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The performance of the Elecsys® anti-Müllerian hormone assay in predicting extremes of ovarian response to corifollitropin alfa

Published:April 30, 2020DOI:https://doi.org/10.1016/j.rbmo.2020.03.023

      Abstract

      Research question

      What is the performance of anti-Müllerian hormone (AMH) as measured by the Elecsys® AMH assay in predicting ovarian response in women treated with 150 µg corifollitropin alfa (CFA)?

      Design

      Multicentre, prospective study conducted between December 2015 and April 2018. Women were aged 18–43 years, had regular menstrual bleeding, a body mass index of 17–35 kg/m2 and weighed 60 kg or over. Exclusion criteria: previous oophorectomy, history of ovarian hyperstimulation syndrome, a previous IVF and intracytoplasmic sperm injection cycle producing over 30 follicles measuring 11 mm or wider, basal antral follicle count (AFC) over 20 or polycystic ovarian syndrome. All women were treated with 150 μg CFA followed by recombinant FSH (150–300 IU/day) in a fixed gonadotrophin releasing hormone antagonist protocol.

      Results

      Of the 219 patients enrolled, 22.8% had low ovarian response (three or fewer oocytes), 66.2% had normal response and 11% had high ovarian response (15 or more oocytes). The AMH and AFC presented an area under the curve of 0.883 (95% CI 0.830 to 0.936) and 0.879 (95% CI 0.826 to 0.930), respectively, for low ovarian response; and an AUC of 0.865 (95% CI 0.793 to 0.935) and 0.822 (95% CI 0.734 to 0.909) for high ovarian response. An AMH cut-off of 1.0 ng/ml provided a sensitivity of 92.0% and a specificity of 66.9% in the prediction of low ovarian response; a cut-off of 2.25 ng/ml predicted high ovarian response with a sensitivity of 54.2% and a specificity of 91.8%.

      Conclusions

      The automated Elecsys® AMH assay predicts ovarian response in a CFA antagonist protocol. The best predictors of ovarian response in CFA-treated patients were AMH and AFC.

      Keywords

      Introduction

      Ovarian stimulation is a key part of the IVF and intracytoplasmic sperm injection (ICSI) procedure. The anticipated yield of oocytes varies according to patient age and ovarian reserve. Therefore, individualization of ovarian stimulation is of paramount importance, which makes ovarian reserve marker analysis essential for treatment and dose selection (
      • Popovic-Todorovic B.
      • Loft A.
      • Ejdrup Bredkjæer H.
      • Bangsbøll S.
      • Nielsen I.K.
      • Nyboe Andersen A.
      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.
      ;
      • Olivennes F.
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      • Borini A.
      • Germond M.
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      Individualizing FSH dose for assisted reproduction using a novel algorithm: The CONSORT study.
      ;
      • La Marca A.
      • Sunkara S.K.
      Individualization of controlled ovarian stimulation in IVF using ovarian reserve markers: From theory to practice.
      ). Therefore, a wide range of markers have been proposed as predictors of ovarian response. Antral follicle count (AFC) and anti-Müllerian hormone (AMH) are now recognized as the most accurate (
      • Broer S.
      • Dólleman M.
      • Opmeer B.
      • Fauser B.
      • Mol B.
      • Broekmans F.
      AMH and AFC as predictors of excessive response in controlled ovarian hyperstimulation: A meta-analysis.
      ;
      • Broer S.
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      Anti-Müllerian hormone: Ovarian reserve testing and its potential clinical implications.
      ;
      • Martínez F.
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      • Carreras O.
      • Tur R.
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      • Barri P.N.
      Is AMH useful to reduce low ovarian response to GnRH antagonist protocol in oocyte donors?.
      ;
      • Polyzos N.P.
      • Tournaye H.
      • Guzman L.
      • Camus M.
      • Nelson S.M.
      Predictors of ovarian response in women treated with corifollitropin alfa for in vitro fertilization/intracytoplasmic sperm injection.
      ;
      • Lerman T.
      • Depenbusch M.
      • Schultze-Mosgau A.
      • von Otte S.
      • Scheinhardt M.
      • Koenig I.
      • Griesinger G.
      Ovarian response to 150 µg corifollitropin alfa in a GnRH-antagonist multiple-dose protocol: a prospective cohort study.
      ;
      • Scheinhardt M.O.
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      • König I.R.
      • Griesinger G.
      Performance of prognostic modeling of high and low ovarian response to ovarian stimulation for IVF.
      . The advantages of AMH include its low intra- and inter-cycle variability (
      • Van Disseldorp J.
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      • Looman C.W.N.
      • Eijkemans M.J.C.
      • Fauser B.C.
      • Broekmans F.J.
      Comparison of inter-and intra-cycle variability of anti-Müllerian hormone and antral follicle counts.
      ;
      • Polyzos N.P.
      • Nelson S.M.
      • Stoop D.
      • Nwoye M.
      • Humaidan P.
      • Anckaert E.
      • Tournaye H.
      Does the time interval between antimüllerian hormone serum sampling and initiation of ovarian stimulation affect its predictive ability in in vitro fertilization – intracytoplasmic sperm injection cycles with a gonadotropin-releasing hormone antagonist? A retrospective single-center study.
      ;
      • Kissell K.A.
      • Danaher M.R.
      • Schisterman E.F.
      • Wactawski-Wende J.
      • Ahrens K.A.
      • Schliep K.
      • Mumford S.L.
      Biological variability in serum anti-Müllerian hormone throughout the menstrual cycle in ovulatory and sporadic anovulatory cycles in eumenorrheic women.
      ;
      • Gracia C.
      • Shin S.
      • Prewitt M.
      • Chamberlin J.
      • Lofaro L.
      • Jones K.
      • Broyles D.
      Multi-center clinical evaluation of the Access AMH assay to determine AMH levels in reproductive age women during normal menstrual cycles.
      ), as well as the fact that it is less prone to observer biases compared with AFC (
      • Iliodromiti S.
      • Anderson R.A.
      • Nelson S.M.
      Technical and performance characteristics of anti-Müllerian hormone and antral follicle count as biomarkers of ovarian response.
      ). Different AMH assays have been developed over the past few years (
      • Li H.W.R.
      • Wong B.P.C.
      • Ip W.K.
      • Yeung W.S.B.
      • Ho P.C.
      • Ng E.H.Y.
      Commercial immunoassays for anti-Möllerian hormonemeasurement.
      ;
      • Iliodromiti S.
      • Salje B.
      • Dewailly D.
      • Fairburn C.
      • Fanchin R.
      • Fleming R.
      • Nelson S.M.
      Non-equivalence of anti-Müllerian hormone automated assays - Clinical implications for use as a companion diagnostic for individualised gonadotrophin dosing.
      ). Most studies have been used manual plate-based ELISAs and, although these reports provide valuable information, the reproducibility of the results among different laboratories has been controversial (
      • Zuvela E.
      • Walls M.
      • Matson P.
      Within-laboratory and between-laboratory variability in the measurement of anti-müllerian hormone determined within an external quality assurance scheme.
      ). Conversely, excellent intra- and inter-assay correlation has been reported among different automated assays (
      • Li H.W.R.
      • Wong B.P.C.
      • Ip W.K.
      • Yeung W.S.B.
      • Ho P.C.
      • Ng E.H.Y.
      Commercial immunoassays for anti-Möllerian hormonemeasurement.
      ). Comparisons between manual and automated assays, however, should be analysed with caution, taking into account the 20–30% higher values reported with manual assays (
      • Gassner D.
      • Jung R.
      First fully automated immunoassay for anti-Müllerian hormone.
      ).
      The Elecsys® AMH assay is an electrochemiluminescence immunoassay for quantitative determination of serum AMH and was the first automated AMH assay to be approved by the US Food and Drug Administration. Its analytical performance, in terms of precision and increased sensitivity, has been reported in several trials (
      • Anderson R.A.
      • Anckaert E.
      • Bosch E.
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      • Fehr D.
      • Hund M.
      Prospective study into the value of the automated Elecsys antimüllerian hormone assay for the assessment of the ovarian growing follicle pool.
      ;
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      • Öktem M.
      • Thies A.
      • Cohen-Bacrie M.
      • Daan N.M.P.
      • Schiettecatte J.
      • Milczynski C.
      Multicenter analytical performance evaluation of a fully automated anti-Müllerian hormone assay and reference interval determination.
      ;
      • Anckaert E
      • Denk B.
      • He Y.
      • Torrance H.L.
      • Broekmans F.
      • Hund M.
      Evaluation of the Elecsys® anti-Müllerian hormone assay for the prediction of hyper-response to controlled ovarian stimulation with a gonadotrophin-releasing hormone antagonist protocol.
      ;

      Jacobs, M. H., Reuter, L. M., Baker, V. L., Craig, L. B., Sakkas, D., Surrey, E., … Timm, B. (2019). A multicentre evaluation of the Elecsys® anti-Müllerian hormone immunoassay for prediction of antral follicle count. Reproductive BioMedicine Online, (pii), S1472-6483(19)30006-9.https://doi.org/10.1016/j.rbmo.2018.12.041

      ). Few studies have assessed the new automated Elecsys® AMH assay in predicting ovarian response to stimulation, and all were focused on patients receiving daily gonadotrophin injections with different daily doses. Corifollitropin alfa (CFA) is a fusion product of human FSH and the C-terminal peptide of the β-subunit of HCG, produced by recombinant DNA technology (
      • Fauser B.C.J.M.
      • Mannaerts M.J.L.
      • Devroey P.
      • Leader A.
      • Boime I.
      • Baird D.T.
      Advances in recombinant DNA technology: Corifollitropin alfa, a hybrid molecule with sustained follicle-stimulating activity and reduced injection frequency.
      ). It has the same activity as FSH and recombinant FSH, with an increased serum half-life, which allows it to induce and sustain multi-follicular growth for 7 days after a single subcutaneous injection (
      • Fauser B.C.J.M.
      • Mannaerts M.J.L.
      • Devroey P.
      • Leader A.
      • Boime I.
      • Baird D.T.
      Advances in recombinant DNA technology: Corifollitropin alfa, a hybrid molecule with sustained follicle-stimulating activity and reduced injection frequency.
      ). Its proven superiority in the number of oocytes retrieved, ongoing pregnancy rates and live birth rates compared with daily recombinant FSH (
      • Corifollitropin Alfa Dose-finding Study Group
      A randomized dose-response trial of a single injection of corifollitropin alfa to sustain multifollicular growth during controlled ovarian stimulation.
      ;
      • Devroey P.
      • Boostanfar R.
      • Koper N.P.
      • Mannaerts B.M.J.L.
      • Ijzerman-Boon P.C.
      • Fauser B.C.J.M.
      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.
      ;
      • Boostanfar R.
      • Shapiro B.
      • Levy M.
      • Rosenwaks Z.
      • Witjes H.
      • Stegmann B.J.
      • Yeko T.
      Large, comparative, randomized double-blind trial confirming noninferiority of pregnancy rates for corifollitropin alfa compared with recombinant follicle-stimulating hormone in a gonadotropin-releasing hormone antagonist controlled ovarian stimulation pr.
      ;
      • Pouwer A.
      • Farquhar C.
      • Kremer J.
      Long‐acting FSH versus daily FSH for women undergoing assisted reproduction.
      ;
      • Griesinger G.
      • Boostanfar R.
      • Gordon K.
      • Gates D.
      • McCrary Sisk C.
      • Stegmann B.J.
      Corifollitropin alfa versus recombinant follicle-stimulating hormone: an individual patient data meta-analysis.
      ), have generalized its use among reproductive medicine physicians.
      The scope of our study was to evaluate the predictive ability of AMH as measured using the Elecsys® AMH assay in women treated with CFA.

      Materials and methods

      A multicentre, prospective study of patients who underwent an IVF/ICSI cycle was conducted between December 2015 and April 2018. Patients were recruited in five centres (Dexeus University Hospital; Centre for Reproductive Medicine of the Universitair Ziekenhuis (UZ) Brussel, Belgium; IVI Madrid, Spain; Universitäres Kinderwunschzentrum Lübeck und Manhagen, Lübeck, Germany; Università degli Studi di Modena e Reggio Emilia, Italy).

       Ethical approval

      The study was conducted in accordance with the Declaration of Helsinki and with approval of the Institutional Review Board of the institutions involved in the study (Dates of final approval: Dexeus University Hospital, Barcelona, 23 January 2017; Centre for Reproductive Medicine of the Universitair Ziekenhuis (UZ) Brussel, 23 December 2015; IVI Madrid, 7 July 2016; Universitäres Kinderwunschzentrum Lübeck und Manhagen, 23 September 2016; Università degli Studi di Modena e Reggio Emilia, 8 November 2016). After detailed written and oral information regarding the study, all patients signed an informed consent sheet.

       Patient selection criteria

      The study included patients aged between 18 and 43 years old, with regular menstrual bleeding, a body mass index (BMI) of 17–35 kg/m2, weighing over 60 kg who planned to undergo ovarian stimulation with 150 μg CFA followed by recombinant FSH either for IVF or ICSI or in order to undergo fertility preservation for social or medical reasons. Patients were excluded if they had undergone a previous oophorectomy, had a history of ovarian hyperstimulation syndrome (OHSS), had undergone a previous ovarian stimulation cycle that resulted in more than 30 follicles measuring 11 mm or wider as determined by ultrasound examination, a basal AFC over 20, polycystic ovarian syndrome according to the Rotterdam criteria (
      • Teede H.
      • Misso M.
      • Costello M.
      • Dokras A.
      • Laven J.
      • Moran L.
      • Network I.P.
      Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome.
      ) or clinically relevant endocrine disorders.

       Stimulation protocol

      All women planned to be treated with 150 μg CFA followed by recombinant FSH in a fixed gonadotrophin releasing hormone (GnRH) antagonist protocol were enrolled. They received no pre-treatment with oral contraceptive pills. On day 2 or 3 of the menstrual cycle, a single subcutaneous injection of 150 µg CFA was administered (stimulation day 1). Starting on stimulation day 6, patients received a daily subcutaneous injection of 0.25 mg ganirelix up to and including the day of HCG administration to prevent premature LH surges. From stimulation day 8 onwards, treatment continued with a daily subcutaneous dose of recombinant FSH (150–300 IU/day) up to the day of HCG administration based on the patient’s ovarian reserve. Recombinant FSH dose was selected based on age, AFC, AMH and BMI as described in previous studies (
      • Yovich J.L.
      • Keane K.N.
      • Borude G.
      • Dhaliwal S.S.
      • Hinchliffe P.M.
      Finding a place for corifollitropin within the PIVET FSH dosing algorithms.
      ). No stepping up or down was allowed. In the case of monofollicular development and in the case of non-tubal factor infertility and adequate sperm quality, either rescue intrauterine insemination was considered or the cycle was cancelled. In case of no follicular development the treatment cycle was cancelled. Criteria for cycle cancellation or rescue intrauterine insemination were implemented on stimulation day 10. In both circumstances, the cycle was considered cancelled and the number of oocytes imputed was set to zero. These patients were included in the low response group. The allocated interventions are presented in Figure 1.
      Figure 1
      Figure 1Treatment schedule. GnRH, gonadotrophin releasing hormone; ICSI, intracytoplasmatic sperm injection; rFSH, recombinant FSH.

       Ovulation trigger and oocyte retrieval

      As soon as three follicles measuring 17 mm or wider were observed by ultrasound, recombinant 250 μg subcutaneous HCG was administered the same day or the day after to induce final oocyte maturation.
      In case of excessive ovarian response (17 or more follicles measuring more than 11 mm on the day of final oocyte maturation) triggering with a GnRH agonist (triptorelin 0.2 mg) was used for safety reasons, followed by either freezing all embryos, or fresh embryo transfer with modified luteal phase support. About 34–36 h thereafter, oocyte retrieval followed by IVF/ICSI was carried out.

       Blood sampling and sample analysis

      At the routine blood sampling visit on the day of initiation of CFA, part of the blood sample collected for routine analysis was used to allow the measurement of AMH, oestradiol, FSH and LH.
      Blood drawn in plain serum tubes for routine blood analysis during treatment underwent centrifugation within 1 h, and serum was separated and immediately stored at −80°C until analysis. All samples were analysed together at the end of the study in the central laboratory of UZ Brussel.
      Elecsys® AMH assay (Roche Diagnostics GmbH, Germany) was used to analyse AMH, with a coefficient of variation for intermediate precision less than 3.0% and a detection range of 0.01 to 23 ng/ml (0.07–164 pmol/l).

       Outcomes

      The primary outcome was to evaluate the incidence of low and high ovarian response by serum AMH level. Secondary outcomes were to evaluate the ability of AFC, age and FSH to predict low and high ovarian response and to compare the ability of AMH, AFC, age and FSH as predictors of ovarian response. The cut-off for defining low ovarian response was three or fewer oocytes retrieved, in accordance with the Bologna criteria for ovarian response (
      • Ferraretti A.P.
      • La Marca A.
      • Fauser B.C.J.M.
      • Tarlatzis B.
      • Nargund G.
      • Gianaroli L.
      ESHRE consensus on the definition of “poor response” to ovarian stimulation for in vitro fertilization: the Bologna criteria.
      ). Excessive ovarian response was defined as more than 15 oocytes retrieved, in accordance with earlier studies demonstrating an association between more than 15 oocytes retrieved and OHSS (
      • Steward R.G.
      • Lan L.
      • Shah A.A.
      • Yeh J.S.
      • Price T.M.
      • Goldfarb J.M.
      • Muasher S.J.
      Oocyte number as a predictor for ovarian hyperstimulation syndrome and live birth: An analysis of 256,381 in vitro fertilization cycles.
      ).

       Statistical analysis

      Sample size calculation was carried out on the assumption that up to five predictive factors will be selected in each logistic regression model. Therefore, assuming that for each predictive factor at least 10 events are required, a total of around 50 events are needed (
      • Moons K.
      • Royston P.
      • Vergouwe Y.
      • Grobbee D.
      • Altman D.
      Prognosis and prognostic research: what, why, and how?.
      ). A total sample size of 200 participants was planned, with an additional 20 participants (10%) to compensate for discontinued participants.
      Continuous variables were expressed as mean and SD, and categorical variables as frequencies and percentages. Univariate logistic regression analysis was conducted to identify the best predictors for high (more than 15 oocytes) and low (fewer than three oocytes) ovarian responses. Categorical variables were compared using chi-squared test or Fisher’s exact test. Continuous variables were compared using the Student’s t-test or Wilcoxon Mann–Whitney Test. All tests were bilateral with a significance level set to 0.05. Receiver operating characteristic (ROC) curves were generated and the area under the ROC curves (AUC) was determined to assess the discriminative power of independent ovarian reserve markers (AMH, AFC, age and FSH) to predict low and high ovarian response. Subsequently, associated factors for prediction of high and low ovarian reserve were entered into logistic regression models. The performance of each model was evaluated using ROC curves and AUCs. The pROC package (Robin et al., 2011) in R Software (R Core Team, 2018) was used for statistical analyses.

      Results

      A total of 219 patients were enrolled in the study, of whom 22.8% (n = 50) had a low ovarian response, 66.2% (n = 145) had a normal response and 11% (n = 24) had a high ovarian response. Patients’ baseline characteristics and ovarian stimulation cycle characteristics according to the level of ovarian response are presented in Table 1.
      Table 1Patient and cycle characteristics
      Normal ovarian response (n=145)High ovarian response (n=24)Low ovarian response (n=50)P-value (HOR versus others)P-value (LOR versus others)
      Age, years36.08 ± 4.2433.58 ± 4.6237.54 ± 3.190.0030.011
      BMI, kg/m224.18 ± 4.4925.27 ± 3.0224.25 ± 3.990.1200.360
      Race, % (n)White80.0 (116)91.7 (22)84.0 (42)
      Asian4.8 (7)02.0 (1)0.5070.599
      Black or African American2.8 (4)4.2 (1)6.0 (3)
      Other12.4 (18)4.2 (1)8.0 (4)
      Smokers21.4 (31)29.2 (7)20.0 (10)0.3630.709
      Cause of infertilityMale39.3 (57)54.2 (13)26.0 (13)
      Idiopathic33.1 (48)33.3 (8)28.0 (14)
      Endometriosis6.2 (9)8.3 (2)14.0 (7)0.5540.001
      Tubal6.9 (10)4.2 (1)10.0 (5)
      Ovulatory disorders2.8 (4)018.0 (9)
      Single mother2.1 (3)02.0 (1)
      Information not available9.7 (14)02.0 (1)
      Type of infertilityPrimary66.2 (96)45.8 (11)48.0 (24)0.1390.052
      Secondary33.8 (49)54.2 (13)52.0 (26)
      Duration of infertility34.61 ± 33.2924.13 ± 15.1851.00 ± 45.280.0640.003
      AMH, ng/ml1.3 ± 0.722.47 ± 1.080.50 ± 0.38<0.001<0.001
      AFC, n9.47 ± 3.9114.29 ± 8.354.76 ± 2.44<0.001<0.001
      FSH, mIU/ml8.52 ± 2.647.16 ± 1.9710.14 ±3.720.0260.040
      LH, mIU/ml6.43 ± 2.356.36 ± 2.326.72 ± 2.660.7900.748
      Oestradiol, pg/ml42.04 ± 20.8840.52 ± 17.8748.33 ± 68.180.9860.253
      Progesterone, ng/ml0.74 ± 3.310.30 ± 0.170.39 ± 0.210.2490.586
      Duration of stimulation, days9.57 ± 2.169.88 ± 1.429.58 ± 2.950.5020.729
      Total gonadotrophin dose, IU646.63 ± 413.5617.05 ± 342.90865.85 ± 664.780.7780.103
      Oocytes retrieved, n8.21 ± 3.1120.71 ± 4.141.46 ± 1.15<0.001<0.001
      Mature oocytes retrieved, n6.34 ± 3.2814.13 ± 6.371.39 ± 0.86<0.001<0.001
      Fertilized oocytes, n4.08 ± 3.019.63 ± 5.630.71 ± 0.87<0.001<0.001
      Quantitative variables are presented as mean ± SD and qualitative variables as or % (n).
      AFC, antral follicle count; AMH, anti-Müllerian hormone; HOR, high ovarian response; LOR, low ovarian response.

       Predictors of low ovarian response

      The clinical performance of the different ovarian reserve markers in the prediction of low ovarian response was assessed by ROC curve analysis (Figure 2a). The best predictors of low ovarian response were AMH and AFC, with an AUC of 0.883 (95% CI 0.830 to 0.936) and an AUC of 0.879 (95% CI 0.826 to 0.930). A cut-off of 1.0 ng/ml provided a sensitivity of 92.0% and a specificity of 66.9% in the prediction of three or fewer oocytes retrieved, with a positive likelihood ratio (LR+) of 2.78 and a negative likelihood ratio (LR–) of 0.12. The addition of AFC, age and FSH to AMH in the prediction model slightly increased the AUC to 0.926 (95% CI 0.871 to 0.981), although the difference was not statistically significant compared with AMH or AFC alone (Figure 3).
      Figure 2
      Figure 2Receiver operating characteristics curve analysis for ovarian reserve markers as predictors of low (a) and high (b) ovarian response. AFC, antral follicle count; AMH, anti-Müllerian hormone; AUC, area under the curve; LR, likelihood ratio.
      Figure 3
      Figure 3Receiver operating characteristics curve analysis for predictors of low ovarian response. AFC, antral follicle count; AMH, anti-Müllerian hormone; AUC, area under the curve.

       Predictors of high ovarian response

      The ROC curve analysis also confirmed that AMH and AFC were the best predictors of high ovarian response, with an AUC of 0.865 (95% CI 0.793 to 0.935) and 0.822 (95% CI 0.734 to 0.909), respectively (Figure 2b). A cut-off of 2.25 ng/ml predicted more than 15 oocytes retrieved, with a sensitivity of 54.2% and a specificity of 91.8%, with a LR+ of 6.60 and a LR– of 0.50. Adding AFC, age and FSH to AMH slightly increased the AUC of the predictive model to 0.918 (95% CI 0.856 to 0.981), although the difference was not statistically significant compared with AMH or AFC alone (Figure 4). Of note, the oocyte retrieval process yielded more than 20 oocytes in only nine patients (4.1%).
      Figure 4
      Figure 4Receiver operating characteristics curve analysis for predictors of high ovarian response. AFC, antral follicle count; AMH, anti-Müllerian hormone; AUC, area under the curve.

      Discussion

      In this prospective, multicentre study, the Elecsys® AMH assay demonstrated excellent clinical performance in identifying low and high ovarian response in women treated with CFA in an antagonist protocol. For a cut-off of 1.0 ng/ml, low ovarian response was predicted with a sensitivity of 92.0% and a specificity of 66.9%. Similarly, excellent predictive ability was demonstrated for high ovarian response. A cut-off of 2.25 ng/ml presented a sensitivity of 54.2% and a specificity of 91.8% in the prediction of high ovarian response. ROC curve analysis comparing different ovarian reserve markers also confirmed that AMH and AFC performed best as predictors of ovarian response for both low and high responders.
      Anti-Müllerian hormone has proven its clinical utility in the prediction of ovarian response among different ovarian stimulation protocols (
      • Anckaert Ellen
      • Smitz J.
      • Schiettecatte J.
      • Klein B.M.
      • Arce J.C.
      The value of anti-Mllerian hormone measurement in the long GnRH agonist protocol: Association with ovarian response and gonadotrophin-dose adjustments.
      ;
      • Anckaert E
      • Denk B.
      • He Y.
      • Torrance H.L.
      • Broekmans F.
      • Hund M.
      Evaluation of the Elecsys® anti-Müllerian hormone assay for the prediction of hyper-response to controlled ovarian stimulation with a gonadotrophin-releasing hormone antagonist protocol.
      ;
      • Baker V.L.
      • Gracia C.
      • Glassner M.J.
      • Schnell V.L.
      • Doody K.
      • Coddington C.C.
      • Broyles D.L.
      Multicenter evaluation of the Access AMH antimüllerian hormone assay for the prediction of antral follicle count and poor ovarian response to controlled ovarian stimulation.
      ). In patients stimulated with CFA, previous studies have also reported AMH as the best predictor of ovarian response (
      • Polyzos N.P.
      • Nelson S.M.
      • Stoop D.
      • Nwoye M.
      • Humaidan P.
      • Anckaert E.
      • Tournaye H.
      Does the time interval between antimüllerian hormone serum sampling and initiation of ovarian stimulation affect its predictive ability in in vitro fertilization – intracytoplasmic sperm injection cycles with a gonadotropin-releasing hormone antagonist? A retrospective single-center study.
      ;
      • Oehninger S.
      • Nelson S.M.
      • Verweij P.
      • Stegmann B.J.
      Predictive factors for ovarian response in a corifollitropin alfa/GnRH antagonist protocol for controlled ovarian stimulation in IVF/ICSI cycles.
      ;
      • Lerman T.
      • Depenbusch M.
      • Schultze-Mosgau A.
      • von Otte S.
      • Scheinhardt M.
      • Koenig I.
      • Griesinger G.
      Ovarian response to 150 µg corifollitropin alfa in a GnRH-antagonist multiple-dose protocol: a prospective cohort study.
      ). These studies, however, were carried out with manual plate-based ELISA assays, with inherent variability within and between laboratories (
      • Zuvela E.
      • Walls M.
      • Matson P.
      Within-laboratory and between-laboratory variability in the measurement of anti-müllerian hormone determined within an external quality assurance scheme.
      ). To the best of our knowledge, this is the first study to analyse the ability of the automated Elecsys® AMH assay to predict ovarian response in a CFA antagonist protocol. The AUC for the prediction of low ovarian response in this study was 0.883, which is in line with previous studies reporting AUCs between 0.836 and 0.929 with other assays (
      • Oehninger S.
      • Nelson S.M.
      • Verweij P.
      • Stegmann B.J.
      Predictive factors for ovarian response in a corifollitropin alfa/GnRH antagonist protocol for controlled ovarian stimulation in IVF/ICSI cycles.
      ;
      • Lerman T.
      • Depenbusch M.
      • Schultze-Mosgau A.
      • von Otte S.
      • Scheinhardt M.
      • Koenig I.
      • Griesinger G.
      Ovarian response to 150 µg corifollitropin alfa in a GnRH-antagonist multiple-dose protocol: a prospective cohort study.
      • Baker V.L.
      • Gracia C.
      • Glassner M.J.
      • Schnell V.L.
      • Doody K.
      • Coddington C.C.
      • Broyles D.L.
      Multicenter evaluation of the Access AMH antimüllerian hormone assay for the prediction of antral follicle count and poor ovarian response to controlled ovarian stimulation.
      ;
      • Scheinhardt M.O.
      • Lerman T.
      • König I.R.
      • Griesinger G.
      Performance of prognostic modeling of high and low ovarian response to ovarian stimulation for IVF.

      Jacobs, M. H., Reuter, L. M., Baker, V. L., Craig, L. B., Sakkas, D., Surrey, E., … Timm, B. (2019). A multicentre evaluation of the Elecsys® anti-Müllerian hormone immunoassay for prediction of antral follicle count. Reproductive BioMedicine Online, (pii), S1472-6483(19)30006-9.https://doi.org/10.1016/j.rbmo.2018.12.041

      ). Similarly, the AUC for the prediction of high ovarian response was 0.865, which is in line with previous reports varying between 0.821 and 0.890 (
      • Polyzos N.P.
      • Nelson S.M.
      • Stoop D.
      • Nwoye M.
      • Humaidan P.
      • Anckaert E.
      • Tournaye H.
      Does the time interval between antimüllerian hormone serum sampling and initiation of ovarian stimulation affect its predictive ability in in vitro fertilization – intracytoplasmic sperm injection cycles with a gonadotropin-releasing hormone antagonist? A retrospective single-center study.
      ;
      • Oehninger S.
      • Nelson S.M.
      • Verweij P.
      • Stegmann B.J.
      Predictive factors for ovarian response in a corifollitropin alfa/GnRH antagonist protocol for controlled ovarian stimulation in IVF/ICSI cycles.
      ;
      • Lerman T.
      • Depenbusch M.
      • Schultze-Mosgau A.
      • von Otte S.
      • Scheinhardt M.
      • Koenig I.
      • Griesinger G.
      Ovarian response to 150 µg corifollitropin alfa in a GnRH-antagonist multiple-dose protocol: a prospective cohort study.
      ;
      • Scheinhardt M.O.
      • Lerman T.
      • König I.R.
      • Griesinger G.
      Performance of prognostic modeling of high and low ovarian response to ovarian stimulation for IVF.
      ;
      • Anckaert E
      • Denk B.
      • He Y.
      • Torrance H.L.
      • Broekmans F.
      • Hund M.
      Evaluation of the Elecsys® anti-Müllerian hormone assay for the prediction of hyper-response to controlled ovarian stimulation with a gonadotrophin-releasing hormone antagonist protocol.
      ).
      Regarding AMH optimal cut-off levels for the prediction of the extremes of ovarian response, the cut-off of 1.0 ng/ml, identified as the value with maximal sensitivity and specificity for predicting low response, seems to be comparable with previous studies and close to the proposed cut-offs defined by the Bologna criteria (
      • Ferraretti A.P.
      • La Marca A.
      • Fauser B.C.J.M.
      • Tarlatzis B.
      • Nargund G.
      • Gianaroli L.
      ESHRE consensus on the definition of “poor response” to ovarian stimulation for in vitro fertilization: the Bologna criteria.
      ).
      • Baker V.L.
      • Gracia C.
      • Glassner M.J.
      • Schnell V.L.
      • Doody K.
      • Coddington C.C.
      • Broyles D.L.
      Multicenter evaluation of the Access AMH antimüllerian hormone assay for the prediction of antral follicle count and poor ovarian response to controlled ovarian stimulation.
      reported a cut-off of 0.93 ng/ml in the prediction of four or fewer oocytes retrieved, whereas
      • Lerman T.
      • Depenbusch M.
      • Schultze-Mosgau A.
      • von Otte S.
      • Scheinhardt M.
      • Koenig I.
      • Griesinger G.
      Ovarian response to 150 µg corifollitropin alfa in a GnRH-antagonist multiple-dose protocol: a prospective cohort study.
      and
      • Oehninger S.
      • Nelson S.M.
      • Verweij P.
      • Stegmann B.J.
      Predictive factors for ovarian response in a corifollitropin alfa/GnRH antagonist protocol for controlled ovarian stimulation in IVF/ICSI cycles.
      described a cut-off of 0.91 ng/ml and 1.03 ng/ml, respectively, as the most accurate to predict six or fewer oocytes retrieved.
      For high responders, the cut-off of 2.25 ng/m was selected to optimize specificity. Taking into account that a GnRH antagonist protocol and GnRH agonist trigger were used, and that only women with a basal AFC of 20 or lower were included in the study, in accordance with the summary of product characteristics of CFA, the risk of OHSS is remarkably low. Therefore, a cut-off point with a higher specificity at the expense of a lower sensitivity was selected for high responders. The cut-off of 2.25 ng/ml is similar to the cut-offs of 2.24–3.52 ng/ml previously suggested using the manual assays (
      • Polyzos N.P.
      • Tournaye H.
      • Guzman L.
      • Camus M.
      • Nelson S.M.
      Predictors of ovarian response in women treated with corifollitropin alfa for in vitro fertilization/intracytoplasmic sperm injection.
      ;
      • Oehninger S.
      • Nelson S.M.
      • Verweij P.
      • Stegmann B.J.
      Predictive factors for ovarian response in a corifollitropin alfa/GnRH antagonist protocol for controlled ovarian stimulation in IVF/ICSI cycles.
      ;
      • Lerman T.
      • Depenbusch M.
      • Schultze-Mosgau A.
      • von Otte S.
      • Scheinhardt M.
      • Koenig I.
      • Griesinger G.
      Ovarian response to 150 µg corifollitropin alfa in a GnRH-antagonist multiple-dose protocol: a prospective cohort study.
      ).
      As far as AFC is concerned, this biomarker also showed a good clinical performance in predicting low and high responders (AUC 0.879 and 0.822, respectively). Although AFC has some disadvantages, including inter-observer variability (
      • Iliodromiti S.
      • Anderson R.A.
      • Nelson S.M.
      Technical and performance characteristics of anti-Müllerian hormone and antral follicle count as biomarkers of ovarian response.
      ) and controversies about its variation during the menstrual cycle (
      • Rombauts L.
      • Onwude J.L.
      • Chew H.W.
      • Vollenhoven B.J.
      The predictive value of antral follicle count remains unchanged across the menstrual cycle.
      ;
      • Mavrelos D.
      • Al Chami A.
      • Talaulikar V.
      • Burt E.
      • Webber L.
      • Ploubidis G.
      • Yasmin E.
      Variation in antral follicle counts at different times in the menstrual cycle: does it matter?.
      ;
      • Coelho Neto M.A.
      • Ludwin A.
      • Borrell A.
      • Benacerraf B.
      • Dewailly D.
      • da Silva Costa F.
      • Martins W.P.
      Counting ovarian antral follicles by ultrasound: a practical guide.
      ), the present study demonstrated that the predictive ability of AFC for low and high ovarian responses is comparable in women treated with CFA. Finally, in line with previous studies, age and FSH performed poorly in the prediction of both low and high ovarian responses (
      • Lerman T.
      • Depenbusch M.
      • Schultze-Mosgau A.
      • von Otte S.
      • Scheinhardt M.
      • Koenig I.
      • Griesinger G.
      Ovarian response to 150 µg corifollitropin alfa in a GnRH-antagonist multiple-dose protocol: a prospective cohort study.
      ).
      A limitation of this study is that, although sample size was accurately calculated as per CFA administration instruction and in accordance with the summary of product characteristics, patients’ inclusion had to be restricted based on previous AFC values. Another limitation is that the dose of recombinant FSH administered from stimulation day 8 onwards was not fixed, varying between 150–300 IU/day. Although this dose was calculated based on patients’ age and ovarian reserve (
      • Devroey P.
      • Boostanfar R.
      • Koper N.P.
      • Mannaerts B.M.J.L.
      • Ijzerman-Boon P.C.
      • Fauser B.C.J.M.
      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.
      ;
      • Boostanfar R.
      • Shapiro B.
      • Levy M.
      • Rosenwaks Z.
      • Witjes H.
      • Stegmann B.J.
      • Yeko T.
      Large, comparative, randomized double-blind trial confirming noninferiority of pregnancy rates for corifollitropin alfa compared with recombinant follicle-stimulating hormone in a gonadotropin-releasing hormone antagonist controlled ovarian stimulation pr.
      ), no specific protocol criteria have been followed. This could, however, be seen as a strength because it allows the results to be generalized to the IVF population. Moreover this dose adjustment after stimulation day 8 is highly unlikely to have influenced the number of oocytes retrieved. In fact, considering that follicular recruitment occurs during the first days of ovarian stimulation, the number of growing follicles is not likely to be affected by these dose modifications. Furthermore, recent studies on the individualization of ovarian stimulation protocols have not demonstrated such a significant effect (
      • Nyboe Andersen A.
      • Nelson S.M.
      • Fauser B.C.J.M.
      • García-Velasco J.A.
      • Klein B.M.
      • Arce J.C.
      • Arce J.C.
      Individualized versus conventional ovarian stimulation for in vitro fertilization: a multicenter, randomized, controlled, assessor-blinded, phase 3 noninferiority trial.
      ;
      • Oudshoorn S.C.
      • van Tilborg T.C.
      • Eijkemans M.J.C.
      • Oosterhuis G.J.E.
      • Friederich J.
      • van Hooff M.H.A.
      • Torrance H.L.
      Individualized versus standard FSH dosing in women starting IVF/ICSI: an RCT. Part 2: The predicted hyper responder.
      ;
      • van Tilborg T.C.
      • Torrance H.L.
      • Oudshoorn S.C.
      • Eijkemans M.J.C.
      • Koks C.A.M.
      • Verhoeve H.R.
      • Torrance H.L.
      Individualized versus standard FSH dosing in women starting IVF/ICSI: an RCT. Part 1: The predicted poor responder.
      ;
      • Lensen SF
      • Wilkinson J
      • Leijdekkers JA
      • La Marca A
      • Mol BWJ
      • Marjoribanks J
      • Torrance H
      • B. F.
      Individualised gonadotropin dose selection using markers of ovarian reserve for women undergoing in vitro fertilisation plus intracytoplasmic sperm injection (IVF/ICSI).
      ).
      Finally, AMH was measured systematically on day 2–3 of the cycle, and this may limit the extrapolation of the results to samples obtained on other days of the cycle. Previous studies, however, have demonstrated limited inter- and intracycle variation in AMH levels (
      • Kissell K.A.
      • Danaher M.R.
      • Schisterman E.F.
      • Wactawski-Wende J.
      • Ahrens K.A.
      • Schliep K.
      • Mumford S.L.
      Biological variability in serum anti-Müllerian hormone throughout the menstrual cycle in ovulatory and sporadic anovulatory cycles in eumenorrheic women.
      ;
      • Lambert-Messerlian G.
      • Plante B.
      • Eklund E.E.
      • Raker C.
      • Moore R.G.
      Levels of antimüllerian hormone in serum during the normal menstrual cycle.
      ;
      • Gracia C.
      • Shin S.
      • Prewitt M.
      • Chamberlin J.
      • Lofaro L.
      • Jones K.
      • Broyles D.
      Multi-center clinical evaluation of the Access AMH assay to determine AMH levels in reproductive age women during normal menstrual cycles.
      ).
      A major strength of our study is its prospective, multicentric design, optimizing the extrapolation of our results to the general IVF population. Furthermore, to our knowledge, this was the first study to evaluate the ability of the Elecsys® AMH assay to predict ovarian response in women treated with CFA. Therefore, our results provide clinical guidance for treatment and can be used in the prediction of low ovarian response in patients treated with CFA.
      In the era of the OHSS-free clinic, closely related to the segmentation concept (
      • Devroey Paul
      • Polyzos N.P.
      • Blockeel C.
      An OHSS-Free Clinic by segmentation of IVF treatment.
      ), it might seem that ovarian reserve markers are losing ground. Clinical practice, however, is still guided by validated recombinant FSH dose algorithms, such as the PIVET algorithm, adjusting for patient parameters such as age, AFC, BMI, AMH, day-2 FSH and history of smoking (
      • Yovich J.L.
      • Alsbjerg B.
      • Conceicao J.L.
      • Hinchliffe P.M.
      • Keane K.N.
      PIVET rFSH dosing algorithms for individualized controlled ovarian stimulation enables optimized pregnancy productivity rates and avoidance of ovarian hyperstimulation syndrome.
      ). In particular, this algorithm has also been validated for use with CFA, showing the critical role of age and AFC and the modulator role of AMH in defining recombinant FSH treatment dose (
      • Yovich J.L.
      • Keane K.N.
      • Borude G.
      • Dhaliwal S.S.
      • Hinchliffe P.M.
      Finding a place for corifollitropin within the PIVET FSH dosing algorithms.
      ). These findings highlight the importance of keeping an accurate evaluation of ovarian reserve markers in our daily practice.
      In conclusion, considering the limitations discussed above, our results demonstrate that AMH and AFC are the best predictors of ovarian response in patients treated with CFA, identifying with high sensitivity and specificity patients who are likely to be poor responders. With AMH, a cut-off of 1.00 ng/ml identifies with high sensitivity and specificity patients who are likely to be poor responders. As for high responders, a cut-off of 2.25 ng/ml selects with high specificity those are at risk of high response. It is also of great interest that when the threshold of 20 AFC is set for the selection of patients treated with CFA, only 11% of patients will respond with more than 15 oocytes and 4.1% with more than 20 oocytes, thereby minimizing the risk for OHSS.

      Acknowledgement

      ARN conducted the literature search, contributed to data interpretation and wrote the manuscript; IR performed data collection and statistical analysis; BC, GG, GV, LM, DP, HT and MA contributed to the critical review of the manuscript; NPP designed the study, contributed to the writing and editing of the manuscript and provided critical review of the manuscript; all authors read and approved the final manuscript

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        Human Reproduction. 2017; 32 (https://doi.org/10.1093/humrep/dex319): 2506-2514
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        Fertility and Sterility. 2013; 100 (https://doi.org/10.1016/j.fertnstert.2013.03.031): 438-444
        • Polyzos N.P.
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        Predictors of ovarian response in women treated with corifollitropin alfa for in vitro fertilization/intracytoplasmic sperm injection.
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        Database of Systematic Reviews. 2015; 7 (CD009577.)
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        The predictive value of antral follicle count remains unchanged across the menstrual cycle.
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        Human Reproduction. 2018; 33 (https://doi.org/10.1093/humrep/dey236): 1499-1505
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        Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome.
        Human Reproduction. 2018; 33 (https://doi.org/13:978-0-646-98332-5): 1602-1618
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        Comparison of inter-and intra-cycle variability of anti-Müllerian hormone and antral follicle counts.
        Human Reproduction. 2010; 25 (https://doi.org/10.1093/humrep/dep366): 221-227
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        Individualized versus standard FSH dosing in women starting IVF/ICSI: an RCT. Part 1: The predicted poor responder.
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        PIVET rFSH dosing algorithms for individualized controlled ovarian stimulation enables optimized pregnancy productivity rates and avoidance of ovarian hyperstimulation syndrome.
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        Finding a place for corifollitropin within the PIVET FSH dosing algorithms.
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        Within-laboratory and between-laboratory variability in the measurement of anti-müllerian hormone determined within an external quality assurance scheme.
        Reproductive Biology. 2013; 13 (https://doi.org/10.1016/j.repbio.2013.04.005): 255-257

      Biography

      Professor Polyzos is the Clinical and Scientific Director of the Department of Reproductive Medicine of Dexeus University Hospital and a Professor of Reproductive Endocrinology in the University of Aarhus. He is the author of more than 150 publications, with special focus on reproductive endocrinology, ovarian reserve and poor ovarian response.
      Key Message
      The Elecsys® anti-Müllerian hormone (AMH) assay demonstrated an excellent clinical performance in identifying both low and high ovarian response. To the best of our knowledge, this is the first study to provide evidence on the ability of the automated Elecsys® AMH assay to predict ovarian response in a corifollitropin alfa antagonist protocol.