Diagnosis and Management of Diabetes in Pregnancy Disclosures

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Diagnosis and Management of Diabetes in Pregnancy

Kirsten Salmeen, MDAssistant Professor

Department of Obstetrics, Gynecology & Reproductive Sciences

Maternal-Fetal Medicine

Disclosures

I have nothing to disclose

Type 1GDMA2

Pre-DM/Type 2

GDMA1

Overview

• Impact of Hyperglycemia• Testing• Management• Postpartum

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Glucose & Insulin

Cunningham et al. Williams Obstetrics, 23rd Edition

GLUCOSE

INSULIN

PREGNANT

NON-PREGNANT

PREGNANT

NON-PREGNANT

Normal Pregnancy: - Fasting HYPO glycemia- Postprandial HYPER glycemia- HYPER insulinemia

Normal Glucose In Pregnancy:Non Diabetics

Hernandez Diabetes Care 2011

Glucose & Insulin – Pregnancy

• Pregnancy = “Pancreatic Stress Test”

• Human placental lactogen blocks peripheral uptake and use of glucose in the mother

• Insulin sensitivity is > 50% lower

Glucose & Insulin – The Fetus

• Transfer of glucose across placenta is by facilitated diffusion via glucose transport proteins

• Glucose is the primary substrate for fetal growth

• The fetus makes its own insulin

• Hyperinsulinemia likely drives excess fetal growth

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Overview

• Impact of Hyperglycemia• Testing• Management• Postpartum

Pregnancy Outcomes in GDM

Approximate Overall % Relative Risk/Odds RatioMacrosomia 20 RR ~1.4

Pre-Eclampsia 15 RR ~1.7Cesarean Section Varies RR ~ 1.2Shoulder Dystocia 3-5 OR ~ 1.2

IUFD ~ 0.05 RR ~ 2

HAPO Study Cooperative Research Group N Engl J Med 2008Schmidt M Diabetes Care 2001Wendland E BMC Pregnancy Childbirth 2012

Hyperglycemia & Pregnancy Outcomes

Preeclampsia (%)

Macrosomia(%)

Cesarean Section (%)

50 gram, 1-hour < 100 mg/dL 3.0 12.2 17.5100 – 114 mg/dL 6.3 12.5 20.8116 – 134 mg/dL 5.6 15.4 23.0> 134 mg/dL 5.9 17.2 23.4

P-value for trend 0.01 0.001 0.001

Sermer et al AJOG 1995

Fasting Glucose Macrosomia (%)

< 72 mg/dL 9.774-76 mg/dL 14.478-82 mg/dL 14.1> 82 mg/dL 20.5


Sermer et al AJOG 1995

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Outcome (%) Fasting < 74

Fasting 74-77

Fasting 79-81

Fasting ≥ 83

Odds Ratio 95% CI

Birth weight≥ 4000 g 23.4 27.9 28.5 31.7 1.14 1.06-1.22

Birth weight ≥ 4500 g 4.3 6.3 6.8 8.1 1.23 1.08-1.40

LGA 17.2 18.9 22.7 25.6 1.19 1.10-1.29

PIH/PreE 5.8 6.6 7.1 7.9 1.12 0.99-1.26

Shoulder Dystocia 1.4 0.8 1.7 2.2 1.21 0.92-1.62


Jensen AJOG 2001 Jensen AJOG 2001

Outcome (%) 2 hour < 102

2 hour 102-114

2 hour 115-128

2 hour ≥ 130

Odds Ratio 95% CI

Birthweight≥ 4000 g 22.9 27.4 28.8 32.3 1.16 1.01-1.34

Birthweight> 4500 g 5.2 5.3 5.6 8.6 1.16 1.01-1.34

LGA 16.0 20.7 21.1 27.2 1.23 1.13-1.33

PIH/PreE 4.8 6.9 8.4 7.2 1.16 1.02-1.31

Shoulder Dystocia 0.4 1.2 1.8 2.9 1.78 1.32-2.40


• Does hyperglycemia without overt diabetes during pregnancy increase risk of adverse pregnancy outcomes?

• Blinded study of ~25,000 women at 15 centers in 9 countries

• Primary outcomes: birthweight > 90%ile for GA, primary CD, neonatal hypoglycemia, cord-blood C-peptide level > 90%ile

• Primary predictor: Levels of hyperglycemia

HAPO Study Cooperative Research Group N Engl J Med 2008

HAPO Glucose Levels

Level Fast (mg/dL) 1 hr (mg/dL) 2 hr (mg/dL)1 < 75 ≤ 100 ≤ 902 75-79 106-132 91-1083 80-84 133-155 109-1254 85-89 156-171 126-1395 90-94 172-193 140-1576 95-99 194-211 158-1777 ≥ 100 ≥ 212 ≥ 178


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HAPO Results


Weight Prolonged Labor (%) Excess Bleeding (%) CD (%)3000 – 3999 g 0.9% 0.5 184000 – 4499 g 1.2 0.7 25.54500 – 4999 g 1.3 0.9 35.6

> 5000 g 1.5 1.1 50.6

Boulet SL et al. Am J Obstet Gynecol. 2003;188(5):1372-8; Acker et al. Obstet Gynecol. 1985;66:762; Nesbitt et al. Am J Obstet Gynecol. 1998;179:476; Sandmire et al. Int J Gynaecol Obstet. 1988;26:65; Overland E et al. Am J Obstet Gynecol. 2009;200(5):506

Impacts of Macrosomia – Maternal

Boulet AJOG 2003

Impacts of Macrosomia – Fetal3000 –3999 g 4,000 – 4,499 g 4,500 – 4,999 g ≥ 5,000 g

Outcome % % OR CI % OR CI % OR CI5 min

Apgar ≤ 3 0.1 0.1 1.3 1.2-1.4 0.2 2.0 1.8-2.3 0.5 5.2 4.1-6.6

Assisted ventilation ≥ 30 min

0.3 0.3 1.2 1.1-1.2 0.5 1.9 1.7-2.0 1.3 4.0 3.5-4.6

Birth injury 0.3 0.5 2 1.9-2.1 0.8 3.1 3.0-3.3 1.3 4.5 4.0-5.2

NeonatalMortality

Rate*0.7 0.6 0.87 0.8-1 0.7 1.0 0.8-1.2 1.9 2.7 1.9-3.8

* Per 1,000, < 28 days Gillman Pediatrics 2003

Cumulative hazard (risk) function for development of metabolic syndrome according to birth weight.

P = 0.56

P = 0.004

LGA

LGA

AGA

AGA

Impacts of Macrosomia -Childhood

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• Increasing blood glucose (even without overt diabetes) is associated with worsening pregnancy outcomes including macrosomia, pre-eclampsia and cesarean section in an approximately linear fashion.

Overview

• Impact of Hyperglycemia• Testing• Treatment• Postpartum

When to test?Initial Visit:

• Overweight/obese• History of gestational diabetes or glucose intolerance• Prior LGA infant• Family history of type 2 DM• Maternal age > 35• High-risk ethnic groups (non-Caucasian)• PCOS

24 – 28 Weeks:• Everyone else• High-risk patients who screened negative earlier

How are average-risk patients screened for GDM in your practice?

T wo s t

e p t e s t

. . . O n

e s te p

t e s t. . .

F as t i n

g b lo o d

. . . A

a n d C

B an d C

57%

13%7%

21%

2%

A. Two step testing (1-hour, 50 gram glucose loading test followed by fasting 3-hour, 100 gram loading test if needed) at 24-28 weeks

B. One step testing (fasting 2-hour, 75 gram loading test at 24-28 weeks

C. Fasting blood sugar and/or hemoglobin A1c in the first trimester

D. A and CE. B and C

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GDM Testing Controversy What defines disease?

HAPO Study Cooperative Research Group. N Engl J Med. 2008.

F 75-791 hr 106-1322 hr 91-108

F 90-941 hr 172-1932 hr 140-157

In your opinion, what primary cesarean section rate defines disease?

> 1 5

%

> 2 0

%

> 2 5

%

> 3 0

%

12%

24%

35%30%

A. > 15%B. > 20%C. > 25%D. > 30% More Sensitive, Less Specific

LESS women WITHOUT disease test positive

MORE women WITHOUT disease test positive

Sensitivity v Specificity

Less Sensitive, More Specific

One-Step Two-StepCarpenter Coustan National Diabetes Data GroupUniversal Screening Risk-Based Screening

Early Screening 24-28 Week ScreeningHemoglobin A1c No Hemoglobin A1c

Testing for 1 abnormal value No f/u for 1 abnormal value

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One-Step vs. Two-Step Testing

Two-StepStep 1: Non-Fasting, 50 g, 1 hr serum glucose measurement

≥ 130/140 mg/dL� Step 2Step 2: Fasting, 100 g, 3 hr glucose test

2+ abnormal values � GDM

GDM prevalence ~ 5-10%

One-StepFasting, 75 g, 1 & 2 hr serum glucose measurement

1+ abnormal value � GDM

GDM prevalence ~ 20% ControlCC

IAD-PSG

GDMby CC (%)

GDM by IADPSG (%)

Normal Glucose

Tolerance (%)*PrimaryCesarean 19.5 17.8 14.8

*Shoulder Dystocia 1.2 0.71 0.91

*PPH 1.5 1.4 1.3

Ethridge Obstet Gynecol 2014

Prenatal Outcomes and Screening Strategies

* Not statistically significant


Pregnancy outcomes among 1,750 women diagnosed with GDM by Carpenter-Coustan criteria and 1,526 women diagnosed by IADPSG criteria.

GDM Rate by CC = 10.6%GDM rate by IADPSG = 35.5%

2-Step CC Criteria IADPSG CriteriaGDM

%NGT

%P:

GDM vs NGTGDM

%NGT

%P:

GDM vs NGTGest HTN 4.9 4.0 0.047 5.7 2.2 0.009Delivery 0.049 0.026

Vaginal 57.9 58.4 69.7 73.2CD 27.6 25.7 22.1 18.5Forceps 14.5 15.9 8.2 8.3

LGA 4.9 4.6 0.9 4.8 3.2 0.04Duran Diabetes Care 2014 Mayo AJOG 2014


Outcome OGTT Negative (N=526)

IADPSG (N=155) CDA (N=358)

* Composite 0.9 (0.8-1.2) 1.4 (1.1 – 1.9) 1.4 (1.1-1.8)PIH/Pre-E 0.9 (0.6-1.7) 3.0 (1.7-5.6) 1.2 (0.7-2.1)CD 1.1 (0.9-1.4) 1.4 (1.01-1.2) 1.3 (1.05-1.7)LGA (> 90%ile) 1.2 (0.9-1.6) 1.8 (1.1-2.9) 1.5 (1.1-2.2)

* Composite of: hypertensive disorders, shoulder dystocia, 3rd or 4th degree laceration, LGA, NICU admission, neonatal: respiratory complication, hypoglycemia, jaundiceCDA Guidelines: 1 hr, 50 g > 140 � 2 hr, 75 g < 95/191/160

Odds of Outcome compared to 1 hr, 50 g < 140 mg/dL

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One-Step vs. Two-Step• IADPSG criteria increases rates of GDM

• IADPSG GDM is associated with pregnancy outcomes similar to CC GDM

• If treating CC GDM improves outcomes (it does), diagnosing and treating IADPSG-defined GDM seems clinically appropriate

Alternative Testing Strategies

Trujillo Diab Res Clin Prac 2014

Performance Measures Cut-off for fasting plasma glucose (mg/dL)

80 85 90 92Positive Test (%) 54.3 34.3 19.8 15.6Sensitivity (%) 96.9 92.5 88.3 86.8Specificity (%) 55.0 78.4 95.1 100

Positive Predictive Value (%) 32.0 48.3 79.8 100Negative Predictive Value (%) 98.8 97.9 97.4 97.2

Fasting plasma glucose as a predictor for GDM (by IADPSG criteria)

Alternative Testing Strategies

O’Connor Clin Chem Lab Med 2012

A1c ≥ 6.5 � DM2A1c 5.7-6.4 � Pre-DiabetesA1c < 5.7 � Normal

Non-Pregnant

1st

Trimester2nd

Trimester3rd

TrimesterHbA1c

%4.8 – 5.5

(5.2)4.3 – 5.4

(5.0)4.4 – 5.4

(4.9)4.7 – 5.7

(5.1)

Average HbA1c Values Non-Diabetic Women

4.4%

5.4%5.6%

4.7%

5.1%4.9%

Non-Preg

2nd Tri

3rd Tri

1st Tri

Jelly Beans

Lamar AJOG 1999

• Brach jelly beans, mixed assortment• 28 jellybeans = 50 g simple sugar

50 g Glucose Beverage Jelly BeansCalculated

Value 95% CI Calculated Value 95% CI

Sensitivity 80% 28-99% 40% 5-85%Specificity 82% 75-88% 85% 77-90%Positive Predictive Value 15% 4-34% 9% 1-29%Negative Predictive Value 99% 95-100% 97% 93-99%

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Overview


• Hyperglycemia is associated with worse pregnancy outcomes.

• Does intervention help?

Treatment of GDM

• Crowther et al: – RCT of treatment for gestational diabetes – 958 women with OGT: fasting < 140 & 2 hr 140-198– 485 received dietary intervention, glucose

monitoring, and insulin therapy if indicated– 473 received routine care

Treatment of GDM

Crowther et al. N Engl J Med 2005

Intervention Group N= 490

(%)

Routine Care N= 510

(%)

Adjusted RR or Treatment Effect

Adjusted p-value

*Any serious perinatalcomplication 1 4 0.33 (0.14 – 0.75) 0.01

Admission to NICU 71 61 1.13 (1.03 – 1.23) 0.04

Macrosomia 10 21 0.47 (0.34 – 0.64) < 0.001

Neonatal hypoglycemia 7 5 1.42 (0.87 – 2.32) 0.16

Preeclampsia 12 18 0.7 (0.51 – 0.95) 0.02

Cesarean Delivery 31 32 0.97 (0.81 – 1.16) 0.73* One or more of: death, shoulder dystocia, bone fracture, nerve palsy

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Anxiety & GDM

Crowther NEJM 2005

*

***

*

**

‡ Scores for the SF-36 can range from 0 (worst) to 100 (best).

• Landon et al:– RCT of treatment of mild GDM– 958 patients with fasting glucose < 95, but 2 or

more abnormal values on 3 hour (1 hr > 180, 2 hr > 155, 3 hr > 140)

– 485 were treated (37 required insulin)– 473 had usual care (2 required insulin)

Treatment of GDM

Intervention Group N = 485

(%)

Control Group N = 473

(%)Relative Risk p-value

NICU Admission 9 11.6 0.77 (0.51 – 1.18) 0.19

Macrosomia 5.9 14.3 0.41 (0.26 – 0.66) < 0.001Neonatal

Hypoglycemia 5.3 6.8 0.77 (0.44 – 1.36) 0.32

Shoulder Dystocia 1.5 4.0 0.37 (0.14 – 0.97) 0.02

Cesarean Delivery 26.9 33.8 0.79 (0.64 – 0.99) 0.02Preeclampsia or

GHTN 8.6 13.6 0.63 (0.42 – 0.96) 0.01

Treatment of GDM

Landon et al. N Eng J Med. 2009

• Blood Sugar Monitoring (biofeedback)• Choices for Treatment:

– Dietary modification & exercise– Oral agents– Insulin therapy

Treatment of GDM

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Hawkins Obstet Gynecol 2009

Blood Sugar MonitoringWeekly (N=675) Daily (N=315) p

Vaginal Delivery 67.1% 63.2% 0.22Shoulder Dystocia 1.9% 1.6% 0.71

Birth Weight 3,690 g 3,536 g < 0.001LGA 34.4% 23.1% < 0.001

Treatment of GDM• No evidence to-date to support a

specific diet.• Carb-restriction (< 40%) seems to

improve outcomes • Usual advice: 25-30 kcal/kg/day, limit

carbs to < 40% of total calories, 20% protein, 40% fat.

Treatment of GDM – Diet

Han et al. Cochrane Database of Systematic Reviews 2013, Issue 3.Major et al. Obstet Gynecol 1998;91:600-4.

� Exercise data is lacking with regards to pregnancy outcomes

Avoiding Ketosis• Severe carb restriction can result in ketosis – resulting

from breakdown of fatty acids in absence of sufficient carbohydrates

• Ketosis may be associated with behavioral and intellectual abnormalities in offspring

• Rizzo et al: Children’s developmental scores correlated inversely with 3rd trimester beta-hydroxybutyrate levels

• Onyeije et al: Maternal ketonuria associated with increased risk of oligohydramnios, nonreactive NST, fetal heart rate decelerations

Rizzo et al. N Engl J Med 1991;325:911-6.Onyeije et al. Am J Obstet Gynecol. 2001;184(4):713-8.

In your practice, for patients who fail diet/exercise management of diabetes, what is your preferred first-line agent?

Me t f o

r m in

G ly b u

r i d e

I n su l i n

19% 22%

59%A. MetforminB. GlyburideC. Insulin

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• Glyburide (sulfonylurea) – Increases insulin release from beta cells in pancreas

• Metformin (biguanide) – Increases insulin sensitivity, decreases gluconeogenesis

Treatment of GDM – Oral Agents 400 women, GDM requiring medication, randomized to Glybruide or insulin.

Treatment of GDM – Glyburide

Langer et al. N Engl J Med 2000;343:1134-8.


Langer et al. N Engl J Med 2000

Outcome Glyburide (N=201)

Insulin (N=203)

P Value

NeonatalLGA 12% 13% 0.76Birth Weight 3256 g 3194 g 0.28Hypoglycemia 9% 6% 0.25

Maternal Blood Glucose < 40 mg/dL 2% 20% 0.03Preeclampsia 6% 6% 1Cesarean Section 23% 24% NS

Langer: Secondary data analysis of RCT• Glyburide and insulin are equally efficient for treatment of

GDM in all levels of disease severity.

Langer et al. Am J Obstet Gynecol. 2005


Fasting plasma glucose on oral GTT

< 95 mg/dL > 95 mg/dLInsulin Glyburide Insulin Glyburide

LGA 7.7% 8.8% 17.8% 18.4%Macrosomia 2.0% 6.3% 8.0% 9.2%Composite Outcome* 25.3% 27.5% 30.7% 29.1%

* At least one of: metabolic complications, LGA/macrosomia, neonatal ICU admission > 24 hrs, need for respiratory support.

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Glyburide should be administered 30-60 minutes before a meal

Caritis et al. Obstet Gynecol. 2013;121:1309-12.

Glyburide – Timing of AdministrationGlyburide crosses the placenta

Rochon et al: Retrospective cohort study of 235 women• Odds of Glyburide failure were 2.84 (1.01 – 7.98) times higher among

patients with glucose challenge test ≥ 200 mg/dL• Neonates born to successfully Glyburide-treated mothers were more

likely to go to the ICN as compared to women with Glyburide-failures (33% vs 10%, p = 0.037).

Jacobson et al: Retrospective study comparing outcomes between 236 Glyburide-treated patients and 268 insulin-treated patients

• Patients treated with Glyburide had higher incidence of pre-eclampsia (12% vs 6%, p = 0.02, aOR 2.32)

• Neonates more likely to receive phototherapy (9% vs 5%, p < 0.05)Schwartz et al. Abstract SMFM. Am J Obstet Gynecol 2003;S25.Rochon et al. Am J Obstet Gynecol. 2006;195:1090-4.Jacobson et al. Am J Obstet Gynecol. 2005;193:118-24.

Downsides of Glyburide

Trends in Glyburide Use

Castillo Obstet Gynecol 2014

Propo

rtion

of Pa

tients

on Gl

yburi

de

0.4

0.8

0.2

0.0

0.6

1.0Glyburide use increased from

7.4% to 64.5% from 2000 to 2011

2001 2011

Metformin• Rowan et al: RCT of 751 women to compare Metformin &

insulin in the treatment of GDM. – Primary outcome was composite of neonatal

complications– Rate of primary outcome was equal in both groups– 46% required supplemental insulin. – More women in the metformin group than in the

insulin group would choose to receive their assigned treatment again (76.6% vs 27.2%, p < 0.001).

Rowan et al. N Engl J Med. 2008;358:2003-15.Moore et al. Obstet Gynecol. 2010;115:55-9.

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Treatment of GDM - Metformin

Rowan et al. N Engl J Med. 2008;358:2003-15.

Treatment of GDM - Metformin

• Moore: RCT of 149 women comparing Metformin to Glyburide. – Generally similar outcomes– Failure rate for metformin was 2.1 x higher

than Glyburide.

Moore Obstet Gynecol 2010

Insulin

Type Onset Peak (hours) Duration (hours)Insulin Lispro/Aspart 1-15 min 1-2 hrs 4-5 hrs

NPH 1-3 hrs 5-7 hrs 13-18 hrsInsulin Glargine (Lantus) 1 hr None 24 hrs

Insulin Detemir (Levemir) 1-2 hrs None 24 hrs

Oral Agents vs. Insulin

Dhulkotia AJOG 2010

Meta-analysis of oral hypoglycemics vs insulin: No difference in birthweight

FAVORS ORAL AGENTS FAVORS INSULIN

Pooled Weighted Mean Difference 0

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Oral Agents vs Insulin

Dhulkotia AJOG 2010

Meta-analysis of oral hypoglycemics vs insulin: No difference in CS Rates

FAVORS ORAL AGENTS FAVORS INSULIN

Induction of Labor• Rosenstein: Infant mortality rates at 39 weeks are lower than

overall mortality risk of expectant management.

Rosenstein et al. Am J Obstet Gynecol. 2012;206:309.e1-7.

Overview


Postpartum – Impact of Activity

Bao JAMA Intern Med 2014

Each 100 min/wk increase in moderate-intensity physical activity reduced the risk of DM2 by 9%.

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Postpartum – Impact of Activity

RR for Type 2 DM associated with TV watching: 0-5 hrs = 16-10 hrs = 1.28 11-20 hrs = 1.41> 20 hrs = 1.77

Bao JAMA Intern Med 2014

Effect of Life Style on Risk of DM

Ratner J Clin Endocrinol Metab 2008

Conclusions• The goal of blood sugar testing is to identify

women at increased risk for poor perinatal outcomes and provide intervention where possible

• Given the low risk of intervention and the high-potential for gain, the most sensitive testing strategy should be considered

• Testing strategy must be tailored to patients/population

Conclusions

• Dietary intervention is often adequate treatment

• Oral antihyperglycemics are an appropriate alternative to insulin

• Careful attention to diet and exercise in the postpartum period reduces the long term risk of type 2 diabetes

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Thank You!

Documents

Diagnosis and Management of Diabetes in Pregnancy Disclosures