Cooper and colleagues9
reported an increased risk of congenital malformations in fetuses exposed to ACE inhibitors during the first trimester. They studied a cohort of 29 507 infants who were enrolled in Tennessee Medicaid, who were born between 1985 and 2000, and for whom there was no evidence of maternal diabetes. Out of this cohort, 209 infants with exposure to ACE inhibitors in the first trimester were identified. The risk ratio for major congenital malformations was 2.71 (95% 1.72 to 4.27). It has been argued that these findings were affected by confounding and ascertainment biases. These include the inability to exclude women with undiagnosed or diet-controlled type 2 diabetes mellitus, no adjustment for prepregnancy body mass, which is a considerable predictor of risk of type 2 diabetes mellitus, and uncontrolled hypertension.10
In infants, maternal obesity is an independent risk factor for neural tube defects and cardiac malformations.11,12
conducted a systematic review of the literature and meta-analysis evaluating the use of ACE inhibitors during the first trimester of pregnancy and their association with major congenital malformations. We identified 5 cohort studies for the meta-analysis and included 19 case reports, case series, or case-control studies in the descriptive part of the systematic review. The meta-analysis failed to demonstrate an increase in major malformations after use of ACE inhibitors or angiotensin II receptor blockers (ARBs) specifically, with no difference from exposure compared with other antihypertensive medications. The systematic review of the case reports and case series published in the past 25 years involved 424 pregnancies. These reports do not suggest a specific pattern of malformations.
Diav-Citrin et al recently studied 252 pregnancies exposed to ACE inhibitors and ARBs, 256 pregnancies exposed to other antihypertensive medications, and 495 control pregnancies from 2 teratology information services in Israel and Italy. They concluded that ACE inhibitors and ARBs are not major teratogens when used in the first trimester, and the risk of major congenital malformations was comparable between the groups (P
= .95). In this study, women with known diabetes (both preexisting and gestational) were not excluded, and there was no adjustment for maternal body mass index.14
Serreau et al reported on 10 cases of pregnant women exposed to ARBs during early pregnancy. One out of the 8 fetuses exposed exclusively during the first trimester was reported to have craniofacial dysmorphia, clinodactyly, and tubular dysplasia.15
In a cohort retrospective review of 348 989 infants or fetuses from all pregnancies in Finland (N = 343 324), exposure of infants or fetuses to ACE inhibitors (n = 137) was associated with an increased risk of major congenital malformations, mostly cardiac. However, when adjusted for diabetes, the excess risk was nullified.16
Lennestål et al17
reported on a cohort of 1418 women from the Swedish Medical Birth Register who had used antihypertensive drugs in early pregnancy but who did not have diabetes. Cardiovascular defects occurred with an adjusted odds ratio of 2.59 (95% CI 1.92 to 3.51). However, the results were similar when the women had used ACE inhibitors or other antihypertensive drugs, without any clear drug specificity.
In France, data on 159 pregnancies with exposure to ACE inhibitors and 159 controls were obtained. Pregnancies with confirmed first-trimester exposure to ACE inhibitors were included. The rate of major malformations in live births or stillbirth was not different between the 2 groups (relative risk 1.5, 95% CI 0.3 to 6.5).18