Non-invasive embryo evaluation and selection using time-lapse monitoring: Results of a randomized controlled study.

OBJECTIVE: Continuous monitoring of embryos via time-lapse (TL) provides more information on embryo kinetics and morphology compared to standard daily evaluation. Embryo selection by TL could support single embryo transfer (SET). With SET multiple gestations are avoided and perinatal outcome is improved. Our primary goal was to determine whether selection of a single blastocyst based on an algorithm comprising kinetic and morphologic scores assessed through continuous TL monitoring results in superior clinical outcome compared to embryo selection based on morphology alone. A secondary goal was to assess whether a time-lapse score based on kinetic and morphologic parameters was predictive of implantation. STUDY DESIGN: Randomized controlled trial performed in two private IVF centers in Hungary. Infertile couples scheduled to undergo 1st or 2nd IVF cycles were enrolled. Female age had to be under 36 years. The intervention was embryo evaluation/selection based on TL algorithm. Patients were randomized to SET with TL monitoring (TL-eSET) vs. SET with standard evaluation (control-eSET). Assuming an increase in pregnancy from 44% to 58%, a sample size of 202 per group was calculated based on the interim analysis at 10% information fraction. The primary outcome of the study was pregnancy rate. Secondary outcomes were miscarriage rates, live birth, perinatal outcome and the ability of a time-lapse score constructed based on kinetic and morphologic parameters to predict implantation. Chi-square tests, likelihood-ratio tests and exact tests were used for the analysis of categorical variables. Continuous variables were compared using independent group t-test and analysis of variance. RESULTS: The study was closed after three years. Eventually 161 patients were randomized and analyzed (N = 80 TL-eSET and N = 81 control-eSET). Pregnancy rate did not significantly differ between the groups though there was a trend favoring TL selection (TL-eSET: 46.3% vs control-eSET: 34.6%, p = 0.150; OR: 1.628 (95% CI: 0.857-3.092)). The time-lapse score based on morphologic and kinetic parameters was significantly higher for blastocysts that implanted vs. those that did not (14.5 ± 1.8 vs. 12.1 ± 2.9, p = 0.0001). There were no adverse effects of the intervention. CONCLUSIONS: Selection of a single blastocyst based on information derived from time-lapse monitoring can aid embryo selection for SET.

Does it really matter how far from the fundus embryos are transferred?

OBJECTIVE: Embryo transfer (ET) is an important last step during the process of IVF. Over the years much has been learned about the importance of the details of this procedure including the potential impact of transfer depth on outcome. The objective of our study was to evaluate whether transfer depth assessed by air bubble location after ET is associated with clinical outcome. STUDY DESIGN: Retrospective analysis of the association between transfer distance from the fundus (assessed by air bubble location after ET) and IVF outcome based on cycles (N=409) of patients with good prognosis undergoing infertility treatment for various indications. Treatments followed standard stimulation, IVF-ICSI and ET procedures. The distance of the air bubble as a surrogate marker of embryo location after transfer was measured and was correlated with implantation (IR) and pregnancy rates (PR) after day 3 and day 5 ET. Univariate comparisons were performed by nonparametric methods and multiple logistic regression was used to further evaluate the association between pregnancy rate and those factors that might influence outcome. RESULTS: The distance of the bubble was similar in those cycles that led to a pregnancy and those that did not (6.7 vs 6.5mm; p=0.48) and PR were comparable when the transfer was in the upper or middle third of the cavity. The IR did not differ when embryos were transferred into the upper, middle or lower third of the uterine cavity. Outcome was analyzed separately based on the day of transfer (cleavage vs blastocyst stage) and the IR did not differ based on the location of the transfer. CONCLUSIONS: Transfer depth does not affect implantation and pregnancy rates when the ET is in the middle or upper third of the uterus.

Detrimental effects of high-dose gonadotropin on outcome of IVF: making a case for gentle ovarian stimulation strategies.

OBJECTIVE: Limited data identify detrimental influences of aggressive use of gonadotropins (G) for controlled ovarian hyperstimulation (COH); the underlying mechanisms however remain unclear. We report on the relationship between G dose and in vitro fertilization (IVF) cycle parameters (ovarian response, endometrial thickness [EMT]) and cycle outcome (implantation rate [IR] and clinical pregnancy [CP] rate) in a cohort of women undergoing IVF. METHODS: Retrospective analysis of fresh embryo transfer (ET) cycles. Univariate and multivariable regression analyses assessed relationship between G dose and outcomes of interest. RESULTS: Higher G dose related positively with advancing age (P < .001) and inversely with EMT (P < .001). The overall CP rate was 30%. Significantly lower IR (.003) and CP rate (.002) were observed across increasing tertiles of G dose. Increasing G dose was identified as an independent negative predictor of EMT after adjusting for age, COH protocol and duration, infertility diagnosis, and ovarian response (P = .016). Adjusting for age, suppression protocol (gonadotropin-releasing hormone agonist vs antagonist), infertility diagnoses, EMT, quality, and cleavage of ET, lower G dose was an independent positive predictor of CP rate (odds ratio for CP rate was 1.57 for G dose in middle compared to the highest G dose quartile (95% confidence interval 1.09-2.24). Stratified analyses identified detrimental associations of higher G dose with CP rate to be relevant in women aged 35 years and younger. CONCLUSIONS: Our analyses suggest detrimental influences of higher G dose on the endometrium and confirm the previously reported adverse association between higher G dose and IVF outcome. Gentler COH regimens may be of particular benefit in women aged ≤35 years.

The role of hyaluronic acid binding assay in choosing the fertilization method for patients undergoing IVF for unexplained infertility.

PURPOSE: Patients with unexplained infertility may have fertilization problems. Split fertilization (ICSI and conventional IVF on sibling oocytes) is often used to avoid poor fertilization. Our aim was to assess the ability of hyaluronic acid binding (HA-binding) assay to predict spontaneous fertilization during IVF. METHODS: Prospective, blinded, controlled trial. Patients undergoing their first IVF cycle for unexplained infertility were eligible. Split fertilization was used. IVF and ICSI fertilization rates and embryo development based on 3 HA-binding cut-offs (< 60%; 60-80%; >80%) were compared. RESULTS: ICSI fertilization was higher than IVF, but none of the HA-binding cut-off levels predicted those cases where IVF was less effective, therefore ICSI only would have lead to improved outcome. Embryo development and morphology were similar in all cut-off groups. CONCLUSIONS: HA-binding did not predict spontaneous fertilization in patients with unexplained infertility undergoing IVF treatment. When it was used for "screening" it did not help to select the method of fertilization.