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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.
      • Male V.
      Menstrual changes after covid-19 vaccination.
      Royal College of Obstetricians and Gynaecologists
      RCOG/FSRH respond to reports of 30,000 women’s periods affected after COVID-19 vaccine.
      Centers for Disease Control and Prevention
      Selected adverse events reported after COVID-19 vaccination.
      We therefore evaluated whether vaccination was associated with an increase in diagnosis of postmenopausal bleeding in a large, diverse, community-based 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 self-controlled risk interval methodology was used,
      • McClure D.L.
      • Glanz J.M.
      • Xu S.
      • Hambidge S.J.
      • Mullooly J.P.
      • Baggs J.
      Comparison of epidemiologic methods for active surveillance of vaccine safety.
      comparing the incidence of PMB during 3 consecutive 16-week “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.

      Results

      Among 485,644 women meeting inclusion criteria, 47% were of non-White race with a median age of 67 years (range, 55–105), with 95.4% receiving a messenger RNA (mRNA) vaccine: 52.4% received BNT162b2 (Pfizer–BioNTech, New York, NY) and 43% received mRNA-1273 (Moderna, Cambridge, MA). During the prevaccination interval (Interval 0), the incidence of PMB was 0.39% (95% confidence interval [CI], 0.38–0.41), increasing slightly after vaccination to 0.47% during Interval 1 (95% CI, 0.45–0.49), and then decreasing to 0.43% (95% CI, 0.41–0.45) during Interval 2 (2-sided Cochran–Armitage test for linear trend in proportions; P=.004), (Table). The proportion of women whose diagnosis of PMB was delayed >2 months from the date of onset of bleeding was similar across the 3 consecutive time intervals (23.6%, 22.8%, and 20.4%, respectively; P=.39).
      TableIncidence of postmenopausal bleeding before and after vaccination
      Prevaccination interval 0 (16 wk)Postvaccination interval 1 (1–16 wk)Postvaccination interval 2 (17–34 wk)P value for trend
      Cochran–Armitage test for linear trend in proportions, 2-tailed P value
      Fisher exact test P value with adjustments for multiple comparisons
      The Bonferroni method was used for P value adjustment for multiple comparisons
      Women at risk of incident bleeding (N)485,132484,971484,572
      Incident PMB diagnoses
      Incident cases defined by diagnosis of PMB among women without a previous diagnosis of PMB during the preceding 12 months.
      191422652099
      Incidence of PMB0.39% (0.38–0.41)0.47% (0.45–0.49)0.43% (0.41–0.45).004Pre vs Post 1, P<.001

      Pre vs Post 2, P=.012

      Post 1 vs Post 2, P=.051

      Pre vs (Post 1+Post 2), P<.001
      PMB, postmenopausal bleeding.
      Suh-Burgmann. Association between vaccination against COVID-19 and postmenopausal bleeding. Am J Obstet Gynecol 2022.
      a Cochran–Armitage test for linear trend in proportions, 2-tailed P value
      b The Bonferroni method was used for P value adjustment for multiple comparisons
      c Incident cases defined by diagnosis of PMB among women without a previous diagnosis of PMB during the preceding 12 months.

      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.
      • Edelman A.
      • Boniface E.R.
      • Benhar E.
      • et al.
      Association between menstrual cycle length and coronavirus disease 2019 (COVID-19) vaccination: a U.S. cohort.
      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 so small that the clinical impact at the population level is negligible. The findings provide reassurance that COVID-19 vaccination is not associated with a clinically meaningful increase in the incidence of postmenopausal bleeding.

      References

        • Male V.
        Menstrual changes after covid-19 vaccination.
        BMJ. 2021; 374: n2211
        • Royal College of Obstetricians and Gynaecologists
        RCOG/FSRH respond to reports of 30,000 women’s periods affected after COVID-19 vaccine.
        (Available at:)
        • Centers for Disease Control and Prevention
        Selected adverse events reported after COVID-19 vaccination.
        (Available at:)
        • McClure D.L.
        • Glanz J.M.
        • Xu S.
        • Hambidge S.J.
        • Mullooly J.P.
        • Baggs J.
        Comparison of epidemiologic methods for active surveillance of vaccine safety.
        Vaccine. 2008; 26: 3341-3345
        • Edelman A.
        • Boniface E.R.
        • Benhar E.
        • et al.
        Association between menstrual cycle length and coronavirus disease 2019 (COVID-19) vaccination: a U.S. cohort.
        Obstet Gynecol. 2022; 139: 481-489