Cycle length

Cycle length is a distinct measurement defined as the time period from the first day of the last menstrual period until the day before the next menses starts. The bulk of research on COVID-19 vaccination and menstrual health has been focused on cycle length as it is a well-defined and, often, routinely tracked outcome. Formal passive reporting systems and public reports described both longer and shorter cycle lengths in the cycle during which COVID-19 vaccination occurs.12 13 The first prospective study to identify an association between COVID-19 vaccination and temporary alterations to menstrual cycle length was a retrospective cohort study of prospectively tracked menstrual cycles in approximately 4000 US-based individuals.14 The study utilised de-identified period tracking data from the Food and Drug Administration (FDA)-cleared menstrual tracking application Natural Cycles to compare cycle length differences between vaccinated and unvaccinated individuals. The population analysed had to be not recently pregnant, naturally cycling (no use of hormones) and demonstrate normal menstrual cycle length pre-vaccination. As compared with the unvaccinated control group, vaccinated individuals experienced a slightly longer cycle of less than 1 day after vaccination. A subsequent study broadening the population to include individuals outside the United States confirmed the findings with data from nearly 20 000 individuals and additionally found that for most individuals the increase in cycle length resolved in the cycle following vaccination.15

Although the average cycle length change observed in these population analyses was small, there were individuals in both the vaccinated and unvaccinated groups who experienced a greater magnitude of change. Of the total, 1342 participants experienced a change in cycle length of eight or more days, comprising 6.2% of vaccinated individuals and 5.0% of unvaccinated individuals. Individuals who were younger and who had a longer cycle length before vaccination were more likely to experience the increase. This study also found no difference in the type of COVID vaccine (eg, mRNA, attenuated virus, etc.) and no change in menstrual cycle length (eg, days of bleeding).

With regard to menstrual cycle phase at the time of vaccination, one retrospective cohort study of individuals using a menstrual tracking application demonstrated that individuals who received vaccine in the follicular phase were more likely to experience a cycle length disturbance then those who received vaccine in the luteal phase.16 This study was not designed to determine causation as it did not include a control group or use a validated ovulation date.

Much less is known about the extent to which adolescent girls experience menstrual cycle changes following COVID-19 vaccination – likely given the greater difficulties in studying this vulnerable population. One study included 39 adolescent girls (aged 12–16 years) and assessed menstrual regularity following vaccination. Although this study did not include a control group, the data showed that eight girls (of the 23 with pre-vaccine regular cycles) reported some kind of menstrual irregularity 3 months post-vaccination.17 A separate study in Norway asked mothers of both vaccinated and unvaccinated adolescent girls to retrospectively report any menstrual cycle disturbances in their daughters.18 The data showed mothers reported more menstrual disturbances (shorter and longer cycles, increased pain, and increased heavy bleeding) in the girls who had been vaccinated compared with those who were not, although the authors mentioned that menstrual disturbances were common in both groups.

The published literature has continued to demonstrate that COVID-19 vaccination is associated with a slightly longer average cycle length among reproductive-aged individuals who prior to vaccination had regular cycles.16 19–22 We now know the COVID-19 vaccine is associated with changes in cycle length, at least in adult populations, and although a small change in menstrual cycle length may not be meaningful to healthcare professionals and researchers as it does not signify the need for a clinical workup or intervention, the significance of this body of research is that unanticipated, even small disturbances for a key patient outcome like menstrual health can trigger an exponential rise in concerns, as has been the case with the COVID-19 vaccine.

Cycle irregularity/missed periods/intermenstrual bleeding

Studies investigating altered menstrual patterns (ie, missed periods, intermenstrual bleeding and cycle irregularity) remain sparse. These outcomes, specifically missed periods and cycle irregularity, overlap somewhat with one another and with cycle length outcomes and may be viewed and defined differently by patients and the scientific community. Intermenstrual bleeding is more straightforward to define, any bleeding that occurs outside of menses, but the data have not been available prospectively or have been inconsistently tracked by patients. Just three prospective cohort studies in the United States and the UK have reported on pre- and post-vaccination menstrual cycle characteristics; all concluded that COVID-19 vaccination was not associated with a change in menstrual regularity.21–23 Additionally, one Swedish national register-based cohort study found that COVID-19 vaccinations were not associated with incident menstrual cycle irregularity that was “at least of sufficient concern to warrant seeking medical care” among premenopausal women.24

The evidence is less clear regarding any impact of COVID-19 vaccination on other bleeding disorders. Evidence from any longitudinal studies is absent. We found seven cross-sectional surveys of individuals reporting missed periods and intermenstrual bleeding after receiving COVID-19 vaccination (especially in subsequent and booster doses compared with the first dose).25–31 However, none of the studies was able to ascertain the extent to which these findings were attributable to a natural menstrual variation, selection bias, or causally affected by the vaccines given the cross-sectional study design.

At the present time, the current evidence is insufficient to determine if COVID-19 vaccination is associated with cycle irregularity or other altered menstrual patterns.

Flow effects/bleeding intensity, quantity and duration

Menstrual flow is truly a patient-oriented outcome where the patient determines what is heavy or light; thus any reported change from an individual’s baseline is the outcome of interest.32 Reported menstrual flow effects around COVID-19 vaccination have been mainly retrospectively collected but duration of menses or number of bleeding days have been more available prospectively as they are tracked routinely by individuals and are a main data point captured by menstrual tracking applications.

A large-scale investigation of 9555 menstruating individuals (7401 vaccinated and 2154 unvaccinated) who tracked menstrual cycles using an app found no differences in number of heavy bleeding days, although vaccinated individuals did report greater total bleeding quantity in the cycle when the vaccine was received.33 Other studies have found no significant changes in self-reported menstrual flow in a large prospective and retrospective sample of women19 and no differences in relative risk of reporting “heavier” or “lighter” periods in those vaccinated compared with those who were not.34 Similar self-report studies have found no differences in menstrual flow following vaccination.35 However, contradictory findings have also been published suggesting there are changes to menstrual flow following vaccination, with many participants reporting “heavier” menstrual flow.12 36 37 These findings also have support from research demonstrating changes to menstrual flow following vaccination,31 38 although there have also been a mix of reported changes including “heavier” and “lighter” flow.39 Despite these mixed findings, the UK Medicines and Healthcare products Regulatory Agency (MHRA) determined that “heavy flow” be included as a potential vaccine side effect, given the strength of the evidence supporting this outcome, and Pfizer and Moderna product information has now added this as a possible side effect.40

Menstrual pain and endometriosis

Menstrual pain is a self-reported outcome measure, defined as pain and discomfort in and around the pelvic region that begins with the onset of menstruation. Data on menstrual pain and COVID-19 vaccination are limited, although existing studies do suggest increased menstrual pain after COVID-19 vaccination, affecting around 20–40% of menstruating people after vaccination; estimated prevalence was similar after both the first and second vaccination dose.28 41–43 Heterogeneity by type of vaccination in relation to post-vaccination menstrual pain experience remains inconclusive.39 41 However, a longitudinal study that included pre-pandemic and pre-vaccination follow-up data did not observe that menstrual cycle pain complaints varied appreciably according to vaccination status.22 Importantly, post-vaccination change in menstrual pain could also be attributed to background variability in menstrual pain driven by, for example, between-cycle fluctuations, age-related menstrual changes or pandemic-related stress.44 Unlike menstrual length and regularity, menstrual pain and other menstruation-related symptoms can be perceived differently when reported in real time versus recalled and influenced by the format of questions, increasing the risk of misclassification or recall bias.

One of the most common medical conditions associated with menstrual pain is endometriosis. Endometriosis is a disease where the lining of the uterus (the endometrium) grows outside of the uterus. Endometriosis is associated with other painful conditions including dyspareunia, dysuria and dyschezia, and can be a source of chronic pelvic pain. It is associated with inflammatory processes, and thus, individuals with endometriosis may be particularly susceptible to effects from the COVID-19 vaccine. Emerging research suggests that people with endometriosis immunised with SARS-CoV-2 mRNA vaccines perceived worsening menstrual cycle abnormalities – namely fatigue, pain and regularity disorders – compared with those without a history of endometriosis.43 45 Among people with endometriosis, those taking hormonal treatment reported less change in menstrual-associated symptoms,43 suggesting a possible protective or stabilising effect of oestrogen or progesterone. Notably, in these studies, endometriosis was confirmed by either transvaginal sonography or by hospital record, so it is not clear if participants received surgical confirmation of endometriosis at any point, which is the gold standard for diagnosis.

Postmenopausal individuals

The diagnosis of menopause is quite clear, diagnosed 12 months after an individual’s last period. Although one small study of 64 postmenopausal Lebanese women found no evidence of vaginal bleeding following receipt of the COVID-19 vaccine,46 many larger studies examining population data have found evidence of a slightly increased risk of bleeding in postmenopausal women. In an examination of clinical records of 485 644 postmenopausal women, there was a small but statistically significant increase in the likelihood of receiving an abnormal bleeding diagnostic code in the 16 weeks following COVID-19 vaccination.47 However, the authors note that this temporary increase was so small that it translated to fewer than 1 in 1000 women experiencing this change. Another study of over 1.5 million Swedish postmenopausal women also reported a small but significantly increased risk of bleeding, particularly after receiving a third dose of the vaccine.24 An evaluation of reports of COVID-19 vaccine side effects to “v-safe” – an independent and voluntary vaccine monitoring system for individuals in the United States – found that approximately 4% of the 84 943 responses of menstrual disturbances reported postmenopausal bleeding.48 Additionally, a supplementary analysis of 14 577 Danish self-reported postmenopausal women showed 2% (n=347) reported some “menstrual changes” following vaccination.49 Postmenopausal women, by definition, are not menstruating, although the authors did not clarify the specific “menstrual” changes reported by postmenopausal women. Taken together, it does appear that many postmenopausal individuals experienced some abnormal vaginal bleeding following COVID-19 vaccination and this information is critically important information for this population to know when considering the potential side effects of the COVID-19 vaccination.

Hormonal contraception users

Hormonal contraception encompasses a wide range of methods, method delivery systems and dosing, and can contain only progestogen or oestrogen combined with a progestogen. The few studies that have specifically evaluated the impact of hormonal contraception on menstrual cycle changes following COVID-19 vaccination have suggested that hormonal use has a protective effect against changes to the menstrual cycle but not all studies are able to differentiate between different methods.

One large study including prospective and retrospectively collected self-report data found a delay in the menstrual period following vaccination of 0.37 days, which was a smaller delay than in those not using hormonal contraception. There were no significant changes to menstrual flow following vaccination in those using hormonal contraception generally; although when type of hormone was analysed separately, those using progesterone-only hormones reported heavier flow following vaccination.19 A separate study also reported heavier menstrual flow post-vaccine among those using hormonal contraception, although type of hormonal contraceptive was not analysed separately. Those using hormonal treatments also reported more breakthrough bleeding.12 However, one additional study reported fewer menstrual cycle changes and less bleeding changes following each of the first and second dose vaccinations in those using hormonal contraceptives compared with those who were not.43

Stress

The term “stress” is a broad and wide-ranging term that encompasses a number of areas related to psychological distress, worry or concern.50 Many different measures can reflect different aspects of stress including depression, anxiety, perceived stress and COVID-19 pandemic-related stress. There have been mixed results with regard to the impact of psychological stress on menstrual disturbances following receipt of the COVID-19 vaccine. Wang and colleagues reported that adult vaccinated women had a higher risk of increased cycle length compared with unvaccinated women, and this finding persisted after accounting for pandemic-related stress, which was assessed as depression, anxiety, posttraumatic stress, perceived stress and worry about COVID-19.21 Similarly, another study found no relationship between perceived stress and vaccination status or menstrual cycle characteristics.22 However, another study found that changes in menstrual cycle characteristics were correlated with symptoms of depression, suggesting that the menstrual cycle effects of the vaccine may be related to changes in mood.51 However, these inconsistent findings may result from different assessments of stress and how those measures related to changes in the menstrual cycle.

Long/short pre-vaccination cycles

Almost all of the research published to date is focused on individuals with regular pre-vaccination menstrual cycles.32 The restriction of analyses to this ‘normal’ cycle population was by design, otherwise it would have been impossible to determine if an actual signal existed due to the vaccine. Individuals with baseline irregular cycles did report menstrual disturbances through official passive reporting systems (Vaccine Adverse Event Reporting System, VAERS) and social media-based surveys. However, due to the inherent increased variability with irregular cycles, it will be a challenge to determine what changes are due to the vaccine.