Female reproduction and abnormal uterine bleeding after COVID-19 vaccination.

Since its outbreak in 2019, the coronavirus disease 2019 (COVID-19) pandemic has swept through the globe with catastrophic consequences. According to the World Health Organization (WHO), as of December 23, 2022, there have been 660.75 million confirmed cases of COVID-19 and 6.69 million deaths worldwide [ 1 ]. The deleterious effects of COVID-19 have led to the development of vaccines to halt the disease's rapid spread worldwide and minimize its impact. COVID-19 vaccination began in December 2020, almost a year after the pandemic began. Several COVID-19 vaccines have been validated for use by the WHO. The most prominent makers of vaccines are Pfizer-BioNTech, Moderna, Oxford-AstraZeneca, and Johnson & Johnson (J&J)/Janssen. Consequently, the scientific community has expanded its scope of interest from the pandemic itself to the adverse effects of vaccines. There have been many investigations regarding the relationship between COVID-19 vaccination and female reproductive health. This research is critical, as it serves as a basis for altering the health-related behaviors of the general population, with potential impacts on overall health outcomes, and as evidence for many governmental policies. The Korean Specialized Committee for the compensation of loss after COVID-19 vaccination has decided to include abnormal uterine bleeding (AUB) as a "suspected related symptom" after COVID-19 vaccination on August 16, 2021, for all vaccine types, including those manufactured by Oxford-AstraZeneca, Moderna, Pfizer-BioNTech, and J&J. This decision has enabled those who developed AUB after vaccination for COVID-19 to claim compensation from the committee and receive support. The scientific basis for this decision was the analysis by the COVID-19 Vaccine Safety Committee of the National Academy of Medicine of Korea. After a comprehensive analysis of domestic and international data on adverse reactions reported after COVID-19 vaccination, the committee has announced the discovery of a statistically significant association between AUB and COVID-19 vaccination, which is sufficient evidence to establish a causal relationship. This article specifically focuses on the effect of COVID-19 vaccines on female reproductive health, including thrombosis, ovarian function, in vitro fertilization (IVF) outcomes, and the menstrual cycle.

The incidence of menstruation-related changes after COVID-19 vaccination varies significantly among published studies. A retrospective study in Saudi Arabia investigated patients who received either the Pfizer or AstraZeneca vaccine. An abnormal menstrual cycle was reported by 0.69% of those vaccinated with the Pfizer vaccine and 0.45% of those who received the AstraZeneca vaccine [ 29 ]. In an African study where individuals were vaccinated with mostly AstraZeneca (77.8%, followed by Pfizer [9.1%]), menstrual disorders were reported in 0.5% of patients [ 30 ]. A Chinese study that investigated the side effects of healthcare workers after administration of the inactivated vaccine (Sinopharm) showed menstrual changes in 2.1% [ 31 ]. The most frequent type of menstrual change was menstrual delay, followed by early menstruation. In some reports, the percentage tended to be higher when the reproductive-age population was targeted. One study showed that when the population was narrowed down to menstruating, reproductive-age women, 4.8% of patients reported menstruation-related symptoms [ 32 ]. A proposed mechanism for COVID-19 vaccination-induced alterations in the menstrual cycle is that vaccination may function as a potential stressor to the human body, disrupting the hypothalamic-pituitary-ovarian axis [ 33 ]. Furthermore, immunological or inflammatory reactions following vaccine administration may play a role, interfering with menstrual homeostasis and creating hormonal disruptions [ 34 ]. Heavy menstrual bleeding may be due to the increased bleeding tendency after COVID-19 vaccination [ 35 ]. The specific mechanisms underlying the clinical symptoms may need further investigation and validation. Studies have reported a higher incidence of menstrual irregularities after COVID-19 vaccination. A prospective cohort study by Edelman et al. [ 36 ] recruited volunteers to investigate the effects of COVID-19 vaccines on menstrual symptoms (n=545) and found that 25% of patients reported changes in their menstrual cycle. Another similar study reported that about 50% to 60% of women of reproductive-age had menstrual irregularities [ 34 ]. An Israel survey-based study that enrolled only pre-menopausal non-pregnant patients (n=7,904) reported that 47.2% of patients had changes in menstrual patterns [ 35 ]. These discrepancies in the incidence of menstrual side effects after the vaccine may be because larger population-based studies include all female patients regardless of their menstrual status or reproductive function, and specific information on incidence in tailored populations is unavailable. The short duration of surveillance, up to about a week in a larger population study, may have also had an impact. Additionally, there is a selection bias for recruiting those who participate in questionnaires related to menstrual irregularities; reproductive-age women with a keen interest in their menstrual patterns are more likely to be included in the questionnaire cohort. COVID-19 vaccines influence the interval between cycles, the duration of the cycle, and the severity of symptoms, including menorrhagia and dysmenorrhea. Among various features presented as menstruation-related side effects of COVID-19 vaccines, the most commonly reported symptom is menstrual irregularity. In a study by Wong et al. [ 37 ] that analyzed 5,975,363 text responses entered into the V-safe surveillance application administered by the government, 1% (n=62,679) reported menstrual irregularities or vaginal bleeding as a complication after COVID-19 vaccination. The most common theme was the timing of menstruation (83.6%), followed by menstrual symptom severity (67.0%). The reported symptoms were mainly within 0 to 7 days after vaccination [ 37 ]. In another study by Farland et al. [ 38 ], 25% of 545 individuals reported menstrual cycle changes after vaccination, and the most common change was irregular menstruation (43%). Rodriguez Quejada et al. [ 39 ] reported that among 184 patients with menstrual alterations after vaccination of various types, 42.9% had menstrual irregularities. Regarding the quantification of menstrual cycle irregularities, Edelman et al. [ 36 ] reported that the change was less than a day. In a prospective cohort study including 3,959 patients, the authors showed that the cycle length increased by 0.71 days after the first dose and 0.91 days after the second dose, with statistical significance. There was no significant change in the duration of menstruation [ 36 ]. In a survey study of 164 women by Lagana et al. [ 34 ], the participants reported varying frequencies and duration of menstruation. After the first dose of the COVID-19 vaccine, 18% to 33.3% of women reported menstruation 1 to 5 days earlier than expected. Regarding the length of menstruation, 16% to 67% of women reported that menstruation lasted for more than 7 days, while 11% to 37% reported that it lasted for less than 3 days. After the second dose, the trend of the answers was similar; although variation existed, the participants tended to have earlier (12% to 38%), longer (21% to 50%), and heavier (28% to 62%) menstruation [ 34 ]. Menorrhagia has also been commonly reported after COVID-19 vaccination. An Israeli survey of 7,904 pre-menopausal non-pregnant women by Issakov et al. [ 35 ] reported that 80.6% of those who reported menstrual alterations had menorrhagia, the most common menstrual problem encountered by the COVID-19 vaccinated population. In a study by Wong et al. [ 37 ], menstrual severity, or heavy bleeding, was the second most commonly reported event (67.0%). Another retrospective study reported heavy menstrual bleeding among 41.8% of 184 patients with menstrual alterations [ 39 ]. Other reported problems include a higher frequency of premenstrual symptoms in 34% of the population and increased dysmenorrhea in 30%. Amenorrhea was less common but reported in 3% to 11% of the population [ 39 ]. Conflicting results have been reported on whether menstruation-related side effects are more severe with the first or second dose. Farland et al. [ 38 ] and Lagana et al. [ 34 ] reported a higher frequency of menstruation-related side effects after the second dose. In the former study, 56% of participants reported alterations after the second dose and 18% after the first dose. In the latter study, 60% to 70% of women reported menstrual irregularities after the second dose, whereas only 50% to 60% reported menstrual irregularities after the first dose. However, Muhaidat et al. [ 40 ] reported more frequent symptoms after the first dose, with 46.7% reporting symptoms after the first dose and 32.4% after the second dose. The type of vaccine seems unrelated, as studies comparing menstruation-related symptoms in populations with different vaccines did not show inter-group differences [ 34 , 39 ]. Interestingly, according to a cross-sectional survey by Muhaidat et al. [ 40 ], menstrual alterations after the COVID-19 vaccine did not seem to be affected by underlying diseases such as polycystic ovarian syndrome, thyroid disease, myomas, endometriosis, and adenomyosis. Several studies have shown that menstrual changes are only transient, usually resolving within 2 months [ 34 , 40 ].

Although COVID-19 vaccines have been proven to be generally safe, they may produce unwanted consequences. The main findings of this review are as follows: Although rare, thrombosis may occur after vaccine administration (incidence, 0.00006% to 0.005%) The impact of COVID-19 vaccines on ovarian reserve (AMH and AFC) is minimal. IVF outcomes are not impaired after COVID-19 vaccine administration. COVID-19 vaccines certainly seem to affect the menstrual cycle; however, the effects are generally well-tolerated and transient. The most frequently reported problems are menstrual irregularities, followed by menorrhagia. However, the findings of recent studies are generally reassuring, as symptoms resolve within about 2 months. It remains unclear whether certain groups are particularly vulnerable to menstruation-related adverse events following COVID-19 vaccination. The natural pregnancy rates following vaccination also remain unclear. Further investigations may help the scientific community understand the remaining questions regarding the effects of COVID-19 vaccines on female reproductive function and menstruation.