Part II of the Australasian guideline for the investigation and management of recurrent pregnancy loss (RPL) provides evidence-based guidance on the management of RPL provided. The implications of inherited and acquired thrombophilia with respect to RPL and suggestions for clinical management are provided. Autoimmune factors, including human leukocyte antigen, cytokines, antinuclear antibodies and coeliac antibodies, and guidance for management are discussed. Infective, inflammatory and endometrial causes of RPL are discussed in detail. Environmental and lifestyle factors, male factor and unexplained causes are outlined. Levels of evidence and grades of consensus are provided for all evidence-based statements.

Guidelines for the investigation and management of recurrent pregnancy loss (RPL) have been developed in Europe, USA and UK, but there is currently no Australasian guideline. The Australasian Certificate of Reproductive Endocrinology and Infertility Consensus Expert Panel on Trial Evidence group has prepared a two-part guideline to provide guidance on the management of RPL. In Part I chromosomal, anatomical, and endocrine factors are outlined along with relevant recommendations for clinical management, levels of evidence and grades of consensus. In Part II thrombophilia, autoimmune factors, infective, inflammatory, and endometrial causes, environmental and lifestyle factors, male factor and unexplained causes will be outlined.

Purpose The aim of this guideline is to standardize the diagnosis and therapy of recurrent miscarriage (RM) using evidence from the recent literature. This is done by using consistent definitions, objective evaluations and standardized treatment protocols. Methods When this guideline was compiled, special consideration was given to previous recommendations in prior versions of this guideline and the recommendations of the European Society of Human Reproduction and Embryology, the Royal College of Obstetricians and Gynecologists, the American College of Obstetricians and Gynecologists and the American Society for Reproductive Medicine, and a detailed individual search of the literature about the different topics was carried out. Recommendations Recommendations about the diagnostic and therapeutic procedures offered to couples with RM were developed based on the international literature. Special attention was paid to known risk factors such as chromosomal, anatomical, endocrinological, physiological coagulation, psychological, infectious and immune disorders. Recommendations were also developed for those cases where investigations are unable to find any abnormality (idiopathic RM).

OBJECTIVE: What are the updates for the recommended management of women with recurrent pregnancy loss (RPL) based on the best available evidence in the literature from 2017 to 2022?
CONCLUSIONS: The guideline development group (GDG) updated 11 existing recommendations on investigations and treatments for RPL, and how care should be organized, and added one new recommendation on adenomyosis investigation in women with RPL.
BACKGROUND: A previous ESHRE guideline on RPL was published in 2017 and needs to be updated.
UNASSIGNED: The guideline was developed and updated according to the structured methodology for development and update of ESHRE guidelines. The literature searches were updated, and assessments of relevant new evidence were performed. Relevant papers published between 31 March 2017 and 28 February 2022 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.
METHODS: Based on the collected evidence, recommendations were updated and discussed until consensus was reached within the GDG. A stakeholder review was organized after the updated draft was finalized. The final version was approved by the GDG and the ESHRE Executive Committee.
RESULTS: The new version of the guideline provides 39 recommendations on risk factors, prevention, and investigation in couples with RPL, and 38 recommendations on treatments. These includes 62 evidence-based recommendations-of which 33 were formulated as strong recommendations and 29 as conditional-and 15 good practice points. Of the evidence-based recommendations, 12 (19.4%) were supported by moderate-quality evidence. The remaining recommendations were supported by low (34 recommendations; 54.8%), or very low-quality evidence (16 recommendations; 25.8%). Owing to the lack of evidence-based investigations and treatments in RPL care, the guideline also clearly mentions those investigations and treatments that should not be used for couples with RPL.
CONCLUSIONS: The guidelines have been updated; however, several investigations and treatments currently offered to couples with RPL have not been well studied; for most of these investigations and treatments, a recommendation against using the intervention or treatment was formulated based on insufficient evidence. Future studies may require these recommendations to be revised.
CONCLUSIONS: The guideline provides clinicians with clear advice on best practice in RPL, based on the best and most recent evidence available. In addition, a list of research recommendations is provided to stimulate further studies in RPL. Still, the absence of a unified definition of RPL is one of the most critical consequences of the limited scientific evidence in the field.
BACKGROUND: 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.O.B.C. reports being a member of the executive board of the European Society for Reproductive Immunology and has received payment for honoraria for giving lectures about RPL in Australia in 2020. M.G. reports unconditional research and educational grant received by the Centre for Reproductive Medicine, Amsterdam UMC from Guerbet, Merck and Ferring, not related to the presented work. S.L. reports position funding from EXAMENLAB Ltd. and ownership interest by stock or partnership of EXAMENLAB Ltd (CEO). S.Q. reports being a deputy director of Tommy\'s National centre for miscarriage research, with payment received by the institution for research, staff time, and consumables for research. H.S.N. reports grants with payment to institution from Freya Biosciences ApS, Ferring Pharmaceuticals, BioInnovation Institute, the Danish ministry of Education, Novo Nordic Foundation, Augustinus Fonden, Oda og Hans Svenningsens Fond, Demant Fonden, Ole Kirks Fond, and Independent Research Fund Denmark and speakers\' fees for lectures from Ferring Pharmaceuticals, Merck A/S, Astra Zeneca, IBSA Nordic and Cook Medical. She also reports to be an unpaid founder and chairman of a maternity foundation. M.-L.v.d.H. received small honoraria for lectures on RPL care. The other authors have no conflicts of interest to declare.
CONCLUSIONS: This guideline represents the views of ESHRE, which were achieved after careful consideration of the scientific evidence available at the time of preparation. In the absence of scientific evidence on certain aspects, a consensus between the relevant ESHRE stakeholders has been obtained.Adherence to these clinical practice guidelines does not guarantee a successful or specific outcome, nor does it establish a standard of care. Clinical practice guidelines do not replace the need for application of clinical judgment to each individual presentation, nor variations based on locality and facility type.ESHRE makes no warranty, express or implied, regarding the clinical practice guidelines and specifically excludes any warranties of merchantability and fitness for a particular use or purpose. (Full disclaimer available at www.eshre.eu/guidelines.).

OBJECTIVE: International guidelines for the management of recurrent miscarriage (RM) do not provide detailed guidance for the care of women/couples with concurrent infertility. Research studies concerning the investigation and treatment of RM frequently omit this cohort. The aim of this study was to assess the care of women/couples with infertility attending a RM clinic in a large tertiary unit in the Republic of Ireland.
METHODS: We conducted an audit of women with RM and infertility attending our RM clinic from 2008 to 2020 against 110 established guideline-based key performance indicators (KPIs) for RM care, encompassing five categories: structure of care, counselling/supportive care, investigation, treatment and outcomes. Information was gathered from documentation from the RM clinic, hospital laboratory and electronic health records.
RESULTS: We identified 128 women with infertility and RM. Information provision in RM clinics regarding modifiable risk factors (71 %; 91/128) and unexplained RM (53 %; 69/128) could be improved. Most women were investigated in line with KPIs, except for pelvic ultrasound (40 %; 51/128), cytogenetic analysis (27 %; 34/128) and 3D ultrasound (2 %; 2/128). Immunotherapies were seldom prescribed (<1%); however, 98 % (125/128) of women received aspirin, 48 % LMWH (62/128) and 16 % corticosteroids (21/128). Surgical interventions were uncommon (5 %; 6/128)). The subsequent pregnancy rate was 70 % (89/128), with 36 % undergoing artificial reproductive technology (32/89). The livebirth rate was 63 % (56/89); 37 % had a further pregnancy loss (33/89), of which two were second-trimester miscarriages.
CONCLUSIONS: Women with RM and infertility received care largely in line with RM guideline-based KPIs. However, we identified areas for improvement, including the quality of information provision, and access to certain investigations. While guideline-based KPIs allow for internationally applicable and reproducible audit that can direct service improvements, the experiences and needs of service-users are not captured, meriting further qualitative research.

Recurrent miscarriage affects 1-2% of women of reproductive age, depending on the definition used. A systematic review was conducted to identify, appraise and describe clinical practice guidelines (CPG) published since 2000 for the investigation, management, and/or follow-up of recurrent miscarriage within high-income countries. Six major databases, eight guideline repositories and the websites of 11 professional organizations were searched to identify potentially eligible studies. The quality of eligible CPG was assessed using the Appraisal of Guidelines for Research and Evaluation (AGREE II) Tool. A narrative synthesis was conducted to describe, compare and contrast the CPG and recommendations therein. Thirty-two CPG were included, from which 373 recommendations concerning first-trimester recurrent miscarriage were identified across four sub-categories: structure of care (42 recommendations, nine CPG), investigations (134 recommendations, 23 CPG), treatment (153 recommendations, 24 CPG), and counselling and supportive care (46 recommendations, nine CPG). Most CPG scored \'poor\' on applicability (84%) and editorial independence (69%); and to a lesser extent stakeholder involvement (38%) and rigour of development (31%). Varying levels of consensus were found across CPG, with some conflicting recommendations. Greater efforts are required to improve the quality of evidence underpinning CPG, the rigour of their development and the inclusion of multi-disciplinary perspectives, including those with lived experience of recurrent miscarriage.

Around 1-5% of all couples experience recurrent pregnancy loss (RPL). Established risk factors include anatomical, genetic, endocrine, and hemostatic alterations. With around 50% of idiopathic cases, immunological risk factors are getting into the scientific focus, however international guidelines hardly take them into account. Within this review, the current state of immunological risk factors in RPL in international guidelines of the European Society of Reproduction and Embryology (ESHRE), American Society of Reproductive Medicine (ASRM), German/Austrian/Swiss Society of Obstetrics and Gynecology (DGGG/OEGGG/SGGG) and the Royal College of Obstetricians and Gynecologists (RCOG) are evaluated. Special attention was drawn to recommendations in the guidelines regarding diagnostic factors such as autoantibodies, natural killer cells, regulatory T cells, dendritic cells, plasma cells, and human leukocyte antigen system (HLA)-sharing as well as treatment options such as corticosteroids, intralipids, intravenous immunoglobulins, aspirin and heparin in RPL. Finally, the current state of the art focusing on both diagnostic and therapeutic options was summarized.

The objective of this guideline from the Canadian Fertility and Andrology Society is to synthesize the evidence on preimplantation genetic testing for aneuploidies (PGT-A) using trophectoderm biopsy and 24-chromosome analysis and to provide clinical recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. To date, randomized controlled trials have been limited to good-prognosis patients who were able to generate two or more blastocysts for biopsy. In this specific population the GRADE analysis of PGT-A shows an increase in the implantation rate and ongoing pregnancy or delivery rate per transfer. Clearly, it is difficult to generalize from this subgroup of patients to the infertility population at large. As a result, the application of PGT-A should be individualized, and patient factors such as age and ability to generate embryos will influence decision-making. Comprehensive patient counselling and informed consent are imperative before undertaking PGT-A. Potential benefits must be weighed against the costs and limitations of the technology, including the risk of embryo damage, false positives, false negatives and the detection of embryonic mosaicism. Future research is required, especially with regard to the use of PGT-A in poorer prognosis patients, and with respect to reporting outcomes per cycle start and cumulatively per retrieval.

Recurrent miscarriage (RM) was recently re-defined by the European Society of Human Reproduction and Embryology (ESHRE) as the loss of two or more consecutive pregnancies. Before this, and indeed still in some countries, RM was defined as three or more consecutive pregnancy losses. While the incidence of RM depends on the definition employed and population studied, it is generally accepted to affect 1-6% of women of reproductive age. Clinical practice guidelines (CPGs) for RM have been published by some professional organisations. While there are CPGs on miscarriage in Ireland, there are none concerning RM specifically. The aim of this systematic review is to identify, appraise and describe published CPGs for the management, investigation and/or follow-up of RM within high-income countries. Electronic databases (MEDLINE (Ovid ®; 1946), Embase ® (Elsevier; 1980), CINAHL Complete (EBSCOhost; 1994), Web of Science™ (Thomson Reuters), Scopus (Elsevier; 2004), and Open Grey (INIST-CNRS; 2011)), selected guideline repositories, and the websites of professional societies will be searched to identify CPGs, published within the last 20 years, for potential inclusion. Two reviewers will review abstracts and full texts independently against the eligibility criteria. Characteristics and recommendations of included CPGs will be extracted by one reviewer and double-checked by another. Two reviewers will use the Appraisal of Guidelines for Research and Evaluation version 2 (AGREE II) instrument independently to assess the quality of the included CPGs. Narrative synthesis will be conducted to appraise and compare CPGs and their recommendations or guidance therein. The identification, appraisal and description of published CPGs in other high-income countries will be a valuable first step in informing efforts to promote the optimisation and standardisation of RM care.

OBJECTIVE: What is the recommended management of women with recurrent pregnancy loss (RPL) based on the best available evidence in the literature?
UNASSIGNED: The guideline development group formulated 77 recommendations answering 18 key questions on investigations and treatments for RPL, and on how care should be organized.
UNASSIGNED: A previous guideline for the investigation and medical treatment of recurrent miscarriage was published in 2006 and is in need of an update.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.