Mild Approaches in Ovarian Stimulation

doi:10.1017/9781316477021.007

Chapter 4 - Mild Approaches in Ovarian Stimulation

from Section 1 - Mild Forms of Ovarian Stimulation

Published online by Cambridge University Press: 14 April 2022

Adrija Kumar Datta ,

Stuart Campbell and

Geeta Nargund

Edited by

Mohamed Aboulghar and

Botros Rizk

Show author details

Mohamed Aboulghar: Affiliation:
University of Cairo IVF Centre
Botros Rizk: Affiliation:
University of South Alabama

Book contents

Get access

Summary

Conventional ovarian stimulation protocols intend to yield as many oocytes and embryos as possible to try to maximize the success of an in vitro fertilization (IVF) program. In reality, however, a series of studies over the last few years observed that live birth rates (LBRs) do not increase after a certain number of retrieved oocytes [1–3]; some studies even found a decline in LBRs when the number of oocytes was in excess of 18 [4] or blastocyst numbers above 5 [5]. Although the cumulative LBR keeps rising over and above the number of oocytes/embryos that maximizes per cycle live birth, the incidence of ovarian hyperstimulation syndrome (OHSS) and venous thromboembolism (VTE) also escalate in a parallel fashion [2;3;6]. A recent study, by restricting the stimulation dose to 150 IU/day, found only nine oocytes or four embryos optimizing the fresh cycle LBR [7].

Information

Type: Chapter
Information: Ovarian Stimulation , pp. 36 - 46

DOI: https://doi.org/10.1017/9781316477021.007 [Opens in a new window]

Publisher: Cambridge University Press

Print publication year: 2022

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Book purchase

Temporarily unavailable

References

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;26(7):1768–1774.Google Scholar

Steward, RG, Lan, L, Shah, AA, et al. Oocyte number as a predictor for ovarian hyperstimulation syndrome and live birth: an analysis of 256,381 in vitro fertilization cycles. Fertil Steril 2014;101(4):967–973.Google Scholar

Drakopoulos, P, Blockeel, C, Stoop, D, et al. Conventional ovarian stimulation and single embryo transfer for IVF/ICSI. How many oocytes do we need to maximize cumulative live birth rates after utilization of all fresh and frozen embryos? Hum Reprod 2016;31(2):370–376.Google Scholar

Polyzos, NP, Drakopoulos, P, Parra, J, et al. Cumulative live birth rates according to the number of oocytes retrieved after the first ovarian stimulation for in vitro fertilization/intracytoplasmic sperm injection: a multicenter multinational analysis including approximately 15,000 women. Fertil Steril 2018;110(4):661.e1–670.e1.CrossRef Google Scholar

Smeltzer, S, Acharya, K, Truong, T, Pieper, C, Muasher, S. Clinical pregnancy and live birth increase significantly with every additional blastocyst up to five and decline after that: an analysis of 16,666 first fresh single-blastocyst transfers from the Society for Assisted Reproductive Technology registry. Fertil Steril 2019;112(5):866.e1–873.e1.Google Scholar

Magnusson, A, Wennerholm, UB, Källén, K, et al. The association between the number of oocytes retrieved for IVF, perinatal outcome and obstetric complications. Hum Reprod 2018;33(10):1939–1947.Google Scholar

Datta, AK, Campbell, S, Felix, N, Singh, JSH, Nargund, G. Oocyte or embryo number needed to optimize live birth and cumulative live birth rates in mild stimulation IVF cycles. Reprod Biomed Online 2021;S1472-6483(21)00096-1. doi: 10.1016/j.rbmo.2021.02.010.Google Scholar

Nargund, G, Chian, RC. ISMAAR: leading the global agenda for a more physiological, patient-centred, accessible and safer approaches in ART. J Assist Reprod Genet 2013;30(2):155–156.CrossRef Google Scholar PubMed

Nargund, G, Fauser, BC, Macklon, NS, et al.; Rotterdam ISMAAR Consensus Group on Terminology for Ovarian Stimulation for IVF. The ISMAAR proposal on terminology for ovarian stimulation for IVF. Hum Reprod 2007;22(11):2801–2804.Google Scholar

Zegers-Hochschild, F, Adamson, GD, de Mouzon, J, et al.; International Committee for Monitoring Assisted Reproductive Technology; World Health Organization. The International Committee for Monitoring Assisted Reproductive Technology (ICMART) and the World Health Organization (WHO) Revised Glossary on ART Terminology, 2009. Hum Reprod 2009;24(11):2683–2687.Google Scholar

de Klerk, C, Macklon, NS, Heijnen, EM, et al. The psychological impact of IVF failure after two or more cycles of IVF with a mild versus standard treatment strategy. Hum Reprod 2007;22(9):2554–2558.Google Scholar

Verberg, MF, Eijkemans, MJ, Heijnen, EM, et al. Why do couples drop-out from IVF treatment? A prospective cohort study. Hum Reprod 2008;23(9):2050–2055.CrossRef Google Scholar PubMed

Seyhan, A, Ata, B, Polat, M, et al. Severe early ovarian hyperstimulation syndrome following GnRH agonist trigger with the addition of 1500 IU hCG. Hum Reprod 2013;28(9):2522–2528.CrossRef Google Scholar PubMed

Valbuena, D, Martin, J, de Pablo, JL, et al. Increasing levels of estradiol are deleterious to embryonic implantation because they directly affect the embryo. Fertil Steril 2001;76(5):962–968.CrossRef Google Scholar PubMed

Labarta, E, Martínez-Conejero, JA, Alamá, P, et al. Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis. Hum Reprod 2011;26(7):1813–1825.Google Scholar

Haouzi, D, Assou, S, Dechanet, C, et al. Controlled ovarian hyperstimulation for in vitro fertilization alters endometrial receptivity in humans: protocol effects. Biol Reprod 2010;82(4):679–686.Google Scholar

Kato, K, Takehara, Y, Segawa, T, et al. Minimal ovarian stimulation combined with elective single embryo transfer policy: age-specific results of a large, single-centre, Japanese cohort. Reprod Biol Endocrinol 2012;10:35.Google Scholar

Zhang, JJ, Merhi, Z, Yang, M, et al. Minimal stimulation IVF vs conventional IVF: a randomized controlled trial. Am J Obstet Gynecol 2016;214(1):96.e1–96.e8.Google Scholar

Hojgaard, A, Ingerslev, HJ, Dinesen, J. Friendly IVF: patient opinions. Hum Reprod 2001;16(7):1391–1396.Google Scholar

Aleyamma, TK, Kamath, MS, Muthukumar, K, Mangalaraj, AM, George, K. Affordable ART: a different perspective. Hum Reprod 2011;26(12):3312–3318.Google Scholar

Paulson, RJ, Fauser, BCJM, Vuong, LTN, Doody, K. Can we modify assisted reproductive technology practice to broaden reproductive care access? Fertil Steril 2016;105(5):1138–1143.Google Scholar

Practice Committee of the American Society for Reproductive Medicine. Electronic address: ASRM@asrm.org. Comparison of pregnancy rates for poor responders using IVF with mild ovarian stimulation versus conventional IVF: a guideline. Fertil Steril 2018;109(6):993–999.Google Scholar

Morgia, F, Sbracia, M, Schimberni, M, et al. A controlled trial of natural cycle versus microdose gonadotropin-releasing hormone analog flare cycles in poor responders undergoing in vitro fertilization. Fertil Steril 2004;81(6):1542–1547.Google Scholar

Kim, CH, Kim, SR, Cheon, YP, et al. 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;92(6):2082–2084.Google Scholar

Lainas, TG, Sfontouris, IA, Venetis, CA, et al. Live birth rates after modified natural cycle compared with high-dose FSH stimulation using GnRH antagonists in poor responders. Hum Reprod 2015;30(10):2321–2330.CrossRef Google Scholar PubMed

Datta, AK, Campbell, S, Felix, N, Nargund, G. Accumulation of embryos over 3 natural modified IVF (ICSI) cycles followed by transfer to improve the outcome of poor responders. Facts Views Vis Obgyn 2019;11(1):77–84.Google Scholar

Baart, EB, Martini, E, Eijkemans, MJ, et al. Milder ovarian stimulation for in-vitro fertilization reduces aneuploidy in the human preimplantation embryo: a randomized controlled trial. Hum Reprod 2007;22(4):980–988.CrossRef Google Scholar PubMed

von Wolff, M, Kollmann, Z, Flück, CE, et al. Gonadotrophin stimulation for in vitro fertilization significantly alters the hormone milieu in follicular fluid: a comparative study between natural cycle IVF and conventional IVF. Hum Reprod 2014;29(5):1049–1057.CrossRef Google Scholar PubMed

Arce, JC, Andersen, AN, Fernández-Sánchez, M, et al. Ovarian response to recombinant human follicle-stimulating hormone: a randomized, antimullerian hormone-stratified, dose-response trial in women undergoing in vitro fertilization/intracytoplasmic sperm injection. Fertil Steril 2014;102(6):1633.e5–1640.e5.Google Scholar

Patrizio, P, Sakkas, D. From oocyte to baby: a clinical evaluation of the biological efficiency of in vitro fertilization. Fertil Steril 2009;91(4):1061–1066.CrossRef Google Scholar

Silber, SJ, Kato, K, Aoyama, N, et al. Intrinsic fertility of human oocytes. Fertil Steril 2017;107(5):1232–1237.Google Scholar

Baker, VL, Brown, MB, Luke, B, Smith, GW, Ireland, JJ. Gonadotropin dose is negatively correlated with live birth rate: analysis of more than 650,000 assisted reproductive technology cycles. Fertil Steril 2015;104(5):1145.e5–1152.e5.Google Scholar

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):233–240.Google Scholar

Heijnen, EM, Eijkemans, MJ, De Klerk, C, et al. A mild treatment strategy for in-vitro fertilisation: a randomised non-inferiority trial. Lancet 2007;369(9563):743–749.Google Scholar

Datta, AK, Maheshwari, A, Felix, N, Campbell, S, Nargund, G. Mild versus conventional ovarian stimulation for IVF in poor responders: a systematic review and meta-analysis. Reprod Biomed Online 2020;41:225–238.Google Scholar

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;27:229–253.Google Scholar

Aboulghar, MA, Mansour, RT, Serour, GA, et al. In vitro fertilization in a spontaneous cycle: a successful simple protocol. J Obstet Gynaecol (Tokyo 1995) 1995;21(4):337–340.CrossRef Google Scholar

Nargund, G, Waterstone, J, Bland, J, et al. Cumulative conception and live birth rates in natural (unstimulated) IVF cycles. Hum Reprod 2001;16(2):259–262.Google Scholar

Bensdorp, AJ, Tjon-Kon-Fat, RI, Bossuyt, PM, et al. Prevention of multiple pregnancies in couples with unexplained or mild male subfertility: randomised controlled trial of in vitro fertilisation with single embryo transfer or in vitro fertilisation in modified natural cycle compared with intrauterine insemination with controlled ovarian hyperstimulation. BMJ 2015;350:g7771.Google Scholar

Sunkara, SK, La Marca, A, Seed, PT, Khalaf, Y. Increased risk of preterm birth and low birthweight with very high number of oocytes following IVF: an analysis of 65 868 singleton live birth outcomes. Hum Reprod 2015;30(6):1473–1480.Google Scholar

Kamath, MS, Kirubakaran, R, Mascarenhas, M, Sunkara, SK. Perinatal outcomes after stimulated versus natural cycle IVF: a systematic review and meta-analysis. Reprod Biomed Online 2018;36(1):94–101.CrossRef Google Scholar PubMed

Pelinck, MJ, Hoek, A, Simons, AH, Heineman, MJ. Efficacy of natural cycle IVF: a review of the literature. Hum Reprod Update 2002;8(2):129–139.Google Scholar

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;2:CD012693.Google Scholar

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;96:1122–1128.Google Scholar

Casano, S, Guidetti, D, Patriarca, A, et al. MILD ovarian stimulation with GnRH-antagonist vs. long protocol with low dose FSH for non-PCO high responders undergoing IVF: a prospective, randomized study including thawing cycles. J Assist Reprod Genet 2012;29:1343–1351.CrossRef Google Scholar PubMed

Dhont, M, Onghena, A, Coetsier, T, De Sutter, P. Prospective randomized study of clomiphene citrate and gonadotrophins versus goserelin and gonadotrophins for follicular stimulation in assisted reproduction. Hum Reprod 1995;10:791–796.CrossRef Google Scholar PubMed

Elnashar, I, Farghaly, TA, Abdalbadie, AS, et al. Low cost ovarian stimulation protocol is associated with lower pregnancy rate in normal responders in comparison to long protocol. Fertil Steril 2016;106 (Suppl 3):e194–e195.Google Scholar

Ghoshdastidar, S, Maity, S, Ghoshdastidar, B. Improved ICSI outcome in poor responders using a novel stimulation regime with micro-dose flare followed by GnRH antagonist in mid follicular phase. Hum Reprod 2010;1:i316.Google Scholar

Grochowski, D, Wolczynski, S, Kuczynski, W, et al. Good results of milder form of ovarian stimulation in an in vitro fertilization/intracytoplasmic sperm injection program. Gynecol Endocrinol 1999;13:297–304.Google Scholar

Harrison, RF, Kondaveeti, U, Barry-Kinsella, C, et al. Should gonadotropin-releasing hormone down-regulation therapy be routine in in vitro fertilization? Fertil Steril 1994;62:568–573.Google Scholar

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;88:166–173.CrossRef Google Scholar PubMed

Karimzadeh, MA, Ahmadi, S, Oskouian, H, Rahmani, E. Comparison of mild stimulation and conventional stimulation in ART outcome. Arch Gynecol Obstet 2010;281:741–746.CrossRef Google Scholar PubMed

Long, CA, Sopelak, VM, Lincoln, SR, Cowan, BD. Luteal phase consequences of low-dose gonadotropin-releasing hormone agonist therapy in nonluteal-supported in vitro fertilization cycles. Fertil Steril 1995;64:573–576.Google Scholar

Lou, HY, Huang, XY. Modified natural cycle for in vitro fertilization and embryo transfer in normal ovarian responders. J Int Med Res 2010;38:2070–2076.Google Scholar

Mukherjee, S, Sharma, S, Chakravarty, BN. Letrozole in a low-cost in vitro fertilization protocol in intracytoplasmic sperm injection cycles for male factor infertility: a randomized controlled trial. J Hum Reprod Sci 2012;5:170–174.Google Scholar

Oudshoorn, SC, van Tilborg, TC, Eijkemans, MJC, et al. Individualized versus standard FSH dosing in women starting IVF/ICSI: an RCT. Part 2: The predicted hyper responder. Hum Reprod 2017;32:2506–2514.Google Scholar

Tummon, IS, Daniel, SA, Kaplan, BR, Nisker, JA, Yuzpe, AA. Randomized, prospective comparison of luteal leuprolide acetate and gonadotropins versus clomiphene citrate and gonadotropins in 408 first cycles of in vitro fertilization. Fertil Steril 1992;58:563–568.Google Scholar

Bastu, E, Buyru, F, Ozsurmeli, M, et al. A randomized, single-blind, prospective trial comparing three different gonadotropin doses with or without addition of letrozole during ovulation stimulation in patients with poor ovarian response. Eur J Obstet Gynecol Reprod Biol 2016;203:30–34.CrossRef Google Scholar PubMed

Goswami, SK, Das, T, Chattopadhyay, R, et al. A randomized single-blind controlled trial of letrozole as a low-cost IVF protocol in women with poor ovarian response: a preliminary report. Hum Reprod 2004;19:2031–2035.Google Scholar

Huang, R, Wang, B, Yang, X, Li, TT, Liang, XY. The comparison of mild stimulation vs. controlled ovarian hyperstimulation protocol in poor ovarian responders: a prospective randomized study. Hum Reprod 2015;1:i49–i50.Google Scholar

Martinez, F, Coroleu, B, Marques, L, et al. Comparison of “short protocol” versus “antagonists” with or without clomiphene citrate for stimulation in IVF of patients with “low response”. [Spanish]. Rev Iberoam Fertil Reprod Hum 2003;20:355–360.Google Scholar

Mohsen, IA, El Din, RE. Minimal stimulation protocol using letrozole versus microdose flare up GnRH agonist protocol in women with poor ovarian response undergoing ICSI. Gynecol Endocrinol 2013;29:105–108.Google Scholar

Pilehvari, S, Shahrokh Tehraninejad, E, Hosseinrashidi, B, et al. Comparison pregnancy outcomes between minimal stimulation protocol and conventional GnRH antagonist protocols in poor ovarian responders. J Family Reprod Health 2016;10:35–42.Google Scholar

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;10:114.Google Scholar

Revelli, A, Chiadò, A, Dalmasso, P, et al. “Mild” vs. “long” protocol for controlled ovarian hyperstimulation in patients with expected poor ovarian responsiveness undergoing in vitro fertilization (IVF): a large prospective randomized trial. J Assist Reprod Genet 2014;31:809–815.Google Scholar

van Tilborg, TC, Torrance, HL, Oudshoorn, SC, et al.; OPTIMIST study group. The end for individualized dosing in IVF ovarian stimulation? Reply to letters-to-the-editor regarding the OPTIMIST papers. Hum Reprod 2018;33:984–988.Google Scholar

Youssef, MA, van Wely, M, Al-Inany, H, et al. A mild ovarian stimulation strategy in women with poor ovarian reserve undergoing IVF: a multicenter randomized non-inferiority trial. Hum Reprod 2017;32:112–118.Google Scholar

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;46:2327–2337.Google Scholar

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;17:184–196.Google Scholar

Gibreel, A, Maheshwari, A, Bhattacharya, S. Clomiphene citrate in combination with gonadotropins for controlled ovarian stimulation in women undergoing in vitro fertilization. Cochrane Database Syst Rev 2012;11:CD008528.Google Scholar

Figueiredo, JB, Nastri, CO, Vieira, AD, Martins, WP. Clomiphene combined with gonadotropins and GnRH antagonist versus conventional controlled ovarian hyperstimulation without clomiphene in women undergoing assisted reproductive techniques: systematic review and meta-analysis. Arch Gynecol Obstet 2013;287:779–790.Google Scholar

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;50:315–323.Google Scholar

Fan, Y, Zhang, X, Hao, Z, et al. Effectiveness of mild ovarian stimulation versus GnRH agonist protocol in women undergoing assisted reproductive technology: a meta-analysis. Gynecol Endocrinol 2017;33:746–756.Google Scholar

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;11:CD008528.Google Scholar

Song, D, Shi, Y, Zhong, Y, et al. Efficiency of mild ovarian stimulation with clomiphene on poor ovarian responders during IVF\ICSI procedures: a meta-analysis. Eur J Obstet Gynecol Reprod Biol 2016;204:36–43.Google Scholar

Youssef, MA, van Wely, M, Mochtar, M, et al. Low dosing of gonadotropins in in vitro fertilization cycles for women with poor ovarian reserve: systematic review and meta-analysis. Fertil Steril 2018;109:289–301.Google Scholar

Montoya-Botero, P, Drakopoulos, P, Gonzalez-Foruria, I, Polyzos, NP. Fresh and cumulative live birth rates in mild versus conventional stimulation for IVF cycles in poor ovarian responders: a systematic review and meta-analysis. Hum Reprod Open 2021;2021:hoaa066.Google Scholar

Accessibility standard: Unknown

Why this information is here

This section outlines the accessibility features of this content - including support for screen readers, full keyboard navigation and high-contrast display options. This may not be relevant for you.

Accessibility Information

Accessibility compliance for the PDF of this book is currently unknown and may be updated in the future.