Recurrent miscarriage: evidence to accelerate action.

Women who have had repeated miscarriages often have uncertainties about the cause, the likelihood of recurrence, the investigations they need, and the treatments that might help. Health-care policy makers and providers have uncertainties about the optimal ways to organise and provide care. For this Series paper, we have developed recommendations for practice from literature reviews, appraisal of guidelines, and a UK-wide consensus conference that was held in December, 2019. Caregivers should individualise care according to the clinical needs and preferences of women and their partners. We define a minimum set of investigations and treatments to be offered to couples who have had recurrent miscarriages, and urge health-care policy makers and providers to make them universally available. The essential investigations include measurements of lupus anticoagulant, anticardiolipin antibodies, thyroid function, and a transvaginal pelvic ultrasound scan. The key treatments to consider are first trimester progesterone administration, levothyroxine in women with subclinical hypothyroidism, and the combination of aspirin and heparin in women with antiphospholipid antibodies. Appropriate screening and care for mental health issues and future obstetric risks, particularly preterm birth, fetal growth restriction, and stillbirth, will need to be incorporated into the care pathway for couples with a history of recurrent miscarriage. We suggest health-care services structure care using a graded model in which women are offered online health-care advice and support, care in a nurse or midwifery-led clinic, and care in a medical consultant-led clinic, according to clinical needs.

The metabolomic profile of endometrial receptivity in recurrent miscarriage.

BACKGROUND: Endometrial receptivity has been the focus of continuous research for over eight decades; however, current clinical practice lacks an accurate test of endometrial receptivity to allow the prediction of successful pregnancy. We aimed to characterize the endometrial metabolomic profiles of women who suffered recurrent miscarriage using discovery metabolomics and to set the foundation for the development of an endometrial receptivity test. METHODS: This was a prospective multicenter cohort study led by the Tommy's National Centre for Miscarriage Research in Birmingham. Endometrial biopsies were obtained during the window of implantation from 24 women aged 18-35 years, who were not pregnant and regularly menstruating, diagnosed with unexplained recurrent miscarriage. The metabolite composition and relative concentrations of samples were analyzed applying ultra-high performance liquid chromatography-mass spectrometry to investigate water-soluble and lipid metabolites. RESULTS: Various metabolic perturbations are associated with observation of increased numbers of miscarriages. They relate to fatty acid metabolism including increased lipolysis and decreased medium chain fatty acid beta-oxidation, poorer mitochondrial health, and redox-active co-factors which are present at higher oxidative levels. Other metabolic perturbations are associated with observation of live birth following miscarriages. They relate to perturbed cholesterol-cholesterol sulphate metabolism, fatty acid metabolism including increased diacylglyceride lipolysis and decreased medium chain fatty acid beta-oxidation, and improved mitochondrial health. CONCLUSIONS: The present endometrial metabolomics discovery studies have implicated a small number of metabolic pathways and biological functions which are biologically important in miscarriage mechanisms.

The association between dietary patterns and risk of miscarriage: a systematic review and meta-analysis.

IMPORTANCE: The evidence on the association between diet and miscarriage risk is scant and conflicting. OBJECTIVE: To summarize the evidence on the association between periconceptual diet and miscarriage risk in healthy women of reproductive age. DATA SOURCES: Electronic databases were searched from inception to August 2022 without restriction of regions, publication types, or languages. STUDY SELECTION AND SYNTHESIS: Experimental or observational studies were considered for inclusion. The population was healthy women of reproductive age. Exposure was periconception diet. Study quality was assessed using the modified Newcastle-Ottawa Scale. Summary effect sizes (odds ratio [OR] with 95% confidence interval [CI]) were calculated for each food category. MAIN OUTCOMES: Miscarriage rate (as defined by primary studies). RESULTS: We included 20 studies (11 cohort and 9 case-control), of which 6 presented data suitable for meta-analysis (2 cohort and 4 case-control, n = 13,183 women). Our primary analyses suggest a reduction in miscarriage odds with high intake of the following food groups: fruit (OR, 0.39; 95% CI, 0.33-0.46), vegetables (OR, 0.59; 95% CI, 0.46-0.76), fruit and vegetables (OR, 0.63; 95% CI, 0.50-0.81), seafood (OR, 0.81; 95% CI, 0.71-0.92), dairy products (OR, 0.63; 95% CI, 0.54-0.73), eggs (OR, 0.81; 95% CI, 0.72-0.90), and cereal (grains) (OR, 0.67; 95% CI, 0.52-0.87). The evidence was uncertain for meat, red meat, white meat, fat and oil, and sugar substitutes. We did not find evidence of an association between adherence to predefined dietary patterns and miscarriage risk. However, a whole diet containing healthy foods as perceived by the trialists, or with a high Dietary Antioxidant Index score (OR, 0.43; 95% CI, 0.20-0.91) may be associated with a reduction in miscarriage risk. In contrast, a diet rich in processed food was demonstrated to be associated with increased miscarriage risk (OR, 1.97; 95% CI, 1.36-3.34). CONCLUSION AND RELEVANCE: A diet abundant in fruit, vegetables, seafood, dairy, eggs, and grain may be associated with lower miscarriage odds. Further interventional studies are required to accurately assess the effectiveness of periconception dietary modifications on miscarriage risk. PROSPERO REGISTRATION: CRD42020218133.

Electronic Patient Reported Outcomes for Miscarriage Research in Tommy's Net.

The Tommy's National Centre for Miscarriage Research aims to support the diagnosis and treatment for couples suffering from recurrent miscarriage. Tommy's Net is an electronic data gathering tool, collecting miscarriage data and links with hospital Clinical Information System databases. The gathering of patient reported data is an important aspect, especially as data relating to pregnancy and miscarriage events are often left unreported. METHODS: Both traditional paper-based and electronic patient reported outcome (ePRO) solutions have been explored to improve response rates, minimize data redundancy and reduce burden on staff. Popular ePRO survey solutions have been compared, including REDCap, SurveyMonkey, Qualtrics and LimeSurvey. RESULTS: LimeSurvey was selected as the most appropriate solution as it provided self-hosting capability, SMS integration and ease of use. CONCLUSION: We have implemented a LimeSurvey based ePRO system for collection of baseline and follow-up data for participants on the Tommy's study.

The transcriptomic profile of endometrial receptivity in recurrent miscarriage.

OBJECTIVE: To characterise the endometrial transcriptomic profiles of women who suffered recurrent miscarriage and to set the foundation for the development of an endometrial receptivity test that could predict the fate of subsequent pregnancies. STUDY DESIGN: This was a prospective multicentre cohort study performed at the Tommy's National Centre for Miscarriage Research in Birmingham, Saint Mary's Hospital in Manchester and Royal Devon & Exeter Hospital, United Kingdom. The study was conducted between December 2017 and December 2019. Endometrial biopsies were obtained during the window of implantation from 24 women aged 18-35 years, who were not pregnant and regularly menstruating, diagnosed with unexplained recurrent miscarriage by standard investigations as per the ESHRE guidelines. Exclusion criteria included risk factors such as smoking, obesity or hyperprolactinemia. The RNA transcripts abundances were quantified using Kallisto. R packages tximport and DESeq2 were used to summarize count estimates at the gene level and to analyse the differential gene expression. RESULTS: Women who suffered four or more miscarriages had 19 differently expressed genes after adjustment for multiple comparisons. They were related to biological processes such as immunity (HLA-DMA, CCR8, ALOX5), energy production (ATP12A), hormone secretion (CGA), adhesion (CHAD, ADGRF2, AQP5, TBCD, CTNND1, NKD2) and cell proliferation (NCCRP1). Based on 421 differently expressed genes, women who achieved a subsequent live birth displayed an enrichment of processes related to the regulation of cell structure and proliferation, and a depletion of processes related to immunity, trans-membrane transport and coagulation. CONCLUSIONS: Women in the extreme miscarriage cohort had a distinctive endometrial transcriptomic signature compared to women with low order miscarriages. There was a partial overlap with the transcriptome of asynchronous endometrium suggesting the endometrial factor to be a different entity in the context of recurrent miscarriage. Women who achieved a live birth in their subsequent pregnancy displayed an enrichment of genes related to the regulation of cell structure and proliferation, while women who suffered a subsequent miscarriage displayed an enrichment of genes related to immunity, trans-membrane transport and coagulation.

Serum luteal phase progesterone in women undergoing frozen embryo transfer in assisted conception: a systematic review and meta-analysis.

OBJECTIVE: To investigate the association between luteal serum progesterone levels and frozen embryo transfer (FET) outcomes. DESIGN: Systematic review and meta-analysis. SETTING: Not applicable. PATIENT(S): Women undergoing FET. INTERVENTION(S): We conducted electronic searches of MEDLINE, PubMed, CINAHL, EMBASE, the Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Web of Science, ClinicalTrials.gov, and grey literature (not widely available) from inception to March 2021 to identify cohort studies in which the serum luteal progesterone level was measured around the time of FET. MAIN OUTCOME MEASURE(S): Ongoing pregnancy or live birth rate, clinical pregnancy rate, and miscarriage rate. RESULT(S): Among the studies analyzing serum progesterone level thresholds <10 ng/mL, a higher serum progesterone level was associated with increased rates of ongoing pregnancy or live birth (relative risk [RR] 1.47, 95% confidence interval [CI] 1.28 to 1.70), higher chance of clinical pregnancy (RR 1.31, 95% CI 1.16 to 1.49), and lower risk of miscarriage (RR 0.62, 95% CI 0.50 to 0.77) in cycles using exclusively vaginal progesterone and blastocyst embryos. There was uncertainty about whether progesterone thresholds ≥10 ng/mL were associated with FET outcomes in sensitivity analyses including all studies, owing to high interstudy heterogeneity and wide CIs. CONCLUSION(S): Our findings indicate that there may be a minimum clinically important luteal serum concentration of progesterone required to ensure an optimal endocrine milieu during embryo implantation and early pregnancy after FET treatment. Future clinical trials are required to assess whether administering higher-dose luteal phase support improves outcomes in women with a low serum progesterone level at the time of FET. PROSPERO NUMBER: CRD42019157071.

Target Product Profile for an endometrial receptivity test: women's perspective.

OBJECTIVE: To assess the women's views in relation to the characteristics of an endometrial receptivity test in the context of recurrent miscarriage with an overarching aim to guide the development of a Target Product Profile (TPP) based on minimum acceptable ("worst-case") and ideal ("best-case") features. STUDY DESIGN: This was a descriptive cross-sectional study involving a total of 131 women who answered questions related to the development of an endometrial receptivity test between December 2017 and May 2018. Women attending the recurrent miscarriage clinic at the Tommy's National Centre for Miscarriage Research in Birmingham, United Kingdom, were invited to participate. Referral criteria included two or more miscarriages irrespective of the timing in relation to successful pregnancies. The 'best-case' (ideal) and 'worst-case' (minimum acceptable) thresholds were arbitrary set to satisfy at least 80% and 40% of responders, respectively. RESULTS: The ideal endometrial receptivity test should be indicated after two miscarriages to comply with the wish of 80.9% (106 women) of responders. It should be performed in a window of three to four days within the menstrual cycle (93.2%; 122 women) and results should be available within one to two days (87.7%; 115 women). Invasiveness of testing should not extend beyond a vaginal examination (85.4%; 112 women). Repeating the test should not be required more than twice (96.1%; 125 women) and the results should remain useful for at least six menstrual cycles (89.3%; 117 women). The importance score given for the endometrium was weakly associated with the willingness to pay for testing; however, there was no evidence to suggest this correlation was different from 0 (Kendall's tau = 0.1101765, z = 1.4327, p-value = 0.1519; Spearman's rho = 0.1268444, S = 327136, p-value = 0.1488). CONCLUSIONS: Women understand the important role the endometrium plays for a successful pregnancy and they have specific views in relation to the indication, timing and invasiveness of testing, need for test repetition, validity of results and costs of testing.