Maternal urinary metabolic signatures of fetal growth and associated clinical and environmental factors in the INMA study

Abstract

BackgroundMaternal metabolism during pregnancy is a major determinant of the intra-uterine environment and fetal outcomes. Herein, we characterize the maternal urinary metabolome throughout pregnancy to identify maternal metabolic signatures of fetal growth in two subcohorts and explain potential sources of variation in metabolic profiles based on lifestyle and clinical data.MethodsWe used 1H nuclear magnetic resonance (NMR) spectroscopy to characterize maternal urine samples collected in the INMA birth cohort at the first (n = 412 and n = 394, respectively, in Gipuzkoa and Sabadell cohorts) and third trimesters of gestation (n = 417 and 469). Metabolic phenotypes that reflected longitudinal intra- and inter-individual variation were used to predict measures of fetal growth and birth weight.ResultsA metabolic shift between the first and third trimesters of gestation was characterized by 1H NMR signals arising predominantly from steroid by-products. We identified 10 significant and reproducible metabolic associations in the third trimester with estimated fetal, birth, and placental weight in two independent subcohorts. These included branched-chain amino acids; isoleucine, valine, leucine, alanine and 3 hydroxyisobutyrate (metabolite of valine), which were associated with a significant fetal weight increase at week 34 of up to 2.4 % in Gipuzkoa (P < 0.005) and 1 % in Sabadell (P < 0.05). Other metabolites included pregnancy-related hormone by-products of estrogens and progesterone, and the methyl donor choline. We could explain a total of 48–53 % of the total variance in birth weight of which urine metabolites had an independent predictive power of 12 % adjusting for all other lifestyle/clinical factors. First trimester metabolic phenotypes could not predict reproducibly weight at later stages of development. Physical activity, as well as other modifiable lifestyle/clinical factors, such as coffee consumption, vitamin D intake, and smoking, were identified as potential sources of metabolic variation during pregnancy.ConclusionsSignificant reproducible maternal urinary metabolic signatures of fetal growth and birth weight are identified for the first time and linked to modifiable lifestyle factors. This novel approach to prenatal screening, combining multiple risk factors, present a great opportunity to personalize pregnancy management and reduce newborn disease risk in later life.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-016-0706-3) contains supplementary material, which is available to authorized users.

Maternal metabolites during pregnancy are associated with newborn outcomes and hyperinsulinaemia across ancestries

“…Few existing studies have investigated associations between maternal pregnancy metabolites and newborn size [9,10] and none have examined maternal metabolite profiles post glucose load or evaluated the relationship between maternal metabolites and newborn adiposity or cord C-peptide. A Spanish cohort of 800 mother-newborn pairs related maternal urinary metabolites during pregnancy with fetal and newborn size and similarly found that maternal urinary BCAAs, alanine, steroid hormones and choline were associated with greater intrauterine fetal growth and birthweight [9]. In a Polish cohort, mothers with lower lipid metabolites and higher adipocyte fatty acid-binding protein at 12-14 weeks of gestation had infants with larger birthweights, hypothesised to be due to greater mother-fetus transport of lipids [10].…”

“…In adults, branched-chain amino acids (BCAAs), aromatic amino acids (AAAs), short-chain acylcarnitines (C2, C6, C8; see ESM Table 1 for acylcarnitine nomenclature) and the carnitine ester of 3-hydroxybutyrate (acylcarnitine C4-OH) have all been associated with insulin resistance, higher HbA 1c and/or postprandial glucose levels [5][6][7][8]. However, the impact of the maternal metabolome on the developing fetus, as evidenced by newborn outcomes, is largely unknown and understudied [9,10].…”

Associations of cord blood metabolites with perinatal characteristics, newborn anthropometry, and cord blood hormones in project viva

“…Accordingly, metabolomics analyses of cord blood may improve assessment of neonatal metabolic status beyond current knowledge of the implications of newborn size, and possibly may enhance assessment of future metabolic disease risk. To date, the literature includes only a few case-control studies comparing cord blood metabolite profiles of SGA (15) low birthweight (16), and very low birthweight (17–19) newborn vs. their AGA or normal birthweight counterparts, as well as a few studies exploring associations of maternal urinary metabolites and with fetal growth restriction (20, 21). In general, these analyses revealed associations of low birthweight and poor fetal growth with alterations in amino acid and lipid metabolites (15, 16, 18, 19) indicative of impaired nutrient transfer to the fetus during development, as well as compounds on energy and polyamine metabolism pathways (17) that are upregulated during period of rapid cell turnover.…”

A Scoping Review on the Characteristics of Human Exposome Studies

“…Approximately a third of the retained exposome studies had a prospective longitudinal design (n = 30, 37%), of which 26 were based on nine large population-based cohorts; the rest four longitudinal studies were relatively small in size, including between 6 and 378 subjects [46][47][48][49]. Out of the 26 studies, eleven were published as part of the Human Early-Life Exposome (HELIX) project using data from six European birth cohorts ( [50][51][52][53][54][55][56]), and among these studies, four belonged to the Spanish INMA (INfancia y Medio Ambiente) [57][58][59][60][61]. Four studies (of the 26) were published as part of the Avon Longitudinal Study of Parents and Children (ALSPAC), a 20-year population-based cohort designed to determine the influence of environmental (physical and psychological) and genetic factors on the health status and development of the offspring.…”