L.F.J.M.M. Bancsi

Predictors of poor ovarian response in in vitro fertilization: a prospective study comparing basal markers of ovarian reserve

OBJECTIVE To identify and quantify predictors of poor ovarian response in in vitro fertilization (IVF). DESIGN; Prospective study. SETTING; Tertiary fertility center. PATIENT(S) One hundred twenty women undergoing their first IVF cycle. INTERVENTION(S) Measurement of the number of antral follicles and the total ovarian volume by ultrasound, and of basal levels of FSH, E(2), and inhibin B on cycle day 3. MAIN OUTCOME MEASURE(S) Ovarian response, and clinical and ongoing pregnancy rates. RESULT(S); The antral follicle count was the best single predictor for poor ovarian response: area under the receiver operating characteristic curve = 0.87. Addition of basal FSH and inhibin B levels to a logistic model with the antral follicle count significantly improved the prediction of poor response; the addition of basal E(2) levels and total ovarian volume did not improve the prediction. To express the discriminative performance of this model toward poor response, a maximum area under the receiver operating characteristic curve of 0.92 was calculated. Poor responders had significantly lower clinical and ongoing pregnancy rates than did normal responders. CONCLUSION(S) Our data demonstrate that the antral follicle count provides better prognostic information on the occurrence of poor response during hormone stimulation for IVF than does the patients chronological age and the currently used endocrine markers. However, endocrine tests remain informative. Multivariate models can achieve more accurate predictions of outcomes of complex events like ovarian response in IVF.

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.

Performance of basal follicle-stimulating hormone in the prediction of poor ovarian response and failure to become pregnant after in vitro fertilization: a meta-analysis

OBJECTIVE To assess the predictive performance and clinical value of basal FSH as a test for ovarian reserve in in vitro fertilization (IVF) patients. DESIGN Meta-analysis. SETTING Tertiary fertility center. PATIENT(S) Patients undergoing IVF. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Poor ovarian response, nonpregnancy. RESULT(S) We located 21 studies that had reported on basal FSH and IVF outcome. No single study met high standards of methodological rigor; most studies are of moderate methodological quality only. The summary receiver operating characteristic curve indicated a moderate predictive performance for poor response, and a low predictive performance for nonpregnancy. Predictions with a substantial shift from pre-FSH-test probability to post-FSH test probability are only achieved at extreme cut-off levels for basal FSH. Sensitivity of such cut-off levels, for both the prediction of poor response and nonpregnancy, is limited. CONCLUSION(S) Clinical value of testing for basal FSH is restricted to a small minority of patients. Basal FSH should not be regarded as a useful routine test for the prediction of IVF outcome. The development of better tests to assess ovarian reserve remains of importance.

Women older than 40 years of age and those with elevated follicle-stimulating hormone levels differ in poor response rate and embryo quality in in vitro fertilization

OBJECTIVE To investigate whether IVF outcome of patients older than 40 years of age with basal FSH levels less than 15 IU/L differs from that in patients 40 years of age or younger with basal FSH levels of 15 IU/L or greater. DESIGN Prospective observational study. SETTING Tertiary academic fertility center. PATIENT(S) Women 41 years of age or older with basal FSH levels less than 15 IU/L (n = 50), and women 40 years of age or younger with elevated basal FSH levels (n = 36) undergoing their first IVF cycle. INTERVENTION(S) IVF treatment using a long suppression protocol with recombinant FSH at a fixed starting dose of 150 IU/L. MAIN OUTCOME MEASURE(S) Ovarian response, ongoing pregnancy rates, and implantation rates. RESULT(S) The high FSH group experienced more cycle cancellations due to absent follicular growth than did the high age group (31% vs. 8%). However, the high FSH group had better implantation rates per embryo (34% vs. 11%), higher ongoing rates per ET (40% vs.13%), and higher ongoing pregnancy rates per cycle (25% vs. 10%). In both groups, poor responders had lower pregnancy rates. CONCLUSION(S) The outcome of IVF differs between patients older than 40 years of age with normal FSH levels and relatively young patients with elevated FSH levels. This finding may have implications for the management of these patients.

Basal follicle-stimulating hormone levels are of limited value in predicting ongoing pregnancy rates after in vitro fertilization.

OBJECTIVE To evaluate whether basal FSH (bFSH; measured on menstrual day 1-4) adds relevant clinical information to the prediction of ongoing pregnancy rates (OPRs) after IVF, once age and diagnostic characteristics have been taken into account. DESIGN Retrospective. SETTING Academic fertility center. PATIENT(S) 435 women undergoing their first IVF cycle. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Ongoing pregnancy rate. RESULT(S) The likelihood ratio of bFSH as a single prognosticator for treatment failure at a cutoff level of 15 IU/L was 3.87. The proportion of patients with such a bFSH level was 5%. Multivariate logistic regression analysis selected age, bFSH level, and infertility diagnosis as relevant predictors of ongoing pregnancy. When compared to a predictive model for OPRs based on age and infertility diagnosis, the inclusion of bFSH into this model helped to identify more patients (22 vs. 1) whose predicted OPR decreased from a low level (5%-12%) towards an extremely low level (<5%). CONCLUSION(S) An acceptable performance of bFSH as a single test to predict treatment failure is only obtained above a high cutoff level. Thus, the number of patients for whom bFSH provides relevant information is small. The predictive model including bFSH identified significantly more patients with an extremely poor prognosis than did the predictive model without bFSH. However, predictions based solely on age and infertility diagnosis usually were already poor in these patients. Measurement of bFSH adds little in only a few patients and is, therefore, debatable.

The accuracy of multivariate models predicting ovarian reserve and pregnancy after in vitro fertilization: a meta-analysis

BACKGROUND To review the accuracy of multivariate models for the prediction of ovarian reserve and pregnancy in women undergoing IVF compared with the antral follicle count (AFC) as single test. METHODS We performed a computerized MEDLINE and EMBASE search to identify articles published on multivariate models for ovarian reserve testing in patients undergoing IVF. In order to be selected, articles had to contain data on the outcome of IVF in terms of either pregnancy and/or poor response and on the prediction of these events based on a multivariate model. For the selected studies, sensitivity and specificity of the test in the prediction of poor ovarian response and non-pregnancy were calculated. Overall performance was assessed by estimating a summary receiver operating characteristic (ROC) curve, which was compared with the ROC curve for the AFC as the current best single test. RESULTS We identified 11 studies reporting on the predictive capacity of multivariate models in ovarian reserve testing. All studies reported on the prediction of poor ovarian response, whereas none reported on the occurrence of pregnancy. The sensitivity for prediction of poor ovarian response varied between 39% and 97% and the specificity between 50% and 96%. Logistic regression analysis indicated that cohort studies provided a significantly better discriminative performance than case-control studies. As cohort studies are superior to case-control studies, further analysis was limited to the cohort studies. For the cohort studies, a summary ROC curve could be estimated, which had a shape similar to that previously made for the AFC. CONCLUSIONS The accuracy of multivariate models for the prediction of ovarian response in women undergoing IVF is similar to the accuracy of AFC. No data are available on the capacity of these models to predict pregnancy, let alone live birth. On the basis of these findings, the use of more than one single test for the assessment of ovarian reserve cannot currently be supported.

Ovarian reserve tests in infertility practice and normal fertile women

The decline in fecundity with the age of the woman is mainly attributed to the loss of follicles from the ovary and a decrease in oocyte quality. Evaluation of the aging status of the ovary in an individual woman has been hampered by a lack of knowledge with regard to the relative contribution of these two factors. Most if not all so called ovarian reserve tests (ORT) reflect indirectly the remaining follicle pool in the ovary. Direct a priori assessment of oocyte quality is not possible to date. In this section the predictive value of several ovarian reserve tests for the outcome of fertility treatment is listed and commented. In addition, the study of several of the ORTs in normal, fertile women is described. From the data presented dynamic testing of the ovarian function by the clomiphene citrate and GnRH agonist stimulation test, as well as static testing by the use of ultrasound based antral follicle counts seem to offer the highest clinical value. Studies performing direct comparison of these tests are needed, as well as analysis of the way these tests should direct decision making in infertility diagnosis and treatment.

Expected poor ovarian response in predicting cumulative pregnancy rates: a powerful tool

Poor ovarian response in IVF cycles is associated with poor pregnancy rates. Expected poor responders may represent the worst prognostic group. Data were used from 222 patients starting the first of three IVF treatment cycles. The predictability of ongoing pregnancy after three cycles was analysed using survival analysis and hazard rate ratios. If first cycle poor responders were also predicted to have a poor response, they were classified as expected poor responders. The predicted pregnancy rate in cycles 2 and 3 for women with an observed poor response in the first cycle was approximately 24% for women aged 30 years and approximately 14% for women aged 40 years. For women with an expected poor response these rates were 12% and 6%, respectively. In contrast, women aged 40 years with an unexpected poor response still had a predicted cumulative pregnancy rate of 24%. Age as a sole predictor of cumulative pregnancy does not help to identify poor prognosis cases. Cumulative pregnancy rates in subsequent cycles for patients with an observed poor response in the first cycle may be a reason to refrain from further treatment. However, if such poor response has been expected, further treatment may be avoided because of an unfavourable prognosis for pregnancy.

Single and Repeated GnRH Agonist Stimulation Tests Compared With Basal Markers of Ovarian Reserve in the Prediction of Outcome in IVF

Purpose: To study the value of a single or repeated GnRH agonist stimulation test (GAST) in predicting outcome in IVF compared to basal ovarian reserve tests.Methods: A total of 57 women was included. In a cycle prior to the IVF treatment, on day 3, an antral follicle count (AFC) was performed and blood taken for basal FSH, inhibin B and E2 measurements, followed by a subcutaneous injection of 100 μg triptorelin for the purpose of the GAST. Twenty-four hours later blood sampling was repeated. All the tests were repeated in a subsequent cycle. From the GAST E2 and inhibin B response were used as test parameters. The outcome measures were poor ovarian response and ongoing pregnancy. Group comparisons were done using the Mann– Whitney or chi-square test. Univariate and multivariate logistic regression was applied to assess which test revealed the highest predictive accuracy as expressed in the area under receiver-operating characteristic curve (ROCAUC). Clinical value was compared by calculating classical test characteristics for the best logistic models.Results: All the basal and GAST variables were significantly different in the poor responders (n = 19) compared to normal responders (n = 38). In the univariate analysis on cycle 1 tests the AFC was the best predictor for poor ovarian response, while in cycle 2 the E2 response in the GAST performed best (ROCAUC of 0.91 for both). Multivariate analysis of the basal variables led to the selection of AFC and inhibin B in cycle 1, yielding a ROCAUC of 0.96. Mean E2 response was selected in a multivariate analysis of the repeated GAST variables (ROCAUC 0.91). At a specificity level of ∼0.90, several logistic models including GAST variables appeared to have a sensitivity (∼0.80), positive predictive value (∼0.82) and false positive rate (∼0.18), comparable to a logistic model containing AFC and inhibin B. None of the test variables showed a significant relation with ongoing pregnancy.Conclusions: The GAST has a rather good ability to predict poor response in IVF. However, comparing the predictive accuracy and clinical value of the GAST with a day 3 AFC and inhibin B, it appeared that neither a single nor a repeated GAST performed better. In addition, the predictive ability towards ongoing pregnancy is poor. Therefore, the use of the GAST as a predictor of outcome in IVF should not be advocated.

Use of Stimulated Serum Estradiol Measurements for the Prediction of Hyperresponse to Ovarian Stimulation in in Vitro Fertilization (IVF)

AbstractPurpose: In ovarian stimulation an exaggerated ovarian response is often seen and is related to medical complications, such as ovarian hyperstimulation syndrome (OHSS), and increased patient discomfort. If it were possible to identify hyperresponders at an early stage of the stimulation phase, adaptation of the stimulation protocol would become feasible to minimize potential complications. Therefore, we studied the usefulness of measuring stimulated serum estradiol (E2) levels in predicting ovarian hyperresponse. Methods: A total of 109 patients undergoing their first IVF treatment cycle using a long protocol with GnRH agonist was prospectively included. The E2 level was evaluated on day 3 and 5 of the stimulation phase. Two outcome measures were defined. The first was ovarian hyperresponse (collection of ≥15 oocytes at retrieval and/or peak E2 >10000 pmol/L, or cancellation due to ≥30 follicles growing and/or peak E2 >15000 pmol/L, or OHSS developed). The second outcome measure comprised a subgroup representing the more severe hyperresponders, named extreme-response (cancellation or OHSS developed). Results: The data of 108 patients were analyzed. The predictive accuracy of E2 measured on stimulation day 3 towards ovarian hyperresponse was clearly lower than that of E2 measured on stimulation day 5 (area under the receiver operating characteristic curve (ROCAUC) 0.75 and 0.81, respectively). For extreme-response the predictive accuracy of E2 measured on stimulation day 3 or 5 was comparable (ROCAUC 0.81 and 0.82, respectively). For both outcome measures the stimulated E2 tests yielded only acceptable specificity with moderate sensitivity at higher cutoff levels. Prediction of extreme-response seemed slightly more effective due to a lower error rate. Conclusions: There is a significant predictive association between E2 levels measured on stimulation day 3 and 5 and both ovarian hyperresponse and extreme-response in IVF. However, the clinical value of stimulated E2 levels for the prediction of hyperresponse is low because of the modest sensitivity and the high false positive rate. For the prediction of extreme-response the clinical value of stimulated E2 levels is moderate.