Effects of SARS‐CoV‐2 infection and COVID‐19 pandemic on menstrual health of women: A systematic review

Abstract Background The menstrual cycle in women is the main indicator of their reproductive health which is affected by the ongoing coronavirus disease 2019 (COVID‐19) pandemic. This review aims to summarize the effects of the COVID‐19 infection and the global pandemic on the menstrual health of women. Methods The literature search was conducted in PubMed, Cochrane library, and Google Scholar using keywords “COVID‐19,” “Menstrual Cycle,” “Menstrual Cycle Irregularities,” “Amenorrhea,” “Polymenorrhea,” and “Dysmenorrhea.” The articles were selected according to the following inclusion criteria: (i) cross‐sectional studies, (ii) cohort studies, (iii) surveys, and (iv) other observational studies observing the effects of SARS‐CoV‐2 infection or COVID‐19 pandemic on menstrual health of women. Exclusion criteria included: case reports, gray literature, and website articles regarding menstrual health. Results A total of 30,510 articles were shortlisted after a comprehensive search. Sixteen articles were included out of which 13 studies investigated the effects of the COVID‐19 pandemic on the menstrual cycle while 3 evaluated the possible effects of COVID‐19 infection on the menstrual health of women. Menstrual disorders or irregularities were a more common finding during the pandemic as compared to before (p = 0.008). Women affected by pandemic‐related stress were more prone to changes in the duration of their menses (p = 0.0008), reported heavier bleeding (p = 0.028), and increased incidence of painful periods (p < 0.0001). COVID‐19 infected women also reported changes in their menstrual cycle including irregular menstruation, increased symptoms of premenstrual syndrome, and infrequent menstruation. Conclusions Women suffering from COVID‐19 infection or pandemic‐associated stress and anxiety were more likely to experience irregular menstruation, dysmenorrhea, amenorrhea, and other menstrual abnormalities compared to those who were less exposed.


| INTRODUCTION
The ongoing coronavirus disease 2019 (COVID- 19) pandemic has not only created burdens on the healthcare system but also led to the disruption of the social structure of societies. While the pandemic has taken its toll on almost everyone, women have had to deal with more profound challenges, both at the workplace and at home. During the pandemic, chronic symptoms of psychological distress such as anxiety and stress have become rampant among populations across the globe. 1 A previous study showed that a significant increase in the anxiety of women was reported as the State-Trait Anxiety Inventory scores-I (STAI-I) during the course of the pandemic as compared to the State-Trait Anxiety Inventory scores-II (STAI-II) that highlighted the general anxiety of the participants. 1 Amidst the peak of the coronavirus outbreak in 2020, CARE International conducted a report inculcating the first-person accounts of more than 10,000 participants regarding the challenges they faced during the COVID-19 pandemic. The results showed that 27% of the female participants reported an increase in mental health issues compared to only 10% of the males. 2 Exactly a year later in 2021, CARE's rapid gender analysis based on the impact of COVID-19 on the daily lives of individuals revealed that women were three times more prone to experiencing adverse mental health struggles, as compared to men. This disparity can somewhat be attributed to the widely accepted notion that women are more susceptible to mental health troubles, owing to their more anxious temperament. 3 Due to this trait-like phenotype, women are naturally at a higher risk of experiencing mental health problems such as chronic anxiety, stress, depression, sleep disturbances, and posttraumatic stress disorder. 4 The pandemic has not only exacerbated mental health issues within the female population but led to poor outcomes.
Following the coronavirus outbreak in 2020, numerous reports from various countries highlighted a significant increase in cases of domestic violence against women. 5 Due to the lockdown, people were forced to stay indoors and this, unfortunately, resulted in more women being subjected to physical and mental abuse within their homes.
According to a Jordanian cross-sectional study, 20.5% of females reported that they suffered from domestic abuse during the COVID-19 pandemic. 6 This can be attributed to causative factors such as financial insecurity, lack of social support, quarantine, unstable relationships, and limited healthcare and domestic violence support options.
The menstrual cycle is an integral regulator of the female reproductive function and is highly susceptible to psychological disruptions such as stress, depression, and insomnia. 7,8 Various factors like menstrual frequency, the amount of menstrual bleeding, and the length of bleeding have an intimate correlation with the type of psychological stressors affecting the individual. Pre-COVID-19 findings highlighted that acute stress affects the regions of the brain that regulate emotions during the luteal phase of the cycle, in contrast to the findings in the late follicular phase. It was observed that increased sympathetic activity during stages of acute stress has a trickle-down effect on different areas of the brain, particularly the amygdala which is associated with strong emotions like pleasure and fear. This increase in neural activity of the brain, especially due to psychological distress during the late luteal phase, causes disruptions in the normal pregnenolone levels of the body, leading to grave menstrual complications. 9 A prior study conducted among Korean women determined a correlation between mental health and the menstrual cycle. The findings also disclosed that poor mental health status leads to irregularities in the menstrual cycle of women. 10 These were also validated by the findings of an observational study that assessed the changes in women's reproductive health following the COVID-19 outbreak. The statistics from this study show that there were significant changes in the length of menstruation in women who had reported their quality of life is adversely affected by the pandemic. 11 There are several factors associated with the COVID-19 pandemic that have contributed to triggering such mental health challenges in women. Social isolation coupled with an unhealthy household environment during the quarantine periods proved to be detrimental to the mental well-being of women. There was also a strong correlation between episodic depression and unemployment among women who lost their jobs during the pandemic. 12 Furthermore, the fear of infection and related mortality proved to be another major risk factor for the deteriorating mental health of women during the pandemic.
In a nutshell, COVID-19 is not just a respiratory illness, but has several adverse effects throughout the body, especially in women.

COVID-19 infection along with the associated stress of the COVID-19
pandemic has had a serious impact on the reproductive health of women leading to a change in the duration of menstrual cycles. 11 The present review reports aimed to discuss the changes caused by COVID-19 infection and its pandemic on the menstrual health of women.

| Study selection
Two reviewers independently screened titles and abstracts for eligibility. All the articles that addressed the menstrual experience of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infected and noninfected women during the pandemic were retained separately. Full-text articles were then independently reviewed by the two reviewers for inclusion. Finally, discrepancies were resolved through discussion between the two reviewers, and a third reviewer if necessary.

| Inclusion and exclusion criteria
All the cross-sectional surveys, cohort analyses, and observational studies investigating the effects of the COVID-19 pandemic or SARS-CoV-2 infection on the menstrual health of women were included in this review. Case reports, gray literature, and website articles were excluded from data extraction. Studies evaluating the effects of COVID-19 vaccination on menstrual cycles were also excluded from this review. There was no language-based exclusion since all the available articles were published primarily in English.

| Population
The following two groups of the population were considered eligible for this review. Studies that compared the menstrual changes in SARS-CoV-2 infected women with the cycles of noninfected women or their own cycles before infection are included in this review.
Outcomes: Menstrual irregularities (early or delayed cycle), duration of menstruation (prolonged menstrual cycle), dysmenorrhea, amenorrhea, the volume of bleeding (heavy periods), endometriosis symptoms, premenstrual syndrome symptoms were the outcomes that have been extracted from the included studies. The relation of these outcomes with anxiety and fear of the COVID-19 pandemic and SARS-CoV-2 infection has been assessed separately.

| Data extraction
Data extraction was completed by two independent reviewers, and discrepancies were resolved through feedback from a third reviewer.
Data were extracted from the articles including the patient characteristics, COVID-19 infection, anxiety or stress during the pandemic, and menstrual health factors (e.g., cycle duration, blood flow, volume, pain during the cycle, premenstrual symptoms, and irregular or missed periods during the pandemic). All data were extracted in a predesigned excel sheet. Menstrual experiences of COVID-19-infected and noninfected women were retrieved in a separate sheet.

| Data synthesis
The outcomes of recruited studies were qualitatively synthesized and not combined for meta-analysis due to the different clinical and methodological approaches used in the studies. Study findings are summarized in Section 3 and tabulated in summary tables.

| Quality assessment
The Newcastle Ottawa scale was used for assessing the quality of the included observational studies (Supporting Information: File 3). It was based on the selection of participants, comparability of participants, and outcome/exposure criterion of included studies.

| RESULTS
After performing a comprehensive search on 3 electronic databases, a total of 30510 articles were recruited ( Figure 1). These articles were exported to EndNote Reference Manager (Version X 7.5; Clarivate Analytics). After removing duplicate articles and abstract screening, 24 articles were shortlisted and 8 articles were further excluded after a full-text review. Finally, 17 articles were included out of which 9 were cross-sectional studies, 6 cohort studies, 1 survey, and 1 anonymous observational study. Of these, 13 studies investigated TAYYABA REHAN ET AL. | 3 of 10 the effects of the COVID-19 pandemic on the menstrual cycle (see Table 1), while 3 evaluated the possible effects of COVID-19 infection on the menstrual health of women (see Table 2).

| Quality assessment
Newcastle Ottawa scale was used to carry out a quality assessment of the included studies with scores ranging between 4 and 8 inclusive out of a maximum of 8 for cross-sectional studies and between 6 and 7 inclusive out of a maximum of 9 for cohort studies as depicted in the quality assessment in Table S1 and S2 of the Supporting Information: File 3, respectively.

| Irregularities in the menstrual cycle
It was observed that menstrual disorders or irregularities were a more common finding during the pandemic as compared to before (27.6% vs. 12.1%, p = 0.008). 13 A study reports that women who suffered from mood swings, anxiety, or stress were at a higher risk of experiencing changes in their menstrual cycles since the beginning of the pandemic (50% vs. 34%, p < 0.0001). 14 Women who had started working from home during the pandemic also experienced menstrual irregularities compared to their menstrual cycles earlier. 15 On the contrary, one study showed that women reported a decrease in menstrual abnormalities amidst the curfew imposed during the pandemic, 10.5% during the pandemic versus 17.5% before it. 6 Data from another study show that the incidence of abnormal cycle length and anovulatory cycles decreased during the pandemic from 8.7% to 8.0% and 2.9% to 2.5%, respectively. Participants over the age of 45 were more prone to experiencing menstrual aberrations like anovulatory cycles and abnormal cycle length. 16 While stress and anxiety associated with the pandemic were found to be the major

| Duration of the menstrual cycle
Fifty-six percent of women enrolled in a study reported experiencing a difference in their menstrual cycle since the start of the pandemic with a greater variability seen in cycle length (18 during the pandemic. 16 The Cohort study This survey is aimed to investigate the relationship between COVID-19 disease and ovarian function in reproductive-aged women No significant association between COVID-19 infection and menstrual changes (p > 0.05).
TAYYABA REHAN ET AL. | 7 of 10 menses (34%) and schedule of the cycle (50%). It was observed that participants with high COVID-19 Perceived Stress Scale (PSS) scores were more prone to changes in the duration of their menses compared to those with relatively lower scores (58% vs. 29%, p = 0.0008). 20

| Heavy periods
Out of the 1031 participants included in a study by Phelan et al.,14 47% of women experienced heavy periods, and 5% reported that the incidence had increased during the pandemic (p = 0.003

| Dysmenorrhea
According to a study conducted by Phelan et al., 14 49% of the women reported painful periods and 7% stated that the incidence of painful periods had increased during the pandemic (p < 0.0001).
For 30% of the women, painful periods were a new occurrence while 12% of the women who experienced painful periods before the pandemic, reported that the pain had improved during the pandemic. It was observed that women who struggled with their mental health were more predisposed to painful periods (54% vs. 36%, p < 0.0001). 14 COVID-19-associated anxiety was linked to an increase in the severity of dysmenorrhea in women (p = 0.025) whereas depression caused by COVID-19 was also linked with worsening dysmenorrhea (p = 0.008). The incidence and severity of dysmenorrhea increased during the pandemic as 49.9% of the women involved in the study experienced it as compared to 36.9% before the pandemic. 21 This is supported by evidence from another study which shows that out of 125 participants, 22.4% experienced increased menstrual pain during the pandemic as compared to before, and 25.6% of women reported worsening menstrual cycles. 22    We found that amidst the pandemic while most of the women remain unaffected in terms of their menstrual cycles, the ones who were suffering from anxiety, stress, and depression reported changes in their menstrual patterns. [14][15][16][17] Major changes that were recorded include increased or decreased menstrual volume, prolonged duration of the cycle, increased episodes of pain, and occurrence of PMS symptoms. 16,17,[19][20][21][22] The participants who were already suffering from endometriosis reported a significant increase in pain frequency during the pandemic time period. 23 The SARS-CoV-2 infection itself has proven to be a systemic disorder. Studies disclose the effects of the lethal virus on the reproductive health of women that include dysregulation in several regulatory and inhibitory reproductive hormones e.g., prolactin, AMH, and testosterone. 26 The regular menstrual cycle assures the maintenance of the uterus through its periodic shedding and regeneration. Irregularities in the menstrual cycle can pave the path for certain complications including pre-eclampsia, low birth weight of the fetus, spontaneous delivery, and increased risk of metabolic disorders. 27,28 Factors contributing to psychological illness should be analyzed and discussed to break the chain of poor mental effects on the reproductive activity of women.

| Limitations
The long-term impact of COVID-19 infection and subsequent pandemic on menstrual health had not been studied in any of the included surveys. This review did not address the effects of the COVID-19 vaccine on women's reproductive health.

| Strengths
The review encourages researchers to investigate the long-term effects of the COVID-19 pandemic and SARS-CoV-2 infectionrelated menstrual irregularities in-depth, and it calls for psychosocial committees to design preventive measures and protocols for any future crises.

| CONCLUSIONS
Our review discloses a significant relation between abnormal

CONFLICT OF INTEREST
The authors declare no conflict of interest.

DATA AVAILABILITY STATEMENT
The data sets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

TRANSPARENCY STATEMENT
The lead author Mohammed Mahmmoud Fadelallah Eljack affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.