Association between in utero exposure to acetaminophen and external genital tract malformations in boys and girls: a systematic review and meta-analysis

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STUDY QUESTION: Is the use of acetaminophen during pregnancy associated with external genital tract malformations in boys and girls? SUMMARY ANSWER: This meta-analysis found no evidence linking in utero acetaminophen exposure to external genital malformations in boys but further research focusing on girls and considering relevant confounding factors is needed. WHAT IS KNOWN ALREADY: Acetaminophen is widely used by pregnant women, but findings are conflicting regarding a possible increased risk of genital malformations in the offspring of both sexes. STUDY DESIGN, SIZE, DURATION: In this systematic review and meta-analysis, we searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, International Clinical Trials Registry Platform, ClinicalTrials.gov on 18 April 2024, and subsequently updated the search on 20 September 2025 for randomized controlled trials and observational studies. This meta-analysis included randomized controlled trials and observational studies focusing on the association between in utero exposure to acetaminophen, with no restriction on publication dates and languages. PARTICIPANTS/MATERIALS, SETTING, METHODS: Two reviewers independently screened studies, extracted data, and assessed risk of bias. The two primary outcomes were a composite endpoint including cryptorchidism, hypospadias, and penile hypoplasia in boys, and a composite outcome including clitoral enlargement, labial fusion, vulvar malformations, and rectovaginal fistula in girls. Secondary outcomes included individual genital malformations and differences in anogenital distance (AGD). GRADE was used to evaluate the level of certainty. MAIN RESULTS AND THE ROLE OF CHANCE: Ten observational studies were included. Regarding boys, meta-analysis of the predefined primary outcome could not be performed as no studies reported penile hypoplasia. Another composite endpoint including cryptorchidism and/or hypospadias was reconstructed and no significant association was found with acetaminophen, pooled crude odds ratio (OR) 1.27 [95% CI (0.18, 8.94), studies = 2, participants = 155 362, I2=79%, phet=0.03, random-effects model (REM)]. No significant association was found for cryptorchidism or hypospadias separately based on adjusted estimates with pooled OR of 1.02 [95% CI (0.78, 1.35), studies = 3, participants = 155 852, I2=32%, phet=0.23, REM] and 1.02 [95% CI (0.89, 1.17), studies = 3, participants = 159 572, I2=40%, phet=0.19, REM], respectively. No significant difference was found for short AGD. No meta-analysis was possible for girls for any of the predefined outcomes due to lack of data. The level of certainty was low to very low. LIMITATIONS, REASONS FOR CAUTION: The predefined primary outcomes in boys and girls could not be fully evaluated. Small study effects could not be assessed as the number of included studies was limited. There was significant heterogeneity in the reporting of results and information regarding maternal characteristics was lacking. Lastly, all included studies had a serious or critical risk of bias due to the limited control of confounding factors and the level of certainty was low to very low. WIDER IMPLICATIONS OF THE FINDINGS: Acetaminophen remains an indispensable medication and abstaining from pain and fever treatment during pregnancy may have harmful effects on the developing fetus. Further research on external genital malformation risks following in utero exposure to acetaminophen should be directed toward developing validated and robust drug-exposure and outcome assessment tools, that control for confounding factors and confounding by indication. STUDY FUNDING/COMPETING INTEREST(S): No funding was used to conduct this study. No relationship or activity could appear to have influenced the submitted work. REGISTRATION NUMBER: CRD42024536483, available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024536483.

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