Pa ge 1 6 Pa ge 12 American Journal of Multidisciplinary Research and Innovation (AJMRI) Does the COVID-19 Vaccines Effect on the Menstrual Cycle, Cross-Sectional Study Among Adult Females at King Saud University Taghread Saadi Alghamdi1*, Eltigani O. M. Omer2 Volume 3 Issue 6, Year 2024 ISSN: 2158-8155 (Online), 2832-4854 (Print) DOI: https://doi.org/10.54536/ajmri.v3i6.3091 https://journals.e-palli.com/home/index.php/ajmri Article Information ABSTRACT Received: May 08, 2024 Accepted: June 12, 2024 Published: November 13, 2024 COVID-19 vaccinations have been associated with irregularities in the menstrual cycle and symptoms occurring pre and post-menstruation, affecting women’s reproductive health. This study aimed to demonstrate the impact of COVID-19 vaccines on women’s reproduc- tive health by examining the association between COVID-19 vaccines and disturbed men- strual cycles. This cross-sectional survey-based study was conducted among adult females at King Saud University, Saudi Arabia, from April 2022 to August 2022. A total of 380 partic- ipants were selected through a stratified random sampling technique. Ethical approval was obtained from the Deanship of Scientific Research at King Saud University. The data were analysed using descriptive statistics and appropriate statistical tests. The results revealed that 53.9% of the participants experienced disturbances in the menstrual cycle after receiving the COVID-19 vaccination. Adult females aged 18-25 showed the highest rate of disorders. Menstrual disruptions were substantially correlated with marital status (p = 0.05), with a significant association between the number of COVID-19 vaccine doses and the occur- rence of menstrual disturbances (p = 0.001). The administration of the vaccination during menstruation was linked to a notable occurrence of menstrual disturbances, although the p-value showed no statistical significance. A significant correlation was examined (p < 0.05) between pre-existing menstrual problems and the occurrence of disorders after receiving the COVID-19 vaccine (p < 0.05). The study emphasised the importance of tailored healthcare treatments for women following COVID-19 vaccination and the need for regular evaluation of reproductive health outcomes post-COVID-19 vaccination. Keywords Contraceptive Pills, COVID-19 Vaccine, Menstrual Cycle, Oligomenorrhea, Polycystic Ovaries INTRODUCTION The menstrual cycle is a regular and natural process that occurs within the female reproductive system (Schmalenberger et al., 2021). The reproductive cycle starts with menarche, the initial occurrence of menstruation in adolescence, and ends with menopause, a stage that facilitates fertilisation and potential pregnancy (Patricio & Sergio, 2019; Vogazianou, 2019). The duration of healthy menstrual cycles can range from 21 to 37 days, with cycles < 21 days being identified as polymenorrhea and cycles > 37 days as oligomenorrhea (De Sanctis et al., 2014). Typically, a normal menstrual cycle lasts for 28 days, starting from the beginning of menstruation and ending the day before the next period onset (Thiyagarajan et al., 2022). Estradiol or estrogen (E2) and progesterone (P4) exhibit regular variations in hormone levels that regulate this cyclic process (Schmalenberger et al., 2021). The follicular phase, originating with menstruation and extending until ovulation, can be identified by the development of ovarian follicles containing oocytes. During this stage, the levels of P4 remain low, while the levels of E2 gradually increase as they achieve a pre- ovulatory surge (Murray & Orr, 2020). In the following luteal phase, which occurs after ovulation until the start of menstruation, the primary follicle transforms into the corpus luteum, which releases progesterone and estrogen (Barbieri, 2014; K. Schmalenberger et al., 2021). During the mid-luteal phase, there is a noticeable increase in P4 levels, reaching their highest point, as well as a subsequent spike in E2 levels. The corpus luteum is involved in the event that fertilisation is unsuccessful, which results in a perimenstrual decline in E2 and P4 and the start of menstruation (Reed & Carr, 2015). This cycle continues with the onset of the subsequent menstrual period (Schmalenberger et al., 2021). Numerous experimental and long-term studies validate the presence of a particular subset of females who exhibit an abnormal response to regular changes in ovarian hormone levels (Berga, 2020; Wei et al., 2018). The condition manifests as behavioural, emotional, and cognitive symptoms that primarily occur during the usual hormonal changes observed in the premenstrual and mid-luteal phases of the menstrual cycle (Schmalenberger et al., 2021). A woman’s menstrual cycle may exhibit abnormal or unusual characteristics. Menstrual cycle disorders encompass dysmenorrhea, amenorrhea lasting at least three months in the absence of pregnancy, and menorrhagia, which refers to heavy bleeding. Approximately 14% to 25% of women experience menstrual irregularities during childbearing, and these irregularities may differ between women (Male, 2021). However, irregular menstruation can occur due to hormonal imbalances, pregnancy, trauma, inflammation, and infections (Critchley et al., 2020). 1 Public Health Department, College of Public Health, Imam Abdurrahman Bin Fisal University, Dammam, Saudi Arabia 2 Community Health Department, College of Applied Medical Sciences, Northern Border University, Arar, Saudi Arabia * Corresponding author’s e-mail: taghread.sa@gmail.com Pa ge 13 https://journals.e-palli.com/home/index.php/ajmri Am. J. Multidis. Res. Innov. 3(6) 12-24, 2024 Additionally, physical factors like excessive exercise, unhealthy food, and stress can impact the menstrual cycle (Huhmann, 2020). Other health issues like thyroid disorders, liver and kidney diseases, and certain medications like anticoagulants can also cause menstrual changes (Gray, 2013). Therefore, understanding these factors is crucial for managing menstrual cycles (Vladimirovna et al., 2023). A gynaecologist can address menstrual issues, but factors like medication use, cycle duration, and gynaecological surgery increase the risk. Symptoms can be alleviated with dietary adjustments, hormone supplementation, oral contraceptives, diuretics, tranquillisers, antidepressants, and regular physical activity (Roos et al., 2022). Vaccination has played a major role in keeping infectious diseases under control. The emergence of COVID-19 triggered a worldwide health crisis, prompting the development of numerous vaccines and the implementation of widespread immunisation programs across the world (Sualeh et al., 2022). Several vaccines were developed to control the infection announced by the World Health Organisation (WHO), such as Sinopharm, Sinovac, Novavax, and Pfizer (BNT162b2) (Polack et al., 2020). However, there was evidence of vaccine hesitation, particularly among women of reproductive age who were concerned that the vaccination may interfere with their menstrual cycle (Sualeh et al., 2022). A study by Li et al. (2021) showed that about 20% of COVID-19 patients had shortened menstrual cycles, while 19% experienced prolonged cycles and 28% experienced changes in menstruation (Li et al., 2021). In another study, Naina Kumar et al. 2023 demonstrated that COVISHIELD and COVAXIN vaccinations were linked to irregularities in the menstrual cycle and pre- and post-menstrual symptoms in a small subset of patients (Kumar et al., 2023). The reluctance regarding vaccination could result from the association between the vaccine and menstruation complications (Sualeh et al., 2022). LITERATURE REVIEW A regular menstrual cycle serves as a reliable indicator of a well-functioning Hypothalamic-Pituitary-Ovarian (HPO) system and a woman’s state of health. The menstrual characteristics exhibit variability on a monthly basis throughout an individual’s lifespan (Bull et al., 2019). Changes in frequency, intensity, duration, or regularity can identify menstrual irregularities (Jung et al., 2018). These variations arise due to several reasons, including coagulopathy, ovulatory dysfunction, medication usage, and modifiable elements such as abrupt weight loss, severe exercise, obesity, and psychological disorders (Polack et al., 2020). However, mental stress is considered a significant factor; recent research has linked irregular menstrual cycles to increased levels of stress and anxiety during the COVID-19 pandemic (Demir et al., 2021). Recent studies suggest that COVID-19 infection and vaccination can impact menstrual cycles (Alvergne et al., 2021; Male, 2021; Taşkaldıran et al., 2022). In a case- control study conducted in the United Kingdom, 20% of the female participants reported experiencing irregular menstrual cycles post-vaccination (Alzahrani et al., 2023). COVID-19 Vaccination and its Side Effects Vaccines are constantly monitored and managed for safety and efficacy, but they can still cause side effects. These symptoms often manifest as minor pain and redness at the injection site or a fever, and they usually disappear within a few days (Hatmal et al., 2021). In 2022, approximately 1,871,932,835 people (23.61% of the global population) received two doses of a COVID-19 vaccine; meanwhile, in Saudi Arabia, 21,449,067 people (60.69% of the population) were fully vaccinated with two doses (Organization, 2022). A third dose of COVID-19 vaccine was given to low-immunity individuals after 10 months of the first dose (Moreira Jr et al., 2022). Despite FDA approval and difficulty in predicting side effects, many have been reported through surveillance systems issued by the Centers for Disease Control & Prevention (CDC) for the Vaccine Adverse Events Reporting System (VAERS) and After Vaccination Health Checker (V-Safe) (Organization, 2022). Side effects range from mild to severe and include redness, chest pain, swelling, fatigue, headache, muscle ache, nausea, fever, chills, difficulty in breathing, and menstrual irregularities in women (Beatty et al., 2021). A report by CDC 2023 showed 2,403,628 cases of side effects due to COVID-19 vaccines, including 98,163 cases of blood and lymphatic disorders, 124,613 cases of heart disorders, and 103,310 cases of reproductive system and breast disorders (Centers for Disease Control and Prevention., 2023). A study conducted in Saudi Arabia by Alghamdi et al. (2021) reported that adverse side effects were observed by the Pfizer vaccine after the second dose (13.22%) compared to the first dose (4.17%). Breathlessness and chest pain were recorded following the administration of the Oxford-AstraZeneca (ChAdOx1) vaccine and less frequently through the Pfizer vaccine (Alghamdi et al., 2021). Another study by Alhazmi et al. (2021) found that 60% of participants experienced adverse effects from COVID-19 vaccines, with fatigue (90%) and soreness at the injection site (85%) being common (Alhazmi et al., 2021). COVID-19 Vaccination and Menstrual Cycle Disturbances According to a CDC report, 26,450 (19.19%) cases among adult females experienced heavy menstrual bleeding, 14,835 (10.76%) cases suffered from delayed menstruation, and 14,560 cases had menstrual disorders and several other side effects related to breast injuries (Centers for Disease Control and Prevention, 2023). A study conducted by Al-Mousa et al. (2022) in Saudi Arabia found that the COVID-19 vaccine caused changes in the menstrual cycle, including increased duration, abundance, and pain. Around 60% of cases experienced these disorders after the vaccine. Females aged 15-24 Pa ge 14 https://journals.e-palli.com/home/index.php/ajmri Am. J. Multidis. Res. Innov. 3(6) 12-24, 2024 years were two times more likely to experience these changes, indicating a significant impact of the vaccine on the menstrual cycle (Almousa, 2022). Moreover, a study by Gibson et al. (2022) found that 55% of participants received the Pfizer vaccination, 37% received Moderna’s vaccine, and 8% received the Johnson and Janssen vaccine (Gibson et al., 2022). This study found a slight increase in menstrual cycle duration following COVID-19 vaccination, with a significant increase in the likelihood of a cycle lasting over 38 days (Gibson et al., 2022). However, this effect was not persistent. The duration of menstrual cycles increased for 1-2 cycles after vaccination but then recovered to their original length. The increase was associated with dosages administered during the early and mid-follicular phase (Gibson et al., 2022). A second dosage within the final 14 days of the cycle, typically aligning with the luteal phase, shortened the average cycle length. The study suggests that the association between vaccination and menstrual cycle length depends on the timing of the dosage and may align with specific phases of the menstrual cycle (Gibson et al., 2022). Previous studies demonstrated a correlation between the administration of the COVID-19 vaccine and elongation of the menstrual cycle, as well as irregularities in its pattern (Alghamdi et al., 2021; Muhaidat et al., 2022). Studies conducted by Alvergne et al. (2022) and Edelman et al. (2022) reported a certain degree of correlation between vaccination doses and menstrual disturbances (Alvergne et al., 2022). Consequently, the study by Farland et al. (2023) found that 25% of the participants who received vaccine experienced menstrual cycle disruptions, with the majority occurring after the second dose (56%) (Farland et al., 2023). Common issues included irregular menstruation (43%), heavy bleeding (31%), increased period discomfort (30%), and intensified premenstrual symptoms (34%). The study results revealed that individuals with higher BMI and higher self-reported perceived stress levels were more likely to experience these changes after vaccination (Farland et al., 2023). Similarly, H. M. Al Kadri et al. (2023) found menorrhagia, oligomenorrhea, and polymenorrhea as the most common menstrual irregularities post-vaccination, highlighting the significant number of women experiencing irregular menstruation (Al Kadri et al., 2023). However, a study by Isılay Taşkaldıran et al. (2022) & Tayyab et al. (2022) revealed that 35.7% of 241 COVID-19-infected women experienced menstrual changes within the first three cycles. Among 537 individuals who received various COVID-19 vaccinations, 15.1% reported changes (Taşkaldıran et al., 2022). Women who received the Sinovac and Pfizer vaccines had a higher incidence of menstrual irregularities post-vaccination (Tayyaba Rehan et al., 2022). A study by Chavin D. Gopaul et al. (2023) revealed that menstrual cycle issues were common among those who received the COVID-19 vaccine, including delayed menstruation and excessive bleeding (Gopaul et al., 2023). The results were consistent with a previous study by Woon & Male et al. (2022), who observed a 2.3-day delay in menstrual cycles after the first and second doses. The Norwegian Institute of Public Health also found increased menstrual flow in young women aged 18-30 after receiving the first and second doses, with 13.6% and 15.3%, respectively (Von Woon & Male, 2022). However, no conclusive evidence was found between the COVID-19 vaccination and other menstrual irregularities, such as missed periods (Gopaul et al., 2023). Therefore, this study aimed to demonstrate the impact of COVID-19 vaccines on women’s reproductive health by examining the association between COVID-19 vaccines and disturbed menstrual cycles. MATERIALS AND METHODS Study Design and Population This cross-sectional study was conducted among adult females at King Saud University, Riyadh, from April 2022 to August 2022. The study population consists of 380 participants who experienced menstrual cycle disturbances after receiving COVID-19 vaccine. Ethical Approval Ethical approval was obtained from the Deanship of Scientific Research at King Saud University (Ref No: KSU-HE-22-156). Written informed consent was also obtained from the participants, and the study was carried out in conformity with the 1964 Declaration of Helsinki. The STROBE guidelines were followed, and any subsequent revisions or with comparable ethical standards. Inclusion and Exclusion Criteria The study included a clinically suitable participant cohort: adult females aged 18 to 50 years. Participants who received the COVID-19 vaccine and menstruating were selected for the study. Conversely, the exclusion criteria included participants aged below 18, lactating and pregnant, who had previously experienced ovarian dysfunction, who used intrauterine or oral contraceptives, and who did not receive the COVID-19 vaccine. Data Collection and Sampling Technique The data was collected through a structured questionnaire consisting of different components such as demographics, physical exercise behaviour, menstrual disorders, the impact of the COVID-19 vaccine on the menstrual cycle, and side effects associated with the COVID-19 vaccine. The questionnaire was designed using Google Forms and distributed through online social media platforms. Furthermore, a stratified random sampling technique was employed to collect the data. Data Analysis The data was analysed using Statistical Package for Social Sciences (SPSS Inc., Chicago, IL, USA) version 20.0. Frequencies and percentages were calculated using descriptive statistics, and association analysis was done to Pa ge 15 https://journals.e-palli.com/home/index.php/ajmri Am. J. Multidis. Res. Innov. 3(6) 12-24, 2024 evaluate the correlation between variables. The p-value of < 0.05 was considered statistically significant. RESULTS AND DISCUSSION The results section presents a comprehensive analysis and statistical interpretations based on data collection. A total of 380 participants were included in the study. Table 1 presents the association between menstrual disorders and the COVID-19 vaccine among adult females at King Saud University. Notably, 59.5% of females aged 18- 25 experienced menstrual disorders, with a decreasing percentage for older age groups. While single women exhibited a higher percentage (71.8%) compared to married and divorced. Females with normal weight showed a higher percentage (54.5%) compared to obese females. Tables 2(a), 2(b), and 2(c) present characteristics of female participants, COVID-19 vaccination, infection history, and impact of vaccination on menstrual cycle, respectively. Table 3 shows an association between diet, physical exercise and menstrual disorders after obtaining the COVID-19 vaccine. The highest number of females with unhealthy diets (54.5%) and moderate- intensity exercise (92.6%) had menstrual disorders. Among participants, (39.2%) of females had troubled psychological health post-COVID-19 vaccination. Table 4 reveals an association between menstrual disorders post-COVID-19 vaccination and chronic diseases. The highest number of menstrual disturbances was observed in females with chronic disease (14.6%) compared to hormone imbalance (12.9%). However, the association analysis was not significant. The correlation between menstrual disorders post-COVID-19 vaccination and the health behaviours and practices, medical treatments and reproductive health of the participants is presented in Table 5. There was no significant link between infection and vaccination, but higher rates of infection were observed after vaccination. The analysis revealed that (76.8%) females did not use any therapeutic drugs; reproductive health was better, but breastfeeding was less common among women with children. Further, there was no significant association between vaccination stages and menstruation issues, but higher rates were observed for those receiving two or three doses. Figure 1 displays the use of therapeutic drugs among participants, whereas Figures 2 and 3 illustrate common types of disturbances during the menstrual cycle post-COVID-19 vaccination and the duration of side effects among adult females at King Saud University. Table 1: Demographic characteristics and impact of COVID-19 vaccine on menstrual cycle Frequency (n = 380) Percentage (n %) Participant Consent No 4 1.1 Yes 376 98.9 Age 18–25 226 59.5 26–35 87 22.9 36–49 67 17.6 Nationality Non-Saudi 15 3.9 Saudi 365 96.1 Marital Status Single 273 71.8 Married 92 24.2 Divorced 15 3.9 Profession Bachelors Student 207 54.5 Post-Graduate Student 70 18.4 Employee 71 18.7 Faculty Member 32 8.4 Body Mass Index Underweight 40 10.5 Normal weight 207 54.5 Overweight 80 21.1 Obese class 1 30 7.9 Obese class 2 16 4.2 Obese class 3 7 1.8 Pa ge 16 https://journals.e-palli.com/home/index.php/ajmri Am. J. Multidis. Res. Innov. 3(6) 12-24, 2024 Table 1 shows that menstrual problems following the COVID-19 vaccination reduced with increasing age, with the association not being statistically significant. Adult females aged 18 to 25 had the highest rate of disorders following COVID-19 vaccination. Menstrual disruptions were substantially correlated with marital status with single women reporting the highest occurrence. The comparison was significant, with p = 0.05. There was no significant correlation observed between BMI levels and disruptions in the menstrual cycle. However, obese females reported fewer disorders than normal-weight females, who reported the most disorders. Table 2(a): Characteristics of female participants Characteristics Frequency (n = 380) Percentage (n %) Are you pregnant? No 377 99.2 Yes 3 0.8 Are you breastfeeding? No 374 98.4 Yes 6 1.6 Do you have menstrual disorders? No 181 47.6 Yes 199 52.4 Do you have a thyroid disorder? No 358 94.2 Yes 22 5.8 Do you have a hormone imbalance? No 331 87.1 Yes 49 12.9 Do you have children? No 297 78.2 Yes 83 21.8 Do you use any of these contraceptives? Nothing 354 93.2 The oral contraceptive pill 21 5.5 Intrauterine device 5 1.3 Table 2(b): COVID-19 vaccination and infection history Characteristics Frequency (n = 380) Percentage (n %) Have you been infected with Acute Respiratory Syndrome Coronavirus 2 before getting COVID-19 vaccination? No 334 87.9 Yes 46 12.1 Have you been infected with Acute Respiratory Syndrome Coronavirus 2 after getting COVID-19 vaccination? No 286 75.3 Yes 94 24.7 How many doses of COVID-19 vaccine did you receive? One dose 3 8 Two doses 129 33.9 Three doses 248 65.3 What kind of vaccine did you receive? Pfizer Biontec 316 83.2 Oxford AstraZeneca 64 16.8 What kind of vaccine did you receive for the second time? Pa ge 17 https://journals.e-palli.com/home/index.php/ajmri Am. J. Multidis. Res. Innov. 3(6) 12-24, 2024 Did not receive the second dose 1 0.3 Pfizer Biontec 334 87.9 Oxford AstraZeneca 40 10.5 Moderna 5 1.3 What kind of vaccine did you receive for the third time? Did not receive third dose 111 29.2 Pfizer Biontec 214 56.3 Oxford AstraZeneca 9 2.4 Moderna 46 12.1 Table 2(c): Impact of COVID-19 vaccine on menstrual cycle Characteristics Frequency (n =380) Percentage (n %) Have you experienced any side effects after the vaccine? No 111 29.2 Yes 269 70.8 When did the side effects appear? Immediately after the vaccine 49 12.9 Within 24 hours after the vaccine 277 72.9 During the first week 17 4.5 After more than a week 37 9.7 How long did the side effects last? After few hours of vaccination 57 15 Two days or less 142 37.4 One week 50 13.2 A month or less 16 4.2 More than a week 115 30.3 Did you receive the COVID-19 vaccine during the menstrual cycle? No 272 71.6 Yes 108 28.4 Have you experienced one of these symptoms related to the menstrual cycle after the vaccine? Not applicable 181 47.6 Amenorrhea 28 7.4 Oligomenorrhea 56 14.7 Menorrhagia 32 8.4 Length of menstruation more than 8 days 5 1.3 Dysmenorrhea 25 6.6 Polymenorrhea 30 7.9 Short period (< 2 days) 17 4.5 Bleeding between menstruation cycles 6 1.6 How long have you had symptoms of menstrual disorder after the vaccine? Not applicable 159 41.8 One month 38 10.0 Two months 43 11.3 Three months and more 140 36.8 Do you think these symptoms of the menstrual cycle that you experienced are related to the COVID-19 vaccines? No 175 46.1 Pa ge 18 https://journals.e-palli.com/home/index.php/ajmri Am. J. Multidis. Res. Innov. 3(6) 12-24, 2024 Yes 205 53.9 In which dose did you get the side effects related to the menstrual cycle? I do not know 216 56.8 First dose 64 16.8 Second dose 58 15.3 Third dose 42 11.1 Figure 1: Use of Therapeutic Drugs in between COVID-19 vaccination or menstrual cycle period Tables 2(a, b, and c) show female participant’s medical history, COVID-19 vaccination status, and the impact of the vaccine on their menstrual cycle. Most participants did not exhibit hormonal abnormalities, were not breastfeeding, and were pregnant. The majority of the participants received three doses of the vaccination, with Pfizzer being the largest. The majority reported negative effects on their menstrual cycle, with 72.9% occurring within 24 hours and 30.3% lasting over a week (CI: 95%). However, 269 participants (70.8%) responded that they experienced side effects after vaccine. Side effects like fever, fatigue, headaches, muscle discomfort, and injection site pain typically were the most common among participants. Table 3: Associations of Diet and Physical Exercise Behavior with Menstrual Disorders after Obtaining a COVID-19 Vaccine Variables Frequency (n =380) Percentage of females who had menstrual disorders after vaccination (n %) Association analysis Value Sig. Diet Unhealthy and unbalanced diet 207 54.5 10.229 .332 Healthy and balanced diet 173 45.5 Exercise Practising daily exercise 6.075 .732 No 255 67.1 Yes 125 32.9 Moderate-intensity exercise 352 92.6 17.634 .04 Vigorous-intensity exercise 28 7.4 Spent 75 min or less per week 277 72 15.212 .647 Spent 76–150 min per week 84 22.1 Spent 151–300 min per week 19 5.0 Psychological Health Troubled psychological health 149 39.2 20.345 .016 Balanced psychological health 231 60.8 Pa ge 19 https://journals.e-palli.com/home/index.php/ajmri Am. J. Multidis. Res. Innov. 3(6) 12-24, 2024 Table 4: Associations between Menstrual Disorders after Obtaining a COVID-19 Vaccine and Adult Females Suffering from Chronic Diseases Variables Association analysis Value Sig. Disorders Chronic disease 106.356 .115 Thyroid disorder 4.212 .897 Hormone imbalance 8.734 .462 Menstrual disorders before the COVID-19 vaccine 77.210 .001 No reproductive disease 61.179 .234 Polycystic ovaries Uterine fibrosis Uterine tumours Migratory endometrium Pelvic inflammation Any other inflammation COVID-19 Infection Infected with SARS-CoV-2 before vaccination 5.589 .78 Infected with SARS-CoV-2 after vaccination 10.234 .332 Table 4 indicated a significant correlation (p = < 0.05) between pre-existing menstrual problems and the occurrence of disorders after receiving the COVID-19 vaccine (p < 0.05). While certain chronic diseases and other health-related factors were linked to menstrual irregularities, the p-value showed no statistical significance (p = 0.115). Polycystic ovaries had a higher percentage (14.16%) compared to those without reproductive diseases (80.53%), but the association analysis lacks statistical significance. Other reproductive issues showed negligible associations. The occurrence of menstrual disturbances was associated with SARS- CoV-2 infection both before and after vaccination, with respective percentages of (12.1%) and (24.7%). However, the p-value showed no significant correlation between the variables. Table 3 shows that adult females with an unhealthy and unbalanced diet reported the highest rate of disorders (54.5%), and the P-value was not statistically significant (p = 0.332). Menstrual disorders were reported by approximately (32.9%) of females who exercised daily. Meanwhile, (92.6%) of adult females who engaged in moderate exercise and received the COVID-19 vaccine reported suffering from a disorder with a P-value < 0.05 (P = 0.04), considered statistically significant. The exercise duration, 75 minutes or less per week, was associated with the menstrual cycle (72%) compared to 150-300 mins per week. However, the p-value (p= 0.647) was not statistically significant at (CI; 95%). Table 5: Associations between Menstrual Disorders after Obtaining a COVID-19 Vaccine and Health Related Behaviours and Practices Variables Association analysis Value Sig. Infected with SARS-CoV-2 before vaccination 5.589 .78 Infected with SARS-CoV-2 after vaccination 10.234 .332 Therapeutic drug consumption 84.485 .954 Have children 14.539 .104 Breastfeeding 19.599 .021 No contraceptive use 21.084 .275 Oral contraceptive pill use Intrauterine device use Received one dose 66.620 < .001 Received two doses Received three doses Obtained a COVID-19 vaccine dose during the menstrual cycle 11.787 .226 Pa ge 20 https://journals.e-palli.com/home/index.php/ajmri Am. J. Multidis. Res. Innov. 3(6) 12-24, 2024 Figure 2: The Most Common Types of Disturbances Related to Menstrual Cycle Disturbances among Adult Females at King Saudi University after COVID-19 Vaccination Discussion During the COVID-19 pandemic, various vaccines were introduced worldwide to overcome the symptoms of infection. Saudi Arabia has approved the use of three SARS-CoV-2 vaccines: Pfizer-BioNTech, Oxford- AstraZeneca ChAdOx1 chimpanzee adenovirus vector, and Moderna. The vaccines were approved in December 2020, February 2021, and July 2021 (ALHUR, 2023). As of November 2022, Saudi Arabia had administered around 67 million vaccine doses, with 15 million individuals receiving booster doses. The vaccines have been validated through clinical trials, and common side effects like fever, fatigue, headaches, muscle discomfort, and injection site pain typically resolve within a few days (Alahmadi et al., 2022). Menstrual irregularities, often unnoticed symptoms, have become more prevalent after the COVID-19 vaccination (Alahmadi et al., 2022). These irregularities significantly impact women’s quality of life and have sparked concerns about a potential link between the vaccine and menstruation patterns. Furthermore, the hesitance of young women to receive the COVID-19 vaccination has been intensified by unfounded claims suggesting that the vaccine could have adverse effects on their future fertility (Male, 2021). There was a global Table 5 demonstrates a significant correlation between breastfeeding and menstrual disturbances (p = 0.021), as well as a significant association between the number of COVID-19 vaccine doses and the occurrence of menstrual disturbances (p = 0.001). The administration of the vaccination during menstruation was linked to a notable occurrence of menstrual disturbances, although the p-value showed no statistical significance. Moreover, the prevalence of menstrual disturbances was remarkably high (93.2%) in females who did not take contraceptive pills. However, the correlation was not statistically significant. Figure 3: Duration of Side Effects Associated with the Menstrual Cycle after Receiving a COVID-19 Vaccin Pa ge 21 https://journals.e-palli.com/home/index.php/ajmri Am. J. Multidis. Res. Innov. 3(6) 12-24, 2024 apprehension about the potential correlation between menstrual irregularities and the COVID-19 vaccine, with women concerned about the duration of these negative effects and hesitant to receive more doses (Alaamri et al., 2022). A study by Fadi et al. (2022) identified a potential correlation between irregular menstrual cycles and the COVID-19 vaccine, which may affect the overall well- being of women (Qashqari et al., 2022). The present study results revealed that 71.8% of adult females with menstrual disturbances were single, 54.5% had an average weight, and were between the ages of 18 and 25. Additionally, 67.1% of the participants did not exercise regularly, 54.5% had unhealthy diet patterns, and 60.8% reported good psychological health. Further, only 12.9% of participants had an imbalance in hormones, 5.8% had a thyroid gland problem, and 13.72% had a chronic condition. Among participants, 3.1% had uterine fibrosis, 14.16% had polycystic ovaries, 3.2% took antidepressants, and 7.4% used conventional analgesics. In addition, 93.2% of participants did not use contraceptive pills, and 1.6% of participants breastfed their children. These risk factors intensify the effects of COVID-19 vaccinations on menstrual cycles, as the majority did not indicate any irregularities in menstruation. However, the study found minor impacts in relation to diet quality, increased physical activity, thyroid issues, and venereal illnesses during the menstrual cycle. A total of 33.9% of participants received two doses of COVID-19 vaccination, while 65.3% received three doses. Pfizer was the most commonly administered vaccine, with 83.2% receiving the first dose, 87.9% receiving the second, and 56.3% receiving the third dose. These results are consistent with Isılay Tas kaldıran et al. (2022), who reported that women who received Pfizer and Sinovac vaccinations had a higher incidence of menstruation changes post- vaccination (Taşkaldıran et al., 2022). Gibson et al. (2022) similarly documented a consistent outcome, revealing that 58% of participants who received Pfizer vaccination experienced this consequence (Gibson et al., 2022). Moreover, 28.4% of participants had the vaccination while they were menstruating. The findings of the chi-square test indicated that there was a highly significant association (p = 0.001) between the number of vaccine doses and the effects of the vaccines on menstrual disruptions. The incidence of menstrual cycle disturbances increased with the number of received vaccine doses, with the Pfizer and AstraZeneca vaccination participants experiencing the highest incidence of disturbances. These findings are in line with Farland et al. (2023), who demonstrated that a slight increase in menstrual cycle length was correlated with the number of COVID-19 vaccination doses (Farland et al., 2023). Trogstad et al. (2022) reported that the most common disturbances related to various menstrual cycle changes following COVID-19 vaccination were heavier than usual periods, delayed periods, and unexpected vaginal bleeding (Trogstad et al., 2022). However, the present study results showed that menorrhagia (8.4%), polymenorrhagia (7.9%), and amenorrhoea (7.4%) were the most common disturbances following oligomenorrhea (14.7%). Conversely, 47.6% of participants reported no menstrual cycle-related negative effects post-vaccination. According to Almousa et al. (2022), women who previously experienced irregular menstruation were less likely than those who previously experienced normal menstruation to experience menstrual disturbances post- vaccination. However, this difference was not statistically significant (Almousa, 2022). In contrast, a study by Chao et al. (2022) demonstrated a statistically significant ( P < 0.0001) correlation between COVID-19 vaccination and menstrual disturbances (Chao et al., 2022). In comparison, Alahmari et al. (2022) evaluated that there was no significant correlation between COVID-19 vaccination and menstruation problems. The side effects can be the result of an immunological response rather than the vaccine or any of its elements (Alahmari & El, 2022). This study’s findings suggest that COVID-19 vaccination impacted women’s menstrual cycles and reproductive health. The interaction between the immune system and endocrine system was likely responsible for the negative effects of these vaccinations. However, the findings by Chavin et al. (2023) partially supported previous studies indicating an association between COVID-19 vaccination and subsequent irregular menstrual periods (Gopaul et al., 2023). With the exception of delayed periods and other menstrual issues like abnormal bleeding, severe symptoms, and miscellaneous symptoms, this study found that self-reported menstrual cycle disturbances such as missed periods, spotting, irregular cycles, and flow fluctuations did not show significant differences after the first and second dose of vaccination (Gopaul et al., 2023). Consequently, the study indicated that the irregularities in the menstrual cycle post-COVID-19 vaccination were temporary and returned to normal after a short period (Gopaul et al., 2023). This information is crucial for reducing young women’s vaccine reluctance and improving the effectiveness of the vaccination campaign. Understanding the link between vaccination and post-vaccination changes can help young women prepare for potential changes in their menstrual cycles. CONCLUSION In conclusion, the study showed the impact of COVID-19 vaccination on menstrual disturbances in adult females in KSU. Over half of the females experienced at least one issue related to the menstrual cycle after receiving the vaccine. The study suggests that people receiving COVID-19 vaccines engage in more beneficial interventions, but the precipitating factors should be considered when administering the vaccine to mitigate disruption. The Pfizer-BioNTech vaccine was among the most widely used and induced changes in menstrual disturbances after vaccination. Further research is needed on the long-term safety of COVID-19 vaccines on females and the overall population’s health. Pa ge 22 https://journals.e-palli.com/home/index.php/ajmri Am. J. Multidis. Res. Innov. 3(6) 12-24, 2024 Limitation and Strengths • The study’s limitations may include a small sample size and cross-sectional design, which can hinder the ability to establish causality and generalizability. Selection bias may be introduced due to the online distribution of the questionnaire. • However, the study provided valuable insights into the association between menstrual cycle disturbances and COVID-19 vaccination, highlighting areas for further research and emphasising public health concerns. Recommendations • Future studies and clinical trials should investigate the menstrual-related adverse effects to develop vaccines. • Education programs should be developed to enhance understanding of the impact of COVID-19 vaccination on menstrual cycles. • Establishing a systematic health monitoring system is necessary in order to monitor and report adverse events. • Future research should include a comprehensive assessment of mental health status in order to understand the association between menstrual health and psychological well-being. • It is essential to improve public health communication strategies and update guidelines for healthcare professionals managing menstruation disorders. • Policymakers should include menstrual health when implementing vaccination safety monitoring activities. Acknowledgement The authors are thankful to King Saud University for their continuous support throughout the study. The authors also appreciate the Public Health Department at Imam Abdurrahman Bin Faisal University for supervising this study. REFERENCES Al Kadri, H. M., Al Sudairy, A. A., Alangari, A. S., Al Khateeb, B. F., & El-Metwally, A. A. (2023). COVID-19 vaccination and menstrual disorders among women: Findings from a meta-analysis study. Journal of Infection and Public Health. Alaamri, O., Okmi, E. A., & Suliman, Y. (2022). Vaccine hesitancy in Saudi Arabia: A cross-sectional study. Tropical Medicine and Infectious Disease, 7(4), 60. Alahmadi, A. M., Aljohani, A. H., Fadhloun, R. A., Almohammadi, A. S., Alharbi, D. F., Alrefai, L. S., Fadhloun, R., Almohammadi, A., & Alharbi, D. (2022). The effect of the COVID-19 vaccine on the menstrual cycle among reproductive-aged females in Saudi Arabia. Cureus, 14(12). Alahmari, A. M., & Rahman, S. K. a. E. (2022). Relationship between menstrual cycle changes and types of covid-19 vaccines among women living in Riyadh, Saudi Arabia 2022. Medical Science, 26(126), 1–9. https://doi.org/10.54905/disssi/v26i126/ ms340e2306 Alghamdi, A. N., Alotaibi, M. I., Alqahtani, A. S., Al Aboud, D., & Abdel-Moneim, A. S. (2021). BNT162b2 and ChAdOx1 SARS-CoV-2 post-vaccination side- effects among Saudi vaccinees. Frontiers in Medicine, 8, 760047. Alhazmi, A., Alamer, E., Daws, D., Hakami, M., Darraj, M., Abdelwahab, S., Maghfuri, A., & Algaissi, A. (2021). Evaluation of side effects associated with COVID-19 vaccines in Saudi Arabia. Vaccines, 9(6), 674. ALHUR, A. A. (2023). Public Health Informatics: The Importance of Covid-19 Dashboard in KSA for Sharing and Visualizing Health Information. Journal of Information Systems and Digital Technologies, 5(1), 43- 59. Almousa, I. A. (2022). Changes In the Menstrual Cycle Among the Covid-19 Vaccinated Women in The Eastern Province of Saudi Arabia: A Cross-Sectional Survey, 2022. The Egyptian Journal of Hospital Medicine, 89(1), 4260-4264. Alvergne, A., Kountourides, G., Argentieri, M. A., Agyen, L., Rogers, N., Knight, D., Sharp, G. C., Maybin, J. A., & Olszewska, Z. (2021). COVID-19 vaccination and menstrual cycle changes: A United Kingdom (UK) retrospective case-control study. medRxiv (Cold Spring Harbor Laboratory). https://doi. org/10.1101/2021.11.23.21266709 Alvergne, A., Woon, E. V., & Male, V. (2022). Effect of COVID-19 vaccination on the timing and flow of menstrual periods in two cohorts. Frontiers in reproductive health, 4. Barbieri, R. L. (2014). The endocrinology of the menstrual cycle. Human fertility: methods and protocols, 145-169. Beatty, A. L., Peyser, N. D., Butcher, X. E., Cocohoba, J. M., Lin, F., Olgin, J. E., Pletcher, M. J., & Marcus, G. M. (2021). Analysis of COVID-19 vaccine type and adverse effects following vaccination. JAMA network open, 4(12), e2140364-e2140364. Berga, S. L. (2020). The Menstrual Cycle and Related Disorders. Female Reproductive Dysfunction, 23-37. Bull, J. R., Rowland, S. P., Scherwitzl, E. B., Scherwitzl, R., Danielsson, K. G., & Harper, J. (2019). Real-world menstrual cycle characteristics of more than 600,000 menstrual cycles. NPJ digital medicine, 2(1), 83. About V-Safe. (2024, August 8). Vaccine Safety Systems. https://www.cdc.gov/vaccine-safety-systems/v- safe/index.html Chao, M. J., Menon, C., & Elgendi, M. (2022). Effect of COVID-19 vaccination on the menstrual cycle. Frontiers in Medicine, 9, 1065421. Critchley, H. O., Babayev, E., Bulun, S. E., Clark, S., Garcia-Grau, I., Gregersen, P. K., Kilcoyne, A., Kim, J. Y. J., Lavender, M., & Marsh, E. E. (2020). Menstruation: science and society. American journal of obstetrics and gynecology, 223(5), 624-664. De Sanctis, V., Bernasconi, S., Bianchin, L., Bona, G., Bozzola, M., Buzi, F., De Sanctis, C., Rigon, F., Tatò, L., & Tonini, G. (2014). Onset of menstrual cycle and menses features among secondary school girls in Italy: Pa ge 23 https://journals.e-palli.com/home/index.php/ajmri Am. J. Multidis. Res. Innov. 3(6) 12-24, 2024 A questionnaire study on 3,783 students. Indian journal of endocrinology and metabolism, 18(Suppl 1), S84. Demir, O., Sal, H., & Comba, C. (2021). Triangle of COVID, anxiety and menstrual cycle. Journal of Obstetrics and Gynaecology, 41(8), 1257-1261. Farland, L. V., Khan, S. M., Shilen, A., Heslin, K. M., Ishimwe, P., Allen, A. M., Herbst-Kralovetz, M. M., Mahnert, N. D., Pogreba-Brown, K., & Ernst, K. C. (2023). COVID-19 vaccination and changes in the menstrual cycle among vaccinated persons. Fertility and sterility, 119(3), 392-400. Gibson, E. A., Li, H., Fruh, V., Gabra, M., Asokan, G., Jukic, A. M. Z., Baird, D. D., Curry, C. L., Fischer- Colbrie, T., & Onnela, J. P. (2022). Covid-19 vaccination and menstrual cycle length in the Apple Women’s Health Study. NPJ digital medicine, 5(1), 165. Gopaul, C. D., Bassaw, B., Ventour, D., & Thomas, D. (2023). Effects of Covid-19 vaccines on the menstrual cycle: A cross-sectional study. The Open Public Health Journal, 16(1). Gray, S. H. (2013). Menstrual disorders. Pediatrics in review, 34(1), 6-18. Hatmal, M. M., Al-Hatamleh, M. a. I., Olaimat, A. N., Hatmal, M., Alhaj-Qasem, D. M., Olaimat, T. M., & Mohamud, R. (2021). Side effects and perceptions following COVID-19 vaccination in Jordan: A randomized, Cross-Sectional study implementing machine learning for predicting severity of side effects. Vaccines, 9(6), 556. https://doi.org/10.3390/ vaccines9060556 Huhmann, K. (2020). Menses requires energy: A review of how disordered eating, excessive exercise, and high stress lead to menstrual irregularities. Clinical Therapeutics, 42(3), 401-407. Jung, E. K., Kim, S. W., Ock, S. M., Jung, K. I., & Song, C. H. (2018). Prevalence and related factors of irregular menstrual cycles in Korean women: The 5th Korean National Health and Nutrition Examination Survey (KNHANES-V, 2010–2012). Journal of Psychosomatic Obstetrics & Gynecology, 39(3), 196-202. Kumar, N., Gangane, N., Mohapatra, I., Rukadikar, C., Sharmila, V., Pushpalatha, K., Eerike, M., Santhoshi, G., Samantaray, S. R., Seth, S., Trigunait, P., Reddy, N. J., Patel, S., Rani, S., Mishra, R., & Negi, K. (2023). Effect of COVID-19 vaccination on menstrual cycle patterns of reproductiveage women: a multi-centric observational study. Current Drug Research Reviews, 16(2), 237–248. https://doi.org/10.2174/258997751 5666230608140606 Li, K., Chen, G., Hou, H., Liao, Q., Chen, J., Bai, H., Lee, S., Wang, C., Li, H., & Cheng, L. (2021). Analysis of sex hormones and menstruation in COVID-19 women of child-bearing age. Reproductive biomedicine online, 42(1), 260-267. Male, V. (2021). Menstrual changes after covid-19 vaccination. BMJ, n2211. https://doi.org/10.1136/ bmj.n2211 Moreira Jr, E. D., Kitchin, N., Xu, X., Dychter, S. S., Lockhart, S., Gurtman, A., Perez, J. L., Zerbini, C., Dever, M. E., & Jennings, T. W. (2022). Safety and efficacy of a third dose of BNT162b2 Covid-19 vaccine. New England journal of medicine, 386(20), 1910- 1921. Muhaidat, N., Alshrouf, M. A., Azzam, M. I., Karam, A. M., Al-Nazer, M. W., & Al-Ani, A. (2022). Menstrual symptoms after COVID-19 vaccine: a cross-sectional investigation in the MENA region. International journal of women’s health, 395-404. Murray, C. M., & Orr, C. J. (2019). Hormonal regulation of the menstrual cycle and ovulation. In Elsevier eBooks (pp. 159–167). https://doi.org/10.1016/b978- 0-12-814823-5.00012-x World Health Organization: WHO. (2021, July 9). COVID-19 subcommittee of the WHO Global Advisory Committee on Vaccine Safety (GACVS): updated guidance regarding myocarditis and pericarditis reported with COVID-19 mRNA vaccines. In. https://www.who.int/news/item/09- 07-2021-gacvs-guidance-myocarditis-pericarditis- covid-19-mrna-vaccines Patricio, B.-P., & Sergio, B.-G. (2019). Normal menstrual cycle. Menstrual Cycle, 15. Polack, F. P., Thomas, S. J., Kitchin, N., Absalon, J., Gurtman, A., Lockhart, S., Perez, J. L., Pérez Marc, G., Moreira, E. D., & Zerbini, C. (2020). Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. New England journal of medicine, 383(27), 2603-2615. Qashqari, F. S., Dahlawi, M., Assaggaf, H. M., Alsafi, R., Gari, A., Abudawood, A., Al-Doboke, A., Alsulami, S., Bukhari, R., & Majeed, S. A. (2022). Effect of the COVID-19 vaccine on the menstrual cycle among females in Saudi Arabia. Ethiopian journal of health sciences, 32(6). Reed, B. G., & Carr, B. R. (2018, August 5). The normal menstrual cycle and the control of ovulation. Endotext - NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/ books/NBK279054/ Roos, E. J., Simms-Cendan, J., Cheung, C., Laufer, D., & Grover, S. R. (2021). Pediatric and adolescent gynecology through a global lens. International Journal of Gynecology & Obstetrics, 156(2), 189–196. https:// doi.org/10.1002/ijgo.13723 Saleh Alzahrani, H., Ali Algashami, S., Abdulaziz Alharkan, A., Sultan Alotaibi, N., & Waseem Algahs, N. (2023). The effect of COVID-19 vaccination on the menstrual cycle in female in Riyadh, Saudi Arabia. Saudi Pharmaceutical Journal, 31(5), 746-751. https://doi. org/https://doi.org/10.1016/j.jsps.2023.03.015 Schmalenberger, K. M., Tauseef, H. A., Barone, J. C., Owens, S. A., Lieberman, L., Jarczok, M. N., Girdler, S. S., Kiesner, J., Ditzen, B., & Eisenlohr-Moul, T. A. (2020). How to study the menstrual cycle: Practical tools and recommendations. Psychoneuroendocrinology, 123, 104895. https://doi.org/10.1016/j. psyneuen.2020.104895 Pa ge 24 https://journals.e-palli.com/home/index.php/ajmri Am. J. Multidis. Res. Innov. 3(6) 12-24, 2024 Schmalenberger, K. M., Tauseef, H. A., Barone, J. C., Owens, S. A., Lieberman, L., Jarczok, M. N., Girdler, S. S., Kiesner, J., Ditzen, B., & Eisenlohr-Moul, T. A. (2021). How to study the menstrual cycle: Practical tools and recommendations. Psychoneuroendocrinology, 123, 104895. https://doi.org/https://doi. org/10.1016/j.psyneuen.2020.104895 Sualeh, M., Uddin, M. R., Junaid, N., Khan, M., Pario, A., & Ain, Q. (2022). Impact of COVID-19 Vaccination on Menstrual Cycle: A Cross-Sectional Study From Karachi, Pakistan. Cureus, 14(8). Taşkaldıran, I., Vuraloğlu, E., Bozkuş, Y., İyidir, Ö. T., Nar, A., & Tütüncü, N. B. (2022). Menstrual Changes after COVID-19 Infection and COVID-19 Vaccination. International Journal of Clinical Practice, 2022, 1–5. https://doi.org/10.1155/2022/3199758 Tayyaba Rehan, S., Imran, L., Mansoor, H., Sayyeda, Q., Hussain, H. u., Cheema, M. S., Tahir, M. J., Asghar, M. S., Mahmmoud Fadelallah Eljack, M., & Islam, M. S. (2022). Effects of SARS-CoV-2 infection and COVID-19 pandemic on menstrual health of women: A systematic review. Health Science Reports, 5(6), e881. Thiyagarajan, D. K., Basit, H., & Jeanmonod, R. (2024, September 27). Physiology, menstrual cycle. StatPearls- NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/ books/NBK500020/ Trogstad, L., Juvet, L., Feiring, B., & Blix, K. (2022). Covid-19 vaccines and menstrual changes. BMJ medicine, 1(1). Vladimirovna, S. V., Anvarovna, S. L., Vladimirovna, M. E., & Khidirovna, L. Z. (2023). Menstrual Cycle Disturbances in the Reproductive Period. Central Asian Journal of Medical and Natural Science, 4(2), 389- 397. Vogazianou, A. (2019). Anatomy and physiology of the female reproductive system. Advanced Practice in Endocrinology Nursing, 739-752. Von Woon, E., & Male, V. (2022). Effect of COVID-19 vaccination on menstrual periods in a prospectively recruited cohort. medRxiv (Cold Spring Harbor Laboratory). https://doi.org/10.1101/2022.03.30.22273165 Wei, S.-M., Schiller, C. E., Schmidt, P. J., & Rubinow, D. R. (2018). The role of ovarian steroids in affective disorders. Current opinion in behavioral sciences, 23, 103- 112.