Comparative evaluation of pregnancy-related adverse events associated with proton pump inhibitors using the FDA...

Proton pump inhibitors (PPIs) are widely prescribed as acid-suppressive agents; however, their use during pregnancy remains controversial. Although generally considered safe, omeprazole is classified as Food and Drug Administration (FDA) pregnancy category C, whereas other PPIs are classified as category B, raising concerns regarding potential maternal and fetal risks. Clarifying the safety profile during pregnancy is critical to inform clinical decision making.

This study aimed to evaluate pregnancy-related adverse event (AE) signals associated with omeprazole, esomeprazole, lansoprazole, rabeprazole, and pantoprazole using data from the US FDA Adverse Event Reporting System (FAERS) from Q1 2004 to Q1 2025.

A total of 625,127 AE reports listing PPIs as primary suspect drugs were retrieved, among which 1,099 pregnancy-related reports were identified. Signal detection employs two disproportionality algorithms: the Reporting Odds Ratio (ROR) and Bayesian Confidence Propagation Neural Network (BCPNN). Each PPI was compared with all other drugs in the database, all other PPIs, and ranitidine, a comparator that is considered relatively safe during pregnancy.

Disproportionality signals for pregnancy-related AEs associated with PPIs included premature labor, low birth weight, fetal growth restriction (FGR), abortion, fetal macrosomia, pregnancy on contraception, morning sickness, pre-eclampsia, and hemorrhagic complications. Compared with all the other drugs, omeprazole showed notable signals of postpartum hemorrhage (ROR: 3.14, 95% CI 1.63-6.04; E(IC): 1.36, IC025:0.45), FGR (ROR: 2.14, 95% CI 1.52-3.01; E(IC): 1.046, IC025:0.55), and pre-eclampsia (ROR: 1.95, 95% CI 1.27-3; E(IC): 0.9, IC025:0.28). These associations persisted when compared with other PPIs or ranitidine. Pantoprazole showed consistent risk signal trends, such as premature labor (ROR: 1.48, 95% CI 1.26-1.74; E(IC): 0.56, IC025:0.32), low birth weight babies (ROR: 2.08, 95% CI 1.56-2.76; E(IC): 1.02, IC025:0.6), and morning sickness (ROR: 3.9, 95% CI 1.75-8.7; E(IC): 1.46, IC025:0.36).

This study detected potential disproportionality signals, suggesting an association between PPIs use during pregnancy and reported AEs. Certain signals appeared to be drug-specific rather than class-specific, such as omeprazole for postpartum hemorrhage and preeclampsia, lansoprazole for pregnancy on contraceptives, and pantoprazole for morning sickness. However, these findings should be regarded as exploratory and hypothesis generating, warranting cautious interpretation and confirmation through rigorously designed epidemiological and clinical studies.