Major Congenital Malformations after First-Trimester Exposure to ACE Inhibitors

Although angiotensin-converting enzyme (ACE) inhibitors are avoided in the second and third trimesters of pregnancy because of an increased risk of fetal pathology, adverse fetal outcomes have not been related to first-trimester exposure. For the most part, however, evidence that exposure early in pregnancy is safe comes from a limited number of animal studies and case report analyses. This cohort study included 29,507 infants enrolled in Medicaid in Tennessee who were born in the years 1985 to 2000 and for whom there was no evidence of maternal diabetes. A total of 411 infants had been exposed to some kind of antihypertensive medication only in the first trimester: 209 infants had been exposed to ACE inhibitors and 202 were exposed to other antihypertensive drugs. Among the 202 infants exposed to other antihypertensive agents in the first trimester, the risk of any major congenital malformation was not increased. Of the 209 infants exposed to ACE inhibitors in the first trimester, 18 had major congenital malformations (8.6%); the adjusted proportion was 7.1%. Seven of these 18 infants had multiple malformations, but 5 of the 7 had been exposed in the second trimester as well and 3 had been exposed in all 3 trimesters. The risk ratio (RR) for first-trimester exposure, compared with children not exposed to any type of antihypertensive drug, was 2.71 (95% confidence interval [CI], 1.72–4.27). This RR was the result of an increased number of cardiovascular malformations (n = 8; RR, 3.72; 95% CI, 1.89–7.30) and central nervous system malformations (n = 3; RR, 4.39; 95% CI, 1.37–14.02). Other malformations included renal dysplasia (n = 2), hypospadius, intestinal and choanal atresia, Hirschsprung disease, and diaphragmatic hernia (n = 1 each). A post hoc analysis revealed a significantly increased risk of renal malformations (RR, 9.32; 95% CI, 1.79–48.5), but the risk of the other malformations was not significantly increased. Women of childbearing age, like other individuals, are increasingly being given ACE inhibitors as the indications for these drugs continue to expand. The present findings strongly suggest that these drugs should not be given to pregnant women during the first trimester.