HSA would like to bring the attention of healthcare professionals to a recent study published in the New England Journal of Medicine ¹ (NEJM) which suggests that there is an increased risk of major congenital malformations in infants exposed to angiotensin-converting enzymes (ACE) inhibitors during the first trimester of pregnancy when compared with infants who had no exposure during first trimester.

The new finding is in contrast to the knowledge that ACE inhibitors, whilst contraindicated during the second and third trimester due to the known risk of fetopathy, has generally not been linked to adverse birth outcomes when used in the first trimester.

The study concerned is an observational cohort study which included 29,507 infants born between 1985 and 2000 whose mothers had no evidence of diabetes before or during pregnancy. The authors identified 209 infants with exposure to ACE inhibitors in the first trimester alone, 202 infants with exposure to other antihypertensive drugs in the first trimester alone, and 29,096 infants with no exposure to antihypertensive drugs at any time during gestation. They found that infants exposed to ACE inhibitors were at an increased risk for major congenital malformations (risk ratio 2.71; 95% confidence interval, 1.72–4.27), as compared to those with no exposure to antihypertensive medications. The former group had an increased risk for malformations of cardiovascular system (risk ratio 3.72; 95% confidence interval, 1.89–7.30) and the central nervous system (risk ratio 4.39; 95% confidence interval, 1.37–14.02). In contrast, foetal exposure to other antihypertensive medications during only the first trimester did not confer an increased risk (risk ratio 0.66; 95% confidence interval, 0.25–1.75).

The ACE inhibitors that are available locally include captopril, cilazapril, enalapril, fosinopril, imidapril, lisinopril, moexipril, perindopril, quinapril and ramipril.

The use of ACE inhibitor is contraindicated during the second and third trimesters of pregnancy. In utero exposure during this period is associated with ACE inhibitor fetopathy, a group of conditions that includes oligohydramnios, intrauterine growth retardation, renal dysplasia, anuria, renal failure and death. Although the above findings of an increased risk in first trimester use is considered preliminary due to the nature of the study and the small number of birth defects in the study group, healthcare
professionals should take these findings into consideration together with other information about a patient's medical situation during early pregnancy. The current labelling generally recommends discontinuation of the ACE inhibitor as soon as possible if a patient becomes pregnant.

HSA will continue to monitor this emerging safety concern and take appropriate regulatory actions such as strengthening of the package inserts of the affected drugs to reflect this safety concern when necessary.

1. NEJM 354: 2443-2451.