Maternal Dipyrone Exposure and Risk of Major Congenital Malformations, Adverse Perinatal and Postnatal Outcomes: A Population‐Based Cohort Study

Pain and fever are common in pregnancy. Dipyrone is widely used in Europe, Latin America, and parts of Asia, but is banned in other countries due to concerns about agranulocytosis. Evidence on its safety in pregnancy remains limited and inconsistent. This study aimed to evaluate whether maternal dipyrone use during the first‐ and third‐trimesters is associated with major congenital malformations (MCMs) and adverse perinatal or early neonatal outcomes. A population‐based cohort of all pregnancies that delivered or underwent elective termination at Soroka University Medical Center from 1998 to 2018, linking maternal, neonatal, and termination records with pharmacy dispensations. Generalized full matching and Poisson regression were used to study the association of first‐and third‐trimester dipyrone exposure and risks of MCMs, perinatal outcomes, and early neonatal complications, including preterm ductal closure and renal injury. Among 264,858 singleton pregnancies analyzed for first‐trimester exposure, 8,987 (3.4%) were exposed to Dipyrone. MCMs occurred in 8.0% of exposed vs. 7.0% of unexposed; however, no association was found after matching (adjusted risk ratio (RR) 1.04, 95% CI: 0.88–1.22). No associations were observed with malformation in other organ systems. In third‐trimester analyses ( n  = 257,285; 6,362 (2.5%) exposed), dipyrone was not associated with preterm birth, low birthweight, perinatal death, low Apgar scores, or evidence of renal toxicity or premature ductus arteriosus constriction. No dose–response was observed. Sensitivity Analysis for over‐the‐counter use indicated minimal possible misclassification bias. This study provides evidence supporting maternal dipyrone use in early or late pregnancy is not associated with MCMs, adverse perinatal outcomes, or early neonatal complications.