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

INTRODUCTION: 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. MATERIAL AND METHODS: Electronic databases searched were PubMed, Embase, and Cochrane. The primary outcome was live birth rate. The secondary outcomes included pregnancy rate, costs, and safety. Papers were critically appraised by two reviewers. RESULTS: A total of 7022 articles were retrieved and assessed for eligibility, of which seven randomized controlled trials were selected. All studies used gonadotropin-releasing hormone agonist co-treatment. Clinical and methodological heterogeneity was present, so data could not be pooled for meta-analysis. Only one study, that mainly included women with a good prognosis, revealed an increased chance of ongoing pregnancy in the individualized dosing group compared with standard treatment. With respect to safety, individualized dosing might reduce the occurrence of hyper-response and ovarian hyperstimulation syndrome, without affecting the outcome of pregnancy. In predicted poor responders, higher than standard dosages do not reduce the incidence of poor response. A cost-efficacy analysis was not performed in any of the studies included. CONCLUSION: It is currently not possible to conclude whether individualized dosing leads to higher pregnancy or live birth rates compared with standard dosing, because evidence from well-designed studies that are adequately powered for one of these outcomes is lacking. So, large well-designed studies that evaluate the impact of individualized dosing on live birth rates are needed to assess whether individualized dosing should become the standard in IVF practice.

Added value of anti-Müllerian hormone in prediction of menopause: results from a large prospective cohort study.

STUDY QUESTION: What is the added value of anti-Müllerian hormone (AMH) on top of patient characteristics for predicting the risk to enter menopause within 10 years? SUMMARY ANSWER: For women who did enter menopause, the risk of entering menopause within 10 years assigned by the model with AMH was on average 3% higher than that assigned by the model without AMH, and in the subgroup of young women with regular cycles, this increase was 14%. WHAT IS KNOWN ALREADY: Prediction of age at menopause may be useful in predicting the end of female fertility. AMH may be useful for this, but the current evidence is based on small studies or specific subgroups, and does not take into account predictors other than age. STUDY DESIGN, SIZE, DURATION: This was a retrospective cohort study among 1163 premenopausal women participating in the second follow-up round of the Doetinchem Cohort Study with follow-up assessments of menopausal status and age after 5 and 10 years of follow-up. PARTICIPANTS/MATERIALS, SETTING, METHODS: This study included premenopausal women from the general population with a mean age of 41 (SD 7) years. A Cox proportional hazards' model without AMH was fitted using variables selected based on Akaike's information criterion. Performance of the prediction rule was assessed with C-statistics and compared with a model additionally including AMH and to a model with age only. The added value of AMH was assessed with Net Reclassification Index and change in absolute predicted risk. Performance of these three models was compared in subgroups based on age and reproductive characteristics. MAIN RESULTS AND THE ROLE OF CHANCE: The final model included age, BMI, packyears of smoking and menstrual cycle status (regular, irregular, pregnant or taking oral contraceptives). This model had a C-statistic of 0.89 (0.01 SD), compared with 0.88 (0.01 SD) for the model including age only. Addition of AMH increased it to 0.91 (0.03 SD). In a subgroup of 25-43 year olds with regular menstrual cycles, the model with age only had a C-statistic of 0.79 (0.04 SD) and for the models without and with AMH the C-stastic was 0.79 (0.04 SD) and 0.87 (0.03 SD), respectively. The risk of entering menopause within 10 years assigned by the model with AMH was on average 3% higher than that assigned by the model without AMH, for women who did enter menopause. In the subgroup of young women with regular cycles, this increase was 14%. LIMITATIONS, REASONS FOR CAUTION: Longer follow-up would have resulted in more of the young women becoming menopausal, improving the precision of the predictions for these women. WIDER IMPLICATIONS OF THE FINDINGS: This study clearly shows the added value of AMH in predicting time to menopause on top of clinical predictors, in particular for younger women. New studies in specific target populations in clinical practice are needed to develop a prediction model for use in that target population. STUDY FUNDING/COMPETING INTERESTS: The Doetinchem Cohort Study is carried out by the National Institute for Public Health and the Environment which works under the authority of the Ministry of Health, Welfare and Sport of The Netherlands. F.J.M.B. declares to have received fees and grant support from the following companies (in alphabetical order); Ferring, Gedeon Richter, Merck Serono, MSD and Roche. The remaining authors declare no conflict of interest.

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.

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.

Prediction of an excessive response in in vitro fertilization from patient characteristics and ovarian reserve tests and comparison in subgroups: an individual patient data meta-analysis.

OBJECTIVE: To evaluate whether ovarian reserve tests (ORTs) add prognostic value to patient characteristics, such as female age, in the prediction of excessive response to ovarian hyperstimulation in patients undergoing IVF, and whether their performance differs across clinical subgroups. DESIGN: Authors of studies reporting on basal FSH, antimüllerian hormone (AMH), or antral follicle count (AFC) in relation to ovarian response to ovarian hyperstimulation were invited to share original data. Random intercept logistic regression models were used to estimate added value of ORTs on patient characteristics, while accounting for between-study heterogeneity. Receiver operating characteristic regression analyses were performed to study the effect of patient characteristics on ORT accuracy. SETTING: In vitro fertilization clinics. PATIENT(S): A total of 4,786 women for the main analysis, with a subgroup of 1,023 women with information on all three ORTs. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Excessive response prediction. RESULT(S): We included 57 studies reporting on 32 databases. Female age had an area under the receiver operating characteristic curve of 0.61 for excessive response prediction. Antral follicle count and AMH significantly added prognostic value to this. A model with female age, AFC, and AMH had an area under the receiver operating characteristic curve of 0.85. The combination of AMH and AFC, without age, had similar accuracy. Subgroup analysis indicated that FSH performed significantly worse in predicting excessive response in higher age groups, AFC did significantly better, and AMH performed the same. CONCLUSION(S): We demonstrate that AFC and AMH add value to female age in the prediction of excessive response and that, for AFC and FSH, the discriminatory performance is affected by female age.

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.