Paracetamol exposure during pregnancy, the risk of major congenital malformations, and perinatal and postnatal outcomes: a population-based cohort study

STUDY QUESTION: Is maternal paracetamol exposure during the first and third trimesters of pregnancy associated with major congenital malformations and adverse perinatal and postnatal outcomes? SUMMARY ANSWER: Maternal paracetamol use during the first or third trimester was not associated with major congenital malformations or adverse perinatal and postnatal outcomes. WHAT IS KNOWN ALREADY: Paracetamol is the most commonly used analgesic and antipyretic during pregnancy and has long been considered safe. However, recent concerns have been raised regarding potential fetal and perinatal risks, with inconsistent findings across studies. STUDY DESIGN, SIZE, DURATION: In this population-based retrospective study, the cohort included 265 143 singleton pregnancies resulting in delivery or elective termination at a single tertiary medical center between 1998 and 2018. Separate analytic cohorts comprised 264 858 pregnancies for first-trimester analyses and 257 285 pregnancies for third-trimester analyses. Follow-up extended through delivery and the first year of life for congenital malformation ascertainment. There was no loss to follow-up for primary outcomes due to complete registry linkage. PARTICIPANTS/MATERIALS, SETTING, METHODS: All singleton pregnancies among women aged 15–45 years, insured by a regional health maintenance organization and managed at a tertiary university medical center, were included. Pregnancies with chromosomal or genetic abnormalities, teratogenic drug exposure, or multiple gestations were excluded. Paracetamol exposure (prescription and over-the-counter dispensations) was assessed separately for the first trimester (≤13 weeks) and third trimester (≥27 weeks) and categorized by total defined daily doses. Exposed and unexposed pregnancies were compared using multivariable Poisson regression and propensity score-based generalized full matching. Matching incorporated maternal demographics, comorbidities, pregnancy characteristics, and indications for paracetamol use. After matching, covariate balance was achieved (standardized mean differences <0.1 for all variables). MAIN RESULTS AND THE ROLE OF CHANCE: During the first trimester, paracetamol exposure was recorded in 41 011 pregnancies (15.5%); major congenital malformations occurred in 7.9% of exposed versus 6.9% of unexposed pregnancies (crude RR 1.14; 95% CI, 1.1–1.18), with no association after matching (adjusted RR 1.04; 95% CI, 0.98–1.10) and no associations with organ-specific malformations. Third-trimester exposure was recorded in 36 375 pregnancies (14.1%) and was not associated, in the matched analyses, with preterm birth, low or very low birth weight, perinatal death, low Apgar scores, or markers of premature ductus arteriosus closure or neonatal renal impairment. Dose–response and sensitivity analyses showed no evidence of increased risk, and the results were robust to plausible levels of exposure misclassification. LIMITATIONS, REASONS FOR CAUTION: Paracetamol exposure was based on dispensation rather than confirmed intake, and miscarriages were not captured. Exposure misclassification due to unrecorded over-the-counter use is possible; however, sensitivity analyses suggest it is unlikely to materially affect the findings. WIDER IMPLICATIONS OF THE FINDINGS: These findings are consistent with large cohort studies and contribute to the evidence supporting the relative safety of paracetamol use during early and late pregnancy. STUDY FUNDING/COMPETING INTEREST(S): No funding was received for this study. All authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.