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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-β (TGF-β) 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-β 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-β–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-β downstream effector SMAD3. In summary, TGF-β signaling plays a key role in human placental development governing the differentiation program of EVTs.

Research on adoptive parents of anonymously born children is still scarce. Open issues are (1) examining how much biographical information is available to adoptive parents, (2) considering differences between adoptive mothers and fathers, and (3) understanding what affects their dyadic coping. Hence, this study set out to compare adoptive mothers’ and fathers’ mental health, attachment styles, dyadic coping, and biographical knowledge, and to identify predictors of dyadic coping. 62 mothers and 40 fathers (mean age: 46 years) raising an anonymously born adoptee answered online or paper-pencil versions of the Brief Symptom Inventory, Vulnerable Attachment Style Questionnaire, Dyadic Coping Inventory, Child Behavior Checklist, and a checklist of biographical data. Descriptive analyses showed that biographical knowledge was generally low in adoptive parents. More information was available on the birth mother than the birth father, with letters being the most common memorial. Furthermore, student t-tests revealed few differences: adoptive mothers reported to be more anxious and rated their ability to communicate stress and common dyadic coping as higher than did adoptive fathers. Finally, a hierarchical linear regression identified knowledge of more biographical data, parents’ older age as well as child’s younger age and higher psychopathology scores as predictors of better adoptive parents’ dyadic coping. These findings highlight the difficult task of gathering biographical information whilst maintaining the birth mother’s anonymity. They also stress the need of further research which may inform policies tailored to the specific needs of adoptive parents in the context of anonymous birth.

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.

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.

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 β-hCG levels correlated to ultrasound findings, and decline in β-hCG after successful VEMA. 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). 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 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 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., Summary: This study provides versatile tools for the isolation, phenotyping and expansion of human fetal skin T cells, enabling the study of their complexity and heterogeneity allowing new research in skin development and immunity.

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.

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.

Since the start of the COVID-19 outbreak, the race for testing new platforms designed to confer immunity against SARS-CoV-2, has been rampant and unprecedented, leading to conditional emergency authorization of various vaccines. Despite progress on early multidrug therapy for COVID-19 patients, the current mandate is to immunize the world population as quickly as possible. The lack of thorough testing in animals prior to clinical trials, and authorization based on safety data generated during trials that lasted less than 3.5 months, raise questions regarding vaccine safety. The recently identified role of SARS-CoV-2 Spike glycoprotein for inducing endothelial damage characteristic of COVID-19, even in absence of infection, is extremely relevant given that most of the authorized vaccines induce endogenous production of Spike. Given the high rate of occurrence of adverse effects that have been reported to date, as well as the potential for vaccine-driven disease enhancement, Th2-immunopathology, autoimmunity, and immune evasion, there is a need for a better understanding of the benefits and risks of mass vaccination, particularly in groups excluded from clinical trials. Despite calls for caution, the risks of SARS-CoV-2 vaccination have been minimized or ignored by health organizations and government authorities. As for any investigational biomedical program, data safety monitoring boards (DSMB) and event adjudication committees (EAC), should be enacting risk mitigation. If DSMBs and EACs do not do so, we will call for a pause in mass vaccination. If DSMBs and EACs do not exist, then vaccination should be halted immediately, in particular for demographic groups at highest risk of vaccine-associated death or serious adverse effects, during such time as it takes to assemble these boards and commence critical and independent assessments. We urge for pluralistic dialogue in the context of health policies, emphasizing critical questions that require urgent answers, particularly if we wish to avoid a global erosion of public confidence in science and public health.

By characterizing the poorly defined T cell composition in developing human fetal skin, Reitermaier et al. identify a unique population of TCR αβγδ+ T cells. These cells may contribute to early skin development and immune defense against invading pathogens in utero., 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 αβ 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) αβγδ T cells displayed little overlap of CDR3 sequences with single-positive αβ T cells. Gene signatures, cytokine profiles and in silico receptor–ligand interaction studies indicate their contribution to early skin development. DP αβγδ 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., Graphical Abstract

Over the last 100 years we have seen a fundamental change in fertility: from natural fertility leading to 12–15 pregnancies in a woman’s lifetime to effective family planning, enabling people to only have the children they want. This revolution, the domination of natural fertility, represents the second most important cultural achievement in history after the domination of fire. The fact that we have today “Children and menstruation by choice, not chance” has changed everything on this world. But the happy end occurred only very recently with the development of the pill and effective IUDs. To reach this goal has been a long, painful, and mostly unsuccessful struggle, which has cost countless lives and destroyed so many families. Meanwhile, 60 years after the pill has enabled us to effectively separate fertility and sexuality, most have forgotten what natural fertility is really about. And we can observe the consequence of the lost perception about the incredible force of fertility: many people lost the motivation to use effective contraception. We find ourselves in a situation, nobody has foreseen: we have an unprecedented high number of highly effective contraceptive methods especially for women but many don’t use them. Instead many women still get pregnant unwantedly, a real contraceptive paradox.

Significance Defects in development and differentiation of the placenta are associated with various pregnancy disorders such as miscarriage, stillbirth, preeclampsia, and intrauterine growth restriction. However, our knowledge on critical regulators of human placentation is scarce. In the present study, we show that the Hippo signaling-dependent transcriptional coactivator YAP plays a pivotal role in the maintenance of proliferative trophoblasts, the epithelial cells of the placenta. By binding to the transcription factor TEAD4, YAP stimulates expression of genes promoting trophoblast stemness. Additionally, YAP–TEAD4 complexes actively repress genes associated with the differentiated syncytiotrophoblast, the hormone-secreting cell type of the human placenta. Hence, YAP orchestrates a complex developmental program ensuring growth and expansion of the 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.

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.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.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.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.

Summary 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., Highlights • Derivation of cytotrophoblast organoids from human placenta • Long-term expansion of trophoblast organoids in a chemically defined medium • Formation of the extravillous trophoblast lineage under defined culture conditions, Failures in human placental development have been associated with severe pregnancy complications. However, due to the lack of a self-renewing model system, mimicking 3D in vivo growth and differentiation of placental trophoblast, the underlying mechanisms remain poorly understood. Herein, long-term expanding trophoblasts organoids were established that proliferate and differentiate under defined culture conditions allowing investigating normal and pathological placentation.

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.a self-administered internet survey, developed by a group of European experts on medical abortion, was circulated internationally among medical abortion providers.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.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.

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.

Objective To assess the efficacy and safety of medical termination of pregnancy (MTOP) when no intrauterine pregnancy (IUP) is confirmed on ultrasound. Design Retrospective case-note review. Setting Two gynaecological clinics in Vienna, Austria, and Gothenburg, Sweden. Population All women with gestations of ≤49 days undergoing an MTOP during 2004-14 (Vienna) and 2012-15 (Gothenburg). Methods Two study cohorts were created: women with and women without a confirmed IUP. An IUP was defined as the intrauterine location of a yolk sac or fetal structure visible by ultrasound. Women with an IUP were selected randomly and included in the IUP cohort. Main outcome measures Efficacy of MTOP, defined as no continuing pregnancy and with no need of surgery for incomplete TOP. Results After excluding 11 women diagnosed with an extra-uterine or molar pregnancy, 2643 cases were included in the final analysis; 1120 (98.2%) had a successful TOP in the no-IUP group, compared with 1458 (97.1%) in the IUP group, with a risk difference of 1.09% (95% confidence interval, 95% CI, -0.14, 2.32%; P = 0.077). Significantly more women with confirmed IUP were diagnosed with incomplete TOP, and were treated with either surgery or additional medical treatment of misoprostol [64 (4.3%) versus 21 (1.8%); risk difference -2.42%; 95% CI -3.9, -1.1%; P Conclusions There was no difference between the groups in efficacy of MTOP, whereas early treatment resulted in significantly fewer interventions for incomplete TOP. The risk of ectopic pregnancy needs to be considered if treatment is initiated before an IUP is confirmed, but with structured clinical protocols the possibility of the early detection of an ectopic pregnancy in an asymptomatic phase may increase. Tweetable abstract MTOP before confirmed intrauterine pregnancy is as effective as at later gestation with less incomplete TOP.

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.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).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.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.

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.

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.

International audience; Objectives: Oral hormonal contraception is an effective contraceptive method as long as regular daily intake is maintained. However, a daily routine is a constraint for many women and can lead to missed pills, pill discontinuation and/or unintended pregnancy. This article describes the frequency of inconsistent use, the consequences, the risk factors and the possible solutions.Methods: The article comprises a narrative review of the literature.Results: Forgetting one to three pills per cycle is a frequent problem among 15–51% of users, generally adolescents. The reasons for this are age, inability to establish a routine, pill unavailability, side effects, loss of motivation and lack of involvement in the initial decision to use oral contraceptives. The consequences are ‘escape ovulations’ and, possibly, unintended pregnancy. Solutions are either to use a long-acting method or, for women who prefer to take oral contraceptives, use a continuous or long-cycle regimen to reduce the risks of follicular development and thus the likelihood of ovulation and unintended pregnancy. A progestogen with a long half-life can increase ovarian suppression.Conclusions: For women deciding to use oral contraceptives, a shortened or eliminated hormone-free interval and a progestogen with a long half-life may be an option to reduce the negative consequences of missed oral contraceptive pills.

Children and adolescents who have been anonymously adopted are an understudied subgroup of adoptees, particularly with regards to their mental health. Hence, the objective of this study was to assess whether the mental health of anonymously adopted children and adolescents differs from a representative norm population, with particular regards to age and gender specific norms. Additionally, possible predictors of anonymous adoptees’ mental health, such as the adoptive parents’ mental health, their attachment styles and demographic variables were evaluated. Data was collected between 2018 and 2019 using an online survey or paper pencil questionnaires (parents’ choice). The sample consisted of 97 adoptive parents, who reported on their anonymously adopted children aged between 2 and 17 years using the Child Behavior Checklist (CBCL). Older adoptees born anonymously showed a higher overall score and more externalising behaviours, when compared to a representative German (non-adopted) reference norm population. The younger anonymously born adoptee group showed significantly lower overall, internalising and externalising behaviour problem scores in comparisons to the norm population. Child mental health problems were positively associated with parental mental health problems and children’s age. Additionally, adoptive parents’ anxious attachment style was a predictor for children’s mental health problems. The current results imply that prevention and treatment of existing mental health problems should target the whole adoptive family and should be implemented by default in post-adoption services.

Evidence-based guidelines on the management of pain associated with first-trimester medical abortion are lacking. Most published clinical trials have failed to report on this important aspect of the procedure. The aim of this comprehensive work was to provide clinical advice based on a comprehensive literature review, supplemented by the clinical experience of a group of European experts in case no evidence is available. Pain level ranged from 5 to 8 in 80% of studies where pain was measured on a 0–10 visual analogue scale; severe pain was reported by 20–80% of women. Pain assessment was rarely reported in studies. Pain treatment should be preventive and avoidance of unnecessary uterine contractions should be considered. Analgesic treatment should follow the WHO three-step ladder, starting with the use of NSAIDs and allowing for easily available back-up treatment with weak opioids.

Reproductive health care is the only field in medicine where health care professionals (HCPs) are allowed to limit a patient's access to a legal medical treatment - usually abortion or contraception - by citing their 'freedom of conscience.' However, the authors' position is that 'conscientious objection' ('CO') in reproductive health care should be called dishonourable disobedience because it violates medical ethics and the right to lawful health care, and should therefore be disallowed. Three countries - Sweden, Finland, and Iceland - do not generally permit HCPs in the public health care system to refuse to perform a legal medical service for reasons of 'CO' when the service is part of their professional duties. The purpose of investigating the laws and experiences of these countries was to show that disallowing 'CO' is workable and beneficial. It facilitates good access to reproductive health services because it reduces barriers and delays. Other benefits include the prioritisation of evidence-based medicine, rational arguments, and democratic laws over faith-based refusals. Most notably, disallowing 'CO' protects women's basic human rights, avoiding both discrimination and harms to health. Finally, holding HCPs accountable for their professional obligations to patients does not result in negative impacts. Almost all HCPs and medical students in Sweden, Finland, and Iceland who object to abortion or contraception are able to find work in another field of medicine. The key to successfully disallowing 'CO' is a country's strong prior acceptance of women's civil rights, including their right to health care.

The aims of this study are to assess the impact of Austria's anonymous birth law from the time relevant statistical records are available and to evaluate the use of hatches versus anonymous hospital delivery. This study is a complete census of police-reported neonaticides (1975-2012) as well as anonymous births including baby hatches in Austria during 2002-2012. The time trends of neonaticide rates, anonymous births and baby hatches were analysed by means of Poisson and logistic regression model. Predicted and observed rates were derived and compared using a Bayesian Poisson regression model. Predicted numbers of neonaticides for the period of the active awareness campaign, 2002-2004, were more than three times larger than the observed number (p = 0.0067). Of the 365 women who benefitted from this legislation, only 11.5% chose to put their babies in a baby hatch. Since the law was introduced, a significant decreasing tendency of numbers of anonymous births (p = 047) was observed, while there was significant increase of neonaticide rates (p = 0.0001). The implementation of the anonymous delivery law is associated with a decrease in the number of police-reported neonaticides. The subsequent significantly decreasing numbers of anonymous births with an accompanying increase of neonaticides represents additional evidence for the effectiveness of the measure.

STUDY QUESTION Do trophoblast subtypes differ in their expression of erythroblastic leukaemia viral oncogene homologue (ERBB) receptor family members and responsiveness towards specific growth factor ligands? SUMMARY ANSWER Our data reveal a reciprocal expression pattern of epidermal growth factor receptor (EGFR)/ERBB4 in proliferative and ERBB2/ERBB3 in invasive trophoblast subtypes, as well as a restricted responsiveness to epidermal growth factor (EGF) and heparin-binding (HB)-EGF. WHAT IS KNOWN ALREADY EGFR is expressed by villous cytotrophoblasts (vCTBs), but absent from extravillous trophoblasts (EVTs), which specifically up-regulate ERBB2. STUDY DESIGN, SIZE, DURATION Tissue samples of human first trimester placentae (n = 50) and deciduae (n = 5) obtained from elective pregnancy terminations were used to study trophoblast subtype-specific ERBB receptor expression and responsiveness to recombinant human EGF and HB-EGF. Age-matched complete hydatidiform mole (CHM) placentae (n = 12) were assessed for EGFR and ERBB4 expression in proliferation-competent regions. PARTICIPANTS/MATERIALS, SETTING, METHODS ERBB receptor expression was analysed in primary trophoblast cell isolates by means of microarray, quantitative real-time PCR and western blotting, as well as immunofluorescence stainings of placental and decidual tissue sections. EGF and HB-EGF were tested for their potential to activate ERBB receptors in purified EGFR(+) and HLA-G(+) trophoblasts. 5-Ethynyl-2'-deoxyuridine incorporation assays were performed to study the effect of both ligands on the proliferative capacity of primary trophoblasts as well as of vCTBs and proximal cell column trophoblasts (pCCTs) in placental floating explants. Finally, the average number of EGFR(+) vCTB and pCCT layers was determined in CHM placentae and compared with healthy age-matched controls. MAIN RESULTS AND THE ROLE OF CHANCE Proliferative vCTBs and pCCTs co-express EGFR and ERBB4, but are devoid of ERBB2 and ERBB3. In contrast, HLA-G(+) trophoblast subtypes exhibit an EGFR/ERBB4(-) and ERBB2/ERBB3(+) phenotype. EGF and HB-EGF activate EGFR, ERBB4, AKT and extracellular signal-regulated kinase 1/2 in EGFR(+) primary trophoblasts; however, they do not show an effect on HLA-G(+) EVTs. Both ligands strongly induce cell cycle progression in primary trophoblasts (P < 0.05) and placental explant-associated vCTBs (P < 0.05) and pCCTs (P < 0.05). Notably, EGFR(+) vCTB (P < 0.0001) and pCCT (P < 0.0001) layers are significantly expanded in CHM placentae when compared with healthy controls. LIMITATIONS, REASONS FOR CAUTION Cells were removed from their physiological context and may therefore respond differently to various stimuli. WIDER IMPLICATIONS OF THE FINDINGS In this study we define EGFR as a marker for proliferative trophoblast subtypes within the human placenta. Manipulation of EGFR signalling might thus offer a promising therapeutic avenue for the treatment of molar pregnancies associated with trophoblast hyperplasia. STUDY FUNDING/COMPETING INTERESTS This study was supported by the Austrian Science Fund (grant P-25187-B13 to J.P.). There are no competing interests to declare.

Summary Background Medical abortion with mifepristone and prostaglandins is well established. We compared clinical assessment with self-assessment of abortion outcome. Methods This randomised, controlled, non-inferiority trial was done in four clinics in Austria, Finland, Norway, and Sweden, between Aug 16, 2011, and Jan 31, 2013. Women aged 18 years and older who had requested medical termination of a pregnancy up to 63 days of gestation were eligible. Computer-generated block randomisation (block size ten) assigned women in a 1:1 ratio to attend routine clinical follow-up or to self-assess outcome at home with a semiquantitative urine human chorionic gonadotropin (hCG) test 1–3 weeks after abortion. The primary outcome was the percentage of women with complete abortion not requiring further medical or surgical intervention within 3 months. Analysis was per protocol and by intention to treat. The non-inferiority margin was five percentage points. This trial is registered with ClinicalTrials.gov, number NCT01487213. Findings 924 women were assigned routine follow-up (n=466) or self-assessment (n=458) and included in the intention-to-treat analysis. 901 were included in the per-protocol analysis (n=446 and n=455, respectively). Complete abortion was reported in 432 (95%) of 455 in the routine follow-up group and 419 (94%) of 446 women in the self-assessment group (crude difference −1·0, 95% CI −4·0 to 2·0). 20 (4%) women in the routine follow-up group and 17 (4%) in the self-assessment group required surgery. No women in the routine follow-up group versus three in the self-assessment group had undetected continuing pregnancies. Eight (1·8%) and one (0·2%) women, respectively, had infections (p=0·038). Interpretation Self-assessment was non-inferior to routine follow-up and could save resources. Funding Nordic Federation of Obstetrics and Gynaecology, European Society of Contraception, Helsinki University Central Hospital, Helse Finnmark, Swedish Research Council, and Stockholm County Council and Karolinska University Hospital.

The aim of this research was to develop a questionnaire to facilitate choice of the most appropriate contraceptive method for individual women.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.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.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.

Although medical abortion with home use of misoprostol has been shown to be safe and acceptable, there are few data about the experience of pain during the procedure. The aims of this study were to assess the intensity of pain associated with home use of misoprostol for medical abortion and to identify variables associated with severe pain.This was an observational study using an anonymous web-based questionnaire in patients having a medical abortion at home in France between 1 December 2013 and 30 April 2014.The questionnaire was completed by 232 women and the results of 193 were retained for analysis. The average pain score was 5.6 on a 10 point scale. A pain score ≥6 was rated as severe and was reported by 105 patients (54%). Nulliparity (odds ratio [OR] 4.10; 95% confidence interval [CI] 2.04, 8.22; p .0001), lack of choice regarding the method of abortion (OR 2.32; 95% CI 1.13, 4.78; p = .0218) and lack of information about the level of pain associated with the procedure (OR 3.27; 95% CI 1.09, 9.74; p = .0334) were significantly correlated with severe pain. Analgesic prescriptions were very heterogeneous.Pain remains the main side effect of medical abortion. More studies are needed on pain assessment and the effectiveness of analgesic treatments in women using misoprostol at home for medical abortion, in order to improve their care and improve evidence-based guidelines.

Few studies in the scientific literature provide clear direction on the prevention or management of pain associated with intrauterine contraceptive (IUC) placement. Those that have been published have studied small numbers of women and fail to provide definitive conclusions. There are also no guidelines available detailing recognised standard approaches to this problem. The consensus recommendations in this review focus primarily on non-pharmacological and often non-evidence-based interventions. This review includes general considerations, practical recommendations for both routine and more difficult cases and guidance on the optimal choice of instruments. General considerations, including pre-insertion counselling, the setting for the procedure, the confidence and technique of the provider and the interplay between the provider and assistant, can influence women's level of anxiety and, in turn, influence their perception of pain and their overall experience. Further studies are required to refine the optimal strategy for managing pain associated with IUC insertion.

Introduction TGF-β superfamily members are thought to play a pivotal role in placental development and differentiation. However, their downstream effectors, the Smad transcription factors, have been poorly investigated in human trophoblasts. Methods Expression and localisation of the canonical TGF-β targets Smad2/3 and their regulators (Smad4 and Smad7) were investigated in first trimester placenta and purified cytotrophoblast (CTB) subtypes using immunofluorescence, western blotting and qPCR. Canonical and non-canonical activation was analysed in nuclear/cytoplasmic extracts of trophoblast subtypes as well as in tissue sections using antibodies against Smad2/3, phosphorylated either at the C-terminus (pSmad2C/3C) or in their linker regions (pSmad2L/3L). Smad phosphorylation was also examined in differentiating extravillous trophoblasts (EVTs) in the absence or presence of decidual stromal cell (DSC)-conditioned medium. Results Smad2, Smad4 and Smad7 protein were uniformly expressed between 6th and 12th week placentae and the different isolated CTB subtypes. Activated pSmad2L was mainly detected in nuclei and cytoplasm of villous CTBs, whereas pSmad2C was absent from these cells. In contrast, pSmad2C could be detected in the cytoplasm of cell column trophoblasts and in the cytoplasm/nuclei of EVTs. Smad3 and its phosphorylated forms pSmad3C and pSmad3L specifically localised to EVT nuclei. During EVT differentiation autocrine activation of pSmad2C/3C and pSmad3L was observed. DSC-conditioned medium further increased Smad2/3 phosphorylation in EVTs. Discussion The lack of pSmad2C in villous CTBs suggests that other mitogens than TGF-β could promote Smad2 linker phosphorylation under homeostatic conditions. Whereas autocrine signalling activates Smad2/3 in differentiating EVTs, paracrine factors contribute to Smad phosphorylation in these cells.

STUDY QUESTION Do extravillous trophoblasts (EVTs) invade non-arterial decidual vessels in healthy and pathological pregnancies? SUMMARY ANSWER Our results reveal that trophoblast invasion of venous and lymphatic vessels is a frequent event during the first trimester of pregnancy and is compromised in recurrent spontaneous abortion (RSA). In addition, the present data suggest that EVTs populate regional lymph nodes during pregnancy. WHAT IS ALREADY KNOWN Human trophoblasts remodel and invade decidual spiral arteries. In addition, a recent report demonstrates that trophoblasts contact and invade decidual veins. STUDY DESIGN, SIZE, DURATION Tissue samples of human first trimester deciduae basalis (n = 54, 6th-13th weeks of gestation) obtained from elective pregnancy terminations were used to study trophoblast invasion into veins and lymphatics, in comparison to arteries. Age-matched cases of idiopathic, recurrent spontaneous abortions tissue samples (n = 23) were assessed for cell numbers of EVTs in these decidual vessels. In addition, lymph nodes of four pregnant women were analysed for the presence of EVTs. PARTICIPANTS/MATERIALS, SETTING, METHODS Localization, frequency and EVT-mediated targeting and invasion of arterial, venous as well as lymphatic vessels were determined in first trimester decidua basalis tissue sections using immunofluorescence staining with antibodies against CD31, CD34, ephrin B2 (EFNB2), ephrin receptor B4 (EPHB4), HLA-G, podoplanin, prospero-related homeobox 1 (Prox-1), alpha-smooth muscle actin 2 (ATCTA2), von willebrand factor (vWF) and proteoglycan 2 (PRG2). Arterial, venous and lymphatic-associated EVTs were further characterized according to their position in the vascular structure and classified as intramural (im) or intraluminal (il). MAIN RESULTS AND THE ROLE OF CHANCE EVTs, specifically expressing PRG2, target and invade veins and lymphatics in first trimester decidua basalis since HLA-G+ trophoblast were detected in the vascular wall (intramural EVT, imEVTs) and in the lumen of these vessels (intraluminal EVT, ilEVTs). In total, 276 arteries, 793 veins and 113 lymphatics were analysed. While EVTs contact and invade arteries and veins to a similar extent we found that lymphatics are significantly less affected by EVTs (P = 0.001). Moreover, ilEVTs were detected in the lumen of venous and lymphatic vessels, whereas ilEVTs were only found occasionally in the lumen of arteries. Interestingly, RSA tissue sections contained significantly more arterial (P = 0.037), venous (P = 0.002) and lymphatic vessels (P < 0.001), compared to healthy controls. However, while RSA-associated arterial remodeling was unchanged (P = 0.39) the ratios of EVT-affected versus total number of veins (P = 0.039) and lymphatics (P < 0.001) were significantly lower in RSA compared to age-matched healthy decidual sections. Finally, HLA-G+/PRG2+/CD45-EVTs can be detected in regional lymph nodes of pregnant women diagnosed with cervical cancer. LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION In this study, first trimester decidual tissues from elective terminations of pregnancies have been examined and used as a reference for healthy pregnancy. However, this collective may also include pregnancies which would have developed placental disorders later in gestation. Due to limitations in tissue availability our staining results for EVT-specific marker expression in regional lymph nodes of pregnant women are based on four cases only. WIDER IMPLICATIONS OF THE FINDINGS In this study, we propose migration of HLA-G+ cells into regional lymph nodes during pregnancy suggesting that the human EVT is capable of infiltrating maternal tissues via the blood stream. Moreover, the description of compromised EVT invasion into the venous and lymphatic vasculature in RSA may help to better understand the pathological characteristics of idiopathic recurrent pregnancy loss. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by the Austrian Science Fund (grant P-25187-B13 to J.P. and grant P-28417-B30 to M.K.). There are no competing interests to declare.

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.

Toll-like receptors (TLRs) initiate innate immune responses and direct subsequent adaptive immunity. They play a major role in cutaneous host defense against micro-organisms and in the pathophysiology of several inflammatory skin diseases. To understand the role of TLRs in the acquisition of immunological competence, we conducted a comprehensive study to evaluate TLR expression and function in the developing human skin before and after birth and compared it with adults. We found that prenatal skin already expresses the same spectrum of TLRs as adult skin. Strikingly, many TLRs were significantly higher expressed in prenatal (TLRs 1-5) and infant and child (TLRs 1 and 3) skin than in adult skin. Surprisingly, neither dendritic cell precursors in prenatal skin nor epidermal Langerhans cells and dermal dendritic cells in adult skin expressed TLRs 3 and 6, whereas the staining pattern and intensity of both TLRs in fetal basal keratinocytes was almost comparable to those of adults. Stimulation of primary human keratinocytes from fetal, neonatal and adult donors with selected TLR agonists revealed that the synthetic TLR3 ligand poly (I:C) specifically, mimicking viral double-stranded RNA, induced a significantly enhanced secretion of CXCL8/IL8, CXCL10/IP-10 and TNFα in fetal and neonatal keratinocytes compared with adult keratinocytes. This study demonstrates quantitative age-specific modifications in TLR expression and innate skin immune reactivity in response to TLR activation. Thus, antiviral innate immunity already in prenatal skin may contribute to protect the developing human body from viral infections in utero in a scenario where the adaptive immune system is not yet fully functional.

The adult human skin harbors a variety of leukocytes providing immune surveillance and host defense, but knowledge about their ontogeny is scarce. In this study we investigated the number and phenotype of leukocytes in prenatal human skin (dermal dendritic cells (DDCs), macrophages, T cells (including FoxP3(+) regulatory T cells), and mast cells) to unravel their derivation and to get a clue as to their putative function in utero. By flow cytometry and immunofluorescence, we found a distinction between CD206(+)CD1c(+)CD11c(+) DDCs and CD206(+)CD209(+)CD1c(-) skin macrophages by 9 weeks estimated gestational age (EGA). T cells appear at the end of the first trimester, expressing CD3 intracytoplasmatically. During midgestation, CD3(+)FoxP3(-) and CD3(+)FoxP3(+) cells can exclusively be found in the dermis. Similarly, other leukocytes such as CD117(+) (c-kit) mast cells were not identified before 12-14 weeks EGA and only slowly acquire a mature phenotype during gestation. Our data show at which time point during gestation antigen-presenting cells, T cells, and mast cells populate the human dermis and provide a step forward to a better understanding of the development of the human skin immune system.

background: Misoprostol has been shown to be an effective agent for cervical ripening and termination of early pregnancy especially when administered vaginally. Our objective was to evaluate whether bacterial vaginosis (BV) affected the pharmacokinetics of vaginally administered misoprostol during early pregnancy. methods: Ten women with BV and 10 healthy women requesting medical abortion up to 9 weeks of pregnancy were administered 200 mg mifepristone followed 24 –48 h later by a single dose of 800 mg misoprostol vaginally. Blood samples were taken before (0 h) and 0.5, 1, 2, 3 and 4 h after misoprostol administration. Misoprostol acid was determined in serum samples using liquid chromatography/tandem mass spectrometry. results: All women with BV had a vaginal pH . 4.7. The mean bioavailability measured as the area under the curve (AUC) and maximum concentration (Cmax) appeared higher in the control than in the BV group (1458.7 versus 878.1 pg h/ml) and (630.7 versus 342.5 pg/ml), respectively, but did not achieve statistical significance and there was no other significant difference in the pharmacokinetics between the two groups. However, if two women with vaginal pH . 4.7 were excluded from the control group the difference in AUC240 (1359 versus 878.1 pg h/ml) reached statistical significance (P ¼ 0.048). conclusions: BV had an effect on pharmacokinetics of vaginally administered misoprostol in early pregnancy. However, the results should be interpreted with caution due to the small sample size and marked individual variations.

We write to offer feedback on the new Faculty of Sexual & Reproductive Healthcare (FSRH) guideline1 on conscientious objection (CO) that was the subject of an editorial2 in the January 2018 issue of this journal. Our position, for which we have a clear evidence base, is set out below. Essential parts of the new FSRH guideline,1 as well as the reasoning behind it, contradict the available evidence around the practice of CO, so we predict that the guideline will largely fail in practice. We have written extensively on the problem of so-called CO in reproductive healthcare.3 The available evidence clearly shows that CO is a violation of medical ethics and patients’ rights, has no place in reproductive healthcare, and has misleadingly been co-opted from military CO. CO in healthcare is about imposing one’s religious or personal beliefs, including any negative …

Approximately 12 million women worldwide use the levonorgestrel-releasing intrauterine system (IUS), with approximately 180,000 users of this IUS currently reported in Austria. A patient satisfaction study of 591 women in Austria revealed a high number of 'very satisfied' (79%) and 'satisfied' (19%) patients. Reliability, comfort, excellent compatibility and less severe, shorter and less painful monthly periods were the most frequently named advantages of the levonorgestrel-releasing IUS. Medication-induced cervical priming before insertion can be carried out on a routine or selective basis (for example in nullipara, in women who have undergone cervical conisation or in women who have previously experienced painful insertion). There is, at present, no evidence of an increased rate of breast cancer through use of the levonorgestrel-releasing IUS. A directly comparative study with oral contraceptives in young nullipara showed excellent results for the levonorgestrel-releasing IUS, with no perforations, inflammation or pregnancies.

Adequate numbers and functional maturity are needed for leukocytes to exhibit a protective role in host defense. During intrauterine life, the skin immune system has to acquire these prerequisites to protect the newborn from infection in the hostile external environment after birth. We investigated the quantitative, phenotypic, and functional development of skin leukocytes and analyzed the factors controlling their proliferation and trafficking during skin development. We show that CD45+ leukocytes are scattered in embryonic human skin and that their numbers continuously increase as the developing skin generates an environment that promotes proliferation of skin resident leukocytes as well as the influx of leukocytes from the circulation. We also found that CD45+HLA-DRhighCD1c+ dendritic cells (DCs) are already present in the epidermis and dermis at 9 wk estimated gestational age (EGA) and that transforming growth factor β1 production precedes Langerin and CD1a expression on CD45+CD1c+ Langerhans cell (LC) precursors. Functionally, embryonic antigen-presenting cells (APCs) are able to phagocytose antigen, to up-regulate costimulatory molecules upon culture, and to efficiently stimulate T cells in a mixed lymphocyte reaction. Collectively, our data provide insight into skin DC biology and the mechanisms through which skin DCs presumably populate the skin during development.

Our aim was to assess the level of inconvenience associated with monthly bleeding, determine how many women would prefer a bleeding frequency of less than once a month, and what would motivate their choice.A 15-min quantitative online survey was carried out among 2883 women aged between 18 and 45 years in six European countries (Austria, Belgium, France, Italy, Poland and Spain).Of those surveyed, 1319 women used a combined hormonal contraceptive (CHC group) and 1564 used a non-hormonal contraceptive or no contraceptive (non-HC group). The menstrual period was significantly longer (5 vs. 4.5 days), heavier (16% vs. 8% heavy menstrual flow) and associated with more symptoms (6.1 vs. 5.6) in non-HC users than in CHC users (p 0.0001). More than half of the women in each group reported pelvic pain, bloating/swelling, mood swings and irritability, but the rate was significantly higher in the non-HC group. Given the choice, 57% of women in both groups said they would opt for longer intervals between periods. Sexuality, social life, work and sporting activities were key factors affecting their decision.The majority of women would prefer to have menstrual periods less than once a month, with a frequency ranging from once every 3 months to no periods at all. This can be explained by the desire to avoid the unpleasant aspects of menstruation and its negative impact on private and professional life.

Cervical priming with misoprostol has shown to facilitate transcervical procedures and to reduce side-effects. Cervical priming is recommended by several evidence-based guidelines prior to surgical abortion, dilatation and curettage, hysteroscopy and intrauterine device insertion. It is effective in pregnant as well as in non-pregnant women while the results in post-menopausal women are conflicting. Misoprostol is the best suited prostaglandin for a number of reasons: it has a short half-life, few side effects, it is stable at room temperature, it is relatively cheap and the dosage can easily be adjusted according to the clinical need. Various doses, routes, and time intervals between misoprostol application and the intervention have been evaluated. A single dose of 400 microg given sublingually or vaginally 3h before the intervention has given the best efficacy with the least side effects. Higher doses or longer intervals do not improve the effect on the cervix. Pain is a frequent side effect, but usually responds well to NSAIDs. Other side effects are rare.

BACKGROUND: It has been shown that the route of administration of misoprostol has a strong impact on the pharmacokinetic profile and result in different clinical efficacy. No study has so far evaluated the pharmacokinetics beyond 6 hours. Furthermore a new slow-release misoprostol formulation was included in the study. METHODS: Pharmacokinetics of a novel slow-release (SR) oral misoprostol was compared during 12 h after administration to conventional misoprostol administered vaginally or sublingually. Thirty-three women requesting surgical abortion up to 12 weeks were randomly allocated to groups receiving a single dose of 400 μg conventional misoprostol administered vaginally or sublingually or 800 μg SR oral misoprostol. Blood samples were taken before (0 h) and 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 h after misoprostol administration. Misoprostol acid (MPA) was determined in serum samples using liquid chromatography/tandem mass spectrometry. RESULTS: Three women did not complete the study. Serum concentrations reached their highest level following sublingual misoprostol (P < 0.0001) and the time to peak concentration was shortest for this group (P = 0.0094). The area under the curve (AUC) up to 12 h was greater following sublingual treatment than for the other alternatives (P < 0.0001) and lowest for SR misoprostol. Cumulative serum levels of MPA did not increase beyond 6 h following sublingual and vaginal administration, while they continued to increase up to 12 h following SR misoprostol. CONCLUSIONS: The new SR form of misoprostol demonstrated lower peak levels and a lower AUC but longer lasting elevation in serum levels when compared to conventional misoprostol administered sublingually or vaginally. SR misoprostol may offer an alternative to repeated administration of conventional misoprostol.