Ductus Arteriosus Variability Linked to Maternal Drug Exposure: Assessment of the USFDA Adverse Event Reporting System using Disproportionality Analysis.

Abstract

Introduction: The ductus arteriosus is a vital fetal vessel connecting the pulmonary artery to the aorta, facilitating blood flow away from the non-functional fetal lungs. Drug exposure during pregnancy may affect DA physiology, leading to conditions like premature DA closure, DA stenosis, or Patent Ductus Arteriosus (PDA). To identify drugs with maternal exposure that may be linked to alterations in the fetal and neonatal Ductus Arteriosus (DA). This study examines associations between various drugs and alterations in DA using data from the USFDA Adverse Event Reporting System (AERS) through disproportionality analysis.

Methods: Data from March 2004 to June 2024 were extracted from the AERS database, focusing on MedDRA Preferred Terms (PTs) for PDA, DA premature closure, and DA stenosis, combined with "fetal exposure during pregnancy." Following deduplication, 1,878 unique cases (PDA: 1,444; DA stenosis: 213; DA closure: 221) were analyzed. Disproportionality signals were detected using frequentist [Reporting Odds Ratio and Proportional Reporting Ratio (PRR)] and Bayesian (Bayesian Confidence Propagation Neural Network and Multi-Item Gamma Poisson Shrinker) methods to assess associations. Signals were considered when there were at least three cases, a PRR value of ≥ 2, and a Chi-square (χ2) value of ≥ 4 according to Evan's criteria. Amongst the Bayesian methods, signals were considered when the lower limit of the IC's 95% CI (IC025) >0 and the lower limit of the 95% CI of the Empirical Bayes Geometric Mean (EBGM05) exceeded 2.

Results: Diclofenac had the highest number of reports for DA stenosis (number of reports: 118; PRR: 163; χ2: 8401.7; IC025: 4.7; and EBGM05: 55.9) and premature closure stenosis (number of reports: 68; PRR: 58.3; χ2: 2612.8; IC025: 4; and EBGM05: 30.6). Drugs linked with DA stenosis included analgesics (e.g., acetaminophen), antiemetics, and anti-inflammatory agents (e.g., ibuprofen). Premature DA closure was associated with analgesics, anti-inflammatory drugs, and psychoanaleptics. For PDA, signals were detected for a broad spectrum of drugs, including analgesics, antibacterials, anesthetics, antiepileptics, and antihypertensives. PDA cases showed a significantly higher rate of mortality compared to other DA conditions.

Discussion: These findings highlighted significant associations between maternal drug exposure and DA alterations, reinforcing known risks (such as NSAID-induced DA closure) and suggesting potential signals for SSRIs and antiepileptics. These results align with established pharmacological mechanisms and regulatory warnings, but must be interpreted cautiously given the limitations of spontaneous reporting data. The study underscores the need for targeted fetal monitoring, provider education, and prospective research to validate signals and refine drug safety guidelines in pregnancy.

Conclusion: This disproportionality analysis identified significant associations between maternal drug exposure and alterations in the fetal and neonatal DA, including premature closure, stenosis, and PDA. The findings highlighted the need for further pharmacovigilance studies to validate these signals, particularly for drugs with strong disproportionality signals but limited mechanistic evidence. Future research should focus on prospective cohort studies and mechanistic investigations to clarify causality and assess clinical implications. Additionally, risk-benefit evaluations of drug use during pregnancy, especially for analgesics, anti-inflammatory agents, and psychoanaleptics, are warranted to guide safer therapeutic decisions.