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

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

Abstract

Purpose

To provide an agreed upon definition of hyper-response for women undergoing ovarian stimulation (OS)?

Methods

A literature search was performed regarding hyper-response to ovarian stimulation for assisted reproductive technology. A scientific committee consisting of 5 experts discussed, amended, and selected the final statements in the questionnaire for the first round of the Delphi consensus. The questionnaire was distributed to 31 experts, 22 of whom responded (with representation selected for global coverage), each anonymous to the others. 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.

Results

17/18 statements reached consensus. The most relevant are summarized here. (I) Definition of a hyper-response: Collection of ≥ 15 oocytes is characterized as a hyper-response (72.7% agreement). OHSS is not relevant for the definition of hyper-response if the number of collected oocytes is above a threshold (≥ 15) (77.3% agreement). The most important factor in defining a hyper-response during stimulation is the number of follicles ≥ 10 mm in mean diameter (86.4% agreement). (II) Risk factors for hyper-response: AMH values (95.5% agreement), AFC (95.5% agreement), patient’s age (77.3% agreement) but not ovarian volume (72.7% agreement). In a patient without previous ovarian stimulation, the most important risk factor for a hyper-response is the antral follicular count (AFC) (68.2% agreement). In a patient without previous ovarian stimulation, when AMH and AFC are discordant, one suggesting a hyper-response and the other not, AFC is the more reliable marker (68.2% agreement). The lowest serum AMH value that would place one at risk for a hyper-response is ≥ 2 ng/ml (14.3 pmol/L) (72.7% agreement). The lowest AFC that would place one at risk for a hyper-response is ≥ 18 (81.8% agreement). Women with polycystic ovarian syndrome (PCOS) as per Rotterdam criteria are at a higher risk of hyper-response than women without PCOS with equivalent follicle counts and gonadotropin doses during ovarian stimulation for IVF (86.4% agreement). No consensus was reached regarding the number of growing follicles ≥ 10 mm that would define a hyper-response.

Conclusion

The definition of hyper-response and its risk factors can be useful for harmonizing research, improving understanding of the subject, and tailoring patient care.

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Data availability

The data underlying this article will be shared on reasonable request to the corresponding author.

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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.

Author information

Authors and Affiliations

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

    Ido Feferkorn & S. L. Tan

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

    B. Ata

  3. ART Fertility Clinics, Dubai, United Arab Emirates

    B. Ata

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

    S. C. Esteves

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

    S. C. Esteves

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

    S. C. Esteves

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

    A. La Marca

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

    R. Paulson

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

    C. Blockeel

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

    A. Conforti

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

    H. M. Fatemi

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

    P. Humaidan

  13. Eugonia IVF Unit, Athens, Greece

    G. T. Lainas

  14. Department of Obstetrics and Gynaecology, Monash University, Clayton, Australia

    B. W. Mol

  15. Aberdeen Centre for Women’s Health Research, Institute of Applied Health Sciences, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK

    B. W. Mol

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

    R. J. Norman

  17. FertilitySA, Adelaide, South Australia

    R. J. Norman

  18. Monash Centre for Health Research and Implementation MCHRI, Monash University, Clayton, Australia

    R. J. Norman

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

    R. J. Norman

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

    R. Orvieto

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

    R. Orvieto

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

    R. Orvieto

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

    N. P. Polyzos

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

    S. Santos-Ribeiro

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

    S. K. Sunkara

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

    S. L. Tan

  27. Scientific Executive Committee – GeneraLife Centers for Reproductive Medicine, Rome, Italy

    F. M. Ubaldi

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

    B. Urman

  29. IVI RMA Madrid, Madrid, Spain

    J. G. Velasco

  30. 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

  31. School of Medicine, Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Hacettepe University, Ankara, Turkey

    H. Yarali

  32. Anatolia IVF and Women’s Health Center, Ankara, Turkey

    H. Yarali

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

    M. H. Dahan

Authors
  1. Ido Feferkorn
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  2. B. Ata
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  3. S. C. Esteves
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  4. A. La Marca
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  5. R. Paulson
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  6. C. Blockeel
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  7. A. Conforti
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Corresponding author

Correspondence to Ido Feferkorn.

Ethics declarations

All declarations of interest are outside the submitted work.

• Peter Humaidan reports reception of lecture honoraria from Merck, Gedoeon 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; recpetion 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 president of SIFES-MR (the Italian Society of Fertility, Sterility and Reproductive Medicine), and member of the scientific board of Medea. In the last three 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 lectured 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.

• Ben Mol reports reception of an investigator grant from NHMRC, he reports consultancy at an hourly rate for ObsEva, Merck Merck KGaA and Guerbet and reception of travel support from Merck Merck KGaA.

• Hakan Yarali reports unrestricted grants from Merck, honoraria for lectures from Merck and IBSA, 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).

Conflicts of interest

• Ariel Weissman reports no conflicts of interest.

• Christophe Blockeel reports no conflicts of interest.

• Seang Lin Tan reports no conflicts of interest.

• Michael Dahan reports no conflicts of interest.

• Bulent Urman reports no conflicts of interest.

• RJ Norman reports no conflict of interest.

• Richard Paulson reports no conflicts of interest.

• Ido Feferkorn reports no conflicts of interest.

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Feferkorn, I., Ata, B., Esteves, S.C. et al. The HERA (Hyper-response Risk Assessment) Delphi consensus definition of hyper-responders for in-vitro fertilization. J Assist Reprod Genet 40, 1071–1081 (2023). https://doi.org/10.1007/s10815-023-02757-4

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