Original Paper

Adverse pregnancy outcomes associated with maternal enalapril antihypertensive treatment†

  1. Sonia Tabacova1,*,
  2. Ruth Little2,
  3. Yi Tsong3,
  4. Amarilys Vega3,
  5. Carole A. Kimmel4

Article first published online: 3 JAN 2003

DOI: 10.1002/pds.796

Issue

Pharmacoepidemiology and Drug Safety

Pharmacoepidemiology and Drug Safety

Volume 12, Issue 8, pages 633–646, December 2003

Additional Information

How to Cite

Tabacova, S., Little, R., Tsong, Y., Vega, A. and Kimmel, C. A. (2003), Adverse pregnancy outcomes associated with maternal enalapril antihypertensive treatment. Pharmacoepidem. Drug Safe., 12: 633–646. doi: 10.1002/pds.796

Author Information

  1. 1

    National Center for Toxicological Research, US Food and Drug Administration, Rockville, MD, USA

  2. 2

    National Institute for Environmental Health Sciences, Research Triangle Park, NC, USA

  3. 3

    Center for Drug Evaluation and Research, US Food and Drug Administration, Rockville, MD, USA

  4. 4

    National Center for Environmental Assessment, Office for Research and Development, US Environmental Protection Agency, Washington, DC, USA

*Food and Drug Administration, Center for Drug Evaluation and Research, DNDP, HFD-120, 5600 Fishers Lane, Rockville, MD 20857, USA.

  1. †

    The views expressed in this article are those of the authors and do not necessarily represent the views or policies of the Food and Drug Administration or the US Environmental Protection Agency.

Publication History

  1. Issue published online: 2 DEC 2003
  2. Article first published online: 3 JAN 2003
  3. Manuscript Accepted: 2 OCT 2002
  4. Manuscript Revised: 9 SEP 2002
  5. Manuscript Received: 2 JAN 2002

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Keywords:

  • anti-hypertensive drugs;
  • ACE inhibitors;
  • enalapril maternal exposure;
  • adverse pregnancy outcomes;
  • oligohydramnios;
  • congenital abnormalities;
  • neonatal renal failure

Abstract

Background

Adverse pregnancy outcomes following the use of angiotensin-converting enzyme (ACE) inhibitors, including enalapril, have been reported in descriptive studies. However, no analytical studies on the relationship between the adverse outcomes and enalapril gestational exposures are available.

Objectives

To explore the association between enalapril exposure and adverse outcomes in pregnancy, taking into account other possible risk factors.

Methods

We analyzed a series of all usable cases reported to the FDA between 1986 and 2000 in which enalapril was a suspect drug for the observed adverse outcomes (N = 110). Parameters of exposure and reported outcomes as well as information on potentially confounding variables were systematically abstracted from this series by a single physician. Because exposure to ACE inhibitors after the first trimester of pregnancy had been associated with adverse outcomes in the existing literature, we divided the cases into those exposed in the first trimester only (considered as the baseline group) and cases exposed beyond or after this time. Frequency of reported adverse outcomes in the second group was compared with those in the baseline group; odds ratios were computed, taking account of potentially confounding variables by logistic regression where appropriate.

Results

Exposure to enalapril after the first trimester of pregnancy was strongly associated with oligohydramnios and specific adverse outcomes thought to be secondary to reduced amniotic fluid volume (limb deformities, cranial ossification deficits, lung hypoplasia), as well as with neonatal renal failure. The relationship did not change after taking numerous potential confounders into account, including duration of exposure, concomitant drug use, maternal age, concurrent disease, neonatal gender, and gestational age at birth. Such a pattern of abnormalities is considered to be a consequence of the effect of ACE inhibition on fetal renal function that develops after the first trimester.

Conclusion

The specificity and temporality of the observed adverse manifestations suggest a causal relationship to enalapril exposure. Copyright © 2003 John Wiley & Sons, Ltd.

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