ESHRE guideline: recurrent pregnancy loss: an update in 2022

Abstract

STUDY QUESTION 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? SUMMARY ANSWER 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. WHAT IS KNOWN ALREADY A previous ESHRE guideline on RPL was published in 2017 and needs to be updated. STUDY DESIGN, SIZE, DURATION 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. PARTICIPANTS/MATERIALS, SETTING, 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. MAIN RESULTS AND THE ROLE OF CHANCE 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. LIMITATIONS, REASONS FOR CAUTION 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. WIDER IMPLICATIONS OF THE FINDINGS 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. 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. 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. DISCLAIMER 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.)

ESHRE guideline update 2022: New perspectives in the management of couples with recurrent pregnancy loss

“…Leukocyte Antigen (HLA) Class II in women with secondary RPL after the birth of a boy (recommendation number [RN] #17), evaluation of adenomyosis in two-dimensional ultrasound (RN #38), and partner assessment (lifestyle, sperm quality, and sperm DNA fragmentation) (RN #39 and #40). 1 The GDG points out that the investigation of HLA Class II can be performed for explanatory and prognostic purposes (RN #17), in the same way as the genetic analysis of pregnancy tissues fol- Recently, Liu et al 5 published an extensive systematic review and meta-analysis (89 studies involving 30 254 individuals) on the association between hereditary thrombophilia and RPL. The authors noted that G1691A mutation of the factor V Leiden (FVL) gene (odds ratio (OR): 2.44, 95% CI: 1.96−3.03), G20210A mutation of the prothrombin gene (OR: 2.08, 95% CI: 1.61−2.68), and Protein S deficiency (OR: 3.45, 95% CI: 1.15−10.35) are associated with an increased risk of RPL.…”

“…5 Also, GDG admits a probable association between the FVL variant and prothrombin variant with RPL. 1 Given this evidence, the next update might interestingly include a recommendation to evaluate these hereditary thrombophilias for explanatory and prognostic purposes.…”

“…In the section that reviews risk factors and health behavior modifications, the negative impact of smoking on pregnancy is highlighted, with reduced rates of live births. 1 The use of electronic cigarettes (ecigarettes) has substantially increased in several countries. In 2022, the National Youth Tobacco Survey noted that 2.55 million middle-and high-school students in the United States currently use e-cigarettes.…”

“…The new version of the RPL Guideline, among inclusions and updates, presented five new recommendations in the RPL investigation section and seven in the prognosis and treatment section. 1 First, we would like to congratulate the ESHRE Guideline Group on RPL for their excellent work and highlight the Guideline Group's concern in warning that couples should receive sufficient information during their management. However, we would like to make some considerations on topics that remain controversial.…”

Obesity and recurrent miscarriage: The interconnections between adipose tissue and the immune system

“…Also, ESHRE recommends that patients with RM should use heparin and aspirin only in cases of APS 14 . Despite being controversial, studies report that heparin and aspirin have immunomodulatory effects that may justify the therapeutic use of these drugs in cases of uRM 129,130 .…”