The effect of COVID-19 vaccination on the menstrual cycle in female in Riyadh, Saudi Arabia.

Hayat Saleh Alzahrani: Writing – review & editing. Saba Ali Algashami: Methodology. Alanoud Abdulaziz Alharkan: Writing – original draft, Formal analysis. Noura Sultan Alotaibi: Data curation, Writing – original draft. Naelah Waseem Algahs: Writing – review & editing.

Data from 1066 participants were analyzed in the current study. The majority of respondents were Saudis (93.1%) and had obtained a Bachelor's degree or above (80.8%). More than half of women aged 19 to 29 years (64.3%), and were single (64.4%). Students represented 45.9% of the sample. Approximately less than half of the study population was infected with COVID-19 (44.3%), and 60.4% had received three doses of the COVID-19 vaccine ( Table 1 ). The most common morbidities among women included iron deficiency anaemia (21.1%) and hypothyroidism (6.3%, Table 2 ). Table 1 Demographic and COVID-19 related data and their association with abnormal menstruation after receiving the COVID-19 vaccine. Parameter Category Overall, N = 1,066 Abnormal menstruation after the COVID-19 vaccine No, N = 785 Yes, N = 281 p-value Age 12 to 18 91 (8.5%) 71 (9.0%) 20 (7.1%) 0.254 19 to 29 685 (64.3%) 510 (65.0%) 175 (62.3%) 30 to 39 185 (17.4%) 126 (16.1%) 59 (21.0%) 40 to 50 105 (9.8%) 78 (9.9%) 27 (9.6%) Nationality Saudi 992 (93.1%) 733 (93.4%) 259 (92.2%) 0.495 Non-Saudi 74 (6.9%) 52 (6.6%) 22 (7.8%) Educational Illiterate 7 (0.7%) 7 (0.9%) 0 (0.0%) 0.174 Primary or middle school 15 (1.4%) 11 (1.4%) 4 (1.4%) High school 183 (17.2%) 143 (18.2%) 40 (14.2%) Bachelor's degree or above 861 (80.8%) 624 (79.5%) 237 (84.3%) Occupation Student 489 (45.9%) 378 (48.2%) 111 (39.5%) 0.042 Employee 339 (31.8%) 238 (30.3%) 101 (35.9%) Retired 10 (0.9%) 9 (1.1%) 1 (0.4%) Housewife 228 (21.4%) 160 (20.4%) 68 (24.2%) Marital status Married 344 (32.3%) 241 (30.7%) 103 (36.7%) 0.064 Single 686 (64.4%) 519 (66.1%) 167 (59.4%) Divorced 29 (2.7%) 22 (2.8%) 7 (2.5%) Widow 7 (0.7%) 3 (0.4%) 4 (1.4%) COVID-19 infection No 594 (55.7%) 439 (55.9%) 155 (55.2%) 0.825 Yes 472 (44.3%) 346 (44.1%) 126 (44.8%) Doses Twice 422 (39.6%) 301 (38.3%) 121 (43.1%) 0.177 Three times 644 (60.4%) 484 (61.7%) 160 (56.9%) First dose type Pfizer-BioNTech 851 (79.8%) 624 (79.5%) 227 (80.8%) 0.966 Oxford-AstraZeneca 202 (18.9%) 151 (19.2%) 51 (18.1%) Moderna 9 (0.8%) 7 (0.9%) 2 (0.7%) I do not know 4 (0.4%) 3 (0.4%) 1 (0.4%) Second dose type Pfizer-BioNTech 842 (79.0%) 622 (79.2%) 220 (78.3%) 0.827 Oxford-AstraZeneca 172 (16.1%) 125 (15.9%) 47 (16.7%) Moderna 40 (3.8%) 28 (3.6%) 12 (4.3%) I do not know 12 (1.1%) 10 (1.3%) 2 (0.7%) Third dose type Pfizer-BioNTech 503 (47.2%) 382 (48.7%) 121 (43.1%) 0.324 Oxford-AstraZeneca 5 (0.5%) 4 (0.5%) 1 (0.4%) Moderna 132 (12.4%) 96 (12.2%) 36 (12.8%) I do not know 14 (1.3%) 8 (1.0%) 6 (2.1%) Does not apply 412 (38.6%) 295 (37.6%) 117 (41.6%) Abnormal menstruation before vaccine No 591 (55.4%) 339 (43.2%) 252 (89.7%) <0.001 Yes 475 (44.6%) 446 (56.8%) 29 (10.3%) Table 2 Morbidities and their association with abnormal menstruation after receiving the COVID-19 vaccine. Parameter Category Overall, N = 1,066 Abnormal menstruation after the COVID-19 vaccine No, N = 785 Yes, N = 281 p-value Hypertension No 1,039 (97.5%) 760 (96.8%) 279 (99.3%) 0.024 Yes 27 (2.5%) 25 (3.2%) 2 (0.7%) Diabetes mellitus No 1,048 (98.3%) 771 (98.2%) 277 (98.6%) 0.794 Yes 18 (1.7%) 14 (1.8%) 4 (1.4%) Hypothyroidism No 999 (93.7%) 734 (93.5%) 265 (94.3%) 0.634 Yes 67 (6.3%) 51 (6.5%) 16 (5.7%) Bleeding disorders No 1,063 (99.7%) 782 (99.6%) 281 (100.0%) 0.570 Yes 3 (0.3%) 3 (0.4%) 0 (0.0%) Iron deficiency anaemia No 841 (78.9%) 613 (78.1%) 228 (81.1%) 0.282 Yes 225 (21.1%) 172 (21.9%) 53 (18.9%) Demographic and COVID-19 related data and their association with abnormal menstruation after receiving the COVID-19 vaccine. Morbidities and their association with abnormal menstruation after receiving the COVID-19 vaccine. Abnormal menstruation before receiving the COVID-19 vaccine was prevalent among 475 participants (44.6%, 95% CI, 41.6 to 47.6). The most common abnormalities were irregular menstruation (26.6%) and decreased amount of blood (9.8%, Fig. 1 ). Menstrual irregularity after receiving the COVID-19 vaccine (defined as having at least one symptom of abnormalities) was prevalent among 281 participants, accounting for a prevalence of 26.4% (95% CI, 23.8 to 29.1). The most common abnormalities included irregular menstruation (12.0%) and increased time between one cycle and the next cycle (7.5%, Fig. 1 ). Fig. 1 M enstrual abnormalities before and after receiving the COVID-19 vaccine. M enstrual abnormalities before and after receiving the COVID-19 vaccine. Results of the association analysis showed that the number of vaccine doses was not significantly associated with menstrual abnormality after the COVID-19 vaccine (p = 0.177). Additionally, the types of the vaccine were not associated with menstrual abnormality (p = 0.966 for the types of the first dose, p = 0.827 for the types of the second dose and p = 0.324 for the types of the third dose). However, abnormal menstruation after receiving the COVID-19 vaccine was significantly associated with participants’ occupation (p = 0.042) and irregular menstruation before receiving the vaccine (p < 0.001, Table 1 ). Furthermore, abnormal menstruation was significantly associated with hypertension (p = 0.024, Table 2 ), polycystic ovary syndrome (p = 0.001) and at least one gynaecological condition (p < 0.001, Table 3 ). In the multivariate regression analysis, we included the significantly associated variables with having menstrual abnormalities. No variables showed a risk of multicollinearity since the variance inflation factor (VIF) of independent variables did not exceed 5. However, we had to exclude the hypertension variable because we had only two patients in the hypertension category; therefore, the outcomes could be limited and unreliable. Results showed that menstrual abnormality before receiving the COVID-19 vaccine (OR = 0.09, 95% CI, 0.06 to 0.14, p < 0.001) was less likely to be associated with abnormal menstruation after receiving the vaccine ( Table 4 ). Table 3 Gynaecological conditions and their association with abnormal menstruation after receiving the COVID-19 vaccine. Parameter Category Overall, N = 1,066 Abnormal menstruation after the COVID-19 vaccine No, N = 785 Yes, N = 281 p-value Uterine polyps No 1,051 (98.6%) 774 (98.6%) 277 (98.6%) >0.999 Yes 15 (1.4%) 11 (1.4%) 4 (1.4%) Fibroid No 1,053 (98.8%) 774 (98.6%) 279 (99.3%) 0.532 Yes 13 (1.2%) 11 (1.4%) 2 (0.7%) Endometriosis No 1,066 (100.0%) 785 (100.0%) 281 (100.0%) >0.999 Yes 0 (0.0%) 0 (0.0%) 0 (0.0%) Pelvic Inflammatory Disease No 1,061 (99.5%) 781 (99.5%) 280 (99.6%) >0.999 Yes 5 (0.5%) 4 (0.5%) 1 (0.4%) Polycystic ovarian syndrome No 980 (91.9%) 709 (90.3%) 271 (96.4%) 0.001 Yes 86 (8.1%) 76 (9.7%) 10 (3.6%) Premature ovarian insufficiency No 1,064 (99.8%) 783 (99.7%) 281 (100.0%) >0.999 Yes 2 (0.2%) 2 (0.3%) 0 (0.0%) Uterine cancer No 1,066 (100.0%) 785 (100.0%) 281 (100.0%) >0.999 Yes 0 (0.0%) 0 (0.0%) 0 (0.0%) Cervical cancer No 1,066 (100.0%) 785 (100.0%) 281 (100.0%) >0.999 Yes 0 (0.0%) 0 (0.0%) 0 (0.0%) Any gynaecological condition No 953 (89.4%) 687 (87.5%) 266 (94.7%) <0.001 Yes 113 (10.6%) 98 (12.5%) 15 (5.3%) Use of contraceptives while you were vaccinated? No 964 (90.4%) 710 (90.4%) 254 (90.4%) 0.979 Yes 102 (9.6%) 75 (9.6%) 27 (9.6%) Table 4 The analysis of independent associations with abnormal menstruation after receiving the COVID-19 vaccine. Parameter Category OR 95% CI p-value Occupation Student Ref Ref Employee 1.33 0.94, 1.88 0.110 Retired 0.28 0.01, 1.65 0.237 House wife 1.23 0.83, 1.81 0.305 Menstrual abnormality before the COVID-19 vaccine No Ref Ref Yes 0.09 0.06, 0.14 <0.001 Polycystic ovarian syndrome No Ref Ref Yes 0.60 0.17, 2.31 0.436 Gynecological conditions No Ref Ref Yes 0.83 0.25, 2.35 0.733 Ref indicates a reference category; OR: odds ratio; CI: confidence interval. Gynaecological conditions and their association with abnormal menstruation after receiving the COVID-19 vaccine. The analysis of independent associations with abnormal menstruation after receiving the COVID-19 vaccine. Ref indicates a reference category; OR: odds ratio; CI: confidence interval.

Informed consent was obtained from all subjects involved in the study.

This observational cross-sectional study was conducted from Dec 2021 to June 2022 in Riyadh, Saudi Arabia. The study was carried out by using a convenience sampling technique. Furthermore, an online self-administered questionnaire was developed and distributed on social media platforms. The questionnaire was designed to assess the menstruation changes after COVID-19 vaccination. The questionnaire is divided into three sections. The first section comprises socio-demographic data such as age, nationality, marital status, and medical conditions. The second section included six questions about COVID-19 infection and its type and vaccination doses. The third section has nine questions assessing the menstrual cycle before and after COVID-19 vaccines, gynaecological conditions and history of contraceptive medications among females of childbearing age in Riyadh. The questionnaire was validated using face validity. It was determined by the faculty members of the family medicine department. The questionnaire was developed in English, then translated into Arabic, and back-translated into English to ensure comprehensibility and content validity. The questionnaire was also tested on some patients before the study was conducted (participants not included in the survey) to evaluate the questionnaire's content. The respondents gave valuable feedback, and based on that, unclear questions were modified. Regarding the sample size, if we are expecting that 10% of the population who got the vaccine developed any menstrual irregularity with a margin of error of 2%, level of confidence of 95%, and power of study of 80%, the minimal sample size required for this study will be 865. However, 1066 participants enrolled in the current study, higher than the calculated minimum sample size. This should increase the reliability of the study’s findings and compensate for any missing data. All females aged 18–50 (Saudi and Non-Saudi) who lived in Riyadh, Saudi Arabia and consented to participate in the study were included. The exclusion criteria were those women who did not receive the vaccine, had one dose of the vaccine, lived outside Riyadh and were postmenopausal. The study was approved by the institutional review board of Princess Nourah Bint Abdulrahman University (IRB Log Number 22–0312). Data analysis were performed using RStudio (R version 4.1.1). Categorical variables were expressed as frequencies and percentages. We used Pearson's Chi-squared test or Fisher's exact test to assess factors associated with having abnormal menstruation after receiving the COVID-19 vaccine. The significantly associated factors were used as independent variables in a binary logistic regression analysis to determine the predictors of abnormal menstruation. A p-value of < 0.05 indicated statistical significance.

The coronavirus pandemic has been alarming since late 2019; the COVID-19 vaccine is a saving solution to protect us. However, its side effects still need to be studied. Our study findings show that the number and types of COVID-19 vaccines were not associated with menstrual abnormality. However, abnormal menstruation before the COVID-19 vaccine was significantly associated with irregular menstruation after receiving the vaccine. In our studied cohort, Pfizer-BioNTech was the most used vaccine for the first, second, and third doses, with 79.83%, 78.99%, and 47.19%, respectively. Notably, the Pfizer-BioNTech vaccine was the first approved vaccine in Saudi Arabia ( Mohammed et al., 2021 ). According to Francis et al. [12], the relative efficacy of vaccines was “Pfizer—95%, Moderna—94.1%, AstraZeneca—70.4% and Janssen—66.9%,” and these vaccines are effective in reducing cases incidence as well as the severity of covid-19 infection. This supports our finding that only 44.28% of people who had the vaccine got a covid-19 infection. Our study confirmed that type of vaccination is not associated with an abnormal menstrual cycle. Likewise, a study found only irregular menses in 0.69% after Pfizer-BioNTech administration and 0.45% of cases after Oxford-AstraZeneca ( Alghamdi et al., 2021 ). However, another study reported contrasting findings, and they reported menstrual cycle disturbance after the administration of Pfizer-BioNTech and Oxford-AstraZeneca in 643 cases ( Hunter 2021 ). These rare events can occur due to underlying conditions like thrombocytopenia, platelets disorders or hormonal changes that can lead to excessive bleeding during periods in women( Akiyama et al., 2021 , Razzaq and Al-Jasim, 2021 ). Many women worldwide have reported irregular menstrual periods after receiving the COVID-19 vaccine ( Male, 2021 , Bouchard et al., 2022 ). This can be explained by the female menstrual cycle being affected by several stressful conditions such as infections, certain medical conditions, sudden weight loss, eating disorders and over-exercising ( Nagma et al., 2015 ). Hypothalamic-pituitary gonadal axis can be affected by such stressors leading to disruption in the physiological release of hormones ( Kurdoğlu 2021 ). Our study demonstrated that 55.16% of the participants experienced menstrual problems after being vaccinated against COVID-19 compared to 22.89% of the participants who had no menstrual problems after the vaccination. A cross-sectional investigation in the MENA region found that 66.3% of women participants in their study experienced abnormal periods after vaccination ( Muhaidat et al., 2022 ). Our findings reveal that the majority of the problems reported after receiving the second dose of the vaccine with 25.72%. Almost one-third had symptoms of irregularity or other problems in the first period after receiving the vaccine. Compared to the MHRA statement about the yellow card reports that don’t support the association between menstrual irregularity and vaccination, our study has determined that there is a significant relationship between receiving the covid-19 vaccine and menstrual irregularity in our study participants with 12.01% (P < 0.05) ( Male 2021 ). In our study participants, out of the listed problems in the survey, we found that a significant number of participants had an absence of the menstrual cycle after taking the vaccine, 4.6% (P < 0.05). The other problems listed in the survey include an increase in time between one cycle and the next cycle, decrease the time between one cycle and the next cycle, increase in the number of days of bleeding, a decreasing number of days of bleeding, an increasing amount of blood, decrease the amount of blood, were insignificantly related to vaccination. In this study, The majority of the participants (71.11%) have not been diagnosed with any chronic diseases, and only 2.53% of the participants who were previously diagnosed with Hypertension had a significant association with post-vaccine menstrual changes after the second dose of the vaccine (4.03%). In comparison, only (1.55%) after the third dose (P < 0.05); however, there is no published information supporting this finding. Likewise, many studies have confirmed that although women have reported changes in the menstrual cycle followed by covid-19 vaccination, it was returned to regular after a few cycles ( Bentov et al., 2021 , Male, 2021 ). However, these studies were conducted or published in 2021, when the covid-19 vaccination was newly introduced, which might be the reason for vaccination hesitation among females ( Hsu et al., 2022 , Berenson et al., 2021 ). We found that 8.07% of the studied participant had the polycystic ovarian syndrome, which was significantly associated with post-vaccine menstrual changes (P < 0.05). A previously published study suggests menstrual changes after the COVID-19 vaccine are associated with hormonal disturbance found in PCOS patients ( Alghamdi et al., 2021 ). Yet a survey conducted in the MENA area in 2022 stated that there was no significant association between the post-COVID-19 vaccines and PCOS( Muhaidat et al., 2022 ). On the other hand, 89.12% of this study's participants reported no gynaecological disorders or abnormalities. Our study did not find a considerable correlation between using contraceptives and post-vaccine menstrual changes. This is supported by the same research conducted in the MENA area, whose results found no significant association between contraceptive methods ( Muhaidat et al., 2022 ). In contrast, a study conducted in the UK found menstrual abnormalities in 20% of the participants, which was associated with a smoking history and a history of covid-19 infection. At the same time, contraceptives act as a protective factor ( Alvergne et al., 2021 ). Another study reported these irregularities in 50% of the cohort followed by the first dose of vaccination and 70% followed by the second dose; however, these were resolved within two months ( Laganà et al., 2022 ). It is also noted that there is a paucity of studies in this regard, and as per our knowledge, we did not find any clinical trial to confirm the causality. Our study is also observational; therefore, the association is cautiously interpreted. There might be an alleged relationship that can be investigated through large longitudinal prospective studies and clinical trials.

In conclusion, our study findings showed a significant association between covid-19 vaccination and menstruation irregularity before administering the covid-19 vaccine and hypertension, irrespective of vaccine type or the number of doses administered. However, this study is cross-sectional, and this association needs thorough investigation. Future and ongoing clinical trials should investigate menstrual abnormalities, other abnormal vaginal bleeding and hormonal changes post-vaccination, especially the covid-19 vaccine. Furthermore, women who are willing to receive a covid-19 vaccine should be counselled that these abnormalities are temporary and self-resolving within a few months.

COVID-19 vaccination has got extraordinary curiosity in 2021 and 2022 as it becomes a primary prevention against the COVID-19 infection pandemic. Several types of vaccines have been discovered, and they are widely available. Up to June 2022, 11,902,271,619 vaccine doses have been administered globally, and 66,580,990 vaccine doses in Saudi Arabia ( Organization 2022a ). Around 72% Saudi population is fully vaccinated against COVID-19 currently, while 76% received at least the first dose to date ( 2022 ). According to estimates by the World Health Organization (WHO), cases have been reduced greatly, with only 147 confirmed cases reported recently in Saudi Arabia ( Organization 2022b ). The total number of cumulative active cases in Saudi Arabia is 3419( Ministry of Health 2023 ). Various platforms, including traditional and newer media platforms, have been used to spread information about the covid-19, vaccine availability and administration ( Hassan et al., 2022 ). Four vaccine types were approved in Saudi Arabia: Moderna, Pfizer, Janssen, and AstraZeneca ( Alqurashi et al., 2022 ). These vaccines offer protection against Covid-19 disease by stimulating the human immune system in a particular manner ( Anand and Stahel 2021 ). Some individuals might face mild side effects such as fever, headache, and myalgia within 1 to 2 days after receiving the vaccine ( Anand and Stahel 2021 ). Likewise, males aged 40–49 years and Saudi nationals have higher odds of experiencing severe side effects from the vaccine ( Al-Hanawi et al., 2022 ). In Saudi Arabia, several measures have been placed to overcome vaccine-related hindrances and ensure safe vaccine coverage in the Kingdom ( Assiri et al., 2021 ). Many factors are documented that were associated with abnormal menstrual cycles, like stress, anxiety, autoimmune conditions, infection etc. Recently studies have reported that COVID-19 infection and vaccination have some effect on menstruation ( Alvergne et al., 2021 , Male, 2021 , Taşkaldıran et al., 2022 ). A case-control study conducted in the United Kingdom found that one-fifth of women who participated in the survey had menstrual disturbances ( Alvergne et al., 2021 ). A recent systematic review of 14 studies (including preprints) reported that 52% of the participants had some menstrual problem post-vaccination ( Nazir et al., 2022 ). This review found menstrual abnormalities ranged from 0.8% to 91% ( Nazir et al., 2022 ). Evidence is scarce regarding the side effects of vaccination against covid-19 in Saudi Arabia. Recently, few studies have mentioned minor changes in the menstrual cycle after covid-19 vaccination in women ( Bouchard et al., 2022 ). Furthermore, there were many reported cases in primary health care clinics in Riyadh, Saudi Arabia, regarding female menstrual cycle problems after the COVID-19 vaccination. The patients showed concern regarding vaccination safety. Therefore, this research was conducted to investigate these cases' prevalence, specify the type of irregularity, and explore the effect of the covid-19 vaccine on the female menstrual cycle. This study will provide an opportunity to assess these problems among childbearing females in Riyadh, Saudi Arabia. This has given insight into the relationship between the covid-19 vaccine and the menstrual cycle, which will eventually help guide proper interventions, raising covid-19 vaccination trends in the country. The study's major objectives are to determine the prevalence of menstrual irregularity after the COVID-19 vaccine among females of childbearing age in Riyadh.

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Ethical review was conducted by the Institutional Review Board of Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia (protocol code HAP-01–059) and approval were exempted for this study due to no more than minimal risk to the participants.