Review 2: "Covid-19 Vaccination and Menstrual Cycle Length in the Apple Women’s Health Study"

Jacqueline Maybin

doi:doi:10.1162/2e3983f5.5dd33a4e

Covid-19 vaccination and menstrual cycle length in the Apple Women’s Health Study

by Elizabeth A. Gibson, Huichu Li, Victoria Fruh, Malaika 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, and Shruthi Mahalingaiah

Show Description
dx.doi.org

Description

AbstractBackgroundCOVID-19 vaccination may be associated with change in menstrual cycle length following vaccination.MethodsWe conducted a longitudinal analysis within a subgroup of 14,915 participants in the Apple Women’s Health Study (AWHS) who enrolled between November 2019 and December 2021 and met the following eligibility criteria: were living in the U.S., met minimum age requirements for consent, were English speaking, actively tracked their menstrual cycles, and responded to the COVID-19 Vaccine Update survey. In the main analysis, we included tracked cycles recorded when premenopausal participants were not pregnant, lactating, or using hormonal contraceptives. We used conditional linear regression and multivariable linear mixed-effects models with random intercepts to estimate the covariate-adjusted difference in mean cycle length, measured in days, between pre-vaccination cycles, cycles in which a vaccine was administered, and post-vaccination cycles within vaccinated participants, and between vaccinated and unvaccinated participants. We further compared associations between vaccination and menstrual cycle length by the timing of vaccine dose within a menstrual cycle (i.e., in follicular or luteal phase). We present Bonferroni-adjusted 95% confidence intervals to account for multiple comparisons.ResultsA total of 128,094 cycles (median = 10 cycles per participant; interquartile range: 4-22) from 9,652 participants (8,486 vaccinated; 1,166 unvaccinated) were included. The average within-individual standard deviation in cycle length was 4.2 days. Fifty-five percent of vaccinated participants received Pfizer-BioNTech’s mRNA vaccine, 37% received Moderna’s mRNA vaccine, and 7% received the Johnson & Johnson/Janssen vaccine (J&J). We found no evidence of a difference between mean menstrual cycle length in the unvaccinated and vaccinated participants prior to vaccination (0.24 days, 95% CI: −0.34, 0.82).Among vaccinated participants, COVID-19 vaccination was associated with a small increase in mean cycle length (MCL) for cycles in which participants received the first dose (0.50 days, 95% CI: 0.22, 0.78) and cycles in which participants received the second dose (0.39 days, 95% CI: 0.11, 0.67) of mRNA vaccines compared with pre-vaccination cycles. Cycles in which the single dose of J&J was administered were, on average, 1.26 days longer (95% CI: 0.45, 2.07) than pre-vaccination cycles. Post-vaccination cycles returned to average pre-vaccination length. Estimates for pre vs post cycle lengths were 0.14 days (95% CI: −0.13, 0.40) in the first cycle following vaccination, 0.13 days (95% CI: −0.14, 0.40) in the second, −0.17 days (95% CI: −0.43, 0.10) in the third, and −0.25 days (95% CI: −0.52, 0.01) in the fourth cycle post-vaccination. Follicular phase vaccination was associated with an increase in MCL in cycles in which participants received the first dose (0.97 days, 95% CI: 0.53, 1.42) or the second dose (1.43 days, 95% CI: 1.06, 1.80) of mRNA vaccines or the J&J dose (2.27 days, 95% CI: 1.04, 3.50), compared with pre-vaccination cycles.ConclusionsCOVID-19 vaccination was associated with an immediate short-term increase in menstrual cycle length overall, which appeared to be driven by doses received in the follicular phase. However, the magnitude of this increase was small and diminished in each cycle following vaccination. No association with cycle length persisted over time. The magnitude of change associated with vaccination was well within the natural variability in the study population. Menstrual cycle change following COVID-19 vaccination appears small and temporary and should not discourage individuals from becoming vaccinated.

RR:C19 Evidence Scale rating by reviewer:

Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.

***************************************

Review:

This well written manuscript addresses an important public health issue. The methodologies used are appropriate and conclusions backed by data. The strengths of the study include its large sample size and longitudinal design, including retrospective and prospective data collection. There is appropriate limitation of selection and recall bias. There is appropriate consideration of covariates with one exception (detailed below). The authors set out to examine the impact of vaccination of menstrual cycle length and appropriately use FIGO AUB parameters for cycle frequency.

The major limitation of the data is lack of adjustment or record of COVID-19 infection, which is known to affect menstruation. Authors mention this at the end of their discussion but should include appropriate references to fully discuss this limitation. In addition, I would recommend use of menstrual ‘frequency’ in place of ‘length’, which is open to misinterpretation as ‘duration’. This will standardise menstrual terminology and increase the clarity of the manuscript. It is disappointing that the authors could not assess other menstrual parameters, including duration, regularity or volume. This is understandable but I would recommend that this is stated in the introduction.

This manuscript confirms findings previously published, some of which are mentioned in the discussion. I would recommend updating the discussion with recent publications, including DOI: 10.1089/jwh.2022.0097, DOI: 10.1371/journal.pone.0258314, doi.org/10.3389/frph.2022.952976, DOI: 10.1126/sciadv.abm7201. The authors appropriately state strengths and limitations of their work and highlight the more novel finding of menstrual cycle timing of vaccination and impact on frequency. The manuscript is well written, clear and accurately presented. Ethics and equality and diversity issues are adequately discussed.

Review 2: "Covid-19 Vaccination and Menstrual Cycle Length in the Apple Women’s Health Study"

Connections