Angiotensin-Converting Enzyme Inhibitors and the Risk of Congenital Malformations

Abstract

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.

Figures

Figure 1

Patient flowchart. *A short eligibility period is allowed in case of death. ACE, angiotensin-converting-enzyme.

Figure 2

For the analysis of overall (A) and cardiac malformations (B), we assume 20% of nonmalformed pregnancies in the unexposed end in non–live birth (spontaneous or therapeutic abortion or stillbirth) and between 25% and 45% of the pregnancies complicated by malformation end in non–live birth. The 3 curves show the impact of non–live birth frequencies in the angiotensin-converting-enzyme (ACE) inhibitor exposed that are 0%, 10%, or 20% higher. For the analysis of central nervous system malformations (C), we assume 20% of non-malformed pregnancies in the unexposed end in non–live birth, but that 45% to 65% of malformed pregnancies in the exposed end in non–live birth. The 3 curves again show the impact of non–live birth frequencies in the ACE inhibitor exposed that are 0%, 10%, or 20% higher.