{"paper_id":"34afedf9-5550-4cb2-b0ff-d090d7edb04b","body_text":"Effect of COVID-19 vaccination on menstrual\nperiods in a prospectively recruited cohort\nEe Von Woon1 and Victoria Male1\n1Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK\nCOVID-19 vaccination protects against the potentially serious\nconsequences of SARS-CoV2 infection, but some people have\nbeen hesitant to receive the vaccine because of reports that it\ncould affect menstrual bleeding. To determine whether this oc-\ncurs, we prospectively recruited a cohort of 79 individuals, each\nof whom recorded details of at least three consecutive menstrual\ncycles, during which time they each received at least one dose\nof COVID-19 vaccine. We find that either dose of the COVID-\n19 vaccine is associated with a delay to the subsequent period\nin spontaneously cycling participants (2.3 days after dose 1; 1.3\ndays after dose 2) but this change rapidly reverses. No change to\ntiming was detected in those on hormonal contraception. We de-\ntected no change in menstrual flow associated with either dose\nof the vaccine, in either spontaneously cycling participants or\nthose on hormonal contraception. We detected no association\nbetween menstrual changes and other commonly-reported side\neffects of vaccination, such as sore arm, fever and fatigue.\nCorrespondence: v.male @imperial.ac.uk\nIntroduction\nAs the UK COVID-19 vaccination programme was rolled out\nto younger participants, the MHRA’s surveillance scheme,\nYellow Card, increasingly received reports from people who\nhad noticed a change to their menstrual cycle following vac-\ncination: at 29 March 2022, 39,494 individuals had made\nsuch reports to Yellow Card [1]. It is important to note that\nmost people who report such a change following vaccination\nfind that their period returns to normal the following cycle\n[2] and extensive investigation has found no evidence that\nCOVID-19 vaccination adversely impacts female fertility [3-\n10]. Nonetheless, people are concerned by these reports. In-\nvestigating the potential link between COVID-19 vaccination\nand menstrual changes is important for maintaining public\ntrust in the vaccination programme and, if a link is found, to\nallow people to plan for potential changes to their cycles [11].\nIn response to similar reports to the USA’s vaccine safety\nsurveillance scheme, V AERS, the National Institutes of\nHealth allocated $1.67m (£1.2m;\nC1.4m) for studies into\na possible connection between COVID-19 vaccination and\nmenstrual changes [12] and the first of these studies has re-\ncently reported [13]. The authors used prospectively logged\ndata from a menstrual cycle tracking app: 3959 Americans\nlogged at least six consecutive cycles; 2403 of them were\nvaccinated and 1556 acted as a control group. In individuals\nreceiving only one dose of the vaccine per cycle, the first dose\nof vaccine had no effect on timing of the subsequent period,\nwhile the second dose was associated with a delay of 0.45\ndays. Individuals who received both doses of the vaccine in a\nsingle cycle experienced a 2.32 day delay to their next period.\nIn all groups, cycle lengths returned to normal by two cycles\nafter vaccination.\nA Norwegian study used mobile-phone questionnaires to ret-\nrospectively solicit reports of menstrual changes from 5688\nwomen aged 18-30 years who had been recruited prospec-\ntively to the Norwegian Young Adult Cohort [14]. This study\nfound high levels of variation, even in unvaccinated cycles,\nwith 37.8% of participants reporting at least one difference\nfrom normal in their pre-vaccination cycles. However, the\nstudy was still able to identify heavier than normal bleeding\nas a change associated with vaccination, with a relative risk\nof 1.9 after the first dose of the vaccine and 1.8 after the sec-\nond dose.\nHere, we describe the effects of COVID-19 vaccination on\nmenstrual timing and flow in a cohort of 79 individuals who\nregularly experience either menstrual periods or withdrawal\nbleeding as a result of breaks in taking hormonal contracep-\ntion. These people were recruited before receiving either\ntheir first or second dose of the COVID-19 vaccine, and kept\na daily record of their vaginal bleeding, and of any vaccine\nside effects they experienced.\nMethods\nCohort. 253 people who were over 18, have regular periods\nor withdrawal bleeds and who were planning to receive ei-\nther their first or their second dose of the COVID-19 vaccine\nwere recruited by advertising on social media and in newslet-\nters with a largely female readership in the UK. Of these, 43\nwithdrew for reasons including pregnancy, having entered the\nmenopause, having received a diagnosis of a gynaecological\ncondition that they felt was affecting their periods, or not hav-\ning the time to journal every day (Figure 1). Of the remaining\nparticipants, 87 returned their journals and 79 of these jour-\nnals logged at least three consecutive cycles, including one in\nwhich a dose of the vaccine was given. Those who did not\nreturn their journals were contacted up to twice to find out\nwhy they had not completed their journals: 31 participants\nresponded and 92 were lost to follow up.\nJournals recorded the participant’s age, reproductive his-\ntory, use of hormonal contraception during the study period,\nbreastfeeding during the study period and whether they have\never been diagnosed with a menstrual or gynaecological con-\ndition (Table 1). Participants then completed a daily journal\nWoon et al. | bioRχiv | March 30, 2022 | 1–5\n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 30, 2022. ; https://doi.org/10.1101/2022.03.30.22273165doi: medRxiv preprint \nNOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.\n\nFigure 1. Cohort flowchart.\nin which they reported their bleeding as “heavier than usual\nfor this day of my cycle”, “normal”, “lighter than usual for\nthis day of my cycle”, “spotting (normal for me)”, “spotting\n(not normal for me)” or “no bleeding”. For each cycle, par-\nticipants also reported whether their period had come on the\nday they had expected it, and if not how many days early or\nlate it was. Participants noted the day on which they received\na dose of the vaccine, which brand they received, whether\nit was the first or second dose, and for seven days afterwards\nrecorded whether they experienced any of the following: sore\narm, fever, fatigue, headache, body aches.\nThe study was approved by the Research Governance and\nIntegrity Team at Imperial College London, study number\n21IC6988.\nStatistical analysis. The timing of each cycle was desig-\nnated as “0” when the period or withdrawal bleed started on\nthe expected day, with negative values indicating days early\nand positive values days late. For each cycle, a “flow score”\nwas calculated by assigning “no bleeding” as 0, “spotting\n(normal for me)” and “spotting (not normal for me)” as 1,\n“lighter than usual” as 3, “normal” as 5 and “heavier than\nusual” as 7, and then totalling the responses for the first seven\ndays of the cycle. Where participants logged more than one\ncycle in a particular category (for example, pre-vaccine, in-\nterdose or post-vaccine cycles) the mean of the timing and\nflow scores was taken.\nFor each dose of the vaccine, a “side effect score” was cal-\nculated by the total number of days that the participant re-\nsponded “yes” to each of the side effect questions.\nChanges in cycling timing and flow score were assessed us-\ning a mixed-effects model, with the Geisser-Greenhouse cor-\nTable 1. Participant characteristics.\nrection for sphericity, and Tukey’s test for multiple com-\nparisons. Where significant changes were found, sensitivity\nanalyses were carried out by assuming that every participant\nwho had not returned their journal had experienced scores for\nevery cycle with the same distribution as the pre-vaccine cy-\ncle scores recorded by those who did return their journals:\nthe distribution was produced by randomly selecting a score\nfrom the pre-vaccine cycle data distribution for each missing\nvalue.\nAssociations between side effect, timing and flow scores\nwere assessed using Spearman’s correlation with the Holm-\nBonferroni correction for multiple testing.\nAnalysis was carried out and graphs generated using Graph-\npad Prism 9.0.0.\nResults\nCOVID-19 vaccination is associated with a delay to\nthe next period in spontaneously cycling individuals.\nConsidering only those who were spontaneously cycling, we\nfound that the period after both the first and the second dose\nof the vaccine came significantly later than expected: com-\npared to the day on which the participant expected their\nperiod, pre-vaccine periods occurred on average 0.17 days\n2 | bioRχiv Woon et al. | COVID-19 vaccination and menstruation\n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 30, 2022. ; https://doi.org/10.1101/2022.03.30.22273165doi: medRxiv preprint \n\nFigure 2. Violin plots showing\nthe distribution by which periods\nor withdrawal bleeds began in\npre-vaccine cycles, the cycle fol-\nlowing dose 1 of the COVID-19\nvaccine, interdose cycles, the\ncycle following dose 2 of the\nCOVID-19 vaccine, and subse-\nquent cycles, where “0” denotes\nthe period or withdrawal bleed\nbeginning on the expected day,\nnegative numbers denote days\nearly and positive numbers days\nlate. Data for spontaneously\ncycling (A) and participants on\nhormonal contraception (B) are\nshown. * p’ < 0.05, ** P < 0.01.\nFigure 3. Violin plots showing\nthe distribution of flow scores for\nperiods or withdrawal bleeds in\npre-vaccine cycles, the cycle fol-\nlowing dose 1 of the COVID-19\nvaccine, interdose cycles, the\ncycle following dose 2 of the\nCOVID-19 vaccine, and subse-\nquent cycles. Data for sponta-\nneously cycling (A) and partic-\nipants on hormonal contracep-\ntion (B) are shown.\nearly, whereas the period following dose one occurred a mean\nof 2.3 days late (p’ = 0.0045) and the period following dose\ntwo occurred a mean of 1.3 days late (p’ = 0.041) (Figure\n2a). Periods in interdose cycles and post-vaccination cycles\noccurred a mean of 0.3 days late and 0.47 days early, respec-\ntively, values which were not significantly different from the\npre-vaccination average. Therefore, in spontaneously cycling\nindividuals, vaccination was associated with a delay to the\nsubsequent period, but this quickly reversed.\nAlthough this finding was in line with that from a large and\nwell-designed study carried out in the USA which also de-\ntected delays to the period following a dose of the vaccine\n[13], the delays we found were somewhat larger. We there-\nfore considered the possibility that those participants who\nhad returned their journals were more likely to have no-\nticed any change than those who did not, inflating the post-\nvaccination changes. To address this possibility, we carried\nout two sensitivity analyses. We generated distributions con-\nsistent with no change occurring and used them to impute the\ndata that we would have expected to see had the participants\nwho responded that they had stopped logging their periods\nbecause they had not noticed a change returned their jour-\nnals: the differences between pre-vaccination cycle timing\nand post-dose 1 and -dose 2 timing remained significant at p’\n= 0.0013 and p’ = 0.011, respectively. Even assuming that\nnone of the participants who failed to return their journals\nhad noticed any change, significant delays to the post-dose 1\nperiod (p’ = 0.0035) and the post-dose 2 period (p’ = 0.045)\nremained.\nConsidering only those participants who were taking hor-\nmonal contraception, and considering all types of hormonal\ncontraception together due to the small numbers of these par-\nticipants, we found no effect of vaccination on the timing of\nthe subsequent withdrawal bleed (Figure 2b).\nCOVID-19 vaccination is not associated with any\nchange to menstrual flow.We found no significant change\nto self-reported menstrual flow in the period or withdrawal\nbleed following vaccination, either in spontaneously cycling\nparticipants (Figure 3a), or in those taking hormonal contra-\nception (Figure 3b).\nCommonly-reported side effects are not associated\nwith menstrual changes. One hypothesis that has been put\nforward to explain the existence of menstrual changes follow-\ning vaccination is that immune activation may transiently in-\nterfere with the hypothalamic-pituitary-adrenal axis [15,16].\nor with immune cells in the lining of the uterus, which con-\ntrol the breakdown and regeneration of this tissue [17]. In ei-\nther of these cases, we might consider that menstrual changes\nare not dissimilar to other short-term and reversible side ef-\nfects of vaccination. Therefore, we might expect menstrual\nchanges to be more likely to occur in those who experienced\ncommon side effects.\nTo explore this hypothesis, we examined correlations be-\ntween self-reported side effect score and either the timing or\nthe flow score of the subsequent period: no significant corre-\nlations were found (Table 2). Therefore, in this small cohort\nwe were unable to find evidence that menstrual changes cor-\nrelate with other common side effects of vaccination.\nWoon et al. | COVID-19 vaccination and menstruation bioRχiv | 3\n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 30, 2022. ; https://doi.org/10.1101/2022.03.30.22273165doi: medRxiv preprint \n\nTable 2. Spearman’s r, p and p’ values are shown for the comparisons indicated.\nDiscussion\nHere we report that, in a prospectively-recruited cohort, post-\nvaccination periods occurred later than expected after both\nthe first and second dose of the vaccine, and this finding was\nrobust to a sensitivity analysis designed to account for the\npossibility that participants who noticed a change may be\nmore likely to return their journals. Importantly, periods re-\nturned to coming at the expected time in the interdose and\npost-vaccine cycles. These findings are in line with those\nfrom a recent study in the USA, which reported increases in\ncycle length associated with receiving either the second dose\nof vaccine, or both doses in the same cycle, but again noted\nthat cycles rapidly returned to normal [13].\nIn this cohort, we were unable to identify any change in self-\nreported flow associated with COVID-19 vaccination, and\nthis is in contrast to findings from a Norwegian study, which\nidentified an increase in reports of heavier than normal bleed-\ning after either dose of the vaccine [14]. This cohort was\nsmaller than the Norwegian one, so it is possible that we were\nnot powered to detect a real change in menstrual flow. On\nthe other hand, our participants recorded data in real time,\nwhereas participants in the Norwegian cohort were asked to\nrecall their experiences, so it is also possible that the differ-\nence reported in the Norwegian cohort is at least partially\nimpacted by recall bias.\nBecause our participants were prospectively recruited, this\nstudy should be less affected by recruitment bias than survey-\nbased studies [18-20] and because the participants were asked\nto record their experiences in real-time the data is unlikely to\nbe affected by recall bias. However, there are also a number\nof important weaknesses. Because the cohort is small, we\nmay not have been able to detect real effects of vaccination\non menstrual flow, or real relationships between menstrual\nand non-menstrual side effects. Some bias is also likely to\nhave been introduced because it is unlikely that the partici-\npants who did not return their sheets did so at random, al-\nthough we did attempt to account for this with a sensitivity\nanalysis. Some bias is also likely to be introduced because\n“expected date of period” and “menstrual flow” are at least\npartially subjective, so there is the potential for participant’s\nexpectations of how vaccination will impact their periods to\nimpact their reports.\nIn conclusion, in this small, prospectively-recruited cohort,\nwe found that both the first and second doses of the COVID-\n19 vaccine were associated with a small delay to the sub-\nsequent period. This delay was not reported in interdose\nand post-vaccination cycles, suggesting that any changes\nare temporary. We were unable to detect changes to men-\nstrual flow. These findings are reassuring, but work in larger\nprospectively-recruited cohorts is needed to more accurately\ndetermine how vaccination affects menstrual parameters.\nData availability\nCleaned, fully anonymised data, together with our analy-\nsis files, are available from the Open Science Framework at\nhttps://osf.io/upbyg/.\nACKNOWLEDGEMENTS\nThis study did not receive any specific funding. The investigators were funded by\nthe preterm birth research charity Borne.\nReferences\n1. Medicine and Healthcare Products Regula-\ntory Agency. Coronavirus vaccine—weekly sum-\nmary of Yellow Card reporting. 25 March 2022.\n2021.https://www.gov.uk/government/publications/coronavirus-\ncovid-19-vaccine-adverse-reactions/coronavirus-vaccine-\nsummary-of-yellow-card-reporting 2. Medicines and Health-\ncare Products Regulatory Agency. COVID-19 vaccines:\nupdates for August 2021. https://www.gov.uk/drug-safety-\nupdate/covid-19-vaccines-updates-for-august-2021 3. Male\nV . Are covid-19 vaccines safe in pregnancy? Nat Rev\nImmunol 2021;21:200-1. doi:10.1038/s41577-021-00525-y\n4. Hillson K, Clemens SC, Madhi SA, V oysey M, Pollard\nAJ, Minassian AM, Oxford COVID Vaccine Trial Group.\nFertility rates and birth outcomes after ChAdOx1 nCoV-\n19 (AZD1222) vaccination. Lancet 2021;398:1683-4. doi:\n10.1016/S0140-6736(21)02282-0.\n5. Morris RS. SARS-CoV-2 spike protein seropositivity from\nvaccination or infection does not cause sterility. F S Rep\n2021; 2:253-255. doi: doi:10.1016/j.xfre.2021.05.010.\n6. Orvieto R, Noach-Hirsh M, Segev-Zahav A, Haas J,\nNahum R, Aizer A. Does mRNA SARS-CoV-2 vaccine in-\nfluence patients’ performance during IVF-ET cycle?Reprod\nBiol Endocrinol2021;19:69. doi:10.1186/s12958-021-\n00757-6\n7. Bentov Y , Beharier O, Moav-Zafrir A, et al. Ovar-\nian follicular function is not altered by SARS-Cov-\n2 infection or BNT162b2 mRNA Covid-19 vaccina-\ntion. medRxiv 2021:2021.04.09.21255195. [Preprint.]\ndoi:10.1101/2021.04.09.21255195\n8. Safrai M, Rottenstreich A, Herzberg S, Imbar T, Reubinoff\nB, Ben-Meir A. Stopping the misinformation: BNT162b2\nCOVID-19 vaccine has no negative effect on women’s\nfertility. medRxiv 2021:2021.05.30.21258079 [Preprint.]\ndoi:10.1101/2021.05.30.21258079 9. Aharon C; Lederman\nM; Ghofranian A et al. In Vitro Fertilization and Early Preg-\nnancy Outcomes After Coronavirus Disease 2019 (COVID-\n19) Vaccination, Obstetrics Gynecology 2022 doi:\n10 Wesselink AK, Hatch EE, Rothman KJ et al. A Prospec-\ntive Cohort Study of COVID-19 Vaccination, SARS-CoV-\n4 | bioRχiv Woon et al. | COVID-19 vaccination and menstruation\n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 30, 2022. ; https://doi.org/10.1101/2022.03.30.22273165doi: medRxiv preprint \n\n2 Infection, and Fertility. Am J Epidemiol 2022;, doi:\n10.1097/AOG.0000000000004713\n11. Male V . Menstrual changes after covid-19 vaccination.\nBMJ 2021;374:n2211 doi: 10.1136/bmj.n2211\n12. Eunice Kennedy Shriver National Institute of\nChild Health and Human Development. Item of\ninterest: NIH funds studies to assess potential ef-\nfects of COVID-19 vaccination on menstruation.\n2021.https://www.nichd.nih.gov/newsroom/news/083021-\nCOVID-19-vaccination-menstruation\n13. Edelman A, Boniface ER, Benhar E, et al. Association\nbetween menstrual cycle length and coronavirus disease 2019\n(covid-19) vaccination: a US cohort. Obstet Gynecol 2022.\ndoi:10.1097/AOG.0000000000004695\n14. Tragostad L. Increased occurrence of menstrual distur-\nbances in 18- to 30-year-old women after covid-19 vaccina-\ntion. [Preprint.] 2022. doi:10.2139/ssrn.3998180\n15. Turnbull A V , Rivier CL. Regulation of the hypothalamic-\npituitary-adrenal axis by cytokines: actions and mechanisms\nof action. Physiol Rev 1999;79:1–71. doi: 10.1152/phys-\nrev.1999.79.1.1\n16. Karagiannis A, Harsoulis F. Gonadal dysfunction in\nsystemic diseases. Eur J Endocrinol 2005; 152:501-13.\ndoi:10.1530/eje.1.01886 pmid:15817904\n17. Monin L, Whettlock EM, Male V . Immune responses\nin the human female reproductive tract. Immunology\n2020;160:106-15. doi:10.1111/imm.13136\n18. Alvergne A, Kountourides G, Argentieri MA, et\nal. COVID-19 vaccination and menstrual cycle changes:\nA United Kingdom (UK) retrospective case-control study.\nMedRXiv 2021: 2021.11.23.21266709 [Preprint.]\n19. Male V . Effect of COVID-19 vaccination on\nmenstrual periods in a retrospectively recruited cohort.\nMedRXiv 2021: 2021.11.15.21266317 [Preprint] doi:\n10.1101/2021.11.15.21266317\n20. Lee KLM, Junkins EJ, Luo C, Fatima UA, Cox ML,\nClancy KBH. Investigating trends in those who experi-\nence menstrual bleeding changes after SARS-CoV-2 vacci-\nnation. MedRXiv 2021 2021.10.11.21264863 [Preprint] doi:\n10.1101/2021.10.11.21264863\nWoon et al. | COVID-19 vaccination and menstruation bioRχiv | 5\n . CC-BY 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprint this version posted March 30, 2022. ; https://doi.org/10.1101/2022.03.30.22273165doi: medRxiv preprint","source_license":"CC-BY-4.0","license_restricted":false}