Ethnic group and reason for assisted reproductive technology failure: analysis of the Human Fertilisation and Embryology Authority registry data from 2017 to 2018.

OBJECTIVE: To understand how the risk of different assisted reproductive technology (ART) failure types varies by ethnic group and explore the role of mediation by maternal age and suspected etiology. DESIGN: An observational study of 48,750 women who undertook treatment with ART in the United Kingdom between January 2017 and December 2018. SETTING: The Human Fertilisation and Embryology Authority national ART registry of the United Kingdom. PATIENT(S): Women who commenced a first cycle of ART for the purpose of primary fresh embryo transfer using their own oocytes were included. INTERVENTION(S): Maternal ethnic group. MAIN OUTCOME MEASURE(S): The ART failure types were modeled on the maternal ethnic group using the Poisson regression to produce relative risks (RRs) with 95% confidence intervals. The potential indirect effects of maternal age and etiology of subfertility were estimated, and the RRs with 95% confidence intervals were produced. RESULT(S): Black women were at greater risk of treatment failure with respect to live birth than women who were white: cycle cancellation, RR of 2.15 (1.78-2.62); failed fertilization, RR of 2.36 (1.90-2.93); unintended freeze-all, RR of 1.71 (1.43-2.05); failed implantation, RR of 1.23 (1.12-1.34); and pregnancy loss, RR of 1.38 (1.15-1.64). Women who were Asian were at moderately increased risk: RRs of 1.31 (1.17-1.47), 1.60 (1.42-1.80), 1.25 (1.14-1.38), 1.11 (1.07-1.16), and 1.13 (1.03-1.23), across the same outcomes, respectively. Inequality may have been reduced had women of all ethnicities initiated treatment at the same age. CONCLUSION(S): Black women were at greatest risk of all failure types, and women who were Asian were at intermediate risk compared with women who were white. Some of the risks among women who were black may be mediated by maternal age.

Metformin in obese pregnancy has no adverse effects on cardiovascular risk in early childhood.

Metformin is widely used in pregnancy, despite lack of long-term safety for children. We hypothesised that metformin exposure in utero is associated with increased cardiovascular risk. We tested this hypothesis in a follow-up study of children born to obese mothers who had participated in a randomised controlled trial of metformin versus placebo in pregnancy (EMPOWaR). We measured body composition, peripheral blood pressure (BP), arterial pulse wave velocity and central haemodynamics (central BP and augmentation index) using an oscillometric device in 40 children of mean (SD) age 5.78 (0.93) years, exposed to metformin (n = 19) or placebo (n = 21) in utero. There were no differences in any of the anthropometric or vascular measures between metformin and placebo-exposed groups in univariate analyses, or after adjustment for potential confounders including the child's behaviour, diet and activity levels. Post-hoc sample size calculation indicated we would have detected large clinically significant differences between the groups but would need an unfeasible large number to detect possible subtle differences in key cardiovascular risk parameters in children at this age of follow-up. Our findings suggest no evidence of increased cardiovascular risk in children born to obese mothers who took metformin in pregnancy and increase available knowledge of the long-term safety of metformin on childhood outcomes.

Assisted hatching on assisted conception (in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI)).

BACKGROUND: Failure of implantation and conception may result from inability of the blastocyst to escape from its outer coat, which is known as the zona pellucida. Artificial disruption of this coat is known as assisted hatching and has been proposed as a method for improving the success of assisted conception by facilitating embryo implantation. OBJECTIVES: To determine effects of assisted hatching (AH) of embryos derived from assisted conception on live birth and multiple pregnancy rates.  SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group Specialised Register (until May 2020), the Cochrane Central Register of Controlled Trials (CENTRAL; until May 2020), in the Cochrane Library; MEDLINE (1966 to May 2020); and Embase (1980 to May 2020). We also searched trial registers for ongoing and registered trials (http://www.clinicaltrials.gov - a service of the US National Institutes of Health; http://www.who.int/trialsearch/Default.aspx - The World Health Organization International Trials Registry Platform search portal) (May 2020). SELECTION CRITERIA: Two review authors identified and independently screened trials. We included randomised controlled trials (RCTs) of AH (mechanical, chemical, or laser disruption of the zona pellucida before embryo replacement) versus no AH that reported live birth or clinical pregnancy data. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane. Two review authors independently performed quality assessments and data extraction. MAIN RESULTS: We included 39 RCTs (7249 women). All reported clinical pregnancy data, including 2486 clinical pregnancies. Only 14 studies reported live birth data, with 834 live birth events. The quality of evidence ranged from very low to low. The main limitations were serious risk of bias associated with poor reporting of study methods, inconsistency, imprecision, and publication bias. Five trials are currently ongoing. We are uncertain whether assisted hatching improved live birth rates compared to no assisted hatching (odds ratio (OR) 1.09, 95% confidence interval (CI) 0.92 to 1.29; 14 RCTs, N = 2849; I² = 20%; low-quality evidence). This analysis suggests that if the live birth rate in women not using assisted hatching is about 28%, the rate in those using assisted hatching will be between 27% and 34%. Analysis of multiple pregnancy rates per woman showed that in women who were randomised to AH compared with women randomised to no AH, there may have been a slight increase in multiple pregnancy rates (OR 1.38, 95% CI 1.13 to 1.68; 18 RCTs, N = 4308; I² = 48%; low-quality evidence). This suggests that if the multiple pregnancy rate in women not using assisted hatching is about 9%, the rate in those using assisted hatching will be between 10% and 14%. When all of the included studies (39) are pooled, the clinical pregnancy rate in women who underwent AH may improve slightly in comparison to no AH (OR 1.20, 95% CI 1.09 to 1.33; 39 RCTs, N = 7249; I² = 55%; low-quality evidence). However, when a random-effects model is used due to high heterogeneity, there may be little to no difference in clinical pregnancy rate (P = 0.04). All 14 RCTs that reported live birth rates also reported clinical pregnancy rates, and analysis of these studies illustrates that AH may make little to no difference in clinical pregnancy rates when compared to no AH (OR 1.07, 95% CI 0.92 to 1.25; 14 RCTs, N = 2848; I² = 45%). We are uncertain about whether AH affects miscarriage rates due to the quality of the evidence (OR 1.13, 95% CI 0.82 to 1.56; 17 RCTs, N = 2810; I² = 0%; very low-quality evidence). AUTHORS' CONCLUSIONS: This update suggests that we are uncertain of the effects of assisted hatching (AH) on live birth rates. AH may lead to increased risk of multiple pregnancy. The risks of complications associated with multiple pregnancy may be increased without evidence to demonstrate an increase in live birth rate, warranting careful consideration of the routine use of AH for couples undergoing in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI). AH may offer a slightly increased chance of achieving a clinical pregnancy, but data quality was of low grade. We are uncertain about whether AH influences miscarriage rates.

Volatile organic compound analysis, a new tool in the quest for preterm birth prediction-an observational cohort study.

Preterm birth is the leading cause of death worldwide in children under five years. Due to its complex multifactorial nature, prediction is a challenge. Current research is aiming to develop accurate predictive models using patient history, ultrasound and biochemical markers. Volatile organic compound (VOC) analysis is an approach, which has good diagnostic potential to predict many disease states. Analysis of VOCs can reflect both the microbiome and host response to a condition. We aimed to ascertain if VOC analysis of vaginal swabs, taken throughout pregnancy, could predict which women go on to deliver preterm. Our prospective observational cohort study demonstrates that VOC analysis of vaginal swabs, taken in the midtrimester, is a fair test (AUC 0.79) for preterm prediction, with a sensitivity of 0.66 (95%CI 0.56-0.75) and specificity 0.89 (95%CI 0.82-0.94). Using vaginal swabs taken closest to delivery, VOC analysis is a good test (AUC 0.84) for the prediction of preterm birth with a sensitivity of 0.73 (95%CI 0.64-0.81) and specificity of 0.90 (95%CI 0.82-0.95). Consequently, VOC analysis of vaginal swabs has potential to be used as a predictive tool. With further work it could be considered as an additional component in models for predicting preterm birth.

Impact of sitagliptin on endometrial mesenchymal stem-like progenitor cells: A randomised, double-blind placebo-controlled feasibility trial.

BACKGROUND: Recurrent pregnancy loss (RPL) is associated with the loss of endometrial mesenchymal stem-like progenitor cells (eMSC). DPP4 inhibitors may increase homing and engraftment of bone marrow-derived cells to sites of tissue injury. Here, we evaluated the effect of the DPP4 inhibitor sitagliptin on eMSC in women with RPL, determined the impact on endometrial decidualization, and assessed the feasibility of a full-scale clinical trial. METHODS: A double-blind, randomised, placebo-controlled feasibility trial on women aged 18 to 42 years with a history of 3 or more miscarriages, regular menstrual cycles, and no contraindications to sitagliptin. Thirty-eight subjects were randomised to either 100 mg sitagliptin daily for 3 consecutive cycles or identical placebo capsules. Computer generated, permuted block randomisation was used to allocate treatment packs. Colony forming unit (CFU) assays were used to quantify eMSC in midluteal endometrial biopsies. The primary outcome measure was CFU counts. Secondary outcome measures were endometrial thickness, study acceptability, and first pregnancy outcome within 12 months following the study. Tissue samples were subjected to explorative investigations. FINDINGS: CFU counts following sitagliptin were higher compared to placebo only when adjusted for baseline CFU counts and age (RR: 1.52, 95% CI: 1.32-1.75, P<0.01). The change in CFU count was 1.68 in the sitagliptin group and 1.08 in the placebo group. Trial recruitment, acceptability, and drug compliance were high. There were no serious adverse events. Explorative investigations showed that sitagliptin inhibits the expression of DIO2, a marker gene of senescent decidual cells. INTERPRETATION: Sitagliptin increases eMSCs and decreases decidual senescence. A large-scale clinical trial evaluating the impact of preconception sitagliptin treatment on pregnancy outcome in RPL is feasible and warranted. FUNDING: Tommy's Baby Charity. CLINICAL TRIAL REGISTRATION: EU Clinical Trials Register no. 2016-001120-54.

Detection of Group B Streptococcus in pregnancy by vaginal volatile organic compound analysis: a prospective exploratory study.

Our objective was to assess whether volatile organic compound (VOC) analysis of vaginal swabs can detect maternal Group B Streptococcus (GBS) during pregnancy in a prospective exploratory study. Around 243 women attending a high-risk antenatal clinic at one university teaching hospital in the UK consented to take part and provide vaginal swabs throughout pregnancy. VOC analysis of vaginal swabs was undertaken and compared with the reference standard of GBS detected using enrichment culture method. The chemical components that emanated from the vaginal swabs were measured by gas chromatograph ion mobility spectrometry. This platform has both high sensitivity and good specificity to a range of chemical compounds. Our main outcome was to determine the sensitivity and specificity of VOC analysis for the detection of maternal GBS in vaginal swabs during pregnancy. Our study has demonstrated that the sensitivity and specificity of the VOC analysis by GC-IMS for the detection of GBS from vaginal swabs was 0.81 (95% confidence interval [CI], 0.71-0.89) and 0.97 (95% CI, 0.91-1) respectively. We conclude that the use of VOCs as biomarkers for the detection of maternal GBS in the vagina is a novel tool. As this test produces results within minutes and is of low unit test cost, it has the potential to be used in clinical settings, where fast diagnosis is important, for example, a patient in early labour.

The use of Episcissors-60 to reduce the rate of Obstetric Anal Sphincter Injuries: A systematic review.

OBJECTIVES: The aim of this systematic review is to evaluate the effect of Episcissors-60, which were designed to improve the accuracy of episiotomies, on the rate of Obstetric Anal Sphincter Injuries. STUDY DESIGN: This review is registered with the International Prospective Register of Systematic Reviews (PROSPERO) database (CRD42018094935). A literature search of the PubMed, Embase and Cochrane databases was performed from inception to May 2018. All peer-reviewed studies evaluating the use of Episcissors-60 in clinical practice and the resulting Obstetric Anal Sphincter Injury incidence were included. Data on study population demographics, incidence of Obstetric Anal Sphincter Injuries, rate of episiotomies and angle of episiotomy achieved while using the Episcissors-60 were recorded. RESULTS: A total of seven studies were identified, five of which were included in the review. A total of 3509 women of whom 1050 had episiotomies performed. Included studies demonstrated that introduction of Episcissors-60, when combined with other preventative measures including manual perineal support at delivery, can reduce Obstetric Anal Sphincter Injuries by up to 50%. In all studies, operators were able to consistently achieve post-suturing episiotomy angles of more than 40°. An increase in episiotomy rates, especially during spontaneous vaginal deliveries, was also reported. CONCLUSION: The results of this systematic review support the use of Episcissors-60, combined with other preventative measures, to reduce the incidence of Obstetric Anal Sphincter Injuries.

Progesterone-Dependent Induction of Phospholipase C-Related Catalytically Inactive Protein 1 (PRIP-1) in Decidualizing Human Endometrial Stromal Cells.

Decidualization denotes the transformation of endometrial stromal cells into specialized decidual cells. In pregnancy, decidual cells form a protective matrix around the implanting embryo, enabling coordinated trophoblast invasion and formation of a functional placenta. Continuous progesterone (P4) signaling renders decidual cells resistant to various environmental stressors, whereas withdrawal inevitably triggers tissue breakdown and menstruation or miscarriage. Here, we show that PLCL1, coding phospholipase C (PLC)-related catalytically inactive protein 1 (PRIP-1), is highly induced in response to P4 signaling in decidualizing human endometrial stromal cells (HESCs). Knockdown experiments in undifferentiated HESCs revealed that PRIP-1 maintains basal phosphoinositide 3-kinase/Protein kinase B activity, which in turn prevents illicit nuclear translocation of the transcription factor forkhead box protein O1 and induction of the apoptotic activator BIM. By contrast, loss of this scaffold protein did not compromise survival of decidual cells. PRIP-1 knockdown did also not interfere with the responsiveness of HESCs to deciduogenic cues, although the overall expression of differentiation markers, such as PRL, IGFBP1, and WNT4, was blunted. Finally, we show that PRIP-1 in decidual cells uncouples PLC activation from intracellular Ca(2+) release by attenuating inositol 1,4,5-trisphosphate signaling. In summary, PRIP-1 is a multifaceted P4-inducible scaffold protein that gates the activity of major signal transduction pathways in the endometrium. It prevents apoptosis of proliferating stromal cells and contributes to the relative autonomy of decidual cells by silencing PLC signaling downstream of Gq protein-coupled receptors.

The clock protein period 2 synchronizes mitotic expansion and decidual transformation of human endometrial stromal cells.

Implantation requires coordinated interactions between the conceptus and surrounding decidual cells, but the involvement of clock genes in this process is incompletely understood. Circadian oscillations are predicated on transcriptional-translational feedback loops, which balance the activities of the transcriptional activators CLOCK (circadian locomotor output cycles kaput) and brain muscle arnt-like 1 and repressors encoded by PER (Period) and Cryptochrome genes. We show that loss of PER2 expression silences circadian oscillations in decidualizing human endometrial stromal cells (HESCs). Down-regulation occurred between 12 and 24 hours following differentiation and coincided with reduced CLOCK binding to a noncanonical E-box enhancer in the PER2 promoter. RNA sequencing revealed that premature inhibition of PER2 by small interfering RNA knockdown leads to a grossly disorganized decidual response. Gene ontology analysis highlighted a preponderance of cell cycle regulators among the 1121 genes perturbed upon PER2 knockdown. Congruently, PER2 inhibition abrogated mitotic expansion of differentiating HESCs by inducing cell cycle block at G2/M. Analysis of 70 midluteal endometrial biopsies revealed an inverse correlation between PER2 transcript levels and the number of miscarriages in women suffering reproductive failure (Spearman rank test, ρ = -0.3260; P = 0.0046). Thus, PER2 synchronizes endometrial proliferation with initiation of aperiodic decidual gene expression; uncoupling of these events may cause recurrent pregnancy loss.