Effect of COVID-19 vaccine on menstrual experience among females in six Arab countries: A cross sectional study.

Sajeda Ghassan Matar: Conceptualization; data curation; formal analysis; investigation; methodology; project administration; resources; software; supervision; validation; visualization; writing‐original draft; writing‐review and editing. Anas Zakarya Nourelden: Formal analysis. Ahmed Assar: Conceptualization; investigation; methodology. Eshak I. Bahbah: Conceptualization. Areej M. Alfryjat: Conceptualization. Elfatih A. Hasabo: Conceptualization; investigation; project administration; writing‐original draft; writing‐review and editing. Suzan A. Matar: Conceptualization; writing‐review and editing. Shatha Nizar Bishtawi: Conceptualization; writing‐original draft. Mays Alhoubani: Formal analysis. Ahmad Bassam Yahia: Conceptualization. Khaled Mohamed Ragab: Conceptualization. Lina Mohammad Salameh: Conceptualization. Lana Saif Eddin Salameh: Conceptualization. Mohamed Sayed Zaazouee: Conceptualization. Mohammed Al‐kafarna: Data curation. Alaa Ahmed Elshanbary: Data curation. Hossam Waleed Almadhoon: Data curation. Shahed Toulaq Bakdash: Data curation. Ola Awad Babiker Adam: Data curation. Abdelkader Nabeel Malih: Data curation. Shimaa Abo elfotoh Habash: Data curation. Rakia Mohamed Taha Basiouny: Data curation. Afaf Ahmad: Data curation. Raghda Mohammed Ahmed Hamid: Data curation. Balsam Younan Habib: Data curation. Dalia Nasr Elokl: Data curation. Hiba Hatim Abdalraheem: Data curation. Esraa Adel Atia: Data curation. Nazik Ibrahim Ahmed Yousif: Data curation. Fida Hussien Al‐Ali: Data curation. Israa mohammed Alshaer: Data curation. Fatima Elsidieg Abdulali: Data curation. Hadil Abu Ayesh: Data curation. Anwar Yousef Jabari: Data curation. Raneem Ahmed Egzait: Data curation. Nameer Amer Abu Munshar: Data curation. Aseel Ahmad Alkhraibat: Data curation. Aisha Hasan ibreerah: Data curation. Iman A. Basheti: Conceptualization; data curation; project administration; supervision; writing‐review and editing.

Ethical approval of research (No. 2022‐PHA‐1) was obtained from the Institutional Review Board (IRB) of the Applied Science Private University (ASU), Jordan. Informed consent was obtained from all participants. All methods were performed in accordance with the relevant guidelines and regulations.

A multicenter cross‐sectional study was conducted using a self‐administered pre‐piloted anonymous questionnaire ( Supporting Information S1 ). The study was conducted according to the STROBE guidelines for reporting and conducting cross‐sectional studies. 10 Females from six Arab countries were invited to participate in this study; females who did not receive any dose of the COVID‐19 vaccine were considered the control group. The study was conducted online by distributing the questionnaire among females via social media platforms in six Arab countries including Jordan, Palestine, Syria, Egypt, Sudan, and Libya. We included menstruating female participants above 18 years of age, and we excluded females who were pregnant, breastfeeding, taking oral contraceptives or any other hormonal therapy, using intrauterine devices, or those who had endometriosis or polycystic ovarian syndrome. Questions about the following information were included: 1‐Demographic Characteristics : Females were invited to answer questions regarding their age, country, residency, education, work status, weight, height, smoking status, exercise, and exposure to stressful conditions. 2‐Menstruation Experience : The Women's Health Symptoms Survey (WHSS) 11 questionnaire was used to assess women's answers regarding their pain during menstruation and if it had an impact on their physical activities, such as going to work or doing sports, or if they developed thigh, anal and/or back pains, and dysuria. Questions about severity, frequency of pelvic pain, and analgesic use were included, and pain score associated with menstruation was scored on average and in worst cases. Furthermore, questions regarding bleeding heaviness, duration of menstruation, the number of days between the start of one period and the beginning of the next one were enclosed as well. Five questions were added to cover other aspects such as bowel movements associated with pain and the frequency of defecation and the texture of the stool during menses. 3‐COVID‐19 Vaccine Administration Data : All participants who administered the COVID‐19 vaccine were asked about the type, the number of doses, and the time period since they received the vaccine. 4‐History of COVID‐19 infection Data : All participants who had a history of COVID‐19 infection were asked about the severity of their infection, assessed by the requirement of oxygen therapy, presence of pneumonia, requirement of any type of ventilation, admission to hospital status, and duration since they got COVID‐19 infection. 1‐Demographic Characteristics : Females were invited to answer questions regarding their age, country, residency, education, work status, weight, height, smoking status, exercise, and exposure to stressful conditions. 2‐Menstruation Experience : The Women's Health Symptoms Survey (WHSS) 11 questionnaire was used to assess women's answers regarding their pain during menstruation and if it had an impact on their physical activities, such as going to work or doing sports, or if they developed thigh, anal and/or back pains, and dysuria. Questions about severity, frequency of pelvic pain, and analgesic use were included, and pain score associated with menstruation was scored on average and in worst cases. Furthermore, questions regarding bleeding heaviness, duration of menstruation, the number of days between the start of one period and the beginning of the next one were enclosed as well. Five questions were added to cover other aspects such as bowel movements associated with pain and the frequency of defecation and the texture of the stool during menses. 3‐COVID‐19 Vaccine Administration Data : All participants who administered the COVID‐19 vaccine were asked about the type, the number of doses, and the time period since they received the vaccine. 4‐History of COVID‐19 infection Data : All participants who had a history of COVID‐19 infection were asked about the severity of their infection, assessed by the requirement of oxygen therapy, presence of pneumonia, requirement of any type of ventilation, admission to hospital status, and duration since they got COVID‐19 infection. A convenience sampling method was used to acquire online responses from the participants to the e‐survey questionnaire. The sample size was calculated as two independent female samples from each country; one for the control group for females who did not receive the COVID‐19 vaccine, and the second for females who previously received one dose or more of the COVID‐19 vaccine. The equation n  =  z 2 P(1 − P)/d 2 was used with 95% CI, 50% response distribution, and 0.05 margin of error. 1 A sample of 384 participants was considered a minimal sample for each group in each country. Data collection started in November 2021 and ended in December 2021 by online distributed questionnaires on different internet platforms in the six participating Arab countries. Voluntary participation and comprehension of informed consent among females were set and confidentiality was ensured through proper data management and security. Ethical approval of research (No. 2022‐PHA‐1) was obtained from the Institutional Review Board (IRB) of the Applied Science Private University (ASU), Jordan. Descriptive analyses were conducted (frequency and percentage) to describe demographic characteristics, COVID‐19 vaccine administration data, COVID‐19 infection data, and menstruation experience and symptoms. A Chi‐square test was used to explore the relationship between menstruation experience and vaccination status, and to compare the different types of vaccines in association with the reported menstrual experience. Mann–Whitney U test was used to compare pain scores with the vaccination status. Logistic regression was used to assess the association of vaccination with menstrual experience outcomes adjusting for the demographics. Three models were employed in the data analysis, the first included demographic characteristics that are known to not affect the menstrual experience (country, residency, education, and work), whereas the second included demographics that potentially affect the menstrual experience (smoking, stressful conditions, entertainment sports, COVID‐19 infection, BMI, age), and the third model included all the demographic characteristics. A p‐value of less than 0.05 was considered significant.

A total of 6454 females participated in this study, although 1512 were excluded since they did not meet the inclusion criteria. Among 4942 female participants who were included from six Arab countries with a mean age of 24.02 (SD = 5.73) were included in the study. The mean Body Mass Index (BMI) of the sample was 23.56 (SD = 4.79), 84.6% of them had a college degree or above, and 2919 (59.1%) of them were vaccinated against COVID‐19. The most common types of vaccine received were Pfizer (27.2%), Sinopharm (24.7%) or Sinovac, and AstraZeneca (24.3%). Full demographic characteristics can be found in Table  1 . Demographic characteristics Jordan Syria Palestine Egypt Libya Sudan Urban Rural Below college College and above Unemployed Part‐time Full‐time Currently smoker Not at all Ex‐smoker Yes No AstraZeneca Johnson and Johnson Moderna Pfizer Sinopharm or Sinovac Sputnik First dose only Two doses Two doses and third additional One dose of Johnson and Johnson Yes No No symptoms Mild (cough, muscle and joint pain, loss of smell or taste sensations%) More severe symptoms Yes No Not sure Yes No Not sure Yes No Not sure Yes No Not sure Home Hospital ICU Yes No Not sure Yes No Not sure Yes No No Sometimes Regularly Frequently Daily Not sure Yes No Yes No Valid percent. Only 1838 (48.7%) participants reported a history of COVID‐19 infection, nearly two thirds of them (72.6%) suffered from mild symptoms only (cough, muscle, and joint pain, loss of smell or taste sensations), while 152 (9.3%) had oxygen saturation below 90%. Minority (4.5%) received oxygen therapy, and (2.1%) required a ventilator. Most of the participants were isolated at home (97.4%). Full COVID‐19 related characteristics can be found in Table  1 . The mean age for menarche was 13.25 (SD = 1.58) years and nearly two‐thirds of the participants (74.2%) had regular cycles. Most of the participants (74.2%) experienced stressful situations, mentally or physically, during the 3 months before participation in the current study, and 1542 (31.2%) practiced sports activity during the past 3 months. Full data can be found in Table  1 . Participants who received one or more dose of COVID‐19 vaccine had a significantly higher frequency of pelvic pain (84.5%) than the unvaccinated participants (81.6%, p  = 0.006). Similar outcomes were reported for back pain experienced by vaccinated participants (82.9%) versus non‐vaccinated participants (77.9%, p  < 0.001), thigh pain (63.9% vs. 61%, p  = 0.045), nausea (43% vs. 40%, p  = 0.036), tiredness (89.7% vs. 87.1%, p  = 0.005), pelvic pain (85.6% vs. 81.9%, p  < 0.001), and taking pain‐killers for the pain without prescription (62.7% vs. 57.2%, p  < 0.001). Average menstrual pain and worst menstrual pain scores were reported significantly more frequently in the vaccinated group than the unvaccinated. Full comparison can be found in Table  2 . Comparing vaccinated (either fully or partially%) and not vaccinated using chi‐square Mild Moderate Heavy Cannot remember Less than 21 days 22–24 days 25–28 days 29–32 days 33–35 days More than 36 days Cannot determine due to irregularity Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Sometimes Usually Always Yes No Yes No Occasionally (with 1 in 3 of my periods%) Often (with 2 in 3 of my periods%) Always (with every period) Never Occasionally (with 1 in 3 of my periods%) Often (with 2 in 3 of my periods%) Always (with every period) Never Always Most of the times Often Sometimes Rarely or never Always Most of the times Often Sometimes Rarely or never Always Most of the times Often Sometimes Rarely or never Always Most of the times Often Sometimes Rarely or never Always Most of the times Often Sometimes Rarely or never Note : Statistically significant values are presented in bold. Valid percent. Participants who were fully vaccinated (received two doses or one dose of Johnson and Johnson for 3 months or more) were more likely to experience back pain (82.3%) when compared to unvaccinated participants (77.9%, p  = 0.004). The frequency of all of the following was also higher in the fully vaccinated group compared to the non‐vaccinated; nausea (44.2% vs. 40%, p  = 0.024), tiredness (90.5% vs. 87.1%, p  = 0.004), pelvic pain with periods (85.3% vs. 81.9%, p  = 0.013), taking pain‐killers for the pain without prescription (65.1% vs. 57.2%, p  < 0.001), the fully vaccinated participants also had higher average and worst pain scores and significantly more days of bleeding. Full comparisons are shown in Table  3 . Comparing fully vaccinated and not vaccinated people Mild Moderate Heavy Cannot remember Less than 21 days 22–24 days 25–28 days 29–32 days 33–35 days More than 36 days Cannot determine due to irregularity Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No Sometimes Usually Always Yes No Yes No Occasionally (with 1 in 3 of my periods%) Often (with 2 in 3 of my periods%) Always (with every period) Never Occasionally (with 1 in 3 of my periods%) Often (with 2 in 3 of my periods%) Always (with every period) Never Always Most of the times Often Sometimes Rarely or never Always Most of the times Often Sometimes Rarely or never Always Most of the times Often Sometimes Rarely or never Always Most of the times Often Sometimes Rarely or never Always Most of the times Often Sometimes Rarely or never Note : Statistically significant values are presented in bold. Valid percent. To sum the difference up, females who had received one or more dose of vaccination reported a higher frequency of back pain, nausea, tiredness, pelvic pain with periods, unprescribed analgesics use, and passage of loose stools. They also reported higher scores describing average and worst menstrual pain. Only fully vaccinated females had heavier flow and more days of bleeding. Vaccinated females with Moderna and Pfizer vaccines had the highest average pain score during menstruation (6.43 and 5.94, respectively) significantly higher than other vaccines. They also had significantly higher number of bleeding days (5.92 for Pfizer and 5.76 for Moderna) compared to other vaccines. a higher percentage of menstrual irregularity was observed in Johnson & Johnson, followed by Sinopharm, Moderna, and AstraZeneca ( p  = 0.022). Similarly, Johnson & Johnson was associated with a higher percentage of heavy bleeding with coagulations, followed by Pfizer, Sinopharm, AstraZeneca, and Moderna ( p  = 0.003). Rectal bleeding was more common in participants vaccinated with Moderna, Pfizer, and Johnson & Johnson ( p  = 0.026). The rest of the menstruation experience did not show significant differences among different vaccine groups. Full comparison between vaccines is written in Table  4 . The comparison of different types of vaccines effect on menstrual experience Note : Statistically significant values are presented in bold. Valid percent. The group of females who were vaccinated and have a history of COVID‐19 had a significantly higher heaviness of bleeding, a higher prevalence of pelvic pain, anal pain, back pain, thigh pain, general weakness, menstrual pain prevalence, use of analgesics, and higher pain scores. A full table to compare the four groups including vaccinated and had COVID‐19, vaccinated with no history of COVID‐19, not vaccinated with a history of COVID‐19, and not vaccinated with no history of COVID‐19 is found as Supporting Information S2 . In addition, a post hoc analysis was performed to assess difference between mentioned groups, results showed that group one had the highest pain score on average, pain score in worst cases, and highest days of bleeding; this indicated an association between pain scores and both vaccination and COVID‐19 infection. Full table for post hoc analysis is available in Table  5 . Post hoc ANOVA test to compare four groups in this study Note : Means that carry the same letter in the same raw are not statistically significant. In all the three regression models applied on the data, receiving the vaccine was a significant predictor for higher frequency of all of pelvic pain, back pain, nausea, general weakness, menstrual pain, unprescribed analgesics use, more frequent bowel movement, and more loose stool status, after adjustment for demographics. Full analysis can be found in Supporting Information S3 .

The peer review history for this article is available at https://publons.com/publon/10.1111/irv.13088 .

This study is one of the first studies to assess the effect of the COVID‐19 vaccine on menstrual experience among females in the middle‐east region and worldwide. Same outcomes were assessed for both females who received the the COVID‐19 vaccine and females who did not receive any vaccine doses to avoid any subjective reviews by considering females who did not receive the COVID‐19 vaccine as a control group. This study revealed that receipt of the COVID‐19 vaccine was significantly associated with increased back pain, nausea, tiredness, pelvic pain with periods, administration of over the counter analgesics, bowel movement, looseness of the stool, and pain score on average. An increase in the heaviness of bleeding was reported among females who were fully vaccinated. It was critical to perform menstrual health research in the context of the COVID‐19 pandemic considering the strong relationship between regular normal cycles and the general health of females. Irregular menstrual cycles has been linked to an increased risk of breast and ovarian cancer, early menopause, infertility, chronic renal failure, diabetes mellitus, and cardiovascular disease, 12 , 13 , 14 , 15 furthermore, having menstrual health issues may have a significant impact on quality of life. 16 In addition, women's menstrual health might be adversely affected by situations of emotional or physical stress, which can result in a condition known as functional hypothalamic amenorrhea (FHA), in which there is no underlying biological cause of anovulation. 17 , 18 In addition to missing periods, psychological distress has been linked to aggravation of menstrual and psychosexual health complications. Depression, emotional instability, and high‐stress levels have been linked to dysmenorrhea. 19 , 20 Menorrhagia and premenstrual symptoms (PMS) have also been linked to significant levels of psychological distress. 21 , 22 Based on the findings of this study, a direct comparison between participants who have been vaccinated against COVID‐19 and those who have not been vaccinated showed that females who were vaccinated had a higher frequency of back pain, nausea, tiredness, pelvic pain with periods, unprescribed analgesics use, and passage of loose stools. They also had higher scores reported describing average and worst menstrual pain. By September 2021, 30 000 reports of changes in menstrual cycle were reported to the Medicines and Healthcare Products Regulatory Agency (MHRA) although no reported side effect that the vaccine can affect the menstrual cycle were found. 8 A study conducted in the MENA region among Palestine, Iraq, Lebanon, Al‐Bahrain, Tunisia, Kuwait, Qatar, Turkey, Jordan, UAE, KSA, Egypt, Oman, Morocco, Sudan, and Syria on the effect of COVID‐19 vaccine in the menstrual experience indicated that 66.3% of females experienced menstrual abnormalities after getting vaccinated with COVID‐19 vaccine. 23 Another study conducted by Laganà et. al, indicated that 50%–60% of participants have reported menstrual cycle irregularities after receiving the first dose of COVID‐19 vaccine. 24 In a prospective study that aimed to investigate the impact of the COVID‐19 pandemic on the reproductive system of women, authors reported an overall menstrual change of 46%, and that 53% experienced worse premenstrual symptoms, 49% experienced painful periods, 47% reported heaviness of bleeding, 45% had decreased libido, 29% had increased period length, 28% experienced reduced period length, and 9% reported new missed periods. 25 A cross‐sectional study of 200 women in Jordan found a substantial decrease in menstruation disorders during the COVID‐19 lockdown ( p  = 0.016), pre‐curfew, curfew, and post‐curfew, and access to healthcare facilities for menstruation difficulties did not change statistically, however phone consultations increased dramatically during the curfew. 26 Since Jordan's curfew only lasted a few days, some researchers hypothesized that the population's stress levels were not high enough to cause additional menstruation irregularities. On the other hand, an observational study in Turkey revealed an increase in menstrual abnormalities during the lockdown vs. pre‐lockdown ( p  = 0.008), although these results should be interpreted with caution, as the study included only 58 participants. 27 According to previously published studies, premenstrual symptoms are more common in women with a high degree of psychosocial stress. 18 A large percentage of women with heavy and painful periods is expected, given both have been linked to stress, psychological distress, and depressed mood. 19 , 20 , 21 , 28 When it comes to COVID‐19 infection, in China, a single‐center retrospective study compared menstrual patterns among mildly and severely ill women with COVID‐19. 29 Menstrual bleeding was observed to be reduced in 20% of women who had confirmed COVID‐19 infection, in addition, compared to a control group, COVID‐19 patients had an increased menstrual volume and menstrual cycle abnormalities. 29 As previously reported, anovulation occurs in a variety of acute disorders to ensure that vital organs operate properly. 30 By comparing the six vaccine types, a higher percentage of menstrual irregularity was observed in Johnson & Johnson, followed by Sinopharm, Moderna, and AstraZeneca ( p  = 0.022). Similarly, Johnson & Johnson was associated with a higher percentage of heavy bleeding with coagulations, followed by Pfizer, Sinopharm, AstraZeneca, and Moderna ( p  = 0.003). Rectal bleeding was more common in participants vaccinated with Moderna, Pfizer, and Johnson & Johnson ( p  = 0.026). Moreover, binary logistic regression showed that COVID‐19 vaccination was associated with an increased risk of pelvic pain, back pain, thigh pain, nausea, general weakness, menstrual pain, receiving analgesics for menstrual pain, experiencing bowel movement more than usual, and experiencing stool more liquid than usual. In a large observational study of 3959 participants (61% vaccinated and 39% non‐vaccinated), authors aimed to determine the impact of COVID‐19 vaccination on the menstrual cycle in those receiving vaccination as compared with an unvaccinated cohort. They showed that the Pfizer‐BioNTech vaccine was used by the majority of the vaccinated group (55%), followed by Moderna (35%) and Johnson & Johnson (7%). Their findings showed that the COVID‐19 vaccine was linked to a minimal change in cycle length (less than 1 day) compared with pre‐vaccine cycles. There was no substantial change in the three baseline cycles for unvaccinated individuals. The difference in cycle duration between the vaccinated and unvaccinated populations was less than 1 day in adjusted models for both dosages (first and second doses). Finally, they concluded that COVID‐19 vaccination was associated with a small change in cycle length but not menses length. 9 mRNA vaccinations might cause a strong immunological response or stressor, which can temporarily disrupt the hypothalamic–pituitary‐ovarian axis. 31 , 32 , 33 Given the dosage schedule for the mRNA COVID‐19 vaccines in certain countries (21 days for Pfizer and 28 days for Moderna), a person getting two doses in a single cycle would have received the first dose during the early follicular phase. During the follicular phase, factors that contribute to the recruitment and maturation of the dominant follicle are known to impact cycle duration variability. 34 , 35 Our study has a number of limitations; first of all, a potential limitation of the study may arise from the cross‐sectional study design that prevents any conclusions regarding the causal relationships between the COVID19 vaccine and psychological menstrual disturbances, in addition to that, the online nature of the data collection and the convenience sampling of the study participants stand as a limitation regarding the generalizability of the results, and finally, the pool of the concluded countries lacks the representation of some countries in the MENA region as the gulf countries. In conclusion, the current evidence suggests that the COVID‐19 vaccine significantly affects the menstrual cycle in terms of increasing pain score, aggravating the menstrual pain including back pain, pelvic pain, thigh pain, increasing the heaviness of bleeding, and changing the bowel movement, which collectively affects the quality of life of infected women, however, further data are required to confirm this finding. Nevertheless, COVID‐19 vaccination can reduce the risk of infection and severe disease and numerous studies have confirmed that the benefits of vaccination outweigh the risks.

After the spread of the new coronavirus by the end of 2019, 1 many pharmaceutical companies worked on developing a vaccine for COVID‐19, but only a few have successfully released vaccines that later were distributed worldwide. Vaccine development was claimed to help limit the spread of the virus, prevent death, and decrease hospitalization. Multiple technology platforms were applied to develop vaccines, including mRNA vaccines, viral vector vaccines, and inactivated vaccines. 2 Emergency approvals were provided for those vaccines to limit the spread of the coronavirus and reduce its impact. While these vaccines proved to be safe for human use in the short term, some side effects were associated with their administration including pain at the site of injection, swelling, and redness, as well as fatigue, chills, fever, myalgia, headache, and nausea. 3 On the other hand, several reports of thromboembolic events in subjects who had been administered Vaxzevria were reported 4 as well as rare side effects associated with Pfizer‐BioNTech vaccines such as Bell's palsy and lymph node swelling and tenderness. 5 Sputnik vaccine was associated with side effects that were not common, such as a temporary increase in liver enzymes such as serum creatinine and CPK, a decrease in neutrophils, an increase in lymphocytes, and either an increase or decrease in platelets. 6 Some cases of thrombotic thrombocytopenia were reported after the administration of the Johnson and Johnson vaccine. 7 A few studies have raised the possibility of menstrual changes after receipt of COVID‐19 vaccination. 8 , 9 To alleviate concerns about the safety of these vaccines among menstruating females, this study was designed to assess the severity of post‐vaccination changes to menstruation including the median cycle length, days of bleeding, bleeding heaviness, and menstrual pain.

The authors declare no conflict of interest.

Supporting Information S1. The questionnaire Click here for additional data file. Supporting Information S2. Comparison between four groups of participants: Click here for additional data file. Supporting Information S3. Effect of demographic characteristics on menstrual experience (a binary logistic regression) Click here for additional data file.