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Maternal exposure to angiotensin converting enzyme inhibitors in the first trimester and risk of malformations in offspring: a retrospective cohort study

BMJ 2011; 343 doi: (Published 18 October 2011) Cite this as: BMJ 2011;343:d5931
  1. De-Kun Li, principal investigator1,
  2. Chunmei Yang, program analyst1,
  3. Susan Andrade, research associate professor2,
  4. Venessa Tavares, program analyst1,
  5. Jeannette R Ferber, program analyst1
  1. 1Division of Research, Kaiser Foundation Research Institute, Kaiser Permanente, Oakland, CA 94612, US
  2. 2Meyers Primary Care Institute, Worcester, MA 01605, US
  1. Correspondence to: D-K Li{at}
  • Accepted 5 September 2011


Objective To examine a reported association between use of angiotensin converting enzyme (ACE) inhibitors during the first trimester and risk of malformations in offspring.

Design A population based, retrospective cohort study linking automated clinical and pharmacy databases including comprehensive electronic medical records.

Participants Pregnant women and their live born offspring (465 754 mother-infant pairs) in the Kaiser Permanente Northern California region from 1995 to 2008.

Main outcome measure Congenital malformation in live births.

Results The prevalence of ACE inhibitor use in the first trimester only was 0.9/1000, and the use of other antihypertensive medications was 2.4/1000. After adjustment for maternal age, ethnicity, parity, and obesity, use of ACE inhibitors during the first trimester only seemed to be associated with increased risk of congenital heart defects in offspring compared with normal controls (those with neither hypertension nor use of any antihypertensives during pregnancy) (15/381 (3.9%) v 6232/400 021 (1.6%) cases, odds ratio 1.54 (95% confidence interval 0.90 to 2.62)). A similar association was observed for use of other antihypertensives (28/1090 (2.6%) cases of congenital heart defects, odds ratio 1.52 (1.04 to 2.21)). However, compared with hypertension controls (those with a diagnosis of hypertension but without use of antihypertensives) (708/29 735 (2.4%) cases of congenital heart defects), neither use of ACE inhibitors or of other antihypertensives in the first trimester was associated with increased congenital heart defects risk (odds ratios 1.14 (0.65 to 1.98) and1.12 (0.76 to 1.64) respectively).

Conclusions Maternal use of ACE inhibitors in the first trimester has a risk profile similar to the use of other antihypertensives regarding malformations in live born offspring. The apparent increased risk of malformations associated with use of ACE inhibitors (and other antihypertensives) in the first trimester is likely due to the underlying hypertension rather than the medications.


  • We thank Roxana Odouli for her help during preparation of the manuscript.

  • Contributors: D-KL (study guarantor) was responsible for the design of the study, obtaining funding, analysis and interpretation of the data, and preparation of the manuscript. CY, VT, and JRF contributed to the preparation of datasets for analyses. CY conducted data analyses. SA contributed to obtaining funding. JRF and SA reviewed the manuscript.

  • Funding: This project was funded under Contract No 290050033I from the Agency for Healthcare Research and Quality, US Department of Health and Human Services as part of the Developing Evidence to Inform Decisions about Effectiveness (DEcIDE) programme. The Food and Drug Administration, Office of Women’s Health also contributed funds. The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the Agency for Healthcare Research and Quality, the Food and Drug Administration, or the US Department of Health and Human Services.

  • Competing interests: All authors have completed the Unified Competing Interest form at (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years, no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: Institutional Review Boards of Kaiser Permanente in Northern California and California State Committee for the Protection of Human Subjects.

  • Data sharing: No additional data available.

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