Venous thromboembolism with use of hormonal contraception and non-steroidal anti-inflammatory drugs: nationwide cohort study.

OBJECTIVE: To study the influence of concomitant use of hormonal contraception and non-steroidal anti-inflammatory drugs (NSAIDs) on the risk of venous thromboembolism. DESIGN: Nationwide cohort study. SETTING: Denmark through national registries. PARTICIPANTS: All 15-49 year old women living in Denmark between 1996 and 2017 with no medical history of any venous or arterial thrombotic event, cancer, thrombophilia, hysterectomy, bilateral oophorectomy, sterilisation, or infertility treatment (n=2 029 065). MAIN OUTCOME MEASURE: A first time discharge diagnosis of lower limb deep venous thrombosis or pulmonary embolism. RESULTS: Among 2.0 million women followed for 21.0 million person years, 8710 venous thromboembolic events occurred. Compared with non-use of NSAIDs, use of NSAIDs was associated with an adjusted incidence rate ratio of venous thromboembolism of 7.2 (95% confidence interval 6.0 to 8.5) in women not using hormonal contraception, 11.0 (9.6 to 12.6) in women using high risk hormonal contraception, 7.9 (5.9 to 10.6) in those using medium risk hormonal contraception, and 4.5 (2.6 to 8.1) in users of low/no risk hormonal contraception. The corresponding numbers of extra venous thromboembolic events per 100 000 women over the first week of NSAID treatment compared with non-use of NSAIDs were 4 (3 to 5) in women not using hormonal contraception, 23 (19 to 27) in women using high risk hormonal contraception, 11 (7 to 15) in those using medium risk hormonal contraception, and 3 (0 to 5) in users of low/no risk hormonal contraception. CONCLUSIONS: NSAID use was positively associated with the development of venous thromboembolism in women of reproductive age. The number of extra venous thromboembolic events with NSAID use compared with non-use was significantly larger with concomitant use of high/medium risk hormonal contraception compared with concomitant use of low/no risk hormonal contraception. Women needing both hormonal contraception and regular use of NSAIDs should be advised accordingly.

Oral tranexamic acid and thrombosis risk in women.

BACKGROUND: Oral tranexamic acid is effective for heavy menstrual bleeding, but the thrombosis risk with this treatment is largely not studied. METHODS: Using nationwide registries, we assessed associations between use of oral tranexamic acid and risk of deep-vein thrombosis or pulmonary embolism and arterial thrombosis in heart or brain in a nationwide historical prospective cohort of Danish women aged 15 to 49 years in the period 1996-2017. Exclusion criteria included potential confounding factors such as history of thromboembolism, anticoagulation therapy, thrombophilia, and cancer. FINDINGS: Among 2·0 million women followed for 13·8 million person-years, 3,392 venous thromboembolisms and 4,198 arterial thromboses occurred. A total of 63,896 women (3·2%) filled 146,729 prescriptions of oral tranexamic acid during follow-up with median filled prescription per user being one of 15 g. The age-standardised incidence rate of venous thromboembolism was 11·8 (95% CI 4·6 to 30·2) per 10,000 person-years in oral tranexamic acid use compared to 2·5 (2·4 to 2·6) per 10,000 person-years in non-use. For arterial thrombosis, the age-standardised incidence rate per 10,000 person-years was 3·4 (1·1 to 10·7) among exposed compared to 3·0 (2·9 to 3·1) in non-exposed. Comparing oral tranexamic acid use with non-use, the adjusted incidence rate ratio was 4·0 (1·8 to 8·8) for venous thromboembolism and 1·3 (0·4 to 4·2) for arterial thrombosis.Number needed to harm per five days of treatment was 78,549 women for venous thromboembolism. INTERPRETATION: We found use of oral tranexamic acid to be positively associated with venous thromboembolism. However, number needed to harm per five days of treatment was high.

Decline in Danish use of oral tranexamic acid with increasing use of the levonorgestrel-releasing intrauterine system: a nationwide drug utilization study.

OBJECTIVE: To study patterns of oral tranexamic acid use among pre- and perimenopausal Danish women following the introduction of the levonorgestrel-releasing intrauterine system. STUDY DESIGN: We conducted a nationwide descriptive drug utilization study including all 15-54-year-old Danish women during the period 1996-2017. National health registers provided information on use of oral tranexamic acid, the levonorgestrel-releasing intrauterine system, other hormonal contraceptives, and cyclical oral progestogens as well as incidence rates of endometrial ablations and hysterectomies. Linear calendar time trends in usage of these treatments were tested using Poisson and logistic regression models, which adjusted for user age and provided p-values for significance. RESULTS: During the study period, use of the levonorgestrel-releasing intrauterine system increased 14-fold among women aged 15-54 years, from 2.3 in 1996 to 32 users per 1000 person-years in 2017 (p < 0.001). The increase happened consistently throughout the study period for women aged 20-54 years, but not for the youngest age group, 15-19 years, among whom the increase only happened in the end of study period following the introduction of a levonorgestrel-releasing intrauterine system with a smaller frame. Use of oral tranexamic acid declined from 11.3 in 1996 to 6.3 per 1000 person-years in 2017 among women aged 20-54 years (p < 0.001) but increased from 1.4 to 1.9 users per 1000 person-years among those aged 15-19 years (p < 0.001). Use of other hormonal contraceptives remained stable over time at around 300 users per 1000 person-years, while the use of cyclical oral progestogens decreased from 4 to 0.1 users per 1000 person-years (p < 0.001). The incidence of hysterectomies decreased from 3.1 to 2.1 per 1000 person-years (p < 0.001), while the incidence rate of endometrial ablations increased from 0.7 to 1.3 per 1000 person-years (p < 0.001). CONCLUSIONS: In Denmark, increasing use of the levonorgestrel-releasing intrauterine system has been accompanied by a decrease in use of oral tranexamic acid, cyclical oral progestogens, and hysterectomy. IMPLICATION: Increasing use of the levonorgestrel-releasing intrauterine system was accompanied by declining use of other therapies used to decrease menstrual bleeding. The non-contraceptive benefits of hormonal contraception should be considered in cost-effectiveness analyses.

Risk factors for surgical intervention of early medical abortion.

BACKGROUND: By being noninvasive, medical termination of pregnancy has increased worldwide access to abortion and improved safety of unsafe abortion. However, secondary surgical intervention is the most frequent complication to medical abortion. OBJECTIVE: We aimed to identify and quantify risk factors for surgical intervention in women undergoing medically induced termination of pregnancy before 9 completed weeks of gestation. STUDY DESIGN: We conducted a nationwide cohort study, including all pregnancies terminated before 63 gestational days in women aged 15-49 years during the period 2005-2015. Induction regimen was 200 mg mifepristone followed 24-48 hours later by 0.8 mg vaginal misoprostol. All included pregnancies were followed up for 8 weeks from mifepristone administration. Data were retrieved from national health registers. Multiple logistic regression provided adjusted odds ratios of surgical intervention with 95% confidence intervals. The discriminative ability of the risk factors in identifying surgical intervention was assessed by cross-validated area under the receiver operating characteristic curve. RESULTS: Of 86,437 early medical abortions, 5320 (6.2%) underwent a surgical intervention within 8 weeks after induction. The proportion of surgical interventions increased from 3.5% in the 5th to 6th gestational week to 10.3% in week 9, odds ratio, 3.2 (95% confidence interval, 2.9-3.6). Compared with women aged 15-19 years, the risk of surgical intervention increased with increasing maternal age until the age of 30-34 years, odds ratio, 1.7 (95% confidence interval, 1.5-1.9), where after the risk decreased to an odds ratio for age group 40-49 of 1.2 (95% confidence interval, 1.0-1.4). Compared with nulliparous women, a history of only vaginal deliveries with spontaneous delivery of placenta implied an odds ratio of 1.1 (95% confidence interval, 1.0-1.2), women with a history of at least 1 cesarean delivery, an odds ratio of 1.5 (95% confidence interval, 1.3-1.6), and women having experienced a manual removal of placenta after a vaginal birth, an odds ratio of 2.0 (95% confidence interval, 1.7-2.4). Previous medically induced abortion decreased the risk of surgical intervention, odds ratio 0.84 (95% confidence interval, 0.78-0.91), whereas previous early (before 56 days of gestation) surgically induced abortion implied a 53% (95% confidence interval, 1.4-1.7) increased risk of surgical intervention. Previous surgical abortion after 55 days of gestation increased the risk by 17% (95% confidence interval, 1.1-1.3). The area under the receiver operating characteristic curve of the model including all quantified risk factors was 63% (95% confidence interval, 62-64%). CONCLUSION: Gestational age, maternal age, previous deliveries, and history of medically and surgically induced abortions all had a significant influence on the risk of surgical intervention of early medical abortion. However, inclusion of all quantified risk factors still left most interventions unpredictable.

Use of vaginal estrogen in Danish women: a nationwide cross-sectional study.

INTRODUCTION: We know little about the use of vaginal estrogen in perimenopausal and postmenopausal women. We aimed to assess the prevalence of vaginal estrogen use in Denmark. MATERIAL AND METHODS: The study was designed as a nationwide cross-sectional study of all Danish women aged 40-79 years, living in Denmark during the period 2007-2013. The Danish Prescription Register delivered data permitting us to assess the prevalence, age and regional geographical belonging of women purchasing prescribed vaginal estradiol. The number of women using over-the-counter vaginal estriol products was estimated from sale statistics from the same register. RESULTS: In 2013, 10.2% of all Danish women between 40 and 79 years of age used vaginal estradiol. The prevalence of women using this type of vaginal estrogen increased from 8.5% in year 2007 to 10.2% in 2013. The use peaked at 16.5% in women aged 60-74 years. The vaginal tablet was purchased more than the vaginal ring. We found no relevant difference in use between the five regions of Denmark. Taking the sale of vaginal estriol into account, the prevalence of vaginal estrogen use in 2013 could be estimated to a total of 12.1%. CONCLUSIONS: Comparing our result to the prevalence of urogenital atrophy-related symptoms reported in the literature, our study suggests an under-diagnosis and under-treatment of this condition. Teaching women and primary-care physicians about symptomatic urogenital atrophy and its treatment options may increase the quality of life for many women.

Pregnancy following breast cancer using assisted reproduction and its effect on long-term outcome.

INTRODUCTION AND AIMS: We have previously shown that pregnancy is safe following breast cancer, even in endocrine sensitive disease. Yet infertility remains common following systemic treatment. To date, no study has evaluated the safety of assisted reproductive technology (ART) after breast cancer treatment. In this study, we evaluated the impact of ART on pregnancy and long-term outcomes of young breast cancer survivors. METHODS: This is a multi-centre retrospective study in which women who were diagnosed with breast cancer between 2000 and 2009, and had a pregnancy following breast cancer diagnosis were eligible. Patients were divided into two groups according to whether ART following primary systemic therapy was performed to achieve pregnancy. We evaluated the association between ART use and clinic-pathological characteristics, pregnancy outcome and long-term breast cancer outcome. RESULTS: A total of 198 patients were evaluated; of whom 25 underwent ART. No significant differences in tumour characteristics were observed between both groups, except for histological grade 3 tumours, which were fewer in the ART group (36% versus 59%, p=0.033). Around 90% of patients received primary adjuvant chemotherapy and more than 50% had an endocrine sensitive disease. Patients in the ART group were older at diagnosis (31.4 versus 33.7 years, p=0.009), at conception (38 versus 35 years, p<0.001), and experienced more miscarriages (23.5 versus 12.6%, p=0.082). Full term pregnancies were achieved in 77% and 76% of the spontaneous and ART groups, respectively. Mean follow-up between conception and last follow-up was 63 and 50 months in the spontaneous and ART groups, respectively with no difference in breast cancer outcome observed between the two groups (p=0.54). CONCLUSION: Pregnancy using ART in women with history of breast cancer is feasible and does not seem to be detrimental to cancer outcome. Larger studies are needed to further confirm this observation.

Success and spontaneous pregnancy rates following systemic methotrexate versus laparoscopic surgery for tubal pregnancies: a randomized trial.

OBJECTIVE: To determine which treatment should be offered to women with a non-ruptured tubal pregnancy: a single dose of methotrexate (MTX) or laparoscopic surgery. DESIGN: Prospective, randomized, open multicenter study. SETTING: Seven Danish departments of obstetrics and gynecology. SAMPLE: A total of 106 women diagnosed with ectopic pregnancy (EP). METHODS: Between March 1997 and September 2000, 1,265 women were diagnosed with EP, 395 (31%) were eligible, 109 (9%) were randomized of whom 106 had an EP. The study was originally powered to a sample size of 422 patients. The women were randomized to either medical (MTX; 53) or surgical (laparoscopic salpingotomy; 53) treatment. Follow-up by questionnaire and through national patient databases for a maximum of 10 years. MAIN OUTCOME MEASURES: Uneventful decline of plasma-human chorionic gonadotropin to less than 5 IU/L, rates of spontaneous, subsequent intrauterine, and recurrent ectopic pregnancies. RESULTS: The success rates were 74% following MTX treatment and 87% after surgery (n.s.); the subsequent spontaneous intrauterine pregnancy rate was 73% after MTX and 62% after surgery; and the EP rate was 9.6% after MTX and 17.3% following surgery (n.s.). CONCLUSIONS: In women with an EP, who are hemodynamically stable and wishing to preserve their fertility, medical treatment with single dose MTX tends to be equal to treatment with laparoscopic surgery regarding success rate, complications, and subsequent fertility. Although the two treatment modalities seemed to be similar in outcome, it is crucial that the diagnosis is based on a high-quality ultrasonographic evaluation, as two patients had intrauterine pregnancies despite fulfilling the diagnostic algorithm for EP.