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THERAPEUTIC CONTROVERSIES

Oral Antidiabetic Agents in Pregnancy and Lactation: A Paradigm Shift?

Associate Professor, Departments of Medicine, Obstetrics and Gynecology, and Health, Policy, Management and Evaluation, University of Toronto; Division of Endocrinology and Metabolism, Mount Sinai Hospital, Toronto, Ontario, Canada

Gerald G Briggs, BPharm

Pharmacist Clinical Specialist, Women's Pavilion, Miller Children's Hospital, Long Beach, CA

Gideon Koren, MD FABMT FRCP MBBS

Professor, Departments of Medicine and Pharmacology, University of Toronto; MotherRisk Program, Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto

Reprints: Dr. Feig, Mount Sinai Hospital, 60 Murray St., Suite 5027, Mail Box 14, Toronto, Ontario, Canada, M5G 1X5, fax 416/361-2657, d.feig{at}utoronto.ca

OBJECTIVE: To provide information on the use of oral antidiabetic agents in pregnancy and breast-feeding.

DATA SOURCES: Primary articles were identified by a MEDLINE search (1966-March 2007) using the MeSH headings: pregnancy in diabetics, pregnancy, polycystic ovary syndrome, hypoglycemic agents, glipizide, glyburide, metformin, rosiglitazone, pioglitazone, clinical trial, controlled clinical trial, multicenter study, randomized controlled trial, case-control studies, and cohort studies.

STUDY SELECTION AND DATA EXTRACTION: All studies using oral antidiabetic agents in pregnancy were evaluated and relevant data were included in the discussion.

DATA SYNTHESIS: Studies of glyburide and glipizide have found little or no transfer of these drugs across the placenta, whereas metformin and rosiglitazone cross readily. Animal studies have found no evidence to suggest that glyburide, glipizide, metformin, or rosiglitazone are teratogenic. In gestational diabetes, glyburide was safe and efficacious; however, 16-19% of women failed to achieve optimal glucose control. No developmental toxicity in infants was observed when metformin was used before and throughout pregnancy in women with polycystic ovarian syndrome (PCOS). Some of the studies involving patients with type 2 diabetes had methodological problems. A randomized controlled trial using metformin for gestational diabetes in the third trimester is underway. The human information is inadequate to evaluate the risk of glipizide or the thiazolidinediones in pregnancy. In breast milk, 3 studies measured nonsignificant amounts of metformin and one study was unable to detect either glyburide or glipizide.

CONCLUSIONS: Neither glyburide nor metformin has caused developmental toxicity in humans. Glyburide has been used for the treatment of gestational diabetes, and metformin has been used in women with PCOS who eventually became pregnant. Additional trials are needed to better define the benefits and risks of oral antidiabetic agents in pregnancy. Metformin, glyburide, and glipizide appear to be compatible with breast-feeding.

Key Words: diabetes, glyburide, metformin, polycystic ovary syndrome, pregnancy

Published Online, May 29, 2007. www.theannals.com, DOI 10.1345/aph.1K045