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The HERA (Hyper-response Risk Assessment) Delphi consensus for the management of hyper-responders in in vitro fertilization

  • Assisted Reproduction Technologies
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

A Correction to this article was published on 11 December 2023

This article has been updated

Abstract

Purpose

To provide agreed-upon guidelines on the management of a hyper-responsive patient undergoing ovarian stimulation (OS)

Methods

A literature search was performed regarding the management of hyper-response to OS for assisted reproductive technology. A scientific committee consisting of 4 experts discussed, amended, and selected the final statements. A priori, it was decided that consensus would be reached when ≥66% of the participants agreed, and ≤3 rounds would be used to obtain this consensus. A total of 28/31 experts responded (selected for global coverage), anonymous to each other.

Results

A total of 26/28 statements reached consensus. The most relevant are summarized here. The target number of oocytes to be collected in a stimulation cycle for IVF in an anticipated hyper-responder is 15–19 (89.3% consensus). For a potential hyper-responder, it is preferable to achieve a hyper-response and freeze all than aim for a fresh transfer (71.4% consensus). GnRH agonists should be avoided for pituitary suppression in anticipated hyper-responders performing IVF (96.4% consensus). The preferred starting dose in the first IVF stimulation cycle of an anticipated hyper-responder of average weight is 150 IU/day (82.1% consensus). ICoasting in order to decrease the risk of OHSS should not be used (89.7% consensus). Metformin should be added before/during ovarian stimulation to anticipated hyper-responders only if the patient has PCOS and is insulin resistant (82.1% consensus). In the case of a hyper-response, a dopaminergic agent should be used only if hCG will be used as a trigger (including dual/double trigger) with or without a fresh transfer (67.9% consensus). After using a GnRH agonist trigger due to a perceived risk of OHSS, luteal phase rescue with hCG and an attempt of a fresh transfer is discouraged regardless of the number of oocytes collected (72.4% consensus). The choice of the FET protocol is not influenced by the fact that the patient is a hyper-responder (82.8% consensus). In the cases of freeze all due to OHSS risk, a FET cycle can be performed in the immediate first menstrual cycle (92.9% consensus).

Conclusion

These guidelines for the management of hyper-response can be useful for tailoring patient care and for harmonizing future research.

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Data availability

Authors agree to make data and materials supporting the results or analyses presented in their paper available upon reasonable request.

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Acknowledgements

Hera was the goddess of women, marriage, family, and childbirth in ancient Greek mythology and, as such, was felt to make a fitting title for a woman with hyper-response.

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Authors and Affiliations

  1. IVF Unit, Lis Maternity Hospital, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    I. Feferkorn

  2. IVI-RMA Lisboa, 1800-282, Lisbon, Portugal

    S. Santos-Ribeiro

  3. GeneraLife Centers for Reproductive Medicine, Rome, Italy

    F. M. Ubaldi

  4. IVI RMA Madrid, Madrid, Spain

    J. G. Velasco

  5. Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Koc University School of Medicine, Istanbul, Turkey

    B. Ata

  6. ART Fertility Clinics, Dubai, United Arab Emirates

    B. Ata

  7. Centre for Reproductive Medicine, Universitair Ziekenhuis Brussel, Laarbeeklaan 101, 1090, Jette, Belgium

    C. Blockeel

  8. Department of Neuroscience, Reproductive Science and Odontostomatology, University of Naples Federico II, Naples, Italy

    A. Conforti

  9. ANDROFERT, Andrology and Human Reproduction Clinic, Av. Dr. Heitor Penteado 1464, Campinas, SP, 13075-460, Brazil

    S. C. Esteves

  10. Department of Surgery (Division of Urology), University of Campinas (UNICAMP), Campinas, SP, Brazil

    S. C. Esteves

  11. Faculty of Health, Aarhus University, C, 8000, Aarhus, Denmark

    S. C. Esteves

  12. ART Fertility Clinics, Abu Dhabi, United Arab Emirates

    H. M. Fatemi

  13. Società Italiana Studi di Medicina della Riproduzione, S.I.S.Me.R. Reproductive Medicine Institute, Bologna, Emilia-Romagna, Italy

    L. Gianaroli

  14. Department of Reproductive Medicine, Hôpital Antoine-Béclère, University Paris-Sud (Paris XI), Le Kremlin-Bicêtre, Clamart, France

    M. Grynberg

  15. The Fertility Clinic, Skive Regional Hospital, Faculty of Health, Aarhus University, Resenvej 25, 7800, Skive, Denmark

    P. Humaidan

  16. Eugonia IVF Unit, Athens, Greece

    G.T Lainas

  17. Obstetrics, Gynecology and Reproductive Medicine, University of Modena and Reggio Emilia, Policlinico di Modena, via del Pozzo 71, 41124, Modena, Italy

    A. La Marca

  18. Section of Reproductive Endocrinology & Infertility, Department of Obstetrics & Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, USA

    L. B. Craig

  19. Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Stanford University, Stanford, CA, USA

    R. Lathi

  20. Robinson Research Institute, School of Medicine, University of Adelaide, Adelaide, South Australia, Australia

    R. J. Norman

  21. FertilitySA, Adelaide, South Australia, Australia

    R. J. Norman

  22. Monash Centre for Health Research and Implementation MCHRI, Monash University, Melbourne, Australia

    R. J. Norman

  23. NHMRC Centre of Research Excellence in Women’s Health in Reproductive Life (CRE-WHiRL), Melbourne, Australia

    R. J. Norman

  24. Department of Obstetrics and Gynecology, Chaim Sheba Medical Center (Tel Hashomer), Ramat Gan, Israel

    R. Orvieto

  25. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    R. Orvieto

  26. Tarnesby-Tarnowski Chair for Family Planning and Fertility Regulation, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel

    R. Orvieto

  27. University of Southern California, Los Angeles, CA, 90033, USA

    R. Paulson

  28. Department of Pediatrics, Obstetrics and Gynecology, School of Medicine, University of Valencia, Valencia, Spain

    A. Pellicer

  29. IVI Roma Parioli, IVI-RMA Global, Rome, Italy

    A. Pellicer

  30. Department of Reproductive Medicine, Dexeus Mujer, Hospital Universitario Dexeus, Barcelona, Spain

    N. P. Polyzos

  31. Department of Reproductive Medicine, ORIGEN-Center for Reproductive Medicine, Rio de Janeiro, RJ, Brazil

    M. Roque

  32. Department of Obstetrics and Gynecology, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil

    M. Roque

  33. Department of Women and Children’s Health, King’s College London, London, UK

    S. K. Sunkara

  34. OriginElle Fertility Clinic 2110 Boul. Decarie, Montreal, QC, Canada

    S. L. Tan

  35. Department of Obstetrics and Gynecology and Assisted Reproduction, American Hospital, Istanbul, Koc University School of Medicine, Istanbul, Turkey

    B. Urman

  36. Unit for Human Reproduction, 1st Dept of OB/Gyn, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece

    C. Venetis

  37. Centre for Big Data Research in Health, Faculty of Medicine & Health, University of New South Wales, Sydney, New South Wales, Australia

    C. Venetis

  38. Virtus Health, Sydney, Australia

    C. Venetis

  39. In Vitro Fertilization Unit, Department of Obstetrics and Gynecology, Edith Wolfson Medical Center, Holon, affiliated with the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    A. Weissman

  40. Division of Reproductive Endocrinology and Infertility, Dept. of Obstetrics and Gynecology, Hacettepe University, School of Medicine, Anatolia IVF and Women’s Health Center, Ankara, Turkey

    H. Yarali

  41. Division of Reproductive Endocrinology and Infertility, McGill University Health Care Center, 888 Boul. de Maisonneuve E #200, Montreal, QC, H2L 4S8, Canada

    M. H. Dahan

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  1. I. Feferkorn
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  2. S. Santos-Ribeiro
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Corresponding author

Correspondence to I. Feferkorn.

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Competing interests

All declarations of interest are outside the submitted work. Peter Humaidan reports reception of lecture honoraria from Merck, Gedeon Richter, and IBSA. Antonio La Marca reports reception of consulting fees from Merck, Organon, Ferring, Gedeon Richter, Theramex, Beckman Coulter, and Roche. Samuel Santos-Ribeiro reports reception of research funding from Roche Diagnostics, Organon, and Theramex; reception of consulting fees from Organon, MSD, and Ferring; honoraria for lectures from Ferring, Besins, MSD/Organon, Theramex, and Gedeon Richter; reception of equipment materials or other services from Roche Diagnostics and Ferring; and is deputy of the SQART SIG in ESHRE. Alessandro Conforti reports reception of grants from the University of Naples Federico II; reception honoraria from Medea, Event Planet, and Merck. Baris Ata reports reception of consulting fees from Merck GmBH–Turkey; reception of payment or honoraria from Abbott, Merck GmBH, and Ferring; reception of support for attending meetings or travel from IBSA; is president of the Turkish Society of Reproductive Medicine; and is an executive committee member of ESHRE. Juan Garcia Velasco reports reception of payment or honoraria for lectures or educational events from Merck, Ferring, MSD, Organon, Theramex, and Gedeon Richter. George Lainas reports reception of payment or honoraria for lectures or educational events from Merck and Ferring, payment for expert testimony from Merck, and support for attending meetings from ESHRE. He also participated in data safety monitoring or advisory board of Merck. Filippo Maria Ubaldi is the scientific director of GeneraLife and minority shareholder of the company. He is also the president of SIFES-MR (the Italian Society of Fertility, Sterility and Reproductive Medicine) and a member of the scientific board of Medea. In the last 3 years, F.M. Ubaldi has received honoraria or consultation fees from Merck, MSD, Ferring, Gedeon Richter, Organon, and IBSA. Sesh Sunkara reports reception of payment or honoraria for lectures from Merck Ferring and MSD. Raoul Orvieto reports reception of consulting fees from Merck and Ferring and payment or honoraria for lectures from Merck and Ferring. Nikolaos Polyzos reports reception of grants or contracts from Merck Serono, IBSA, Organon, Ferring, Roche, Theramex, Besins Healthcare, and Gedeon Richter and reception of consulting fees from Merck Serono, IBSA, Organon, Ferring, Besins Healthcare, and Gedeon Richter. Hakan Yarali reports unrestricted grants from Merck, honoraria for lectures from Merck and IBSA, and support for attending meetings from Merck, IBSA, and Ferring. Human Fatemi reports receiving research grants from Merck Serono and Organon; consulting fees from Ferring Global; speaker honoraria from Organon, Merck Serono, and Ferring; and participation in data safety monitoring or advisory board for Ferring. Sandro Esteves reports unrestricted research grants from Merck KGaA; reception of consulting fees from Merck, MeD.E.A, and event planet; reception of honoraria for lectures from Merck, MeD.E.A, and event planet; has a patent on the ART calculator, is an unpaid advisory board member for Nature Reviews and for Urology, Is the Head, Department of Education and Research, Brazilian Society of Urology (São Paulo section; unpaid), and is the Co-chair, Male Infertility Special Interest Group, WHO Infertility Guidelines (unpaid). Craig LaTasha is a site investigator for Ferring Pharmaceuticals. He was an advisory board member for Ferring Pharmaceuticals. Ariel Weissman, Christophe Blockeel, Christos Venetis, Seang Lin Tan, Michael Dahan, Bulent Urman, RJ Norman, Richard Paulson, and Ido Feferkorn report no conflicts of interest.

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Feferkorn, I., Santos-Ribeiro, S., Ubaldi, F.M. et al. The HERA (Hyper-response Risk Assessment) Delphi consensus for the management of hyper-responders in in vitro fertilization. J Assist Reprod Genet 40, 2681–2695 (2023). https://doi.org/10.1007/s10815-023-02918-5

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