Metabonomic and epidemiological analyses of maternal parameters and exposures during pregnancy and their influence on fetal growth amongst the INMA birth cohort
Creators: name: Maitre, Léa
Publisher: name: Imperial College London
Year: 2016

description: Fetal growth aberrations, including fetal growth restriction (FGR) and macrosomia, convey the highest risk of perinatal mortality and morbidity, as well as increasing the chance of developing chronic disease in later life. Using Metabolic profiling/metabolomics approaches in maternal urine samples collected in a prospective mother-child cohort can provide information on the early-life exposome and can be linked to child health outcomes as well as potentially identify new biomarkers of exposure. The aims of this PhD were to characterise intra and inter-individual variations in maternal urine profiles during pregnancy, predict fetal growth outcomes and identify environmental sources of metabolic variations. We applied an exploratory metabolic profiling approach using 1H nuclear magnetic resonance (NMR) spectroscopy to maternal urine samples at the first (n=806) and third trimesters of gestation (n=886), collected as part of the Infancia y Medio Ambiente (INMA)–Environment and Childhood Study, a large prospective mother-child population-based cohort study cohorts based in eight Spanish cities. An exploratory metabolomics approach was applied using 1H nuclear magnetic resonance (NMR) spectroscopy for profiling and LC-MS/MS for metabolite identification. Metabolites were used to predict longitudinal measures of fetal growth in terms of body weight and head size (estimated at 12th, 20th and 34th gestational weeks and at birth) and placental weight at birth using linear regression adjusting for main confounding factors. To our knowledge the present study represents the largest human investigation (n &gt;800) in which non-targeted proton nuclear magnetic resonance spectroscopy has been used to understand the progression of normal fetal growth in two different Spanish populations. We identified 10 reproducible metabolic associations at week 34 with estimated fetal weight, birth weight and placental weight. These signatures included pregnancy-related hormone breakdown products that were newly characterised in our study and branched-amino acids (BCAAs) isoleucine, valine and leucine with its catabolic intermediate 3-hyrdoxyisobutyrate. Overall metabolic phenotypes at week 12 could not predict fetal weight at week 34 or at birth, but only at weeks 12 and 20 and with little consistency across the two populations. Unique adverse metabolic signatures at week 12 of fetal growth were found in Sabadell related to mitochondrial oxidative stress, systemic inflammation and renal function. These findings captured the metabolic signatures of a myriad of physiological (both maternal and fetal), environmental, and other lifestyle characteristics associated with fetal growth. Sensitive measures of environmental exposure to HAA toxins were also created using LC-MS, a non-volatile sub-type of water contaminants, using gold-standard urine biomarker (TCAA), in a case-control study for use in future epidemiological studies of fetal growth outcomes. This work provides ground breaking evidence of clinical relevance with the potential to personalise pre-natal care and ensure healthy fetal development.