Non-equivalence of anti-Müllerian hormone automated assays—clinical implications for use as a companion diagnostic for individualised gonadotrophin dosing

Abstract

STUDY QUESTIONCan anti-Müllerian hormone (AMH) automated immunoassays (Elecsys® and Access) be used interchangeably as a companion diagnostic for individualisation of follitropin delta dosing?SUMMARY ANSWERThe Access assay gives systematically higher AMH values than the Elecsys® assay which results in over 29% of women being misclassified to a different follitropin delta dose.WHAT IS KNOWN ALREADYFollitropin delta is the first gonadotrophin to be licenced with a companion diagnostic, the Roche Elecsys® AMH Plus assay. Alternative automated AMH assays including the Beckman Coulter Access immunoassay are considered to provide similar results, but clarification of their suitability as an off-licence companion diagnostic for follitropin delta is required.STUDY DESIGN, SIZE, DURATIONWe systematically searched the existing literature for studies that had measured AMH using both automated assays in the same cohort of women. Individual paired patient data were acquired from each author and combined with unpublished data.PARTICIPANTS/MATERIALS, SETTING, METHODSWe identified five eligible prospective published studies and one additional unpublished study. A 100% response from the authors was achieved. We collected paired AMH data on samples from 848 women. Passing–Bablok regression and Bland–Altman plots were used to compare the analytical performance of the two assays. The degree of misclassification to different treatment categories was estimated should the Access AMH be used as a companion diagnostic instead of the Elecsys AMH in determining the dosing of follitropin delta.MAIN RESULTS AND THE ROLE OF CHANCEThe Passing–Bablok regression shows a linear relationship (Access = −0.05 + 1.10 × Elecsys). The Access assay systematically gave higher values by an average of 10% compared with the Elecsys assay (slope = 1.10, 95% CI: 1.09 to 1.12). The average of the difference between the two assays was 2.7 pmol/l. The 95% limits of agreement were −11.7 to 6.3. Overall 253 (29.3%) women would have received an inappropriate follitropin delta dose if the Beckman Coulter Access assay was used. Specifically, a substantial proportion of women (ranging from 49% to 90% depending on the AMH category) would receive a lower dose of follitropin delta based on the Access AMH assay. Up to 10% (ranging from 2.5% to 10%) of women with high ovarian reserve would have been misclassified to a greater dose of follitropin delta based on the Access AMH assay.LIMITATIONS REASONS FOR CAUTIONWe compared the values of the two principal automated assays, extrapolation of our findings to other automated AMH assays would require similar comprehensive examination.WIDER IMPLICATIONS OF THE FINDINGSAn international standard for the calibration of the automated AMH assays is warranted to facilitate efficient use of AMH as a companion diagnostic. The variable calibration of alternative automated AMH assays may adversely impact on the performance of the follitropin delta dosing algorithm.STUDY FUNDING/COMPETING INTEREST(S)No formal funding has been receiv...

Anti‐Müllerian hormone variability and its implications for the number of oocytes retrieved following individualized dosing with follitropin delta

“…As AMH has been incorporated into gonadotropin dosing algorithms, concerns have been expressed that biological or analytical variability in AMH measurements may result in over‐ or under‐dosing . The absence of an international AMH standard and the lack of awareness among some clinicians regarding differences in assay performance have also contributed to these concerns .…”

“…29 As AMH has been incorporated into gonadotropin dosing algorithms, concerns have been expressed that biological or analytical variability in AMH measurements may result in over-or under-dosing. 30 The absence of an international AMH standard and the lack of awareness among some clinicians regarding differences in assay performance have also contributed to these concerns. 27 For example, the algorithm developed by La Marca and colleagues for the individualization of follitropin alpha doses was initially derived using the Beckman Coulter AMH assay, 4 but was subsequently externally validated 31 and assessed in a randomized controlled trial 6 using the modified AMH Generation II assay from Beckman.…”

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

“…As differences in analytical performance have been demonstrated between commercially available AMH immunoassays, cut-offs proposed for one assay may not be directly transferable to other assays [18,19]. Specifically, the AMH Gen 2 ELISA systematically measures 10% higher than the Elecsys 1 AMH assay, which would potentially lead to misclassification of 29% of women [25]. Furthermore, poor assay reproducibility was observed with the AMH Gen 2 ELISA assay [26].…”

Ovarian biomarkers predict controlled ovarian stimulation for in vitro fertilisation treatment in Singapore

“…(14) AMH measurements can also be affected by differences between generations of immunoassays; both technical aspects and a lack of standardisation between these assays may affect reliability and interpretation of AMH level results. (15)(16)(17) Accordingly, we evaluated the performance of serum AMH, early follicular phase Day 2 or 3 FSH and E2 levels, AFC, BMI, ovarian volume and age as biomarkers for ovarian response to IVF treatment, and established thresholds for the prediction of poor and excessive responses to COH in patients undergoing IVF.…”