The advent of SARS-CoV-2 vaccines represented a pivotal advancement in controlling the COVID-19 pandemic, significantly reducing the severity of infections, hospitalisations, and deaths globally. However, as vaccination campaigns expanded rapidly, reports of potential adverse effects emerged, raising questions about their nature, frequency, and clinical significance. Among these, menstrual disturbances have gathered considerable attention, prompting discussions about whether these changes are incidental or vaccine-related.
Nature and Reporting of Menstrual Disturbances
Menstrual disturbances reported in association with SARS-CoV-2 vaccines encompass a range of symptoms, including excessive, frequent, irregular, absent, scant, or rare menstruation. Reports have been submitted to pharmacovigilance systems worldwide, such as the US Vaccine Adverse Event Reporting System (VAERS), the UK Medicines and Healthcare Products Regulatory Agency’s Yellow Card scheme, and Sweden’s Medical Products Agency. These systems have received significant numbers of reports highlighting menstrual changes following vaccination.
Public discussion of these issues has been amplified on social media platforms, contributing to greater awareness and, in some cases, anxiety. Survey-based studies and data from menstrual tracking apps have further indicated that changes in menstrual cycles may occur after vaccination. However, menstrual cycle variations are natural, and minor disturbances are typically not considered clinically significant. Nonetheless, during a mass vaccination campaign, even minor changes can cause distress, especially when concerns about adverse effects are heavily publicised.
Regulatory Actions and Recommendations
The European Medicines Agency’s (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) recently recommended listing heavy menstrual bleeding as a potential side effect of mRNA vaccines, including BNT162b2 and mRNA-1273. This decision followed an extensive review of evidence, including clinical trial data, spontaneous reports in Eudravigilance, and findings from the medical literature. While the EMA acknowledged an association with heavy menstrual bleeding, they concluded that the available data do not support a causal link between these vaccines and absence of menstruation.
Historical concerns about menstrual disturbances have arisen with other vaccines, such as those against human papillomavirus (HPV). However, investigations into HPV vaccines did not establish a clear association with menstrual effects, and similar findings have been reported for influenza and hepatitis vaccines. These historical comparisons emphasise the need for robust, data-driven evaluations when assessing potential vaccine-related adverse events.
Findings from the Swedish Nationwide Cohort Study
To better understand the potential link between SARS-CoV-2 vaccination and menstrual disturbances, a nationwide cohort study in Sweden evaluated nearly three million women, both pre- and postmenopausal. Leveraging data from national registers, the study examined healthcare contacts related to menstrual disturbances and bleeding. High-quality data enabled researchers to assess risks by vaccine product and dose number.
The study found weak but reasonably precise associations between vaccination and healthcare contacts for postmenopausal bleeding. An increased risk was observed after the second and third doses, particularly within the 8–90-day risk window, and a similar pattern emerged in the 1–7-day window following the third dose. Interestingly, the risk appeared more pronounced with mRNA vaccines, particularly BNT162b2 and mRNA-1273, while the ChAdOx1 nCoV-19 vaccine showed a less clear association.
For menstrual disturbances in premenopausal women, the study found that adjusting for covariates, such as socioeconomic factors and pre-existing health conditions, largely mitigated the associations seen in unadjusted estimates. Only a weak association remained after the first dose, limited to the 1–7-day risk window. The study concluded that a causal effect confined to this narrow timeframe is unlikely. Furthermore, the number of healthcare contacts for premenstrual bleeding was relatively low, leading to imprecise risk estimates. Overall, the findings did not strongly support a link between SARS-CoV-2 vaccination and premenstrual bleeding.
Limitations and Challenges in Interpretation
While the Swedish cohort study offers valuable insights, it is not without limitations. The reliance on healthcare contact data may underestimate the true prevalence of menstrual disturbances, as not all affected women seek medical attention. Sensitivity may also vary, with postmenopausal bleeding being more likely to prompt healthcare visits than premenopausal disturbances. Additionally, delays between symptom onset and healthcare contact may result in misclassification of cases within specific risk windows.
The study also faced challenges in identifying the exact onset of menopause, relying instead on diagnostic codes to differentiate between premenopausal and postmenopausal bleeding. Reverse causation, where women may receive vaccination before a planned healthcare visit, further complicates interpretation. Media coverage of vaccine-related side effects may have influenced reporting behaviours, creating recall bias in self-reported data and potentially overstating the issue.
Another limitation is the lack of data on factors such as body mass index, smoking status, and ease of access to healthcare, all of which could influence outcomes. These gaps highlight the need for further research to validate findings and refine understanding.
Mechanistic Insights and Broader Context
The absence of a clear mechanistic explanation for vaccine-related menstrual disturbances complicates efforts to establish causality. One hypothesis suggests that unspecific activation of the immune system could influence menstrual cycles. While plausible, this mechanism has not been conclusively demonstrated. Studies on other vaccines, including those for HPV, have similarly struggled to identify specific pathways linking vaccination to menstrual effects.
In the context of SARS-CoV-2 vaccines, most data on menstrual disturbances come from spontaneous reports and self-reported surveys. These data sources are prone to recall bias and may capture events that would not typically result in healthcare visits. For instance, women may report minor changes in their menstrual cycles that are distressing but not clinically significant. Media coverage and public attention can further amplify reporting, potentially skewing perceptions of risk.
Comparisons with other vaccines, such as influenza and hepatitis vaccines, highlight the rarity of menstrual effects as a labelled side effect. Despite widespread use, these vaccines do not include menstrual disturbances in their product information, suggesting that such effects, if present, are uncommon and not a general characteristic of vaccination.
Regulatory and Public Health Implications
The PRAC’s recommendation to list heavy menstrual bleeding as a potential side effect of mRNA vaccines reflects a cautious approach to pharmacovigilance. While the evidence does not establish causality, acknowledging the potential risk ensures transparency and supports informed decision-making. This approach aligns with the principles of patient-centred care, recognising the importance of addressing concerns that may affect vaccine uptake.
To further characterise and quantify the risks of menstrual disturbances, large observational studies with individual-level data are essential. Such studies can complement findings from clinical trials, which may lack the power to detect rare or delayed adverse effects. High-quality data, including comprehensive information on vaccination and health outcomes, will be critical in refining risk estimates and guiding public health responses.
Conclusion
Concerns about menstrual disturbances following SARS-CoV-2 vaccination have sparked significant interest and debate. While reports from pharmacovigilance systems and self-reported surveys suggest a potential link, large-scale observational studies, such as the Swedish cohort study, provide a more nuanced perspective. The findings indicate weak associations between vaccination and menstrual disturbances, with substantial variation by vaccine type and dose.
Regulatory agencies have responded appropriately by reviewing available evidence and updating product information to reflect potential risks. However, further research is needed to clarify causality, identify underlying mechanisms, and address gaps in data. As vaccination campaigns continue, transparent communication and evidence-based guidance will be essential in maintaining public trust and ensuring the success of global immunisation efforts.
References
Ljung, R., Xu, Y., Sundström, A., Leach, S., Hallberg, E., Bygdell, M., Larsson, M., Arthurson, V., Gisslén, M., Gedeborg, R., & Nyberg, F. (2023). Association between SARS-CoV-2 vaccination and healthcare contacts for menstrual disturbance and bleeding in women before and after menopause: nationwide, register based cohort study. BMJ (Clinical Research Ed.), 381, e074778. https://doi.org/10.1136/bmj-2023-074778
European Medicines Agency (EMA). Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 24-27 October 2022. European Medicines Agency (europa. eu), https://www.ema.europa.eu/en/news/meeting-highlightspharmacovigilance-risk-assessment-committee-prac-24-27october-2022