First trimester exposure to hydroxychloroquine during pregnancy and major congenital malformations: a systematic review and meta-analysis

OBJECTIVE: To assess the association between hydroxychloroquine (HCQ) use during the first trimester of pregnancy and the risk of major congenital malformations (MCMs). METHODS: In this systematic review and meta-analysis, we searched MEDLINE, EMBASE, CENTRAL, clinical trials registers and specialised databases from inception to 9 July 2025. We included randomised controlled trials (RCTs) and comparative observational studies. Study selection and data extraction were performed independently by two reviewers. Risk of bias was assessed using Risk of Bias in Non-Randomised Studies of Interventions or Risk of Bias 2. Primary outcome was any MCM. Meta-analyses used fixed-effects and random-effects models (REM) based on adjusted or crude ORs. RESULTS: From 4311 records, we included 20 studies (18 cohorts, 1 case-control and 1 RCT) including 4260 HCQ-exposed and 361 802 unexposed-pregnancies. The risk of bias was serious (n=4), critical (n=15) and ‘some concern’ (n=1, RCT). A significant association was found between HCQ and any MCM (OR=1.27, 95% CI (1.11 to 1.45) for REM, I2=0.0%, Tau2=0, n=19 studies). The pooled association based on adjusted OR was also statistically significant (aOR 1.29, 95% CI (1.09 to 1.53) for REM, I²=0.0%, Tau2=0, n=8). The certainty of evidence was low. CONCLUSION: A slight association between HCQ exposure and MCM was observed, with low certainty of evidence. Given the well-established maternal/fetal benefits of HCQ in systemic lupus erythematosus, these results do not support changes in current clinical practice regarding its use during pregnancy. For other indications where alternatives exist, its use during pregnancy should be considered on a case-by-case basis. PROSPERO REGISTRATION NUMBER: CRD420250609725.