Metabolomics as a tool to identify biomarkers to predict and improve outcomes in reproductive medicine: a systematic review

BACKGROUND: Infertility is a complex disorder with significant medical, psychological and financial consequences for patients. With live-birth rates per cycle below 30% and a drive from the Human Fertilisation and Embryology Authority (HFEA) to encourage single embryo transfer, there is significant research in different areas aiming to improve success rates of fertility treatments. One such area is investigating the causes of infertility at a molecular level, and metabolomics techniques provide a platform for studying relevant biofluids in the reproductive tract. OBJECTIVE AND RATIONALE: The aim of this systematic review is to examine the recent findings for the potential application of metabolomics to female reproduction, specifically to the metabolomics of follicular fluid (FF), embryo culture medium (ECM) and endometrial fluid. To our knowledge no other systematic review has investigated this topic. SEARCH METHODS: English peer-reviewed journals on PubMed, Science Direct, SciFinder, were systematically searched for studies investigating metabolomics and the female reproductive tract with no time restriction set for publications. Studies were assessed for quality using the risk of bias assessment and ROBIN-I. OUTCOMES: There were 21 studies that met the inclusion criteria and were included in the systematic review. Metabolomic studies have been employed for the compositional analysis of various biofluids in the female reproductive tract, including FF, ECM, blastocoele fluid and endometrial fluid. There is some weak evidence that metabolomics technologies studying ECM might be able to predict the viability of individual embryos and implantation rate better than standard embryo morphology, However these data were not supported by randomized the controlled trials (RCTs) which showed no evidence that using metabolomics is able to improve the most important reproductive outcomes, such as clinical pregnancy and live-birth rates. This systematic review provides guidance for future metabolomic studies on biofluids of the female reproductive tract, with a summary of the current findings, promise and pitfalls in metabolomic techniques. The approaches discussed can be adapted by other metabolomic studies. WIDER IMPLICATIONS: A range of sophisticated modern metabolomic techniques are now more widely available and have been applied to the analysis of the female reproductive tract. However, this review has revealed the paucity of metabolomic studies in the field of fertility and the inconsistencies of findings between different studies, as well as a lack of research examining the metabolic effects of various gynecological diseases. By incorporating metabolomic technology into an increased number of well designed studies, a much greater understanding of infertility at a molecular level could be achieved. However, there is currently no evidence for the use of metabolomics in clinical practice to improve fertility outcomes.