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Angiotensin-Converting Enzyme Inhibitors and the Risk of Congenital Malformations

Bateman, Brian T. MD, MSc; Patorno, Elisabetta MD, DrPH; Desai, Rishi J. MS, PhD; Seely, Ellen W. MD; Mogun, Helen MS; Dejene, Sara Z. BS; Fischer, Michael A. MD, MS; Friedman, Alexander M. MD; Hernandez-Diaz, Sonia MD, DrPH; Huybrechts, Krista F. MS, PhD

doi: 10.1097/AOG.0000000000001775
Contents: Original Research

OBJECTIVE: To examine the association between first-trimester angiotensin-converting enzyme (ACE) inhibitor exposure and the risk of overall major congenital, cardiac, and central nervous system malformations.

METHODS: We used a cohort of completed pregnancies linked to liveborn neonates derived from Medicaid claims from 2000 to 2010. We examined the risk of malformations associated with first-trimester exposure to an ACE inhibitor. Propensity score–based methods were used to control for potential confounders including maternal demographics, medical conditions, exposure to other medications, and measures of health care utilization.

RESULTS: The cohort included 1,333,624 pregnancies, of which 4,107 (0.31%) were exposed to ACE inhibitors during the first trimester. The prevalence of overall malformations in the ACE inhibitor–exposed pregnancies was 5.9% compared with 3.3% in the unexposed (unadjusted relative risk, 1.82; 95% confidence interval [CI] 1.61–2.06), of cardiac malformations was 3.4% compared with 1.2% (relative risk 2.95, 95% CI 2.50–3.47), and of central nervous system malformations was 0.27% compared with 0.18% (relative risk 1.46, 95% CI 0.81–2.64). After restricting the cohort to pregnancies complicated by chronic hypertension (both exposed and unexposed) and accounting for other confounding factors, there was no significant increase in the risk of any of the outcomes assessed. Relative risks associated with first-trimester ACE inhibitor exposure were 0.89 (95% CI 0.75–1.06) for overall malformations, 0.95 (95% CI 0.75–1.21) for cardiac malformations, and 0.54 (95% CI 0.26–1.11) for CNS malformations.

CONCLUSIONS: After accounting for confounders, among women with hypertension, exposure to ACE inhibitors during the first trimester was not associated with an increased risk of major congenital malformations.

Supplemental Digital Content is Available in the Text.After accounting for confounders, particularly hypertension and diabetes, angiotensin-converting enzyme inhibitor exposure during the first trimester is not associated with an increased risk of malformations.

Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine and the Division of Endocrinology, Diabetes and Metabolism, Brigham and Women's Hospital, Harvard Medical School, the Department of Anesthesiology, Critical Care, and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, and the Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts; and the Department of Obstetrics and Gynecology, College of Physicians and Surgeons, Columbia University, New York, New York.

Corresponding author: Brian T. Bateman, MD, MSc, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, 1620 Tremont Street, Suite 3030, Boston, MA 02120; email:

Research reported in this publication was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (Bethesda, Maryland) under Award Number K08HD075831 (B.T.B.), the National Heart Lung and Blood Institute at the National Institutes of Health under grant number K24HL096141 (E.W.S.), and the National Institute of Mental Health under grant number K01MH099141 (K.F.H.).

Financial Disclosure Drs. Huybrechts, Brian T. Bateman, and Sonia Hernandez-Diaz are investigators on grants to the Brigham and Women's Hospital from Lilly and Pfizer and Dr. Bateman on grants from Baxalta unrelated to the topic of this article. Dr. Bateman consults for Optum for unrelated projects. Dr. Hernandez-Diaz has consulted for Boehringer-Ingelheim and UCB for unrelated projects. The Pharmacoepidemiology Program at the Harvard School of Public Health is supported by Pfizer, Takeda, Bayer, and Asisa. The other authors did not report any potential conflicts of interest.

Presented at the 31st International Conference on Pharmacoepidemiology and Therapeutic Risk Management, August 22–26, 2015, Boston, Massachusetts.

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Each author has indicated that he or she has met the journal's requirements for authorship.

© 2017 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.