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.

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

BACKGROUND: Medical 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/DESIGN: The 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. DISCUSSION: This 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 REGISTRATION: Dutch Trial Register: NTR3110.

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.

Ultrasonography as a tool for the prediction of outcome in IVF patients: a comparative meta-analysis of ovarian volume and antral follicle count.

OBJECTIVE: To investigate by meta-analysis the predictive capacity of ovarian volume as an ovarian reserve test in comparison to the antral follicle count (AFC). 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): A total of 10 studies were detected reporting on ovarian volume and 17 studies on AFC. Because of heterogeneity among studies, calculation of one summary point estimate for sensitivity and specificity was not meaningful. However, for both tests, summary receiver operating characteristic curves for the outcome measures poor response and nonpregnancy could be estimated and compared. The AFC performed statistically significantly better than ovarian volume in the prediction of poor response. The overall accuracy for predicting nonpregnancy was poor for both tests. The clinical value in poor response prediction was only evident for the AFC as a considerable number of cases can be identified who will have a high chance of producing a poor response to stimulation. The clinical value for nonpregnancy was virtually absent for both tests. CONCLUSION(S): In conclusion, the predictive performance of ovarian volume toward poor response is clearly inferior compared with that of AFC. Therefore, the AFC may be considered the test of first choice when estimating quantitative ovarian reserve before IVF. For the prediction of cases with a very low chance for pregnancy, ovarian reserve testing with the use of ultrasound appears inadequate.

The clomiphene citrate challenge test for the prediction of poor ovarian response and nonpregnancy in patients undergoing in vitro fertilization: a systematic review.

OBJECTIVE: To systematically review the value of the clomiphene citrate challenge test (CCCT) in the prediction of poor ovarian response and pregnancy in IVF. DESIGN: Systematic review. SETTING: All studies that evaluated the CCCT in the prediction of poor ovarian response or pregnancy after IVF. PATIENT(S): Infertility population undergoing an IVF treatment. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Poor ovarian response, nonpregnancy. RESULT(S): From the literature we identified and analyzed 12 studies on the CCCT according to preset criteria. In predicting poor response, the sensitivity and specificity of the CCCT varied from 35% to 93% and 47% to 98%, respectively. In predicting nonpregnancy, the sensitivity and specificity varied from 13% to 66% and 73% to 97%, respectively. Because of heterogeneity among studies, a summary receiver operating characteristics (ROC) curve could not be estimated. Back-to-back comparison of the CCCT with basal FSH was possible in six studies. In predicting poor response, the sensitivity of the CCCT increased to some extent, whereas specificity did not increase or even diminished. In predicting nonpregnancy, the CCCT also showed an increase in sensitivity, counteracted by a decrease in specificity. CONCLUSION(S): Summary estimates of test accuracy for the CCCT in IVF are not possible, because of heterogeneity among individual studies. A subanalysis of studies comparing basal FSH and the full CCCT showed that the CCCT has hardly any additional value.

Value of ovarian reserve testing before IVF: a clinical decision analysis.

BACKGROUND: To assess the value of testing for ovarian reserve prior to a first cycle IVF incorporating patient and doctor valuation of mismatches between test results and treatment outcome. METHODS: A decision model was developed for couples who were considering participation in an IVF programme. Three strategies were evaluated: (I) withholding IVF without prior testing, (II) testing for ovarian reserve, and then deciding on IVF treatment if ovarian reserve was estimated to be sufficient, and (III) treatment with IVF without prior ovarian reserve testing. The outcome considered was the birth of a child. The valuation of the combination of the strategy conducted and the outcome accomplished was expressed on a distress scale in units of 'IVF cycles that were performed in vain'. Correct treatment with IVF and correct withholding of IVF were considered to bring no distress. The distress of withholding IVF in case pregnancy occurred is consequently specified by the ratio of the expected distress after incorrect withholding IVF to the expected distress after incorrect performing IVF (distress ratio). We interviewed both patients and doctors to determine realistic estimates for this distress ratio. RESULTS: The value of testing for ovarian reserve depends strongly on the expected pregnancy rate after IVF as well as on the valuation of the incorrect decisions from testing. For realistic ranges of the success rate after IVF and for distress ranges as were measured, treatment of all couples without testing was found to generate less distress than testing for ovarian reserve. The sensitivity and specificity of testing for ovarian reserve has to improve to 50 and 96% respectively, to make testing a valuable strategy. CONCLUSION: Based on the decision analysis, where current test accuracy and preference inventory among patients and physicians were used, testing for ovarian reserve seems not useful for current IVF programmes.

Antral follicle count in the prediction of poor ovarian response and pregnancy after in vitro fertilization: a meta-analysis and comparison with basal follicle-stimulating hormone level.

OBJECTIVE: To assess the predictive performance of the antral follicle count (AFC) as a test for ovarian reserve in IVF patients and to compare this performance with that of basal FSH level. 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 identified 11 studies on AFC and an updated total of 32 studies on basal FSH from the literature on the basis of preset criteria. The estimated summary receiver operating characteristic (ROC) curves showed AFC to perform well in the prediction of poor ovarian response. Also, prediction of poor ovarian response seemed to be more accurate with AFC compared with basal FSH. The estimated summary ROC curves for the prediction of nonpregnancy indicated a poor performance for both AFC and basal FSH. CONCLUSION(S): Transvaginal ultrasonography is an easy-to-perform and noninvasive method that provides essential predictive information on ovarian responsiveness. The predictive performance of AFC toward poor response is significantly better than that of basal FSH. Therefore, AFC might be considered the test of first choice in the assessment of ovarian reserve prior to IVF.