STUDY QUESTION What is the recommended management of women with recurrent pregnancy loss (RPL) based on the best available evidence in the literature? SUMMARY ANSWER The guideline development group formulated 77 recommendations answering 18 key questions on investigations and treatments for RPL, and on how care should be organized. WHAT IS KNOWN ALREADY A previous guideline for the investigation and medical treatment of recurrent miscarriage was published in 2006 and is in need of an update. STUDY DESIGN, SIZE, DURATION The guideline was developed according to the structured methodology for development of ESHRE guidelines. After formulation of key questions by a group of experts, literature searches and assessments were performed. Papers published up to 31 March 2017 and written in English were included. Cumulative live birth rate, live birth rate and pregnancy loss rate (or miscarriage rate) were considered the critical outcomes. PARTICIPANTS/MATERIALS, SETTING, METHODS Based on the collected evidence, recommendations were formulated and discussed until consensus was reached within the guideline group. A stakeholder review was organized after finalization of the draft. The final version was approved by the guideline group and the ESHRE Executive Committee. MAIN RESULTS AND THE ROLE OF CHANCE The guideline provides 38 recommendations on risk factors, prevention and investigations in couples with RPL, and 39 recommendations on treatments. These include 60 evidence-based recommendations – of which 31 were formulated as strong recommendations and 29 as conditional – and 17 good practice points. The evidence supporting investigations and treatment of couples with RPL is limited and of moderate quality. Of the evidence-based recommendations, only 10 (16.3%) were supported by moderate quality evidence. The remaining recommendations were supported by low (35 recommendations: 57.4%), or very low quality evidence (16 recommendations: 26.2%). There were no recommendations based on high quality evidence. Owing to the lack of evidence-based investigations and treatments in RPL care, the guideline also clearly mentions investigations and treatments that should not be used for couples with RPL. LIMITATIONS, REASONS FOR CAUTION Several investigations and treatments are offered to couples with RPL, but most of them are not well studied. For most of these investigations and treatments, a recommendation against the intervention or treatment was formulated based on insufficient evidence. Future studies may require these recommendations to be revised. WIDER IMPLICATIONS OF THE FINDINGS The guideline provides clinicians with clear advice on best practice in RPL, based on the best evidence available. In addition, a list of research recommendations is provided to stimulate further studies in RPL. One of the most important consequences of the limited evidence is the absence of evidence for a definition of RPL. STUDY FUNDING/COMPETING INTEREST(S) The guideline was developed and funded by ESHRE, covering expenses associated with the guideline meetings, with the literature searches and with the dissemination of the guideline. The guideline group members did not receive payment. J.E. reports position funding from CARE Fertility. S.L. reports position funding from SpermComet Ltd. S.M. reports research grants, consulting and speaker’s fees from GSK, BMS/Pfizer, Sanquin, Aspen, Bayer and Daiichi Sankyo. S.Q. reports speaker’s fees from Ferring. The other authors report no conflicts of interest. ESHRE Pages are not externally peer reviewed. This article has been approved by the Executive Committee of ESHRE.

BackgroundAlthough anandamide (AEA) had been measured in human follicular fluid and is suggested to play a role in ovarian follicle and oocyte maturity, its exact source and role in the human ovary remains unclear.Methods and FindingsImmunohistochemical examination of normal human ovaries indicated that the endocannabinoid system was present and widely expressed in the ovarian medulla and cortex with more intense cannabinoid receptor 2 (CB2) than CB1 immunoreactivity in the granulosa cells of primordial, primary, secondary, tertiary follicles, corpus luteum and corpus albicans. The enzymes, fatty acid amide hydrolase (FAAH) and N-acyclphosphatidylethanolamine-phospholipase D (NAPE-PLD), were only found in growing secondary and tertiary follicles and corpora lutea and albicantes. The follicular fluid (FF) AEA concentrations of 260 FF samples, taken from 37 infertile women undergoing controlled ovarian hyperstimulation for in vitro fertilisation and intracytoplasmic sperm injection with embryo transfer, were correlated with ovarian follicle size (P = 0.03). Significantly higher FF AEA concentrations were also observed in mature follicles (1.43±0.04 nM; mean±SEM) compared to immature follicles (1.26±0.06 nM), P = 0.0142 and from follicles containing morphologically assessed mature oocytes (1.56±0.11 nM) compared to that containing immature oocytes (0.99±0.09 nM), P = 0.0011. ROC analysis indicated that a FF AEA level of 1.09 nM could discriminate between mature and immature oocytes with 72.2% sensitivity and 77.14% specificity, whilst plasma AEA levels and FF AEA levels on oocyte retrieval day were not significantly different (P = 0.23).ConclusionsThese data suggest that AEA is produced in the ovary, is under hormonal control and plays a role in folliculogenesis, preovulatory follicle maturation, oocyte maturity and ovulation.

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Objective To assess prospectively the ability of two multiparameter diagnostic models and their individual components to predict the outcome of early pregnancies which could not be identi®ed on transvaginal ultrasound scan.Design Prospective observational study. Setting Dedicated early pregnancy unit in an inner city teaching hospital.Population Women with a positive urine pregnancy test and clinical suspicion of early pregnancy complications.Methods A full medical history, clinical examination and transvaginal ultrasound scan were carried out at the initial visit. When the location of the pregnancy could not be ascertained by ultrasound, serum beta-human chorionic gonadotrophin (b -hCG) and progesterone levels were measured. All women were managed expectantly until either a normal pregnancy was visualised on scan; the pregnancy resolved spontaneously or intervention was required due to a worsening of clinical symptoms or non-declining b -hCG levels. Main outcome measures Spontaneous resolution of pregnancy (i.e. cessation of symptoms and decline in serum b -hCG level to , 20 iu/L) without need for any active intervention. Results Of the 104 women recruited, 72 (69%) pregnancies resolved spontaneously. Both multiparameter diagnostic models identi®ed resolving pregnancies with positive predictive values $ 95%. Their performances were not signi®cantly better compared with individual progesterone levels which achieved a positive predictive value of 97% using a cutoff level of 20 nmol/L. ConclusionSerum progesterone measurement alone is as accurate as more complex diagnostic models for the prediction of successful expectant management in pregnancies of unknown location.