Evolution of embryo selection for IVF from subjective morphology assessment to objective time-lapse algorithms improves chance of live birth.

RESEARCH QUESTION: Does using an objective time-lapse imaging algorithm (TLIA) after IVF relate to conventional morphological assessment of human blastocysts as a prognosticator for live birth? DESIGN: Prospective use of a TLIA to select embryos in multicentre IVF clinics all using the same strictly controlled laboratory protocols. Each blastocyst was given a ranking from A to D, with the highest rank preferred for fresh transfer. This ranking was retrospectively compared with a given morphological score, which was blinded to the TLIA rank; all embryos were cultured under the same conditions. RESULTS: Using multiple variable logistic regression models, TLIA embryo rank enabled greater discrimination between cycles with and without live births than the conventional morphology grade, even when considered in isolation, and when adjusting for covariates related to treatment and patient criteria. Of the 1810 cycles of single blastocyst transfer, 894 (49.4%) resulted in a live birth. A Vuong non-nested test including covariates showed strong evidence of the superiority of the embryo rank model compared with the transfer grade model (P = 0.0008 [raw], P = 0.0003 [Akaike information criterion - corrected]). From the receiver operating characteristic (ROC) curves across all possible thresholds the TLIA rank showed better true positive and true negative rates and had a higher area under the curve [AUC] of 67.43% compared with 61.74% for the blastocyst morphology grade. The same analysis but excluding covariates demonstrated an AUC of 62.86% versus 54.02%, respectively. CONCLUSION: Objective TLIA is superior for selecting embryos for their propensity to generate a live birth over a conventional, subjective blastocyst morphology scoring system.

Time-lapse imaging algorithms rank human preimplantation embryos according to the probability of live birth.

RESEARCH QUESTION: Can blastocysts leading to live births be ranked according to morphokinetic-based algorithms? DESIGN: Retrospective analysis of 781 single blastocyst embryo transfers, including all patient clinical factors that might be potential confounders for the primary outcome measure of live birth, was weighed using separate multi-variable logistic regression models. RESULTS: There was strong evidence of effect of embryo rank on odds of live birth. Embryos were classified A, B, C or D according to calculated variables; time to start (tSB) and duration (dB{tB - tSB}) of blastulation. Embryos of rank D were less likely to result in live birth than embryos of rank A (odds ratio [OR] 0.3046; 95% confidence interval [CI] 0.129, 0.660; P < 0.005). Embryos ranked B were less likely to result in live birth than those ranked A (OR 0.7114; 95% Cl 0.505, 1.001; P < 0.01), and embryos ranked C were less likely to result in live birth than those ranked A (OR 0.6501, 95% Cl 0.373, 1.118; P < 0.01). Overall, the LRT (Likelihood Ratio Test) p-value for embryo rank shows that there is strong evidence that embryo rank is informative as a whole in discriminating between live birth and no live birth outcomes (p = 0.0101). The incidence of live birth was 52.5% from rank A, 39.2% from rank B, 31.4% from rank C and 13.2% from rank D. CONCLUSIONS: Time-lapse imaging morphokinetic-based algorithms for blastocysts can provide objective hierarchical ranking of embryos for predicting live birth and may have greater discriminating power than conventional blastocyst morphology assessment.

Live births after embryo selection using morphokinetics versus conventional morphology: a retrospective analysis.

The increasing corpus of clinical studies using time-lapse imaging for embryo selection demonstrates considerable variation in study protocols and only limited-sized study cohorts. Outcome measures are based on implantation or clinical pregnancy; some predict blastulation from early cleavage-stage data, and few have evaluated live birth. Erroneously, most studies treat the embryos as independent variables and do not include patient or treatment variables in the statistical analyses. In this study, cohort size was 14,793 patients and 23,762 cycles. The incidence of live birth (n = 973 deliveries) after embryo selection by objective morphokinetic algorithms was compared with conventional embryology selection parameters (n = 6948 deliveries). A 19% increase in the incidence of live birth was observed when morphokinetic data were used to select embryos for the patient cohort aged younger than 38 years (OR 1.19 with 95% CI 1.06 to 1.34) using their own eggs, and an increase of 37% for oocyte recipients aged over 37 years (OR 1.370; 95% Cl 0.763 to 2.450). This is the largest study of the prospective use of time-lapse imaging algorithms in IVF reporting on live birth outcome, although the nature of purely a closed system versus standard incubation could not be assessed.

Precision Medicine in Assisted Conception: A Multicenter Observational Treatment Cohort Study of the Annexin A5 M2 Haplotype as a Biomarker for Antithrombotic Treatment to Improve Pregnancy Outcome.

BACKGROUND: Pregnancy failure and placenta mediated pregnancy complications affect >25% of pregnancies. Although there is biological plausibility for a procoagulant mechanism underlying some of these events, antithrombotic intervention trials demonstrate limited benefit, possibly through lack of stratification in heterogeneous patient groups. The ANXA5 M2 haplotype is a possible procoagulant biomarker and was tested pragmatically to determine whether this screening and LMWH treatment normalized the outcome for ANXA5 M2 positive couples. This was a pragmatic study that aimed to measure the effectiveness of a testing (for the M2 haplotype) and treatment (LMWH) pathway in routine clinical practice where there is variation between patients. Such a study in couples with fertility problems can inform choices between treatments; it is then the management protocol which is the subject of the investigation, not the individual treatments. METHODS: Couples (N=77) with one or both partners ANXA5 M2 positive demonstrated association of this haplotype with adverse IVF outcome. A pragmatic, multicenter, prospective cohort study of ANXA5 M2 haplotype screening, and LWMH treatment following embryo transfer (ET) in 103 IVF couples positive for ANXA5 M2 was performed. They were compared with a group of 1000 contemporaneous randomly selected unscreened and untreated couples undergoing assisted conception, from which 103 matched control couples were derived. The primary outcome measure was live birth incidence. Secondary outcomes were results following embryo transfer (ET) and live birth outcome by gender and M2 carriage, and allelic dose influence. FINDINGS: The tested and treated cohort of ANXA5 M2 carriers achieved a similar live birth rate (37.9%) per ET cycle compared to both the more fertile comparison group (38.5%), and to the 103 matched controls (33.0%). Significantly more treated male carrier only couples had a live birth versus female M2 only (47.7% vs. 25.0% p=0.045). INTERPRETATION: Pragmatic ANXA5 M5 screening and treatment with LMWH in couples undergoing IVF is associated with similar outcome to couples with more favorable prognostic factors. The difference in live birth outcome for treated male only carrier couples may be consistent with an additional maternal thrombophilic factor that may adversely affect pregnancy, although other mechanisms are possible. This study suggests that LMWH treatment should be started prior to clinical pregnancy.