Abstract: We included four trials with a total of 924 women, with a mean age of 33 years. All assessed the role of metabolomic investigation of embryo viability. We found no RCTs that addressed the metabolomic assessment of oocyte quality or endometrial receptivity. We found low-quality evidence of little or no difference between metabolomic and non-metabolomic assessment of embryos for rates of live birth or ongoing pregnancy (OR 1.02, 95% CI 0.77 to 1.35, I² = 0%; four RCTs; N = 924), live birth alone (OR 0.99, 95% CI 0.69 to 1.44, I² = 0%; three RCTs; N = 597), or miscarriage (OR 1.18, 95% CI 0.77 to 1.82; I² = 0%; three RCTs; N = 869). A sensitivity analysis excluding studies at high risk of bias did not change the interpretation of the results for live birth or ongoing pregnancy (OR 0.90, 95% CI 0.66 to 1.25, I² = 0%; two RCTs; N = 744). Our findings suggested that if the rate of live birth or ongoing pregnancy was 36% in the non-metabolomic group, it would be between 32% and 45% with the use of metabolomics. We found low-quality evidence of little or no difference between groups in rates of clinical pregnancy (OR 1.11, 95% CI 0.85 to 1.45; I²= 44%; four trials; N = 924) or multiple pregnancy (OR 1.50, 95% CI 0.70 to 3.19; I² = 0%; two RCTs, N = 180). Rates of cycle cancellation were higher in the metabolomics group (OR 1.78, 95% CI 1.18 to 2.69; I² = 51%; two RCTs; N = 744, low quality evidence). There was very low-quality evidence of little or no difference between groups in rates of ectopic pregnancy rates (OR 3.00, 95% CI 0.12 to 74.07; one RCT; N = 417), and foetal abnormality (no events; one RCT; N = 125). Data were lacking on other adverse effects. A sensitivity analysis excluding studies at high risk of bias did not change the interpretation of the results for clinical pregnancy (OR 1.03, 95% CI 0.76 to 1.38; I² = 40%; two RCTs; N = 744). The overall quality of the evidence ranged from very low to low. Limitations included serious risk of bias (associated with poor reporting of methods, attrition bias, selective reporting, and other biases), imprecision, and inconsistency across trials. According to current trials in women undergoing ART, there is no evidence to show that metabolomic assessment of embryos before implantation has any meaningful effect on rates of live birth, ongoing pregnancy, miscarriage, multiple pregnancy, ectopic pregnancy or foetal abnormalities. The existing evidence varied from very low to low-quality. Data on other adverse events were sparse, so we could not reach conclusions on these. At the moment, there is no evidence to support or refute the use of this technique for subfertile women undergoing ART. Robust evidence is needed from further RCTs, which study the effects on live birth and miscarriage rates for the metabolomic assessment of embryo viability. Well designed and executed trials are also needed to study the effects on oocyte quality and endometrial receptivity, since none are currently available.

Plain-language summary: We found four randomised controlled trials, with a total of 924 women, that compared metabolomic profile assessment with morphology assessment of embryos. The women were an average age of 33 years old. All studies were conducted between 2011 and 2013; length of follow-up was not specified in any of them. The evidence is current to 26 Feburary 2018. One study was supported by an unconditional grant from a biotechnology company (Molecular Biometrics Inc.). The very low conditional superiority for the primary outcome and premature termination of the trial were potentially associated with the funder's interest in the results. One study received funding from a national health organisation, but the equipment was provided by Molecular Biometrics Inc., one was self-funded, while the source of funding was not stated in the fourth study. We found low-quality evidence of no meaningful difference between the intervention and control groups in rates of live birth, ongoing pregnancy, miscarriage, or clinical pregnancy, and multiple pregnancy. We found very low-quality evidence of no meaningful difference between the groups for ectopic pregnancy, and low-quality evidence that cancellation rates were higher in the intervention group. Our findings suggest that if the rate of live birth or ongoing pregnancy was 36% in the non-metabolomic group, it would be between 32% and 45% with the use of metabolomics. Data were lacking on other adverse effects. No properly designed studies reported metabolomic assessment of oocyte quality or endometrium receptivity. The overall quality of evidence ranged from low to very low. Limitations included serious risk of bias (associated with poor reporting of methods, attrition bias, selective reporting and other bias), imprecision, and inconsistency across trials.