Menstrual Cycle Phase Alters COVID-19 Vaccine Outcomes

Shortly after the COVID-19 vaccine became available, women started reporting changes to their menstrual cycles on social media—heavier bleeding, longer cycles, and more painful periods. What followed these anecdotes were several large-scale studies and surveys that confirmed these patterns.^1,2

But the opposite effect had remained unstudied: How does the menstrual cycle affect COVID-19 vaccination outcomes?

To tackle this question, researchers used menstrual cycle information from a period tracking app and a COVID-19 vaccination survey from 1,474 women to look for patterns. "With those two datasets, we were able to match the vaccine dates they reported…to where they were in the cycle," said Poppy Cooper, a doctoral student in epidemiology and public health at the London School of Hygiene & Tropical Medicine and coauthor on this study. The team published their findings in npj Women's Health.³

The menstrual cycle typically occurs over the course of about 28 days. The researchers defined the luteal phase of the menstrual cycle as the 14 days preceding the start of menstruation and the rest of the cycle as the follicular phase. They compared vaccine outcomes between people who got vaccinated during the follicular phase versus those that got vaccinated during the luteal phase. They found that those vaccinated in the follicular phase had a 35 percent higher odds of reporting side effects such as injection site pain, fatigue, and aches and pains. However, they also had a 35-day longer median time to infection, suggesting that vaccination during the follicular phase could be linked to a heightened immune response.

However, one challenge of looking at infection rates after vaccination is that the fraction of vaccinated people who develop an infection is rather small, making it difficult to do more detailed analyses. "We only had 82 in our entire sample, so we really can't draw any firm conclusions from that," said Cooper. "It's an interesting result, and we would like to investigate it further."

One explanation behind these findings could be that the rising estrogen levels of the follicular phase could be contributing to an increased immune response, because increased estrogen levels are known to cause a heightened immune response.⁴ In contrast, the progesterone levels, which rise during the luteal phase, have been associated with immunosuppressive effects.⁵ Sabra Klein, an immunologist at Johns Hopkins Bloomberg School of Public Health who was not involved in this study, said via email, "Their observation fits well with my own research showing that estrogens are associated with greater immune responses to vaccines in females compared with males."

The team’s initial analysis categorized the menstrual cycle into two phases, which could obscure any effects from daily hormonal fluctuations throughout the cycle. To overcome this, Cooper standardized diverse cycle lengths onto a scale that broke down the menstrual cycle into 20 parts. She noticed that there were changes to the probability of reporting side effects fluctuating within each phase of the menstrual cycle. For instance, within the follicular phase, the probability of reporting side effects was highest at menses onset, lowest two-thirds of the way into the follicular phase, and then peaked again near ovulation. After ovulation, there was a drop in the probability of reporting side effects, which subsequently increased at the end of the luteal phase. Dóra Zelena, a neuroscientist and physiologist from University of Pécs who was not involved in this work, believes that a more detailed analysis of the menstrual cycle phases could help better predict side effects and immunogenicity, particularly if it had a larger sample size to give it more statistical power. "There are constant changes during the whole menstrual cycle that we should take into consideration," she said.

In the future, Cooper hopes to use hormone and immune markers to more precisely pinpoint a participant’s menstrual cycle phase and link it to immune outcomes. She noted that the results from the current study are preliminary and that it would be important to do similar studies in different populations in the future. The current study's population was very homogeneous: Most of the participants were white, educated, and affluent US residents. Zelena also noted that this data was "limited to participants who are using these apps," which might not be fully representative of the general population. Still, she doesn't believe that this would "fundamentally alter the study's main conclusions," she added in an email.

Looking more broadly, Cooper sees this study as part of a "growing interest in how hormones influence non-reproductive health as well as reproductive health." She added, the menstrual cycle is "something that has traditionally been ignored or just treated as background noise, so this I think is proof of concept that it's an important variable to include."