Noninvasive metabolomic profiling of embryo culture media using Raman and near-infrared spectroscopy correlates with reproductive potential of embryos in women undergoing in vitro fertilization

Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520-8063, USA.
Fertility and sterility (Impact Factor: 4.59). 12/2007; 88(5):1350-7. DOI: 10.1016/j.fertnstert.2007.07.1390
Source: PubMed


To determine if metabolomic profiling of embryo culture media correlates with reproductive potential of individual embryos.
Prospective study.
An academic and a private assisted reproduction program; a university research center.
Women undergoing assisted reproduction treatment.
Sixty-nine spent media samples from 30 patients with known outcome (0 or 100% sustained implantation rates) were individually collected after embryo transfer on day 3 and were evaluated using Raman and/or near-infrared spectroscopy. The spectra obtained from each instrument were separately analyzed using a wavelength selective genetic algorithm to determine regions predictive of pregnancy outcome. Viability indices reflective of reproductive potential were calculated for each sample. To avoid random correlations, a leave-one-out cross-validation was used. Sensitivity and specificity of predicting viability (described as implantation and delivery) were calculated.
Metabolomic profile of culture media and embryo viability.
Viability indices calculated by Raman or near-infrared spectroscopy were higher for embryos that implanted and resulted in a delivery, compared with those that failed to implant. Raman spectroscopy predicted viability of individual embryos with a sensitivity of 86% and a specificity of 76.5%; near-infrared provided a sensitivity of 75% and a specificity of 83.3%.
Rapid, noninvasive metabolomic profiling of human embryo culture media using Raman or near-infrared spectroscopy combined with bioinformatics correlates with pregnancy outcome.

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    • "The purpose is to derive a unified measure discriminating between viable and non-viable embryos (Ahlström et al., 2011). The advantages of NIR include that measurements can be made directly on even small sample volumes (<15 μl), with no requirements for sample preparation and with results being available within 1 minute per sample (Seli et al., 2007). This is in contrast to other spectroscopic platforms, such as Raman and nuclear magnetic resonance (NMR) spectroscopy, characterized by expensive and complicated equipment, low sensitivity, lengthy and extensive sample processing, or the need for complex statistical analysis for interpretation of results making them impractical in clinical settings (Rinaudo et al., 2012; Seli et al., 2010). "
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    ABSTRACT: Although IVF has been performed routinely for many years to help couples with fertility problems and in relation to modern breeding of farm animals, pregnancy rates after transfer to a recipient have not improved during the last decade. Early prediction of the viability of in-vitro developed embryos before the transfer to a recipient still remains challenging. Presently, the predominant non-invasive technique for selecting viable embryos is based on morphology, where parameters such as rates of cleavage and blastocyst formation as well as developmental kinetics are evaluated mostly subjectively. The simple morphological approach is, however, inadequate for the prediction of embryo quality, and several studies have focused on developing new non-invasive methods using molecular approaches based particularly on proteomics, metabolomics and most recently small non-coding RNA, including microRNA. This review outlines the potential of several non-invasive in-vitro methods based on analysis of spent embryo culture medium.
    Reproductive biomedicine online 09/2015; DOI:10.1016/j.rbmo.2015.08.003 · 3.02 Impact Factor
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    • "Recently, a new technology has been applied to the study of embryo metabolism, namely metabolomics (Hollywood et al. 2006; Brison et al. 2007; Seli et al. 2007). Metabolomics, a new member of the '-omics' family, offers the ability to measure physiology and, as such, links genotype with phenotype (Tachibana 2014). "
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    ABSTRACT: The advent of metabolomics technology and its application to small samples has allowed us to non-invasively monitor the metabolic activity of embryos in a complex culture environment. The aim of this study was to apply metabolomics technology to the analysis of individual embryos from several species during in vitro development to gain an insight into the metabolomics pathways used by embryos and their relationship with embryo quality. Alanine is produced by both in vivo- and in vitro-derived human, murine, bovine and porcine embryos. Glutamine is also produced by the embryos of these four species, but only those produced in vitro. Across species, blastocysts significantly consumed amino acids from the culture medium, whereas glucose was not significantly taken up. There are significant differences in the metabolic profile of in vivo- compared with in vitro-produced embryos at the blastocyst stage. For example, in vitro-produced murine embryos consume arginine, asparagine, glutamate and proline, whereas in vivo-produced embryos do not. Human embryos produce more alanine, glutamate and glutamine, and consume less pyruvate, at the blastocyst compared with cleavage stages. Glucose was consumed by human blastocysts, but not at a high enough level to reach significance. Consumption of tyrosine by cleavage stage human embryos is indicative of blastocyst development, although tyrosine consumption is not predictive of blastocyst quality. Similarly, although in vivo-produced murine blastocysts consumed less aspartate, lactate, taurine and tyrosine than those produced in vitro, consumption of these four amino acids by in vitro-derived embryos with high octamer-binding transcription factor 4 (Oct4) expression, indicative of high quality, did not differ from those with low Oct4 expression. Further application of metabolomic technologies to studies of the consumption and/or production of metabolites from individual embryos in a complete culture medium could transform our understanding of embryo physiology and improve our ability to produce developmentally competent embryos in vitro.
    Reproduction Fertility and Development 03/2015; 27(4). DOI:10.1071/RD14359 · 2.40 Impact Factor
    • "One of the core approaches of nontargeted metabolomics is metabolic fingerprinting (MF), which considers the whole metabolic profile as a pattern that can be used for sample classification. In human in vitro fertilization (IVF), after analyzing CM by Raman and near-infrared spectroscopy (NIR) as spectroscopy approaches , the MF obtained predicted viability in oocytes and embryos (Seli et al., 2007; Scott et al., 2008). This shows that IVP embryos bearing a high reproductive potential modify their CM differently compared with embryos that do not lead to pregnancy, although the use of NIR did not lead to increased pregnancy rates in randomized prospective trials (Hardarson et al., 2012). "
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    ABSTRACT: We analyzed embryo culture medium (CM) and recipient blood plasma using Fourier transform infrared (FTIR) metabolomics to predict pregnancy outcome. Individually cultured, in vitro-produced (IVP) blastocysts were transferred to recipients as fresh and vitrified-warmed. Spent CM and plasma samples were evaluated using FTIR. The discrimination capability of the classifiers was assessed for accuracy, sensitivity (pregnancy), specificity (nonpregnancy), and area under the receiver operator characteristic curve (AUC). Within all IVP fresh embryos (birth rate = 52%), high AUC were obtained at birth, especially with expanded blastocysts (CM: 0.80 ± 0.053; plasma: 0.89 ± 0.034). The AUC of vitrified IVP embryos (birth rate = 31%) were 0.607 ± 0.038 (CM, expanded blastocysts) and 0.672 ± 0.023 (plasma, all stages). Recipient plasma generally predicted pregnancy outcome better than did embryo CM. Embryos and recipients with improved pregnancy viability were identified, which could increase the economic benefit to the breeding industry.
    Journal of Dairy Science 07/2014; 97(9). DOI:10.3168/jds.2014-8067 · 2.57 Impact Factor
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