Deficient H2A.Z deposition is associated with genesis of uterine leiomyoma.

One in four women suffers from uterine leiomyomas (ULs)-benign tumours of the uterine wall, also known as uterine fibroids-at some point in premenopausal life. ULs can cause excessive bleeding, pain and infertility1, and are a common cause of hysterectomy2. They emerge through at least three distinct genetic drivers: mutations in MED12 or FH, or genomic rearrangement of HMGA23. Here we created genome-wide datasets, using DNA, RNA, assay for transposase-accessible chromatin (ATAC), chromatin immunoprecipitation (ChIP) and HiC chromatin immunoprecipitation (HiChIP) sequencing of primary tissues to profoundly understand the genesis of UL. We identified somatic mutations in genes encoding six members of the SRCAP histone-loading complex4, and found that germline mutations in the SRCAP members YEATS4 and ZNHIT1 predispose women to UL. Tumours bearing these mutations showed defective deposition of the histone variant H2A.Z. In ULs, H2A.Z occupancy correlated positively with chromatin accessibility and gene expression, and negatively with DNA methylation, but these correlations were weak in tumours bearing SRCAP complex mutations. In these tumours, open chromatin emerged at transcription start sites where H2A.Z was lost, which was associated with upregulation of genes. Furthermore, YEATS4 defects were associated with abnormal upregulation of bivalent embryonic stem cell genes, as previously shown in mice5. Our work describes a potential mechanism of tumorigenesis-epigenetic instability caused by deficient H2A.Z deposition-and suggests that ULs arise through an aberrant differentiation program driven by deranged chromatin, emanating from a small number of mutually exclusive driver mutations.

Inherited mutations affecting the SRCAP complex are central in moderate-penetrance predisposition to uterine leiomyomas.

Uterine leiomyomas (ULs) are benign smooth muscle tumors that are common in premenopausal women. Somatic alterations in MED12, HMGA2, FH, genes encoding subunits of the SRCAP complex, and genes involved in Cullin 3-RING E3 ligase neddylation are mutually exclusive UL drivers. Established predisposition genes explain only partially the estimated heritability of leiomyomas. Here, we examined loss-of-function variants across 18,899 genes in a cohort of 233,614 White European women, revealing variants in four genes encoding SRCAP complex subunits (YEATS4, ZNHIT1, DMAP1, and ACTL6A) with a significant association to ULs, and YEATS4 and ZNHIT1 strikingly rank first and second, respectively. Positive mutation status was also associated with younger age at diagnosis and hysterectomy. Moderate-penetrance UL risk was largely attributed to rare non-synonymous mutations affecting the SRCAP complex. To examine this disease phenotype more closely, we set out to identify inherited mutations affecting the SRCAP complex in our in-house sample collection of Finnish individuals with ULs (n = 860). We detected one individual with an ACTL6A splice-site mutation, two individuals with a YEATS4 missense mutation, and four individuals with DMAP1 mutations: one splice-site, one nonsense, and two missense variants. These individuals had large and/or multiple ULs, were often diagnosed at an early age, and many had family history of ULs. When a somatic second hit was found, ACTL6A and DMAP1 were silenced in tumors by somatic mutation and YEATS4 by promoter hypermethylation. Decreased H2A.Z staining was observed in the tumors, providing further evidence for the pathogenic nature of the germline mutations. Our results establish inactivation of genes encoding SRCAP complex subunits as a central contributor to moderate-penetrance UL predisposition.

Molecular subclass of uterine fibroids predicts tumor shrinkage in response to ulipristal acetate.

Precision medicine carries great potential for management of all tumor types. The aim of this retrospective study was to investigate if the two most common genetically distinct uterine fibroid subclasses, driven by aberrations in MED12 and HMGA2 genes, respectively, influence response to treatment with the progesterone receptor modulator ulipristal acetate. Changes in diameter and mutation status were derived for 101 uterine fibroids surgically removed after ulipristal acetate treatment. A significant difference in treatment response between the two major subclasses was detected. MED12 mutant fibroids had 4.4 times higher odds of shrinking in response to ulipristal acetate treatment as compared to HMGA2 driven fibroids (95% confidence interval 1.37-13.9; P = 0.013), and in a multivariate analysis molecular subclassification was an independent predictive factor. Compatible with this finding, gene expression and DNA methylation analyses revealed subclass specific differences in progesterone receptor signaling. The work provides a proof-of-principle that uterine fibroid treatment response is influenced by molecular subclass and that the genetic subclasses should be taken into account when evaluating current and future uterine fibroid therapies.

Psychiatric disorders and mortality due to external causes following diagnosis of endometriosis at a young age: a longitudinal register-based cohort study in Finland.

BACKGROUND: Endometriosis diagnosed in adults is associated with increased risk of various psychiatric disorders. However, little is known concerning psychiatric comorbidity and mortality due to external causes associated with endometriosis diagnosed at a young age. OBJECTIVE: This longitudinal cohort study aimed to investigate the link between surgical diagnosis of endometriosis at a young age and subsequent psychiatric disorders and mortality due to external causes. In addition, we compared the occurrence of the most common psychiatric disorders between different sites of surgically confirmed endometriosis (ovarian vs other) because of possible differences in pain manifestations. STUDY DESIGN: We conducted a retrospective register-based cohort study. Altogether 4532 women with surgically confirmed diagnosis of endometriosis before the age of 25 years from 1987 to 2012 were identified from the Finnish Hospital Discharge Register. They were matched with women without surgically diagnosed endometriosis for age and municipality on the index day (n=9014). Women were followed up from the index day until the end of 2019 for the outcomes of interest, which included 9 groups of psychiatric disorders (inpatient episodes since 1987, outpatient episodes since 1998) and death due to external causes, including deaths due to accidents, suicides, and violence (Finnish Register of Causes of Death). Cox proportional hazard models were applied to assess the crude and parity-adjusted hazard ratios and 95% confidence intervals. RESULTS: The cohort's median age was 22.9 years (interquartile range, 21.3-24.1) at the beginning and 42.5 years (36.7-48.3) after a median follow-up time of 20.0 years (14.5-25.7). We observed a higher hazard of depressive, anxiety, and bipolar disorders in women with endometriosis compared with the reference cohort, with depressive and anxiety disorders being the two most common psychiatric disorders. These differences appeared early and remained the same during the entire follow-up, irrespective of whether assessed from the data on inpatient episodes only or the data on both in- and outpatient episodes. The corresponding adjusted hazard ratios were 2.57 (95% confidence interval, 2.11-3.14) and 1.87 (1.65-2.12) for depressive disorders, 2.40 (1.81-3.17) and 2.09 (1.84-2.37) for anxiety disorders, and 1.71 (1.30-2.26) and 1.66 (1.28-2.15) for bipolar disorders, respectively. A higher hazard was observed for nonorganic sleeping disorders for the first 10 years only (3.83; 2.01-7.30) when assessed using the data on both in- and outpatient episodes. When based on inpatient records, a higher hazard for alcohol/drug dependence after 15 years of follow-up (2.07; 1.21-3.54) was observed. The difference in hazard for personality disorders tended to increase during follow-up (<10 years, 2.12 [1.28-3.52]; ≥10 years, 3.08 [1.44-6.57]). Depressive and anxiety disorders occurred more frequently in women with types of endometriosis other than ovarian endometriosis. No difference in deaths due to external causes was observed between the endometriosis and reference cohorts. CONCLUSION: Surgical diagnosis of endometriosis at a young age was associated with increased incidence of several psychiatric disorders. Moreover, within the endometriosis population, psychiatric comorbidity was more common in women with types of endometriosis other than ovarian endometriosis. We speculate that chronic pain is essential in the development of these psychiatric disorders, and that early and effective pain management is important in reducing the risk of psychiatric morbidity in young women. More research concerning the associations and management of endometriosis and associated psychiatric disorders is warranted.

Pregnancy outcomes following routine early provision of intrauterine device after first-trimester induced abortion-A secondary analysis of a randomized controlled trial with a 5-year follow up.

INTRODUCTION: Women undergoing an induced abortion are highly fertile and at risk of subsequent unplanned pregnancy. We recently completed a randomized clinical trial showing that routine provision of intrauterine device (IUD) at the time of abortion significantly reduced the risk of subsequent abortion during a 5-year follow up. As the use of highly effective contraception may affect all subsequent pregnancies, we analyzed the rate and distribution of all subsequent pregnancies (deliveries, miscarriages, and abortions), and the risk factors for these various pregnancy outcomes in the above-mentioned randomized clinical trial. MATERIAL AND METHODS: We enrolled adult women requesting first-trimester induced abortion and candidates for IUD for post-abortion contraception. Women (n = 751) were randomized to receive an IUD (either levonorgestrel-releasing IUD or copper IUD) by the clinic responsible for abortion care vs. routine care of IUD provision in primary health care with oral contraceptives for interval contraception. In the present secondary analysis, we identified all deliveries, miscarriages, and abortions in the intervention (n = 375) and control (n = 373) cohorts during the 5-year follow up using the Finnish national registries. The trial is registered at Clinical Trials (NTC01223521). RESULTS: The overall delivery, miscarriage, and abortion rates were 42.0, 12.0 and 32.1/1000 years of follow up (yFU). Any new pregnancy occurred in 98 women in the intervention and in 129 women in the control cohort (hazard ratio 0.73, 95% confidence interval 0.56-0.95, p = 0.023). The effect of routine IUD provision in reducing pregnancies was limited to the first 2 yFU. The number of subsequent induced abortions and of women undergoing it were significantly reduced, and time to abortion was prolonged by the intervention. However, the overall number, the number of women with subsequent delivery or miscarriage, and the times to these events were not significantly affected. History of previous pregnancy (delivery or abortion) and smoking were risk factors for subsequent induced abortion, but not for delivery or miscarriage. CONCLUSIONS: Routine provision of IUD as part of abortion care did not reduce the rates of delivery or miscarriage during the 5-year follow up. The rates of all pregnancies and the need of subsequent induced abortion were reduced by IUD provision during the first 2 yFU.

Fear of childbirth after induced abortion in primiparous women: Population-based register study from Finland.

INTRODUCTION: Fear of childbirth (FOC) is a common obstetrical challenge that complicates about every 10th pregnancy. Background factors of FOC are diverse. We evaluated the association of induced abortion (IA) and FOC in subsequent pregnancy. MATERIAL AND METHODS: Population-based register study based on three Finnish national registers: the Register of Induced Abortions, the Medical Birth Register and the Hospital Discharge Register. The study cases were primigravid women undergoing an IA in 2000-2015 and subsequent pregnancy ending in live singleton birth up to 2017. Each case had three controls, matched by age and residential area, whose first pregnancy ended in a live birth. The main outcome was the incidence of FOC in the subsequent pregnancy. In a secondary analysis, we assessed other risk factors for FOC. RESULTS: The study cohort consisted of 21 455 women and 63 425 controls. Altogether, 4.2% of women had a diagnosis of FOC. The incidence was higher in women with a history of IA than in controls (5.6% vs 3.7%, P < 0.001). A history of IA was associated with higher odds for FOC: adjusted odds ratio [aOR] 1.20 with 95% confidence interval (CI) 1.11-1.30. In addition, a history of psychiatric diagnosis (aOR 3.48, 95% CI 3.15-3.83), high maternal age, 30-39 years old (aOR 1.55, 95% CI 1.43-1.67; P < 0.001) and ≥40 years old (aOR 3.00, 95% CI 2.37-3.77; P < 0.001) and smoking (aOR 1.20, 95% CI 1.11-1.31; P < 0.001) were associated with increased odds for FOC. Women living in densely populated or rural areas and those with lower socioeconomic class had lower odds for FOC. CONCLUSIONS: A history of IA is associated with increased odds for FOC in subsequent pregnancy. However, the associations of FOC with a history of psychiatric diagnosis and elevated maternal age (especially ≥40 years old) are more pronounced.

Risk Factors for Lichen Sclerosus: A Case-Control Study of 43,000 Finnish Women.

OBJECTIVES: Lichen sclerosus (LS) is an inflammatory skin disease probably arising from an interplay of genetics, local irritation, and autoimmune processes. We identified potential risk factors for the disease using data from nationwide Finnish registries. METHODS: We identified all women diagnosed with LS within specialized health care during 1998-2016 (n = 10,692) and selected 3 age-matched population control women for each case. We calculated odds ratios (ORs) for possible risk factors using conditional logistic regression. RESULTS: Dermatological autoimmune conditions were strongly associated with LS (OR = 15.1, 95% confidence interval [CI] = 13.6-16.7 for morphea; OR = 10.3, 95% CI = 5.02-19.0 for lichen planus; OR = 6.86, 95% CI = 5.65-8.33 for alopecia; OR = 2.20, 95% CI = 1.88-2.56 for vitiligo). A diagnosis of Crohn or celiac disease increased the odds of LS (OR = 1.80, 95% CI = 1.71-1.89; OR = 1.49, 95% CI = 1.28-1.73, respectively) as did urge and stress incontinence (OR = 1.79, 95% CI = 1.71-1.87; OR = 1.28, 95% CI = 1.22-1.35, respectively).The odds of LS were lower in women after a diagnosis of type 1 diabetes (OR = 0.43, 95% CI = 0.41-0.45), coronary artery disease (OR = 0.41, 95% CI = 0.38-0.43), and rheumatoid arthritis (OR = 0.38, 95% CI = 0.36-0.41).Parous women had higher odds of LS (OR = 1.11, 95% CI = 1.04-1.17) than nulliparous ones, but increasing number of births decreased the risk. Lichen sclerosus was not associated with socioeconomic status nor the urbanicity level of the place of residence. CONCLUSIONS: Certain autoimmune diseases and urinary incontinence were associated with LS.

Embryonic mouse medial neocortex as a model system for studying the radial glial scaffold in fetal human neocortex.

Neocortex is the evolutionarily newest region in the brain, and is a structure with diversified size and morphology among mammalian species. Humans have the biggest neocortex compared to the body size, and their neocortex has many foldings, that is, gyri and sulci. Despite the recent methodological advances in in vitro models such as cerebral organoids, mice have been continuously used as a model system for studying human neocortical development because of the accessibility and practicality of in vivo gene manipulation. The commonly studied neocortical region, the lateral neocortex, generally recapitulates the developmental process of the human neocortex, however, there are several important factors missing in the lateral neocortex. First, basal (outer) radial glia (bRG), which are the main cell type providing the radial scaffold to the migrating neurons in the fetal human neocortex, are very few in the mouse lateral neocortex, thus the radial glial scaffold is different from the fetal human neocortex. Second, as a consequence of the difference in the radial glial scaffold, migrating neurons might exhibit different migratory behavior and thus distribution. To overcome those problems, we propose the mouse medial neocortex, where we have earlier revealed an abundance of bRG similar to the fetal human neocortex, as an alternative model system. We found that similar to the fetal human neocortex, the radial glial scaffold, neuronal migration and neuronal distribution are tangentially scattered in the mouse medial neocortex. Taken together, the embryonic mouse medial neocortex could be a suitable and accessible in vivo model system to study human neocortical development and its pathogenesis.

Metabolomics profile of 5649 users and nonusers of hormonal intrauterine devices in Finland.

BACKGROUND: Use of hormonal intrauterine devices has grown during the last decades. Although hormonal intrauterine devices act mostly via local effects on the uterus, measurable concentrations of levonorgestrel are absorbed into the systemic circulation. The possible metabolic changes and large-scale biomarker profiles associated with hormonal intrauterine devices have not yet been studied in detail. OBJECTIVE: To examine through the metabolomics approach the metabolic profile of patients using hormonal intrauterine devices and how this metabolic profile is affected by duration and discontinuation of use. STUDY DESIGN: The study consisted of cross-sectional analyses of 5 population-based surveys (FINRISK and FinHealth studies), spanning from 1997 to 2017. All fertile-aged participants (18-49 years) in the surveys with available information on hormonal contraceptive use and metabolomics data (n=5649) were included in the study. Altogether, 211 metabolic measures of users of hormonal intrauterine devices (n=1006) were compared with those of nonusers of hormonal contraception (n=4643) via multivariable linear regression models. To allow comparison across multiple measures, association magnitudes were reported in standard deviation units of difference in biomarker concentration compared with the reference group. RESULTS: After adjustment for covariates, levels of 141 metabolites differed in current users of hormonal intrauterine devices compared with nonusers of hormonal contraception (median difference in biomarker concentration, 0.09 standard deviation): lower levels of particle concentration of larger lipoprotein subclasses, triglycerides, cholesterol and derivatives, apolipoproteins A and B, fatty acids, glycoprotein acetyls, and aromatic amino acids. The metabolic pattern of hormonal intrauterine device use did not change according to duration of use. When comparing previous users and never-users of hormonal intrauterine devices, no significant metabolic differences were observed. CONCLUSION: The use of hormonal intrauterine devices was associated with several moderate metabolic changes previously associated with reduced arterial cardiometabolic risk. The metabolic effects were independent of duration of use of the hormonal intrauterine devices. Moreover, the metabolic profiles were similar after discontinuation of hormonal intrauterine device use and in never-users.

Systemic hormonal contraception and risk of venous thromboembolism.

INTRODUCTION: The increased risk of venous thromboembolism associated with the use of hormonal contraception is well recognized, but evidence regarding hormonal contraception containing natural estradiol is limited. This study aimed to assess the associations between the patterns of use of different systemic hormonal contraceptives and the risk of venous thromboembolism during 2017-2019. MATERIAL AND METHODS: All fertile-aged women (15-49 years) living in Finland in 2017 and using hormonal contraception in 2017 and their 1:1 age- and residence-matched controls not using hormonal contraception in 2017 (altogether 587 559 women) were selected from the Prescription Centre. All incident venous thromboembolism cases during 2018-2019 and their 4:1 age-matched controls were further analyzed in a prospective nested case-control design to assess the associations between the use (starting, stopping, continuous vs no use) of different hormonal contraception types and venous thromboembolism. RESULTS: Altogether, 1334 venous thromboembolism cases occurred during the follow-up period (incidence rate 1.14 per 1000 person-years, 95% confidence interval [CI] 1.08-1.20), with an incidence rate ratio of hormonal contraception vs no hormonal contraception use of 1.42 (95% CI 1.27-1.58). Compared with non-use, starting the use of gestodene and ethinylestradiol (adjusted odds ratio [aOR] 2.85; 95% CI 1.62-5.03), drospirenone and ethinylestradiol (aOR 1.55; 95% CI 0.98-2.44), desogestrel and ethinylestradiol (aOR 1.97; 95% CI 0.99-3.92), and transdermal patch releasing norelgestromin and ethinylestradiol (aOR 5.10; 95% CI 1.12-23.16), as well as continuing the use of gestodene and ethinylestradiol (aOR 2.60; 95% CI 1.61-4.21), drospirenone and ethinylestradiol (aOR 1.55; 95% CI 1.02-2.37), cyproterone-acetate and estrogen/ethinylestradiol (aOR 1.66; 95% CI 1.06-2.61), and vaginal ring releasing etonogestrel and ethinylestradiol (aOR 3.27; 95% CI 1.95-5.48) were associated with venous thromboembolism risk. Regarding the type of estrogen, the highest risk was associated with current use (vs non use in the previous 180 days) of ethinylestradiol-containing preparations (aOR 2.20; 95% CI 1.82-2.65), followed by estradiol-containing preparations (aOR 1.39; 95% CI 1.04-1.87) with no risk for progestin-only hormonal contraception. Current use of estradiol-containing preparations was not associated with venous thromboembolism risk after exclusion of cyproterone-acetate and estrogen/ethinylestradiol (aOR 1.05; 95% CI 0.66-1.66). CONCLUSIONS: An increased risk of venous thromboembolism is associated with ethinylestradiol-containing combined preparations. The use of estradiol-containing combined preparations confers only a slightly increased risk, possibly driven by cyproterone-containing combined oral contraceptives, whereas the use of progestin-only contraception is not associated with venous thromboembolism.

Reproductive changes among women in their 40s: A cross-sectional study.

INTRODUCTION: The aim was to describe and compare changes in the reproductive pattern of women in their 40s observed over a decade in Scandinavia. MATERIAL AND METHODS: Cross-sectional study using the total population of women aged 40-49 years between 2008-2018 in Denmark, Norway and Sweden (on average n = 1.5 million). Aggregated data concerning birth and induced abortion rate were collected and analyzed from national health registers. National data on redeemed prescriptions of hormonal contraceptives in the three countries were collected from prescription registers. Births after spontaneous and assisted conceptions were identified by using cross-linked data on deliveries from the Medical Birth Registers and National Registers of Assisted Reproduction in the three countries. RESULTS: Use of hormonal contraception increased among women aged 40-44 years in Denmark from 24% to 31%, in Sweden from 27% to 30%, and in Norway from 22% to 24%. The levonorgestrel-releasing intrauterine device was the most frequently used method in all countries. Birth rates among women 40-44 years increased continuously from 9.5 to 12/1000 women in Denmark and from 11.7 to 14.3/1000 in Sweden, but remained stable in Norway at ~11/1000 women. There was a doubling of assisted conceptions in Denmark from 0.71 to 1.71/1000 women, Sweden from 0.43 to 0.81/1000 and Norway from 0.25 to 0.53/1000 women 40-49 years of age. Sweden had the highest induced abortion rate (7.7 to 8.1/1000 women) in women aged 40-49 years during the study period. CONCLUSIONS: From 2008 to 2018, birth rates continuously increased among women aged 40-49 years in Denmark and Sweden and births resulting from assisted reproductive technology doubled in all three countries.

National register data are of value in studies on miscarriage-Validation of the healthcare register data in Finland.

INTRODUCTION: Despite the high prevalence of miscarriages, they are not systematically registered and few epidemiological studies have been done. As Finnish health registries are comprehensive and widely used in research, we validated the Finnish register data concerning diagnostics and treatment of miscarriage, and treatment-related adverse events. MATERIAL AND METHODS: We conducted a validation study regarding miscarriage-related codes of diagnoses and surgical procedures in a Finnish National Hospital Discharge Registry (NHDR) by comparing the information from the NHDR with that of the hospital records. We selected a random sample of 4 months during 1998-2016 from three hospitals, comprising 687 women aged 15-49 experiencing a first miscarriage during follow-up. Women with diagnoses unrelated to miscarriage, or proven to be other than miscarriage, were excluded. The final sample consisted of 643 women with confirmed miscarriage, which was used for analyses regarding the diagnosis, treatment and adverse events of miscarriage treatment. RESULTS: The majority of miscarriages registered in the NHDR were confirmed by the hospital records (positive predictive value [PPV] = 93.6% [95% confidence interval [CI] 91.8%-95.4%]). Different types of miscarriage were also reliably identified; spontaneous abortion with PPV = 85.6% (95% CI 80.9%-89.2%), missed abortion with PPV = 92.7% (95% CI 88.8%-95.3%) and blighted ovum with PPV = 91.1% (95% CI 84.3%-95.1%). The PPV of surgical treatment (62.2% [95% CI 55.7%-68.3%]) was lower than the PPV of non-surgical treatment (93.3% [95% CI 90.5%-95.3%]). The diagnoses regarding adverse events of miscarriage treatment could be reliably identified. The PPV for clinical infections was 76.0% (95% CI 56.6%-88.5%) and for retained products of conception or/and vaginal bleeding 96.8% (95% CI 83.8%-99.4%). CONCLUSIONS: The coverage of the NHDR was good concerning identification of miscarriages, different types of miscarriages and non-surgical treatment. Nevertheless, there is a need for clearly defined procedural codes concerning to medical treatment of miscarriage. The register-based data are reliable and practicable for both clinical evaluation and research concerning miscarriage.

Surgically confirmed endometriosis in adolescents in Finland-A register-based cross-sectional cohort study.

INTRODUCTION: Increasing awareness of endometriosis in adolescents requires data on the nature of the disease and its management. Our objective was to investigate the subtypes of surgically confirmed endometriosis in adolescents (aged <20 years) and trends in the incidence rates and endometriosis-related procedures during the study period, 1987-2012. MATERIAL AND METHODS: In this register-based cohort study, we identified 526 adolescents receiving their initial surgical diagnosis of endometriosis between 1987 and 2012 from the Finnish Hospital Discharge Register. The age-specific incidence rate of surgically confirmed endometriosis was calculated by dividing the number of adolescents during specific periods by person-years. We calculated the relative differences in incidence rates between the periods using crude incidence ratios. RESULTS: Adolescents were divided into three age groups, <17, 17-18, and 19 years, which comprised 8.2% (43/526), 39.7% (209/526), and 52.1% (274/526) of the study cohort, respectively. Peritoneal endometriosis and ovarian endometriosis were the most common types (379/526 [72%] and 119/526 [23%], respectively). The incidence rate of surgically confirmed endometriosis per 100 000 person-years varied from 5.63 (95% confidence interval [CI] 4.24-7.33) to 11.42 (95% CI 9.64-13.44). The incidence rate in 2001-2005 was significantly higher and was 1.6- to 2.0-fold that of the periods 1987-1990 and 2006-2012, respectively. Comparing the periods in which International Classification of Diseases, Ninth Revision (ICD-9; 1987-1995) and Tenth Revision (ICD-10; 1996-2012) codes were used, the use of laparoscopy (78.2% vs 88.9%), day surgery (10.3% vs 31.6%), and procedures for ovarian (18.8% vs 34.1%) and deep (0.6% vs 10.8%) endometriosis increased. The types of endometriosis and procedures did not differ between the age groups. CONCLUSIONS: Peritoneal endometriosis was the most common type of endometriosis overall and by age group. During the 26-year period, the incidence rate of initial surgical diagnosis of endometriosis peaked in 2001-2005 and decreased thereafter. The proportion of procedures performed for ovarian and deep endometriosis increased, as did the use of laparoscopy and day surgery.

Combined oral contraceptives containing estradiol valerate vs ethinylestradiol on coagulation: A randomized clinical trial.

INTRODUCTION: Contraceptives containing ethinylestradiol (EE) induce changes in the coagulation system and are associated with a risk of venous thromboembolism. However, studies comparing the effects of combined oral contraceptives containing EE and low-potency estrogens (ie, estradiol [E2 ] and estradiol valerate [EV]) on coagulation biomarkers are limited. This study represents secondary outcomes of a randomized trial comparing combined oral contraceptives containing EV + dienogest (DNG), EE + DNG, and DNG alone on selected coagulation biomarkers. We could compare the specific effects of the different estrogen components owing to the inclusion of preparations containing the same progestin. MATERIAL AND METHODS: We enrolled 59 healthy, 18- to 35-year-old, non-smoking women, of whom three discontinued. The participants were randomly allocated to 9 weeks of continuous treatment with EV 2 mg + DNG 2-3 mg (n = 20), EE 0.03 mg + DNG 2 mg (n = 20), or DNG 2 mg (n = 19). Blood samples were collected at baseline and after 9 weeks. We assessed coagulation in vitro by thrombin generation using the Calibrated Automated Thrombogram. Thrombin generation was evaluated by lag time, time to thrombin peak, thrombin peak, and endogenous thrombin potential in response to tissue factor (1 pm). In vivo coagulation assessment was based on levels of prothrombin fragment 1 + 2 (F1 + 2) (thrombin generation) and D-dimer (fibrin turnover). CLINICAL TRIAL REGISTRATION: NCT02352090. RESULTS: Lag time and time to thrombin peak remained unaltered after exposure to EV + DNG, whereas EE + DNG shortened both lag time (mean percentage change -24%, 95% confidence interval [CI] -32% to -15%; p < 0.01) and time to thrombin peak (-26%, 95% CI -37% to -16%; p < 0.01). EV + DNG induced lower thrombin peak and endogenous thrombin potential than EE + DNG (peak; +45%, 95% CI 22%-67% vs +147%,95% CI 96%-198%; p < 0.01, and endogenous thrombin potential; +26%, 95% CI 15%-38% vs +64%, 95% CI 51%-76%; p < 0.01). Median F1 + 2 levels remained unchanged with EV + DNG (p = 0.22) but increased within normal ranges with EE + DNG (from 152 pmol/L, 95% CI 127-206] pmol/L to 194 pmol/L, 95% CI 149-250 pmol/L, p = 0.04). The within-group change in D-dimer levels was not significant in any of the groups. DNG alone did not affect these biomarkers. CONCLUSIONS: Both in vitro and in vivo thrombin generation was lower after exposure to EV + DNG compared with EE + DNG. The lower thrombin generation measures after treatment with EV + DNG indicate less enhancement of coagulation potential and suggest that EV may be favorable to EE as a component of combined oral contraceptives.

Use of universally offered family planning services - a cohort study in the city of Vantaa, Helsinki metropolitan area, Finland.

Aims: Knowledge about the women reached by public family planning services is scarce. The means for provision of these services that are pivotal for women's health and empowerment varies globally. In Finland, family planning services are offered free of charge, but often separately for different age groups. City of Vantaa offers these services for all female residents without age limit. The aim of this study was to describe the characteristics of the women using public family planning services. Methods: We assessed the sociodemographic and reproductive characteristics of women aged 15-44 using (n = 11,790) and not using (n = 42,931) these services in 2013-2014. We obtained adjusted odds ratios (AORs) and 95% confidence intervals (95%CIs) for service use by multivariate logistic regression. Results: Women under 35 years of age had higher odds of service use compared with those over 35 (AORs ranging from 2.79 [95%CI 2.54-3.07] for 15-19 year-olds to 1.81 [95%CI 1.69-1.95] for 30-34 year-olds). Women speaking a foreign native language used services less when aged under 30 and more when aged 35-44 compared with women speaking the national languages. Women with a history of delivery, induced abortion or sexually transmitted infections, or with a lower socioeconomic or educational status were more likely to use the services. Conclusions: Young women in general were more likely to use free-of-charge family planning services. In contrast, young women speaking a foreign native language were underrepresented among service users. It is important to recognise and actively reach underrepresented groups, such as young women with a foreign background, to optimise equal access to family planning services.

Use of reproductive health services among women using long- or short-acting contraceptive methods - a register-based cohort study from Finland.

BACKGROUND: Long-acting reversible contraceptives (LARCs) have superior contraceptive efficacy compared to short-acting reversible contraceptives (SARCs) and choosing LARCs over SARC methods reduces the need for abortion care. However, little is known how initiating these methods associates with the subsequent overall need of reproductive health services including family planning services, and visits for gynecological reasons in primary and specialized care. METHODS: We followed altogether 5839 non-sterilized women aged 15-44 years initiating free-of-charge LARC methods (n = 1689), initiating or switching SARC methods (n = 1524), or continuing with the same SARC method (n = 2626) at primary care family planning clinics in the City of Vantaa, Finland, 2013-2014 for 2 years using Finnish national health registers. We assessed the use of reproductive health services, namely attending public primary or specialized health care for gynecological reasons or attending the family planning clinics by applying unadjusted and adjusted negative binomial regression models on visit counts. RESULTS: A total of 11,290 visits accumulated during the two-year follow-up: 7260 (64.3%) at family planning clinics, 3385 (30.0%) for gynecological reasons in primary, and 645 (5.7%) in specialized health care. Altogether 3804 (52.4%) visits at the family planning clinics were for routine checkup, and 3456 (47.6%) for other reasons. Women initiating LARC methods used reproductive health services for reasons other than routine checkups similarly as women initiating or switching SARC methods (adjusted incidence rate ratio 0.93, 95% CI 0.82-1.05), while women continuing with SARC methods used the services less frequently (0.65, 0.59-0.72). Women initiating free-of-charge LARC and those continuing with the same SARC method used services less for abortion care than women initiating or switching SARC (adjusted incidence rate ratios 0.05, 95% CI 0.03-0.08 and 0.16, 95% CI 0.11-0.24, respectively). CONCLUSIONS: While women initiating LARC methods have lower need for abortion care compared to women initiating SARC methods, women initiating both LARC and SARC methods have similar overall need for reproductive health services. In contrast, women continuing with their SARC method need reproductive health services less than women initiating LARC or a new SARC method. These service needs should be acknowledged when planning and organizing family planning services, and when promoting long-acting reversible contraception.

Thirty years of mirena: A story of innovation and change in women's healthcare.

Since its introduction in 1990, the levonorgestrel-releasing intrauterine system (LNG-IUS) has played a key role in shaping the healthcare landscape of women. Here we explore the development of the first LNG-IUS (Mirena®) and the early clinical trials that demonstrated its potential. We highlight the contraceptive and therapeutic benefits of Mirena®, and discuss how clinical practice has been changed since the introduction of LNG-IUS and other long-acting reversible contraceptive methods. The history of Mirena® is rich in innovation and has also paved the way to the development of smaller intrauterine systems with lower hormone doses. Along with Mirena®, these newer LNG-IUS contribute to improving contraceptive choices for women, allowing them to select the option that is right for them and that meets their needs no matter their age, parity or circumstances.

Fear of childbirth after medical vs surgical abortion. Population-based register study from Finland.

INTRODUCTION: To evaluate the effect of method of induced abortion and other abortion-associated variables on the incidence of fear of childbirth in subsequent pregnancy. MATERIAL AND METHODS: This population-based register study cohort includes all nulliparous women with their first pregnancy ending in an induced abortion in 2000-2015 and subsequent pregnancy with live singleton delivery between 2000 and 2017 (n = 21 479). Data were derived from three national registers maintained by the Finnish Institute for Health and Welfare. We divided the study population in three cohorts: (a) medical and (b) surgical abortion during first trimester (≤84 days of gestation), and (c) medical abortion during second trimester (85-168 days of gestation). Primary outcome measures were the incidence of registry-identified fear of childbirth and cesarean delivery related to it. RESULTS: The overall incidence of fear of childbirth was 5.6% (n = 1209). Altogether, 19.2% (n = 4121) of women underwent cesarean delivery. The odds were elevated especially for elective cesarean delivery (odds ratio [OR] 9.30, 95% CI 7.95-10.88, P < .001) in women with fear of childbirth. In multivariable analysis, the odds for fear of childbirth (adjusted OR [aOR] 0.80, 95% CI 0.68-0.94) and cesarean delivery (aOR 0.66, 95% CI 0.84-0.90) were decreased in women with a history of first-trimester medical abortion compared with those with first-trimester surgical abortion. Second-trimester medical abortion had no effect on the odds for fear of childbirth (aOR 1.04, 95% CI 0.71-1.50). Maternal age of 30-39 years and interpregnancy interval over 2 years were additional risk factors for both fear of childbirth and cesarean delivery, but surgical evacuation of uterus after the abortion was not. CONCLUSIONS: One first- or second-trimester medical abortion does not increase the odds for fear of childbirth, and cesarean delivery related to it in subsequent pregnancy when compared with first-trimester surgical abortion. Older maternal age and longer interpregnancy interval emerged as risk factors for fear of childbirth.

A multi-centre, open label, randomised, parallel-group, superiority Trial to compare the efficacy of URsodeoxycholic acid with RIFampicin in the management of women with severe early onset Intrahepatic Cholestasis of pregnancy: the TURRIFIC randomised trial.

BACKGROUND: Severe early onset (less than 34 weeks gestation) intrahepatic cholestasis of pregnancy (ICP) affects 0.1% of pregnant women in Australia and is associated with a 3-fold increased risk of stillbirth, fetal hypoxia and compromise, spontaneous preterm birth, as well as increased frequencies of pre-eclampsia and gestational diabetes. ICP is often familial and overlaps with other cholestatic disorders. Treatment options for ICP are not well established, although there are limited data to support the use of ursodeoxycholic acid (UDCA) to relieve pruritus, the main symptom. Rifampicin, a widely used antibiotic including in pregnant women, is effective in reducing pruritus in non-pregnancy cholestasis and has been used as a supplement to UDCA in severe ICP. Many women with ICP are electively delivered preterm, although there are no randomised data to support this approach. METHODS: We have initiated an international multicentre randomised clinical trial to compare the clinical efficacy of rifampicin tablets (300 mg bd) with that of UDCA tablets (up to 2000 mg daily) in reducing pruritus in women with ICP, using visual pruritus scores as a measuring tool. DISCUSSION: Our study will be the first to examine the outcomes of treatment specifically in the severe early onset form of ICP, comparing "standard" UDCA therapy with rifampicin, and so be able to provide for the first-time high-quality evidence for use of rifampicin in severe ICP. It will also allow an assessment of feasibility of a future trial to test whether elective early delivery in severe ICP is beneficial. TRIAL IDENTIFIERS: Australian New Zealand Clinical Trials Registration Number (ANZCTR): 12618000332224p (29/08/2018). HREC No: HREC/18/WCHN/36. EudraCT number: 2018-004011-44. IRAS: 272398. NHMRC registration: APP1152418 and APP117853.

Population-level indicators associated with hormonal contraception use: a register-based matched case-control study.

BACKGROUND: Monitoring factors related to hormonal contraception (HC) use is essential to evaluating public health strategies and promoting access to contraception. We aimed to examine municipal social and health indicators of HC use at the population level, and to identify patterns of inequality across Finnish municipalities. METHODS: We identified all women (15-49 years) with a redeemed HC prescription in Finland in 2017 (n = 294,445), and a control group of non-users. Municipal social and health indicators at the population level were retrieved from the nationwide Statistics and Indicator Bank. Differences between the groups across 309 municipalities were calculated, and associations of municipal-specific proportions of HC users with municipal-specific indicators were studied using LASSO (Least Absolute Shrinkage and Selection Operator) models. RESULTS: Sociodemographic differences between HC users and non-users were non-homogenous across municipalities. Indicators positively associated with HC use included: larger population and higher proportions of population aged 16-24 years, of household-dwelling units with one person, of persons with higher education, and of divorces among those aged 25-64. Lower HC use was associated with higher proportions of Swedish-speaking population, of those aged 7-15 years, of young people not in education/training, and of household-dwelling units in overcrowded conditions. Lower HC use was also associated with indicators of outpatient and inpatient healthcare, and of municipal finances in welfare and healthcare. CONCLUSIONS: Sociodemographic differences in relation to HC use exist across Finnish municipalities. Municipal indicators of social structure, health and welfare, and investment in and use of healthcare services are related to HC use.