Madeleine Dólleman

AMH and AFC as predictors of excessive response in controlled ovarian hyperstimulation: a meta-analysis

BACKGROUND Anti-Mullerian hormone (AMH) is a marker of ovarian reserve status and represents a good predictor of ovarian response to ovarian hyperstimulation. The aim of this study was to assess the accuracy of AMH and antral follicle count (AFC) as predictors of an excessive response in IVF/ICSI treatment. METHODS A systematic review and meta-analysis of the existing literature was performed. Studies were included if 2 × 2 tables for the outcome excessive response in IVF patients in relation to AMH/AFC could be constructed. Using a bivariate meta-analytic model, both summary point estimates for sensitivity and specificity were calculated, as well as summary ROC curves. Clinical value was analysed by calculating post-test probabilities of excessive response at optimal cut-off levels, as well as the corresponding abnormal test rates. RESULTS Nine studies reporting on AMH and five reporting on AFC were found. Summary estimates of sensitivity and specificity for AMH were 82 and 76%, respectively, and 82 and 80%, respectively, for AFC. Comparison of the summary estimates and ROC curves for AMH and AFC showed no statistical difference. Abnormal test rates for AMH and AFC amounted to ∼14 and 16%, respectively, at cut-off levels where test performance is optimal [likelihood ratio for a positive result (LR + ) > 8], with a post-test probability of ± 70%. CONCLUSIONS Both AMH and AFC are accurate predictors of excessive response to ovarian hyperstimulation. Moreover, both tests appear to have clinical value. This opens ways to explore the potential of individualized FSH dose regimens based on ovarian reserve testing.

Added value of ovarian reserve testing on patient characteristics in the prediction of ovarian response and ongoing pregnancy: an individual patient data approach

BACKGROUND Although ovarian reserve tests (ORTs) are frequently used prior to IVF treatment for outcome prediction, their added predictive value is unclear. We assessed the added value of ORTs to patient characteristics in the prediction of IVF outcome. METHODS An individual patient data (IPD) meta-analysis from published studies was performed. Studies on FSH, anti-Müllerian hormone (AMH) or antral follicle count (AFC) in women undergoing IVF were identified and authors were contacted. Using random intercept logistic regression models, we estimated the added predictive value of ORTs for poor response and ongoing pregnancy after IVF, relative to patient characteristics. RESULTS We were able to collect 28 study databases, comprising 5705 women undergoing IVF. The area under the receiver-operating characteristic curve (AUC) for female age in predicting poor response was 0.61. AFC and AMH each significantly improved the model fit (P-value <0.001). Moreover, almost a similar accuracy was reached using AMH or AFC alone (AUC 0.78 and 0.76, respectively). Combining the two tests, however, did not improve prediction (AUC 0.80, P = 0.19) of poor response. In predicting ongoing pregnancy after IVF, age was the best single predictor (AUC 0.57), and none of the ORTs added any value. CONCLUSIONS This IPD meta-analysis demonstrates that AFC and AMH clearly add to age in predicting poor response. As single tests, AFC and AMH both fully cover the prediction of poor ovarian response. In contrast, none of the ORTs add any information to the limited capacity of female age to predict ongoing pregnancy after IVF. The clinical usefulness of ORTs prior to IVF will be limited to the prediction of ovarian response.

The role of anti-Müllerian hormone assessment in assisted reproductive technology outcome

Purpose of review The purpose of this study is to summarize the role of anti-Müllerian hormone (AMH) in assisted reproductive technology (ART) treatment. Recent findings AMH is a good marker in the prediction of ovarian response to controlled ovarian hyperstimulation. In clinical practice, this means that AMH may be used for identifying poor or excessive responders. So far, studies show that AMH is not a good predictor for the occurrence of pregnancy after ART treatment. Therefore, routine screening for a poor ovarian reserve status using AMH is not to be advocated. Still, ovarian response prediction using AMH may open ways for patient-tailored stimulation protocols in order to reduce cancellations for excessive response, possibly improve pregnancy prospects and reduce costs. Summary AMH is able to predict extremes in ovarian response to controlled ovarian hyperstimulation but cannot predict pregnancy after ART treatment. Its future clinical role may be in the individualization of ART stimulation protocols.

Reproductive and Lifestyle Determinants of Anti-Müllerian Hormone in a Large Population-based Study

CONTEXT Anti-müllerian hormone (AMH) is an ovarian reserve marker that is increasingly applied in clinical practice as a prognostic and diagnostic tool. Despite increased use of AMH in clinical practice, large-scale studies addressing the influence of possible determinants on AMH levels are scarce. OBJECTIVE We aimed to address the role of reproductive and lifestyle determinants of AMH in a large population-based cohort of women. DESIGN In this cross-sectional study, age-specific AMH percentiles were calculated using general linear modeling with CG-LMS (Cole and Green, Lambda, Mu, and Sigma model, an established method to calculate growth curves for children). SETTING Women from the general community participating in the Doetinchem Cohort study were assessed. PARTICIPANTS Two thousand three hundred twenty premenopausal women were included. MAIN OUTCOME MEASURE The effect of female reproductive and lifestyle factors on shifts in age-specific AMH percentiles was studied. RESULTS In comparison to women with a regular menstrual cycle, current oral contraceptive (OC) users, women with menstrual cycle irregularity, and pregnant women had significantly lower age-specific AMH percentiles (for OC use, 11 percentiles lower; for cycle irregularity, 11 percentiles lower; and for pregnancy, 17 percentiles lower [P value for all <.0001]). Age at menarche and age at first childbirth were not associated with the age-specific AMH percentile. Higher parity was associated with 2 percentiles higher age-specific AMH (P = .02). Of the lifestyle factors investigated, current smoking was associated with 4 percentiles lower age-specific AMH percentiles (P = .02), irrespective of the smoking dose. Body mass index, waist circumference, alcohol consumption, physical exercise, and socioeconomic status were not significantly associated with age-specific AMH percentiles. CONCLUSIONS This study demonstrates that several reproductive and lifestyle factors are associated with age-specific AMH levels. The lower AMH levels associated with OC use and smoking seem reversible, as effects were confined to current use of OC or cigarettes. It is important to give careful consideration to the effect of such determinants when interpreting AMH in a clinical setting and basing patient management on AMH.

Anti-Müllerian hormone is a more accurate predictor of individual time to menopause than mother's age at menopause

STUDY QUESTION In the prediction of time to menopause (TTM), what is the added value of anti-Müllerian hormone (AMH) when mothers age at natural menopause (ANM) is also known? SUMMARY ANSWER AMH is a more accurate predictor of individual TTM than mothers age at menopause. WHAT IS KNOWN ALREADY Mothers ANM is considered a proxy for daughters ANM although studies on its predictive accuracy are non-existent. AMH is a biomarker with a known capacity to predict ANM. However, its added value on top of known predictors, like mothers ANM, is unknown. STUDY DESIGN, SIZE, DURATION Population-based cohort studies were used. To assess any additive predictive value of mothers ANM, 164 mother-daughter pairs were used (Group 1). To assess the added value of AMH, a second group of 150 women in whom AMH and mothers ANM were recorded prior to a 12-year follow-up period during which daughters ANM was assessed was used (Group 2). PARTICIPANTS/MATERIALS, SETTING, METHODS Group 1 consisted of participants of the DOM cohort (an ongoing breast cancer study). Group 2 was a pooled cohort of women with regular menstrual cycles from two independent published studies. Cox proportional hazards analysis estimated uni- and multivariate regression coefficients for female age at study entry, mothers ANM and AMH in the prediction of TTM. Discrimination of models was assessed with C-statistics. Clinical added value of AMH was quantified with a net reclassification index (NRI). MAIN RESULTS AND THE ROLE OF CHANCE A model with female age and mothers ANM had a c-statistic of 79 and 85% in groups 1 and 2, respectively. Both age and mothers ANM were significantly associated with TTM (HR 1.54 and HR 0.93 for age and mothers ANM in Cohort 1 and HR 1.59 and HR 0.89 in Group 2, respectively. P-value for all <0.001). In Group 2, the multivariate model with age, mothers ANM and AMH had a c-statistic of 92%, and only female age and AMH remained significantly associated with TTM (HR 1.41 P < 0.0001; HR 0.93 P = 0.08 and HR 0.06 P < 0.0001 for age, mothers ANM and AMH, respectively). The mean weighted NRI suggests that a 47% improvement in predictive accuracy is offered by adding AMH to the model of age and mothers ANM. In conclusion, AMH and mothers ANM both have added value in forecasting TTM for the daughter based on her age. In comparison, AMH is a more accurate added predictor of TTM than mothers ANM. LIMITATIONS, REASONS FOR CAUTION The cohort of women is relatively small and different cohorts of women were pooled. WIDER IMPLICATIONS OF THE FINDINGS This study shows that AMH is a more accurate predictor of ANM than mothers ANM. However, before achieving clinical applicability, the certainty with which a womans prediction is made must improve. The association between mothers ANM and TTM in daughters did not appear to be influenced by whether ANM was recorded by mothers or daughters--an important finding because in the clinical setting daughters usually provide this information. STUDY FUNDING/COMPETING INTEREST(S) No funding was received and there were no competing interests in direct relation to this study.

The Relationship Between Anti-Müllerian Hormone in Women Receiving Fertility Assessments and Age at Menopause in Subfertile Women: Evidence From Large Population Studies

CONTEXT Anti-Müllerian hormone (AMH) concentration reflects ovarian aging and is argued to be a useful predictor of age at menopause (AMP). It is hypothesized that AMH falling below a critical threshold corresponds to follicle depletion, which results in menopause. With this threshold, theoretical predictions of AMP can be made. Comparisons of such predictions with observed AMP from population studies support the role for AMH as a forecaster of menopause. OBJECTIVE The objective of the study was to investigate whether previous relationships between AMH and AMP are valid using a much larger data set. SETTING AMH was measured in 27 563 women attending fertility clinics. STUDY DESIGN From these data a model of age-related AMH change was constructed using a robust regression analysis. Data on AMP from subfertile women were obtained from the population-based Prospect-European Prospective Investigation into Cancer and Nutrition (Prospect-EPIC) cohort (n = 2249). By constructing a probability distribution of age at which AMH falls below a critical threshold and fitting this to Prospect-EPIC menopausal age data using maximum likelihood, such a threshold was estimated. MAIN OUTCOME The main outcome was conformity between observed and predicted AMP. RESULTS To get a distribution of AMH-predicted AMP that fit the Prospect-EPIC data, we found the critical AMH threshold should vary among women in such a way that women with low age-specific AMH would have lower thresholds, whereas women with high age-specific AMH would have higher thresholds (mean 0.075 ng/mL; interquartile range 0.038-0.15 ng/mL). Such a varying AMH threshold for menopause is a novel and biologically plausible finding. AMH became undetectable (<0.2 ng/mL) approximately 5 years before the occurrence of menopause, in line with a previous report. CONCLUSIONS The conformity of the observed and predicted distributions of AMP supports the hypothesis that declining population averages of AMH are associated with menopause, making AMH an excellent candidate biomarker for AMP prediction. Further research will help establish the accuracy of AMH levels to predict AMP within individuals.

Antimüllerian hormone as predictor of reproductive outcome in subfertile women with elevated basal follicle-stimulating hormone levels: a follow-up study

OBJECTIVE To investigate the role of serum antimüllerian hormone (AMH) as a predictor of live birth and reproductive stage in subfertile women with elevated basal FSH levels. DESIGN A prospective observational cohort study conducted between February 2005 and June 2009. SETTING Tertiary fertility center. PATIENT(S) Subfertile women with [1] a regular menstrual cycle (mean cycle length 25-35 days); [2] basal FSH concentrations ≥12.3 IU/L; and [3] younger than 40 years (n = 96). INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Live birth and reproductive stage according to the Stages of Reproductive Aging Workshop. RESULT(S) A cumulative live birth rate of 63.5% was observed during a median follow-up of 3.3 years (n = 85). The AMH level was significantly associated with live birth. There was evidence of a nonlinear prediction pattern, with an increase in chances of live birth until an AMH level of 1 μg/L. Other ovarian reserve tests and chronological age appeared of limited value in predicting live birth. In addition, AMH was significantly associated with the timing of reproductive stages (n = 68) (i.e., the occurrence of menopausal transition or menopause during follow-up). CONCLUSION(S) The present findings suggest applicability of AMH determination as a marker for actual fertility in subfertile women with elevated basal FSH levels.

Predicting menopausal age with anti-Müllerian hormone: a cross-validation study of two existing models

Abstract Objective This study aimed to cross-validate two comparable Weibull models of prediction of age at natural menopause from two cohorts, the Scheffer, van Rooij, de Vet (SRV) cohort and the Tehran Lipid and Glucose Study (TLGS) cohort. It summarizes advantages and disadvantages of the models and underlines the need for achieving correct time dependency in dynamic variables like anti-Müllerian hormone. Methods Models were fitted in the original datasets and then applied to the cross-validation datasets. The discriminatory capacity of each model was assessed by calculating C-statistics for the models in their own data and in the cross-validation data. Calibration of the models on the cross-validation data was assessed by measuring the slope, intercept and Weibull shape parameter. Results The C-statistic for the SRV model on the SRV data was 0.7 (95% confidence interval (CI) 0.7–0.8) and on the TLGS data it was 0.8 (95% CI 0.8–0.9). For the TLGS model on the TLGS data, it was 0.9 (95% CI 0.8–0.9) and on the SRV data it was 0.7 (95% CI 0.6–0.8). After calibration of the SRV model on the TLGS data, the slope was 1, the intercept -0.3 and the shape parameter 1.1. The TLGS model on the SRV data had a slope of 0.3, an intercept of 12.7 and a shape parameter of 0.6. Conclusions Both models discriminate well between women that enter menopause early or late during follow-up. While the SRV model showed good agreement between the predicted risk of entering menopause and the observed proportion of women who entered menopause during follow-up (calibration) in the cross-validation dataset, the TLGS model showed poor calibration.

Individualized follicle‐stimulating hormone dosing and in vitro fertilization outcome in agonist downregulated cycles: a systematic review

This systematic review examines whether individualized gonadotropin dosing in in vitro fertilization (IVF) leads to better outcomes with respect to safety, costs, and live birth rates compared with standard dosing.

Using individual patient data to adjust for indirectness did not successfully remove the bias in this case of comparative test accuracy

OBJECTIVES In comparative systematic reviews of diagnostic accuracy, inconsistencies between direct and indirect comparisons may lead to bias. We investigated whether using individual patient data (IPD) can adjust for this form of bias. STUDY DESIGN AND SETTING We included IPD of 3 ovarian reserve tests from 32 studies. Inconsistency was defined as a statistically significant difference in relative accuracy or different comparative results between the direct and indirect evidence. We adjusted for the effect of threshold and reference standard, as well as for patient-specific variables. RESULTS Anti-Müllerian hormone (AMH) and follicle stimulation hormone (FSH) differed significantly in sensitivity (-0.1563, P = 0.04). AMH and antral follicle count (AFC) differed significantly in sensitivity (0.1465, P < 0.01). AMH and AFC differed significantly in specificity (-0.0607, P = 0.02). The area under the curve (AUC) differed significantly between AFC and FSH (0.0948, P < 0.01) in the direct comparison but not (0.0678, P = 0.09) in the indirect comparison. The AUCs of AFC and AMH differed significantly (-0.0830, P < 0.01) in the indirect comparison but not (-0.0176, P = 0.29) in the direct comparison. These differences remained after adjusting for indirectness. CONCLUSION Estimates of comparative accuracy obtained through indirect comparisons are not always consistent with those obtained through direct comparisons. Using IPD to adjust for indirectness did not successfully remove the bias in this case study.