Charlotte Wessel Skovlund

Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001-9

Objective To assess the risk of venous thromboembolism from use of combined oral contraceptives according to progestogen type and oestrogen dose. Design National historical registry based cohort study. Setting Four registries in Denmark. Participants Non-pregnant Danish women aged 15-49 with no history of thrombotic disease and followed from January 2001 to December 2009. Main outcome measures Relative and absolute risks of first time venous thromboembolism. Results Within 8 010 290 women years of observation, 4307 first ever venous thromboembolic events were recorded and 4246 included, among which 2847 (67%) events were confirmed as certain. Compared with non-users of hormonal contraception, the relative risk of confirmed venous thromboembolism in users of oral contraceptives containing 30-40 µg ethinylestradiol with levonorgestrel was 2.9 (95% confidence interval 2.2 to 3.8), with desogestrel was 6.6 (5.6 to 7.8), with gestodene was 6.2 (5.6 to 7.0), and with drospirenone was 6.4 (5.4 to 7.5). With users of oral contraceptives with levonorgestrel as reference and after adjusting for length of use, the rate ratio of confirmed venous thromboembolism for users of oral contraceptives with desogestrel was 2.2 (1.7 to 3.0), with gestodene was 2.1 (1.6 to 2.8), and with drospirenone was 2.1 (1.6 to 2.8). The risk of confirmed venous thromboembolism was not increased with use of progestogen only pills or hormone releasing intrauterine devices. If oral contraceptives with desogestrel, gestodene, or drospirenone are anticipated to increase the risk of venous thromboembolism sixfold and those with levonorgestrel threefold, and the absolute risk of venous thromboembolism in current users of the former group is on average 10 per 10 000 women years, then 2000 women would need to shift from using oral contraceptives with desogestrel, gestodene, or drospirenone to those with levonorgestrel to prevent one event of venous thromboembolism in one year. Conclusion After adjustment for length of use, users of oral contraceptives with desogestrel, gestodene, or drospirenone were at least at twice the risk of venous thromboembolism compared with users of oral contraceptives with levonorgestrel.

Thrombotic Stroke and Myocardial Infarction with Hormonal Contraception

BACKGROUND Although several studies have assessed the risk of venous thromboembolism with newer hormonal contraception, few have examined thrombotic stroke and myocardial infarction, and results have been conflicting. METHODS In this 15-year Danish historical cohort study, we followed nonpregnant women, 15 to 49 years old, with no history of cardiovascular disease or cancer. Data on use of hormonal contraception, clinical end points, and potential confounders were obtained from four national registries. RESULTS A total of 1,626,158 women contributed 14,251,063 person-years of observation, during which 3311 thrombotic strokes (21.4 per 100,000 person-years) and 1725 myocardial infarctions (10.1 per 100,000 person-years) occurred. As compared with nonuse, current use of oral contraceptives that included ethinyl estradiol at a dose of 30 to 40 μg was associated with the following relative risks (and 95% confidence intervals) for thrombotic stroke and myocardial infarction, according to progestin type: norethindrone, 2.2 (1.5 to 3.2) and 2.3 (1.3 to 3.9); levonorgestrel, 1.7 (1.4 to 2.0) and 2.0 (1.6 to 2.5); norgestimate, 1.5 (1.2 to 1.9) and 1.3 (0.9 to 1.9); desogestrel, 2.2 (1.8 to 2.7) and 2.1 (1.5 to 2.8); gestodene, 1.8 (1.6 to 2.0) and 1.9 (1.6 to 2.3); and drospirenone, 1.6 (1.2 to 2.2) and 1.7 (1.0 to 2.6), respectively. With ethinyl estradiol at a dose of 20 μg, the corresponding relative risks according to progestin type were as follows: desogestrel, 1.5 (1.3 to 1.9) and 1.6 (1.1 to 2.1); gestodene, 1.7 (1.4 to 2.1) and 1.2 (0.8 to 1.9); and drospirenone, 0.9 (0.2 to 3.5) and 0.0. For transdermal patches, the corresponding relative risks were 3.2 (0.8 to 12.6) and 0.0, and for a vaginal ring, 2.5 (1.4 to 4.4) and 2.1 (0.7 to 6.5). CONCLUSIONS Although the absolute risks of thrombotic stroke and myocardial infarction associated with the use of hormonal contraception were low, the risk was increased by a factor of 0.9 to 1.7 with oral contraceptives that included ethinyl estradiol at a dose of 20 μg and by a factor of 1.3 to 2.3 with those that included ethinyl estradiol at a dose of 30 to 40 μg, with relatively small differences in risk according to progestin type. (Funded by the Danish Heart Association.).

Venous thrombosis in users of non-oral hormonal contraception: follow-up study, Denmark 2001-10

Objective To assess the risk of venous thrombosis in current users of non-oral hormonal contraception. Design Historical national registry based cohort study. Setting Four national registries in Denmark. Participants All Danish non-pregnant women aged 15-49 (n=1 626 158), free of previous thrombotic disease or cancer, were followed from 2001 to 2010. Main outcome measures Incidence rate of venous thrombosis in users of transdermal, vaginal, intrauterine, or subcutaneous hormonal contraception, relative risk of venous thrombosis compared with non-users, and rate ratios of venous thrombosis in current users of non-oral products compared with the standard reference oral contraceptive with levonorgestrel and 30-40 µg oestrogen. Diagnoses were confirmed by at least four weeks of anticoagulation therapy after the diagnosis. Results Within 9 429 128 woman years of observation, 5287 first ever venous thrombosis events were recorded, of which 3434 were confirmed. In non-users of hormonal contraception the incidence rate of confirmed events was 2.1 per 10 000 woman years. Compared with non-users of hormonal contraception, and after adjustment for age, calendar year, and education, the relative risk of confirmed venous thrombosis in users of transdermal combined contraceptive patches was 7.9 (95% confidence interval 3.5 to 17.7) and of the vaginal ring was 6.5 (4.7 to 8.9). The corresponding incidences per 10 000 exposure years were 9.7 and 7.8 events. The relative risk was increased in women who used subcutaneous implants (1.4, 0.6 to 3.4) but not in those who used the levonorgestrel intrauterine system (0.6, 0.4 to 0.8). Compared with users of combined oral contraceptives containing levonorgestrel, the adjusted relative risk of venous thrombosis in users of transdermal patches was 2.3 (1.0 to 5.2) and of the vaginal ring was 1.9 (1.3 to 2.7). Conclusion Women who use transdermal patches or vaginal rings for contraception have a 7.9 and 6.5 times increased risk of confirmed venous thrombosis compared with non-users of hormonal contraception of the same age, corresponding to 9.7 and 7.8 events per 10 000 exposure years. The risk was slightly increased in women using subcutaneous implants but not in those using the levonorgestrel intrauterine system.

Association of Hormonal Contraception With Depression.

Importance Millions of women worldwide use hormonal contraception. Despite the clinical evidence of an influence of hormonal contraception on some womens mood, associations between the use of hormonal contraception and mood disturbances remain inadequately addressed. Objective To investigate whether the use of hormonal contraception is positively associated with subsequent use of antidepressants and a diagnosis of depression at a psychiatric hospital. Design, Setting, and Participants This nationwide prospective cohort study combined data from the National Prescription Register and the Psychiatric Central Research Register in Denmark. All women and adolescents aged 15 to 34 years who were living in Denmark were followed up from January 1, 2000, to December 2013, if they had no prior depression diagnosis, redeemed prescription for antidepressants, other major psychiatric diagnosis, cancer, venous thrombosis, or infertility treatment. Data were collected from January 1, 1995, to December 31, 2013, and analyzed from January 1, 2015, through April 1, 2016. Exposures Use of different types of hormonal contraception. Main Outcomes and Measures With time-varying covariates, adjusted incidence rate ratios (RRs) were calculated for first use of an antidepressant and first diagnosis of depression at a psychiatric hospital. Results A total of 1 061 997 women (mean [SD] age, 24.4 [0.001] years; mean [SD] follow-up, 6.4 [0.004] years) were included in the analysis. Compared with nonusers, users of combined oral contraceptives had an RR of first use of an antidepressant of 1.23 (95% CI, 1.22-1.25). Users of progestogen-only pills had an RR for first use of an antidepressant of 1.34 (95% CI, 1.27-1.40); users of a patch (norgestrolmin), 2.0 (95% CI, 1.76-2.18); users of a vaginal ring (etonogestrel), 1.6 (95% CI, 1.55-1.69); and users of a levonorgestrel intrauterine system, 1.4 (95% CI, 1.31-1.42). For depression diagnoses, similar or slightly lower estimates were found. The relative risks generally decreased with increasing age. Adolescents (age range, 15-19 years) using combined oral contraceptives had an RR of a first use of an antidepressant of 1.8 (95% CI, 1.75-1.84) and those using progestin-only pills, 2.2 (95% CI, 1.99-2.52). Six months after starting use of hormonal contraceptives, the RR of antidepressant use peaked at 1.4 (95% CI, 1.34-1.46). When the reference group was changed to those who never used hormonal contraception, the RR estimates for users of combined oral contraceptives increased to 1.7 (95% CI, 1.66-1.71). Conclusions and Relevance Use of hormonal contraception, especially among adolescents, was associated with subsequent use of antidepressants and a first diagnosis of depression, suggesting depression as a potential adverse effect of hormonal contraceptive use.

Reproductive prognosis in endometriosis. A national cohort study

To assess the reproductive long‐term prognosis of women with and without endometriosis, to explore changes over time, and to quantify the contribution of artificial reproductive techniques.

Obstetrical and neonatal outcomes in women following gastric bypass: a Danish national cohort study

To assess obstetrical and neonatal outcomes in women following gastric bypass, compared with adipose women without surgery and with a normal weight control population.

Reduction in stillbirths at term after new birth induction paradigm: results of a national intervention

Objective The risk of fetal death increases steeply after 42 gestational weeks. Since 2009, Denmark has had a more proactive policy including prevention of prolonged pregnancy, and early intervention in women with diabetes, preeclampsia, high body mass index and of a higher age group. The aim of this study was to describe the development in fetal deaths with this more proactive birth induction practice, and to identify and quantify contributing factors for this development. Design National cohort study. Setting Denmark. Participants Delivering women in Denmark, 1 January 2000 to 31 December 2012. Outcome measures Stillbirths per 1000 women at risk (prospective risk of stillbirth) and per 1000 newborn from 37 and 40 gestational weeks, respectively, through the study period. Results During the study period, 829 165 children were live born and 3770 (0.45%) stillborn. Induction of labour increased from 12.4% in year 2000 to 25.1% in 2012 (p<0.001), and the percentage of children born at or after 42 weeks decreased from 8.0% to 1.5% (p<0.001). Through the same period, the prospective risk of stillbirth after 37 weeks fell from 0.70 to 0.41/1000 ongoing pregnancies (p<0.001), and from 2.4 to 1.4/1000 newborn (p<0.001). The regression analysis confirmed the inverse association between year of birth and risk of stillbirth. The lowest risk was observed in the years 2011–2012 as compared with years 2000–2002 with a fully adjusted HR of 0.69 (95% CI 0.57 to 0.83). The general earlier induction, the focused earlier induction of women with body mass index >30, twins, and of women above 40 years and a halving of smoking pregnant women were all independent contributing factors for the decrease. Conclusions A gradually more proactive and differential earlier labour induction practice is likely to have mainly been responsible for the substantial reduction in stillbirths in Denmark.

Salpingectomy as standard at hysterectomy? A Danish cohort study, 1977–2010

Objective To assess if the risk of first-time salpingectomy was affected by prior hysterectomy with retained fallopian tubes and by prior sterilisation. Design A historical cohort study. Setting Denmark. Participants 170 000 randomly selected women born 1947–1963 (10 000/year) were followed from 1977 until the end of 2010. Main outcome measures Effect of hysterectomy with retained fallopian tubes or sterilisation on the risk of salpingectomy. Both were modelled in a Cox proportional hazards model as time-dependent covariates, analysing time to first salpingectomy. End of follow-up period was 31 December 2010. Results Of 9591 hysterectomies, 6456 (67.3%) had both fallopian tubes retained. HRs for salpingectomy after hysterectomy with retained fallopian tubes and sterilisation were 2.13 (95% 1.88 to 2.42) and 2.42 (2.21 to 2.64), as compared with those for non-hysterectomised and non-sterilised women. Conclusions Women undergoing hysterectomy with retained fallopian tubes or sterilisation have at least a doubled risk of subsequent salpingectomy. Removal of the fallopian tubes at hysterectomy should therefore be recommended.

Venous thromboembolism in pregnancy and the puerperal period: a study of 1210 events

The aim of this study was to describe venous thromboembolism (VTE) in pregnancy and the puerperal period, and to validate diagnoses of VTE.

Endometriosis increases the risk of obstetrical and neonatal complications

The objective of this study was to assess obstetrical complications and neonatal outcomes in women with endometriosis as compared with women without endometriosis.