Unexpected vaginal bleeding and COVID-19 vaccination in nonmenstruating women.

The association between coronavirus disease 2019 (COVID-19) vaccination and vaginal bleeding among nonmenstruating women is not well studied. The Norwegian Institute of Public Health followed several cohorts throughout the pandemic and early performed a systematic data collection of self-reported unexpected vaginal bleeding in nonmenstruating women. Among 7725 postmenopausal women, 7148 perimenopausal women, and 7052 premenopausal women, 3.3, 14.1, and 13.1% experienced unexpected vaginal bleeding during a period of 8 to 9 months, respectively. In postmenopausal women, the risk of unexpected vaginal bleeding (i.e., postmenopausal bleeding) in the 4 weeks after COVID-19 vaccination was increased two- to threefold, compared to a prevaccination period. The corresponding risk of unexpected vaginal bleeding after vaccination was increased three- to fivefold in both nonmenstruating peri- and premenopausal women. In the premenopausal women, Spikevax was associated with at 32% increased risk as compared to Comirnaty. Our results must be confirmed in future studies.

Heavy bleeding and other menstrual disturbances in young women after COVID-19 vaccination.

BACKGROUND: Many signals of menstrual disturbances as possible side effects of vaccination against COVID-19 have been reported. Our objective was to compare the risk of menstrual disturbances before and after vaccination among women aged 18-30 years in Oslo, Norway. METHODS: We used electronic questionnaires to collect reports of menstrual disturbances from 3972 women aged 18-30 years, participating in the population-based Norwegian Young Adult Cohort. We examined the occurrence of menstrual disturbances (heavier bleeding than usual, prolonged bleeding, shorter interval between menstruations, longer interval between menstruations, spot bleedings, stronger pain during menstruation, period pain without bleeding) before and after the first and second dose of COVID-19 vaccine. Relative risks (RR) according to vaccination were estimated using a self-controlled case-series design. We performed additional analyses stratified by vaccine brand, contraception/hormone use, and presence of gynecological condition(s). RESULTS: The prevalence of any menstrual disturbance was 36.7 % in the last menstrual cycle prior the first vaccine dose. The RR for heavier bleeding than usual was 1.90 (95 % CI: 1.69-2.13) after the first vaccine dose and 1.84 (95 % CI 1.66-2.03) after the second dose. Increased risks of prolonged bleeding, shorter interval between menstruations, and stronger pain during menstruation were also observed after both doses. The RRs did not differ with vaccine brand, contraception/hormone use, or presence of gynecological condition(s) for any of the menstrual disturbances. CONCLUSION: Menstrual disturbances were common regardless of vaccination. We found increased risk of menstrual disturbances after vaccination, particularly for heavier bleeding than usual, prolonged bleeding, shorter interval between menstruations, and stronger period pain. In the future, menstrual characteristics should be included in vaccine trials.

Determinants of humoral and cellular immune responses to three doses of mRNA SARS-CoV-2 vaccines in older adults: a longitudinal cohort study.

BACKGROUND: Older age is associated with poorer outcomes to COVID-19 infection. The Norwegian Institute of Public Health established a longitudinal cohort of adults aged 65-80 years to study the effects of the COVID-19 pandemic. Here we describe the characteristics of the cohort in general, and specifically the immune responses at baseline and after primary and booster vaccination in a subset of longitudinal blood samples, and the epidemiological factors affecting these responses. METHODS: 4551 participants were recruited, with humoral (n=299) and cellular (n=90) responses measured before vaccination and after two and three vaccine doses. Information on general health, infections, and vaccinations were obtained from questionnaires and national health registries. FINDINGS: Half of the participants had a chronic condition. 849 (18·7%) of 4551 were prefrail and 184 (4%) of 4551 were frail. 483 (10·6%) of 4551 had general activity limitations (scored with the Global Activity Limitation Index). After dose two, 295 (98·7%) of 299 participants were seropositive for anti-receptor binding domain IgG, and 210 (100%) of 210 participants after dose three. Spike-specific CD4 and CD8 T cell responses showed high heterogeneity after vaccination and responded to the alpha (B.1.1.7), delta (B.1.617.2), and omicron (B.1.1.529 or BA.1) variants of concern. Cellular responses to seasonal coronaviruses increased after SARS-CoV-2 vaccination. Heterologous prime boosting with mRNA vaccines was associated with the highest antibody (p=0·019) and CD4 T cell responses (p=0·003), and hypertension with lower antibody levels after three doses (p=0·04). INTERPRETATION: Most older adults, including those with comorbidities, generated good serological and cellular responses after two vaccine doses. Responses further improved after three doses, particularly after heterologous boosting. Vaccination also generated cross-reactive T cells against variants of concern and seasonal coronaviruses. Frailty was not associated with impaired immune responses, but hypertension might indicate reduced responsiveness to vaccines even after three doses. Individual differences identified through longitudinal sampling enables better prediction of the variability of vaccine responses, which can help guide future policy on the need for subsequent doses and their timing. FUNDING: Norwegian Institute of Public Health, Norwegian Ministry of Health, Research Council of Norway, and Coalition for Epidemic Preparedness Innovations.

Effectiveness of mRNA Booster Vaccination Against Mild, Moderate, and Severe COVID-19 Caused by the Omicron Variant in a Large, Population-Based, Norwegian Cohort.

BACKGROUND: Understanding how booster vaccination can prevent moderate and severe illness without hospitalization is crucial to evaluate the full advantage of mRNA boosters. METHODS: We followed 85 801 participants (aged 31-81 years) in 2 large population-based cohorts during the Omicron BA.1/2 wave. Information on home testing, PCR testing, and symptoms of coronavirus disease 2019 (COVID-19) was extracted from biweekly questionnaires covering the period 12 January 2022 to 7 April 2022. Vaccination status and data on previous SARS-CoV-2 infection were obtained from national registries. Cox regression was used to estimate the effectiveness of booster vaccination compared to receipt of 2-dose primary series >130 days previously. RESULTS: The effectiveness of booster vaccination increased with increasing severity of COVID-19 and decreased with time since booster vaccination. The effectiveness against severe COVID-19 was reduced from 80.9% shortly after booster vaccination to 63.4% in the period >90 days after vaccination. There was hardly any effect against mild COVID-19. The effectiveness tended to be lower among subjects aged ≥60 years than those aged <50 years. CONCLUSIONS: This is the first population-based study to evaluate booster effectiveness against self-reported mild, moderate, and severe COVID-19. Our findings contribute valuable information on duration of protection and thus timing of additional booster vaccinations.

Existing data sources in clinical epidemiology: the Scandinavian Thrombosis and Cancer Cohort.

BACKGROUND: Although venous thromboembolism (VTE) is a known common complication in cancer patients, there is limited knowledge on patient-related and cancer-specific risk factors in the general population. The Scandinavian Thrombosis and Cancer (STAC) Cohort was established by merging individual data from three large Scandinavian cohorts (The Tromsø Study, the second Nord-Trøndelag Health Study, and the Danish Diet, Cancer and Health Study). Here, we present the profile of the STAC cohort and provide age-specific incidence rates of VTE and cancer. METHODS: The STAC cohort includes 144,952 subjects aged 19-101 years without previous VTE or cancer. Baseline information collected in 1993-1997 included physical examination, self-administered questionnaires, and blood samples. Validated VTE events and cancer diagnoses were registered up to 2007-2012. RESULTS: There were 2,444 VTE events (1.4 per 1,000 person-years [PY]) during follow-up, and the incidence increased exponentially from 0.3 per 1,000 PY in subjects aged 20-29 years to 6.4 per 1,000 PY in subjects aged 80+. Overall, 51% of the VTE events were provoked, and cancer was the most common provoking factor (19%), followed by immobilization and surgery (both 15%). In total, 19,757 subjects developed cancer during follow-up (9.8 per 1,000 PY), and the 5-year age-specific incidence rates of cancer were coherent with corresponding rates from the Norwegian Cancer Registry. CONCLUSION: The STAC cohort will provide a unique opportunity to explore the epidemiology and impact of genetic and environmental patient-related and cancer-specific risk factors for VTE in the general population.

The increased risk of venous thromboembolism by advancing age cannot be attributed to the higher incidence of cancer in the elderly: the Tromsø study.

UNLABELLED: Whether the high incidence of venous thromboembolism (VTE) in the elderly can be attributed to cancer is not well studied. We assessed the impact of cancer on risk of VTE in young, middle-aged and elderly. 26,094 subjects without a history of cancer or VTE were recruited from the Tromsø study. Incident cancer (n = 2,290) and VTE (n = 531) were recorded from baseline (1994-1995) through December 31st, 2009. Cox regression with cancer as time-varying exposure was used to calculate hazard ratios with 95 % confidence intervals (CI). Overt cancer was associated with a fivefold (95 %CI 4.3, 6.7) increased risk of VTE, with an age-dependent gradient from 26-fold (95 %CI 12.1, 56.5) increased in the young, ninefold (95 % CI 6.6, 12.7) increased in the middle-aged, and threefold (95 % CI 2.5, 4.5) increased risk in the elderly. The population attributable risks were 14, 27 and 18 %, respectively. CONCLUSION: The relative risk of VTE by cancer were higher in young compared to elderly subjects, but the proportion of VTEs in the population due to cancer did not differ much across age groups. Our findings indicate that the increased risk of VTE by advancing age cannot be attributed to higher incidence of cancer in the elderly.

Platelet count measured prior to cancer development is a risk factor for future symptomatic venous thromboembolism: the Tromsø Study.

BACKGROUND: Elevated platelet count is associated with risk of venous thromboembolism in cancer patients initiating chemotherapy. It is not known whether this risk by platelet count is causal or merely reflects the malignant disease. We investigated whether pre-cancer platelet count alone or together with high leukocyte count was associated with risk of venous thromboembolism in subjects who did and did not develop cancer during follow-up in a population-based cohort study. METHODS: Platelet count and other baseline characteristics were measured in 25160 initially cancer-free subjects who participated in the Tromsø Study in 1994-1995. Incident cancer and symptomatic venous thromboembolism events were registered up to December 31st, 2009. Multivariable Cox regression models were used to calculate hazard ratio for venous thromboembolism across categories of platelet count (<40th, 40-80th, and >80th percentile) with 95% confidence interval. RESULTS: During follow-up, 2082 subjects were diagnosed with cancer. Platelet count was measured on average 8.3 years before the cancer diagnosis. There were 129 venous thromboembolism events in the cancer cohort (13.5 per 1000 person-years) and 377 in the non-cancer cohort (1.2 per 1000 person-years). In cancer patients, pre-cancer platelet count above the 80th percentile (≥295×10(9)/L) was associated with a 2-fold higher risk of venous thromboembolism (Hazard ratio: 1.98, 95% confidence interval 1.21-3.23) compared to platelet count below the 40th percentile (<235×10(9)/L). Concomitant high platelet and leukocyte counts showed a synergistic effect on the VTE risk. In cancer-free subjects, no association was found. COMMENT: In conclusion, pre-cancer platelet count was associated with risk of symptomatic venous thromboembolism in cancer patients, but not in cancer-free subjects. Our findings suggest that platelet count and platelet-leukocyte interactions may play a role in the pathogenesis of cancer-related venous thromboembolism.

White blood cell count measured prior to cancer development is associated with future risk of venous thromboembolism--the Tromsø study.

BACKGROUND: Elevated white blood cell (WBC) count is associated with risk of venous thromboembolism (VTE) in cancer patients initiating chemotherapy. It is not known whether the risk of VTE by WBC count in cancer patients is causal or merely a consequence of the malignant disease. To address this question, we studied the association between WBC count, measured prior to cancer development, and risk of VTE in subjects who did and did not develop cancer during follow-up in a prospective population-based study. METHODS: Baseline characteristics, including WBC and neutrophil counts, were measured in 24304 initially cancer-free subjects who participated in the Tromsø Study in 1994-1995. Incident cancer diagnosis and VTE events were registered up to September 1, 2007. In the cancer cohort, WBC and neutrophil counts were measured in average 7.1 years before cancer development. Cox-regression models were used to calculate hazard ratios (HRs) for VTE by WBC and neutrophil counts as categorized variables (<40(th), 40-80(th), and >80(th) percentile) with 95% confidence intervals (CIs). RESULTS: During follow-up, 1720 subjects developed cancer and there were 388 VTE events, of which 116 occurred in the cancer-group (6.9 per 1000 person-years) and 272 in the cancer-free group (1.1 per 1000 person-years). In those who developed cancer, WBC count above the 80(th) percentile (≥ 8.6 x 10(9) cells/L) was associated with a 2.4-fold higher risk (HR 2.36, 95% CI: 1.44-3.87) of VTE compared to WBC count below the 40(th) percentile (<6.4 x 10(9) cells/L). No association was found between WBC count and VTE in those who stayed cancer-free (HR 0.94, 95% CI 0.65-1.36). Similar findings were observed for neutrophils. COMMENT: Pre-cancer WBC count was associated with risk of VTE in cancer patients, but not in cancer-free subjects. Our findings suggest that leukocytes may play a causal role in cancer-related VTE rather than only reflecting the low-grade inflammation associated with cancer.