Abnormal uterine bleeding diagnoses and care following COVID-19 vaccination.

COVID-19 vaccine availability was not associated with changes in medically attended AUB incidence compared to the pre-pandemic period among KPNW members. Additionally, we found no evidence of greater severity of AUB in cases diagnosed shortly after vaccination compared to other AUB cases. These data suggest that COVID-19 vaccination was not a major driver of AUB diagnoses. However, among patients whose AUB symptoms began in the 60 days following vaccination, 57% had no documented bleeding etiology, and at least 12% mentioned or asked about COVID-19 vaccination as a possible cause to their health care providers. Survey findings have suggested a link between COVID-19 vaccination and unexpected, heavy, or long duration of bleeding, 2 – 4 , 6 , 8 , 10 , 31 and recent studies based on prospective data have found an association between COVID-19 vaccination and small increases in the interval between menstrual periods, 12 , 16 , 17 , 19 similar to changes following COVID-19 infection. 15 While our study did not include amenorrhea codes, missed or late periods were reported in 8% of confirmed post-vaccination AUB cases ( Figure 3 ). The most common symptoms reported in confirmed post-vaccination cases were unexpected bleeding and longer than normal duration of bleeding. The finding of unexpected bleeding aligns with findings by Blix et al. of increased reporting of unexpected bleeding following COVID-19 vaccination among nonmenstruating premenopausal women (primarily using hormonal IUDs) in a Norwegian cohort survey study. 18 These effects have not been seen in past studies using prospectively collected data, but this could be because many prospective studies excluded individuals on birth control, while ours and the Blix et al. study did not. The majority (52.6%) of AUB cases in our chart review sample were using hormonal birth control or the copper IUD in the 60 days prior to index diagnosis, and unexpected bleeding may be more common or more likely to lead to healthcare seeking in this population. Additionally, 30.7% of confirmed cases reported heavy bleeding, which has also been associated with vaccination in some prospective data. 14 , 16 As our chart review was limited to cases diagnosed after vaccination, we were not able to not directly compare rates of incident AUB symptoms based on vaccination status. However, when examining individuals with AUB diagnoses in the EHR, we found no differences in the relative frequencies of specific bleeding codes of those with incident diagnoses of AUB based on whether they had never been vaccinated, were vaccinated in the 60 days prior, or were vaccinated more than 60 days prior to diagnosis. In contrast, a higher proportion of those who were never vaccinated than recently or previously vaccinated cases had a first AUB diagnosis in the ED/inpatient setting. While there are many potential confounding factors affecting differences between these groups, these basic comparisons do not suggest any concerning differences between AUB cases following vaccination and AUB cases diagnosed at other times in terms of severity or clinical presentation. Demographic differences between these groups included a higher proportion of never vaccinated AUB patients identified as Black/African American, and a higher proportion of patients vaccinated more than 60 days prior to the index date identified as Asian. These demographic patterns likely reflect overall demographic patterns in vaccination 32 , 33 rather than anything specific regarding AUB. We focused on diagnoses of AUB within the medical system, and found no evidence to suggest that COVID-19 vaccination drove changes in diagnosis. Given that uterine bleeding can vary in response to many factors, it is likely that many people who experienced small changes to their menstrual cycle following vaccination did not seek care or receive a diagnosis; 6 , 21 our study does not provide insight into uterine bleeding changes following vaccination that did not result in medical care. Only 28% of those diagnosed in the 60 days following vaccination were confirmed post-vaccination AUB cases; most cases were found to have onset prior to vaccination. Medical record review may be needed to accurately ascertain AUB symptom onset. Future work could follow up on our descriptive analysis of AUB following COVID-19 vaccination to compare AUB symptoms and outcomes between those who were recently vaccinated and those who were not. While there is a thriving literature on AUB generally, more research is needed to understand typical symptom course and response to treatment. A strength of this study is that it combined broad assessments (n≥79,000 per month in incidence analyses, n=2,715 for demographic and clinical characteristic comparisons) with detailed chart review of over 400 cases of AUB diagnosed after COVID-19 vaccination. This allowed us to thoroughly explore patterns of AUB diagnosis and symptomology and their possible relationship to COVID-19 vaccination. The study also had a few important limitations. As noted above, our confirmation rate for post-vaccination cases was only 28%, indicating that our estimates of AUB incidence based on coded diagnosis data alone may have been inflated. Additionally, our analysis was limited to members of a single health system. There may be differences in health care seeking between health systems based on payment model and/or regional norms. Additionally, the pandemic led to large-scale changes in health care seeking behavior that may not be fully accounted for in our analyses; health care seeking also differs between vaccinated and unvaccinated populations, making comparisons between populations challenging. Most of our analyses did not assess COVID-19 infection, which may also lead to menstrual changes, 15 , 31 and could contribute to trends in AUB symptoms over time. We also did not evaluate uterine pain or amenorrhea, focusing primarily on heavy and prolonged bleeding, consistent with early reports of post-vaccination menstrual symptoms. 2 , 24 – 26 , 34 Future research would be needed to evaluate amenorrhea and dysmenorrhea diagnoses following COVID-19 vaccine approval. While there is increasing data linking COVID-19 vaccination and short-term changes in menstrual cycles, our data indicate that vaccination was not associated with changes in medical diagnoses of AUB. Although a small proportion of cases mentioned or asked about vaccination as a possible cause of their symptoms, our results suggest that COVID-19 vaccination did not result in an increase in health care seeking and diagnoses for abnormal uterine bleeding.

Between 79,000 and 85,000 health system members met inclusion criteria each month from January 2018 through December 2021. A segmented regression analysis showed a stable trend in monthly AUB incidence rates during the pre-pandemic period (January 2018-February 2020), ranging from 0.15 to 0.19 diagnoses per 1000 person-days ( Figure 2 ). There was a significant decline in AUB diagnosis in the period from March through November of 2020, likely due to changes in healthcare utilization and access. After censoring this early pandemic period, there was no significant change in the level or trend of AUB incidence between the pre-pandemic and post-vaccine (December 2020 through December 2021) periods (β=−0.75, SE=0.90, p = 0.41). This pattern was similar across age categories (16–25, 26–35, and 36–44): there were no significant changes in AUB incidence rates or time trends between the pre-pandemic and post-vaccine periods for the older two groups (26–35: β=−1.17, SE=1.22, p = 0.34; 36–44: β=1.39, SE=1.08, p = 0.21); for the youngest group, there was a small but significant decreasing trend in diagnosis (fewer diagnoses over time) in the post-vaccination period compared to the pre-pandemic period (β=−2.92, SE=1.29, p = 0.03). When comparing AUB cases that had never been vaccinated (n=1,391), were vaccinated in the prior 60 days (n=764), and were vaccinated more than 60 days prior to index diagnosis (n=562; see Figure 1 ), there were significant differences in patient age and the proportion of persons identified as Asian or African American ( Table 1 ). The proportion of AUB cases who received their initial diagnosis in the ED or inpatient setting also varied by group and was highest for never vaccinated cases (4.0%). There were no differences by group in bleeding code or receipt of iron infusion, IV fluids, or undergoing a D&C procedure. Figure 1 shows the study flow and Table 2 provides patient characteristics for the chart review sample. Of the 411 cases reviewed, post-vaccination AUB was confirmed for 114 cases, for a case confirmation rate of 28%. Sixty-eight percent of reviewed cases were excluded because AUB onset was prior to the patient’s first COVID-19 vaccination. Among the 114 confirmed post-vaccine AUB cases, the most common symptom reported was change in timing of bleeding ( Figure 3 ). For 59.6% of cases (n=68) AUB was limited to a single episode, and in 82.5% of cases (n=94), reviewers could confirm that AUB had resolved by the time of review. Confirmed post-vaccine cases varied in the amount and type of workup they received related to their AUB, with 37 patients (32.5%) receiving no workup at all ( Figure 4 ). Forty-eight percent of cases (n=55) were using hormonal contraceptives or a copper intrauterine device (IUD) on their index date. The most common contraceptive methods were hormonal IUD (n=18, 30.0%) and oral contraceptive pills (n=17, 28.3%). Table 3 shows the documented bleeding etiologies for confirmed cases using the Federation of Gynecology and Obstetrics classification system. 30 For 57.0% of cases (n=65), there was no attributed etiology noted in the chart. No cases were attributed to COVID-19 vaccination. Eighteen charts mentioned a recent COVID-19 vaccine (all but one mentioned by the patient), and 14 cases, a patient mentioned or asked if the AUB could be related to the vaccine. Of these, 2 (14%) had a documented bleeding etiology (ovulatory dysfunction and endometrial polyp). Eleven (78.6%) of these 14 patients went on to receive additional COVID-19 vaccine doses following their AUB diagnosis; the three who did not had all completed their primary vaccine series prior to the index date.

The Vaccine Safety Datalink (VSD) is a collaborative project between the Centers for Disease Control and Prevention (CDC) Immunization Safety Office and thirteen healthcare organizations to monitor safety of U.S. licensed and approved vaccines and conduct studies about adverse events following immunization. 22 , 23 Data from this study are from a single VSD site, Kaiser Permanente Northwest (KPNW), an integrated healthcare system serving over 635,000 members in Oregon and Southwest Washington. The study protocol was approved by the KPNW institutional review board; a waiver of informed consent was granted. This activity was reviewed by CDC and was conducted consistent with applicable federal law and CDC policy. See, for example, 45 C.F.R. part 46.102(l)(2), 21 C.F.R. part 56; 42 U.S.C. §241(d); 5 U.S.C. §552a; 44 U.S.C. §3501 et seq. All analyses were limited to KPNW members ages 16–44. Based on discussions with physicians in the VSD Menstrual Irregularities Working Group and published literature, 24 – 26 the following ICD-10 diagnosis codes were categorized as AUB: N92.0 (excessive and frequent menstruation with regular cycle), N92.1 (excessive and frequent menstruation with irregular cycle), N92.3 (ovulation bleeding), N92.4 (excessive bleeding in the premenopausal period), N92.5 (other specified irregular menstruation), N92.6 (irregular menstruation, unspecified), N93.8 (other specified abnormal uterine and vaginal bleeding), or N93.9 (abnormal uterine and vaginal bleeding, unspecified). Members were excluded if they had received any AUB code or a postmenopausal bleeding code (N95.0) in the two years prior to the month of analysis/index date or a pregnancy episode in the 90 days prior to and including the month of analysis/index date. Members were also excluded if they had any of the following diagnoses in the 90 days prior to the month of analysis/index date: cancer, platelet dysfunction, thrombocytopenia, renal dialysis, anticoagulation therapies, or end stage liver disease/cirrhosis; or any of the following diagnoses/procedures at any time: Ehlers Danlos syndrome, other coagulation defects, thalassemia, sickle cell disease, organ transplant (including stem cell transplants), congenital and hereditary thrombocytopenia purpura, or total hysterectomy. While many prior studies excluded individuals on oral contraceptive pills and/or long-acting reversible contraception, this was not an exclusion criterion in this study as people using contraception can still experience AUB, although recent changes in contraception were examined in our chart review analyses. Monthly incidence rates of AUB diagnoses from January 2018 through December 2021 were calculated per 100,000 person-days by first counting the number of female members meeting inclusion criteria each month, then calculating the proportion who received an incident AUB diagnosis code that month. We conducted segmented regression analyses 27 of interrupted time series to test for changes in diagnosis in the period after COVID-19 vaccine authorization (December 2020-December 2021) while controlling for the secular trend in the pre-pandemic period (January 2018-January 2020). We censored the period from February 2020-December 2020 from analyses because health care access constraints early in the pandemic likely impacted care health care seeking. We used the Durbin-Watson statistic 28 to test for serial autocorrelation of the error terms in the regression model, with the errors assumed to follow an order 13 autoregressive process considering the nature of the monthly data. When autocorrelation was detected, stepwise autoregression was conducted using the Maximum Likelihood method with a backstep option (Durbin-Watson statistics and stepwise autoregression results provided in supplemental materials ). We examined rates overall and by age group (16–25, 26–35, 36–44 years). All analyses were conducted using SAS version 9.4 (SAS Institute, Cary, North Carolina). We identified and compared clinical and demographic characteristics of patients who received AUB diagnoses from December 14, 2020 through October 13, 2021 who (1) had not received any COVID-19 vaccine at any time prior to index diagnosis; (2) had received a COVID-19 vaccine in the 60 days prior to index diagnosis; and (3) had received at least one COVID-19 vaccine dose prior to index diagnosis, but not in the 60 days immediately prior (see Figure 1 for inclusion criteria). Clinical characteristics included initial AUB code; setting of initial code; hospital or emergency department (ED) visits with an AUB code within 90 days following the index date; receipt of iron infusion or intravenous fluids; and undergoing a dilation and curettage (D&C) procedure within 14 days of any AUB code occurring within 90 days of the index date. Demographic characteristics included age at index date, Hispanic ethnicity, and race. All characteristics were compared using chi-square statistics. We identified all KPNW members ages 16–44 who received an AUB diagnosis (N92.0, N92.1, N92.2, N92.3, N92.4, N92.5, N92.6, N93.8, N93.9) 1–60 days following receipt of any dose of any COVID-19 vaccine available in United States between December 14, 2020 and August 13, 2021 (diagnosis through October 13, 2021) to assess clinical characteristics, diagnostic workup, treatment, and whether patients or providers attributed symptoms to COVID-19 vaccination. The date of the encounter where a patient received their first post-vaccination AUB diagnosis was considered the index date. Patients were included if they had at least two years of continuous enrollment prior to the index date (patching gaps of ≤3 months) and at least 90 days of enrollment after the index date. Patients were excluded based on the study exclusion criteria above and if they had a postmenopausal bleeding code within 60 days following a COVID-19 vaccination. From this population, we conducted chart review of all patients except for those with ICD code N93.9, who were randomly sampled at 50% due to large sample size. Patients were confirmed as post-vaccination AUB cases if: (1) the medical record was available and AUB diagnosis was confirmed through chart review; (2) abstracted data were consistent with inclusion criteria; and (3) AUB symptom onset was not prior to the patient’s first COVID-19 vaccination. If notes provided no indication that the symptoms had recent onset (e.g., “the patient has heavy periods”) the case was excluded from analyses. If the notes indicated that the problem was new, but the abstractor could not determine whether symptom onset was prior to vaccination (e.g., “spotting for a few weeks” noted 20 days after vaccination), symptom onset was marked as “unknown,” and the case was included in analyses. The chart review form was adapted from our prior work on postmenopausal bleeding 29 and is included in Appendix 1 . Chart reviewers examined EHR records from the index visit and other relevant outpatient, inpatient, ED, and telehealth encounters. Among confirmed post-COVID-19-vaccination AUB cases, chart reviewers abstracted clinical history, AUB symptoms, whether the AUB involved one or multiple bleeding episodes (e.g., whether atypical bleeding occurred over multiple menstrual cycles or unexpected bleeding occurred on more than one occasion), and whether symptoms had resolved (based on explicit chart notes or lack of relevant notes at later OBGYN or primary care appointments) by the review date (May to September 2022). Reviewers also abstracted clinical evaluation procedures related to AUB through 90 days after the index date and any abnormal findings related to the bleeding. Using this information and chart notes, along with clinical adjudication by a board-certified OBGYN physician (KV) when needed, reviewers identified whether an etiology of the bleeding was documented, and if so, what it was (see supplemental methods ). Finally, reviewers documented whether there was any mention or question by the patient or provider of a recent COVID-19 vaccination, or that the AUB could be related to COVID-19 vaccination in any AUB-related encounter. A randomly selected 10% of charts were reviewed by a second reviewer; inconsistencies were resolved by consensus.

There is evidence that COVID-19 vaccination could have short-term impacts on menstrual symptoms, including changes in menstruation timing, flow, duration, and pain, for some individuals. 1 – 19 Changes in uterine bleeding can cause anxiety about reproductive health and negatively impact quality of life. 20 Little is known about whether, among premenopausal individuals, changes in uterine bleeding following COVID-19 vaccination cause sufficient concern to increase health care visits. As changes in menstruation are common and occur for many reasons, people may not seek medical care for small variations in cycle timing or flow. However, when symptoms are unrelated to menstruation or are bothersome, persistent, or unusual, people may contact a health care provider. Thus, diagnoses of abnormal uterine bleeding (AUB) may capture changes in uterine bleeding that are particularly concerning or bothersome. A Norwegian cohort study found increases in unexpected vaginal bleeding following COVID-19 vaccination among premenopausal nonmenstruating women (most using hormonal IUDs), but also found that women were less likely to seek care for unexpected bleeding if symptoms began in the 28 days following vaccination (4.5%) than if symptoms began prior to any vaccination (18.6%). 18 Similarly, only 16% of survey respondents in the Middle East who reported menstrual changes following COVID-19 vaccination spoke to a doctor about these changes. 6 A Swedish study of 1.6 million medical encounters for menstrual disturbance within 100 days of mRNA COVID-19 vaccination found a nonsignificant decrease in International Classification of Diseases 10 th revisions (ICD-10) N91 codes (indicating reduced or absent menstruation) and a small increase in excessive (N92) or other abnormal uterine and vaginal bleeding diagnoses (N93), compared to rates among unvaccinated women in 2019. 11 However, later analyses of this population found no plausible evidence of increased risk of “premenopausal bleeding” (ICD codes 93.8 or 93.9) or “menstrual disturbance” (ICD codes N91 and N92) compared to risk prior to vaccination when controlling for potential confounders. 21 We know of no published data on medical care seeking and diagnosis of menstrual irregularities following COVID-19 vaccination in the United States. To understand the impact of COVID-19 vaccination on AUB diagnoses and medical care, we (1) assessed whether rates of incident AUB diagnosis changed following the U.S. Food and Drug Administration’s authorization of COVID-19 vaccines, (2) examined whether clinical and demographic characteristics of patients diagnosed with AUB varied by vaccination status, and (3) conducted manual chart review of individuals with electronic health record (EHR) diagnoses of AUB within 60 days following vaccination.