Menstrual cycle phase and its association with COVID-19 vaccine side effects and subsequent infection: A study of period tracking app users

Abstract Despite known hormonal influences on immune function, the impact of menstrual cycle phase on vaccine side effects and subsequent infection risk remains unexplored. We used prospectively tracked cycle data from the period tracking app, Clue, matched with an in-app vaccine survey conducted between November 2021 and February 2022. In a sample of 1,474 cycling women, we compared reported side effect and post-vaccination infection outcomes of women vaccinated in the estrogen-dominant follicular phase of their cycle, with those vaccinated in the progesterone-dominant luteal phase. Side effect presence, severity and number were analysed using binary, ordinal, and negative binomial regression models respectively. Post vaccination time to infection (over 67-372 days of follow-up) was compared between the two groups using Wilcoxon rank-sum test and a Cox proportional hazards model. Follicular-phase vaccination was associated with 35% higher odds of reporting any side effects (OR: 1.35, 95% CI: 1.05–1.66) compared to luteal-phase vaccination. The association remained significant after excluding individuals vaccinated during the bleed phase, and the perimenstrual phase, indicating that hormonal environment, rather than inflammation caused by menstruation or premenstrual symptoms, may drive the association. Median time to infection was 35 days longer for those vaccinated in the follicular phase (Follicular: 200 (140,237) Luteal 165 (107, 2107), p = 0.05), suggesting potential longer-lasting protection from the vaccine. These findings suggest that menstrual cycle phase should be considered when studying sex-based immune differences and may inform future research on vaccination timing and personalised health strategies. Competing Interest Statement AAS, VJV, and KW were either employees or paid consultants of Biowink GmbH, the developers of the Clue app. The other authors did not report any potential conflicts of interest. Funding Statement The study was funded by UK Research and Innovation Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The London School of Hygiene and Tropical Medicine Observational/Interventional Research Ethics Committee gave Ethical Approval for this work. LSHTM Ethics Ref: 31539 I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability Aggregated data are available in Supplementary Information. The underlying database that supports the findings of this study was made available by Clue by BioWink GmbH. While it is de–identified, it cannot be made directly available to the reader. Researchers interested in gaining access to the underlying data can contact Clue by BioWink GmbH and establish a data use agreement with them.