School performance and educational achievement in children exposed to maternal cancer in utero.

BACKGROUND: In utero exposure to maternal cancer and cancer treatment might influence the child's cognitive development. This study investigated if exposure to maternal cancer during fetal life impacted school performance and educational achievement as adults. METHODS: This nationwide retrospective cohort study identified all live-born children in Denmark between January 1978 and December 2013. Exposure was defined as maternal cancer diagnosis during pregnancy. Four partly overlapping birth cohorts were constructed depending on the outcome of interest: (1) receiving special educational support for birth years 2001-2013; (2) grade point average (GPA) at the final exams after 10th grade for 1986-2003; (3) educational achievement at 20 years for 1978-1998; and (4) education at 30 years for 1978-1988. Logistic and linear models were adjusted for birth year, maternal age, maternal education and maternal death. RESULTS: The estimated probability of receiving special educational support was similar in the exposed group and the reference (adjusted OR 0.96; 95% CI 0.46 to 1.77, non-significant). The GPA did not statistically differ (0.13 grade points; 95% CI -0.18 to 0.45, non-significant). The achieved educational levels were similar for the exposed group and the reference at 20 years, with an adjusted OR of 1.07 (95% CI 0.82 to 1.40) for low versus medium educational level, and at 30 years with an adjusted OR of 0.73 (95% CI 0.35 to 1.50) for low versus high educational level and of 1.07 (95% CI 0.66 to 1.72) for medium versus high educational level. CONCLUSION: Our findings did not indicate poorer performance in compulsory school nor impairment of adult educational achievement after exposure to maternal cancer in utero.

Gender-affirming treatment and mental health diagnoses in Danish transgender persons: a nationwide register-based cohort study.

IMPORTANCE: Gender affirming treatment aims to improve mental health. OBJECTIVE: To investigate longitudinal mental health outcomes in Danish transgender persons. DESIGN: National register-based cohort study in Danish transgender persons with diagnosis code of "gender identity disorder" during the period 2000-2021. PARTICIPANTS: Five age-matched controls of the same sex at birth and five age-matched controls of the other sex at birth were included for each transgender person. MAIN OUTCOMES: Diagnosis codes of mental and behavioral disorders and/or prescription of psychopharmacological agents until June 2022. RESULTS: The cohort included 3812 transgender persons with median age (interquartile range) 19 (15; 24) years for persons assigned female at birth (AFAB, N = 1993) and 23 (19; 33) years for persons assigned male at birth (AMAB, N = 1819) and 38 120 controls. Follow up duration was up to 10 years with mean (standard deviation) 4.5 (4.3) years. In transgender persons AFAB compared to control women, the odds ratio (OR) (95% confidence interval) for mental and behavioral disorders was 6.7 (5.5; 8.1) before the index date, 9.9 (8.4; 11.7) at 1 year, 5.8 (4.4; 7.7) at 5 years, and 3.4 (2.1; 7.5) at 8 years follow up. In transgender persons AMAB compared to control men, corresponding ORs were 5.0 (4.0; 6.4), 11.3 (9.3; 13.7), 4.8 (3.5; 6.5), and 6.6 (4.2; 10.3) at 8 years follow up (all P < .001). CONCLUSION: The OR for mental health disorders was higher in transgender persons compared to controls and remained elevated throughout follow up, especially in transgender persons AMAB.

Endometriosis is associated with pregnancy loss: a nationwide historical cohort study.

OBJECTIVE: To study whether endometriosis is associated with pregnancy loss and recurrent pregnancy loss (RPL). DESIGN: Nationwide historical cohort study with a nested case-control analysis. SETTING: National health registers. PATIENT(S): A total of 29,563 women born between 1957 and 1997 were identified in the national health registers, diagnosed with endometriosis between 1977 and 2017, and age-matched 1:10 with 295,630 women without endometriosis. The number of pregnancy losses was assessed, and data were analyzed with conditional logistic regression. INTERVENTION(S): Endometriosis (International Classification of Diseases, 8th Revision, 62530-62539, and International Classification of Diseases, 10th Revision, DN80.0-9). MAIN OUTCOME MEASURE(S): The primary outcomes of interest were the numbers of pregnancy losses categorized as 0, 1, 2, and ≥ 3 losses, unadjusted and adjusted for gravidity, and RPL. The secondary outcome measures were the predefined types of pregnancy losses. Pregnancy loss was defined as the spontaneous demise of a pregnancy until 22 weeks of gestation. Primary RPL was defined as 3 or more consecutive pregnancy losses with no prior live birth or stillbirth, and secondary RPL was defined as 1 or more births followed by 3 or more consecutive losses. RESULT(S): A total of 18.9%, 3.9%, and 2.1% of ever-pregnant women with endometriosis had 1, 2, and ≥ 3 pregnancy losses compared with 17.3%, 3.5%, and 1.5% of the women without endometriosis, corresponding to the odds ratios of 1.13 (95% confidence interval, 1.09-1.17), 1.18 (1.10-1.26), and 1.44 (1.31-1.59), respectively. When adjusted also for gravidity, the corresponding results were 1.37 (95% confidence interval, 1.32-1.42), 1.75 (1.62-1.89), and 2.57 (2.31-2.85), respectively. The following predefined subgroups of RPL were positively associated with endometriosis: primary; secondary; secondary after giving birth to a boy; after a complicated delivery; and ≥ 3 pregnancy losses before the age of 30 years. Six endometriosis subgroup analyses found an association between endometriosis and pregnancy loss. These analyses were women diagnosed in the 4 decades between 1977 and 2017, women with adenomyosis, and women with adenomyosis only. CONCLUSION(S): This nationwide cohort study found endometriosis to be associated with pregnancy loss and RPL, and the association strengthened with an increasing number of losses.

Does fetal sex influence the risk of venous thrombosis in pregnancy? A cohort study.

BACKGROUND: Venous thromboembolism is a prominent cause of maternal death. OBJECTIVE: As inflammation is a well-known risk factor for venous thromboembolism and several studies have found a higher grade of inflammation in pregnancies bearing a male compared with female fetuses, we investigated the risk of pregnancy-related venous thromboembolism associated with sex of the fetus. METHODS: This cohort study linked data from national registries and compared event rates and hazard ratios of venous thrombosis for pregnancies bearing a male fetus with those bearing a female fetus during pregnancy and in the first 3 months postpartum. National data from 1995 to 2017 were used. All Danish women aged 15 to 49 years with a live or stillbirth were eligible for inclusion; 1 370 583 pregnancies were included. Women with venous thrombosis, ischemic heart disease, cerebrovascular disease, thrombophilia, or cancer before conception were excluded. RESULTS: The event rate for a venous thrombosis was 8.0 per 10.000 pregnancy years with a male fetus compared with 6.8 for a female fetus. The adjusted hazard ratio for venous thrombosis during pregnancies bearing a male was 1.2 (95% CI, 1.1-1.4), whereas in the postpartum period, it was 0.9 (95% CI, 0.7-1.0). The risk was elevated until week 30. CONCLUSION: These findings indicate a slightly greater risk of venous thrombosis during pregnancies bearing a male fetus than during pregnancies bearing a female fetus. There was no increased risk associated with fetal male sex in the postpartum period.

Long-Term Morbidity and Mortality in Children After In Utero Exposure to Maternal Cancer.

PURPOSE: In utero exposure to maternal cancer and cancer treatment might influence the child's short- and long-term health and development. The objective of the study was to investigate short- and long-term somatic and psychiatric outcomes in children exposed to maternal cancer in utero. METHODS: This nationwide cohort study identified all liveborn children in Denmark between January 1978 and December 2018. Exposure was defined as maternal cancer diagnosis during pregnancy, and in a subgroup analysis, exposure to chemotherapy in utero. The main outcomes of interest were overall mortality, somatic diagnoses, and psychiatric diagnoses identified in the National Health Registers. Follow-up started at birth and ended at an event, death, emigration, or end of 2018. Hazard ratios of end points adjusted for potential confounders were estimated using Cox regression analysis. RESULTS: Of 2,526,163 included liveborn children, 690 (0.03%) were exposed to maternal cancer in utero. Compared with unexposed fetuses, children exposed in utero had no higher overall mortality, adjusted hazard ratio 0.8 (95% CI, 0.4 to 1.5), nor increased risk of congenital malformations, overall somatic or psychiatric disease. During the period 2002-2018, of 378 (0.03%) children exposed to cancer in utero, 42 (12.5%) were exposed to chemotherapy. Among these 42 children, in utero exposure to chemotherapy was not associated with selected somatic diseases nor to congenital malformations when compared with in utero exposure to maternal cancer without chemotherapy. CONCLUSION: Overall, findings did not indicate excess risk of mortality or severe morbidity among children exposed to cancer in utero. Fetal exposure to chemotherapy was not associated with adverse health outcomes in childhood.

Gender affirming hormonal treatment in Danish transgender persons: A nationwide register-based study.

BACKGROUND: Gender affirming hormonal treatment (GAHT) is a cornerstone in transgender care. National data are sparse regarding use of hormonal treatment by transgender persons. AIM: To assess use of GAHT in transgender persons. DESIGN: National register-based cohort study in Danish transgender persons followed from 2000 until 2018. The main outcome measure was prescription and purchase of GAHT. Persons with ICD-10 diagnosis code of "gender identity disorder" (CGI-cohort) and persons with legal sex change but without diagnosis (CPR-cohort) were included. In the CGI-cohort, transgender women were defined by prescription of estrogen and/or cyproterone acetate and/or testosterone-5-alpha reductase inhibitors, and transgender men were defined by prescription of testosterone after study inclusion. Discontinuation of GAHT was defined as no purchase of GAHT ≥13 months or shift from feminizing to masculinizing hormone treatment, or vice versa. RESULTS: The cohort included 2789 transgender persons (n = 1717, CGI-cohort and n = 1072, CPR-cohort). The median age (interquartile range) at study inclusion was 26.1 (17.7) years for persons assigned male at birth (n = 1447) and 22.5 (10.5) years for persons assigned female at birth (n = 1342). In the CGI-cohort, the event rate for GAHT in transgender women increased from 4.0 (95% confidence interval [CI]: [3.1; 5.2]) events per 100 person in year 2000-2005 to 20.6 (17.8; 23.7) between 2014 and 2018. In transgender men, the event rate of GAHT increased from 4.2 (2.8; 6.2) to 18.8 (16.4; 21.6). The rate of discontinuation of GAHT was 0.06 (95% CI 0.049; 0.071) per person year. CONCLUSIONS: The event rate of GAHT increased during 2000-2018. Our data suggested high adherence to GAHT.

Environmental factors in declining human fertility.

A severe decline in child births has occurred over the past half century, which will lead to considerable population declines, particularly in industrialized regions. A crucial question is whether this decline can be explained by economic and behavioural factors alone, as suggested by demographic reports, or to what degree biological factors are also involved. Here, we discuss data suggesting that human reproductive health is deteriorating in industrialized regions. Widespread infertility and the need for assisted reproduction due to poor semen quality and/or oocyte failure are now major health issues. Other indicators of declining reproductive health include a worldwide increasing incidence in testicular cancer among young men and alterations in twinning frequency. There is also evidence of a parallel decline in rates of legal abortions, revealing a deterioration in total conception rates. Subtle alterations in fertility rates were already visible around 1900, and most industrialized regions now have rates below levels required to sustain their populations. We hypothesize that these reproductive health problems are partially linked to increasing human exposures to chemicals originating directly or indirectly from fossil fuels. If the current infertility epidemic is indeed linked to such exposures, decisive regulatory action underpinned by unconventional, interdisciplinary research collaborations will be needed to reverse the trends.

Cancer in pregnancy and the risk of adverse pregnancy and neonatal outcomes: A nationwide cohort study.

OBJECTIVES: To investigate the obstetrical management of cancer in pregnancy and to determine adverse pregnancy and neonatal outcomes. DESIGN: A nationwide cohort study. SETTING AND POPULATION: We included all pregnancies (n = 4 071 848) in Denmark from 1 January 1973 to 31 December 2018. METHODS: Exposure was defined as pregnancies exposed to maternal cancer (n = 1068). The control group comprised pregnancies without cancer. The groups were compared using logistic regression analysis and adjusted for potential confounders. MAIN OUTCOME MEASURES: The outcomes were induced abortion, preterm birth and adverse neonatal outcomes. RESULTS: More women with cancer in pregnancy, as compared with the control group, experienced induced abortion (24.8% vs. 20.0%); first-trimester induced abortion adjusted odds ratio (aOR) 3.5 (95% confidence interval [CI] 2.7-4.5), second-trimester induced abortion; aOR 8.8 (95% CI 6.3-12.3), planned preterm birth (11.8% vs. 1.3%); aOR 10.8 (95% CI 8.0-14.6) and planned preterm birth at <32 gestational weeks; aOR 16.3 (95% CI 8.3-31.7). Neonates born to mothers with cancer in pregnancy had a higher risk of respiratory distress syndrome; aOR 3.5 (95% CI 2.8-4.4), low birthweight; aOR 3.8 (95% CI 3.1-4.8), admission to neonatal intensive care unit for >7 days; aOR 5.1 (95% CI 3.9-6.6), neonatal infection; aOR 1.8 (95% CI1.1-3.1) and neonatal mortality; aOR 4.7 (95% CI 2.7-8.2), but not of SGA; aOR 1.0 (95% CI 0.6-1.5) and malformations; 1.2 (95% CI 0.9-1.7). CONCLUSION: Cancer in pregnancy increases the risk of induced abortion and planned premature birth. Neonates born to mothers with cancer in pregnancy had an increased risk of neonatal morbidity and mortality, presumably due to prematurity. TWEETABLE ABSTRACT: Cancer in pregnancy is associated with an increased risk of premature birth leading to adverse neonatal outcomes.

The impact of early pregnancy complications on completed family size-A nationwide, registry-based cohort study with 40 years of data.

INTRODUCTION: The impact of early pregnancy complications on completed family size is unknown. Here, we hypothesize that early pregnancy complications and adverse outcomes may influence family size. MATERIAL AND METHODS: In this nationwide, registry-based study we included all 458 475 women born 1957-1972 who lived in Denmark from age 20-45 years with at least one registered pregnancy. The main outcome of the study was number of children per woman by age 45, estimated using a Generalized Linear Mixed Model. Exposures were: (a) total number of pregnancy losses experienced (0, 1, 2, ≥3); (b) highest number of consecutive pregnancy losses (0, 1, 2, ≥3); (c) sex of firstborn child; (d) outcome of first pregnancy (live birth, stillbirth, pregnancy loss, ectopic pregnancy, or molar pregnancy). RESULTS: Number of live births was negatively influenced by maternal age and adverse first pregnancy outcomes, especially ectopic pregnancies. A 30-year-old woman with a first ectopic pregnancy was expected to have 1.16 children (95% CI 1.11-1.22) compared with 1.95 children (95% CI 1.86-2.03) with a first live birth. Three or more consecutive losses also decreased number of live births significantly: 1.57 (95% CI 1.50-1.65) compared with 1.92 (95% CI 1.84-2.0) with only live births. The total number of pregnancy losses had no effect before the age of 35 years. Sex of firstborn had no effect. CONCLUSIONS: Previous pregnancy history has a significant effect on number of children per woman, which is important at both individual and societal levels. Pathophysiological research of adverse pregnancy outcomes should be an urgent priority as the causes remain poorly understood.

Contemporary hormonal contraception and cervical cancer in women of reproductive age.

To determine cervical cancer risk associated with contemporary hormonal contraceptives, we conducted a cohort study of women aged 15 to 49 living in Denmark from 1995 to 2014, using routinely collected information about redeemed prescriptions, incident cancer and potential confounders. Poisson regression calculated adjusted cervical cancer risks among different contraceptive user groups by duration of use, time since last use, hormonal content and cancer histology. During >20 million person-years, 3643 incident cervical cancers occurred. Ever users of any hormonal contraceptives compared to never users had a relative risk (RR) of 1.19 (95% confidence interval [CI] 1.10-1.29). Increased risks were seen in current or recent users of any hormonal: RR 1.30 (95% CI 1.20-1.42) and combined: RR 1.40 (95% CI 1.28-1.53), but not progestin-only contraception: RR 0.91 (95% CI 0.78-1.07). Current or recent users of any hormonal contraception had an increased risk of both adenocarcinoma (RR 1.29, 95% CI 1.05-1.60) and squamous cancer (RR 1.31, 95% CI 1.19-1.44). The risk pattern among any hormonal and combined contraceptive users generally increased with longer duration of use and declined after stopping, possibly taking longer to disappear among prolonged users. Combined products containing different progestins had similar risks. Approximately one extra cervical cancer occurred for every 14 700 women using combined contraceptives for 1 year. Most women in our study were not vaccinated against human papillomavirus (HPV) infections. Our findings reinforce the urgent need for global interventions such as systematic screening, treatment of cervical intraepithelial neoplasia and HPV vaccination programmes to prevent cervical cancer, especially among users of combined contraceptives.

Chance of live birth: a nationwide, registry-based cohort study.

STUDY QUESTION: Does the sequence of prior pregnancy events (pregnancy losses, live births, ectopic pregnancies, molar pregnancy and still birth), obstetric complications and maternal age affect chance of live birth in the next pregnancy and are prior events predictive for the outcome? SUMMARY ANSWER: The sequence of pregnancy outcomes is significantly associated with chance of live birth; however, pregnancy history and age are insufficient to predict the outcome of an individual woman's next pregnancy. WHAT IS KNOWN ALREADY: Adverse pregnancy outcomes decrease the chance of live birth in the next pregnancy, whereas the impact of prior live births is less clear. STUDY DESIGN, SIZE, DURATION: Nationwide, registry-based cohort study of 1 285 230 women with a total of 2 722 441 pregnancies from 1977 to 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: All women living in Denmark in the study period with at least one pregnancy in either the Danish Medical Birth Registry or the Danish National Patient Registry. Data were analysed using logistic regression with a robust covariance model to account for women with more than one pregnancy. Model discrimination and calibration were ascertained using 20% of the women in the cohort randomly selected as an internal validation set. MAIN RESULTS AND THE ROLE OF CHANCE: Obstetric complications, still birth, ectopic pregnancies and pregnancy losses had a negative effect on the chance of live birth in the next pregnancy. Consecutive, identical pregnancy outcomes (pregnancy losses, live births or ectopic pregnancies) immediately preceding the next pregnancy had a larger impact than the total number of any outcome. Model discrimination was modest (C-index = 0.60, positive predictive value = 0.45), but the models were well calibrated. LIMITATIONS, REASONS FOR CAUTION: While prior pregnancy outcomes and their sequence significantly influenced the chance of live birth, the discriminative abilities of the predictive models demonstrate clearly that pregnancy history and maternal age are insufficient to reliably predict the outcome of a given pregnancy. WIDER IMPLICATIONS OF THE FINDINGS: Prior pregnancy history has a significant impact on the chance of live birth in the next pregnancy. However, the results emphasize that only taking age and number of losses into account does not predict if a pregnancy will end as a live birth or not. A better understanding of biological determinants for pregnancy outcomes is urgently needed. STUDY FUNDING/COMPETING INTEREST(S): The work was supported by the Novo Nordisk Foundation, Ole Kirk Foundation and Rigshospitalet's Research Foundation. The authors have no financial relationships that could appear to have influenced the work. TRIAL REGISTRATION NUMBER: N/A.

Risk of surgical evacuation and risk of major surgery following second-trimester medical abortion in Denmark: A nationwide cohort study.

OBJECTIVE: The primary objectives were to (1) identify risk factors for surgical evacuation following medical termination of second-trimester pregnancies in Denmark and (2) assesses if these risk factors were able to explain the a priori observed variation in risk of surgical evacuation among Danish hospitals and the a priori observed decline in risk throughout time. The secondary objective was to estimate the risk of major surgery following second-trimester medical abortion. STUDY DESIGN: We conducted a nationwide cohort study including all pregnancies terminated with mifepristone/misoprostol in second trimester in women aged 15-49 years through the period 2006-2017 in Denmark. All included pregnancies were followed for eight weeks from induction. Data were retrieved from national health registers. Multiple logistic regression provided adjusted odds ratios (ORs) of surgical evacuation with 95% confidence intervals (CI). Risk of major surgery was assessed and reported descriptively. RESULTS: Of 5702 abortions, 2934 (52%) underwent surgical evacuation. The proportion of surgical evacuations decreased linearly from 72% in 13th gestational week to 17% in week 22 (p < 0.001). Compared to 25-29-year-olds, a reduced risk of surgical evacuation was observed in the youngest age group, 15-19 years (OR 0.77; 95% CI 0.61-0.99), while the risk among women aged 30-49 years did not differ significantly from the reference group. Compared to nulliparas, women with a history of only vaginal deliveries with spontaneous delivery of placenta had a decreased risk of surgical evacuation, OR 0.79 (95% CI 0.68-0.92). The OR of surgical evacuation varied from 0.05 (95% CI 0.02-0.15) to 2.38 (95% CI 1.71-3.31) among the hospitals (Copenhagen University Hospital as the reference) and declined significantly throughout the study period (OR for one-year increase in calendar time 0.82; 95% CI 0.81-0.84). Of the 5702 abortions, ten (0.2%) underwent major surgery following medical induction, including one laparoscopy, three hysterotomies, five laparotomies, and one hysterectomy. CONCLUSION: Risk of surgical evacuation of second-trimester medical abortions decreased with increasing gestational age and was reduced in women aged 15-19 years as well as in women with a history of only vaginal deliveries with spontaneous delivery of the placenta. However, these risk factors could not explain the significant variation in risk of surgical evacuation among hospitals and the decline in risk by time, suggestive of an unwarranted variation in risk of surgical evacuation following second-trimester medical termination of pregnancy in Denmark. Major surgery following medical induction was uncommon. IMPLICATION: Risk of surgical evacuation following medical termination of second-trimester pregnancy declined by calendar time and varied among Danish hospitals. Risk factors for surgical evacuation could not explain the difference by time and site of induction, suggestive of an unwarranted variation in the risk of surgical evacuation following second-trimester medical abortions in Denmark.

Contemporary hormonal contraception and risk of endometrial cancer in women younger than age 50: A retrospective cohort study of Danish women.

OBJECTIVE: To examine the association between contemporary hormonal contraceptives and endometrial cancer risk in women younger than age 50. STUDY DESIGN: Cohort study of women living in Denmark aged 15-49 years through 1995-2014. National registries provided information about hormonal contraception use, incident endometrial cancer and confounders. Ever, current or recent, and former users of any hormonal contraception were compared with non-users, using Poisson regression to calculate incidence rate ratios (RR) with 95% confidence intervals. Duration, time since last use, tumor-specific and product-specific analyses, and population prevented fraction, were calculated. RESULTS: During 21.1 million person-years, 549 incident endometrial cancers occurred, with ever users of any hormonal contraception having a reduced premenopausal endometrial cancer risk compared with non-users; RR 0.60 (95% Confidence Interval 0.49 to 0.73). A lower risk of endometrial cancer was seen in all current or recent users of any hormonal contraception; 0.65 (0.52 to 0.83) and combined contraceptives; 0.57 (0.43 to 0.75), but not progestin-only contraceptives; levonorgestrel intrauterine system, LNG-IUS; 0.97 (0.66 to 1.42); other progestin-only contraceptives; 0.61 (0.27 to 1.37). Increased RRs were found for current use of any hormonal, combined contraceptives or LNG-IUS of ≤one year, probably because of protopathic bias. Longer durations of use were associated with significant reductions that became stronger with longer use. Former users of any hormonal contraception continued to benefit from a reduced risk of endometrial cancer >10 years after stopping. There was little evidence of differences in risk reduction by the type of progestin in combined oral contraceptives. Current or recent use of any hormonal contraception was associated with an approximate halving of risk of the most common tumor type I carcinoma, and an increased risk of the rarer sarcoma. Overall the estimated absolute reduced risk of endometrial cancer in ever users of hormonal contraceptives was 1.4 per 100,000 person-years, or approximately one less endometrial cancer for every 71,400 women of reproductive age who used hormonal contraception for one year. Use of hormonal contraception was estimated to prevent 25% of endometrial cancers in this population. CONCLUSIONS: Currently available combined hormonal contraceptives are still associated with enduring protection against endometrial cancer, particularly for type I carcinomas. IMPLICATIONS: We report substantive evidence of the association between different types of contemporary hormonal contraception and endometrial cancer risk in a national cohort of young Danish women. Currently available combined hormonal contraceptives are still associated with enduring protection against endometrial cancer, particularly for type I carcinomas.

Use of antidepressants in women after prophylactic bilateral oophorectomy: A Danish national cohort study.

OBJECTIVE: To investigate the association between prophylactic bilateral oophorectomy and use of antidepressants in women with a family history of cancer. METHODS: Nationwide population-based cohort study using Danish National Registries including women oophorectomized due to a family history of cancer (n = 2,002) and an age matched reference group (n = 18,018). Analyses were stratified by age at time of bilateral oophorectomy and use of hormone replacement therapy (HRT). RESULTS: Women oophorectomized at age ≤ 45 years were more likely to use antidepressants from the first year after bilateral oophorectomy (OR = 1.34; 95 % CI: 1.08-1.65) compared to the reference group. Women oophorectomized at age 46-55 years and at age >55 years had no significantly increased use of antidepressants (OR = 0.90; 95 % CI: 0.68-1.18 and OR = 1.14; 95 % CI: 0.81-1.61). The increased use of antidepressants in women oophorectomized at age ≤ 45 years was limited to women treated with HRT (OR = 1.51; 95 % CI: 1.18-1.94) whereas women oophorectomized at age ≤ 45 years not treated with HRT had no increased use of antidepressants (OR = 1.03; 95 % CI: 0.70-1.51). CONCLUSIONS: Women oophorectomized due to a family history of cancer at age ≤ 45 years were more likely to use antidepressants after bilateral oophorectomy. The increased use of antidepressants was limited to women treated with HRT. The study calls for further large-scale studies to understand how bilateral oophorectomy and concomitant HRT affects risk of depression in women with a family history of cancer.

Pregnancy Loss and Cancer Risk: A Nationwide Observational Study.

BACKGROUND: Cancer is the second leading cause of death worldwide. Few studies have investigated if recurrent pregnancy loss is associated with an increased risk of cancer. We aimed to assess whether pregnancy loss is associated with later cancer development. METHODS: We identified all invasive cancers after age 40, among all Danish women born between January 1957 and December 1972, ensuring a full reproductive history. Cases were matched by birth year 1:10 to cancer-free controls. Women were followed until the end of 2017. The number of pregnancy losses (miscarriages or still births) was correlated to long-term cancer risk using conditional logistic regression, providing odds ratios for specific cancers with different numbers of pregnancy losses, all adjusted for age, education, and other potential confounders. FINDINGS: The study included 28,785 women with cancer (mean age 48.7 [SD 5.0]) and 283,294 matched controls (mean age 48.6 [SD 5.0]). We found no overall association between pregnancy loss and later development of 11 site-specific types of cancer or cancer overall. Taking the sequence of pregnancy losses into account, primary recurrent pregnancy loss (three consecutive pregnancy losses without prior live birth) was associated with later overall cancer by an odds ratio of 1.27 (1.04-1.56). Secondary recurrent pregnancy loss showed no association to cancer. INTERPRETATION: Pregnancy loss was not associated with later cancer development. Women with primary recurrent pregnancy loss had a borderline significant association to later cancer overall, this may be a chance finding. FUNDING: Ole Kirk's Foundation and Copenhagen University Hospital Rigshospitalet's Research Grant.

Correction: Hormonal contraceptive use and risk of pancreatic cancer-A cohort study among premenopausal women.

[This corrects the article DOI: 10.1371/journal.pone.0206358.].

[Phytoestrogens as a dietary supplement].

Phytoestrogens (PE) are widely used as a dietary supplement. PE affect oestrogen receptors. PE have been investigated regarding menopausal hot flushes, bone mineral density and prostate hyperplasia/cancer. It seems consistent, that PE increase bone mineral density, whereas the effect on hot flushes is controversial. Due to the effect on oestrogen receptors, concerns exist on the risk of cancer and venous thromboembolism related to the intake of PE. To date, no studies with PE have been large enough to clarify their safety. Widespread use of PE should therefore be discouraged.

Association between contemporary hormonal contraception and ovarian cancer in women of reproductive age in Denmark: prospective, nationwide cohort study.

OBJECTIVES: To investigate the association between contemporary combined hormonal contraceptives (including progestogen types in combined preparations and all progestogen-only products) and overall and specific types of ovarian cancer. DESIGN: Prospective, nationwide cohort study. SETTING: Denmark, 1995-2014. PARTICIPANTS: All women aged 15-49 years during 1995-2014 were eligible. Women were excluded if they immigrated after 1995, had cancer (except non-melanoma skin cancer), had venous thrombosis, or were treated for infertility before entry (final study population included 1 879 227 women). Women were categorised as never users (no record of being dispensed hormonal contraception), current or recent users (≤1 year after stopping use), or former users (>1 year after stopping use) of different hormonal contraceptives. MAIN OUTCOME MEASURES: Poisson regression was used to calculate relative risk of ovarian cancer among users of any contemporary combined hormonal contraceptives and by progestogen type in combined preparations and all progestogen-only products, including non-oral preparations. Separate analyses examined women followed up to their first contraception type switch and those with full contraceptive histories. Duration, time since last use, and tumour histology were examined and the population prevented fraction were calculated. RESULTS: During 21.4 million person years, 1249 incident ovarian cancers occurred. Among ever users of hormonal contraception, 478 ovarian cancers were recorded over 13 344 531 person years. Never users had 771 ovarian cancers during 8 150 250 person years. Compared with never users, reduced risks of ovarian cancer occurred with current or recent use and former use of any hormonal contraception (relative risk 0.58 (95% confidence interval 0.49 to 0.68) and 0.77 (0.66 to 0.91), respectively). Relative risks among current or recent users decreased with increasing duration (from 0.82 (0.59 to 1.12) with ≤1 year use to 0.26 (0.16 to 0.43) with >10 years' use; P<0.001 for trend). Similar results were achieved among women followed up to their first switch in contraceptive type. Little evidence of major differences in risk estimates by tumour type or progestogen content of combined oral contraceptives was seen. Use of progestogen-only products were not associated with ovarian cancer risk. Among ever users of hormonal contraception, the reduction in the age standardised absolute rate of ovarian cancer was 3.2 per 100 000 person years. Based on the relative risk for the never use versus ever use categories of hormonal contraception (0.66), the population prevented fraction was estimated to be 21%-that is, use of hormonal contraception prevented 21% of ovarian cancers in the study population. CONCLUSIONS: Use of contemporary combined hormonal contraceptives is associated with a reduction in ovarian cancer risk in women of reproductive age-an effect related to duration of use, which diminishes after stopping use. These data suggest no protective effect from progestogen-only products.

Effect of exogenous estrogens and progestogens on the course of migraine during reproductive age: a consensus statement by the European Headache Federation (EHF) and the European Society of Contraception and Reproductive Health (ESCRH).

We systematically reviewed data about the effect of exogenous estrogens and progestogens on the course of migraine during reproductive age. Thereafter a consensus procedure among international experts was undertaken to develop statements to support clinical decision making, in terms of possible effects on migraine course of exogenous estrogens and progestogens and on possible treatment of headache associated with the use or with the withdrawal of hormones. Overall, quality of current evidence is low. Recommendations are provided for all the compounds with available evidence including the conventional 21/7 combined hormonal contraception, the desogestrel only oral pill, combined oral contraceptives with shortened pill-free interval, combined oral contraceptives with estradiol supplementation during the pill-free interval, extended regimen of combined hormonal contraceptive with pill or patch, combined hormonal contraceptive vaginal ring, transdermal estradiol supplementation with gel, transdermal estradiol supplementation with patch, subcutaneous estrogen implant with cyclical oral progestogen. As the quality of available data is poor, further research is needed on this topic to improve the knowledge about the use of estrogens and progestogens in women with migraine. There is a need for better management of headaches related to the use of hormones or their withdrawal.