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 (captopril, enalapril, fosinopril, imidapril, lisinopril, perindopril, quinapril, ramipril, and trandolapril) are used for the treatment of hypertension, heart failure, nephropathy, and in the prophylaxis of cardiovascular events.

ACE-I fetopathy following exposure in the second and third trimesters of pregnancy is well-described and can 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. These effects are thought to occur via 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 in the second and third trimesters is generally contraindicated and should only be reserved for cases of severe illness that cannot be managed using alternative drugs.

ACE-I exposure during the first trimester has been inconsistently associated with an increased congenital malformation risk, with data suggesting this may be driven by increased frequencies of cardiovascular and urinary malformations. It is noteworthy that where increased risks have been noted, the magnitude of the increase is generally small. Additionally, women taking an ACE-I may be more likely to have cardiac or renal disease, and/or diabetes, suggesting that the infant outcome data may be influenced by factors relating to the maternal condition.

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 no reliable evidence that ACE-I exposure directly increases the risks.

National Institute for Health and Care Excellence (NICE) guidelines advise that women taking an ACE-I who are planning a pregnancy should be offered a medication review. Women who become pregnant while taking an ACE-I should be offered a different antihypertensive if clinically appropriate. NICE recommends labetalol as 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.

In rare cases where an ACE-I is continued beyond the first trimester, either inadvertently or to ensure maternal wellbeing, the woman should be closely monitored by maternal and fetal medicine specialists. This may necessitate transfer to a tertiary referral centre. Serial ultrasound scans to assess fetal growth and wellbeing and amniotic fluid levels are indicated. Discussion with UKTIS is recommended. Women who are pregnant or of childbearing potential who are treated with an ACE-I should be fully informed of the fetal risks. Other risk factors may also be present in individual cases which may independently increase the risk of adverse pregnancy outcome. Clinicians are reminded of the importance of consideration of such factors when performing case-specific risk assessments.