Menstrual Cycle Disturbances after COVID-19 Vaccination: A Cross-Sectional Study

Abstract

Background:

Following COVID-19 vaccination, some women suffered from menstrual cycle disturbances. This study aimed to investigate menstrual cycle disturbances after COVID-19 vaccination in women of reproductive age.

Materials and Methods:

This cross-sectional study was performed on 407 vaccinated women in the vaccination center of Imam Hossein Hospital (Tehran, Iran) between October 2021 and October 2022. They were interviewed based on a research-made checklist which consisted of two areas of questions about the baseline characteristics of participants and menstrual cycle characteristics to explore menstrual characteristics following COVID-19 vaccination.

Results:

The prevalence of menstrual disturbances was higher after the third dose (38.3%) compared with the second (27.9%) and first (17.7%) doses (P<0.001). After the first dose, a history of polycystic ovarian syndrome [PCOS, odds ratio (OR)=7.35, 95% confidential interval (CI)= (3.64-14.82), P<0.001] and menstrual disturbances with unknown etiology [OR=15.23, 95% CI=(6.30-36.80), P<0.001] could predict menstrual disturbances. After the second dose, a history of menstrual disturbances with unknown etiology [OR=3.83, 95% CI=(1.47-9.94), P=0.006] and menstrual disturbances after the first dose [OR=201.96, 95% CI= (40.99-994.90), P<0.001] were predictors of menstrual disturbances. After the third dose, a history of menstrual disturbances with unknown etiology [OR=3.09, 95% CI= (1.00-9.52), P=0.048], menstrual disturbances after the first [OR=9.82, 95% CI=(1.38-69.69), P=0.022] and second [OR=7.83, 95% CI=(1.46-41.92), P=0.016] doses could predict menstrual disturbances.

Conclusion:

We detected that many women experienced various menstrual disturbances after vaccination against SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). Furthermore, a history of menstrual abnormalities (before COVID-19 vaccination and following the previous doses of these vaccines) was associated with developing menstrual disturbances.

Introduction

The COVID-19 pandemic has affected various aspects of human life during the past few years. As a response, vaccination has been the most successful way against SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). However, studies reported numerous vaccine-related side effects, ranging from mild symptoms (like fever, headache, fatigue, and arm pain) to severe side effects (like stroke, thrombosis, and anaphylaxis) (1, 2).

While research on the COVID-19 vaccines and menstrual characteristics is limited and poorly understood, some studies presented several menstrual abnormalities following COVID-19 vaccination (1-3). On the other hand, some of the vaccinated women have complained about menstrual disturbances following vaccination, like hypermenorrhea, polymenorrhea, and postmenopausal hemorrhage, which made them hesitant to receive subsequent doses (4, 5). Nonetheless, the existing reports highlighted that these changes are temporary (3).

Similar to other countries, different types of COVID-19 vaccines have been injected in Iran, including inactivated virus vaccines (like Sinopharm, COVIran Barekat, and Bharat Biotech), viral vector-based vaccines (like AstraZeneca and Sputnik V), and recombinant protein vaccines (like Covax-19/Spikogen and Pastocovac) (6,7). This study aimed to investigate menstrual disturbances after COVID-19 vaccination among Iranian women due to the importance of having regular menstrual cycles for women of reproductive age.

Materials and Methods

Study design and settings

This cross-sectional study was performed on women vaccinated against SARS-CoV-2 in the vaccination center of Imam Hossein Hospital (Tehran, Iran) between October 2021 and October 2022. We included women aged 18-45 willing to participate in the study. Sampling was based on the simple random sampling method. Using Cochrane’s formula and considering prevalence (P)=52.05% (8), d=5.205%, type-I error=5%, and 15% drop in the participants, the sample size was estimated to be 407.

$$n=\frac{Z_{1-\frac{a}{2}}\times P(1-P)}{d^2}$$

Data collection

After the complete explanation, participants completed the informed consent form. They were interviewed based on a research-made checklist by one of the research team members. The checklist consisted of two areas of questions about the baseline characteristics of participants (age, weight, height, marital status, employment status, educational level, past medical history, previous vaccinations, previous history of menstrual disturbances, and the injected vaccine per each dose) and menstrual characteristics following the COVID-19 vaccination (overall menstrual disturbances, details of cycle length, menstruation duration, bleeding volume, dysmenorrhea, metrorrhagia, time interval of menstrual disturbances from vaccination, number of cycles with menstrual disturbances, and the treatment).

Statistical analysis

Data were entered into Statistical Package for the Social Sciences (SPSS) version 23.0 (IBM®, USA). Data were described with frequency, percentage, mean, and standard deviation. Categorical variables were compared between groups using the Chi-square test. Also, we used multivariate logistic regression to determine predictors of menstrual disturbances after COVID-19 vaccination. Potential predictors (P<0.10 in the univariate analysis) were entered into a backward (Wald) regression model. Finally, findings were reported as adjusted odds ratio (OR), 95% confidential interval (CI), and P value. In this study, P<0.05 was considered statistically significant.

Ethical considerations

The Ethics Committee approved the study protocol of Shahid Beheshti University of Medical Sciences, Tehran, Iran (IR.SBMU.RETECH.REC.1401.171). The study was performed concerning the Helsinki declaration.

Results

Baseline characteristics of women

Table 1 presents the baseline characteristics of all the included women in detail. The mean age of 407 included women was 33.30 ± 7.19 years (range: 18- 45 years). Regarding body mass index (BMI), 58.2 % were normal, 30.0% were overweight, and 11.8% were obese. The most frequent underlying disease among participants was thyroid diseases (11.8%), followed by PCOS (6.4%). Furthermore, 55 participants (13.5%) were vaccinated against HPV, HBV, or influenza virus; 9.0% of them experienced menstrual disturbances following vaccination. Also, 21.4% previously had a history of menstrual disturbances (11.1% known etiology and 10.3% unknown etiology). Figure 1 shows the frequency of injected vaccines per dose. Participants were commonly vaccinated with the Sinopharm for all doses: first (80.1%), second (80.4%), and third (59.4%).

Table 1.

Baseline characteristics of included women (n=407)

Variables		Values
Age (Y)		33.30 ± 7.19
Body mass index (kg/m2)		24.82 ± 4.72
Marital status
	Single	155 (38.1)
	Married	252 (61.9)
Educational level
	Primary school	26 (6.4)
	Diploma	110 (27.0)
	Bachelor’s degree	184 (45.2)
	Master’s degree or higher	87 (21.4)
Employment status
	Employed	226 (55.5)
	Unemployed	181 (44.5)
Past medical history
	Thyroid diseases	48 (11.8)
	PCOS	26 (6.4)
	Uterine fibroid	6 (1.5)
	Ovarian cyst	5 (1.2)
OCP consumption		14 (3.4)
History of vaccination against HPV, HBV, or influenza virus		55 (13.5)
History of menstrual disturbances (known etiology)		45 (11.1)
History of menstrual disturbances (unknown etiology)		42 (10.3)

Data are presented as mean ± SD or n (%). PCOS; Polycystic ovary syndrome, OCP; Oral contraceptive pill, HPV; Human papillomavirus, and HBV; Hepatitis B virus.

Fig 1.

Frequency of injected vaccines per dose.

Menstrual characteristics of women

The prevalence of menstrual disturbances was higher after the third dose (38.3%) compared with the second (27.9%) and first (17.7%) doses (χ²=33.999, df=2, P<0.001). We demonstrated details of menstrual disturbances after COVID-19 vaccination in Table 2. Most women experienced menstrual disturbances less than one month after the first dose (80.5%); however, they mainly experienced menstrual disturbances three months after the second (56.8%) and third (60.8%) doses (χ²=78.547, df=4, P<0.001). After the first dose, a considerable proportion of menstrual disturbances lasted more than three months (97.2%). In contrast, this proportion was lower after the second (84.7%) and third (79.4%) doses (χ²=11.16, df=2, P=0.004). Figure 2 depicts the percentage of menstrual disturbances based on vaccine types and doses.

Table 3 depicts the results of the logistic regression model for determining predictors of menstrual disturbances. Based on the findings, a history of menstrual disturbances with unknown etiology [OR=15.23, 95% CI=(6.30-36.80), P<0.001] and PCOS [OR=7.35, 95% CI=(3.64-14.82), P<0.001] could predict menstrual disturbances after the first dose of the vaccine. A history of previous menstrual disturbances with unknown etiology [OR=3.83, 95% CI=(1.47-9.94), P=0.006] and menstrual disturbances after the first dose [OR=201.96, 95% CI=(40.99-994.90), P<0.001] were predictors of menstrual disturbances after the second dose of the vaccine. Moreover, a history of menstrual disturbances with unknown etiology [OR=3.09, 95% CI=(1.00-9.52), P=0.048] menstrual disturbances after the first [OR=9.82, 95% CI=(1.38-69.69), P=0.022] and second [OR=7.83, 95% CI=(1.46-41.92), P=0.016] doses were a predictor of menstrual disturbances after the third dose of the vaccine.

Fig 2.

Percentage of menstrual disturbances based on vaccine types and doses.

Table 2.

Menstrual characteristics after COVID-19 vaccination

Menstrual characteristics		First dose (n=407)	Second dose (n=398)	Third dose (n=240)	P value
Overall menstrual disturbances		72 (17.7)	111 (27.9)	92 (38.3)	<0.001
Cycle length (days)					<0.001
	Polymenorrhea (<21)	11 (2.7)	4 (1.0)	6 (2.5)
	Normal (21-35)	396 (97.3)	383 (96.2)	221 (92.1)
	Oligomenorrhea (>35)	0	11(2.8)	13 (5.4)
Duration of menstruation (days)					<0.001
	Shortened (<2)	1 (0.2)	14 (3.5)	20 (8.4)
	Normal (2-7)	404 (99.3)	375 (94.2)	209 (87.4)
	Elongated (>7)	2 (0.5)	9 (2.3)	10 (4.2)
Bleeding volume (per cycle)					<0.001
	Hypomenorrhea (<30 ml)	0	13 (3.3)	20 (8.3)
	Normal (30-90 ml)	402 (98.8)	360 (90.9)	196 (81.7)
	Hypermenorrhea (>90 ml)	5 (1.2)	23 (5.8)	24 (10.0)
Dysmenorrhea		4 (1.0)	22 (5.5)	14 (5.8)	0.001
Metrorrhagia		0	61 (15.3)	33 (13.8)	<0.001
Time interval of menstrual disturbances from vaccination					<0.001
	< 1 month	58 (80.5)	26 (23.4)	19 (20.7)
	1-3 months	1 (1.4)	22 (19.8)	17 (18.5)
	>3 months	13 (18.1)	63(56.8)	56 (60.8)
Duration of menstrual disturbances					0.008
	< 1 month	1 (1.4)	2 (1.8)	6 (6.5)
	1-3 months	1 (1.4)	15 (13.5)	13 (14.1)
	>3 months	70 (97.2)	94 (84.7)	73 (79.4)
Treatment with hormonal drugs		3 (4.1)	15 (14.7)	15 (16.9)	0.049

Data were reported with n (%). Values were compared between groups using Chi-square test.

Table 3.

Multivariate logistic regression analysis for determining predictors of menstrual disturbances

Variables		Univariate analysis		Multivariate analysis
		OR (95% CI)	P value	OR (95% CI)	P value
First dose
	PCOS	11.19 (4.75-26.37)	<0.001	15.23 (6.30-36.80)	<0.001
	History of menstrual disturbances with unknown etiology	5.47 (2.79-10.72)	<0.001	7.35 (3.64-14.82)	<0.001
Second dose
	Thyroid diseases	1.91 (1.01-3.58)	0.044	1.62 (0.64-4.06)	0.299
	PCOS	5.58 (2.40-12.95)	<0.001	0.71 (0.11-4.46)	0.717
History of menstrual disturbances with unknown etiology		5.96 (2.98-11.93)	<0.001	3.83 (1.47-9.94)	0.006
Menstrual disturbances after the first dose		209.00 (49.44-883.40)	<0.001	201.96 (40.99-994.90)	<0.001
Third dose
	PCOS	3.55 (1.28-9.82)	0.015	1.48 (0.34-6.34)	0.598
	History of menstrual disturbances with unknown etiology	5.95 (2.41-14.67)	<0.001	3.09 (1.00-9.52)	0.048
	Menstrual disturbances after the first dose	66.91 (15.63-286.44)	<0.001	9.82 (1.38-69.69)	0.022
	Menstrual disturbances after the second dose	50.48 (14.99-169.98)	<0.001	7.83 (1.46-41.92)	0.016

OR; Odds ratio, CI; Confidence interval, and PCOS; Polycystic ovary syndrome.

Discussion

Our findings showed that many women experienced post-vaccination menstrual disturbances. The prevalence of menstrual disturbances after the third dose (38.3%) was higher than the second (27.9%) and first (17.7%) doses. Also, multiple regression analysis revealed that the prevalence of menstrual disturbances was not associated with vaccine type.

Consistent with our findings, Trogstad (9) illustrated that menstrual disturbances had a prevalence of close to 40%. The prevalence of heavy bleeding was 7.6% before and 13.6% after the first dose. Additionally, this prevalence was 8.2% before and 15.3% after the second dose. Also, the study of Muhaidat et al. (1) demonstrated that 66.3% of the vaccinated women with Pfizer-BioNTech, Sinopharm, and AstraZeneca vaccines had complained of menstrual disturbances. Vaccine type did not influence the incidence of menstrual disturbances among them.

There are some studies inconsistent with our findings. Cheng et al. (10) found that 2.1 and 1.0% of women aged 18-50 experienced menstrual disturbances after the first and second doses of COVID-19 vaccines (Sinopharm and Sinovac), respectively. Another study revealed that postvaccination menstrual disturbances were higher after Pfizer-BioNTech (0.6% after the first dose, 0.4% after the second dose) compared to AstraZeneca (0.2% after the first dose, 0.2% after the second dose) (11). Besides, a study illustrated that many women had experienced menstrual disturbances after COVID-19 vaccines, including 8% after Sinopharm, 10.7% after AstraZeneca, 5% after Sputnik V, and 17.6% after Covaxin. Based on the type of vaccine analysis, the vaccinated groups with Bharat Biotech, AstraZeneca, Sinopharm, and Sputnik V experienced 11.8, 6.3, 3.5, and 2.5% of metrorrhagia, respectively (12). It seems that the mentioned differences in the prevalence of menstrual disturbances compared with our findings can be attributed to the study design and the vaccine types injected for each dose.

Furthermore, our results revealed that menstrual disturbances mainly manifested with changes in bleeding volume (hypermenorrhea or hypermenorrhea) and metrorrhagia. In agreement with our findings, a study showed that 6% of vaccinated women experienced hypomenorrhea, while 7% experienced hypermenorrhea. In addition, 8% of them reported irregular cycles after taking the vaccine. Women who used hormonal contraception or hormonal therapy had higher menstrual disturbances (about 35% in users vs. 20% in nonusers) (2). Another study illustrated that 23% of participants had a menstrual delay, and 77% had abnormal uterine bleeding, including 47% metrorrhagia, 30% menometrorrhagia, and 23% menorrhagia (13).

In this study, most post-vaccination menstrual disturbances lasted more than three months. In contrast, these disturbances were transient and had no longterm effects in a study by Lee et al. (14). Besides, the prospective cohort study of Wesselink et al. (15) indicated that the one-day average delay in menstruation and higher prevalence of long menstrual cycles following COVID-19 vaccination were resolved by the next menstrual cycle. This difference may be because, in our study, most women did not receive hormonal treatment for menstrual disturbance. Thus, it took longer for these disturbances to improve spontaneously.

In a study by Trogstad (9), almost two out of three women who experienced menstrual disturbances after the first dose had similar experiences after the second dose. In our study, women with a history of menstrual disturbances showed more post-vaccination disturbances, which can likely be explained by having a formerly disturbed hormonal system. Since the vaccines can affect the hormonal system, they will aggravate previous hormonal disruption.

Menstrual disturbances were observed not only after COVID-19 vaccination but also after other vaccines [e.g., typhoid, hepatitis B (HBV), and human papillomavirus (HPV)], or human hormones [e.g., human chorionic gonadotropin (hCG)]. These disturbances may be ascribed to inflammatory and/or immunological reactions. Through direct infection or vaccination, the SARS-CoV-2 spike proteins are presented to women’s tissues via its receptors, which can interfere with the endocrine homeostasis of the menstrual cycle (14, 16, 17). Angiotensin-convertingenzyme- 2 (ACE-2) is the receptor of SARS-CoV-2, expressed in the ovary, uterus, and vagina (17, 18). After the entrance of the virus, SARS-CoV-2 triggers early innate immune responses, such as producing type 1 interferon (IFN-1). These responses serve three leading purposes: limiting viral replication in the cells, creating an antiviral state in the tissue environment, and initiating adaptive immune responses. Subsequently, sufficient populations of effector T cells (helper T cells and cytotoxic T cells) and effector B cells (antibodysecreting cells) work together to clear infected cells and circulating virions (19). Moreover, the stimulation of the immune system following vaccination can lead to the synthesizing and releasing of glucocorticoids (GCs), affecting the hypothalamic-pituitary-gonadal (HPG) axis and inhibiting the production and/or release of hormones (20, 21). The HPG axis regulates reproductive cycles, so any disruption of this axis can result in menstrual disturbances (22). However, we must emphasize that these proposed pathways are subjected to distinct factors, like environment, race, diseases, medicine, and individualbased differences in vaccine response.

The current study had some limitations. Due to the data collection method (interview and subjective reporting), this study might suffer from recall bias and individual differences in reporting menstrual disturbances. Some vaccines (Barekat and Pastocovac) have been injected in a few countries, including Iran. Therefore, due to the lack of previous studies, discussing menstrual disturbances after them was one of the limitations. According to the study design, the regression model explored the possible risk factors of post-vaccination menstrual disturbances.

Conclusion

This study detected that many Iranian women had experienced menstrual disturbances after vaccination against SARS-CoV-2, and the prevalence of these disturbances was higher after the third dose compared to the first and second doses. Moreover, we found that menstrual disturbances mainly included changes in bleeding volume and metrorrhagia, and these postvaccination disturbances lasted more than three months. Furthermore, a history of menstrual abnormalities was associated with developing menstrual disturbances after vaccination. Hence, further research will be needed to understand the underlying mechanisms of menstrual disturbances after vaccination, specifically COVID-19.

Authors’ Contributions

F.R.M.; Conceptualization, Project administration, Investigation, and Writing-original draft. A.K.; Formal analysis, Methodology, and Writing-original draft. H.N.A., S.H.Ch., G.M.; Investigation, Writing-review, and editing. F.F.; Supervision and Review, and Editing the manuscript. All authors read and approved the final manuscript.