INTEnsity of ovariaN Stimulation and Embryo Quality

Summary

The management of suboptimal ovarian responders remains a challenging task in IVF. These patients are frequently managed with an intense stimulation protocol of ovarian stimulation in order obtain the maximum number of embryos and, therefore, maximize the cumulative live birth rate. However, the concept of "the more the better" has been recently defied by the one of "mild stimulation". Defenders of this protocol state that with mild stimulation only the best quality oocytes are allowed to grow and, therefore, higher quality embryos will be obtained. However, the impact of the intensity of ovarian stimulation on embryo quality is far from consensual. Moreover, its effect on early embryo development has never been evaluated. Therefore, the investigators set out to perform this randomized controlled trial comparing the number of GQB and the morphokinetic parameters of early embryo development in infertile patients undergoing two different intensities of ovarian stimulation, a milder approach (CC plus 150 IU daily dose of rFSH) and a more intense approach (300 IU daily dose of rFSH).

Timeline

Start

2021-11-23

Primary completion

2026-03-11

Completion

2026-03-11

Publications

• Background Nargund G, Fauser BC, Macklon NS, Ombelet W, Nygren K, Frydman R; Rotterdam ISMAAR Consensus Group on Terminology for Ovarian Stimulation for IVF. The ISMAAR proposal on terminology for ovarian stimulation for IVF. Hum Reprod. 2007 Nov;22(11):2801-4. doi: 10.1093/humrep/dem285. Epub 2007 Sep 12.
• Background Dickey RP, Holtkamp DE. Development, pharmacology and clinical experience with clomiphene citrate. Hum Reprod Update. 1996 Nov-Dec;2(6):483-506. doi: 10.1093/humupd/2.6.483.
• Background Bechtejew TN, Nadai MN, Nastri CO, Martins WP. Clomiphene citrate and letrozole to reduce follicle-stimulating hormone consumption during ovarian stimulation: systematic review and meta-analysis. Ultrasound Obstet Gynecol. 2017 Sep;50(3):315-323. doi: 10.1002/uog.17442. Epub 2017 Aug 10.
• Background Kamath MS, Maheshwari A, Bhattacharya S, Lor KY, Gibreel A. Oral medications including clomiphene citrate or aromatase inhibitors with gonadotropins for controlled ovarian stimulation in women undergoing in vitro fertilisation. Cochrane Database Syst Rev. 2017 Nov 2;11(11):CD008528. doi: 10.1002/14651858.CD008528.pub3.
• Background ESHRE Reproductive endocrinology guidelines group. Ovarian Stimulation for IVF / ICSI - Guideline of the European Society of Human Reproduction and Embryology. Belgium: ESHRE; 2019
• Background Zhang JJ, Merhi Z, Yang M, Bodri D, Chavez-Badiola A, Repping S, van Wely M. Minimal stimulation IVF vs conventional IVF: a randomized controlled trial. Am J Obstet Gynecol. 2016 Jan;214(1):96.e1-8. doi: 10.1016/j.ajog.2015.08.009. Epub 2015 Aug 8.
• Background Verberg MF, Eijkemans MJ, Heijnen EM, Broekmans FJ, de Klerk C, Fauser BC, Macklon NS. Why do couples drop-out from IVF treatment? A prospective cohort study. Hum Reprod. 2008 Sep;23(9):2050-5. doi: 10.1093/humrep/den219. Epub 2008 Jun 10.
• Background Heijnen EM, Eijkemans MJ, De Klerk C, Polinder S, Beckers NG, Klinkert ER, Broekmans FJ, Passchier J, Te Velde ER, Macklon NS, Fauser BC. A mild treatment strategy for in-vitro fertilisation: a randomised non-inferiority trial. Lancet. 2007 Mar 3;369(9563):743-749. doi: 10.1016/S0140-6736(07)60360-2.
• Background Aleyamma TK, Kamath MS, Muthukumar K, Mangalaraj AM, George K. Affordable ART: a different perspective. Hum Reprod. 2011 Dec;26(12):3312-8. doi: 10.1093/humrep/der323. Epub 2011 Oct 10.
• Background Paulson RJ, Fauser BCJM, Vuong LTN, Doody K. Can we modify assisted reproductive technology practice to broaden reproductive care access? Fertil Steril. 2016 May;105(5):1138-1143. doi: 10.1016/j.fertnstert.2016.03.013. Epub 2016 Apr 4.
• Background Polyzos NP, Popovic-Todorovic B. SAY NO to mild ovarian stimulation for all poor responders: it is time to realize that not all poor responders are the same. Hum Reprod. 2020 Sep 1;35(9):1964-1971. doi: 10.1093/humrep/deaa183.
• Background van Tilborg TC, Torrance HL, Oudshoorn SC, Eijkemans MJC, Koks CAM, Verhoeve HR, Nap AW, Scheffer GJ, Manger AP, Schoot BC, Sluijmer AV, Verhoeff A, Groen H, Laven JSE, Mol BWJ, Broekmans FJM; OPTIMIST study group. Individualized versus standard FSH dosing in women starting IVF/ICSI: an RCT. Part 1: The predicted poor responder. Hum Reprod. 2017 Dec 1;32(12):2496-2505. doi: 10.1093/humrep/dex318.
• Background Verberg MF, Eijkemans MJ, Macklon NS, Heijnen EM, Baart EB, Hohmann FP, Fauser BC, Broekmans FJ. The clinical significance of the retrieval of a low number of oocytes following mild ovarian stimulation for IVF: a meta-analysis. Hum Reprod Update. 2009 Jan-Feb;15(1):5-12. doi: 10.1093/humupd/dmn053.
• Background Matsaseng T, Kruger T, Steyn W. Mild ovarian stimulation for in vitro fertilization: are we ready to change? A meta-analysis. Gynecol Obstet Invest. 2013;76(4):233-40. doi: 10.1159/000355980. Epub 2013 Nov 2.
• Background Sterrenburg MD, Veltman-Verhulst SM, Eijkemans MJ, Hughes EG, Macklon NS, Broekmans FJ, Fauser BC. Clinical outcomes in relation to the daily dose of recombinant follicle-stimulating hormone for ovarian stimulation in in vitro fertilization in presumed normal responders younger than 39 years: a meta-analysis. Hum Reprod Update. 2011 Mar-Apr;17(2):184-96. doi: 10.1093/humupd/dmq041. Epub 2010 Sep 15.
• Background Baart EB, Martini E, Eijkemans MJ, Van Opstal D, Beckers NG, Verhoeff A, Macklon NS, Fauser BC. Milder ovarian stimulation for in-vitro fertilization reduces aneuploidy in the human preimplantation embryo: a randomized controlled trial. Hum Reprod. 2007 Apr;22(4):980-8. doi: 10.1093/humrep/del484. Epub 2007 Jan 4.
• Background La Marca A, Minasi MG, Sighinolfi G, Greco P, Argento C, Grisendi V, Fiorentino F, Greco E. Female age, serum antimullerian hormone level, and number of oocytes affect the rate and number of euploid blastocysts in in vitro fertilization/intracytoplasmic sperm injection cycles. Fertil Steril. 2017 Nov;108(5):777-783.e2. doi: 10.1016/j.fertnstert.2017.08.029. Epub 2017 Oct 4.
• Background Wu Q, Li H, Zhu Y, Jiang W, Lu J, Wei D, Yan J, Chen ZJ. Dosage of exogenous gonadotropins is not associated with blastocyst aneuploidy or live-birth rates in PGS cycles in Chinese women. Hum Reprod. 2018 Oct 1;33(10):1875-1882. doi: 10.1093/humrep/dey270.
• Background Venetis CA, Tilia L, Panlilio E, Kan A. Is more better? A higher oocyte yield is independently associated with more day-3 euploid embryos after ICSI. Hum Reprod. 2019 Jan 1;34(1):79-83. doi: 10.1093/humrep/dey342.
• Background Irani M, Canon C, Robles A, Maddy B, Gunnala V, Qin X, Zhang C, Xu K, Rosenwaks Z. No effect of ovarian stimulation and oocyte yield on euploidy and live birth rates: an analysis of 12 298 trophectoderm biopsies. Hum Reprod. 2020 May 1;35(5):1082-1089. doi: 10.1093/humrep/deaa028.
• Background Ghosh Dastidar S, Maity S, Ghosh Dastidar B. Reappraisal of IVF stimulation in good prognosis patients - a prospective randomized study to compare mild versus standard long protocol. Fertil Steril [Internet]. 2010;94(4):S28. Available from: http://dx.doi.org/10.1016/j.fertnstert.2010.07.108
• Background Golan A, Weissman A. Symposium: Update on prediction and management of OHSS. A modern classification of OHSS. Reprod Biomed Online. 2009 Jul;19(1):28-32. doi: 10.1016/s1472-6483(10)60042-9.
• Background Hohmann FP, Macklon NS, Fauser BC. A randomized comparison of two ovarian stimulation protocols with gonadotropin-releasing hormone (GnRH) antagonist cotreatment for in vitro fertilization commencing recombinant follicle-stimulating hormone on cycle day 2 or 5 with the standard long GnRH agonist protocol. J Clin Endocrinol Metab. 2003 Jan;88(1):166-73. doi: 10.1210/jc.2002-020788.
• Background Datta AK, Maheshwari A, Felix N, Campbell S, Nargund G. Mild versus conventional ovarian stimulation for IVF in poor, normal and hyper-responders: a systematic review and meta-analysis. Hum Reprod Update. 2021 Feb 19;27(2):229-253. doi: 10.1093/humupd/dmaa035.
• Background Vermey BG, Chua SJ, Zafarmand MH, Wang R, Longobardi S, Cottell E, Beckers F, Mol BW, Venetis CA, D'Hooghe T. Is there an association between oocyte number and embryo quality? A systematic review and meta-analysis. Reprod Biomed Online. 2019 Nov;39(5):751-763. doi: 10.1016/j.rbmo.2019.06.013. Epub 2019 Jul 3.
• Background Alpha Scientists in Reproductive Medicine and ESHRE Special Interest Group of Embryology. The Istanbul consensus workshop on embryo assessment: proceedings of an expert meeting. Hum Reprod. 2011 Jun;26(6):1270-83. doi: 10.1093/humrep/der037. Epub 2011 Apr 18.
• Background ESHRE Special Interest Group of Embryology and Alpha Scientists in Reproductive Medicine. Electronic address: [email protected]. The Vienna consensus: report of an expert meeting on the development of ART laboratory performance indicators. Reprod Biomed Online. 2017 Nov;35(5):494-510. doi: 10.1016/j.rbmo.2017.06.015. Epub 2017 Aug 4.
• Background Zegers-Hochschild F, Adamson GD, Dyer S, Racowsky C, de Mouzon J, Sokol R, Rienzi L, Sunde A, Schmidt L, Cooke ID, Simpson JL, van der Poel S. The International Glossary on Infertility and Fertility Care, 2017. Fertil Steril. 2017 Sep;108(3):393-406. doi: 10.1016/j.fertnstert.2017.06.005. Epub 2017 Jul 29.
• Background Montoya-Botero P, Martinez F, Rodriguez-Purata J, Rodriguez I, Coroleu B, Polyzos NP. Erratum. The effect of type of oral contraceptive pill and duration of use on fresh and cumulative live birth rates in IVF/ICSI cycles. Hum Reprod. 2021 Mar 18;36(4):1159-1161. doi: 10.1093/humrep/deaa358. No abstract available.

Drugs

Indications