Predicting the ovarian response: towards a determinant model and implications for practice.

OBJECTIVE: To improve the reliability of prediction models for ovarian response to stimulation in ART. DESIGN: A multicenter retrospective cohort study. SETTING: Twelve reproductive centers. PATIENTS: A total of 25,854 controlled ovarian stimulations between 2005 and 2016, including cycles cancelled for inadequate response, were included. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Precision of the prediction of the number of oocytes at ovarian pickup and of cancellation rate for poor ovarian response. RESULTS: Both AMH and antral follicle count exhibit a non-linear effect on the oocyte yield, with a linear relationship after log-transformation. After adjustment for age, BMI, and center, ovarian response observed in a previous stimulation was found to be the best predictor, followed by AMH and AFC. The zero-inflated binomial negative model showed that predictors of cycle cancellation and number of oocytes at retrieval were different, and assimilating cancellation to zero oocyte greatly reduces the determination of the model. Our model was characterized by the best ever reached determination (R2=0.505 for non-naïve women, 0.313 for all the women) and provided evidence of a very strong difference among centers. The results can be easily converted in the prediction of response levels (poor-medium-good-high). Finally, in case of partial report of the above predictors, we show that the univariate prediction based on the best predictor provides a good approximation. CONCLUSION(S): A substantial improvement of the ovarian response prediction is possible in modelling the possible cancellation decision, followed by the oocyte retrieval itself, according to an appropriate model based on previous stimulation and non-linear effects of AMH and AFC.

Reliability of AMH and AFC measurements and their correlation: a large multicenter study.

PURPOSE: Anti-Müllerian hormone (AMH) and antral follicle count (AFC) are correlated with the ovarian response, but their reliability and reproducibility are questionable. This large multicenter study describes their distribution, inter-cycle and inter-center variability, and their correlation. METHODS: A total of 25,854 IVF cycles among 15,219 patients were selected in 12 ART centers. Statistical distribution of AMH and AFC was studied by using the Kolmogorov-Smirnov test and Shapiro goodness of fit test. The reproducibility of AFC and AMH was measured using a mixed model regressing the logarithmic transformation of AFC with age. RESULTS: The distribution of AMH and AFC was characterized by a wide dispersion of values, twice more important for AFC, and a logarithmic distribution. The faster decline in AMH than in AFC with age suggests that their correlation changes with age. AMH and AFC showed a very low proportion of concordance in the range of expected poor responders according to Bologna cutoffs. The heterogeneity for AMH and AFC across centers was small, but much larger across patients within each center. Concerning the patients with several successive cycles, the reproducibility for AMH seemed much better than for AFC. Comparing respective performances of AMH and AFC for the prediction of ovarian response depended on the local conditions for measuring these indicators and on the reproducibility of results improved over time. CONCLUSION: Distribution of AMH and AFC was characterized by the wide dispersion of values, and a logarithmic distribution. Establishing cutoffs or a direct relationship AMH/AFC without considering age seems hazardous. Correlation between AMH and AFC was very poor in the range of poor responders.

Effect of recombinant LH supplementation on cumulative live birth rate compared with FSH alone in poor ovarian responders: a large, real-world study.

RESEARCH QUESTION: The benefit of LH supplementation (LHS) over sole use of FSH during controlled ovarian stimulation (COS) remains controversial. Meta-analyses have provided some evidence that the benefit of LHS is limited to women with poor ovarian response (POR). This study aimed to assess the effectiveness of LHS on cumulative live birth rate (CLBR) in POR using a large controlled study in a real-world context. DESIGN: This retrospective multicentre controlled study used data from registries at 12 French ART centres. All instances of POR undergoing ovarian stimulation and treated with follitrophin-alfa (FSH-α) with or without lutrophin-α were selected following an intention-to-treat principle. POR was defined according to the ESHRE Bologna criteria, and classified into three categories (Mild, Moderate and Severe) according to the Poor Responder Outcome Prediction (PROsPeR) score. The primary end-point was the CLBR associated with fresh and frozen embryos originating from the same ovarian stimulation. RESULTS: A total of 9787 instances of ovarian stimulation (5218 LHS, 4569 FSH-α only) were analysed, 33.0%, 52.4% and 14.6% being allocated to the Mild, Moderate and Severe PROsPeR categories, respectively. Using a mixed logistic model and adjusting for matched subclasses and baseline POR severity, it was found that the benefit of LHS compared with use of FSH alone differed between baseline severity categories (interaction test, P = 0.007): a significant benefit of LHS for CLBR was found for patients in the Moderate (14.3% versus 11.3%, odds ratio [OR] = 1.37, 95% confidence interval [CI] 1.07-1.75, risk ratio [RR] = 1.29, P = 0.013) and Severe (9.8% versus 4.4%, OR = 2.40, 95% CI- 1.48-3.89, RR = 1.89, P < 0.001) categories, but not for the Mild category (18.8% versus 19.6%, OR = 0.95, 95% CI 0.78-1.15, RR = 0.95, P = 0.60). CONCLUSION: LHS has a significant effect on increasing CLBR in moderately and severely poor ovarian responders.

Equivalent live-birth rate in antagonist IVF/ICSI protocol after oocyte triggering with GnRH agonist supplemented with 1500 r-hCG the day of oocyte retrieval vs r-hCG : A case-control study.

OBJECTIVE: To compare live birth rate after fresh transfer and cumulative birth rates after vitrified embryo transfer in patients triggered by GnRHa, and 1500 r-hCG bolus on the day of the pick up to a selected population of patients triggered by r-hCG. DESIGN: Retrospective case-control study SETTING: Private hospital, Rennes, France PATIENTS: Patients with more than 18 follicles greater than 11 mm on the day of the triggering, or patients with a history of OHSS INTERVENTION: We triggered according to the European protocol by GnRHa and a bolus of 1500 UI of r-HCG on the day of the pick-up and performed if possible a fresh transfer on day 2, 3 or 5. MAIN OUTCOME MEASURE: The live birth rate using fresh transfer (FT) and the cumulative birth rate by cycle of FT and frozen embryo transfer (FET) between patients triggered by GnRHa with a bolus injection of 1500 r-hCG and patients triggered by r-hCG. RESULTS: Patients triggered by GnRHa and supplemented with a bolus injection of 1500 IU r-hCG one hour after the pick up had FT birth rates equivalent to those seen after r-hCG triggering: 32.0% vs 31.8% (p = 0.9687). There was a non significant trend for better results for cumulative birth rates in FT + FET after agonist triggering. CONCLUSION: Our approach proposed may be suitable as an alternative to freeze all in centers where embryonic vitrification is not optimal, and for patients for whom freeze all is not possible for legal or ethical reasons.

Both high and low HCG day progesterone concentrations negatively affect live birth rates in IVF/ICSI cycles.

RESEARCH QUESTION: Can previous reports of a decreased probability of success in stimulated IVF cycles with premature rise of progesterone, as determined by progesterone concentration on HCG day (PHCG), be confirmed? DESIGN: Retrospective, observational, single-centre cohort study conducted on 5447 IVF and intracytoplasmic (ICSI) cycles carried out among 2192 patients between 2009 and 2015, with conventional ovarian stimulation. This large database was used to develop a non-linear mixed prognosis model of live birth rate (LBR) incorporating PHCG as a predictor. RESULTS: In addition to known predictors (age, body mass index, anti-Müllerian hormone, type of infertility), PHCG was associated with a linear effect (OR 0.78 per Log[PHCG]ng/ml, 95% CI 0.611 to 0.997, P = 0.047) combined with a strong quadratic effect (OR 0.585 per Log2(PHCG)ng/ml, 95% CI 0.444 to 0.775, P < 0.001) resulting into a parabolic reverse-U curve. A significant interaction (P = 0.038) was found between PHCG and number of oocytes if three or less, but the effect of PHCG remains modest. For higher oocyte numbers, LBR rapidly increases with number of retrieved oocytes; however, LBR becomes more sensitive to PHCG as the number of oocytes increases. Higher live birth prognoses occur for optimal PHCG but are sharply reduced for lower or higher PHCG. CONCLUSIONS: Evidence is provided of an important negative effect of PHCG at lower and higher values, independent of oocyte number, thus defining appropriate ranges for fresh embryo transfer or freeze-all strategy. In poor responders, premature progesterone rise may be ignored, thus avoiding unnecessary cancellations or embryo freezing. Conversely, in higher responders, the negative effect of progesterone elevation is more pronounced, suggesting that freeze-all policy should be applied more widely.

Acute right-sided heart failure caused by Neisseria meningitidis.

Meningococcal myocarditis is a rarely diagnosed infection and could be the consequence of primary invasive infection or late immunologic complications. An unusual presentation of meningococcemia in an immunocompetent adult is described, with Neisseria meningitidis identified as the cause of selective right-sided heart failure in a case of acute myocarditis.

Programming in vitro fertilization retrievals during working days after a gonadotropin-releasing hormone antagonist protocol with estrogen pretreatment: does the length of exposure to estradiol impact on controlled ovarian hyperstimulation outcomes?

OBJECTIVE: To verify whether a variable number of days beyond the menses of estrogen (E) pretreatment may impact on controlled ovarian hyperstimulation (COH) outcomes and birth rate using a GnRH antagonist protocol. DESIGN: Single center, prospective, nonrandomized study. SETTING: Nonacademic fertility unit. PATIENT(S): A total of 1,080 women, aged 25-38 years, consecutively included (1,603 cycles). INTERVENTION(S): Given 4 mg/d E(2) valerate, started 3 days before the theoretical date of the next menses up to the first day of stimulation (S1). MAIN OUTCOME MEASURE(S): Hormone serum levels, drug exposure, and main IVF outcomes. RESULT(S): The cancellation rate was similar in the six similarly sized groups according to the number of days with E(2) pretreatment beyond the menses (1-8 days). The mean serum E(2) and LH levels at S1 gradually increased along with E(2) exposure, whereas the mean serum P level decreased. The mean serum E(2) level on the day of hCG administration gradually increased along with E(2) exposure. Serum LH level at S1 correlated significantly and positively to the length of E(2) exposure and to E(2) level on the day of hCG administration. No significant difference was observed for the number of oocytes retrieved and the number of embryos obtained. Women exposed the longest to exogenous E(2) tended to have higher pregnancy rates (PR). CONCLUSION(S): Extending E(2) pretreatment beyond the menses had no deleterious effect on the main COH outcomes and proved to be slightly beneficial.