gestational diabetes: define, consequences & management

Gestational Diabetes Gestational Diabetes UpdateUpdate

What is Gestational Diabetes?What is Gestational Diabetes?

• Impaired glucose intolerance due to Impaired glucose intolerance due to insulin resistance coupled with beta-cell insulin resistance coupled with beta-cell insufficiencyinsufficiency

• Associated with:Associated with: BMIBMI maternal agematernal age– Known glucose intoleranceKnown glucose intolerance– Type II DM in 1Type II DM in 1stst degree relative(s) degree relative(s)– Certain racial backgroundsCertain racial backgrounds


• A multigenic condition that may involve A multigenic condition that may involve abnormalities in genes of:abnormalities in genes of:– Insulin secretionInsulin secretion– Insulin or insulin signalingInsulin or insulin signaling– Lipid and glucose metabolismLipid and glucose metabolism– Other pathwaysOther pathways


• Similar in nature to type II DMSimilar in nature to type II DM– ““GDM is a window to reveal a predisposition GDM is a window to reveal a predisposition

to type II DM”to type II DM”– 17% to 63% of women with GDM develop17% to 63% of women with GDM develop

type II DM over 5-16 yearstype II DM over 5-16 years

Gestational Diabetes and Gestational Diabetes and Perinatal MorbidityPerinatal Morbidity

• Worsening glucose tolerance associated Worsening glucose tolerance associated with increasing rates of:with increasing rates of:– PreeclampsiaPreeclampsia– Macrosomia >4,000 gMacrosomia >4,000 g– Birth traumaBirth trauma– HyperbilirubinemiaHyperbilirubinemia– Neonatal hypoglycemiaNeonatal hypoglycemia– Cesarean deliveryCesarean delivery

Metabolic Syndrome in Children of Metabolic Syndrome in Children of Women with GDMWomen with GDM

• Longitudinal cohort study of children at Longitudinal cohort study of children at ages 6, 7, 9 and 11 yearsages 6, 7, 9 and 11 years– LGA offspring of control mothersLGA offspring of control mothers– LGA offspring of mothers with GDMLGA offspring of mothers with GDM– AGA offspring of control mothersAGA offspring of control mothers– AGA offspring of mothers with GDMAGA offspring of mothers with GDM

• Obtained biometric and anthropomorphic Obtained biometric and anthropomorphic measurements, postprandial glucose and measurements, postprandial glucose and insulin levels, triglyceride and HDL insulin levels, triglyceride and HDL cholesterolcholesterol

Boney et al, Pediatr 2005; 115: 290Boney et al, Pediatr 2005; 115: 290

Metabolic Syndrome in Children of Metabolic Syndrome in Children of Women with GDMWomen with GDM

Boney et al, Pediatr 2005; 115: 290Boney et al, Pediatr 2005; 115: 290

1010

2020

3030

4040

5050

6060

Pre

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%)

Pre

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nc

e o

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%)

LGA/GDMLGA/GDM AGA/GDMAGA/GDM LGA/ConLGA/Con AGA/ConAGA/Con

Maternal FuelsMaternal FuelsIn GDMIn GDM

PubertalPubertalIGTIGT

Altered FetalAltered FetalIslet Function & Islet Function &

? Epigenetic Modification? Epigenetic Modification

Impaired AdultImpaired AdultIslet FunctionIslet Function

ChildhoodChildhoodObesityObesity

GDMGDM

Gestational Diabetes and Gestational Diabetes and MorbidityMorbidity

• Worsening glucose intolerance associated with Worsening glucose intolerance associated with increasing rates of:increasing rates of:– PreeclampsiaPreeclampsia– Macrosomia >4,000 gMacrosomia >4,000 g– Birth traumaBirth trauma– HyperbilirubinemiaHyperbilirubinemia– Neonatal hypoglycemiaNeonatal hypoglycemia– Cesarean deliveryCesarean delivery– DM and metabolic syndrome in offspringDM and metabolic syndrome in offspring

• But… there have been doubts about the But… there have been doubts about the effectiveness of diagnosis and treatment!effectiveness of diagnosis and treatment!

Gestational DiabetesGestational DiabetesEffect of TreatmentEffect of Treatment

• Randomized clinical trial in 18 Randomized clinical trial in 18 centers (ACHOIS)centers (ACHOIS)

• Women with GDM, 24-34 weeks’Women with GDM, 24-34 weeks’– Singletons or twinsSingletons or twins– Risk factor(s) for GDM, orRisk factor(s) for GDM, or– Positive 50 g OGCT (Positive 50 g OGCT ( 140 mg/dL), and 140 mg/dL), and– 75 g GTT with FBG 75 g GTT with FBG 140 mg/dL and 2 140 mg/dL and 2

hour BG hour BG 198 mg/dL 198 mg/dL

Crowther et al, N Engl J Med 2005;352:2477


• Intervention groupIntervention group– Dietary counselingDietary counseling– Self monitoring of BGsSelf monitoring of BGs

• 4 times daily until BGs in acceptable range 4 times daily until BGs in acceptable range for 2 weeksfor 2 weeks

• Insulin treatment as necessaryInsulin treatment as necessary

• Routine care groupRoutine care group– OGCT and GTT results not made OGCT and GTT results not made

availableavailable



• Outcome variablesOutcome variables– Infant: Primary – a compositeInfant: Primary – a composite

• One or more “serious” perinatal events One or more “serious” perinatal events – Perinatal death, shoulder dystocia, bone fracture, Perinatal death, shoulder dystocia, bone fracture,

nerve palsynerve palsy

• Admission to NICUAdmission to NICU• Jaundice requiring phototherapyJaundice requiring phototherapy

– MaternalMaternal• Need for induction and cesareanNeed for induction and cesarean• Maternal health status (physical and Maternal health status (physical and

psychological)psychological)



OutcomeOutcome

BirthweightBirthweight

LGALGA

MacrosomiaMacrosomia

TreatedTreated(N=506)(N=506)

Routine CareRoutine Care(N=524)(N=524) P valueP value

<0.001<0.001

<0.001<0.0013,335 3,335 ± ± 551551

68 (13%)68 (13%)

49 (10%)49 (10%)

3,482 ± 6603,482 ± 660

115 (22%)115 (22%)

110 (21%)110 (21%) <0.001<0.001

Crowther et al, N Engl J Med 2005;352:2477Crowther et al, N Engl J Med 2005;352:2477


OutcomeOutcome

DeathDeath

ShoulderShoulder dystociadystocia

Bone fxBone fx


Routine CareRoutine Care(N= 524)(N= 524)

AdjAdjP valueP value

0.070.07

0.080.08

0.380.38

Crowther et al, N Engl J Med 2005;352:2477Crowther et al, N Engl J Med 2005;352:2477

Nerve palsyNerve palsy 0.110.11

CompositeComposite

00

7 (1%)7 (1%)

00

00

7 (1%)7 (1%)

5 (1%)5 (1%)

16 (3%)16 (3%)

1 (<1%)1 (<1%)

3 (1%)3 (1%)

23 (4%)23 (4%) 0.010.01

MFMU Network Randomized MFMU Network Randomized Treatment Trial of Mild GDM Treatment Trial of Mild GDM

• Multicenter randomized trial of Multicenter randomized trial of women withwomen with– Abnormal 50 g OGCAbnormal 50 g OGC– 3-hr GTT 3-hr GTT GDM, but GDM, but – Normal FBS on 3-hr GTTNormal FBS on 3-hr GTT

• Subjects randomized toSubjects randomized to– Usual care (GTT results not available)Usual care (GTT results not available)– Dietary intervention, SBGM, and Dietary intervention, SBGM, and

insulin if requiredinsulin if required

Landon et al, N Engl J Med 2009; 361:1339Landon et al, N Engl J Med 2009; 361:1339


• Primary outcome – compositePrimary outcome – composite– Perinatal deathPerinatal death– HyperbilirubinemiaHyperbilirubinemia– HypoglycemiaHypoglycemia– HyperinsulinemiaHyperinsulinemia– Birth traumaBirth trauma

• Multiple secondary outcomesMultiple secondary outcomes– LGALGA– SDSD– Neonatal adiposityNeonatal adiposity– CSCS– Preeclampsia/GHTNPreeclampsia/GHTN

Landon et al, Am J Obstet Gynecol 2009; 199:S2Landon et al, Am J Obstet Gynecol 2009; 199:S2


OutcomeOutcome

BirthweightBirthweight

LGALGA



Routine CareRoutine Care(N=473)(N=473) P valueP value

<0.001<0.001

<0.001<0.0013,302 3,302 ± ± 502502

34 (7.1%)34 (7.1%)

28 (5.9%)28 (5.9%)

3,408 ± 5893,408 ± 589

66 (14.5%)66 (14.5%)

65 (14.3%)65 (14.3%) <0.001<0.001


Fat Mass (g)Fat Mass (g) 427 427 ± 198± 198 464 464 ±± 222 222

<0.003<0.003


OutcomeOutcomeTreatedTreated(N=485)(N=485)

Routine CareRoutine Care(N= 473)(N= 473) P valueP value

DeathDeath 00 00Hyperbili-Hyperbili- rubinemiarubinemia

0.120.1243 (10%)43 (10%) 54 (13%)54 (13%)

HypoglycemiaHypoglycemia 0.750.7562 (16%)62 (16%) 55 (15%)55 (15%)Elevated cordElevated cord C-peptideC-peptide

0.070.0775 (18%)75 (18%) 92 (23%)92 (23%)

CompositeComposite 149 (32%)149 (32%) 163 (37%)163 (37%) 0.140.143 (<1%)3 (<1%) 6 (1%)6 (1%)Birth traumaBirth trauma 0.330.33



OutcomeOutcomeTreatedTreated(N=485)(N=485)

Routine CareRoutine Care(N= 473)(N= 473) P valueP value

CesareanCesarean 0.020.02128 (27%)128 (27%) 154 (34%)154 (34%)

ShoulderShoulder dystocia dystocia

0.020.027 (1.5%)7 (1.5%) 18 (4%)18 (4%)


GHTN - PEGHTN - PE 41 (9%)41 (9%) 62 (14%)62 (14%) 0.010.01


Landon et al, Am J Obstet Gynecol 2009; 199:S2Landon et al, Am J Obstet Gynecol 2009; 199:S2

OutcomeOutcome Number Needed to TreatNumber Needed to Treat


Cesarean DeliveryCesarean Delivery

Shoulder DystociaShoulder Dystocia

PE+GHTNPE+GHTN

1212

1414

4040

2020

The Treatment of GDMThe Treatment of GDM

• The best studies of GDM treatment The best studies of GDM treatment included self blood glucose included self blood glucose monitoring; “ you manage what you monitoring; “ you manage what you measure.”measure.”

Daily Home Blood Glucose Daily Home Blood Glucose Monitoring in Diet-controlled GDMMonitoring in Diet-controlled GDM

• Retrospective cohort study of diet Retrospective cohort study of diet controlled GDM patients at a single controlled GDM patients at a single institution (institution (UT Southwestern)UT Southwestern)– 675 women tested weekly in the office (1991-675 women tested weekly in the office (1991-

1997)1997)– 315 women tested 4 times daily at home with 315 women tested 4 times daily at home with

a glucose monitora glucose monitor– Women with FBS >105 given insulin and Women with FBS >105 given insulin and

excluded from studyexcluded from study

• Primary outcomes – birthweight Primary outcomes – birthweight >4000 g and LGA>4000 g and LGA

Hawkins et al, Obstet Gynecol 2009; 1307Hawkins et al, Obstet Gynecol 2009; 1307

OutcomeOutcome

BW>4000 gBW>4000 g

LGALGA

CesareanCesarean

WeeklyWeekly(N=675)(N=675)

Daily x 4Daily x 4(N=315)(N=315) P valueP value

Erb’s palsyErb’s palsy

199 (30%)199 (30%)

232 (34%)232 (34%)

222 (33%)222 (33%)

3 (0.4%)3 (0.4%)

69 (22%)69 (22%)

73 (23%)73 (23%)

116 (37%)116 (37%)

2 (0.6%)2 (0.6%)

0.0130.013

<0.001<0.001

0.220.22

0.690.69

Daily Home Blood Glucose Daily Home Blood Glucose Monitoring in Diet-controlled GDMMonitoring in Diet-controlled GDM

Hawkins et al, Obstet Gynecol 2009; 1307Hawkins et al, Obstet Gynecol 2009; 1307

Gestational DiabetesGestational Diabetes

• GDM diagnosis and treatment has a GDM diagnosis and treatment has a beneficial effect on beneficial effect on

• LGA/MacrosomiaLGA/Macrosomia• Cesarean deliveryCesarean delivery• Shoulder dystociaShoulder dystocia• PE+GHTNPE+GHTN

Screening and Diagnosis of Screening and Diagnosis of GDM in the U.S.GDM in the U.S.

• Use the 50 g oral glucose challenge Use the 50 g oral glucose challenge with BS taken 1 hour laterwith BS taken 1 hour later– Screen all pregnant women @ 24-28 Screen all pregnant women @ 24-28

weeksweeks• Test earlier in selected patientsTest earlier in selected patients

– Threshold of 140 mg/dL or greaterThreshold of 140 mg/dL or greater


• Use the 100 g oral glucose tolerance Use the 100 g oral glucose tolerance test for the diagnosis of GDMtest for the diagnosis of GDM– No need to test women with 50 g OCT No need to test women with 50 g OCT

results of 200 mg/dL or greaterresults of 200 mg/dL or greater– Experts recommend against using a Experts recommend against using a

capillary glucose metercapillary glucose meter– Use either NDDG or Carpenter & Use either NDDG or Carpenter &

Coustan modification for diagnosisCoustan modification for diagnosis

Diagnosis of Gestational Diagnosis of Gestational Diabetes using 100 g OGTTDiabetes using 100 g OGTT

Time of BSTime of BS

FastingFasting

1 h1 h

2 h2 h

NDDGNDDG(mg/dL)(mg/dL)

Carpenter/CoustanCarpenter/Coustan(mg/dL)(mg/dL)

105105

190190

165165

9595

180180

155155

3 h3 h 145145 140140


• Women with one abnormal value on Women with one abnormal value on the 3 h OGTT are at increased risk the 3 h OGTT are at increased risk forfor– PreeclampsiaPreeclampsia– MacrosomiaMacrosomia– ? CS? CS

• Treat as GDM versus repeat testing Treat as GDM versus repeat testing in 4 weeks?in 4 weeks?

Treatment of GDMTreatment of GDMDietDiet

• Diet based on ideal prepregnancy Diet based on ideal prepregnancy weightweight– 30 kcal/kg for average weight30 kcal/kg for average weight– 35 kcal/kg for underweight35 kcal/kg for underweight– 25 kcal/kg for overweight25 kcal/kg for overweight

• Generally, 2000-2200 calories per dayGenerally, 2000-2200 calories per day– Avoid concentrated sweets – utilize Avoid concentrated sweets – utilize

complex, high-fiber carbohydratescomplex, high-fiber carbohydrates

Treatment of GDMTreatment of GDMDietDiet

• Experts recommend checking FBS Experts recommend checking FBS and 1 or 2 h postprandial BSs and 1 or 2 h postprandial BSs – Normals:Normals:

• FBS 95 or lessFBS 95 or less• 1 h pp 130-140 or less1 h pp 130-140 or less• 2 h pp 120 or less2 h pp 120 or less

– Decrease monitoring (number of BS per Decrease monitoring (number of BS per day) if BSs are normal after several day) if BSs are normal after several days of testingdays of testing

Treatment of GDMTreatment of GDMMedicationsMedications

• InsulinInsulin• GlyburideGlyburide• MetforminMetformin

Original Article

Metformin versus Insulin for the Metformin versus Insulin for the Treatment of Gestational DiabetesTreatment of Gestational Diabetes

Janet A. Rowan, M.B., Ch.B., William M. Hague, M.D., Wanzhen Janet A. Rowan, M.B., Ch.B., William M. Hague, M.D., Wanzhen Gao, Ph.D., Malcolm R. Battin, M.B., Ch.B., M. Peter Moore, M.B., Gao, Ph.D., Malcolm R. Battin, M.B., Ch.B., M. Peter Moore, M.B.,

Ch.B., for the MiG Trial InvestigatorsCh.B., for the MiG Trial Investigators

N Engl J MedN Engl J MedVolume 358(19):2003-2015Volume 358(19):2003-2015

May 8, 2008May 8, 2008

Metformin for the Treatment of Metformin for the Treatment of GDMGDM

• Randomized, open-label trial comparing Randomized, open-label trial comparing metformin to insulin for the treatment of GDMmetformin to insulin for the treatment of GDM– 363 363 metforminmetformin– 370 370 insulininsulin

• Primary outcomePrimary outcome a composite a composite– Neonatal hypoglycemia, RDS, need for Neonatal hypoglycemia, RDS, need for

phototherapy, birth trauma, 5 min AS <7, phototherapy, birth trauma, 5 min AS <7, prematurityprematurity

Rowan et al, N Engl J Med 2008; 358:19

Metformin for the Treatment Metformin for the Treatment of GDMof GDM

• Metformin started at 500 mg once or twice Metformin started at 500 mg once or twice daily and increased over 2 weeks as daily and increased over 2 weeks as needed to a max dose of 2500 mg dailyneeded to a max dose of 2500 mg daily– Supplemental insulin eventually required in Supplemental insulin eventually required in

46% of metformin patients 46% of metformin patients


Enrollment of Subjects

Rowan JA et al. N Engl J Med 2008;358:2003-2015


• In women with gestational diabetes In women with gestational diabetes mellitus, metformin (alone or with mellitus, metformin (alone or with supplemental insulin) is not associated supplemental insulin) is not associated with increased perinatal complications as with increased perinatal complications as compared with insulincompared with insulin

• Patients prefer metformin over insulinPatients prefer metformin over insulin



• Start with 500 mg once or twice dailyStart with 500 mg once or twice daily

• Increase by 500 mg per weekIncrease by 500 mg per week

• Maximum dose 2000 mg per dayMaximum dose 2000 mg per day

Potential Adverse Effects of Potential Adverse Effects of MetforminMetformin

• Lactic acidosis: Occurs in 1:30,000 cases; Lactic acidosis: Occurs in 1:30,000 cases; predispositions include renal or liver predispositions include renal or liver compromise, heart failure, serious illness, compromise, heart failure, serious illness, dehydrationdehydration

• Nausea, bloating, diarrhea: dose Nausea, bloating, diarrhea: dose dependentdependent

• Drug interactions: cimetadineDrug interactions: cimetadine

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Postpartum Management of GDMPostpartum Management of GDM

• ~15% of women with GDM have impaired ~15% of women with GDM have impaired glucose tolerance or diabetes after glucose tolerance or diabetes after deliverydelivery– Greater likelihood ifGreater likelihood if

• ObeseObese• GDM diagnosed early in pregnancyGDM diagnosed early in pregnancy• Treatment requiredTreatment required

• ADA recommends that all women with ADA recommends that all women with GDM be evaluated postpartum for diabetesGDM be evaluated postpartum for diabetes

Smirnakis et al, Obstet Gynecol 2005;106:1297Smirnakis et al, Obstet Gynecol 2005;106:1297

Kaplan-Meier estimates of the time to screening in women with GDMKaplan-Meier estimates of the time to screening in women with GDM

http://www.greenjournal.org/content/vol106/issue6/images/large/14FF1.jpeg

Postpartum Evaluation for Postpartum Evaluation for DiabetesDiabetes

MethodMethod

Continued homeContinued home monitoringmonitoring

75 g oral glucose75 g oral glucose loadload

NormalNormal

ImpairedImpairedGlucoseGlucose

ToleranceTolerance

FBSFBS< 110< 110

2 h2 h< 140< 140

FBSFBS110-125110-125

2 h2 h140-199 140-199

DiabetesDiabetes

FBSFBS>125>125

2 h2 h>199>199

gestational diabetes: define, consequences & management

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