The public rollout of the COVID-19 vaccines in early 2021 was cause for celebration. Finally, people could get some much-needed protection after the deadly wave of COVID-19 cases in December 2020 and January 2021. But as more and more of the public received their first and second doses of the COVID-19 vaccines, chatter about an unforeseen potential side effect began to bubble up on social media. In addition to the expected fever, aches, and fatigue, the COVID-19 vaccine occasionally seemed to disrupt people’s menstrual periods.

As posts about longer periods, heavier bleeding, or a delayed menstrual cycle began popping up all over the internet, doctors also began receiving similar complaints.

“We started hearing from our patients — even those who have been menopausal for several years — that they had unscheduled bleeding. For [others], the period was delayed,” said Mostafa Borahay, a gynecological researcher at Johns Hopkins University who is investigating the potential connection between COVID-19 vaccines and the menstrual cycle.

For people who menstruate, a monthly period is an important indicator of health. While the menstrual cycle typically follows a 28-day course, it can exhibit a fair amount of variability from month to month and from person to person.

“People have a personal relationship to menstruation. Half the population either is going to menstruate, is menstruating, or did menstruate,” said Alison Edelman, a clinical researcher who studies reproductive health at Oregon Health and Science University. If the COVID-19 vaccines alter the menstrual cycle, some people with already variable cycles might not notice a change, but others who are used to a regular cycle might worry.

Working with the period-tracking app Natural Cycles, Alison Edelman found that the COVID-19 vaccines can lead to a small, but temporary effect on menstrual cycles.

Credit: OHSU News

“If they were off a day or so, or if they were planning for pregnancy or trying to prevent pregnancy, even one day might freak somebody out, or give somebody false hope. That can be really important on a personal level,” Edelman explained.

The reported menstrual changes that many associate with the COVID-19 vaccines led some people to fear that the vaccine might affect fertility. The fact that menstrual data was not collected during any of the clinical trials for the available COVID-19 vaccines means that people who menstruate simply didn’t know how or if the vaccine might affect their cycles.

“If you experience a symptom no one told you about, it might be worrying,” said Alexandra Alvergne, a reproductive health researcher at the University of Montpellier. “As much as we want to know whether getting a vaccine is going to give us a headache, we also want to know whether getting the vaccine is going to mess with our periods.”

As the conversation about the possible connection between the COVID-19 vaccines and menstruation echoed around the globe, scientists and clinicians wondered if the menstrual changes people experienced were caused by the COVID-19 vaccines, or were changes to their cycle that would have happened anyway, regardless of vaccination status.

Researchers jumped into action, collecting retrospective and prospective survey data, partnering with period-tracking apps, and collecting biological samples before and after people received the COVID-19 vaccines. The new data, which is being gathered, analyzed, and published as fast the researchers can manage, provides the necessary scientific insight on the potential connection between the COVID-19 vaccines and menstruation. The research so far suggests that there is in fact a connection between the COVID-19 vaccines and menstruation but that it is small and temporary, validating many people’s experiences and helping to restore trust in the lifesaving COVID-19 vaccines.

The menstruation and vaccination conundrum

During the menstrual cycle, the brain releases hormones over the course of about 28 days that interface with a multitude of different cell types in the uterus to prepare the body for a potential pregnancy.

At the beginning of the menstrual cycle, the hypothalamus produces gonadotropin-releasing hormone (GnRH), which stimulates the anterior pituitary gland to release luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Both LH and FSH act on the ovaries. They closely regulate the production of estrogen, progesterone, and other hormones necessary for the maturation of a new oocyte during the follicular phase and the shedding of the uterine lining during the luteal phase if no fertilization occurs.

While the process of menstruation may seem intricately controlled by this symphony of hormones, outside influences like stress, sudden weight gain or loss, or medical conditions such as diabetes, thyroid conditions, or polycystic ovary syndrome (PCOS) can alter the timing of a person’s period.

“When you have a big immune response, you can have a temporary impact on your hypothalamic pituitary axis, or the body clock that regulates menstrual periods, especially if you see that early in the follicular phase,” said Edelman. By stimulating a large inflammatory response, which is beneficial for priming the immune system, vaccines might influence the release of these reproductive hormones, Edelman added. Unfortunately, there has been very little research into the effect that vaccines may have on the menstrual cycle.

The very first connection between menstruation and vaccination was reported as an offhand comment by Wan Chhüan in a 1549 book on measles and smallpox vaccinations (1). During the course of his inoculation administration, Chhüan noticed that often, after receiving their smallpox inoculation, women began menstruating unexpectedly. 

Another report from a New York hospital in 1913 stated that 53% of female nurses given a typhoid vaccine reported changes to their menstrual periods (2). Some nurses complained of missing two to three periods following vaccination, while others found that their periods came a few days early or late and felt more painful than usual. A 1982 phase I trial of a hepatitis B vaccine in Japan resulted in disrupted menstrual cycles for seven out of 16 vaccinated women (3). Because none of these studies set out to test if vaccinations affected menstruation directly, it’s possible that these observed menstrual cycle changes would have happened anyway.

The only study designed to directly investigate the role of vaccines on the menstrual cycle was a 2018 retrospective case-control survey in Japan of adolescents who received a human papillomavirus (HPV) vaccine (4). The study leaders wanted to know what, if any, of 24 potential side effects associated with the HPV vaccine. These included irregular menstrual periods, fatigue, skin problems, and difficulty sleeping, among others. The only side effects that significantly increased the odds of the vaccinated girls going to the hospital were irregular menstruation, abnormal amounts of menstrual bleeding, and severe headaches.

From the few studies that had queried the connection between vaccines and the menstrual cycle by the beginning of 2021, it seemed like a connection was possible. The mass push to vaccinate the world against COVID-19, it turned out, finally accelerated this line of research.

Surveys say: COVID-19 vaccines may affect menstruation

When Alvergne began collecting survey data in March 2021, she and her team were mostly concerned about the effect of the SARS-CoV-2 virus on the menstrual cycle. At the time, people hadn’t really started talking about menstrual cycle disturbances after COVID-19 vaccination yet.

“In our survey, we had a question at the very end about the experience of menstrual cycle after vaccination. It was really the last question,” Alvergne said.

Originally interested in the influence of COVID-19 infections on the menstrual cycle, anecdotal reports of menstrual cycle changes after COVID-19 vaccinations motivated Alexandra Alvergne to analyze the effect of the vaccine first.

Credit: Alexandra Alvergne

But as the reports started to garner widespread attention on social media and in traditional media outlets, Alvergne and her colleagues at the University of Oxford thought it would be important to analyze their preliminary data to see what it said about the vaccination and menstruation connection.

In a recent preprint, Alvergne and her team reported that one in five people who menstruate in the United Kingdom (UK) experienced menstrual cycle changes after receiving their first COVID-19 vaccination (5).

“On the one hand, maybe it's not very much. It's just one in five. On the other hand, it’s quite common as pharmacovigilance standards go. So, in a way, it was surprising that it was that common,” said Alvergne.

Her team also found that smoking or a previous COVID-19 infection associated with an increased risk of experiencing menstrual disturbances after vaccination, but use of estrogen-based oral contraception associated with a decreased risk.

What she found most interesting was the diversity of menstrual cycle disruptions some people encountered. 

“That's what puzzles me the most,” she said. “Some people report heavier, some people report lighter, earlier, later. It's a bit all over the place, those changes.” Alvergne is now working with the period-tracking application Clue to investigate the association between the menstrual cycle and COVID-19 vaccination and infection further.

Around the same time, researchers at the University of Illinois at Urbana-Champaign began collecting survey data from people who were fully vaccinated against COVID-19. They assessed menstrual changes from those who regularly menstruate and those who do not.

The researchers reported in a preprint that 44% of people who regularly menstruate experienced no changes to their menstrual cycle post-vaccination, but 42% of regular menstruators had heavier periods than normal (6). The researchers also reported that 71% of people on long-acting reversible contraceptives, 39% of people on gender-affirming hormones, and 66% of post-menopausal women experienced breakthrough bleeding post-vaccination.

As one of the first studies to specifically assess menstrual changes in a gender diverse and in a pre- and post-menopausal population, this preprint sheds light on potential changes that a wide spectrum of the population may experience.

Back in the UK, Victoria Male, a reproductive immunologist at Imperial College London kept coming across anecdotes of menstrual changes after the COVID-19 vaccine. 

Victoria Male (right), pictured with her team member Antonia Cuff (left), studies the role of immune cells during different stages of the menstrual cycle.

Credit: Imperial College London

“I originally just wasn't going to do anything,” she said. “Then circa May [2021] time, I was like, ‘No one's doing anything. I'm going to have to do something.’”

In her everyday research, Male studies the immune cells present in the uterus at different stages of the menstrual cycle, so she was interested in learning how vaccination might affect the menstrual cycle.

In her recent preprint, she reported that people using hormonal contraception were more likely to experience a change in their menstrual flow — either lighter or heavier bleeding than usual — following vaccination (7). This result differs from that of Alvergne’s analysis, which Alvergne thinks may be because Male’s team did not separate out the different types of hormonal contraceptives used.

Male also found that people with PCOS or endometriosis were more likely to report an altered menstrual cycle after vaccination, and if people reported a menstrual change after receiving their first dose, they were also likely to experience a change after their second dose.

What surprised Male most about performing her study was the polarized opinions about whether she should even be running the study in the first place.

“Some people, when I started doing the study, said, ‘This is a completely stupid study. There's no point in doing this because actually people aren't experiencing changes in their menstrual cycles; they just think they are,’” Male said. “There were other people who were saying, ‘Why do you even need to do a proper study into this? Isn't it good enough that we say that we've noticed a change in our periods?’ … I had a lot of people who thought that I shouldn't be doing the research, but for completely opposite reasons.”

While revealing important insights about the association of COVID-19 vaccines and the menstrual cycle, these early survey-based studies cannot determine if the COVID-19 vaccines actually cause changes to the menstrual cycle. These analyses may also suffer slightly from selection bias because people who experienced changes to their menstrual cycles after receiving the vaccine may be more inclined to participate in a study addressing that question. Recall bias can also be a problem for these surveys because people may be asked to input information about their menstrual cycles from many months in the past.

Some of the new studies coming out now, however, control for recall and selection bias by collecting data in real time with the help of mobile-based period-tracking apps.

Period-tracking data make the COVID-19 vaccine and menstruation connection

As more of her patients began receiving their doses of the COVID-19 vaccine, Edelman heard increasing numbers of accounts of menstrual cycle changes. So, when the National Institutes of Health (NIH) announced that they would award supplemental grants to study the connection between menstruation and the COVID-19 vaccines, Edelman, who studies how contraception affects the menstrual cycle, jumped into action.

She reached out to the two FDA-approved period tracking applications: Natural Cycles and Clue, who both agreed to collaborate with her.

People use period-tracking apps like Natural Cycles or Clue for both pregnancy planning and prevention purposes by inputting information daily about the length of their periods, heaviness of flow, and other physiological information. When the COVID-19 vaccines became available to the public, theses apps also added a place to record vaccination dates.

“We needed prospective data through the pandemic of people who were tracking their menstrual cycles and then telling us when they got vaccinated,” said Edelman. “Everybody has daily data that they put in [the app], so it is just a data tidal wave.”

Period-tracking apps like Clue and Natural Cycles help people monitor their menstrual cycles and associated symptoms like cramping and menstrual flow.

credit: Doucefleur 

Working with Natural Cycles, Edelman and her team tracked both vaccinated and unvaccinated people for three menstrual cycles before vaccination and three cycles after vaccination. They also tracked unvaccinated people for six cycles as a control group.

Edelman and her team recently published the results of their analyses in Obstetrics & Gynecology, where they reported that people who received the COVID-19 vaccine experienced a less than one-day change in their menstrual cycle length, while those who remained unvaccinated experienced no significant change (8). Only an eight or more day change to the menstrual cycle is clinically relevant. The researchers also saw that menstrual cycles for the people who experienced this small change seemed to go back to normal after one or two cycles.

“A one or two cycle change that comes back to normal is not something that should trigger a clinical evaluation,” explained Edelman. “It's a little early days in that data, but we felt like it was important to say, it looks like it's getting back.” Edelman and her team are still collecting data so that they can provide an even better answer on the timeframe for cycles to get back to normal.

As her team combed through the data, they found that within the group of 3,959 vaccinated individuals they followed, there was a group of 358 people who received both their first and second doses of the COVID-19 vaccines within the same menstrual cycle. These 358 people experienced an average increase of two days to their menstrual cycle.

Male found this result clarifying when comparing her analysis of a UK cohort and Edelman’s of a US one. Because people in the UK have to wait longer than 28 days between their first and second vaccine doses for either the Pfizer or Moderna COVID-19 vaccines, they would never be able to get two doses within the same cycle. 

Overall, she was impressed by Edelman’s work. “It's a really large data set. It's a really unbiased data set, and that gave them a lot of power to detect small changes in a way that we haven't been able to before.”

For people who menstruate, Edelman thinks these findings should be both reassuring and validating.

“I really don't see this as something that should prevent people from getting vaccinated. I think it just gives them more information about what to expect,” she said. “If you didn't know that you got a fever with any vaccination, you'd be totally freaked out about it, right? But knowing that it's temporary, it's okay.”

Boosters, kids, and mechanisms

While the effect of COVID-19 vaccination on the menstrual cycle appears small and temporary, researchers are still digging into the connection. Because many people are already vaccinated, researchers are also investigating how COVID-19 booster doses affect the menstrual cycles of both adults and adolescents.

Like Edelman, Borahay teamed up with Clue to assess the association between the vaccines and menstruation, but he is also performing a prospective study looking into how booster doses influence the menstrual cycle at www.COVIDmenses.org.

Moving beyond reported changes to the menstrual cycle, Borahay wants to see how the COVID-19 vaccines might affect the menstrual cycle at a mechanistic level. He plans to collect menstrual effluent from individuals before and after vaccination.

“The inner lining of the uterus is several types of cells. A group of them are the immune cells, and if there is an association between the vaccine and the abnormal bleeding, then one can think it can be mediated through these,” Borahay hypothesized.

By analyzing hormonal and immune markers before and after COVID-19 vaccination in children, Laura Payne hopes to better characterize how the COVID-19 vaccines influence adolescent menstrual cycles.

Credit: Laura Payne

Laura Payne, a menstrual pain researcher and psychologist at Harvard Medical School, is also interested in understanding how COVID-19 vaccination affects the menstrual cycle on a molecular level, but she focuses on adolescents.

“They're early on in their pubertal development, so both their immune response to the vaccine may be different and the impact that it has on their menstrual cycle may be different because their hormones haven't stabilized in the same way as adult women who've been cycling for many years,” said Payne.

Payne is currently enrolling adolescents aged 13 to 19 who plan to get their COVID-19 booster shots in a prospective study. She collects saliva samples before and after vaccination to assess markers of their immune response, inflammation, and ovarian hormones.

“There's lots of different types of cytokines. They can affect part of the reproductive system,” she said. “My study is attempting to look at this in a kind of crude, but in a more detailed way by getting all these different saliva samples after the vaccine.” Payne hopes to finish collecting data in June 2022 and have results ready for publication in the fall.

As new data about the connection between the COVID-19 vaccines and menstruation continue to come out, the importance of incorporating menstrual cycle tracking as an aspect of clinical trial data collection is increasingly clear.

“I'm just guessing the justification for not including this in the big vaccine trials is it's not a life-or-death situation,” said Payne. “But it's really important, and we have to consider hesitancy about vaccines when we're collecting this data.”

With more knowledge about the potential menstrual side effects to the COVID-19 vaccines, people will know that if they experience a change, or even if they don’t, not to worry.

References

1. Needham, J. & Gwei-Djen, Lu. Science and Civilisation in China: Volume 6, Biology and Biological Technology, Part 6, Medicine. Cambridge University Press, page 134 (2000). 
2. Lamb, A.R. Experiences with Prophylactic Typhoid Vaccination: Its Effect on Menstruation. Arch Intern Med (Chic)  12, 565-577 (1913).
3. Shingu, T. et al. Menstrual Abnormalities after Hepatitis B Vaccine. Kurume Med J  29, 123-125 (1982).
4. Suzuki, S. & Hosono, A. No association between HPV vaccine and reported post-vaccination symptoms in Japanese young women: Results of the Nagoya study. Papillomavirus Research  5, 96-103 (2018).
5. Alvergne, A. et al. COVID-19 vaccination and menstrual cycle changes: A United Kingdom (UK) retrospective case-control study. Preprint at: https://www.medrxiv.org/content/10.1101/2021.11.23.21266709v3.full-text
6. Lee, K.M.N. et al. Characterizing menstrual bleeding changes occurring after SARS-CoV-2 vaccination. Preprint at: https://www.medrxiv.org/content/10.1101/2021.10.11.21264863v1.full-text
7. Male, V. Effect of COVID-19 vaccination on menstrual periods in a retrospectively recruited cohort. Preprint at: https://www.medrxiv.org/content/10.1101/2021.11.15.21266317v1.full-text
8. Edelman, A. et al. Association Between Menstrual Cycle Length and Coronavirus Disease 2019 (COVID-19) Vaccination. A U.S. Cohort. Obstetrics & Gynecology  139, 1-9 (2022).