Key result
First-trimester exposure to ACE-Is or ARBs linked to ~82% higher risk of major congenital malformations.
Why the study?
To evaluate the risk of adverse fetal outcomes after exposure to ACE-Is or ARBs in the first trimester of pregnancy.
Does exposure to ACE-Is or ARBs in the first trimester of pregnancy increase the risk of adverse fetal outcomes compared to no exposure or other antihypertensives?
Meta-Analysis (n=1,883,071)
Does exposure to ACE-Is or ARBs in the first trimester of pregnancy increase the risk of adverse fetal outcomes compared to no exposure or other antihypertensives?
Odds Ratio: 1.82 (95% CI 1.42–2.34)
Exposure to ACE-Is or ARBs during early pregnancy is associated with a significantly increased risk of major congenital malformations and stillbirths, independent of underlying maternal hypertension.
May support avoiding ACE-Is/ARBs in first trimester; extends observational signals but leaves causality open.
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.
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Fu et al. (2021) conducted a meta-analysis in Pregnancy (n=1,883,071). Angiotensin-converting-enzyme inhibitors (ACE-Is) or angiotensin-receptor-blockers (ARBs) vs. Non-exposed controls was evaluated on Major congenital malformations (OR 1.82, 95% CI 1.42-2.34). First-trimester exposure to ACE-Is or ARBs was associated with a higher risk of major congenital malformations compared to non-exposed controls (OR 1.82; 95% CI 1.42-2.34).
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