Dave J. Hendriks

The role of antimullerian hormone in prediction of outcome after IVF: comparison with the antral follicle count

OBJECTIVE To assess the value of antimullerian hormone (AMH) as a test to predict poor ovarian response and pregnancy occurrence after IVF and to compare it with the performance of the antral follicle count (AFC). DESIGN A systematic review of existing literature and a meta-analysis were carried out. After a comprehensive search, studies were included if 2 x 2 tables for outcomes poor response and pregnancy in IVF patients in relation to AMH or AFC could be constructed. SETTING Academic referral center for tertiary care. PATIENT(S) Cases indicated for IVF. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Poor response and nonpregnancy after IVF. RESULT(S) A total of 13 studies were found reporting on AMH and 17 on AFC. Because of heterogeneity among studies, calculation of a summary point estimate for sensitivity and specificity was not possible. However, for both tests summary receiver operating characteristic curves for the outcome measures poor response and nonpregnancy could be estimated and compared. The curves for the prediction of poor response indicated no significant difference between the performances of AMH and AFC. For the prediction of nonpregnancy, poor performance for both AMH and AFC was found. CONCLUSION(S) In this meta-analysis it was shown that AMH has at least the same level of accuracy and clinical value for the prediction of poor response and nonpregnancy as AFC.

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.

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.

Surgical versus expectant management in women with an incomplete evacuation of the uterus after treatment with misoprostol for miscarriage: the MisoREST trial

BackgroundMedical treatment with misoprostol is a non-invasive and inexpensive treatment option in first trimester miscarriage. However, about 30% of women treated with misoprostol have incomplete evacuation of the uterus. Despite being relatively asymptomatic in most cases, this finding often leads to additional surgical treatment (curettage). A comparison of effectiveness and cost-effectiveness of surgical management versus expectant management is lacking in women with incomplete miscarriage after misoprostol.Methods/DesignThe proposed study is a multicentre randomized controlled trial that assesses the costs and effects of curettage versus expectant management in women with incomplete evacuation of the uterus after misoprostol treatment for first trimester miscarriage.Eligible women will be randomized, after informed consent, within 24 hours after identification of incomplete evacuation of the uterus by ultrasound scanning. Women are randomly allocated to surgical or expectant management. Curettage is performed within three days after randomization.Primary outcome is the sonographic finding of an empty uterus (maximal diameter of any contents of the uterine cavity < 10 millimeters) six weeks after study entry. Secondary outcomes are patients’ quality of life, surgical outcome parameters, the type and number of re-interventions during the first three months and pregnancy rates and outcome 12 months after study entry.DiscussionThis trial will provide evidence for the (cost) effectiveness of surgical versus expectant management in women with incomplete evacuation of the uterus after misoprostol treatment for first trimester miscarriage.Trial registrationDutch Trial Register: NTR3110

Gonadotrophins versus clomifene citrate with or without intrauterine insemination in women with normogonadotropic anovulation and clomifene failure (M-OVIN): a randomised, two-by-two factorial trial

BACKGROUND In many countries, clomifene citrate is the treatment of first choice in women with normogonadotropic anovulation (ie, absent or irregular ovulation). If these women ovulate but do not conceive after several cycles with clomifene citrate, medication is usually switched to gonadotrophins, with or without intrauterine insemination. We aimed to assess whether switching to gonadotrophins is more effective than continuing clomifene citrate, and whether intrauterine insemination is more effective than intercourse. METHODS In this two-by-two factorial multicentre randomised clinical trial, we recruited women aged 18 years and older with normogonadotropic anovulation not pregnant after six ovulatory cycles of clomifene citrate (maximum of 150 mg daily for 5 days) from 48 Dutch hospitals. Women were randomly assigned using a central password-protected internet-based randomisation programme to receive six cycles with gonadotrophins plus intrauterine insemination, six cycles with gonadotrophins plus intercourse, six cycles with clomifene citrate plus intrauterine insemination, or six cycles with clomifene citrate plus intercourse. Clomifene citrate dosages varied from 50 to 150 mg daily orally and gonadotrophin starting dose was 50 or 75 IU daily subcutaneously. The primary outcome was conception leading to livebirth within 8 months after randomisation defined as any baby born alive after a gestational age beyond 24 weeks. Primary analysis was by intention to treat. We made two comparisons, one in which gonadotrophins were compared with clomifene citrate and one in which intrauterine insemination was compared with intercourse. This completed study is registered with the Netherlands Trial Register, number NTR1449. FINDINGS Between Dec 8, 2008, and Dec 16, 2015, we randomly assigned 666 women to gonadotrophins and intrauterine insemination (n=166), gonadotrophins and intercourse (n=165), clomifene citrate and intrauterine insemination (n=163), or clomifene citrate and intercourse (n=172). Women allocated to gonadotrophins had more livebirths than those allocated to clomifene citrate (167 [52%] of 327 women vs 138 [41%] of 334 women, relative risk [RR] 1·24 [95% CI 1·05-1·46]; p=0·0124). Addition of intrauterine insemination did not increase livebirths compared with intercourse (161 [49%] vs 144 [43%], RR 1·14 [95% CI 0·97-1·35]; p=0·1152). Multiple pregnancy rates for the two comparisons were low and not different. There were three adverse events: one child with congenital abnormalities and one stillbirth in two women treated with clomifene citrate, and one immature delivery due to cervical insufficiency in a woman treated with gonadotrophins. INTERPRETATION In women with normogonadotropic anovulation and clomifene citrate failure, a switch of treatment to gonadotrophins increased the chance of livebirth over treatment with clomifene citrate; there was no evidence that addition of intrauterine insemination does so. FUNDING The Netherlands Organization for Health Research and Development.