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Gestational Hyperglycemia: Continuum of Risk, Choices for Treatment

Likelihood of adverse pregnancy outcomes increased in proportion to maternal glucose levels; metformin for gestational diabetes was not inferior to insulin.

Controversies have surrounded the diagnosis and treatment of carbohydrate intolerance during pregnancy. In a new study, researchers assessed pregnancy outcomes in women with varying degrees of gestational hyperglycemia; in a second study, investigators compared perinatal outcomes following treatment with metformin or with insulin in women with gestational diabetes.

The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) research group evaluated birth weight, incidence of cesarean delivery, cord-blood C-peptide levels (a surrogate marker for fetal insulin levels), and neonatal hypoglycemia in more than 25,000 pregnant women. All participants underwent standard 75-g oral glucose-tolerance testing between 24 and 32 weeks’ gestation. Maternal glycemia measures were categorized by level, and frequency of adverse outcomes was calculated for each category. For continuous-variable analysis, adjusted odds ratios for adverse pregnancy outcomes were calculated in association with a 1–standard-deviation increase in fasting, 1-hour, and 2-hour plasma glucose levels. Even below the point considered diagnostic of gestational diabetes, maternal glucose levels were directly and continuously correlated with both C-peptide levels and birth weight above the 90th percentile. Glucose levels were more modestly associated with increased rate of cesarean delivery.

In the Metformin in Gestational Diabetes Trial, investigators randomized 751 women with gestational diabetes to treatment with insulin or with metformin plus supplemental insulin as needed. Perinatal outcomes included neonatal hypoglycemia, respiratory distress, 5-minute Apgar scores below 7, prematurity, and birth trauma. Results showed that birth weights were similar for both groups, as was frequency of adverse perinatal outcomes. Patients markedly preferred treatment with metformin over insulin-only treatment (76.6% vs. 27.2%). Almost half the patients in the metformin group required supplemental insulin.

Comment: The current definition of gestational diabetes — established more than 40 years ago — is not based on risk factors for unfavorable perinatal outcomes. We now understand that there is a continuum of increasing carbohydrate intolerance associated with increased risk for adverse pregnancy outcomes. However, no study has yet shown that providing interventions for patients with hyperglycemia below the levels we would traditionally treat will improve clinical outcomes. The finding that women with gestational diabetes markedly preferred oral metformin over insulin (even though almost half required supplemental insulin) is interesting and could be more telling than the results suggest: Patients might be more likely to adhere strictly to treatments they prefer. Nonetheless, a question remains whether other oral agents (e.g., glyburide) would be better than metformin. Editorialists note that, in a trial comparing glyburide with insulin, only 4% of participants receiving glyburide required supplemental insulin. A head-to-head trial would go a long way toward establishing the merits of various oral interventions for gestational diabetes.

— Ann J. Davis, MD

Published in Journal Watch Women's Health May 7, 2008

Citation(s):

The HAPO Study Cooperative Research Group. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med 2008 May 8; 358:1991.

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• Medline abstract (Free)

Rowan JA et al. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med 2008 May 8; 358:2003.

• Original article (Subscription may be required)
• Medline abstract (Free)

Ecker JL and Greene MF. Gestational diabetes — Setting limits, exploring treatments. N Engl J Med 2008 May 8; 358:2061.

• Original article (Subscription may be required)
• Medline abstract (Free)