Ellen Løkkegaard

Hormonal contraception and risk of venous thromboembolism: national follow-up study

Objective To assess the risk of venous thrombosis in current users of different types of hormonal contraception, focusing on regimen, oestrogen dose, type of progestogen, and route of administration. Design National cohort study. Setting Denmark, 1995-2005. Participants Danish women aged 15-49 with no history of cardiovascular or malignant disease. Main outcome measures Adjusted rate ratios for all first time deep venous thrombosis, portal thrombosis, thrombosis of caval vein, thrombosis of renal vein, unspecified deep vein thrombosis, and pulmonary embolism during the study period. Results 10.4 million woman years were recorded, 3.3 million woman years in receipt of oral contraceptives. In total, 4213 venous thrombotic events were observed, 2045 in current users of oral contraceptives. The overall absolute risk of venous thrombosis per 10 000 woman years in non-users of oral contraceptives was 3.01 and in current users was 6.29. Compared with non-users of combined oral contraceptives the rate ratio of venous thrombembolism in current users decreased with duration of use (<1 year 4.17, 95% confidence interval 3.73 to 4.66, 1-4 years 2.98, 2.73 to 3.26, and >4 years 2.76, 2.53 to 3.02; P<0.001) and with decreasing dose of oestrogen. Compared with oral contraceptives containing levonorgestrel and with the same dose of oestrogen and length of use, the rate ratio for oral contraceptives with norethisterone was 0.98 (0.71 to 1.37), with norgestimate 1.19 (0.96 to 1.47), with desogestrel 1.82 (1.49 to 2.22), with gestodene 1.86 (1.59 to 2.18), with drospirenone 1.64 (1.27 to 2.10), and with cyproterone 1.88 (1.47 to 2.42). Compared with non-users of oral contraceptives, the rate ratio for venous thromboembolism in users of progestogen only oral contraceptives with levonorgestrel or norethisterone was 0.59 (0.33 to 1.03) or with 75 μg desogestrel was 1.12 (0.36 to 3.49), and for hormone releasing intrauterine devices was 0.90 (0.64 to 1.26). Conclusion The risk of venous thrombosis in current users of combined oral contraceptives decreases with duration of use and decreasing oestrogen dose. For the same dose of oestrogen and the same length of use, oral contraceptives with desogestrel, gestodene, or drospirenone were associated with a significantly higher risk of venous thrombosis than oral contraceptives with levonorgestrel. Progestogen only pills and hormone releasing intrauterine devices were not associated with any increased risk of venous thrombosis.

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.

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.

Hormone therapy and risk of myocardial infarction: a national register study.

AIM To assess the risk of myocardial infarction (MI) as a result of hormone therapy (HT), with focus on the influence of age, duration of HT, various regimens and routes, progestagen type, and oestrogen dose. METHODS AND RESULTS All healthy Danish women (n = 698,098, aged 51-69) were followed during 1995-2001. On the basis of a central prescription registry, daily updated national capture on HT was determined. National Registers identified 4947 MI incidents. Poisson regression analyses estimated rate ratios (RRs). Overall, we found no increased risk [RR 1.03 (95% CI: 0.95-1.11)] of MI with the current HT compared with women who never used HT; age-stratified RR among women aged 51-54, 55-59, 60-64, and 65-69 years were 1.24 (1.02-1.51), 0.96 (0.82-1.12), 1.11 (0.97-1.27), and 0.92 (0.80-1.06), respectively. An increasing risk with longer duration was found for younger women, which was not observed with older age groups. In all age groups, the highest risk of MI was found with continuous HT regimen. No increased risk was found with unopposed oestrogen, cyclic combined therapy, or tibolone. Significantly lower risk was found with dermal route than oral unopposed oestrogen therapy (P = 0.04). No associations were found with progestagen type or oestrogen dose. CONCLUSION In a National cohort study, we found that HT regimen and route of application could modify the influence of HT on the risk of MI.

Venous thromboembolism in pregnant and puerperal women in Denmark 1995-2005. A national cohort study.

Venous thromboembolism (VTE) is the leading cause of maternal death in the Western world, and the risk increases during pregnancy and puerperal period. It was the objective of the present study to estimate the absolute and the relative risk of VTE at different weeks of gestation and in the postnatal period as compared to non-pregnant women. This was a historical controlled national cohort study. The National Registry of Patients identified relevant diagnoses. These data were linked to The National Registry of Medical Products Statistics for information about current use of oral contraceptives. Danish women 15 to 49 years old during the period January 1995 through December 2005 were included in the study. In total 819,751 pregnant women were identified of whom 727 had a diagnosis of VTE. The absolute risk of VTE per 10,000 pregnancy-years increased from 4.1 (95% CI, 3.2 to 5.2) during week 1-11 up to 59.0 (95% CI: 46.1 to 76.4) in week 40 and decreased in the puerperal period from 60.0 (95% CI:47.2-76.4) during the first week after birth to 2.1 (95% CI:1.1 to 4.2) during week 9-12 after birth. Compared with non-pregnant women, the incidence rate ratio rose from 1.5 (95% CI:1.1 to 1.9) in week 1-11, to 21.0 (95%CI16.7 to 27.4) in week 40 and 21.5 (95% CI:16.8 to 27.6) in the first week after delivery, declining to 3.8 (95% CI:2.5 to 5.8) 5-6 weeks after delivery. In conclusion, the risk of VTE increases almost exponentially through pregnancy and reaches maximum just after delivery and is no longer significantly increased six weeks after delivery.

Relation between hormone replacement therapy and ischaemic heart disease in women: prospective observational study

Abstract Objective: To investigate the risk of ischaemic heart disease and myocardial infarction among women using hormone replacement therapy, especially the potential modifying effect of cardiovascular risk factors. Design: Prospective observational study. Setting: Denmark. Participants: 19 898 nurses aged 45 and over completing a questionnaire on lifestyle and use of hormone replacement therapy in 1993. Main outcome measures: All cases of death and incident cases of ischaemic heart disease and myocardial infarction until the end of 1998. Results: Current users of hormone replacement therapy smoked more, consumed more alcohol, had lower self rated health, but were slimmer and had a lower prevalence of diabetes than never users. In current users compared with never users, hormone replacement therapy had no protective effect on ischaemic heart disease (hazard ratio 1.2, 0.9 to 1.7) or myocardial infarction (1.0, 0.6 to 1.7), whereas current users with diabetes had an increased risk of death (3.2, 1.4 to 7.5), ischaemic heart disease (4.2, 1.4 to 12.5), and myocardial infarction (9.2, 2.0 to 41.4) compared with never users with diabetes. Conclusion: Hormone replacement therapy showed no protective effect on ischaemic heart disease, but there was a significantly increased risk of death from all causes and ischaemic heart disease among women with diabetes. What is already known on this topic Observational studies have shown that hormone replacement therapy protects women against ischaemic heart disease Randomised clinical trials found no such effect Little attention has focused on identifying subgroups of women who would or would not benefit from treatment What this study adds Hormone replacement therapy does not protect against ischaemic heart disease Women with diabetes who use hormone replacement therapy are at an increased risk of death from all causes and ischaemic heart disease

The implementation and evaluation of a mandatory multi-professional obstetric skills training program

Objective. To implement and evaluate a simulation‐based training program. Design. Descriptive. Study period: June 2003–June 2006. Setting. Obstetric Department, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. Population. Two training sessions were provided for all health professionals including doctors, midwives, auxiliary nurses, and 147 out 156 participants (94%) took part in the first training session and 192 out possible 201 (96%) took part in the second session. Methods. An intervention study of the impact of simulation‐based training in management of postpartum bleeding, shoulder dystocia, basic neonatal resuscitation, and severe preeclampsia. Main outcome measures. Before, just after and 9–15 months following the training, data were collected on the confidence and stress levels relating to the carrying out of certain procedures. In addition, a written objective test on basic neonatal resuscitation was administered. Data on any changes in work‐routines experienced by the participants were obtained by open‐ended questions. Registry data from the Danish Medical Birth Registry and from the hospital administration were included in the analysis. Results. Ninety‐two percent of all respondents had a positive attitude toward the training program. They considered management of shoulder dystocia, preeclampsia, and neonatal resuscitation less stresful and less unpleasant to perform after training. Confidence scores for all the trained skills improved significantly. A significant association was found between confidence in neonatal resuscitation and numbers of correct answers in the objective test. More than 90% found the training to have had a positive influence on their work. The need for organizational changes in the department became evident and necessary changes were implemented. Sick leave amongst midwives diminished significantly during the study period. Conclusions. A comprehensive evaluation of a mandatory simulation‐based program, implemented in a obstetric department, demonstrated a positive impact at individual and organizational levels.

Hormone Therapy and Different Ovarian Cancers: A National Cohort Study

Postmenopausal hormone therapy use increases the risk of ovarian cancer. In the present study, the authors examined the risks of different histologic types of ovarian cancer associated with hormone therapy. Using Danish national registers, the authors identified 909,946 women who were followed from 1995-2005. The women were 50-79 years of age and had no prior hormone-sensitive cancers or bilateral oophorectomy. Hormone therapy prescription data were obtained from the National Register of Medicinal Product Statistics. The National Cancer and Pathology Register provided data on ovarian cancers, including information about tumor histology. The authors performed Poisson regression analyses that included hormone exposures and confounders as time-dependent covariates. In an average of 8.0 years of follow up, 2,681 cases of epithelial ovarian cancer were detected. Compared with never users, women taking unopposed oral estrogen therapy had increased risks of both serous tumors (incidence rate ratio (IRR) = 1.7, 95% confidence interval: 1.4, 2.2) and endometrioid tumors (IRR = 1.5, 95% confidence interval: 1.0, 2.4) but decreased risk of mucinous tumors (IRR = 0.3, 95% confidence interval: 0.1, 0.8). Similar increased risks of serous and endometrioid tumors were found with estrogen/progestin therapy, whereas no association was found with mucinous tumors. Consistent with results from recent cohort studies, the authors found that ovarian cancer risk varied according to tumor histology. The types of ovarian tumors should be given attention in future studies.

Hormone replacement therapy in Denmark, 1995–2004

Background. Recently, the Danish National Register of Medicinal Product Statistics (NRM) was opened for research purposes, and therefore, on an individual basis, can merge with other national registers. The aim of this study was to analyse the use of hormones based on the individual data of the entire Danish female population, with the focus on a detailed evaluation of specific hormone regimens and factors associated with systemic hormone replacement therapy (HRT). Methods. All Danish female citizens, aged 15–70 years during the study period 1995–2004, were identified in the Civil Registration System, and their redeemed prescriptions for hormones and medication for diabetes, hypertension, hypercholesterolemia and heart conditions were retrieved from the NRM. Information on habitation, education, employment and gynaecological surgery was obtained from other national registers. Results. After 2002, the use of HRT was reduced by 65%. In 2002, HRT was most prevalent in women aged 55–59 years, when an average of 200 defined daily doses per 1,000 women per day was recorded. In 2002, approximately 39% of women aged 50–57 years were ever exposed to HRT. The mean duration of HRT was 5 years in an 8‐year time window. During the study period, there was a significant decline in the use of systemic hormones, initially due to a decrease in cyclic combined therapy, but after 2002 continuous combined therapy decreased rapidly. HRT was positively associated with middle‐term education, employment status, and living in urban areas. Women treated for diabetes used hormones less frequently than women without diabetes. Women using antiarrhythmics or antihypertensives used hormones more often than women not using this medication. HRT was positively associated with gynaecological surgery. Conclusion. One in five women, aged 50‐59 years, redeemed daily HRT. Use of HRT declined from 1995 to 2002, but more than halved after 2002. HRT is associated to redemption of other medications of significance for health.

Risk factors for venous thromboembolism in 1.3 million pregnancies: a nationwide prospective cohort.

Objective To quantify risk factors for venous thromboembolism during pregnancy and the puerperal period. Design In a nationwide prospective cohort study we followed pregnant and puerperal women in Denmark from 1995 to 2009 for venous thromboembolism. Information on risk factors and confounders was retrieved from national registries. The diagnosis of venous thromboembolism was confirmed through medical charts. We calculated adjusted incidence rates per 10,000 women years and used Poisson regression to estimate effects during pregnancy and the puerperal period. Results We studied 1,297,037 pregnancies and related puerperal periods, during which there were 748 venous thromboembolisms. The incidence rate for venous thromboembolism during a pregnancy with and without hospitalization for hyperemesis was 15.2/10,000 yr and 6.3/10,000 yr, respectively, (adjusted rate ratio: 2.5 (95%-confidence interval; 1.4–4.5)). The incidence rate among women with multiple pregnancies was 18.2/10,000 yr and 6.3/10,000 yr in singletons (adjusted rate ratio: 2.8 (1.9–4.2)). Increased risk was found with hospitalization during pregnancy or the puerperal period with incidence rates of 42.1/10.000 and 54.7/10.000, respectively, (rate ratios: 12.2 (8.7–17) and 5.9 (4.0–8.8)). Women hospitalized with infections during pregnancy had incidence rates of 25.9/10,000 yr and 29.3/10,000 yr during pregnancy and the puerperal period, respectively, and of 62.7/10,000 yr if hospitalized with infection in the puerperal period. Puerperal venous thromboembolism was associated with hospitalization for preeclampsia and intrauterine growth restriction/fetal death with incidence rates of 45.8/10,000 yr and 18.3/10,000 yr, respectively (rate ratio: 5.0 (3.1–7.8) and 1.9 (0.9–4.4)). Additionally puerperal venous thromboembolism was associated with obesity, elective and acute caesarean sections and major postpartum bleeding with incidence rates of 25.5/10,000 yr, 23.2/10,000 yr, 34.0/10,000 yr and 20.3/10,000 yr, respectively (rate ratios 1.7 (1.1–2.7), 2.1 (1.4–3.1), 3.0 (2.3–4.0) and 1.4 (1.0–2.1)). Conclusions Important risk factors for venous thromboembolism during pregnancy or the puerperal period were hospitalization, infection, hyperemesis, multiple pregnancies, preeclampsia, obesity, caesarean section, major postpartum bleeding, and intrauterine growth restriction or fetal death.