USE OF ANGIOTENSIN CONVERTING ENZYME INHIBITORS IN PREGNANCY

Angiotensin converting enzyme (ACE) is an important constituent of the renin angiotensin system (RAS) which regulates fluid volume and controls vascular tone. ACE inhibitors (ACE-I) decrease the activity of ACE to counteract its vasoactive effects, thereby reducing blood pressure. ACE-I are used for the treatment of hypertension, heart failure, nephropathy, and in the prophylaxis of cardiovascular events.

ACE-I fetopathy following exposure to ACE-I in the second and third trimesters of pregnancy is well-described and may include oligohydramnios, renal tubular dysgenesis, neonatal anuria, hypocalvaria, pulmonary hypoplasia, persistent patent ductus arteriosus, mild-to-severe intrauterine growth restriction, and fetal or neonatal death. It is proposed that these effects occur as a result of a direct effect on the fetal RAS which begins to function from approximately 26 weeks gestation. A small prospective case series has suggested that the risk period for ACE-I fetopathy is with exposure beyond 20 weeks gestation. Due to data limitations, the absolute risk of ACE-I fetopathy is unclear.

Due to the risk of ACE-I fetopathy, use of ACE-I in the second and third trimesters is generally contraindicated and should only be reserved for cases of severe maternal illness that cannot be managed using alternative drugs.

There is currently no reliable evidence that exposure to ACE-Is in the first trimester increases the risk of overall infant congenital malformation, or, more specifically, of cardiovascular or CNS malformation. A small number of uncontrolled studies have suggested possible associations with urogenital anomalies, but further research to confirm or refute these observations is required.

Although some studies have described increased risks of miscarriage, preterm delivery and impaired fetal growth following early pregnancy exposure to ACE-I, similar findings have been observed in women taking other antihypertensive medications. As such, these findings are considered confounded by the underlying maternal condition, and there is currently no reliable evidence that first trimester ACE-I exposure directly increases the risk of these outcomes.

The National Institute for Health and Care Excellence (NICE) guidelines state that antihypertensive treatment with ACE-I should be stopped upon recognition of pregnancy and alternatives offered.  NICE guidelines identify labetalol as the first-line antihypertensive for use during pregnancy, with nifedipine or methyldopa being possible alternatives, depending on any pre-existing treatment, side effect profiles, risks (including fetal effects), and the woman’s preference. Where prolonged first trimester exposure has occurred, attendance of the routine 20-week anomaly scan is encouraged. Where prolonged second or third trimester exposure has occurred, assessment and management by a specialist in fetal medicine is indicated. Women of childbearing age who are taking an ACE-I should be fully informed of the potential fetal risks and should ideally seek advice before becoming pregnant. Other risk factors may also be present which may increase the risk of adverse pregnancy outcome. Clinicians are reminded to consider these factors when performing risk assessments.