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Association between vaccination against COVID-19 and postmenopausal bleeding

STUDY DESIGN: Following approval by the Kaiser Permanente Northern California Institutional Review Board, we identified female patients aged >55 years at the time of COVID-19 vaccination between December 1, 2020 and May 31, 2021, excluding those with a history of hysterectomy or without continuous health plan membership for at least 12 months before and 8 months following vaccination. Incident PMB was identified by abnormal bleeding diagnosis codes (N95.0, N93.0, N93.8, N93.9) assigned at an outpatient emergency department or video or telephone visit among women who did not have a previous PMB diagnosis for at least 12 months. A selfcontrolled risk interval methodology was used, comparing the incidence of PMB during 3 consecutive 16week “risk intervals”: 1 interval before vaccination (Interval 0) and 2 intervals following vaccination (Intervals 1 and 2), with incidence assessed as the number of incident diagnoses occurring during that interval divided by the population at risk for incident bleeding. Patient histories documented at diagnosis were manually reviewed for 250 patients in each interval to estimate the proportion who had delayed presentation for >2 months from the onset of bleeding.

Association between vaccination against COVID-19 and postmenopausal bleeding OBJECTIVE: Postmenopausal bleeding (PMB) following vaccination against COVID-19 has been reported anecdotally and may influence attitudes toward vaccination, but formal studies are lacking. 1e3 We therefore evaluated whether vaccination was associated with an increase in diagnosis of postmenopausal bleeding in a large, diverse, communitybased cohort of women.

STUDY DESIGN:
Following approval by the Kaiser Permanente Northern California Institutional Review Board, we identified female patients aged 55 years at the time of COVID-19 vaccination between December 1, 2020 and May 31, 2021, excluding those with a history of hysterectomy or without continuous health plan membership for at least 12 months before and 8 months following vaccination. Incident PMB was identified by abnormal bleeding diagnosis codes (N95.0, N93.0, N93.8, N93.9) assigned at an outpatient emergency department or video or telephone visit among women who did not have a previous PMB diagnosis for at least 12 months. A selfcontrolled risk interval methodology was used, 4 comparing the incidence of PMB during 3 consecutive 16week "risk intervals": 1 interval before vaccination (Interval 0) and 2 intervals following vaccination (Intervals 1 and 2), with incidence assessed as the number of incident diagnoses occurring during that interval divided by the population at risk for incident bleeding. Patient histories documented at diagnosis were manually reviewed for 250 patients in each interval to estimate the proportion who had delayed presentation for 2 months from the onset of bleeding.

CONCLUSION:
In a large, diverse community cohort, vaccination against COVID-19 was associated with a slight increase in the rate of PMB, as assessed by clinical diagnoses, which did not seem to be attributable to delays in presentation. However, in absolute numbers, the observed increase represents <1 in 1000 additional women diagnosed with bleeding after vaccination compared with before vaccination. Among premenopausal women, COVID-19 vaccination was reported to be associated with a <1 day increase in menstrual cycle length but no change in menses length. 5 Although the mechanisms underlying premenopausal and postmenopausal bleeding are expected to be distinct, our study similarly found that vaccination was associated with a change in bleeding that was statistically significant but of a magnitude Despite being at higher risk for COVID-19e related complications, pregnant and lactating women were excluded from the initial trials leading to Emergency Use Authorizations for COVID-19 vaccinations. 1 These exclusions came 2 years after the United States Department of Health and Human Services (HHS) Task Force on Research Specific to Pregnant Women and Lactating Women (PRGLAC) provided recommendations to Congress and HHS on how to increase inclusion of traditionally excluded groups in research. 2 Lack of randomized controlled trials including pregnant and lactating patients limits clinicians' ability to make evidence-based recommendations. The explicit exclusion of these groups from trials means that clinicians must rely on less sound data, often from observational studies or expert opinions, when making recommendations. Although these exclusions are framed as protective, they result in a lack of evidence-based care and harm patients as effects, dosing changes, and metabolic changes are not studied. Patients in other commonly excluded groups are exposed to the same harms, with limited evidence available to steer decisionmaking for patients with disabilities, the elderly, and children. This study aimed to determine if National Institutes of Health (NIH)efunded trials were more likely to include underrepresented groups after the 2018 PRGLAC recommendations.

STUDY DESIGN:
All actively recruiting NIH-funded phase 3 and 4 trials were downloaded from ClinicalTrials.gov on January 7, 2022. These trials were reviewed for inclusion criteria and population of interest. Data collected from this date were then compared with data published before these recommendations. 3

RESULTS:
Of 419 actively recruiting trials, explicit exclusion was noted in 69% for pregnant individuals, 50% for lactating women, 81% for children, 23% for older adults, and 15% for individuals with disabilities. In comparison with