Increased risk of major congenital malformations in early pregnancy use of angiotensin-converting-enzyme inhibitors and angiotensin-receptor-blockers: a meta-analysis

Aims To evaluate the risk of adverse fetal outcomes after exposure to angiotensin converting enzyme inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs) in first trimester of pregnancy, by conducting a systematic review and meta-analysis. Materials and Methods A systematic literature search was conducted using Medline, Embase, Cochrane and PubMed from inception to 25 November 2019. Studies were included if they evaluated pregnancies exposed to ACE-Is or ARBs, reported fetal outcomes, and compared these outcomes with a control group. Pooled odds ratios (ORs) were estimated using inverse variance-weighted random effects model. The protocol was registered with the PROSPERO International Prospective Register of Systematic Reviews (CRD42020160566). Results Studies reporting on 6234 pregnancies exposed to ACE-Is or ARBs, 4104 pregnancies exposed to other oral antihypertensives, and 1,872,733 pregnancies without exposure were included in the meta-analysis. ACE-I or ARB exposed pregnancies, compared to non-exposed controls, had higher risk of major congenital malformations (OR 1.82; 95% confidence interval [CI]: 1.42-2.34), cardiovascular malformations (OR 2.50; 95% CI: 1.62-3.87) and stillbirths (OR 1.75; 95% CI: 1.21-2.53). There was no difference in congenital malformations observed between pregnancies exposed to other antihypertensives compared to non-exposed controls (OR 0.96; 95% CI: 0.69-1.33). Conclusions Women exposed to ACE-Is or ARBs during early pregnancy had higher risk of adverse fetal outcomes, including malformations and stillbirths, than non-exposed controls. This increased risk was independent of underlying maternal hypertension, as those exposed to other antihypertensives did not exhibit a higher risk than healthy controls. Women planning for pregnancy using these medications, including those with diabetic nephropathy, should be counselled appropriately.

Automated summary

This study evaluated the risk of adverse fetal outcomes after exposure to ACE-Is or ARBs in the first trimester of pregnancy. Pregnancies exposed to these medications had a higher risk of major congenital malformations, cardiovascular malformations, and stillbirths compared to non-exposed pregnancies, independent of underlying maternal hypertension. Women planning for pregnancy using these medications should be counselled appropriately.