Limitations of FAERS‐based analyses of paternal drug exposure: The critical need for maternal data integration

Dear Editor, We read the recent article by Zeng et al.,1 who analysed more than 16 million reports in the US Food and Drug Administration Adverse Event Reporting System (FAERS) to evaluate associations between paternal drug exposure and adverse reproductive or developmental outcomes.1 The study represents an important attempt to systematically address a neglected area—whether paternal medication use may influence fertility, pregnancy, and offspring health. While we commend the authors for highlighting this underexplored field, we would like to raise several concerns regarding interpreting their findings and the need for future research directions.1 We acknowledge that Zeng et al. themselves note several limitations, including the lack of maternal exposure information. Our intent is to clarify why this omission is decisive rather than incremental for causal inference and to outline the minimum data elements and study designs required to resolve it. The authors appropriately acknowledge key limitations of FAERS data: reporting bias, under-reporting of common events and difficulty establishing causality in the context of concomitant disease and medication use.1 The most critical limitation, however, is the absence of maternal clinical information. Maternal medical conditions, lifestyle and direct maternal drug exposure strongly determine pregnancy outcomes. Without such data, the possibility of substantial confounding is unavoidable. Therefore, signals detected in FAERS should be interpreted as hypothesis-generating rather than evidence of causal paternal effects.1 Some drugs taken by men can appear in semen and, in theory, be absorbed across the vaginal mucosa; however, quantities are tiny and systemic absorption by the female partner is minimal.2, 3 A limited group of drugs—most notably cytotoxic chemotherapy and certain immunosuppressive agents—poses theoretical risks around conception, for which medical guidance to delay fatherhood can be appropriate.3, 4 Various medications can affect semen parameters; such effects are generally reversible after drug cessation.2 By contrast, cytotoxic agents may cause persistent impairment, and sperm preservation is recommended prior to therapy.3, 4 Notably, reduced fertility does not necessarily translate into increased teratogenic risk, since severely impaired spermatozoa may not achieve fertilization. Emerging research suggests paternal exposures (e.g., smoking, diet or drug treatments) can alter sperm DNA methylation or chromatin structure, potentially influencing offspring development; most evidence remains preclinical and causality in humans is difficult to establish.2 At present, clinical relevance remains speculative. Zeng et al. have drawn attention to an important and understudied topic. Their report should stimulate further discussion, but interpretation of paternal drug exposure signals from FAERS requires extreme caution, especially given the absence of maternal data. Future investigations should prioritise comprehensive datasets that integrate both parents’ exposures to enable more accurate and clinically meaningful risk assessments for families planning pregnancy.