Association Between Menstrual Cycle Length and Coronavirus Disease 2019 (COVID-19) Vaccination: A U.S. Cohort
Authors: Carlotta Favaro
Blair G Darney
Eleonora Benhar
Emily R Boniface
Leo Han
Alison Edelman
Jack T Pearson
Kristen A Matteson
Journal: Obstetrics and Gynecology (2022)
Discipline: CLINICAL MEDICINE
Keywords: COVID-19 vaccination; cycle length; menses length; Natural Cycles; Pfizer-BioNTech
Affiliations: Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, Oregon; Natural Cycles USA Corp, New York, New York; the Department of Obstetrics & Gynecology, Women & Infants Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island; Oregon Health & Science University-Portland State University, School of Public Health, Portland, Oregon; and the National Institute of Public Health, Center for Population Health Research, Cuernavaca, Morelos, Mexico.

Abstract:  Objective: To assess whether coronavirus disease 2019 (COVID-19) vaccination is associated with changes in cycle or menses length in those receiving vaccination as compared with an unvaccinated cohort. Methods: We analyzed prospectively tracked menstrual cycle data using the application "Natural Cycles." We included U.S. residents aged 18-45 years with normal cycle lengths (24-38 days) for three consecutive cycles before the first vaccine dose followed by vaccine-dose cycles (cycles 4-6) or, if unvaccinated, six cycles over a similar time period. We calculated the mean within-individual change in cycle and menses length (three prevaccine cycles vs first- and second-dose cycles in the vaccinated cohort, and the first three cycles vs cycles four and five in the unvaccinated cohort). We used mixed-effects models to estimate the adjusted difference in change in cycle and menses length between the vaccinated and unvaccinated cohorts. Results: We included 3,959 individuals (vaccinated 2,403; unvaccinated 1,556). Most of the vaccinated cohort received the Pfizer-BioNTech vaccine (55%) (Moderna 35%, Johnson &amp; Johnson/Janssen 7%). Overall, COVID-19 vaccine was associated with a less than 1-day change in cycle length for both vaccine-dose cycles compared with prevaccine cycles (first dose 0.71 day-increase, 98.75% CI 0.47-0.94; second dose 0.91, 98.75% CI 0.63-1.19); unvaccinated individuals saw no significant change compared with three baseline cycles (cycle four 0.07, 98.75% CI -0.22 to 0.35; cycle five 0.12, 98.75% CI -0.15 to 0.39). In adjusted models, the difference in change in cycle length between the vaccinated and unvaccinated cohorts was less than 1 day for both doses (difference in change: first dose 0.64 days, 98.75% CI 0.27-1.01; second dose 0.79 days, 98.75% CI 0.40-1.18). Change in menses length was not associated with vaccination. Conclusion: Coronavirus disease 2019 (COVID-19) vaccination is associated with a small change in cycle length but not menses length. 

Retracted: No

PubPeer comments:
 Thank you for this interesting study which is well written and the many funding declarations clearly stated. Please could you clarify the following; (1) Why were women with aberrant cycles (including PCOS and long cycles) excluded from the study given that potentially that group could be most suspectible to any interference with the hypothalimic-pituitary-ovarian axis? If the long cycle patients were excluded on the basis of a need to study  x number of cycles in the study time, could an alternative approach (e.g. within group comparison. serial estradiol or AMH levels) have been used to include this important group? (2) why were endometriosis patients excluded? (3) why were no comments made about the rates of amenorrhoea in each group, given that this is likely the most important factor to exclude to demonstrate safety in this area? Given the large cohort of regularly-cycling women and the expectation of a minimal deviation in the majority of participants, a simple cohort comparison is insufficiently robust to identify the small percentage of women who may be significantly affected. This is particularly relevant to the group of 358 women who appeared to be most affected but on one hand had a  non significant change in cycle length yet on the other hand  individuals receiving two doses in a single cycle return to baseline cycle length quickly... our data do not yet include enough subsequent cycles without vaccine to investigate this fully . This appears to suggest that there is a small but important cohort of women in the study that were severely affected and this should be clarified with a clear statement on the rate of amenorrhoea or persistent long cycle in the cohort. As with all studies in major journals since 2018, the full dataset should be available for inspection. Please could you include a link for the full (deidentified) data set? https: www.thelancet.com journals lancet article PIIS0140-6736(17)31282-5 fulltext Thank you again for this interesting paper. ,