In a recent study posted to the medRxiv* pre-print server, researchers in the United States (US) estimated the association between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination and menstrual cycle length in a large cohort of participants across the US. They focused their assessments on menstrual variations due to the type of coronavirus disease 2019 (COVID-19) vaccine and the timing of its administration.
Study: Covid-19 vaccination and menstrual cycle length in the Apple Women's Health Study. Image Credit: VonaUA / Shutterstock
By April 2022, over 11,000 women self-reported a menstrual-related issue to the US Vaccine Adverse Event Reporting System (VAERS). The adverse outcomes included alterations in menstrual characteristics, including cycle length, increased bleeding, and menstrual irregularities. This anecdotal evidence prompted researchers to improve their understanding of these associations and inform clinicians in counseling women concerning COVID-19 vaccination.
About the study
In the present study, researchers used data from Apple's Women's Health Study (AWHS) to evaluate the temporal evolution of the relationship between COVID-19 vaccination and menstrual cycle length. They compared pre-vaccination menstrual cycle lengths, cycles in which a vaccine dose was administered, and cycles following COVID-19 vaccination. All the study participants were over 18 years old females living in the US who had menstruated at least once, could communicate in English, and owned an iPhone with a compatible iOS version.
These females provided baseline menstrual status along with their demographic details at enrollment. Following enrollment, the researchers surveyed regarding their menstrual health monthly. The team from the National Institute of Environmental Health Science, Health, Apple Inc, and Harvard T.H. Chan School of Public Health inquired about the date of the first and second vaccine dose, the vaccine type, and symptoms in the 48 hours following vaccination from those participants who received a COVID-19 vaccine post-September 2021. The participants used the Apple Health app or a third-party app to track their menstrual cycle with associated dates.
The team limited the study analysis to four cycles post-vaccination. They further categorized vaccination as having occurred during the follicular or luteal phase of a menstrual cycle to assess the impact of the timing of the dose within a menstrual cycle. Since previous studies have suggested a non-linear relationship between age and menstrual cycle length, the team categorized each participant based on age for this analysis. Further, they stratified participants as underweight, normal, overweight, or obese based on their self-reported body mass index (BMI). The study included months and years of the cycle to control the effect of seasonality and pandemic stressors.
Further, the researchers included participant ID as a subject-level fixed effect in conditional linear regression models to estimate the covariate-adjusted within-woman difference and 95% confidence intervals (95% CIs) in the mean cycle length. Finally, the model compared the vaccinated and post-vaccination cycles of each participating female to their pre-vaccine cycles (control cycles).
As per the International Federation of Gynecology and Obstetrics, a menstrual cycle occurring at more than 38 days is a long cycle. The team used generalized estimating equations (GEE) to fit a logistic regression model that computed odds ratio (ORs) and 95% CI for the association between COVID-19 vaccination and the likelihood of a long cycle in vaccinated participants compared with unvaccinated participants. Lastly, the team used two sensitivity analyses to assess the robustness of their primary analysis.
The current study analysis covered 128,094 menstrual cycles of 9,652 participants, who recorded 13 cycles on average. Moreover, the average standard deviation in cycle length for any individual female was 4.2 days. Of all the vaccinated females, 55%, 37%, and 7% had received the Pfizer-BioNTech, Moderna, and Johnson & Johnson/Janssen (J&J) vaccine, respectively.
All vaccinated females had only slightly longer menstrual cycles than their pre-vaccination cycles. On average, the single dose of the J&J vaccine increased the cycle length by 1.26 days. Further, the observed increase in the average length of menstrual cycles was negligible and non-persistent based on the number of vaccine doses (0.50 vs. 0.39 days after the first and second vaccine doses). Moreover, menstrual cycle lengths returned to average pre-vaccination values within 0.14 days to -0.25 days between the first to fourth menstrual cycle following vaccination.
However, the authors observed an association between vaccination and the menstrual cycle phase(s). Subsequently, vaccine doses received in the follicular phase increased the mean cycle length observed in the preliminary study results. Also, when a female received the second vaccine dose in the luteal phase, the subsequent menstrual cycle, on average, was shorter. The covariate-adjusted mixed-effects model and the GEE results did not vary much between vaccinated and unvaccinated participants. The mean menstrual cycle length was 0.24 days for the former, and ORs for the GEE was 1.20.
The current work showed that COVID-19 vaccination was safe for menstruating females, with no adverse effect on fertility. Although vaccination slightly increased menstrual cycle length; yet, it remained well within the natural variability observed in the study population. The alteration in cycle length following vaccination was likely due to vaccine doses received in the follicular phase of the menstrual cycle. However, these changes diminished gradually with each cycle, and none persisted over time. To conclude, since the observed changes in the menstrual cycle were only minor and transient, they should not discourage females from taking the COVID-19 vaccination.
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
- Covid-19 vaccination and menstrual cycle length in the Apple Women's Health Study, Elizabeth A Gibson, Huichu Li, Victoria Fruh, Malaika P Gabra, Gowtham Asokan, Anne Marie Z Jukic, Donna D Baird, Christine L Curry, Tyler Fischer-Colbrie, Jukka-Pekka Onnela, Michelle A Williams, Russ Hauser, Brent A Coull, Shruthi Mahalingaiah, medRxiv pre-print 2022, DOI: https://doi.org/10.1101/2022.07.07.22277371, https://www.medrxiv.org/content/10.1101/2022.07.07.22277371v1