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Miscarriage is generally defined as the loss of a pregnancy before viability. An estimated 23 million miscarriages occur every year worldwide, translating to 44 pregnancy losses each minute. The pooled risk of miscarriage is 15·3% (95% CI 12·5–18·7%) of all recognised pregnancies. The population prevalence of women who have had one miscarriage is 10·8% (10·3–11·4%), two miscarriages is 1·9% (1·8–2·1%), and three or more miscarriages is 0·7% (0·5–0·8%). Risk factors for miscarriage include very young or older female age (younger than 20 years and older than 35 years), older male age (older than 40 years), very low or very high body-mass index, Black ethnicity, previous miscarriages, smoking, alcohol, stress, working night shifts, air pollution, and exposure to pesticides. The consequences of miscarriage are both physical, such as bleeding or infection, and psychological. Psychological consequences include increases in the risk of anxiety, depression, post-traumatic stress disorder, and suicide. Miscarriage, and especially recurrent miscarriage, is also a sentinel risk marker for obstetric complications, including preterm birth, fetal growth restriction, placental abruption, and stillbirth in future pregnancies, and a predictor of longer-term health problems, such as cardiovascular disease and venous thromboembolism. The costs of miscarriage affect individuals, health-care systems, and society. The short-term national economic cost of miscarriage is estimated to be £471 million per year in the UK. As recurrent miscarriage is a sentinel marker for various obstetric risks in future pregnancies, women should receive care in preconception and obstetric clinics specialising in patients at high risk. As psychological morbidity is common after pregnancy loss, effective screening instruments and treatment options for mental health consequences of miscarriage need to be available. We recommend that miscarriage data are gathered and reported to facilitate comparison of rates among countries, to accelerate research, and to improve patient care and policy development.

INTRODUCTION: Curettage is more effective than expectant management in women with suspected incomplete evacuation after misoprostol treatment for first-trimester miscarriage. The cost-effectiveness of curettage vs. expectant management in this group is unknown.MATERIAL AND METHODS: From June 2012 until July 2014 we conducted a randomized controlled trial and parallel cohort study in the Netherlands, comparing curettage with expectant management in women with an incomplete evacuation of the uterus after misoprostol treatment for first-trimester miscarriage. Successful treatment was defined as a sonographic finding of an empty uterus 6 weeks after study entry, or an uneventful course. Cost-effectiveness and cost-utility analyses were performed. We included costs of healthcare utilization, informal care and lost productivity. Cost-effectiveness planes and cost-effectiveness acceptability curves were estimated using bootstrapping.RESULTS: We included 256 women from 27 hospitals; 95 curettage and 161 expectant management. Treatment was successful in 96% of the women treated with curettage vs. 83% of the women after expectant management (mean difference 13%, 95% confidence interval 5-20). Mean costs were significantly higher in the curettage group (mean difference €1157; 95% C confidence interval €955-1388). The incremental cost-effectiveness ratio for curettage vs. expectant management was €8586 per successfully treated woman. The cost-effectiveness acceptability curve showed that at a willingness-to-pay of €18 200/extra successfully treated women, the probability that curettage is cost-effective is 95%.CONCLUSIONS: Curettage is not cost-effective compared with expectant management in women with an incomplete evacuation of the uterus after misoprostol treatment. This indicates that curettage in this group should be restrained.

Background: Nitrous oxide (N2O) is a common inhalation anaesthetic used in medical, paramedical, and veterinary practice. Since the mid 1950's, concerns have been raised regarding occupational exposure to N2O, leading to many epidemiological and experimental animal studies. Previous evaluations resulted in the classification of N2O as a possible risk factor for adverse reproductive health outcomes based on animal data. Human data were deemed inadequate primarily because of simultaneous co-exposures to other risk factors for adverse reproductive and developmental outcomes, including other anaesthetic gases. Since previous evaluations, controversies regarding N2O use remained and new approaches for dose response modelling have been adopted, calling for an update and re-evaluation of the body of evidence. This review aims to assess available animal evidence on N2O reproductive and developmental outcomes to inform a health-based recommended occupational exposure limit (OEL) for N2O with a benchmark dose-response modelling (BMD) approach. Methods: Comprehensive searches in PubMed, EMBASE, and Web of Science were performed to retrieve all relevant studies addressing reproductive and developmental outcomes related to inhalation of N2O in animals. The articles retrieved were screened based on title-abstract and full text by two independent reviewers. After data extraction, an overview of all studies was created for the different endpoints, namely foetal outcomes (e.g. resorption), female outcomes (e.g. implantations), and male outcomes (e.g. sperm count). A subset of studies reporting on exposure relevant to workplace settings and with a sufficient number of tested doses were included in dose-response modelling using the BMD approach. Results: In total, 15.816 articles were retrieved, of which 47 articles were finally included while 4 of those were used for the quantitative data synthesis. The overall risk of bias was judged to be probably high (using OHAT risk of bias tool) and unclear (using SYRCLE's risk of bias tool). From eligible rat studies, three studies provided an acceptable result by fitting a Hill model to the dose-response data. The resulting benchmark dose lower bounds (BMDLs) from three studies converged to an average (±sd) exposure level of 925 ± 2 mg/m3 at an additional risk of one standard deviation of implantation losses above those observed in the control group (i.e. reduced number of live foetuses/mother). For extrapolation from rats to humans, an uncertainty factor of 10 was used and an additional factor of 5 was applied to account for interindividual variability within the population of workers. Conclusion: With this systematic review, all available evidence for reproductive toxicity and adverse developmental outcomes in animals resulting from inhalation exposure to N2O was used to derive a health-based OEL recommendation of 20 mg/m3 as 8-h time-weighted average., SCOPUS: re.j, info:eu-repo/semantics/published

Objective: To assess the effectiveness of curettage versus expectant management in women with an incomplete evacuation of the uterus after misoprostol treatment for first trimester miscarriage.Study design: We conducted a multicenter cohort study alongside a randomized clinical trial (RCT) between June 2012 until July 2014. 27 Dutch hospitals participated. Women with an incomplete evacuation after misoprostol treatment for first trimester miscarriage who declined to participate in the RCT, received treatment of their preference; curettage (n = 65) or expectant management (n = 132). A successful outcome was defined as an empty uterus on sonography at six weeks or uneventful clinical follow-up. We furthermore assessed complication rate and (re)intervention rateResults: Of the 197 women who declined to participate in the RCT, 65 preferred curettage and 132 expectant management. A successful outcome was observed in 62/65 women (95%) in the surgical group versus 112/132 women (85%) in the expectant group (RR 1.1, 95% CI 1.03-1.2), with complication rates of 6.2% versus 2.3%, respectively (RR 2.7, 95% CI 0.6-12).Conclusion: In women with an incomplete evacuation of the uterus after misoprostol treatment, expectant management is an effective and safe option. This finding could restrain the use of curettage in women that have used misoprostol in the treatment of first trimester miscarriage. (C) 2017 Elsevier B.V. All rights reserved.

Background: Stillbirth affects at least 2.6 million families worldwide every year and has enduring consequences for parents and health services. Parents entering a subsequent pregnancy following stillbirth face a risk of stillbirth recurrence, alongside increased risks of other adverse pregnancy outcomes and psychosocial challenges. These parents may benefit from a range of interventions to optimise their short‐ and longer‐term medical health and psychosocial well‐being. Objectives: To assess the effects of different interventions or models of care prior to and during subsequent pregnancies following stillbirth on maternal, fetal, neonatal and family health outcomes, and health service utilisation. Search methods: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (6 June 2018), along with ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) (18 June 2018). Selection criteria: We included randomised controlled trials (RCTs) and quasi‐randomised controlled trials (qRCTs). Trials using a cluster‐randomised design were eligible for inclusion, but we found no such reports. We included trials published as abstract only, provided sufficient information was available to allow assessment of trial eligibility and risk of bias. We excluded cross‐over trials. Data collection and analysis: Two review authors independently assessed trials for eligibility and undertook data extraction and 'Risk of bias' assessments. We extracted data from published reports, or sourced data directly from trialists. We checked the data for accuracy and resolved discrepancies by discussion or correspondence with trialists, or both. We conducted an assessment of the quality of the evidence using the GRADE approach. Main results: We included nine RCTs and one qRCT, and judged them to be at low to moderate risk of bias. Trials were carried out between the years 1964 and 2015 and took place predominantly in high‐income countries in Europe. All trials assessed medical interventions; no trials assessed psychosocial interventions or incorporated psychosocial aspects of care. Trials evaluated the use of antiplatelet agents (low‐dose aspirin (LDA) or low‐molecular‐weight heparin (LMWH), or both), third‐party leukocyte immunisation, intravenous immunoglobulin, and progestogen. Trial participants were women who were either pregnant or attempting to conceive following a pregnancy loss, fetal death, or adverse outcome in a previous pregnancy. We extracted data for 222 women who had experienced a previous stillbirth of 20 weeks' gestation or more from the broader trial data sets, and included them in this review. Our GRADE assessments of the quality of evidence ranged from very low to low, due largely to serious imprecision in effect estimates as a result of small sample sizes, low numbers of events, and wide confidence intervals (CIs) crossing the line of no effect. Most of the analyses in this review were not sufficiently powered to detect differences in the outcomes assessed. The results presented are therefore largely uncertain. Main comparisons: LMWH versus no treatment/standard care (three RCTs, 123 women, depending on the outcome): It was uncertain whether LMWH reduced the risk of stillbirth (risk ratio (RR) 2.58, 95% CI 0.40 to 16.62; 3 trials; 122 participants; low‐quality evidence), adverse perinatal outcome (RR 0.81, 95% CI 0.20 to 3.32; 2 trials; 77 participants; low‐quality evidence), adverse maternal psychological effects (RR 1.00, 95% CI 0.07 to 14.90; 1 trial; 40 participants; very low‐quality evidence), perinatal mortality (RR 2.58, 95% CI 0.40 to 16.62; 3 trials; 122 participants; low‐quality evidence), or any preterm birth (< 37 weeks) (RR 1.01, 0.58 to 1.74; 3 trials; 114 participants; low‐quality evidence). No neonatal deaths were reported in the trials assessed and no data were available for maternal‐infant attachment. There was no clear evidence of a difference between the groups among the remaining secondary outcomes. LDA versus placebo (one RCT, 24 women): It was uncertain whether LDA reduced the risk of stillbirth (RR 0.85, 95% CI 0.06 to 12.01), neonatal death (RR 0.29, 95% CI 0.01 to 6.38), adverse perinatal outcome (RR 0.28, 95% CI 0.03 to 2.34), perinatal mortality, or any preterm birth (< 37 weeks) (both of the latter RR 0.42, 95% CI 0.04 to 4.06; all very low‐quality evidence). No data were available for adverse maternal psychological effects or maternal‐infant attachment. LDA appeared to be associated with an increase in birthweight (mean difference (MD) 790.00 g, 95% CI 295.03 to 1284.97 g) when compared to placebo, but this result was very unstable due to the extremely small sample size. Whether LDA has any effect on the remaining secondary outcomes was also uncertain. Other comparisons: LDA appeared to be associated with an increase in birthweight when compared to LDA + LMWH (MD −650.00 g, 95% CI −1210.33 to −89.67 g; 1 trial; 29 infants), as did third‐party leukocyte immunisation when compared to placebo (MD 1195.00 g, 95% CI 273.35 to 2116.65 g; 1 trial, 4 infants), but these results were again very unstable due to extremely small sample sizes. The effects of the interventions on the remaining outcomes were also uncertain. Authors' conclusions: There is insufficient evidence in this review to inform clinical practice about the effectiveness of interventions to improve care prior to and during subsequent pregnancies following a stillbirth. There is a clear and urgent need for well‐designed trials addressing this research question. The evaluation of medical interventions such as LDA, in the specific context of stillbirth prevention (and recurrent stillbirth prevention), is warranted. However, appropriate methodologies to evaluate such therapies need to be determined, particularly where clinical equipoise may be lacking. Careful trial design and multicentre collaboration is necessary to carry out trials that would be sufficiently large to detect differences in statistically rare outcomes such as stillbirth and neonatal death. The evaluation of psychosocial interventions addressing maternal‐fetal attachment and parental anxiety and depression is also an urgent priority. In a randomised‐trial context, such trials may allocate parents to different forms of support, to determine which have the greatest benefit with the least financial cost. Importantly, consistency in nomenclature and in data collection across all future trials (randomised and non‐randomised) may be facilitated by a core outcomes data set for stillbirth research. All future trials should assess short‐ and longer‐term psychosocial outcomes for parents and families, alongside economic costs of interventions.

Recurrent miscarriage is a reproductive disorder affecting many couples. Although several factors are associated with recurrent miscarriage, in more than 50% of the cases the cause is unknown. Maladaptation of the maternal immune system is associated with recurrent miscarriage and could explain part of its pathophysiology. Modulating the maternal immune system toward pregnancy tolerance could benefit pregnancy outcome. Although there is a clear scientific rationale that modulating the maternal immune system could benefit recurrent miscarriage, only a few studies suggest possible beneficial effects of immune modulators as a therapy for recurrent miscarriage. Therapies skewing the maternal immune response to a tolerating regulatory T cell rich environment seem especially promising; however, more research is needed to find effective and safe maternal immune modulators for reproductive pathologies as recurrent miscarriage. Moreover, the possible side effects on maternal, fetal, and neonatal immune function are essentially unknown, and its elucidation is crucial before any possible therapeutic strategies could be clinically implemented. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

Item does not contain fulltext STUDY QUESTION: Is curettage more effective than expectant management in case of an incomplete evacuation after misoprostol treatment for first trimester miscarriage? SUMMARY ANSWER: Curettage leads to a higher chance of complete evacuation but expectant management is successful in at least 76% of women with an incomplete evacuation of the uterus after misoprostol treatment for first trimester miscarriage. WHAT IS KNOWN ALREADY: In 5-50% of the women treated with misoprostol, there is a suspicion of incomplete evacuation of the uterus on sonography. Although these women generally have minor symptoms, such a finding often leads to additional curettage. STUDY DESIGN, SIZE, DURATION: From June 2012 until July 2014, we conducted a nationwide multicenter randomized controlled trial (RCT). Women who had had primary misoprostol treatment for miscarriage with sonographic evidence of incomplete evacuation of the uterus were randomly allocated to either curettage or expectant management (1:1), using a web-based application. PARTICIPANTS/MATERIALS, SETTING, METHODS: We included 59 women in 27 hospitals; 30 were allocated to curettage and 29 were allocated to expectant management. A successful outcome was defined as sonographic finding of an empty uterus 6 weeks after randomization. MAIN RESULTS AND THE ROLE OF CHANCE: Baseline characteristics of both groups were comparable. Empty uterus on sonography or uneventful clinical follow-up was seen in 29/30 women (97%) allocated to curettage compared with 22/29 women (76%) allocated to expectant management (RR 1.3, 95% CI 1.03-1.6) with complication rates of 10% versus 10%, respectively (RR 0.97, 95% CI 0.21-4.4). In the group allocated to curettage, no woman required re-curettage, while two women (6.7%) underwent hysteroscopy (for other or unknown reasons). In the women allocated to expectant management, curettage was performed in four women (13.8%) and three women (10.3%) underwent hysteroscopy. LIMITATIONS, REASONS FOR CAUTION: Due to a strong patient preference, mainly for expectant management, the targeted sample size could not be included and the trial was stopped prematurely. WIDER IMPLICATIONS OF THE FINDINGS: In women suspected of incomplete evacuation of the uterus after misoprostol, curettage is more effective than expectant management. However, expectant management is equally safe and prevents curettage for most of the women. This finding could further restrain the use of curettage in the treatment of first trimester miscarriage. STUDY FUNDING/COMPETING INTERESTS: This study was funded by ZonMw, a Dutch organization for Health Research and Development, project number 80-82310-97-12066. There were no conflicts of interests. TRIAL REGISTRATION NUMBER: Dutch Trial Register NTR3310, http://www.trialregister.nl TRIAL REGISTRATION DATE: 27 February 2012. DATE OF FIRST PATIENT'S ENROLMENT: 12 June 2012.

BACKGROUND: Adverse reproductive performance has been linked to unhealthy dietary intake and lifestyles. Our objectives were to investigate the prevalence of unhealthy dietary intake and lifestyles before conception and to evaluate whether tailored preconception counselling modifies these behaviours. METHODS: Between October 2007 and April 2009, 419 couples received tailored preconception dietary and lifestyle counselling at the outpatient clinic of Obstetrics and Gynaecology of the Erasmus University Medical Center Rotterdam, the Netherlands. A subgroup (n = 110 couples) was counselled twice with a fixed time interval of 3 months. Self-administered questionnaires were used for tailored dietary and lifestyle counselling. A cumulative score based on six Dutch dietary guidelines was displayed in the personal Preconception Dietary Risk score (PDR score). In a similar manner, the Rotterdam Reproduction Risk score (R3 score) was calculated from lifestyle factors (women: 13 items, men: 10 items). Univariate and paired tests were used. RESULTS: Most couples (93.8%) were subfertile. At the second counselling, the percentage consuming the recommended intake of fruit had increased from 65 to 80 in women and from 49 to 68 in men and the percentage of women getting the recommended intake of fish increased from 39 to 52. As a consequence, the median PDR score was decreased [women: 2.6 (95% CI 2.4-2.9) to 2.4 (95% CI 2.1-2.6), men: 2.5 (95% CI 2.3-2.7) to 2.2 (95% CI 1.9-2.4), both P < 0.05]. The median R3 scores were also lower [women: 4.7 (95% CI 4.3-5.0) to 3.1 (95% CI 2.8-3.4), men: 3.0 (95% CI 2.8-3.3) to 2.0 (95% CI 1.7-2.3), both P < 0.01] due to less alcohol use (-14.6%), more physical exercise and folic acid use in women, and less alcohol use in men (-19.4%) (all P < 0.01). The R3 scores in women and men were decreased in all ethnicity, educational level, neighbourhood and BMI categories. However, low educated women appeared to show a larger reduction than better educated women and men with a normal BMI to showa larger decrease than overweight men. The reduction in the PDR score of women was similar in both ethnic groups. More than 85% women and men found the counselling useful and around 70% would recommend it to others. CONCLUSIONS: Tailored preconception counselling about unhealthy dietary and lifestyle behaviours of subfertile couples in an outpatient tertiary clinic is feasible and seems to decrease the prevalence of harmful behaviours in the short term. These results with subfertile couples are promising and illustrate their opportunities to contribute to reproductive performance and pregnancy outcome.

We investigated the association between total trihalomethanes (TTHMs) and risk of stillbirth and low and very low birth weight in three water regions in England, 1992-1998; associations with individual trihalomethanes (THMs) were also examined. Modeled estimates of quarterly TTHM concentrations in water zones, categorized as low (30 microg/L), medium (30-59 microg/L), or high (or = 60 microg/L), were linked to approximately 1 million routine birth and stillbirth records using maternal residence at time of birth. In one region, where there was a positive socioeconomic deprivation gradient across exposure categories, there was also a positive, significant association of TTHM with risk of stillbirth and low and very low birth weight. Overall summary estimates across the three regions using a random-effects model to allow for between-region heterogeneity in exposure effects showed small excess risks in areas with high TTHM concentrations for stillbirths [odds ratio (OR) = 1.11; 95% confidence interval (CI), 1.00-1.23), low birth weight (OR = 1.09; 95% CI, 0.93-1.27), and very low birth weight (OR = 1.05; 95% CI, 0.82-1.34). Among the individual THMs, chloroform showed a similar pattern of risk as TTHM, but no association was found with concentrations of bromodichloromethane or total brominated THMs. Our findings overall suggest a significant association of stillbirths with maternal residence in areas with high TTHM exposure. Further work is needed looking at cause-specific stillbirths and effects of other disinfection by-products and to help differentiate between alternative (noncausal) explanations and those that may derive from the water supply.

BACKGROUND: Little is known about the effectiveness of misoprostol treatment in women with early pregnancy failure who have been managed expectantly. We therefore performed a randomized trial on this subject. METHODS: Women with early pregnancy failure, who had been managed expectantly for at least 1 week, were assigned randomly (using a computer-generated list) to receive either vaginal misoprostol 800 mug or curettage. If, after 24 h, there had not been complete evacuation, a further 800 mug of misoprostol was administered. In the absence of complete evacuation after >3 days, curettage was performed. The primary end-point was the complete evacuation of the products of conception, with secondary end-points being the occurrence of side effects, pain intensity, need for analgesics, and intensity and duration of bleeding. RESULTS: In the misoprostol group, 47% (37/79) required curettage due to incomplete evacuation. After 1 week, evacuation was complete in 85% (67 out of 79) of the misoprostol group and 93% (70 out of 75) of the curettage group. Severity of pain, bleeding and emergency evacuation was higher in the misoprostol group. The complication rate was 0% for misoprostol and 4% for curettage. CONCLUSIONS: Curettage is superior to misoprostol in the evacuation of early pregnancy failure after failed expectant management. However, misoprostol could be clinically useful since it reduces the need for curettage by half and has a lower complication rate, at the expense of increased pain, vaginal bleeding and emergency evacuation.

To determine whether the use of video display terminals (VDTs) is associated with an increased risk of reduced birthweight (RBW) and preterm birth, a cohort o f telephone operators who used VDTs at work was compared to a cohort of non- VDT- use rs. Am ong 2,430 women interviewed, 713 eligible singleton live births were reported. Exposure was estim ated from company records and a representative sample of electromagnetic fields was m easured at the VDT workstations. For RBW (^2,800 g)t we found no excess risk associated with any VDT use during pregnancy (odds ratio [OR] = 0.9; 95% confidence interval [C l] — 0.5—1,7). For preterm birth 37 weeks), we similarly found no excess risk (OR ~ 0.7; 95% C I = 0.4-1.1). The risks estimated did not change substantially when hours working with VDTs were used as exposure variables. By contrast, increased risks were found fo r several known risk factors fo r LBW and preterm birth. We conclude that occupational VDT use does not increase the risk o f RBW and preterm birth. Am. J. Ind. Med. 32:681-688, 1997. © 1997 Wiley-Liss, lnc.f