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Meta-Analysis
. 2017 May 23;5(5):CD011872.
doi: 10.1002/14651858.CD011872.pub2.

Metabolomics for improving pregnancy outcomes in women undergoing assisted reproductive technologies

Charalampos S Siristatidis  1 , Eleni Sertedaki  2 , Dennis Vaidakis  3
Affiliations
Meta-Analysis

Metabolomics for improving pregnancy outcomes in women undergoing assisted reproductive technologies

Charalampos S Siristatidis et al. Cochrane Database Syst Rev. .

Update in

Abstract

Background: In order to overcome the low effectiveness of assisted reproductive technologies (ART) and the high incidence of multiple births, metabolomics is proposed as a non-invasive method to assess oocyte quality, embryo viability, and endometrial receptivity, and facilitate a targeted subfertility treatment.

Objectives: To evaluate the effectiveness and safety of metabolomic assessment of oocyte quality, embryo viability, and endometrial receptivity for improving live birth or ongoing pregnancy rates in women undergoing ART, compared to conventional methods of assessment.

Search methods: We searched the Cochrane Gynaecology and Fertility Group Trials Register, CENTRAL, MEDLINE, Embase, CINAHL and two trial registers (November 2016). We also examined the reference lists of primary studies and review articles, citation lists of relevant publications, and abstracts of major scientific meetings.

Selection criteria: Randomised controlled trials (RCTs) on metabolomic assessment of oocyte quality, embryo viability, and endometrial receptivity in women undergoing ART.

Data collection and analysis: Two review authors independently assessed trial eligibility and risk of bias, and extracted the data. The primary outcomes were rates of live birth or ongoing pregnancy (composite outcome) and miscarriage. Secondary outcomes were clinical pregnancy, multiple and ectopic pregnancy, cycle cancellation, and foetal abnormalities. We combined data to calculate odds ratios (ORs) for dichotomous data and 95% confidence intervals (CIs). Statistical heterogeneity was assessed using the I² statistic. We assessed the overall quality of the evidence for the main comparisons using GRADE methods.

Main results: We included four trials with a total of 802 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 1.11, 95% CI 0.83 to 1.48; I² = 0%; four RCTs; N = 802), or miscarriage (OR 0.96, 95% CI 0.52 to 1.78; I² = 0%; two RCTs; N = 434). 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 0.99, 95% CI 0.71 to 1.38; I² = 0%; two RCTs; N = 621). 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 1.22, 95% CI 0.92 to 1.62; I²= 26%; four trials; N = 802), or multiple pregnancy (OR 1.52, 95% CI 0.71 to 3.23; I² = 0%; two RCTs, N = 181). There was very low-quality evidence of little or no difference between groups in ectopic pregnancy rates (OR 3.37, 95% CI 0.14 to 83.40; one RCT; N = 309), and foetal abnormalities (no events; one RCT; N = 125), and very low-quality evidence of higher rates of cycle cancellation in the metabolomics group (OR 1.78, 95% CI 1.18 to 2.69; I² = 51%; two RCTs; N = 744). 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 1.14, 95% CI 0.83 to 1.57; I² = 0%; two RCTs; N = 621).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.

Authors' conclusions: According to current trials in women undergoing ART, there is insufficient evidence to show that metabolomic assessment of embryos before implantation has any meaningful effect on rates of live birth, ongoing pregnancy, or miscarriage rates. The existing evidence varied from very low to low-quality. Data on 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.

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Conflict of interest statement

None of the authors have any conflicts of interest to disclose.

Figures

Figure 1
Figure 1
Study flow diagram.
Figure 2
Figure 2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies
Figure 3
Figure 3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study
Figure 4
Figure 4
Forest plot of comparison: 1 Metabolomic profile vs standard or none, outcome: 1.1 Effectiveness: live birth or ongoing pregnancy
Figure 5
Figure 5
Forest plot of comparison: 1 Metabolomic profile vs standard or none, outcome: 1.2 Adverse event: miscarriage
Figure 6
Figure 6
Forest plot of comparison: 1 Metabolomic profile vs standard or none, outcome: 1.3 Effectivenes: clinical pregnancy
Analysis 1.1
Analysis 1.1
Comparison 1 Metabolomic profile vs standard, Outcome 1 Live birth or ongoing pregnancy.
Analysis 1.2
Analysis 1.2
Comparison 1 Metabolomic profile vs standard, Outcome 2 Miscarriage.
Analysis 1.3
Analysis 1.3
Comparison 1 Metabolomic profile vs standard, Outcome 3 Clinical pregnancy.
Analysis 1.4
Analysis 1.4
Comparison 1 Metabolomic profile vs standard, Outcome 4 Cancellation.
Analysis 1.5
Analysis 1.5
Comparison 1 Metabolomic profile vs standard, Outcome 5 Multiple pregnancy.
Analysis 1.6
Analysis 1.6
Comparison 1 Metabolomic profile vs standard, Outcome 6 Ectopic pregnancy.
See this image and copyright information in PMC

References

References to studies included in this review

    1. Economou K, Davies S, Argyrou M, Doriza S, Sisi P, Moschopoulou M, et al. Selection of embryos with the best reproductive potential according to their metabolomics profile using near infrared spectroscopy: a prospective randomized study. Human Reproduction 2011;26(Suppl 1):i1‐i353.
    1. Hardarson T, Ahlström A, Rogberg L, Botros L, Hillensjö T, Westlander G, et al. Non‐invasive metabolomic profiling of Day 2 and 5 embryo culture medium: a prospective randomized trial. Human Reproduction 2012;27(1):89‐96. [DOI: 10.1093/humrep/der373] - DOI - PubMed
    1. Sfontouris IA, Lainas GT, Sakkas D, Zorzovilis IZ, Petsas GK, Lainas TG. Non‐invasive metabolomic analysis using a commercial NIR instrument for embryo selection. Journal of Human Reproductive Sciences 2013;6(2):133‐9. [DOI: 10.4103/0974-1208.117174] - DOI - PMC - PubMed
    1. Vergouw CG, Kieslinger DC, Kostelijk EH, Botros LL, Schats R, Hompes PG, et al. Day 3 embryo selection by metabolomic profiling of culture medium with near‐infrared spectroscopy as an adjunct to morphology: a randomized controlled trial. Human Reproduction 2012;27(8):2304‐11. [DOI: 10.1093/humrep/des175] - DOI - PubMed

References to studies excluded from this review

    1. Ahlström A, Wikland M, Rogberg L, Barnett JS, Tucker M, Hardarson T. Cross‐validation and predictive value of near‐infrared spectroscopy algorithms for day‐5 blastocyst transfer. Reproductive Biomedicine Online 2011;22(5):477‐84. [DOI: 10.1016/j.rbmo.2011.01.009] - DOI - PubMed
    1. Bellver J, Santos MJ, Alamá P, Castelló D, Privitera L, Galliano D, et al. Day 3 embryo metabolomics in the spent culture media is altered in obese women undergoing in vitro fertilization. Fertility and Sterility 2015;103(6):1407‐15.e1. [DOI: 10.1016/j.fertnstert.2015.03.015] - DOI - PubMed
    1. Ciepiela P, Bączkowski T, Drozd A, Kazienko A, Stachowska E, Kurzawa R. Arachidonic and linoleic acid derivatives impact oocyte ICSI fertilization — a prospective analysis of follicular fluid and a matched oocyte in a 'one follicle — one retrieved oocyte — one resulting embryo' investigational setting. PLos One 2015;10(3):e0119087. [doi: 10.1371/journal.pone.0119087. eCollection 2015] - PMC - PubMed
    1. Cordeiro FB, Cataldi TR, Perkel KJ, do Vale Teixeira da Costa L, Rochetti RC, Stevanato J, et al. Lipidomics analysis of follicular fluid by ESI‐MS reveals potential biomarkers for ovarian endometriosis. Journal of Assisted Reproduction and Genetics 2015;32(12):1817‐25. [DOI: 10.1007/s10815-015-0592-1] - DOI - PMC - PubMed
    1. Santos MJ, Gámiz P, Santos JM, Romero JL, Prados N, Alonso C, et al. The metabolomic profile of spent culture media from day 3 human embryos cultured under low oxygen Tension. PLoS One 2015;10(11):e0142724. [DOI: 10.1371/journal.pone.0142724] - DOI - PMC - PubMed

References to ongoing studies

    1. NCT02698488. Embryo selection by metabolomic profiling of embryo culture medium with mass spectroscopy as an adjunct to morphology. clinicaltrials.gov/show/NCT02698488 (first received 29 February 2016).

Additional references

    1. Allen J, Davey HM, Broadhurst D, Heald JK, Rowland JJ, Oliver SG, et al. High‐throughput classification of yeast mutants for functional genomics using metabolic footprinting. Nature Biotechnology 2003;21(6):692–6. [DOI: 10.1038/nbt823] - DOI - PubMed
    1. Altmäe S, Esteban FJ, Stavreus‐Evers A, Simón C, Giudice L, Lessey BA, et al. Guidelines for the design, analysis and interpretation of 'omics' data: focus on human endometrium. Human Reproduction Update 2014;20(1):12‐28. [DOI: 10.1093/humupd/dmt048] - DOI - PMC - PubMed
    1. Armstrong S, Arroll N, Cree LM, Jordan V, Farquhar C. Time‐lapse systems for embryo incubation and assessment in assisted reproduction. Cochrane Database of Systematic Reviews 2015, Issue 2. [DOI: 10.1002/14651858.CD011320.pub2] - DOI - PubMed
    1. Baczkowski T, Kurzawa R, Głabowski W. Methods of embryo scoring in in vitro fertilization. Reproductive Biology 2004;4(1):5‐22. [PUBMED: 15094792] - PubMed
    1. Botros L, Sakkas D, Seli E. Metabolomics and its application for non‐invasive embryo assessment in IVF. Molecular Human Reproduction 2008;14(12):679–90. [DOI: 10.1093/molehr/gan066] - DOI - PMC - PubMed

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