Maternal paracetamol intake and fetal ductus arteriosus constriction/closure: comprehensive signal evaluation using the Austin Bradford Hill criteria.

PURPOSE

Acetaminophen (APAP) is available over-the-counter and widely regarded as safe for use in pregnancy. APAP has been used to close a persistently patent ductus arteriosus. Fetal constriction/closure of the ductus arteriosus (FCCDA), of public health interest given the drug's widespread use during pregnancy, is being monitored globally, including by the European Medicines Agency Pharmacovigilance Risk Assessment Committee. Our objective was to share a comprehensive signal evaluation of FCCDA with in utero APAP exposure to determine if the totality of evidence is sufficiently more consistent with one of the following two possibilities: (1) APAP never contributes to FCCDA (null hypothesis or H) versus (2) APAP may in some cases be at least a contributory cause of in utero DA narrowing (alternative hypothesis or H) to justify risk communication.

METHODS

To assess the relative support for H versus H, we synthesize and interpret within an Austin Bradford Hill criteria framework a comprehensive, cross-disciplinary set of published information and de novo analysis, including toxicology, epidemiology, clinical pharmacology, and clinical and quantitative pharmacovigilance analysis of spontaneous reports.

RESULTS

While residual uncertainty remains, the totality of information is more compatible with H than H, to the extent that it is reasonably possible that APAP may sometimes be at least a contributory cause of FCCDA.

CONCLUSION

It is reasonably possible that APAP may sometimes be at least a contributory cause of FCCDA, and this should therefore be communicated to stakeholders.

TRIAL REGISTRATION

CLINICALTRIALS.

GOV REGISTRATION

NOT APPLICABLE.