Abstract Study question What is the impact of adenomyosis and its phenotypes on spectrum of outcomes ranging from conception to birth? Summary answer Adenomyosis has a negative impact on implantation with reduced clinical pregnancy and live birth rate and increased risk of miscarriage and perinatal morbidity. What is known already Current evidence, including meta-analyses, on the impact of adenomyosis on reproductive outcomes is conflicting. There are data suggesting that adenomyosis has a negative impact on pregnancy outcomes whereas some studies have suggested that adenomyosis appears inert, with no impact on reproductive functions. A wide variation has been observed in the baseline population, type of Assisted Reproductive Technology (ART) stimulation protocol, number, order and type of ART cycles across the pooled observational studies. Alongside, there may be a spectrum of adenomyosis characteristics like the disease type, location, severity, and presence of coexisting endometriosis, resulting in heterogeneity and our interpretation of evidence. Study design, size, duration For this systematic review and meta-analysis, a comprehensive search was conducted in MEDLINE, EMBASE, CINAHL Plus, Web of Science Core Collection, Clinicaltrials.gov and WHO ICTRP from inception until January 2024 with no language restriction. Observational studies were included with participants as women with natural and/or medically assisted reproduction (MAR) conception, exposure as adenomyosis diagnosed on imaging, histology or using WHO International Classification of Disease 10th edition (ICD-10) code (N80.0) and comparator as women without adenomyosis. Participants/materials, setting, methods Data was included from 51 observational studies for the meta-analysis of pregnancy and obstetric outcomes. ROBINS-E tool (Risk Of Bias In Non-randomized Studies-of Exposure) was be used to assess the risk of bias. Odds ratio (OR) from individual studies were pooled using random-effects model to summarise the estimate for dichotomous outcomes with 95% confidence interval (CI) and mean differences for continuous outcomes. This was supplemented by sensitivity analyses. Clinical heterogeneity was assessed with I² statistics. Main results and the role of chance Women with adenomyosis had reduced odds of implantation (OR = 0.78; CI: 0.72-0.86), lower clinical pregnancy (OR = 0.87; CI: 0.82-0.92), higher miscarriage (OR = 1.51; CI: 1.44-1.58), and lower live birth (OR = 0.56; CI: 0.50-0.63) compared to those without. Both, diffuse and focal adenomyosis were associated with lower live birth (OR = 0.56; CI: 0.45-0.72; diffuse and OR = 0.56; CI: 0.45-0.70; focal). The miscarriage risk was higher in junctional zone adenomyosis (OR = 4.04; CI: 1.17-13.94) compared to outer myometrium adenomyosis. The negative impact of adenomyosis was evident in subgroups of women undergoing donor oocyte cycles (OR = 0.62; CI: 0.50-0.76; live birth and OR = 1.83; CI: 1.26-2.66; miscarriage) and first ART cycle (OR = 0.55; CI: 0.48-0.65; live birth and OR = 2.16 CI: 1.72-2.71; miscarriage). Conversely, those with euploid embryo transfer, had a higher odds of miscarriage (OR = 1.90; CI:1.05-3.43) with no significant impact on live birth (OR = 0.78; CI: 0.52-1.19). The impact continued perinatally, including pre-eclampsia (OR = 1.32; CI: 1.23-1.41), small for gestational age (OR = 1.323; CI:1.25-1.40), placenta previa (OR = 3.99, CI: 3.53-4.51), caesarean section (OR = 1.97; CI:1.89-2.05), and low Apgar scores (OR = 0.911; CI:0.88-0.96). Limitations, reasons for caution The inherent heterogeneity among the included observational studies was high; however, subgroup analyses for type of ART cycle, number, and order of ART cycle and by phenotype of adenomyosis had low heterogeneity. This warrants caution when interpreting pooled outcome estimates for pregnancy and obstetric outcomes across general population of women. Wider implications of the findings Adenomyosis has a direct and negative impact on fertility and pregnancy outcomes by virtue of impaired implantation and trophoblastic function. Hence, adenomyosis needs to be factored in when counselling women about the success of MAR cycles and requires closer monitoring in pregnancy as a high-risk pregnancy. Trial registration number not applicable

Abstract Study question Does the history of caesarean births influence miscarriage risk in subsequent pregnancies? Summary answer In women with a history of 3 or more miscarriage(s), the subsequent miscarriage risk may increase with the presence and number of previous caesarean births. What is known already History of caesarean birth increases the risk of complications in subsequent pregnancies, including risks of spontaneous preterm birth. The evidence of association between caesarean births and subsequent miscarriage risk is scant and conflicting. Study design, size, duration We performed a secondary analysis of the dataset from three multicentre, prospective, double-blind, and placebo-controlled randomized trials. Study registration, duration, size, population, and intervention are as follows: 1) PROMISE; ISRCTN92644181; 2010 - 2013, 826 women with a history of unexplained recurrent miscarriages, progesterone. 2) PRISM; ISRCTN14163439; 2015 - 2017, 4038 women who experienced vaginal bleeding in early pregnancy, progesterone. 3) TABLET; ISRCTN15948785; 2011 - 2016, 940 euthyroid women with thyroid peroxidase antibodies, and miscarriages or infertility history, levothyroxine. Participants/materials, setting, methods The primary outcome for this analysis was miscarriage rate, defined as loss of pregnancy <24 weeks of gestation. RR with 95% CI was estimated using the Poisson regression model and adjusted for age, BMI, ethnicity, smoking status, and previous miscarriages. Random-effects two-stage individual participant data meta-analysis approach was used to account for treatment allocation effects. Subgroup analysis was conducted in women with a history of repeated miscarriages (3 or more) at randomisation. Main results and the role of chance After excluding pregnancies with incomplete data, we included 5,039 pregnancies in the final analysis. The overall miscarriage rate was 24.9% (1256/5039). In the non-specific population of women, there was no association between the history of caesarean births and subsequent miscarriage risk (aRR 1.00, 95% CI 0.86 to 1.17; 5,039 pregnancies). In contrast, for the subgroup of women with a history of 3 or more miscarriage(s) at randomisation, the miscarriage rate appears to increase with the history of caesarean births, although with some degree of statistical uncertainty (aRR 1.10, 95% CI 0.97 to 1.26; 1172 pregnancies). The association became significant when the analysis was categorised according to the number of previous caesarean births. With 1 previous caesarean birth, the miscarriage risk increased by 3% (aRR 1.03, 95% CI 1.00 to 1.06; 1080 pregnancies). This risk was increased by 37% with 2 previous caesarean births (aRR 1.37, 95% CI 1.03 to 1.83; 971 pregnancies), therefore indicating the presence of a biological gradient of effect which increases our confidence in the above findings. The history of previous caesarean births may be a valid prognostic risk factor for future miscarriage risk in women with a history of recurrent miscarriage. Limitations, reasons for caution Further analysis by the gestation at miscarriage (early vs. late), the type (elective vs. emergency), indication or cervical dilatation status at caesarean births is required to understand the possible mechanism behind this association and to better identify women at increased risk of miscarriage(s) related to caesarean births. Wider implications of the findings Our findings suggest that a history of caesarean births may be associated with a small increased risk of subsequent miscarriage risk in a subgroup of women with a history of recurrent miscarriage(s). This information may assist women and healthcare providers to reach more informed decisions regarding the mode of delivery. Trial registration number The study is registered with the OSF registry (ve5j4).

ABSTRACT Objective To determine the prevalence of adenomyosis in women with subfertility. Methods A systematic search was conducted in MEDLINE, EMBASE, CINAHL Plus, Google Scholar, PsycINFO and Web of Science Core Collection from database inception to October 2022. The included studies evaluated the prevalence of adenomyosis in women with subfertility, with or without endometriosis and/or uterine fibroids. Secondary analyses were conducted to identify variation in the prevalence of isolated adenomyosis according to geographical location, diagnostic modality, diagnostic criteria, type of ultrasound, ultrasound features of adenomyosis and the use of assisted reproductive technology. Results Among 21 longitudinal studies evaluating 25 600 women, the overall pooled prevalence of isolated adenomyosis was 10% (95% CI, 6–15%) ( I 2 = 99.1%; tau 2 = 0.12). The pooled prevalence was 1% (95% CI, 0–4%) for adenomyosis with concurrent fibroids (eight studies; I 2 = 95.8%; tau 2 = 0.03), 6% (95% CI, 3–11%) for adenomyosis with concurrent endometriosis (18 studies; I 2 = 98.6%; tau 2 = 0.12) and 7% (95% CI, 2–13%) for adenomyosis with concurrent endometriosis and/or fibroids (nine studies; I 2 = 98.3%; tau 2 = 0.09). The prevalence of isolated adenomyosis varied substantially according to geographical location, with Australia exhibiting the highest pooled prevalence of adenomyosis (19% (95% CI, 12–27%)), which was significantly higher compared with that in Asia (5% (95% CI, 1–12%)). The pooled prevalence of isolated adenomyosis diagnosed using a combination of direct and indirect ultrasound features was 11% (95% CI, 7–16%), whereas it was 0.45% (95% CI, 0–1%) in the study in which only an indirect feature was used as the diagnostic criterion. Conclusion One in 10 women with subfertility have a diagnosis of isolated adenomyosis. The prevalence of adenomyosis varies according to the presence of concurrent endometriosis and/or fibroids. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Abstract Study question Does the use of ERA, EMMA (endometrial microbiome metogenomic analysis) or ALICE (analysis of infectious chronic endometritis) improve implantation rate and clinical pregnancy? Summary answer The use of ERA significantly improves the clinical pregnancy rate in women with recurrent implantation failure, no difference was observed for EMMA or ALICE. What is known already The ability of ERA to utilise endometrial tissue transcriptomics to detect asynchronous cycles is controversial. Retrospective studies have demonstrated significantly lower implantation rates for the non-receptive cohort and improved pregnancy rates by personalising the embryo transfer (pET). An RCT reported comparable clinical outcomes for pET and standard FET. There have also been multiple reports of the endometrium being dominated by Lactobacillus, prevalence of this species without bacterial vaginosis leads to positive outcomes in IVF. That said, there is a scarcity of good quality evidence to advocate the use of antibiotics and/or probiotics to treat dysbiosis or pathogens in the subfertile population. Study design, size, duration From Jan 2017 to August 2021 202 patients underwent one or more of ERA (n = 202), EMMA (n = 101), and/or ALICE (n = 97) at CARE Fertility UK. The cycle subsequent to the test was compared to 404 age matched control cycles. Participants/materials, setting, methods This study included patients from all 22 clinics across CARE Fertility UK. Rates of positive pregnancy test and clinical pregnancy were compared between patients with normal and abnormal test results using Chi-squared statistic. Binary logistic regression analysis and odds ratios were used to test for improvements in clinical outcomes by adjusting for the following covariates: age, BMI, parity, 2 or more previous implantation failures, donor eggs and frozen embryos. Main results and the role of chance ERA testing resulted in a normal result in 42.3% of patients, 30.6% were pre-receptive and 17% were early receptive. EMMA resulted in a normal result in 36% of patients, 22% were abnormal, 17% had ultra-low biomass and 25% mild dysbiosis. Only 4% of patients using the ALICE tested positive, therefore this was not included in any modelling due to low event rates. The implantation rate and clinical pregnancy rates showed no statistical significance between those with an abnormal result vs. those who had a normal test. When comparing those tested to matched controls and adjusting for the above covariates, the use of the ERA test was significantly associated with improved implantation rate (OR 3.08, 95% CI 1.57-6.03, p = 0.001) and clinical pregnancy rate (OR 2.7, 95% CI 1.38-5.28, p = 0.004). The use of the EMMA test did not improve implantation (OR 0.42, 95% CI 0.051-3.437, p = 0.418) or clinical pregnancy rate (OR 0.48, 95% CI 0.039-5.89, p = 0.566). When comparing those with an abnormal ERA (i.e. presumed intervention) to matched controls the ERA test was significantly associated with improved clinical pregnancy (OR 5.4, 95% CI 2.007-14.85, p < 0.001). On the other hand, EMMA was not associated with any improvements (p = 1.0). Limitations, reasons for caution The data collection process had limitations since minimal information was available for patients who underwent previous cycles at other clinics. The number of patients with receptive ERA and abnormal EMMA is small (n = 25) vs. those with a normal EMMA and ERA (n = 10). Therefore, a significant limitation is sample size. Wider implications of the findings ERA can be more confidently offered to patients and has been demonstrated to significantly improve clinical pregnancy rates. Further research is needed before we can determine whether EMMA or ALICE is a useful test, particularly when considering very few patients show evidence of chronic endometritis. Trial registration number Not applicable

Background and Aim: The use of time-lapse and its ability to predict, or improve, clinical outcomes remains controversial. Yet, we are increasingly witness to a growing number of models which are proposed to predict live birth. We present a model predicting probability of euploidy, based on embryo morphokinetics and morphology as well as sperm and clinical characteristics using one of the largest datasets published.

Introduction Women presenting with suspected pre-eclampsia are currently triaged on the basis of hypertension and dipstick proteinuria. This may result in significant false positive and negative diagnoses resulting in increased morbidity or unnecessary intervention. Recent data suggest that placental growth factor testing may be a useful adjunct in the management of women presenting with preterm pre-eclampsia. The primary objective of this trial is to determine if the addition of placental growth factor testing to the current clinical assessment of women with suspected preterm pre-eclampsia, is beneficial for both mothers and babies. Methods and analysis This is a multicentre, stepped wedge cluster, randomised trial aiming to recruit 4000 women presenting with symptoms suggestive of preterm pre-eclampsia between 20 and 36+6 weeks’ gestation. The intervention of an unblinded point of care test, performed at enrolment, will quantify maternal levels of circulating plasma placental growth factor. The intervention will be rolled out sequentially, based on randomisation, in the seven largest maternity units on the island of Ireland. Primary outcome is a composite outcome of maternal morbidity (derived from the modified fullPIERS model). To ensure we are not reducing maternal morbidity at the expense of earlier delivery and worse neonatal outcomes, we have established a co-primary outcome which will examine the effect of the intervention on neonatal morbidity, assessed using a composite neonatal score. Secondary analyses will examine further clinical outcomes (such as mode of delivery, antenatal detection of growth restriction and use of antihypertensive agents) as well as a health economic analysis, of incorporation of placental growth factor testing into routine care. Ethics and dissemination Ethical approval has been granted from each of the seven maternity hospitals involved in the trial. The results of the trial will be presented both nationally and internationally at conference and published in an international peer-reviewed journal. Trial registration number NCT02881073.