Prognostic models for high and low ovarian responses in controlled ovarian stimulation using a GnRH antagonist protocol

Frank J Broekmans, Pierre J M Verweij, Marinus J C Eijkemans, Bernadette M J L Mannaerts, Han Witjes, Frank J Broekmans, Pierre J M Verweij, Marinus J C Eijkemans, Bernadette M J L Mannaerts, Han Witjes

Abstract

Study question: Can predictors of low and high ovarian responses be identified in patients undergoing controlled ovarian stimulation (COS) in a GnRH antagonist protocol?

Summary answer: Common prognostic factors for high and low ovarian responses were female age, antral follicle count (AFC) and basal serum FSH and LH.

What is known already: Predictors of ovarian response have been identified in GnRH agonist protocols. With the introduction of GnRH antagonists to prevent premature LH rises during COS, and the gradual shift in use of long GnRH agonist to short GnRH antagonist protocols, there is a need for data on the predictability of ovarian response in GnRH antagonist cycles.

Study design, size, duration: A retrospective analysis of data from the Engage trial and validation with the Xpect trial. Prognostic models were constructed for high (>18 oocytes retrieved) and low (<6 oocytes retrieved) ovarian response. Model building was based on the recombinant FSH (rFSH) arm (n = 747) of the Engage trial. Multivariable logistic regression models were constructed in a stepwise fashion (P < 0.15 for entry). Validation based on calibration was performed in patients with equivalent treatment (n = 199) in the Xpect trial.

Participants/materials, setting, methods: Infertile women with an indication for COS prior to IVF. The Engage and Xpect trials included patients of similar ethnic origins from North America and Europe who had regular menstrual cycles. The main causes of infertility were male factor, tubal factor and endometriosis.

Main results and the role of chance: In the Engage trial, 18.3% of patients had a high and 12.7% had a low ovarian response. Age, AFC, serum FSH and serum LH at stimulation Day 1 were prognostic for both high and low ovarian responses. Higher AFC and LH were associated with an increased chance of high ovarian response. Older age and higher FSH correlated with an increased chance of low ovarian response. Region (North America/Europe) and BMI were prognostic for high ovarian response, and serum estradiol at stimulation Day 1 was associated with low ovarian response. The area under the receiver operating characteristic (ROC) curve (AUC) for the model for a high ovarian response was 0.82. Sensitivity and specificity were 0.82 and 0.73; positive and negative predictive values were 0.40 and 0.95, respectively. The AUC for the model for a low ovarian response was 0.80. Sensitivity and specificity were 0.77 and 0.73, respectively; positive and negative predictive values were 0.29 and 0.96, respectively. In Xpect, 19.1% of patients were high ovarian responders and 16.1% were low ovarian responders. The slope of the calibration line was 0.81 and 1.35 for high and low ovarian responses, respectively, both not statistically different from 1.0. In summary, common prognostic factors for high and low ovarian responses were female age, AFC and basal serum FSH and LH. Simple multivariable models are presented that are able to predict both a too low or too high ovarian response in patients treated with a GnRH antagonist protocol and daily rFSH.

Limitations, reasons for caution: Anti-Müllerian hormone was not included in the prediction modelling.

Wider implications of the findings: The findings will help with the identification of patients at risk of a too high or too low ovarian response and individualization of COS treatment.

Study funding/competing interests: Financial support for this study and the editorial work was provided by Merck, Sharp & Dohme Corp. (MSD), a subsidiary of Merck & Co. Inc., Whitehouse Station, NJ, USA. F.J.B. received a grant from CVZ to his institution; P.J.M.V. and H.W. are employees of MSD, and B.M.J.L.M. was an employee of MSD at the time of development of this manuscript.

Trial registration numbers: NCT00778999.

Trial registration: ClinicalTrials.gov NCT00696800 NCT00778999.

Keywords: GnRH antagonist; ovarian response; predictive modelling; recombinant FSH.

© The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.

Figures

Figure 1
Figure 1
(a). Receiver operating characteristic (ROC) curves for models for a high ovarian response (>18 oocytes) in controlled ovarian stimulation (COS) using a GnRH antagonist protocol. (b). ROC curves for models for a low ovarian response (<6 oocytes) in COS using a GnRH antagonist protocol.
Figure 2
Figure 2
Probability plot for a high or low ovarian response in COS using a GnRH antagonist protocol.

References

    1. Al-Inany HG, Youssef MA, Aboulghar M, Broekmans F, Sterrenburg M, Smit J, Abou-Setta AM. Gonadotrophin-releasing hormone antagonists for assisted reproductive technology. Cochrane Database Syst Rev. 2011:CD001750.
    1. Altman DG, Royston P. What do we mean by validating a prognostic model? Stat Med. 2000;19:453–473.
    1. Broekmans FJ, Kwee J, Hendriks DJ, Mol BW, Lambalk CB. A systematic review of tests predicting ovarian reserve and IVF outcome. Hum Reprod Update. 2006;12:685–718.
    1. Broer SL, Mol BW, Hendriks D, Broekmans FJ. The role of antimullerian hormone in prediction of outcome after IVF: comparison with the antral follicle count. Fertil Steril. 2009;91:705–714.
    1. Broer SL, Dolleman M, Opmeer BC, Fauser BC, Mol BW, Broekmans FJ. AMH and AFC as predictors of excessive response in controlled ovarian hyperstimulation: a meta-analysis. Hum Reprod Update. 2011;17:46–54.
    1. Copas J. Regression, prediction and shrinkage. J R Stat Soc Series B Stat Methodol. 1983;45:311–354.
    1. Devroey P, Boostanfar R, Koper NP, Mannaerts BM, Ijzerman-Boon PC, Fauser BC. A double-blind, non-inferiority RCT comparing corifollitropin alfa and recombinant FSH during the first seven days of ovarian stimulation using a GnRH antagonist protocol. Hum Reprod. 2009;24:3063–3072.
    1. Devroey P, Boostanfar R, Koper NP, Mannaerts BMJL, Verweij PJM, Stegmann BJ, IJzerman-Boon PC, Fauser BCJM on behalf of the ENGAGE Investigators. Corrigendum: a double-blind, non-inferiority RCT comparing corifollitropin alfa and recombinant FSH during the first seven days of ovarian stimulation using a GnRH antagonist protocol. Hum Reprod. 2014 published online 6 Mar 2014 .
    1. Fauser BC, Diedrich K, Devroey P. Predictors of ovarian response: progress towards individualized treatment in ovulation induction and ovarian stimulation. Hum Reprod Update. 2008;14:1–14.
    1. Ferraretti AP, La MA, Fauser BC, Tarlatzis B, Nargund G, Gianaroli L. 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. Harrell FE, Jr, Lee KL, Mark DB. Multivariable prognostic models: issues in developing models, evaluating assumptions and adequacy, and measuring and reducing errors. Stat Med. 1996;15:361–387.
    1. Hehenkamp WJ, Looman CW, Themmen AP, de Jong FH, te Velde ER, Broekmans FJ. Anti-Mullerian hormone levels in the spontaneous menstrual cycle do not show substantial fluctuation. J Clin Endocrinol Metab. 2006;91:4057–4063.
    1. Hendriks DJ, Mol BW, Bancsi LF, te Velde ER, Broekmans FJ. Antral follicle count in the prediction of poor ovarian response and pregnancy after in vitro fertilization: a meta-analysis and comparison with basal follicle-stimulating hormone level. Fertil Steril. 2005;83:291–301.
    1. Hunault CC, Habbema JD, Eijkemans MJ, Collins JA, Evers JL, te Velde ER. Two new prediction rules for spontaneous pregnancy leading to live birth among subfertile couples, based on the synthesis of three previous models. Hum Reprod. 2004;19:2019–2026.
    1. Jayaprakasan K, Chan Y, Islam R, Haoula Z, Hopkisson J, Coomarasamy A, Raine-Fenning N. Prediction of in vitro fertilization outcome at different antral follicle count thresholds in a prospective cohort of 1,012 women. Fertil Steril. 2012;98:657–663.
    1. 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;20:611–615.
    1. Kolibianakis EM, Collins J, Tarlatzis B, Papanikolaou E, Devroey P. Are endogenous LH levels during ovarian stimulation for IVF using GnRH analogues associated with the probability of ongoing pregnancy? A systematic review. Hum Reprod Update. 2006;12:3–12.
    1. Lekamge DN, Lane M, Gilchrist RB, Tremellen KP. Increased gonadotrophin stimulation does not improve IVF outcomes in patients with predicted poor ovarian reserve. J Assist Reprod Genet. 2008;25:515–521.
    1. Leushuis E, van der Steeg JW, Steures P, Bossuyt PM, Eijkemans MJ, van der Veen F, Mol BW, Hompes PG. Prediction models in reproductive medicine: a critical appraisal. Hum Reprod Update. 2009;15:537–552.
    1. Mukherjee T, Copperman AB, Lapinski R, Sandler B, Bustillo M, Grunfeld L. An elevated day three follicle-stimulating hormone:luteinizing hormone ratio (FSH:LH) in the presence of a normal day 3 FSH predicts a poor response to controlled ovarian hyperstimulation. Fertil Steril. 1996;65:588–593.
    1. Nardo LG, Fleming R, Howles CM, Bosch E, Hamamah S, Ubaldi FM, Hugues JN, Balen AH, Nelson SM. Conventional ovarian stimulation no longer exists: welcome to the age of individualized ovarian stimulation. Reprod Biomed Online. 2011;23:141–148.
    1. Nelson SM, La Marca A. The journey from the old to the new AMH assay: how to avoid getting lost in the values. Reprod Biomed Online. 2011;23:411–420.
    1. Nelson SM, Anderson RA, Broekmans FJ, Raine-Fenning N, Fleming R, La MA. Anti-Mullerian hormone: clairvoyance or crystal clear? Hum Reprod. 2012;27:631–636.
    1. Nyboe Andersen A, Witjes H, Gordon K, Mannaerts B. Predictive factors of ovarian response and clinical outcome after IVF/ICSI following a rFSH/GnRH antagonist protocol with or without oral contraceptive pre-treatment. Hum Reprod. 2011;26:3413–3423.
    1. Olivennes F. Ovarian hyperstimulation syndrome prevention strategies: individualizing gonadotropin dose. Semin Reprod Med. 2010;28:463–467.
    1. Overbeek A, Broekmans FJ, Hehenkamp WJ, Wijdeveld ME, van Disseldorp J, van Dulmen-den BE, Lambalk CB. Intra-cycle fluctuations of anti-Mullerian hormone in normal women with a regular cycle: a re-analysis. Reprod Biomed Online. 2012;24:664–669.
    1. Papanikolaou EG, Pozzobon C, Kolibianakis EM, Camus M, Tournaye H, Fatemi HM, Van SA, Devroey P. Incidence and prediction of ovarian hyperstimulation syndrome in women undergoing gonadotropin-releasing hormone antagonist in vitro fertilization cycles. Fertil Steril. 2006;85:112–120.
    1. Popovic-Todorovic B, Loft A, Lindhard A, Bangsboll 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. 2003;18:781–787.
    1. Rustamov O, Smith A, Roberts SA, Yates AP, Fitzgerald C, Krishnan M, Nardo LG, Pemberton PW. Anti-Mullerian hormone: poor assay reproducibility in a large cohort of subjects suggests sample instability. Hum Reprod. 2012;27:3085–3091.
    1. Shrim A, Elizur SE, Seidman DS, Rabinovici J, Wiser A, Dor J. Elevated day 3 FSH/LH ratio due to low LH concentrations predicts reduced ovarian response. Reprod Biomed Online. 2006;12:418–422.
    1. Steyerberg EW, Borsboom GJ, van Houwelingen HC, Eijkemans MJ, Habbema JD. Validation and updating of predictive logistic regression models: a study on sample size and shrinkage. Stat Med. 2004;23:2567–2586.
    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 der Gaast MH, Eijkemans MJ, van der Net JB, de Boer EJ, Burger CW, van Leeuwen FE, Fauser BC, Macklon NS. Optimum number of oocytes for a successful first IVF treatment cycle. Reprod Biomed Online. 2006;13:476–480.
    1. van Disseldorp J, Lambalk CB, Kwee J, Looman CW, Eijkemans MJ, Fauser BC, Broekmans FJ. Comparison of inter- and intra-cycle variability of anti-Mullerian hormone and antral follicle counts. Hum Reprod. 2010;25:221–227.
    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. Verberg MF, Eijkemans MJ, Macklon NS, Heijnen EM, Fauser BC, Broekmans FJ. Predictors of low response to mild ovarian stimulation initiated on cycle day 5 for IVF. Hum Reprod. 2007;22:1919–1924.
    1. Verhagen TE, Hendriks DJ, Bancsi LF, Mol BW, Broekmans FJ. The accuracy of multivariate models predicting ovarian reserve and pregnancy after in vitro fertilization: a meta-analysis. Hum Reprod Update. 2008;14:95–100.

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere