The ESHRE Guideline Group on RPL, Ruth Bender Atik¹, Ole Bjarne Christiansen², Janine Elson³, Astrid Marie Kolte^4,5, Sheena Lewis⁶, Saskia Middeldorp⁷, Saria Mcheik⁸, Braulio Peramo⁹, Siobhan Quenby¹⁰, Henriette Svarre Nielsen¹¹, Marie-Louise van der Hoorn¹², Nathalie Vermeulen⁸, and Mariette Goddijn^13,*

¹Miscarriage Association, Wakefield, UK ²Department of Obstetrics and Gynaecology Aalborg, Aalborg University, Aalborg, Denmark ³Department of Gynaecology, Liverpool Women’s Hospital, Liverpool, UK ⁴Department of Obstetrics and Gynaecology, University Hospital Copenhagen, Rigshospitalet, Copenhagen, Denmark ⁵Recurrent Pregnancy Unit, Department of Obstetrics and Gynaecology, Amager and Hvidovre Hospitals, University Hospital Copenhagen, Hvidovre, Denmark ⁶Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queens University of Belfast, Belfast, UK ⁷Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands ⁸ESHRE Central Office, Strombeek-Bever, Belgium ⁹Al Ain Fertility Clinic, Al Ain, United Arab Emirates ¹⁰Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry, UK ¹¹Department of Clinical Medicine, University of Copenhagen & University Hospital Copenhagen Hvidovre, Hvidovre, Denmark ¹³Department of Obstetrics and
Gynaecology, Leiden University Medical Centre, Leiden, The Netherlands ¹³Department of Obstetrics and Gynaecology, Centre for Reproductive Medicine, Amsterdam University Medical Centre, Amsterdam, The Netherlands

Submitted on January 31, 2023; editorial decision on February 9, 2023

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 recommenda- tions — 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.

ESHRE Pages content is not externally peer reviewed. The manuscript has been approved by the Executive Committee of ESHRE.
VC The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

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. Clinicalpractice 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 merchantabilityand fitness for a particular use or purpose. (Full disclaimer available at www.eshre.eu/guidelines.)

Key words: recurrent pregnancy loss / ESHRE / guideline / evidence-based / recurrent miscarriage / treatment / diagnosis / GRADE