Transforming growth factor-ß signaling governs the differentiation program of extravillous trophoblasts in the developing human placenta.

Abnormal placentation has been noticed in a variety of pregnancy complications such as miscarriage, early-onset preeclampsia, and fetal growth restriction. Defects in the developmental program of extravillous trophoblasts (EVTs), migrating from placental anchoring villi into the maternal decidua and its vessels, is thought to be an underlying cause. Yet, key regulatory mechanisms controlling commitment and differentiation of the invasive trophoblast lineage remain largely elusive. Herein, comparative gene expression analyses of HLA-G-purified EVTs, isolated from donor-matched placenta, decidua, and trophoblast organoids (TB-ORGs), revealed biological processes and signaling pathways governing EVT development. In particular, bioinformatics analyses and manipulations in different versatile trophoblast cell models unraveled transforming growth factor-ß (TGF-ß) signaling as a crucial pathway driving differentiation of placental EVTs into decidual EVTs, the latter showing enrichment of a secretory gene signature. Removal of Wingless signaling and subsequent activation of the TGF-ß pathway were required for the formation of human leukocyte antigen-G+ (HLA-G+) EVTs in TB-ORGs that resemble in situ EVTs at the level of global gene expression. Accordingly, TGF-ß-treated EVTs secreted enzymes, such as DAO and PAPPA2, which were predominantly expressed by decidual EVTs. Their genes were controlled by EVT-specific induction and genomic binding of the TGF-ß downstream effector SMAD3. In summary, TGF-ß signaling plays a key role in human placental development governing the differentiation program of EVTs.

Abortion: legislation and statistics in Europe.

Objective: The Parliamentary Assembly invited the member states of the Council of Europe to 'guarantee women's effective exercise of their right of access to a safe and legal abortion'. While abortion legislation and statistics give an impression of the legislative, cultural, and religious views of the societies and the socio-economic health of the female population, only one study conducted in 2011 looked into the current legislation and trends in terminations of pregnancy in the European Union.Materials and Methods: From January 2017 to December 2018, a group of experts, the authors of the present article, liaised with colleagues practising in 32 European countries to collect data on abortion legislation and statistics using three different questionnaires.Results: The article presents the results of this initiative and compares the status quo and recent trends in abortion legislation and statistics across Europe.Conclusions: The European legislations are still very heterogenous and abortion rates vary widely between countries, confirming that laws do not correlate with abortion rates. This compilation of data, also available on a website (www.abort-report.eu), may help to change laws to better meet the needs of women who decided to have an abortion as a solution to the underlying problem of an unwanted pregnancy.

Detection of ectopic pregnancy and serum beta hCG levels in women undergoing very early medical abortion: a retrospective cohort study.

OBJECTIVE: To evaluate the outcome of the very early medical abortion (VEMA) protocol and whether it could increase early diagnosis and treatment of an asymptomatic ectopic pregnancy (EP). To investigate serum ß-hCG levels correlated to ultrasound findings, and decline in ß-hCG after successful VEMA. STUDY DESIGN: A retrospective case-note review. The population consisted of all women undergoing a VEMA during 2004-14 in Austria and 2012-13 in Sweden. Two cohorts identified based on sonography findings; 106 women with an empty uterine cavity were classified as a pregnancy of unknown location (PUL) and 576 women with an intrauterine sac-like structure without a yolk sac or foetal structure were classified as probable intrauterine pregnancy (probable IUP). RESULTS: Overall, 660 women (97.6%) had a successful VEMA, 94/101 women (93.1%) in the PUL group and 566/575 women (98.4%) in the probable IUP group (p < 0.001). We identified six asymptomatic EP (0.88%). A gestational sac (< 10 mm) was detected at a median/range ß-hCG level 2728 (1600-4497) IU/l. The mean decline in ß-hCG was 93%, (95% CI 91.7-94.2) 5-10 days after successful abortion. CONCLUSIONS: VEMA may be of particular clinical benefit for women. Apart from offering a possibility to start an abortion without delay as soon as the woman has sought abortion care, it may also offer an opportunity to detect and treat EP at an early gestational age. However, the rate of EP was very low.

The molecular and phenotypic makeup of fetal human skin T lymphocytes.

The adult human skin contains a vast number of T cells that are essential for skin homeostasis and pathogen defense. T cells are first observed in the skin at the early stages of gestation; however, our understanding of their contribution to early immunity has been limited by their low abundance and lack of comprehensive methodologies for their assessment. Here, we describe a new workflow for isolating and expanding significant amounts of T cells from fetal human skin. Using multiparametric flow cytometry and in situ immunofluorescence, we found a large population with a naive phenotype and small populations with a memory and regulatory phenotype. Their molecular state was characterized using single-cell transcriptomics and TCR repertoire profiling. Importantly, culture of total fetal skin biopsies facilitated T cell expansion without a substantial impact on their phenotype, a major prerequisite for subsequent functional assays. Collectively, our experimental approaches and data advance the understanding of fetal skin immunity and potential use in future therapeutic interventions.

αßγδ T cells play a vital role in fetal human skin development and immunity.

T cells in human skin play an important role in the immune defense against pathogens and tumors. T cells are present already in fetal skin, where little is known about their cellular phenotype and biological function. Using single-cell analyses, we identified a naive T cell population expressing αß and γδ T cell receptors (TCRs) that was enriched in fetal skin and intestine but not detected in other fetal organs and peripheral blood. TCR sequencing data revealed that double-positive (DP) αßγδ T cells displayed little overlap of CDR3 sequences with single-positive αß T cells. Gene signatures, cytokine profiles and in silico receptor-ligand interaction studies indicate their contribution to early skin development. DP αßγδ T cells were phosphoantigen responsive, suggesting their participation in the protection of the fetus against pathogens in intrauterine infections. Together, our analyses unveil a unique cutaneous T cell type within the native skin microenvironment and point to fundamental differences in the immune surveillance between fetal and adult human skin.

Densities of decidual high endothelial venules correlate with T-cell influx in healthy pregnancies and idiopathic recurrent pregnancy losses.

STUDY QUESTION: Do high endothelial venules (HEVs) appear in the uterus of healthy and pathological pregnancies? SUMMARY ANSWER: Our study reveals that HEVs are present in the non-pregnant endometrium and decidua parietalis (decP) but decline upon placentation in decidua basalis (decB) and are less abundant in decidual tissues from idiopathic, recurrent pregnancy losses (RPLs). WHAT IS KNOWN ALREADY: RPL is associated with a compromised decidual vascular phenotype. STUDY DESIGN, SIZE, DURATION: Endometrial (n = 29) and first trimester decidual (n = 86, 6-12th week of gestation) tissue samples obtained from endometrial biopsies or elective pregnancy terminations were used to determine the number of HEVs and T cells. In addition, quantification of HEVs and immune cells was performed in a cohort of decidual tissues from RPL (n = 25). PARTICIPANTS/MATERIALS, SETTING, METHODS: Position and frequency of HEVs were determined in non-pregnant endometrial as well as decidual tissue sections using immunofluorescence (IF) staining with antibodies against E-selectin, intercellular adhesion molecule, von Willebrand factor, ephrin receptor B4, CD34 and a carbohydrate epitope specific to HEVs (MECA-79). Immune cell distribution and characterization was determined by antibodies recognizing CD45 and CD3 by IF staining- and flow cytometry-based analyses. Antibodies against c-c motif chemokine ligand 21 (CCL21) and lymphotoxin-beta were used in IF staining and Western blot analyses of decidual tissues. MAIN RESULTS AND THE ROLE OF CHANCE: Functional HEVs are found in high numbers in the secretory endometrium and decP but decline in numbers upon placentation in decB (P ≤ 0.001). Decidua parietalis tissues contain higher levels of the HEV-maintaining factor lymphotoxin beta and decP-associated HEVs also express CCL21 (P ≤ 0.05), a potent T-cell chemoattractant. Moreover, there is a positive correlation between the numbers of decidual HEVs and the abundance of CD3+ cells in decidual tissue sections (P ≤ 0.001). In-depth analysis of a RPL tissue collection revealed a decreased decB (P ≤ 0.01) and decP (P ≤ 0.01) HEV density as well as reduced numbers of T cells in decB (P ≤ 0.05) and decP (P ≤ .001) sections when compared with age-matched healthy control samples. Using receiver-operating characteristics analyses, we found significant predictive values for the ratios of CD3/CD45 (P < 0.001) and HEVs/total vessels (P < 0.001) for the occurrence of RPL. LIMITATIONS, REASONS FOR CAUTION: Analyses were performed in first trimester decidual tissues from elective terminations of pregnancy or non-pregnant endometrium samples from patients diagnosed with non-endometrial pathologies including cervical polyps, ovarian cysts and myomas. First trimester decidual tissues may include pregnancies which potentially would have developed placental disorders later in gestation. In addition, our cohort of non-pregnant endometrium may not reflect the endometrial vascular phenotype of healthy women. Finally, determination of immune cell distributions in the patient cohorts studied may be influenced by the different modes of tissue derivation. Pregnancy terminations were performed by surgical aspiration, endometrial tissues were obtained by biopsies and RPL tissues were collected after spontaneous loss of pregnancy. WIDER IMPLICATIONS OF THE FINDINGS: In this study, we propose an inherent mechanism by which the endometrium and in particular the decidua control T-cell recruitment. By demonstrating reduced HEV densities and numbers of T cells in decB and decP tissues of RPL samples we further support previous findings reporting an altered vascular phenotype in early pregnancy loss. Altogether, the findings provide important information to further decipher the etiologies of unexplained RPL. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Austrian Science Fund (P31470 B30 to M.K.) and by the Austrian National Bank (17613ONB to J.P.). There are no competing interests to declare. TRIAL REGISTRATION NUMBER: N/A.

Pivotal role of the transcriptional co-activator YAP in trophoblast stemness of the developing human placenta.

Various pregnancy complications, such as severe forms of preeclampsia or intrauterine growth restriction, are thought to arise from failures in the differentiation of human placental trophoblasts. Progenitors of the latter either develop into invasive extravillous trophoblasts, remodeling the uterine vasculature, or fuse into multinuclear syncytiotrophoblasts transporting oxygen and nutrients to the growing fetus. However, key regulatory factors controlling trophoblast self-renewal and differentiation have been poorly elucidated. Using primary cells, three-dimensional organoids, and CRISPR-Cas9 genome-edited JEG-3 clones, we herein show that YAP, the transcriptional coactivator of the Hippo signaling pathway, promotes maintenance of cytotrophoblast progenitors by different genomic mechanisms. Genetic or chemical manipulation of YAP in these cellular models revealed that it stimulates proliferation and expression of cell cycle regulators and stemness-associated genes, but inhibits cell fusion and production of syncytiotrophoblast (STB)-specific proteins, such as hCG and GDF15. Genome-wide comparisons of primary villous cytotrophoblasts overexpressing constitutively active YAP-5SA with YAP KO cells and syncytializing trophoblasts revealed common target genes involved in trophoblast stemness and differentiation. ChIP-qPCR unraveled that YAP-5SA overexpression increased binding of YAP-TEAD4 complexes to promoters of proliferation-associated genes such as CCNA and CDK6 Moreover, repressive YAP-TEAD4 complexes containing the histone methyltransferase EZH2 were detected in the genomic regions of the STB-specific CGB5 and CGB7 genes. In summary, YAP plays a pivotal role in the maintenance of the human placental trophoblast epithelium. Besides activating stemness factors, it also directly represses genes promoting trophoblast cell fusion.

Experiences of women accessing an abortion clinic confronted by religiously motivated demonstrators: a pilot study.

Objectives: Although abortion is legal in Austria, women are frequently confronted by religiously motivated demonstrators when accessing an abortion. The current study assessed women's experiences in this situation.Methods: Between 2006 and 2010, data were collected from women seeking an abortion who had been approached by demonstrators in front of an abortion clinic. A qualitative content method, descriptive statistics and formal regression analysis were used to examine the data.Results: Participants comprised 98 women, aged 12-47 years. Overall, 91% said their decision was not influenced by the demonstrators, 17% reported feeling threatened, and 93% supported a legal ban on what they perceived as harassment.Conclusion: The demonstrators' behaviour did not influence or change the women's abortion decision. The women reported the activists' behaviour as harassment. Further, the vast majority would support enhanced legal protection for women entering an abortion clinic, to minimise the psychological and physical stress. Future research should explore how such bans could support women and improve their experience at the time of abortion.

Management of very early medical abortion-An international survey among providers.

OBJECTIVE: To record the definition and management of Very Early Medical Abortion (VEMA) in different countries. STUDY DESIGN: An Internet survey was circulated internationally among providers of medical abortion via a website. The questionnaire focused on reasons for performing or delaying medical abortion at a very early gestational age and the perceived advantages and disadvantages of VEMA. RESULTS: Out of 220 completed questionnaires, 50 % came from European abortion providers (n = 110). Most respondents (72 %) defined VEMA as abortion performed in the presence of a positive hCG pregnancy test but with an empty uterine cavity or a gestational sac-like structure, and no signs or symptoms of ectopic pregnancy. A total of 74 % of respondents thought it was not necessary to wait for a diagnosis of intrauterine pregnancy before starting medical abortion. Equally, 74 % were aware of the possibility of an ectopic pregnancy. CONCLUSION: According to European providers of medical abortion, waiting for the diagnosis of an intrauterine pregnancy is not necessary and does not improve treatment of ectopic pregnancy. Providers should know that medical abortion can be performed effectively and safely as soon as the woman has decided. There is no lower gestational age limit.

Estrogen Signaling Drives Ciliogenesis in Human Endometrial Organoids.

The human endometrium is the inner lining of the uterus consisting of stromal and epithelial (secretory and ciliated) cells. It undergoes a hormonally regulated monthly cycle of growth, differentiation, and desquamation. However, how these cyclic changes control the balance between secretory and ciliated cells remains unclear. Here, we established endometrial organoids to investigate the estrogen (E2)-driven control of cell fate decisions in human endometrial epithelium. We demonstrate that they preserve the structure, expression patterns, secretory properties, and E2 responsiveness of their tissue of origin. Next, we show that the induction of ciliated cells is orchestrated by the coordinated action of E2 and NOTCH signaling. Although E2 is the primary driver, inhibition of NOTCH signaling provides a permissive environment. However, inhibition of NOTCH alone is not sufficient to trigger ciliogenesis. Overall, we provide insights into endometrial biology and propose endometrial organoids as a robust and powerful model for studying ciliogenesis in vitro.

Self-Renewing Trophoblast Organoids Recapitulate the Developmental Program of the Early Human Placenta.

Defective placentation is the underlying cause of various pregnancy complications, such as severe intrauterine growth restriction and preeclampsia. However, studies on human placental development are hampered by the lack of a self-renewing in vitro model that would recapitulate formation of trophoblast progenitors and differentiated subtypes, syncytiotrophoblast (STB) and invasive extravillous trophoblast (EVT), in a 3D orientation. Hence, we established long-term expanding organoid cultures from purified first-trimester cytotrophoblasts (CTBs). Molecular analyses revealed that the CTB organoid cultures (CTB-ORGs) express markers of trophoblast stemness and proliferation and are highly similar to primary CTBs at the level of global gene expression. Whereas CTB-ORGs spontaneously generated STBs, withdrawal of factors for self-renewal induced trophoblast outgrowth, expressing the EVT progenitor marker NOTCH1, and provoked formation of adjacent, distally located HLA-G+ EVTs. In summary, we established human CTB-ORGs that grow and differentiate under defined culture conditions, allowing future human placental disease modeling.

Pain management for up to 9 weeks medical abortion - An international survey among abortion providers.

OBJECTIVES: although some degree of pain is inevitable with first trimester medical abortion, little information is available regarding its management in daily practice. The aim of the work was to determine the current regimens in use for managing pain associated with medical abortion. STUDY DESIGN: a self-administered internet survey, developed by a group of European experts on medical abortion, was circulated internationally among medical abortion providers. RESULTS: A total of 283 valid questionnaires were completed, mainly from European providers (59% of respondents, n = 167). Most respondents (n = 267, 94%) reported analgesic prescription/provision for all women, either prophylaxic for 82% (n = 233) or upon request for 12% (n = 34). WHO Step I analgesics (NSAIDs, paracetamol) were the most often used in both cases. A total of 16 (6%) respondents indicated that they never provided analgesics (or prescriptions for them). Female providers of abortion care were significantly more likely to prescribe systematic analgesia for patients than male providers (85% vs 74%, p < 0.04). The majority of respondents (69%, n = 195) did not conduct formal assessments of women's pain. CONCLUSION: Most providers do provide analgesia routinely to women undergoing medical abortion up to 9 weeks gestation. There were widespread variations in analgesic regimens used. There is a clear need for standardised evidence based regimens for management of pain associated with first trimester medical abortion.

Pregnancy-associated diamine oxidase originates from extravillous trophoblasts and is decreased in early-onset preeclampsia.

Human extravillous trophoblast (EVT) invasion of the pregnant uterus constitutes a pivotal event for the establishment of the maternal-fetal interface. Compromised EVT function manifesting in inadequate arterial remodeling is associated with the severe pregnancy disorder early-onset preeclampsia (eoPE). Recent studies suggest that EVTs invade the entire uterine vasculature including arteries, veins and lymphatics in the first trimester of pregnancy. We therefore hypothesized that EVT-derived factors accumulate in the circulation of pregnant women early in gestation and may serve to predict eoPE. In contrast to published literature, we demonstrate that placenta-associated diamine oxidase (DAO) is not expressed by maternal decidual cells but solely by EVTs, especially when in close proximity to decidual vessels. Cultures of primary EVTs express and secret large amounts of bioactive DAO. ELISA measurements indicate a pregnancy-specific rise in maternal DAO plasma levels around gestational week (GW) 7 coinciding with vascular invasion of EVTs. Strikingly, DAO levels from eoPE cases were significantly lower (40%) compared to controls in the first trimester of pregnancy but revealed no difference at mid gestation. Furthermore, DAO-containing pregnancy plasma rapidly inactivates pathophysiologically relevant histamine levels. This study represents the first proof of concept suggesting EVT-specific signatures as diagnostic targets for the prediction of eoPE.

Male perception about the inconveniences associated with monthly bleeding for their partner - an international survey.

OBJECTIVE: To assess men's perceptions about monthly bleeding and associated inconveniences for their partner, as well as men's attitudes regarding the desired menstruation frequency for their partner and knowledge about hormonal contraceptives. METHODS: A 15 min quantitative online survey was conducted among 5044 men aged 18-45 years, who had been in a relationship for more than 6 months, across 13 European countries (Austria, Belgium, Czech Republic, France, Germany, Hungary, Italy, Latvia, The Netherlands, Poland, Portugal, Spain and Switzerland). Responses were compared to those obtained in a similar study among European women. RESULTS: Most men perceived that their partner considered her menstrual flow as moderate, lasting an average of 5.2 d, slightly longer than previously reported by women. Almost all men reported that their partners experience menstruation-related symptoms. However, prevalence of mood-related symptoms was perceived to be more frequent and physical symptoms less frequent, relative to women's self-reported symptoms. Given the option, 71% of men would choose longer intervals between their partner's periods. Maintaining the couple's sex life, social life and relationship quality were key factors cited in their preference. Overall, 42% of respondents stated that women taking hormonal contraceptives needed to have monthly periods. CONCLUSIONS: Men's perception regarding their partner's periods was generally consistent with that previously reported by women. Most men would prefer less frequent bleeding episodes for their partners. Although, the present data suggest that couples are discussing periods, knowledge about contraception could be improved. Health care professionals should intensify counselling to better inform both partners about their contraceptive options.

Outcome of first trimester medical termination of pregnancy: definitions and management.

OBJECTIVE: Medical termination of pregnancy (MToP, or medical abortion) is a highly effective method with a reported efficacy of 95-98%. However, different criteria are currently used to define success, and there are different recommendations for the treatment of what is considered a failure of MToP. This work was undertaken to develop a consensus around a set of well-defined MToP outcomes, as recommended by the Core Outcomes in Women's and Newborn Health initiative. METHODS: A literature search was made of national and international guidelines and of recommendations of expert groups for various outcomes of MToP and subsequent management. Based on a review of the findings, a group of European experts in MToP undertook a consensus process to agree on a set of core MToP outcomes. RESULTS: The following core MToP outcomes were defined: success, failure (ongoing pregnancy), need for additional treatment (medical or surgical) to complete MToP (missed abortion, incomplete abortion), complications and the woman's request for additional treatment (medical or surgical). Recommendations for the management of unsuccessful outcomes were also formulated. CONCLUSION: New definitions of MToP outcomes that are more focused on objective criteria and consequently less dependent on provider interpretation are proposed. This should allow better comparison of the efficacy of different regimens and improve the management of failed or incomplete abortion.

The inconvenience due to women's monthly bleeding (ISY) survey: a study of premenstrual symptoms among 5728 women in Europe.

OBJECTIVES: The aim of the ISY study was to investigate the prevalence of menstrual-related symptoms prior to and/or during menstrual or withdrawal bleeding among women from 12 European countries. METHODS: A 15-min quantitative online survey was conducted in two waves from February to September 2015 among 5728 women aged between 18 and 45 years, with an equal distribution of women using a combined hormonal contraceptive, including regular combined oral contraceptives (COCs) (CHC group, n = 2739) and women using a non-hormonal contraceptive or no contraceptive (non-HC group, n = 2989). RESULTS: The prevalence of at least one menstrual-related symptom was high in CHC users (93%) and in non-HC users (95%) (p < .0001) and the average number of symptoms reported was 5.3 vs. 5.9, respectively, (p < .0001). Pelvic pain, bloating/swelling, irritability and mood swing were reported in more than half of the women in both groups. Although generally modest, symptom severity was higher in non-HC users, except for headache. Overall, during the last four cycles, 60-75% of women did not require a treatment for most symptoms but headaches and pelvic pain. Mood swings/irritability, water retention/weight gain, lack of energy/mood swings and lack of energy/irritability were common symptoms that frequently co-occurred. No associations were reported between symptoms and age, educational qualifications or women's desire to reduce the frequency of menstruation. CONCLUSIONS: Premenstrual and menstrual symptomatology was less frequent, less numerous and less severe (except for headache) in women using CHCs; however, it remains a common concern. Reducing the frequency of menstrual periods could reduce withdrawal-related symptoms.

Development and conceptual validation of a questionnaire to help contraceptive choice: CHLOE (Contraception: HeLping for wOmen's choicE).

OBJECTIVE: The aim of this research was to develop a questionnaire to facilitate choice of the most appropriate contraceptive method for individual women. METHODS: A literature review was conducted to identify key aspects influencing contraceptive choice and inform development of a questionnaire for online completion. Questionnaire development was overseen by a steering committee consisting of eight gynaecologists from across Europe. The initial draft underwent conceptual validation through cognitive debriefing interviews with six native English-speaking women. A qualitative content analysis was conducted to accurately identify potential issues and areas for questionnaire improvement. A revised version of the questionnaire then underwent face-to-face and online evaluation by 115 international gynaecologists/obstetricians with expertise in contraception, prior to development of a final version. RESULTS: The final conceptually validated Contraception: HeLping for wOmen's choicE (CHLOE) questionnaire takes ≤10 min to complete and includes three sections to elicit general information about the individual, the health conditions that might influence contraceptive choice, and the woman's needs and preferences that might influence contraceptive choice. The questionnaire captures the core aspects of personalisation, efficacy and safety, identified as key attributes influencing contraceptive choice, and consists of 24 closed-ended questions for online completion prior to a health care provider (HCP) consultation. The HCP receives a summary of the responses. CONCLUSION: The CHLOE questionnaire has been developed to help women choose the contraception that best suits their needs and situation while optimising the HCP's time.

There is no defence for 'Conscientious objection' in reproductive health care.

A widespread assumption has taken hold in the field of medicine that we must allow health care professionals the right to refuse treatment under the guise of 'conscientious objection' (CO), in particular for women seeking abortions. At the same time, it is widely recognized that the refusal to treat creates harm and barriers for patients receiving reproductive health care. In response, many recommendations have been put forward as solutions to limit those harms. Further, some researchers make a distinction between true CO and 'obstructionist CO', based on the motivations or actions of various objectors. This paper argues that 'CO' in reproductive health care should not be considered a right, but an unethical refusal to treat. Supporters of CO have no real defence of their stance, other than the mistaken assumption that CO in reproductive health care is the same as CO in the military, when the two have nothing in common (for example, objecting doctors are rarely disciplined, while the patient pays the price). Refusals to treat are based on non-verifiable personal beliefs, usually religious beliefs, but introducing religion into medicine undermines best practices that depend on scientific evidence and medical ethics. CO therefore represents an abandonment of professional obligations to patients. Countries should strive to reduce the number of objectors in reproductive health care as much as possible until CO can feasibly be prohibited. Several Scandinavian countries already have a successful ban on CO.

Women's preferences for menstrual bleeding frequency in 12 European countries: the Inconvenience Due to Women's Monthly Bleeding (ISY) survey.

OBJECTIVES: Our aim was to assess the level of inconvenience associated with menstrual bleeding and determine how many women across 12 European countries would prefer a bleeding frequency of less than once a month and what would motivate their choice. METHODS: A 15-min quantitative online survey was conducted in two waves among 5728 women aged between 18 and 45 years, with an equal distribution of women using a combined hormonal contraceptive (CHC group, n = 2739) and women using a non-hormonal contraceptive or no contraceptive (non-HC group, n = 2989). The first wave was carried out in Austria, Belgium, France, Italy, Poland and Spain, in February 2015, and the results have been published. The second wave was conducted in the Czech Republic, Germany, Hungary, Portugal, Latvia and the Netherlands, between August and September 2015. RESULTS: The menstrual period was significantly longer (5.0 versus 4.6 days) and heavier (15 versus 7%) in non-HC users than in CHC users (p < .0001). Given the choice, ∼60% of women would like less frequent menstrual bleeding. There was heterogeneity in the preference across countries. Sexuality, social life, work and sporting activities were key factors affecting women's preference. CONCLUSION: The majority of women in the 12 European countries would prefer to reduce the frequency of menstrual periods. Quality of life was the main factor affecting their preference.