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Review 3: "Covid-19 Vaccination and Menstrual Cycle Length in the Apple Women’s Health Study"

Reviewers found this study to be potentially informative to reliable, with one reviewer suggesting clearer justifications of the analytic methods.

Published onAug 05, 2022
Review 3: "Covid-19 Vaccination and Menstrual Cycle Length in the Apple Women’s Health Study"
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key-enterThis Pub is a Review of
Covid-19 vaccination and menstrual cycle length in the Apple Women’s Health Study
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.

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Review:

Gibson et al. have replicated the findings of another large sample of women (Edelman et al, reference 20) using the Natural Cycles App, showing a <1 day difference in cycle length associated with the COVID-19 vaccination. The sample size in Gibson et al. was larger, and they were able to suggest a possible driver of this change being receiving the vaccination in the follicular phase of the menstrual cycle. They admit (and I agree) that their estimate of the follicular phase was limited in that they had no estimate of ovulation. Our recent study did track ovulation^1 which they failed to reference. In our population, we compared prospectively tracked cycles with subjective impression of change and showed that in women who perceived ovulation changes there was delayed ovulation in the vaccine cycles that returned to normal but did not have adequate power to demonstrate this is the small sub-group. Considering Gibson et al’s finding of a very minor lengthening in menstrual cycles in their large sample which coincides with Edelman et al’s findings in another large sample, their claims seem generally supported, although their proposed mechanism in the Discussion regarding systemic inflammation is entirely speculative and the list of references (41-43) do not seem to fit tightly with their findings. I would suggest that there may be a slight delay in ovulation in a subgroup of women when putting together the findings of increased cycle length with our findings of possible delayed ovulation^1. The mechanism of delayed ovulation may be via an inflammatory pathway, but there have not been any studies to demonstrate this.

Although the strength is in sample size and a diverse population studied, future studies should include objective measures of ovulation to better delineate the follicular and luteal phases, because their basic calculation (follicular phase = first 14 days of the cycle) likely misrepresents ovulation in many cycles. This is especially important given their main conclusion relates to the follicular phase which they have not objectively measured, specifically that vaccination in the purported follicular phase is what drives the longer cycle lengths.

Finally, I would recommend filling out the reference list with several more studies besides ours^1 and consider adding some published and pre-print studies that are relevant to this topic:

  • Alvergne A, Kountourides G, Argentieri MA, et al. COVID-19 vaccination and menstrual cycle changes: A United Kingdom (UK) retrospective case-control study. Medrxiv 2021;2021.11.23.21266709; doi: 10.1101/2021. 11.23.21266709.

  • Nguyen BT, Pang RD, Nelson AL, et al. Detecting variations in ovulation and menstruation during the COVID-19 pandemic, using real-world mobile app data. PLoS One 2021;16(10):e0258314; doi: 10.1371/journal.pone.0258314

  • Ozimek N, Velez K, Anvari H, et al. Impact of stress on menstrual cyclicity during the coronavirus disease 2019 pandemic: A survey study. J Womens Health (Larchmt) 2022;31(1):84–90; doi: 10.1089/jwh.2021.0158.

  • Phelan N, Behan LA, Owens L. The impact of the COVID- 19 pandemic on women’s reproductive health. Front En- docrinol 2021;12:642755; doi: 10.3389/fendo.2021.642755

  • Wesselink AK, Hatch EE, Rothman KJ, et al. A prospective cohort study of COVID-19 vaccination, SARS-CoV-2 in- fection, and fertility. Am J Epidemiol 2022;kwac011; doi: 10.1093/aje/kwac011.

1-Bouchard, T. P., Schneider, M., Schmidt, M., Manhart, M. & Fehring, R. J. Menstrual Cycle Parameters Are Not Significantly Different After COVID-19 Vaccination. J Women’s Heal (2022) doi:10.1089/jwh.2022.0097.

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