 10%)Macrosomia (≥4kg: 21% v. 10%) Postpartum depression (health status)Postpartum depression (health status)

Crowther et al. ResultsCrowther et al. Results

Cesarean delivery rates similar Cesarean delivery rates similar between groupsbetween groups

Control group with reduced:Control group with reduced: Inductions of laborInductions of labor Admissions to neonatal intensive care Admissions to neonatal intensive care

unitunit

Research- Langer et al.Research- Langer et al.

555 gestational diabetics diagnosed after 555 gestational diabetics diagnosed after 37 weeks v. 1110 subjects treated for 37 weeks v. 1110 subjects treated for gestational diabetes mellitus and 1110 gestational diabetes mellitus and 1110 nondiabetic subjectsnondiabetic subjects

Adverse outcomes: 59% for untreated, Adverse outcomes: 59% for untreated, 18% for treated, and 11% for nondiabetic 18% for treated, and 11% for nondiabetic

2- to 4-fold increase in metabolic 2- to 4-fold increase in metabolic complications and macrosomia/LGA in the complications and macrosomia/LGA in the untreated group & no difference between untreated group & no difference between nondiabetic and treated nondiabetic and treated

Increasing evidence that identifying women with GDM is important because appropriate therapy can decrease fetal and maternal morbidity, particularly macrosomia

Upcoming studiesUpcoming studies

Maternal-Fetal Medicine Network Maternal-Fetal Medicine Network multicenter trial of treatment of mild multicenter trial of treatment of mild GDM GDM

HAPO- Hyperglycemia and Adverse HAPO- Hyperglycemia and Adverse Pregnancy Outcome studyPregnancy Outcome study

Treatment Treatment RecommendationsRecommendations

American Diabetes Association:American Diabetes Association: Nutrition counselingNutrition counseling Carbohydrates: 35-40% of daily caloriesCarbohydrates: 35-40% of daily calories (caution for ketosis (caution for ketosis IQ/psychomotor IQ/psychomotor

development)development) BMI >30kg/mBMI >30kg/m22: lowering daily calories : lowering daily calories

by 30% (goal 25kcal/kg actual weight by 30% (goal 25kcal/kg actual weight per day)per day)

Treatment Treatment RecommendationsRecommendations

Trial 2 weeks (if initial fasting <95)Trial 2 weeks (if initial fasting <95) Initial fasting >95 unlikely to be Initial fasting >95 unlikely to be

controlledcontrolled Exercise:Exercise:

Weight reduction and improve glucose Weight reduction and improve glucose metabolismmetabolism

Effects on fasting glucose/tolerance & Effects on fasting glucose/tolerance & macrosomiamacrosomia

Glucose goalsGlucose goals

Fasting <90-105Fasting <90-105 1h <130-1401h <130-140 2h <1202h <120 38% with initial fasting glucose <95 38% with initial fasting glucose <95

required insulin for optimal controlrequired insulin for optimal control 70% with initial fasting glucose 95-70% with initial fasting glucose 95-

104104

MonitoringMonitoring

Frequency not establishedFrequency not established Reduces?:Reduces?:

Perinatal mortality/hypoglycemia/shoulder Perinatal mortality/hypoglycemia/shoulder dystociadystocia

MacrosomiaMacrosomia Timing: Timing:

Fasting v. postprandial (nadirs v. glucose Fasting v. postprandial (nadirs v. glucose excesses)excesses)

1h v. 2h postprandial1h v. 2h postprandial Severe/preexistent v. mild Severe/preexistent v. mild frequency frequency

InsulinInsulin

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 AM 2/3 2/3 NPH, 1/3 Reg 2/3 NPH, 1/3 Reg PM 1/3 PM 1/3 1/2 NPH, 1/2 Reg 1/2 NPH, 1/2 Reg *once daily ultralente with very *once daily ultralente with very

short acting lispro insulinshort acting lispro insulin

Oral hypoglycemicsOral hypoglycemics Previous concerns: (Diabinese & Orinase)Previous concerns: (Diabinese & Orinase)

11stst generation sulfonylureas generation sulfonylureas Potential teratogenicityPotential teratogenicity Transport across placenta (hypoglycemia)Transport across placenta (hypoglycemia)

Glyburide: Glyburide: 22ndnd generation sulfonylurea generation sulfonylurea Does not enter fetal circulation (in vitro/vivo)Does not enter fetal circulation (in vitro/vivo) Comparable maternal/neonatal outcomesComparable maternal/neonatal outcomes Less maternal hypoglycemiaLess maternal hypoglycemia

Metformin (PCOS, gestational diabetes, Metformin (PCOS, gestational diabetes, first trimester miscarriage rates)first trimester miscarriage rates)

GlyburideGlyburide Start: 2.5 mg once or twice dailyStart: 2.5 mg once or twice daily Increase: by 2.5 mg to 5 mg at weekly intervals Increase: by 2.5 mg to 5 mg at weekly intervals

as needed until maximum dose of 20 mg dailyas needed until maximum dose of 20 mg daily Peak plasma level of glyburide: 2–4 hours after Peak plasma level of glyburide: 2–4 hours after

administrationadministration Timing administration with hyperglycemia Timing administration with hyperglycemia

(daytime/fasting)(daytime/fasting) Fasting hyperglycemia on diet: higher dose/bid Fasting hyperglycemia on diet: higher dose/bid 5-20% conversion to insulin5-20% conversion to insulin*fasting plasma glucose <110 & no sulfa allergy *fasting plasma glucose <110 & no sulfa allergy

Question #2Question #2

Does antepartum fetal testing Does antepartum fetal testing prevent stillbirth or infant prevent stillbirth or infant

morbidity?morbidity?

Antepartum Fetal Antepartum Fetal TestingTesting

Purpose: identify patients at risk for stillbirthPurpose: identify patients at risk for stillbirth Stillbirth rare occurrenceStillbirth rare occurrence Practice patterns: starting at 32-40 weeks Practice patterns: starting at 32-40 weeks

gestationgestation ACOG:ACOG:

Glucose not well controlledGlucose not well controlled Requiring insulinRequiring insulin Concomitant hypertensionConcomitant hypertension

NST/AFI, full biophysical profileNST/AFI, full biophysical profile No evidence regarding fetal ultrasound No evidence regarding fetal ultrasound

macrosomiamacrosomia

Insufficient evidence regarding impact of antenatal fetal testing on stillbirth rate, and neonatal morbidity

Question #3Question #3

Does postpartum glucose Does postpartum glucose tolerance testing have an tolerance testing have an

appreciable long term impact on appreciable long term impact on women with a history of GDM?women with a history of GDM?

Postpartum screeningPostpartum screening

50% women with GDM developing diabetes 50% women with GDM developing diabetes mellitus in a 28yr study (v. 7% of controls)mellitus in a 28yr study (v. 7% of controls)

Possible preexistent diabetesPossible preexistent diabetes 6-8wks postpartum6-8wks 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 counselingDiet, exercise, weight reduction counseling

No long-term follow-up studies that verify the benefit of postpartum diagnostic testing

SummarySummary

DefinitionDefinition ScreeningScreening Conventional TreatmentsConventional Treatments New TreatmentsNew Treatments GoalsGoals Postpartum ScreeningPostpartum Screening

BibliographyBibliography 1. Langer O, Conway DL, Berkus MD, Xenakis EM-J, Gonzales O. A 1. Langer O, Conway DL, Berkus MD, Xenakis EM-J, Gonzales O. A

comparison of glyburide and insulin in women with gestational diabetes comparison of glyburide and insulin in women with gestational diabetes mellitus. NEJM 2000;343:1134–8. mellitus. NEJM 2000;343:1134–8.

2. Saade, George. Gestational Diabetes Mellitus: A Pill or a Shot?. 2. Saade, George. Gestational Diabetes Mellitus: A Pill or a Shot?. Obstetrics & Gynecology 2005; 105:456-7.Obstetrics & Gynecology 2005; 105:456-7.

3. Turok d, Ratcliffe S, Baxley E. Management of gestational diabetes 3. Turok d, Ratcliffe S, Baxley E. Management of gestational diabetes mellitus. American Family Physician 2003; 68: 1767-1772.mellitus. American Family Physician 2003; 68: 1767-1772.

4. Greene M, Solomom C. Gestational diabetes mellitus – time to treat. 4. Greene M, Solomom C. Gestational diabetes mellitus – time to treat. NEJM 2005; 352: 2544-2546.NEJM 2005; 352: 2544-2546.

5. Crowther C, Hiller J, Moss J, McPhee A, Jeffries W, Robinson J. Effect 5. Crowther C, Hiller J, Moss J, McPhee A, Jeffries W, Robinson J. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. of treatment of gestational diabetes mellitus on pregnancy outcomes. NEJM 2005; 352: 2477-2486.NEJM 2005; 352: 2477-2486.

6. Kjos S, Buchanan T. Gestational Diabetes Mellitus – current concepts. 6. Kjos S, Buchanan T. Gestational Diabetes Mellitus – current concepts. NEJM 1999; 341: 1749-1756.NEJM 1999; 341: 1749-1756.

7. Naylor C, Phil D, Sermer M, Chen E, Farine D. Selective screening for 7. Naylor C, Phil D, Sermer M, Chen E, Farine D. Selective screening for gestational diabetes mellitus. NEJM 1997; 337: 1591-1597.gestational diabetes mellitus. NEJM 1997; 337: 1591-1597.

8. Caughey A. Management of Diabetes in Pregnancy. Johns Hopkins 8. Caughey A. Management of Diabetes in Pregnancy. Johns Hopkins Advanced Studies in Medicine 2006: 309-318.Advanced Studies in Medicine 2006: 309-318.

9. Gestational Diabetes. ACOG Practice Bulletin. 2006: 518-531.9. Gestational Diabetes. ACOG Practice Bulletin. 2006: 518-531.

Questions?Questions?

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