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Sex Differences in the Risk of Cutaneous Adverse Drug Reactions Induced by Antiseizure Medications: A Systematic Review and Meta-analysis

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Abstract

Background

Cutaneous adverse drug reactions (cADRs) are one of the most common, severe, and life-threatening types of adverse reactions following treatment with antiseizure medications (ASMs). Some studies have reported a higher incidence of ASM-induced cADRs in females than in males.

Objective

This study sought to perform a systematic review, meta-analysis, and meta-regression to compare the ASM cADR risks between females and males.

Methods

We searched the literature using three databases (EMBASE, PubMed, and Web of Science) between October 1998 and November 2018, later updated to October 2019. Studies were included in the meta-analysis if they met the following criteria: (1) observational studies that estimated the incidence of cADRs related to ASMs; (2) provided the risk or odds ratio (OR) for cADRs among female and male patients exposed to ASMs; and (3) provided information on patients’ characteristics. We assessed the impact of study characteristics, publication bias, and measures to reduce bias, and performed a DerSimonian and Laird random effects meta-analysis.

Results

We included 28 studies in this review. Of these, seven studies were eligible for inclusion in the meta-analysis, involving a total of 223,209 patients. Overall, females were more likely to develop cADRs to ASMs than males (OR 1.76, 95% confidence interval [CI] 1.55–1.99). The largest differences were observed in patients prescribed lamotrigine (OR 2.17, 95% CI 1.53–3.08, p < 0.001) and carbamazepine (OR 1.63, 95% CI 1.02–2.60, p = 0.042). Also, the OR trended higher for phenytoin (OR 2.46, 95% CI 0.79–7.65, p = 0.12), followed by oxcarbazepine (OR 1.91, 95% CI 0.75–4.85, p = 0.18) and sodium valproate (OR 0.60, 95% CI 0.12–2.99, p = 0.53), but the difference did not reach statistical significance. In the remaining 21 studies, 13 reported numerically higher risk of cADRs among females compared to male patients, and in five of these, the difference was statistically significant.

Conclusion

Our findings confirmed that females are more susceptible to cADRs induced by ASMs than males. More research is needed to understand the pathophysiological mechanisms for this difference.

Protocol registration

PROSPERO (CRD42018111943).

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Authors and Affiliations

  1. Melbourne Brain Centre, Royal Melbourne Hospital, University of Melbourne, Parkville, VIC, Australia

    Israa Alfares & Patrick Kwan

  2. Department of Neuroscience, Central Clinical School, Monash University, Alfred Hospital, Melbourne, VIC, Australia

    Muhammad Shahid Javaid, Zhibin Chen, Alison Anderson, Ana Antonic-Baker & Patrick Kwan

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  1. Israa Alfares
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Correspondence to Patrick Kwan.

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Funding

No specific funding has been received for the conduct of this study and/or preparation of this manuscript. Israa Alfares was supported as a domestic graduate student by the University of Melbourne and in collaboration with Melbourne Brain Centre at Royal Melbourne Hospital. Muhammad Shahid Javaid is supported by a Monash Graduate Scholarship and Monash International Tuition Scholarship. Zhibin Chen is supported by the NHMRC Early Career Fellowship. Patrick Kwan is supported by a Medical Research Future Fund Fellowship (MRF1136427).

Conflict of interest

Patrick Kwan has received research grants, consulting fees, and speaker fees from Eisai and UCB Pharma, and speaker fees from LivaNova. Zhibin Chen has received a research grant from UCB Pharma. All other authors have no conflicts of interest relevant to the content of this study.

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Author contributions

IA was the first reviewer of the first- and second-level screening, designed the protocol, formally screened the search results against the eligibility criteria, conducted data extraction, interpreted the results, and drafted the manuscript. MSJ was the second reviewer of the first-level screening (abstract and title). ZC conducted the statistical analysis. AA-B designed the protocol, conducted data extraction, and drafted the manuscript. AA drafted and critically reviewed the manuscript and supervised the study. PK designed the protocol, interpreted the results, drafted the manuscript, and supervised the study. All authors contributed to the final manuscript.

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Alfares, I., Javaid, M.S., Chen, Z. et al. Sex Differences in the Risk of Cutaneous Adverse Drug Reactions Induced by Antiseizure Medications: A Systematic Review and Meta-analysis. CNS Drugs 35, 161–176 (2021). https://doi.org/10.1007/s40263-021-00794-0

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