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ObjectivesTo assess the contraceptive efficacy, bleeding pattern and safety of a combined oral contraceptive containing estetrol (E4) 15 mg and drospirenone (DRSP) 3 mg.DesignMulticenter, open-label, phase 3 trial.SettingSixty-nine sites in Europe and Russia.PopulationSexually active women aged 18-50 years with regular menstrual cycles and body mass index ≤35 kg/m2 .MethodsE4/DRSP was administered in a 24 active/4 placebo regimen for up to 13 cycles. Visits were scheduled during Cycles 2, 4, 7 and 10 and after completing treatment during which adverse events (AEs) were collected. Participants recorded medication intake, vaginal bleeding/spotting, use of other contraceptive methods and sexual intercourse on a daily diary.Main outcome measuresPearl Index (PI) for women 18-35 years (overall and method-failure), bleeding pattern and AEs.ResultsA total of 1553 women aged 18-50 years, including 1353 from 18 to 35 years old, received the study medication. PI was 0.47 pregnancies/100 woman-years (95% CI 0.15-1.11); method failure PI was 0.29 pregnancies/100 woman-years (95% CI 0.06-0.83). Scheduled bleeding/spotting occurred in 91.9-94.4% of women over Cycles 1 to 12 and lasted a median of 4-5 days per cycle. The percentage of women with unscheduled bleeding/spotting episodes decreased from 23.5% in Cycle 1 to <16% from Cycle 6 onwards. The most common AEs were headache (7.7%), metrorrhagia (5.5%), vaginal haemorrhage (4.8%) and acne (4.2%). One treatment-related serious AE was reported, a lower extremity venous thromboembolism. One-hundred and forty-one (9.1%) women discontinued study participation because of treatment-related adverse events.ConclusionE4/DRSP provides effective contraception, a predictable bleeding pattern and a favourable safety profile.Tweetable abstractA phase 3 trial with E4/DRSP shows high contraceptive efficacy, a predictable bleeding pattern and favourable safety profile.

Background: A variety of epigenetic clocks utilizing DNA methylation changes have been developed; these clocks are either tissue-independent or designed to predict chronological age based on blood or saliva samples. Whether discordant tick rates between tissue-specific and general epigenetic clocks play a role in health and disease has not yet been explored. Results: Here we analyze 1941 cervical cytology samples, which contain a mixture of hormone-sensitive cervical epithelial cells and immune cells, and develop the WID general clock (Women’s IDentification of risk), an epigenetic clock that is shared by epithelial and immune cells and optimized for cervical samples. We then develop the WID epithelial clock and WID immune clock, which define epithelial- and immune-specific clocks, respectively. We find that the WID-relative-epithelial-age (WID-REA), defined as the difference between the epithelial and general clocks, is significantly reduced in cervical samples from pre-menopausal women with breast cancer (OR 2.7, 95% CI 1.28-5.72). We find the same effect in normal breast tissue samples from pre-menopausal women at high risk of breast cancer and show that potential risk reducing anti-progesterone drugs can reverse this. In post-menopausal women, this directionality is reversed. Hormone replacement therapy consistently leads to a significantly lower WID-REA in cancer-free women, but not in post-menopausal women with breast or ovarian cancer. Conclusions: Our findings imply that there are multiple epigenetic clocks, many of which are tissue-specific, and that the differential tick rate between these clocks may be an informative surrogate measure of disease risk.

Item does not contain fulltext, Many factors, including reproductive hormones, have been linked to a woman's risk of developing breast cancer (BC). We reviewed the literature regarding the relationship between ovulatory menstrual cycles (MCs) and BC risk. Physiological variations in the frequency of MCs and interference with MCs through genetic variations, pathological conditions and or pharmaceutical interventions revealed a strong link between BC risk and the lifetime number of MCs. A substantial reduction in BC risk is observed in situations without MCs. In genetic or transgender situations with normal female breasts and estrogens, but no progesterone (P4), the incidence of BC is very low, suggesting an essential role of P4. During the MC, P4 has a strong proliferative effect on normal breast epithelium, whereas estradiol (E2) has only a minimal effect. The origin of BC has been strongly linked to proliferation associated DNA replication errors, and the repeated stimulation of the breast epithelium by P4 with each MC is likely to impact the epithelial mutational burden. Long-lived cells, such as stem cells, present in the breast epithelium, can carry mutations forward for an extended period of time, and studies show that breast tumors tend to take decades to develop before detection. We therefore postulate that P4 is an important factor in a woman's lifetime risk of developing BC, and that breast tumors arising during hormonal contraception or after menopause, with or without menopausal hormone therapy, are the consequence of the outgrowth of pre-existing neoplastic lesions, eventually stimulated by estrogens and some progestins.

Objectives: To investigate factors associated with multiple induced abortions. Materials and methods: A multi-centre cross-sectional survey among abortion-seeking women (n = 623;14-47y) in Sweden, 2021. ‘Multiple abortions’ was defined as having had ≥2 induced abortions. This group was compared to women with a previous experience of 0-1 induced abortion. Regression analysis was conducted to determine independent factors associated with multiple abortions. Results: 67.4% (n = 420) reported previous experience of 0-1 abortion, and 25.8% (n = 161) ≥2 abortions (42 women chose to not respond). Several factors were associated with multiple abortions, but when adjusted in the regression model, the following factors remained; parity ≥1 (OR = 2.96, 95%CI [1.63, 5.39]), low education (OR = 2.40, 95%CI [1.40, 4.09]), tobacco use (OR = 2.50, 95%CI [1.54, 4.07]) and exposure to violence over the last year (OR = 2.37, 95%CI [1.06, 5.29]). More women in the group who had 0-1 abortion (n = 109/420) believed they could not become pregnant at the time of conception, compared to women who had ≥2 abortions (n = 27/161), p=.038. Mood swings, as a contraceptive side-effect, were more often reported among women with ≥2 abortions (n = 65/161), compared to those with 0-1 abortion (n = 131/420), p=.034. Conclusion: Multiple abortions is associated with vulnerability. Sweden provides high quality and accessible comprehensive abortion care; however, counselling must be improved both to achieve contraceptive adherence and identify and address domestic violence.

Introduction: In spite of societal efforts to strengthen women's sexual and reproductive health in Sweden, many women have unmet contraceptive needs and the abortion rate remains high. The aim of this study was to investigate contraceptive use among abortion-seeking women. Material and methods: Swedish-speaking women seeking an induced abortion up to the end of gestational week 12 at seven hospitals filled out an anonymous paper questionnaire between January and June 2021. Data were analyzed using frequencies and cross-tabulations, and the Chi-square test was used to compare age-groups. Valid percentages are presented. Results: In total, 623 women participated. Median age was 29 years and 13% were born outside the Nordic countries. In the year preceding the abortion, condoms (37%, n = 228) were the most commonly used contraceptive method, followed by short-acting reversible contraception (SARC) (35%, n = 213) and withdrawal (25%, n = 152). Around one in five (n = 113) had not used any method in the year preceding the abortion. Sixteen percent (n = 96) had changed contraceptive method in the last year. At the time around conception, 15% (n = 90) reported use of SARC and 2% (n = 12) of long-acting reversible contraception (LARC). Four out of 10 women (n = 268) reported non-use of contraception at the time around conception, with a higher proportion among adolescents (70%, n = 30, P = 0.001). Among the women who responded to why they had not used any method (n = 387), the main reasons were that they did not believe they could become pregnant at that time (37%, n = 144) or had negative experiences from using contraceptives (32%, n = 123). A majority (88%, n = 527) planned to use contraception after the abortion. Of the women who had decided on method, 55% (n = 271) planned to use LARC, and 38% (n = 188) planned to use SARC. Conclusion: The unmet need for contraception appears to be high among abortion-seeking women in Sweden. Many had discontinued contraception use duri

Objectives: To investigate women’s decision-making on induced abortion. Materials and methods: A multi-centre cross-sectional survey among 623 abortion-seeking women in Sweden (2021). The perceived difficulty to decide on abortion was measured using a 7-point Likert scale, and analysed with univariate and multivariate analysis (odds ratios [OR], 95% confidence intervals [CI]). Results: About half (n = 322;52%) scored 1–4, suggesting the decision was perceived as easier compared to those (n = 292;48%) who scored 5–7. Reasons for the abortion were: poor economy (n = 166;27%), too early in the relationship (n = 154;25.1%), want to work first (n = 147;23.9%), want to study first (n = 132;21.5%), uncertain about the relationship (104;16.9%), and too young (n = 104;16.9%). Predictors for perceiving the decision as difficult: partner’s hesitance (OR = 3.18, CI:1.76–5.73), being born outside the Nordic countries (OR = 2.23, CI:1.28–3.87), having discussed the decision with someone (OR = 2.42, CI:1.67–3.50), age ≥30 (OR = 2.22, CI:1.03–4.76), the Covid-19 pandemic (OR = 2.08, CI:1.20–3.59), and the desire to have children in the future (OR = 1.96, CI:1.18–3.28). After confirmed pregnancy, poor mental well-being was more common among those who scored 5–7 (n = 140;47.9%) compared to those who scored 1–4 (n = 122;37.9), p =.029. Conclusion: Women’s decision-making on abortion is complex; in times of crises, the decision procedure may be even more difficult. This valuable knowledge could be used to improve and promote satisfactory counselling beyond medical routines.

Objective: To investigate whether users of hormonal contraceptives (HCs) are at increased risk of depression compared with non-users. Design: Register-based cohort study. Setting: Sweden. Sample: Women aged 15–25 years between 2010 and 2017 with no prior antidepressant treatment, psychiatric diagnose or contraindication for HCs (n = 739 585). Methods: Women with a prescription of HC were identified via the Swedish Prescribed Drug Register (SPDR). Relative risks (RRs) for first depression diagnosis in current HC-users compared with non-users were modelled by Poisson regression. Adjustments included age, medical indication for HC-use and parental history of mental disorders, among others. Main outcome measures: Depression, captured by a redeemed prescription of antidepressant treatment, or a first depression diagnosis in the SPDR and the National Patient Register. Results: Compared with non-users, women on combined oral contraceptives (COCs) and oral progestogen-only products had lower or no increased risk of depression, relative risk (RR) 0.89 (95% CI 0.87–0.91) and 1.03 (95% CI 0.99–1.06) after adjustments, respectively. Age-stratified analyses demonstrated that COC use in adolescents conferred no increase in risk (RR 0.96, 95% CI 0.93–0.98), whereas use of progestogen-only pills (RR 1.13, 95% CI 1.07–1.19), contraceptive patch/vaginal ring (RR 1.43, 95% CI 1.30–1.58), implant (RR 1.38, 95% CI 1.30–1.45) or a levonorgestrel intrauterine device (RR 1.59, 95% CI 1.46–1.73) were associated with increased risks. Conclusions: This study did not find any association between use of COCs, which is the dominating HC in first time users, and depression. Non-oral products were associated with increased risks. Residual confounding must be addressed in the interpretation of the results. Tweetable abstract: There is no association between combined hormonal contraceptives and depression.

Objectives: To assess the contraceptive efficacy, bleeding pattern and safety of a combined oral contraceptive containing estetrol (E4) 15 mg and drospirenone (DRSP) 3 mg. Design: Multicenter, open-label, phase 3 trial. Setting: Sixty-nine sites in Europe and Russia. Population: Sexually active women aged 18–50 years with regular menstrual cycles and body mass index ≤35 kg/m². Methods: E4/DRSP was administered in a 24 active/4 placebo regimen for up to 13 cycles. Visits were scheduled during Cycles 2, 4, 7 and 10 and after completing treatment during which adverse events (AEs) were collected. Participants recorded medication intake, vaginal bleeding/spotting, use of other contraceptive methods and sexual intercourse on a daily diary. Main outcome measures: Pearl Index (PI) for women 18–35 years (overall and method-failure), bleeding pattern and AEs. Results: A total of 1553 women aged 18–50 years, including 1353 from 18 to 35 years old, received the study medication. PI was 0.47 pregnancies/100 woman-years (95% CI 0.15–1.11); method failure PI was 0.29 pregnancies/100 woman-years (95% CI 0.06–0.83). Scheduled bleeding/spotting occurred in 91.9–94.4% of women over Cycles 1 to 12 and lasted a median of 4–5 days per cycle. The percentage of women with unscheduled bleeding/spotting episodes decreased from 23.5% in Cycle 1 to <16% from Cycle 6 onwards. The most common AEs were headache (7.7%), metrorrhagia (5.5%), vaginal haemorrhage (4.8%) and acne (4.2%). One treatment-related serious AE was reported, a lower extremity venous thromboembolism. One-hundred and forty-one (9.1%) women discontinued study participation because of treatment-related adverse events. Conclusions: E4/DRSP provides effective contraception, a predictable bleeding pattern and a favourable safety profile. Tweetable abstract: A phase 3 trial with E4/DRSP shows high contraceptive efficacy, a predictable bleeding pattern and favourable safety profile.

Following publication of the original article [1], it was brought to our attention that one of the references was incorrect. The text of the article reads: The general, epithelial and immune clocks are significantly, albeit weakly, correlated with two mitotic clocks, the pcgtAge score based on promoter CpGs at polycomb group target genes [24] and an alternative mitotic clock model recently developed using “solo-WCGWs” [25] The correct reference for citation 24 should be as follows: 24. Yang Z, Wong A, Kuh D, Paul DS, Rakyan VK, Leslie RD et al. Correlation of an epigenetic mitotic clock with cancer risk. Genome Biology 2016; 17: 205 Also, we wish to add an additional reference to that cited as citation 25. It has been brought to our attention that it would also be relevant to cite the following: 25. Teschendorff AE. A comparison of epigenetic mitotic-like clocks for cancer risk prediction. Genome Medicine 2020; 12: 56 We apologize for the previous errors in the reference list.

Genetic and non-genetic factors contribute to breast cancer development. An epigenome-based signature capturing these components in easily accessible samples could identify women at risk. Here, we analyse the DNA methylome in 2,818 cervical, 357 and 227 matched buccal and blood samples respectively, and 42 breast tissue samples from women with and without breast cancer. Utilising cervical liquid-based cytology samples, we develop the DNA methylation-based Women's risk IDentification for Breast Cancer index (WID-BC-index) that identifies women with breast cancer with an AUROC (Area Under the Receiver Operator Characteristic) of 0.84 (95% CI: 0.80-0.88) and 0.81 (95% CI: 0.76-0.86) in internal and external validation sets, respectively. CpGs at progesterone receptor binding sites hypomethylated in normal breast tissue of women with breast cancer or in BRCA mutation carriers are also hypomethylated in cervical samples of women with poor prognostic breast cancer. Our data indicate that a systemic epigenetic programming defect is highly prevalent in women who develop breast cancer. Further studies validating the WID-BC-index may enable clinical implementation for monitoring breast cancer risk.

Introduction: Intervention trials of structured contraceptive counseling have proved to increase use of long-acting reversible contraceptives (LARCs) and decrease numbers of unintended pregnancies. However, these interventions have not been evaluated from a user perspective. This study aimed to evaluate both healthcare providers’ and participants’ satisfaction with an intervention used in a large trial in Sweden. Material and methods: A cross-sectional study on the intervention group from a cluster randomized trial conducted at 28 clinics in Stockholm, Sweden. Clinics were randomized (1:1 allocation ratio) to provide either structured contraceptive counseling (intervention) or standard contraceptive counseling (control). The intervention consisted of four parts; an educational video to be seen by the participant prior to contraceptive counseling, key questions to be asked by the healthcare provider, an effectiveness chart, and a box of contraceptive models. Eligible participants were 18 years or older, sexually active without a wish to conceive, and with the main purpose of contraceptive use being pregnancy prevention. Healthcare providers completed an electronic semi-structured survey to evaluate the intervention. This study analyses provider and participant satisfaction with the counseling material used in the intervention and if the intervention was found to be supportive in contraceptive counseling and contraceptive choice. Trial registration: ClinicalTrials.gov (NCT03269357). Results: Fourteen intervention clinics enrolled 658 participants from September 2017 to May 2019. Response rate among providers was 88.0% (55/62) and among participants 97.1% (639/658). Providers found the intervention to be supportive in their counseling. Each separate part of the intervention package received high ratings from both providers and participants. Participants found the educational video and the effectiveness chart to be more helpful than the box of contraceptive models in th