Individualized ovarian stimulation in IVF/ICSI treatment: it is time to stop using high FSH doses in predicted low responders

Jori A Leijdekkers, Helen L Torrance, Nienke E Schouten, Theodora C van Tilborg, Simone C Oudshoorn, Ben Willem J Mol, Marinus J C Eijkemans, Frank J M Broekmans, Jori A Leijdekkers, Helen L Torrance, Nienke E Schouten, Theodora C van Tilborg, Simone C Oudshoorn, Ben Willem J Mol, Marinus J C Eijkemans, Frank J M Broekmans

Abstract

In IVF/ICSI treatment, the FSH starting dose is often increased in predicted low responders from the belief that it improves the chance of having a baby by maximizing the number of retrieved oocytes. This intervention has been evaluated in several randomized controlled trials, and despite a slight increase in the number of oocytes-on average one to two more oocytes in the high versus standard dose group-no beneficial impact on the probability of a live birth has been demonstrated (risk difference, -0.02; 95% CI, -0.11 to 0.06). Still, many clinicians and researchers maintain a highly ingrained belief in 'the more oocytes, the better'. This is mainly based on cross-sectional studies, where the positive correlation between the number of retrieved oocytes and the probability of a live birth is interpreted as a direct causal relation. If the latter would be present, indeed, maximizing the oocyte number would benefit our patients. The current paper argues that the use of high FSH doses may not actually improve the probability of a live birth for predicted low responders undergoing IVF/ICSI treatment and exemplifies the flaws of directly using cross-sectional data to guide FSH dosing in clinical practice. Also, difficulties in the de-implementation of the increased FSH dosing strategy are discussed, which include the prioritization of intermediate outcomes (such as cycle cancellations) and the potential biases in the interpretation of study findings (such as confirmation or rescue bias).

Keywords: FSH dosing; IVF/ICSI; live birth; oocyte number; predicted low responder.

© The Author 2019, Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org.

Figures

Figure 1
Figure 1
The effect of increased FSH doses (follitropin delta) on the number of oocytes, number of embryos and cumulative live birth rates in women with a predicted low response (AMH levels of 0.7–2.1 ng/mL). Adapted with permission from Arce et al. (2014). AMH, anti-Müllerian hormone; rhFSH, recombinant human FSH.
Figure 2
Figure 2
Relationship between the prognostic profile of an individual woman, the number of oocytes and the probability of a live birth in IVF/ICSI treatment.
Figure 3
Figure 3
Relationship between the number of oocytes, embryos and chromosomally normal embryos on the basis of fluorescent in situ hybridization (FISH) results, following a conventional (225 IU/day) and mild (150 IU/day) ovarian stimulation protocol (fromBaart et al., 2007).*P < 0.05, **P < 0.01.
Figure 4
Figure 4
Factors influencing the use of increased FSH starting doses in women with a predicted low response. LBR, live birth rate.

References

    1. Allegra A, Marino A, Volpes A, Coffaro F, Scaglione P, Gullo S, La Marca A. A randomized controlled trial investigating the use of a predictive nomogram for the selection of the FSH starting dose in IVF/ICSI cycles. Reprod Biomed Online 2017;34:429–438.
    1. Amrhein V, Greenland S, McShane B. Scientists rise up against statistical significance. Nature 2019;567:305–307.
    1. Arce J-C, La Marca A, Mirner Klein B, Nyboe Andersen A, Fleming R. Antimüllerian hormone in gonadotropin releasing-hormone antagonist cycles: prediction of ovarian response and cumulative treatment outcome in good-prognosis patients. Fertil Steril 2013;99:1644–1653.
    1. Arce J-C, Nyboe Andersen A, Fernández-Sánchez M, Visnova H, Bosch E, García-Velasco JA, Barri P, de Sutter P, Klein BM, Fauser BC. Ovarian response to recombinant human follicle-stimulating hormone: a randomized, antimüllerian hormone–stratified, dose–response trial in women undergoing in vitro fertilization/intracytoplasmic sperm injection. Fertil Steril 2014;102:1633–1640.e5.
    1. Ata B, Kaplan B, Danzer H, Glassner M, Opsahl M, Tan SL, Munné S. Array CGH analysis shows that aneuploidy is not related to the number of embryos generated. Reprod Biomed Online 2012;24:614–620.
    1. Baart EB, Martini E, Eijkemans MJ, Van Opstal D, NGM B, Verhoeff A, Macklon NS, Fauser BCJM. Milder ovarian stimulation for in-vitro fertilization reduces aneuploidy in the human preimplantation embryo: a randomized controlled trial. Hum Reprod 2007;22:980–988.
    1. Barash OO, Hinckley MD, Rosenbluth EM, Ivani KA, Weckstein LN. High gonadotropin dosage does not affect euploidy and pregnancy rates in IVF PGS cycles with single embryo transfer. Hum Reprod 2017;32:2209–2217.
    1. Bastu E, Buyru F, Ozsurmeli M, Demiral I, Dogan M, Yeh J. 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.
    1. Berkkanoglu M, Ozgur K. What is the optimum maximal gonadotropin dosage used in microdose flare-up cycles in poor responders? Fertil Steril 2010;94:662–665.
    1. Brandes M, van der Steen JOM, Bokdam SB, Hamilton CJCM, de Bruin JP, Nelen WLDM, Kremer JAM. When and why do subfertile couples discontinue their fertility care? A longitudinal cohort study in a secondary care subfertility population. Hum Reprod 2009;24:3127–3135.
    1. Broekmans FJ, Knauff EAH, te Velde ER, Macklon NS, Fauser BC. Female reproductive ageing: current knowledge and future trends. Trends Endocrinol Metab 2007;18:58–65.
    1. Broer SL, van Disseldorp J, Broeze KA, Dolleman M, Opmeer BC, Bossuyt P, Eijkemans MJC, Mol B-WJ, Broekmans FJM, Broer SL et al. . 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 2013a;19:26–36.
    1. Broer SL, Dólleman M, van Disseldorp J, Broeze KA, Opmeer BC, Bossuyt PMM, Eijkemans MJC, Mol BW, Broekmans FJM, Broer SL et al. . Prediction of an excessive response in in vitro fertilization from patient characteristics and ovarian reserve tests and comparison in subgroups: an individual patient data meta-analysis. Fertil Steril 2013b;100:420–429.e7.
    1. Capalbo A, Rienzi L, Cimadomo D, Maggiulli R, Elliott T, Wright G, Nagy ZP, Ubaldi FM. Correlation between standard blastocyst morphology, euploidy and implantation: an observational study in two centers involving 956 screened blastocysts. Hum Reprod 2014;29:1173–1181.
    1. Dancet EAF, Van Empel IWH, Rober P, Nelen WLDM, Kremer JAM, D’Hooghe TM. Patient-centred infertility care: a qualitative study to listen to the patient’s voice. Hum Reprod 2011;26:827–833.
    1. Doherty LF, Martin JR, Kayisli U, Sakkas D, Patrizio P. Fresh transfer outcome predicts the success of a subsequent frozen transfer utilizing blastocysts of the same cohort. Reprod Biomed Online 2014;28:204–208.
    1. Doust J, Del Mar C. Why do doctors use treatments that do not work? BMJ 2004;328:474–475.
    1. Drakopoulos P, Blockeel C, Stoop D, Camus M, de Vos M, Tournaye H, Polyzos NP. 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:dev316.
    1. Ferraretti AP, Gianaroli L. The Bologna criteria for the definition of poor ovarian responders: is there a need for revision? Hum Reprod 2014;29:1842–1845.
    1. Ferraretti AP, Marca A La, Fauser BCJM, Tarlatzis B, Nargund G, Gianaroli L. ESHRE working group on Poor Ovarian Response Definition. ESHRE consensus on the definition of “poor response” to ovarian stimulation for in vitro fertilization: the Bologna criteria Hum Reprod 2011;26:1616–1624.
    1. Gallos ID, Khairy M, Chu J, Rajkhowa M, Tobias A, Campbell A, Dowell K, Fishel S, Coomarasamy A. Optimal endometrial thickness to maximize live births and minimize pregnancy losses: analysis of 25,767 fresh embryo transfers. Reprod Biomed Online 2018;37:542–548.
    1. Haahr T, Esteves SC, Humaidan P. Poor definition of poor-ovarian response results in misleading clinical recommendations. Hum Reprod 2018;33:979–980.
    1. Harrison RF, Jacob S, Spillane H, Mallon E, Hennelly B. A prospective randomized clinical trial of differing starter doses of recombinant follicle-stimulating hormone (follitropin-beta) for first time in vitro fertilization and intracytoplasmic sperm injection treatment cycles. Fertil Steril 2001;75:23–31.
    1. Hassold T, Hunt P. To err (meiotically) is human: the genesis of human aneuploidy. Nat Rev Genet 2001;2:280–291.
    1. Hendriks DJ, te Velde ER, Looman CWN, Bancsi LFJMM, Broekmans FJM. Expected poor ovarian response in predicting cumulative pregnancy rates: a powerful tool. Reprod Biomed Online 2008;17:727–736.
    1. Holter H, Sandin-Bojo A-K, Gejervall A-L, Wikland M, Wilde-Larsson B, Bergh C. Patient-centred quality of care in an IVF programme evaluated by men and women. Hum Reprod 2014;29:2695–2703.
    1. Howles CM, Saunders H, Alam V, Engrand P, FSH Treatment Guidelines Clinical Panel. Predictive factors and a corresponding treatment algorithm for controlled ovarian stimulation in patients treated with recombinant human follicle stimulating hormone (follitropin alfa) during assisted reproduction technology (ART) procedures. An analysis of 1378 patients. Curr Med Res Opin 2006;22:907–918.
    1. Kaptchuk TJ. Effect of interpretive bias on research evidence. BMJ 2003;326:1453–1455.
    1. Klinkert ER, Broekmans FJM, Looman CWN, Habbema JDF, 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;20:611–615.
    1. Kovalevsky G, Patrizio P. High rates of embryo wastage with use of assisted reproductive technology: a look at the trends between 1995 and 2001 in the United States. Fertil Steril 2005;84:325–330.
    1. Lan VTN, Linh NK, Tuong HM, Wong PC, Howles CM. Anti-Müllerian hormone versus antral follicle count for defining the starting dose of FSH. Reprod Biomed Online 2013;27:390–399.
    1. Lefebvre J, Antaki R, Kadoch I-J, Dean NL, Sylvestre C, Bissonnette F, Benoit J, Ménard S, Lapensée L. 450 IU versus 600 IU gonadotropin for controlled ovarian stimulation in poor responders: a randomized controlled trial. Fertil Steril 2015;104:1419–1425.
    1. Leijdekkers JA, Eijkemans MJC, van Tilborg TC, Oudshoorn SC, van Golde RJT, Hoek A, Lambalk CB, de Bruin JP, Fleischer K, Mochtar MH et al. . Cumulative live birth rates in low-prognosis women. Hum Reprod 2019;34:1030–1041.
    1. Leijdekkers JA, Eijkemans MJC, van Tilborg TC, Oudshoorn SC, McLernon DJ, Bhattacharya S, Mol BWJ, Broekmans FJM, Torrance HL, OPTIMIST Group. Predicting the cumulative chance of live birth over multiple complete cycles of in vitro fertilization: an external validation study. Hum Reprod 2018;33:1684–1695.
    1. Lensen SF, Wilkinson J, Leijdekkers JA, La Marca A, Mol BWJ, Marjoribanks J, Torrance H, Broekmans FJ. 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.
    1. Liu KE, Hartman M, Hartman A, Luo Z-C, Mahutte N. The impact of a thin endometrial lining on fresh and frozen–thaw IVF outcomes: an analysis of over 40 000 embryo transfers. Hum Reprod 2018;33:1883–1888.
    1. Macklon NS, Stouffer RL, Giudice LC, Fauser BCJM. The science behind 25 years of ovarian stimulation for in vitro fertilization. Endocr Rev 2006;27:170–207.
    1. Magnusson Å, Nilsson L, Oleröd G, Thurin-Kjellberg A, Bergh C. The addition of anti-Müllerian hormone in an algorithm for individualized hormone dosage did not improve the prediction of ovarian response—a randomized, controlled trial. Hum Reprod 2017;32:811–819.
    1. La Marca A, Blockeel C, Bosch E, Fanchin R, Fatemi HM, Fauser BC, García-Velasco JA, Humaidan P, Tarlatzis BC, Nelson SM. Individualized FSH dosing improves safety and reduces iatrogenic poor response while maintaining live-birth rates. Hum Reprod 2018;33:982–983.
    1. La Marca A, Minasi MG, Sighinolfi G, Greco P, Argento C, Grisendi V, Fiorentino F, Greco E. Female age, serum antimüllerian 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;108:777–783.e2.
    1. La Marca A, Papaleo E, Grisendi V, Argento C, Giulini S, Volpe A. Development of a nomogram based on markers of ovarian reserve for the individualisation of the follicle-stimulating hormone starting dose in in vitro fertilisation cycles. BJOG 2012;119:1171–1179.
    1. Martin JR, Bromer JG, Sakkas D, Patrizio P. Live babies born per oocyte retrieved in a subpopulation of oocyte donors with repetitive reproductive success. Fertil Steril 2010;94:2064–2068.
    1. McLernon DJ, Steyerberg EW, Velde ER, Lee AJ, Bhattacharya S. Predicting the chances of a live birth after one or more complete cycles of in vitro fertilisation: population based study of linked cycle data from 113 873 women. BMJ 2016;355:i5735.
    1. Mendoza-Tesarik R, Tesarik J. Usefulness of individualized FSH, LH and GH dosing in ovarian stimulation of women with low ovarian reserve. Hum Reprod 2018;33:981–982.
    1. Moolenaar LM, Mohiuddin S, Munro Davie M, Merrilees MA, Broekmans FJM, Mol BWJ, Johnson NP. High live birth rate in the subsequent IVF cycle after first-cycle poor response among women with mean age 35 and normal FSH. Reprod Biomed Online 2013;27:362–366.
    1. Munné S, Lee A, Rosenwaks Z, Grifo J, Cohen J. Fertilization and early embryology: diagnosis of major chromosome aneuploidies in human preimplantation embryos. Hum Reprod 1993;8:2185–2191.
    1. Nelson SM, Anderson RA. Derailing individualized ovarian stimulation. Hum Reprod 2018;33:980–981.
    1. Nyboe Andersen A, Nelson SM, Fauser BCJM, García-Velasco JA, Klein BM, Arce J-C, Tournaye H, De Sutter P, Decleer W, Petracco A et al. . Individualized versus conventional ovarian stimulation for in vitro fertilization: a multicenter, randomized, controlled, assessor-blinded, phase 3 noninferiority trial. Fertil Steril 2017;107:387–396.e4.
    1. Olivennes F, Trew G, Borini A, Broekmans F, Arriagada P, Warne DW, Howles CM. Randomized, controlled, open-label, non-inferiority study of the CONSORT algorithm for individualized dosing of follitropin alfa. Reprod Biomed Online 2015;30:248–257.
    1. Olivius C, Friden B, Borg G, Bergh C. Why do couples discontinue in vitro fertilization treatment? A cohort study. Fertil Steril 2004;81:258–261.
    1. Oudendijk JF, Yarde F, Eijkemans MJC, Broekmans FJM, Broer SL. The poor responder in IVF: is the prognosis always poor? A systematic review. Hum Reprod Update 2012;18:1–11.
    1. Patrizio P, Bianchi V, Lalioti MD, Gerasimova T, Sakkas D. High rate of biological loss in assisted reproduction: it is in the seed, not in the soil. Reprod Biomed Online 2007;14:92–95.
    1. Patrizio P, Sakkas D. From oocyte to baby: a clinical evaluation of the biological efficiency of in vitro fertilization. Fertil Steril 2009;91:1061–1066.
    1. Polyzos NP, Drakopoulos P, Parra J, Pellicer A, Santos-Ribeiro S, Tournaye H, Bosch E, Garcia-Velasco J. 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 ∼15,000 women. Fertil Steril 2018;110:661–670.e1.
    1. Popovic-Todorovic B, Loft A, Bredkjaeer HE, Bangsbøll S, Nielsen IK, Andersen AN. A prospective randomized clinical trial comparing an individual dose of recombinant FSH based on predictive factors versus a ‘standard’ dose of 150 IU/day in ‘standard’ patients undergoing IVF/ICSI treatment. Hum Reprod 2003a;18:2275–2282.
    1. Popovic-Todorovic B, Loft A, Lindhard A, Bangsbøll S, Andersson AM, Andersen AN. A prospective study of predictive factors of ovarian response in ‘standard’ IVF/ICSI patients treated with recombinant FSH. A suggestion for a recombinant FSH dosage normogram. Hum Reprod 2003b;18:781–787.
    1. Poseidon Group, Alviggi C, Andersen C, Buehler K, Conforti A, De PG, Esteves S, Fischer R, Galliano D, Polyzos N 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;105:1452–1453.
    1. Rajkhowa M, Mcconnell A, Thomas GE. Reasons for discontinuation of IVF treatment: a questionnaire study. Hum Reprod 2006;21:358–363.
    1. Rustamov O, Wilkinson J, La Marca A, Fitzgerald C, Roberts SA. How much variation in oocyte yield after controlled ovarian stimulation can be explained? A multilevel modelling study. Hum Reprod Open 2017;2017:hox018.
    1. Scott IA, Elshaug AG. Foregoing low-value care: how much evidence is needed to change beliefs? Intern Med J 2013;43:107–109.
    1. Sekhon L, Shaia K, Santistevan A, Cohn KH, Lee JA, Beim PY, Copperman AB. The cumulative dose of gonadotropins used for controlled ovarian stimulation does not influence the odds of embryonic aneuploidy in patients with normal ovarian response. J Assist Reprod Genet 2017;34:749–758.
    1. Simon L, Murphy K, Shamsi MB, Liu L, Emery B, Aston KI, Hotaling J, Carrell DT. Paternal influence of sperm DNA integrity on early embryonic development. Hum Reprod 2014;29:2402–2412.
    1. Sterrenburg MD, Veltman-Verhulst SM, Eijkemans MJC, Hughes EG, Macklon NS, Broekmans FJ, Fauser BCJM. 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.
    1. Sunkara SK, Polyzos NP. OPTIMIST trial: optimistic evidence? Hum Reprod 2018;33:983–984.
    1. Sunkara SK, Rittenberg V, Raine-Fenning N, Bhattacharya S, Zamora J, Coomarasamy A. Association between the number of eggs and live birth in IVF treatment: an analysis of 400 135 treatment cycles. Hum Reprod 2011;26:1768–1774.
    1. van Tilborg TC, Eijkemans MJ, Laven JS, Koks CA, de Bruin JP, Scheffer GJ, van Golde RJ, Fleischer K, Hoek A, Nap AW et al. . The OPTIMIST study: optimisation of cost effectiveness through individualised FSH stimulation dosages for IVF treatment. A randomised controlled trial. BMC Womens Health 2012;12:29.
    1. van Tilborg TC, Oudshoorn SC, Eijkemans MJC, Mochtar MH, van Golde RJT, Hoek A, Kuchenbecker WKH, Fleischer K, de Bruin JP, Groen H et al. . Individualized FSH dosing based on ovarian reserve testing in women starting IVF/ICSI: a multicentre trial and cost-effectiveness analysis. Hum Reprod 2017a;32:2485–2495.
    1. van Tilborg TC, Torrance HL, Oudshoorn SC, Eijkemans MJC, Koks CAM, Verhoeve HR, Nap AW, Scheffer GJ, Manger AP, Schoot BC et al. . Individualized versus standard FSH dosing in women starting IVF/ICSI: an RCT. Part 1: the predicted poor responder. Hum Reprod 2017b;32:2496–2505.
    1. van Tilborg TC, Torrance HL, Oudshoorn SC, Eijkemans MJC, Mol BW, Broekmans FJM, 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.
    1. Troude P, Guibert J, Bouyer J, de La Rochebrochard E, DAIFI Group. Medical factors associated with early IVF discontinuation. Reprod Biomed Online 2014;28:321–329.
    1. Twisk M, Mastenbroek S, van Wely M, Heineman MJ, Van der Veen F, Repping S. Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic sperm injection. Cochrane Database Syst Rev 2006;CD005291..
    1. 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;34:79–83.
    1. Wasserstein RL, Schirm AL, Lazar NA. Moving to a world beyond ‘p < 0.05.’. Am Stat 2019;73:1–19.
    1. Wu Q, Li H, Zhu Y, Jiang W, Lu J, Wei D, Yan J, Chen Z-J. Dosage of exogenous gonadotropins is not associated with blastocyst aneuploidy or live-birth rates in PGS cycles in Chinese women. Hum Reprod 2018;33:1875–1882.
    1. Youssef MA-F, van Wely M, Mochtar M, Fouda UM, Eldaly A, El Abidin EZ, Elhalwagy A, Mageed Abdallah AA, Zaki SS, Abdel Ghafar MS 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.
    1. Youssef MA, van Wely M, Al-Inany H, Madani T, Jahangiri N, Khodabakhshi S, Alhalabi M, Akhondi M, Ansaripour S, Tokhmechy R et al. . A mild ovarian stimulation strategy in women with poor ovarian reserve undergoing IVF: a multicenter randomized non-inferiority trial. Hum Reprod 2016;32:112–118.
    1. Yovich J, Stanger J, Hinchliffe P. Targeted gonadotrophin stimulation using the PIVET algorithm markedly reduces the risk of OHSS. Reprod Biomed Online 2012;24:281–292.

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