Time-lapse systems for embryo incubation and assessment in assisted reproduction.

BACKGROUND: Embryo incubation and assessment is a vital step in assisted reproductive technology (ART). Traditionally, embryo assessment has been achieved by removing embryos from a conventional incubator daily for quality assessment by an embryologist, under a microscope. In recent years time-lapse systems (TLS) have been developed which can take digital images of embryos at frequent time intervals. This allows embryologists, with or without the assistance of embryo selection software, to assess the quality of the embryos without physically removing them from the incubator.The potential advantages of a TLS include the ability to maintain a stable culture environment, therefore limiting the exposure of embryos to changes in gas composition, temperature, and movement. A TLS has the potential advantage of improving embryo selection for ART treatment by utilising additional information gained through continuously monitoring embryo development. Use of a TLS often adds significant extra cost to ART treatment.
OBJECTIVES: To determine the effect of a TLS compared to conventional embryo incubation and assessment on clinical outcomes in couples undergoing ART. SEARCH
METHODS: We used standard methodology recommended by Cochrane. We searched the Cochrane Gynaecology and Fertility (CGF) Group Trials Register, CENTRAL, MEDLINE, Embase, CINAHL, and two trials registers on 7 January 2019 and checked references of appropriate papers. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing TLS, with or without embryo selection software, versus conventional incubation with morphological assessment; and TLS with embryo selection software versus TLS without embryo selection software among couples undergoing ART. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by Cochrane. The primary review outcomes were live birth or ongoing pregnancy, miscarriage and stillbirth, and cumulative live birth or ongoing pregnancy rate. The secondary outcomes were clinical pregnancy and cumulative clinical pregnancy. We assessed the quality of the evidence using GRADE methodology. We made the following comparisons.TLS with conventional morphological assessment of still TLS images versus conventional incubation and assessmentTLS utilising embryo selection software versus TLS with conventional morphological assessment of still TLS images TLS utilising embryo selection software versus conventional incubation and assessment MAIN
RESULTS: We included nine RCTs (N = 2955 infertile couples). The quality of the evidence ranged from very low to low. The main limitations were high risk of bias in the included studies, imprecision, indirectness, and inconsistency. There were no data on cumulative live birth or ongoing pregnancy rate or cumulative clinical pregnancy rate.TLS with conventional morphological assessment of still TLS images versus conventional incubation and assessmentIt is unclear whether there is any difference between interventions in rates of live birth or ongoing pregnancy (odds ratio (OR) 0.91, 95% confidence interval (CI) 0.67 to 1.23, 3 RCTs, N = 826, I2 = 33%, low-quality evidence) or in miscarriage rates (OR 1.90, 95% CI 0.99 to 3.61, 3 RCTs, N = 826, I2 = 0%, low-quality evidence). The evidence suggests that if the rate of live birth or ongoing pregnancy associated with conventional incubation and assessment is 35%, the rate with the use of TLS with conventional morphological assessment of still TLS images would be between 27% and 40%, and if the miscarriage rate with conventional incubation is 4%, the rate associated with conventional morphological assessment of still TLS images would be between 4% and 14%. It is unclear whether there is a difference between the interventions in rates of stillbirth (OR 1.00, 95% CI 0.13 to 7.49, 1 RCT, N = 76, low-quality evidence) or clinical pregnancy (OR 1.06, 95% CI 0.79 to 1.41, 4 RCTs, N = 875, I2 = 0%, low-quality evidence).TLS utilising embryo selection software versus TLS with conventional morphological assessment of still TLS imagesAll findings for this comparison were very uncertain due to the very low-quality of the evidence. No data were available on live birth, but one RCT reported ongoing pregnancy. It is unclear whether there is any difference between the interventions in rates of ongoing pregnancy (OR 0.61, 95% CI 0.32 to 1.20, 1 RCT, N = 163); miscarriage (OR 1.39, 95% CI 0.64 to 3.01, 2 RCTs, N = 463, I2 = 0%); or clinical pregnancy (OR 0.97, 95% CI 0.67 to 1.42, 2 RCTs, N = 463, I2 = 0%). The evidence suggests that if the rate of ongoing pregnancy associated with TLS with conventional morphological assessment of still TLS images is 47%, the rate associated with TLS utilising embryo selection software would be between 22% and 52%, and if the miscarriage rate associated with conventional morphological assessment of still TLS images is 5%, the rate associated with TLS utilising embryo selection software would be between 4% and 15%. No studies reported stillbirth.TLS utilising embryo selection software versus conventional incubation and assessmentThe findings for this comparison were also very uncertain due to the very low quality of the evidence. It is unclear whether there is any difference between the interventions in rates of live birth (OR 1.12, 95% CI 0.92 to 1.36, 3 RCTs, N = 1617, I2 = 84%). There was very low-quality evidence that TLS might reduce miscarriage rates (OR 0.63, 95% CI 0.45 to 0.89, 3 RCTs, N = 1617, I2 = 0%). It is unclear whether there is any difference between the interventions in rates of clinical pregnancy (OR 0.95, 95% CI 0.78 to 1.16, 3 RCTs, N = 1617, I2 = 89%). The evidence suggests that if the rate of live birth associated with conventional incubation and assessment is 48%, the rate with TLS utilising embryo selection software would be between 46% and 55%, and if the miscarriage rate with conventional incubation and assessment is 11%, the rate associated with TLS would be between 5% and 10%. No stillbirths occurred in the only study reporting this outcome. AUTHORS'
CONCLUSIONS: There is insufficient good-quality evidence of differences in live birth or ongoing pregnancy, miscarriage and stillbirth, or clinical pregnancy to choose between TLS, with or without embryo selection software, and conventional incubation. As the evidence is of low or very low-quality, our findings should be interpreted with caution.