How much variation in oocyte yield after controlled ovarian stimulation can be explained? A multilevel modelling study

Abstract

Study question: How much variation in oocyte yield after controlled ovarian stimulation (COS) can be accounted for by known patient and treatment characteristics?

Summary answer: There is substantial variation in the COS responses of similar women and in repeated COS episodes undertaken by the same woman, which cannot be accounted for at present.

What is already known: The goal of individualized COS is to safely collect enough oocytes to maximize the chance of success in an ART cycle. Personalization of treatment rests on the ability to reduce variation in response through modifiable factors.

Study design size duration: Multilevel modelling of a routine ART database covering the period 1 October 2008-8 August 2012 was employed to estimate the amount of variation in COS response and the extent to which this could be explained by immutable patient characteristics and by manipulable treatment variables. A total of 1851 treatment cycles undertaken by 1430 patients were included. The study was not subject to attrition, as cancelled cycles were included in the analysis.

Participants/materials setting methods: Women aged 21-43 years undergoing ovarian stimulation for IVF (possibly with ICSI) using their own eggs at a tertiary care centre.

Main results and the role of chance: Substantial unexplained variation in COS response (oocyte yield): was observed (3.4-fold (95% CI: 3.12 to 3.61)). Only a relatively small amount of this variation (around 19%) can be explained by modifiable factors. A significant, previously undescribed predictor of response was the practitioner performing oocyte retrieval, with 1.5-fold variation between surgeons with the highest and lowest yields.

Limitations reasons for caution: Although a large number of covariables were adjusted for in the analysis, including those that were used for dosing and determination of the stimulation regimen, this study is subject to confounding due to unmeasured variables and measurement error.

Wider implications of the findings: The present study suggests that there are limits to the extent that COS response can be predicted on the basis of known factors, or controlled by manipulation of treatment factors. Moreover, modifiable variation in response appears to be partially attributable to differences between surgeons performing oocyte retrieval. Consequently, consistent prevention of ineffective or unsafe responses to COS is not likely to be possible at present. Our results highlight the importance of blinding surgeons in RCTs. The data also suggest that there is likely to be limited scope for personalized treatment unless additional predictors of ovarian response can be identified.

Study funding/competing interests: J.W. is funded by a Doctoral Research Fellowship from the National Institute for Health Research (DRF-2014-07-050) supervised by S.A.R. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. J.W. is a statistical editor of the Cochrane Gynaecology and Fertility Group. S.A.R. is a statistical editor for Human Reproduction. J.W. also declares that publishing peer-reviewed articles benefits his career. A.L.M. has received consultation fees from MSD, Merck Serono, Ferring, TEVA, Roche, Beckman Coulter.

Keywords: ART; IVF; controlled ovarian stimulation; multilevel modelling; oocyte yield; ovarian response; personalized medicine; stratified medicine; variation.

Figure 1

Yield ratios and 95% CIs from the multivariable Poisson regression model of number of oocytes per cycle. Continuous predictors have been standardized, so that coefficients display the expected multiplicative increase in the yield ratio for a SD change in the variable. Increasing dose effect under a GnRH antagonist regime is shown by the purple connecting line. Increasing dose effect under a GnRH long agonist regime is shown by the blue connecting line.

Figure 2

Distribution of observed egg counts. Distribution of observed egg counts (box and whisker plots) with those predicted under the model for low (DSL assay <5 pmol/l), medium (5–15 pmol/l) and high (>15 pmol/l) anti-Mullerian hormone (AMH) bands for both GnRH long agonist (blue) and GnRH antagonist (purple) regimes. Solid line represents the mean response from the posterior predictive distribution. Shaded area represents ±1 SD. Note that other covariate values are not fixed but reflect the characteristics of the sample. Only groups with five or more observations are shown.