Metabolomic signatures associated with fetal growth restriction and small for gestational age: a systematic review

Abstract

The pathways involved in the pathophysiology of fetal growth restriction (FGR) and small for gestational age (SGA) are incompletely understood. We conduct a systematic review to identify metabolomic signatures in maternal and newborn tissues and body fluids samples associated with FGR/SGA. Here, we report that 825 non-duplicated metabolites were significantly altered across the 48 included studies using 10 different human biological samples, of which only 56 (17 amino acids, 12 acylcarnitines, 11 glycerophosphocholines, six fatty acids, two hydroxy acids, and eight other metabolites) were significantly and consistently up- or down-regulated in more than one study. Three amino acid metabolism-related pathways and one related with lipid metabolism are significantly associated with FGR and/or SGA: biosynthesis of unsaturated fatty acids in umbilical cord blood, and phenylalanine, tyrosine and tryptophan biosynthesis, valine, leucine and isoleucine biosynthesis, and phenylalanine metabolism in newborn dried blood spot. Significantly enriched metabolic pathways were not identified in the remaining biological samples. Whether these metabolites are in the causal pathways or are biomarkers of fetal nutritional deficiency needs to be explored in large, well-phenotyped cohorts.

Fig. 1. PRISMA flow diagram.

This figure illustrates the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow diagram detailing the study selection process. The diagram includes the number of records identified, screened, assessed for eligibility, and included in the systematic review. FGR fetal growth restriction; SGA small for gestational age. Source: Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372:n71. doi: 10.1136/bmj.n71. For more information, visit: https://www.prismastatement.org/prisma-2020-flow-diagram.

Fig. 2. Pathway analysis for significantly and consistently up- and down-regulated metabolites (N = 24) that were reported in more than one study in umbilical cord blood samples.

The metabolome view shows all matched pathways according to the p values from the pathway enrichment analysis and pathway impact values from the pathway topology analysis. Each circle in the figure represents a metabolic pathway. The colour of the circle indicates the significance level (Raw p) in the enrichment analysis; darker colour (redder) indicates greater significance. The size of the circle reflects the pathway impact value in the topology analysis, such that the larger the circle, the larger the impact value. Only the biosynthesis of unsaturated fatty acids was found to be significantly enriched in adjusted analyses (false discovery rate p value < 0.05). FDR false discovery rate. Source data are provided as a Source Data file.

Fig. 3. Pathway analysis for significantly and consistently up- and down-regulated metabolites (N = 18) that were reported in more than one study in newborn dried blood spot samples.

The metabolome view shows all matched pathways according to the p values from the pathway enrichment analysis and pathway impact values from the pathway topology analysis. Each circle in the figure represents a metabolic pathway. The colour of the circle indicates the significance level (Raw p) in the enrichment analysis; darker colour (redder) indicates greater significance. The size of the circle reflects the pathway impact value in the topology analysis, such that the larger the circle, the larger the impact value. Three metabolic pathways were found to be significantly enriched in adjusted analyses (false discovery rate p value < 0.05): phenylalanine, tyrosine and tryptophan biosynthesis; valine, leucine and isoleucine biosynthesis; and phenylalanine metabolism. FDR false discovery rate. Source data are provided as a Source Data file.