The Effect of the Gonadotropin Dose Increment During Controlled Ovarian Hyperstimulation on Live Birth Rates of POSEIDON Group 3-4 Patients

Abstract

This retrospective study seeks to explore whether modifying the gonadotropin dose in cases of poor ovarian response during controlled ovarian hyperstimulation contributes to improved live birth rates in Poseidon Group 3-4 patients. The study took place at a tertiary level university. The electronic database spanning 2012-2021 was scrutinized to identify patients with diminished ovarian reserve (DOR) who underwent intra-cytoplasmic sperm injection – embryo transfer (ICSI-ET). Diminished ovarian reserve was determined using the POSEIDON criteria. Patients were categorized into two groups based on whether dose adjustment was implemented during the initial ultrasound assessment in controlled ovarian hyperstimulation (COH). There were 188 patients in the dose adjustment (DA) group and 310 patients in the fixed-dose (FD) group. The demographic parameters were similar between the groups. The started gonadotropin dose was similar in both groups (300 IU). The median dose adjustment on the first control was +75 IU in the DA group. The follicle output rates, follicle to oocyte indexes, and the embryology parameters were comparable between the groups. The positive pregnancy rate was 19.7% (36/188) in the DA group vs. 19.1% (61/310) in the FD Group (p=0.4). The primary outcome of the study; live birth rates were 12% in the DA group vs. 9% in the FD group, and the results were statistically similar (p=0.3). Our research revealed that adjusting the gonadotropin dose in cases of inadequate ovarian response during COH results in comparable live birth rates to those observed in the fixed-dose group. For patients exhibiting an inadequate response, dose adjustment may be deemed necessary.

Keywords

• Poor Ovarian Response
• Diminished Ovarian Reserve
• Gonadotropin Dosage
• in vitro fertilization
• infertility

Kontrollü Ovaryan Hiperstimülasyon Sırasında Gonadotropin Dozunun Artışının POSEİDON Grubu 3-4 Hastalarının Canlı Doğum Oranlarına Etkisi

Abstract

Bu retrospektif çalışma, kontrollü ovaryan hiperstimülasyon sırasında düşük over yanıtı gösteren Poseidon Grubu 3-4 hastalarında gonadotropin dozunu değiştirmenin, canlı doğum oranlarını artırıp artırmadığını araştırmayı amaçlamaktadır. Çalışma üçüncü basamak bir üniversite hastanesinde gerçekleştirilmiştir. 2012-2021 yıllarını kapsayan elektronik veritabanı, düşük over rezervi (DOR) olan ve intra-sitoplazmik sperm enjeksiyonu - embriyo transferi (ICSI-ET) geçiren hastaları belirlemek için incelenmiştir. Düşük over rezervi, Poseidon kriterlerine göre belirlenmiştir. Hastalar, kontrollü over hiperstimülasyonu (COH) sırasındaki ilk ultrason değerlendirmesi sırasında doz ayarlamasının uygulanıp uygulanmadığına göre iki gruba ayrılmıştır. Doz ayarlaması (DA) grubunda 188 hasta ve sabit doz (FD) grubunda 310 hasta bulunmaktadır. Demografik parametreler gruplar arasında benzerlik göstermektedir. Başlangıç gonadotropin dozu her iki grupta da benzerdi (300 IU). İlk kontroldeki median doz ayarlaması DA grubunda +75 IU idi. FORT (follicle-output rate) oranları, folikül-oosit indeksleri ve embriyoloji parametreleri gruplar arasında karşılaştırılabilir düzeydeydi. Pozitif gebelik oranı DA grubunda %19,7 (36/188) iken, FD Grubunda %19,1 (61/310) idi (p=0,4). Çalışmanın birincil sonucu; canlı doğum oranları DA grubunda %12 iken, FD grubunda %9 olarak bulundu ve sonuçlar istatistiksel olarak benzerdi (p=0,3). Araştırmamız, kontrollü over hiperstimülasyonu sırasında yetersiz over yanıtı olan vakalarda gonadotropin dozunun ayarlanmasının, sabit doz grubunda gözlenen canlı doğum oranlarına benzer sonuçlar verdiğini ortaya koymuştur. Yetersiz yanıt gösteren hastalar için doz ayarlaması gerekli olabilir.

Keywords

• Düşük over rezervi
• kötü over yanıtı
• gonadotropin
• in-vitro fertilizasyon
• infertilite

References

1. 1. Broer SL, van Disseldorp J, Broeze KA, et al. IMPORT study group. Added value of ovarian reserve testing on patient characteristics in the prediction of ovarian response and ongoing pregnancy: an individual patient data approach. Hum Reprod Update. 2013 Jan-Feb;19(1):26-36.
2. 2. Blockeel C, Sterrenburg MD, Broekmans FJ, et al. Follicular phase endocrine characteristics during ovarian stimulation and GnRH antagonist cotreatment for IVF: RCT comparing recFSH initiated on cycle day 2 or 5. J Clin Endocrinol Metab. 2011 Apr;96(4):1122-8.
3. 3. 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.
4. 4. Sterrenburg MD, Veltman-Verhulst SM, Eijkemans MJ, et al. 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.
5. 5. Lensen SF, Wilkinson J, Leijdekkers JA, et al. Individualised gonadotropin dose selection using markers of ovarian reserve for women undergoing in vitro fertilisation plus intracytoplasmic sperm injection (IVF/ICSI). Cochrane Database Syst Rev. 2018 Feb 1;2(2):CD012693.
6. 6. Lefebvre J, Antaki R, Kadoch IJ, et al. 450 IU versus 600 IU gonadotropin for controlled ovarian stimulation in poor responders: a randomized controlled trial. Fertil Steril. 2015 Dec;104(6):1419-25.
7. 7. POSEIDON Group (Patient-Oriented Strategies Encompassing Individualize D Oocyte Number), Alviggi C, Andersen CY, Buehler K, et al. A new more detailed stratification of low responders to ovarian stimulation: from a poor ovarian response to a low prognosis concept. Fertil Steril. 2016; 105(6):1452-1453.
8. 8. Gardner, D.K. and Schoolcraft, W.B. In Vitro Culture of Human Blastocyst. In: Jansen, R. and Mortimer, D., Eds., Towards Reproductive Certainty: Infertility and Genetics Beyond, Parthenon Press, Carnforth, 1999, 377-388.

9. 9. Mahony MH, B. Richter, K. D'Hooghe, T. Abstracts of the 34th Annual Meeting of the European Society of Human Reproduction and Embryology (P−659); Occurrence and characteristics of recombinant human folliclestimulating hormone (r-hFSH) dose adjustments during ovarian stimulation in a real-world US database study of 33,962 IVF patient cycles. Hum Reprod. 2018;33(suppl_1):i444.
10. 10. Ovarian Stimulation TEGGO, Bosch E, Broer S, Griesinger G, et al. ESHRE guideline: ovarian stimulation for IVF/ICSI†. Hum Reprod Open. 2020 May 1;2020(2):hoaa009.
11. 11. Humaidan P, Alviggi C, Fischer R, Esteves Sc. The novel POSEIDON stratification of 'Low prognosis patients in Assisted Reproductive Technology' and its proposed marker of successful outcome. F1000Res. 2016 Dec 23;5:2911.
12. 12. Conforti A, Esteves SC, Picarelli S, et al. Novel approaches for diagnosis and management of low prognosis patients in assisted reproductive technology: the POSEIDON concept. Panminerva Med. 2019 Mar;61(1):24-29.
13. 13. Haahr T, Dosouto C, Alviggi C, Esteves SC, Humaidan P. Management Strategies for POSEIDON Groups 3 and 4. Front Endocrinol (Lausanne). 2019 Sep 11;10:614.
14. 14. Alviggi C, Conforti A, Esteves SC, et al. Understanding Ovarian Hypo-Response to Exogenous Gonadotropin in Ovarian Stimulation and Its New Proposed Marker-The Follicle-To-Oocyte (FOI) Index. Front Endocrinol (Lausanne). 2018 Oct 17;9:589.
15. 15. Drakopoulos P, Santos-Ribeiro S, Bosch E, et al. The Effect of Dose Adjustments in a Subsequent Cycle of Women With Suboptimal Response Following Conventional Ovarian Stimulation. Front Endocrinol (Lausanne). 2018 Jul 23;9:361.
16. 16. Sunkara SK, Rittenberg V, Raine-Fenning N, et al. Association between the number of eggs and live birth in IVF treatment: an analysis of 400 135 treatment cycles. Hum Reprod. 2011 Jul;26(7):1768-74.
17. 17. Fatemi H, Bilger W, Denis D, et al. Dose adjustment of follicle-stimulating hormone (FSH) during ovarian stimulation as part of medically-assisted reproduction in clinical studies: a systematic review covering 10 years (2007-2017). Reprod Biol Endocrinol. 2021 May 11;19(1):68.
18. 18. Klinkert ER, Broekmans FJ, Looman CW, Habbema JD, te Velde ER. Expected poor responders on the basis of an antral follicle count do not benefit from a higher starting dose of gonadotrophins in IVF treatment: a randomized controlled trial. Hum Reprod. 2005 Mar;20(3):611-5.
19. 19. Aboulghar MA, Mansour RT, Serour GI, Al-Inany HG, Amin YM, Aboulghar MM. Increasing the dose of human menopausal gonadotrophins on day of GnRH antagonist administration: randomized controlled trial. Reprod Biomed Online. 2004 May;8(5):524-7.
20. 20. Martin JR, Mahutte NG, Arici A, Sakkas D. Impact of duration and dose of gonadotrophins on IVF outcomes. Reprod Biomed Online. 2006 Nov;13(5):645-50.
21. 21. Kim CH, Kim SR, Cheon YP, Kim SH, Chae HD, Kang BM. Minimal stimulation using gonadotropin-releasing hormone (GnRH) antagonist and recombinant human follicle-stimulating hormone versus GnRH antagonist multiple-dose protocol in low responders undergoing in vitro fertilization/intracytoplasmic sperm injection. Fertil Steril. 2009 Dec;92(6):2082-4.
22. 22. Liu X, Li T, Wang B, et al. Mild stimulation protocol vs conventional controlled ovarian stimulation protocol in poor ovarian response patients: a prospective randomized controlled trial. Arch Gynecol Obstet. 2020 May;301(5):1331-1339.
23. 23. Ragni G, Levi-Setti PE, Fadini R, et al. Clomiphene citrate versus high doses of gonadotropins for in vitro fertilisation in women with compromised ovarian reserve: a randomised controlled non-inferiority trial. Reprod Biol Endocrinol. 2012 Dec 18;10:114.
24. 24. Yu R, Jin H, Huang X, Lin J, Wang P. Comparison of modified agonist, mild-stimulation and antagonist protocols for in vitro fertilization in patients with diminished ovarian reserve. J Int Med Res. 2018 Jun;46(6):2327-2337.
25. 25. Practice Committee of the American Society for Reproductive Medicine. Comparison of pregnancy rates for poor responders using IVF with mild ovarian stimulation versus conventional IVF: a guideline. Fertil Steril. 2018 Jun;109(6):993-999.
26. 26. 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.