Case Report

Association Between COVID-19 Vaccines and Menstrual Disorders: A Systematic Review

Laura Esteban-Cledera^1,2, Marcela Villalobos³, Martín Solorzano¹ and Felipe Villalobos¹*

¹ Fundació Institut Universitari per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina

² Departament of Experimental and Health Sciences, Pompeu Fabra University, Barcelona, Spain

³ Faculty of Health Sciences, Open University of Catalonia, Barcelona, Spain

Submission: November 19, 2024; Published: November 26, 2024

*Corresponding author: Fundació Institut Universitari per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Barcelona, Spain, Email: fvillalobos@idiapjgol.info

How to cite this article: Laura Esteban-C, Marcela V, Martín S, Felipe V. Association Between COVID-19 Vaccines and Menstrual Disorders: A Systematic Review. J Gynecol Women’s Health 2024: 27(2): 556206. DOI: 10.19080/JGWH.2024.27.556206

Abstract

Reports on menstrual disorders following COVID-19 vaccination have emerged. This systematic review seeks to address the existing knowledge gap by providing a critical assessment of the existing evidence on the association between COVID-19 vaccines and menstrual disorders. A systematic literature search was conducted across PubMed, Scopus, and Web of Science. Open access, observational cross-sectional, prospective, or retrospective cohort studies, published between January 2021 to December 2023, reporting on association between COVID-19 vaccines and menstrual disorders in women aged 12-55 years old, without pre-existing menstrual disorders, written in English or Spanish, in any setting, were eligible for inclusion. Two independent reviewers screened articles for eligibility, extracted data, and assessed study quality. A total of 31 studies were included in the review. Studies reported menstrual outcomes following vaccination with any dose of the COVID-19 vaccines, Pfizer/BioNTech®, Moderna®, AstraZeneca® and Janssen®. The most common menstrual disorders reported were changes in cycle length, changes in the amount of bleeding, and changes in pain intensity. Most of the studies found an association with the second and third dose, and with Pfizer/BioNTech®, Moderna® and AstraZeneca® vaccines. This systematic review highlights the importance of monitoring and addressing menstrual health concerns in vaccine recipients.

Keywords: COVID-19 vaccine; menstrual disorders; women’s health

Introduction

The COVID-19 disease, caused by the SARS-CoV-2 virus, was declared a pandemic by the World Health Organization (WHO) on March 11, 2020. Since then, the rapid development and global deployment of vaccines have played a critical role in the fight against the pandemic, with millions of doses administered since the first vaccines were licensed in December 2020[1]. In response to this health emergency, the European Commission initially approved vaccines developed by Pfizer/BioNTech®, Moderna®, AstraZeneca®, and Janssen®. These vaccines demonstrated efficacy rates in initial clinical trials, providing protection against severe forms of COVID-19 infection and various viral variants. Despite their efficacy, reports of adverse events, including menstrual disorders, have emerged irrespective of the dose and the COVID-19 vaccine type administered [2]. Since June 2022, the European Medicines Agency (EMA) mentioned that 30% of reports on COVID-19 vaccines administrated in women could be related to menstrual disorders [3].

Various systematic reviews have summarized studies evaluating the effect of COVID-19 vaccines on menstrual disorders [4–6]. A review by Al Kadri et al., included 16 cross-sectional studies, and the findings indicated that menorrhagia, oligomenorrhea, and polymenorrhea were the most common menstrual disorders after COVID-19 vaccination. Similar results were found in a review by Nazir M. et al., which included 14 studies, and by Chao M. et al., which included 4 observational studies. However, most of studies included in the reviews were unable to report causal relationship between menstrual disorders and dose or type of COVID-19 vaccines.

The rationale behind conducting this systematic review is to establish a comprehensive understanding of the existing evidence on the association of COVID-19 vaccine on menstrual disorders in women aged between 12 - 55 years old, without pre-existing menstrual disorder.

This approach ensures a well-informed and contextualized foundation for the forthcoming research. Therefore, this study not only contributes to the current literature but also plays a pivotal role in providing essential context and support for the upcoming investigation into this matter within vaccination and women’s health. sThe aim of this systematic review is to describe the association between COVID-19 vaccines and menstrual disorders in women aged between 12 - 55 years old, without pre-existing menstrual disorders, with a focus on the evaluation of the association of different COVID-19 vaccine types, and the number of doses administered on menstrual disorders, based on a comprehensive analysis of current evidence.

Materials and Methods

Study design

This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta- Analyses (PRISMA) statement [7] and was registered in the International Prospective Register of Systematic Reviews (PROSPERO: ID no. CRD42024505096).

Search strategy and data source

The PECOt (Population, Exposure, Comparator, Outcome, and time) framework was used to structure the search: 1) Population: women aged between 12 - 55 years old, without pre-existing menstrual disorders; 2) Exposure: any dose of the following COVID-19 vaccines: Pfizer/BioNTech®, Moderna®, AstraZeneca® and Janssen®; 3) Comparator: No applicable; 4) Outcome: any menstrual disturbance reported after any dose of COVID-19 vaccines; 5) time: from January 1, 2021 to December 31, 2023. A systematic literature search was conducted across major electronic databases including PubMed, Scopus, and Web of Science, combining keywords, and using the Boolean operators “AND” and “OR”. The search strategy was flexible to accommodate studies in Spanish and English language. No filters were applied in the initial search. The identified keywords, including (“COVID-19 vaccine” OR “SARS-CoV-2 vaccine”) AND (“menstrual disorders” OR “menstrual disturbances” OR “menstrual irregularities” OR “menstrual cycle” OR “menorrhagia” OR “polymenorrhagia” OR “hypermenorrhoea” OR “oligomenorrhea” OR “abnormal cycle length”), were utilized to search for relevant literature. The search strategy was documented, and results were critically evaluated for relevance and quality. Subsequent iterations and adjustments were made as necessary during the research process (Supplementary Table. 1)

Inclusion and exclusion criteria

The inclusion criteria for this systematic review were: (1) open access, (2) observational cross-sectional, prospective, or retrospective cohort studies, (3) written in English or Spanish, (4) published from January 1, 2021, to December 31, 2023, (5) studies evaluating the association between COVID-19 vaccines and menstrual disorders, (6) in women aged between 12 - 55 years old, without pre-existing menstrual disorders, and (7) vaccinated with any dose of the following COVID-19 vaccines: Pfizer/ BioNTech®, Moderna®, AstraZeneca®, Janssen®, (8) in any setting. The exclusion criteria were: (1) reviews, systematic reviews, meta-analysis, clinical trials, case series, or letters to editor, (2) studies which evaluated pregnant women and/or breastfeeding, and (3) studies that were not peer-reviewed.

Study selection and data management

The identified bibliographic citations were transferred to a tool for collecting, examining, and evaluating the titles and abstracts of the citations; this tool was the Rayyan platform (rayyan.qcri. org). Two reviewers independently (L.E.-C. and F.V.) assessed the titles and abstracts of the studies from the search for inclusion. Subsequently, the same reviewers independently reviewed the full text of all potentially eligible articles before making a final decision on eligibility. Any discrepancies were discussed, and a third reviewer acted as a mediator if no consensus was reached (M.V.). In the event of duplicate study populations, the most recent article was considered. Exclusion reasons were recorded, and the inclusion and exclusion process were documented with a flowchart as recommended by the PRISMA guidelines.

Outcomes measures

The main outcome included in this study was the association between any dose of the following COVID-19 vaccines: Pfizer/ BioNTech®, Moderna®, AstraZeneca®, Janssen®, and any menstrual disturbance reported in women aged 12-55 years, without preexisting menstrual disorders.

Data extraction and data synthesis

Two independent reviewers extracted all relevant information from the included studies into a standardized Excel template and compared it to ensure accuracy. The data of interest were title, author, publication year, study design, sample size, age, inclusion criteria, study duration, vaccination status, menstrual disorders reported, association between exposure and outcome, and conclusion.

Analysis of study quality

To assess the quality of studies included in this systematic review, The Joanna Briggs Institute Critical Appraisal Tools (JBI) checklist was applied [8]. This checklist, developed by the Faculty of Health Sciences at the University of Adelaide, is structured independently based on the specific study design to be assessed

Results

Study selection

The primary search elicited 300 articles. After the removal of duplicates (100), 200 articles were screened for review of the full text. Of these, 169 studies were excluded based on different reasons. A total of 31 observational studies (12 cohort and 19 crosssectional) were included for the analysis (Figure 1). Most of the studies (n = 24) were outside of Europe (EE.UU., Israel, Lebanon, Japan, Saudi Arabia, Jordan, Palestine, Syria, Egypt, Sudan, Libya, India, Latin America and Trinidad and Tobago)[9–32], while only 7 studies were conducted in Europe (UK, Netherlands, Germany, Denmark, Sweden, Spain and Hungary)[33–39]. (Supplementary Table. 2).

Quality appraisal

The quality of 31 studies was objectively assessed using a validated tool. Taken together, the studies provide useful evidence on the association between COVID-19 vaccination and menstrual disorders. However, during the assessment, it was found that some studies have methodological deficiencies, particularly in the identification and management of confounding factors, so it is suggested that the findings should be interpreted carefully. (Supplementary Table. 3)

Inclusion Criteria and Population Characteristics:Of the 31 studies included in this review, 28 clearly described the inclusion criteria for participants and the context in which they were conducted, allowing for a better assessment of the applicability of the results. Only 3 studies lack a detailed description of the setting and characteristics of the included female population.

Breast

Exposure and Outcome Measurement In nearly all studies (n=30), exposure measurement was conducted in a valid and reliable manner, as was the validity and reliability of outcome measurements. However, in one of the included studies, standardized criteria or validated methods were not used to measure outcomes.

Identification and Management of Confounding Factors: In 21 of the included studies, potential confounding factors that could influence the association between COVID-19 vaccination and menstrual disorders in the studied population were identified. This means that a third of the studies did not consider these variables, potentially compromising the internal validity of their findings. Although a considerable number of studies identified confounding variables, only 13 implemented clear strategies to manage them (such as statistical adjustments or the use of multivariate regressions).

Study characteristics

A total of 3,060,573 women were the study population included in this review from 31 studies. Of these, 2,946,448 (96.27%) women were from one retrospective cohort study conducted in Sweden. For most of the studies, the female population was represented by women over the age of 18 years old in general. Seven studies included female adolescents aged between 12–17 years old. The various types of vaccines administered to the women include Pfizer/BioNTech®, Moderna®, AstraZeneca® and Janssen®. In most studies, the Pfizer/BioNTech® vaccine was the most administered vaccine. The majority of the studies (n = 21) used self-reported (online) questionnaires to assess the presence of menstrual disorders, often spread through social media, whereas some used retrospective data (n=10).

COVID-19 vaccines and menstrual disorders

A wide variety of menstrual disorders were reported in the studies. The most common disorders included changes in cycle length (n = 19), changes in the amount of bleeding (n = 13), and changes in pain intensity (n =11), and other menstruated changes, menstrual disturbances, menstrual symptoms or irregular menstruation (n=6). Various studies reported more than one menstrual disorder.

Seventeen studies found an association between COVID-19 vaccines and menstrual disorders and one study found a weak and inconsistent association. Of these, 7 studies reported an association by dose of COVID-19 vaccine, 5 studies by type of COVID-19 vaccine, 2 studies by both conditions, and 4 did not stratify by dose or by type of COVID-19 vaccine. The results are heterogeneous, most of the studies found an association after the second and third dose, and Pfizer/BioNTech®, Moderna® and AstraZeneca® were associated with menstrual disorders.

Discussion

This systematic review summarized evidence on the association between COVID-19 vaccination and menstrual disorders. Our findings are consistent with recent systematic reviews that reported that menstrual disorders such changes in cycle length, changes in the amount of bleeding, and changes in pain intensity are common after COVID-19 vaccination in women aged 12-55 years, without pre-existing menstrual disorders. In addition, in most studies, the Pfizer/BioNTech® vaccine was the most administered vaccine. Heterogeneous results were found regarding menstrual disorders after specific COVID-19 vaccine brands. Some studies did not find differences between the vaccine brands whereas others found that Pfizer/BioNTech®, Moderna® and Astra Zeneca resulted in a higher rate of menstrual disorders, especially after second and third doses.

Research gaps

The systematic review reveals some research gaps in the current literature exploring the association between COVID-19 vaccination and menstrual disorders. Firstly, most studies employ observational designs, which limits the ability to draw definitive conclusions about causality between vaccination and menstrual disorders [40,41]. Without experimental or longitudinal research, it remains challenging to establish a clear association. Additionally, there is a notable lack of investigation into the biological mechanisms that might explain potential links between vaccines and menstrual disorders; exploring these mechanisms is crucial to understanding underlying causes and requires further study. Another gap lies in the scarcity of research addressing the long-term impact of vaccination-related menstrual disorders, with few studies examining the persistence or consequences of these changes over time [42]. Furthermore, many studies did not stratify findings by important factors, such as age, pre-existing clinical conditions, or other relevant variables, which could influence susceptibility or response to vaccination. Addressing these gaps is essential to produce more comprehensive, generalizable findings and to enhance our understanding of this possible side effect of COVID-19 vaccination.

Implications for further research

In further research on menstrual disorders related to vaccination, several areas require deeper exploration. More longitudinal studies are needed to follow women before and after vaccination to determine the timing and type of menstrual changes. Additionally, research should focus on the impact of different vaccine doses and types, as disorders appear more common after the second or third doses. Lastly, specific age groups, particularly adolescents near menarche and perimenopausal women, need targeted studies to assess any age-related differences in the occurrence of these disorders following vaccination [43].

Limitations

This systematic review on the association between COVID-19 vaccines and menstrual disorders faces some limitations that impact the strength and generalizability of its conclusions. A significant limitation is the heterogeneity among the included studies, as variability in study designs, methods of assessing menstrual disorders, and populations studied creates challenges in directly comparing results. This diversity restricts the ability to draw overarching conclusions and reduces the generalizability of findings to broader populations. Additionally, the quality of studies varies, with some relying heavily on self-reported data, which may introduce potential biases related to recall accuracy and subjective interpretation of symptoms. Another limitation is the frequent lack of control for confounding factors, which may influence menstrual outcomes and complicate the ability to isolate the effect of COVID-19 vaccination. Addressing these limitations in future research is essential to strengthen the evidence and provide clearer insights into this association.

Conclusions

In conclusion, this systematic review provides evidence suggesting an association between COVID-19 vaccination and various menstrual disorders, particularly following the second and third vaccine doses, with Pfizer/BioNTech®, Moderna®, and AstraZeneca® vaccines most frequently implicated. Common menstrual disorders reported included alterations in cycle length, bleeding amount, and pain intensity. However, the observational nature of most studies, reliance on self-reported data, and variability in study designs and populations limit the strength of causal inferences and generalizability of the findings. Future research with more robust methodologies, including controlled, longitudinal studies, is needed to better understand these associations, explore underlying biological mechanisms, and evaluate the potential long-term impact of COVID-19 vaccination on menstrual health.

Author Contributions

Conceptualization, L.E.-C., M.V., and F.V.; methodology, M.V. and F.V.; formal analysis, L.E.-C., M.V. and F.V.; investigation, L.E.-C., M.V. and F.V.; data curation, L.E.-C., M.V. and F.V.; writing-original draft preparation, L.E.-C., M.V., M.S., and F.V.; writing-review and editing, L.E.-C., M.V., M.S., and F.V.; supervision, M.V. and F.V. All authors have read and agreed to the published version of the manuscript.

Funding

This research received funding by Jordi Gol i Gurina University Institute for Primary Health Care Research Foundation (IDIAPJGol).

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