Open Access Highly Accessed Research article

Urinary metabolic profiles in early pregnancy are associated with preterm birth and fetal growth restriction in the Rhea mother–child cohort study

Léa Maitre145, Eleni Fthenou23, Toby Athersuch14, Muireann Coen14, Mireille B Toledano45, Elaine Holmes14, Manolis Kogevinas3678, Leda Chatzi2* and Hector C Keun14*

Author Affiliations

1 Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK

2 Department of Social Medicine, Faculty of Medicine, University of Crete, PO Box 2208, 71003 Heraklion, Greece

3 Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain

4 MRC-PHE Centre for Environment and Health, Imperial College London, London W2 1PG, UK

5 Department of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine, Imperial College London, London W2 1PG, UK

6 National School of Public Health, Alexandras Avenue 196, 115 21 Athens, Greece

7 IMIM (Hospital del Mar Research Institute), Barcelona, Spain

8 CIBER Epidemiologia y Salud Pública (CIBERESP), Barcelona, Spain

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BMC Medicine 2014, 12:110  doi:10.1186/1741-7015-12-110

Published: 11 July 2014

Abstract

Background

Preterm birth (PB) and fetal growth restriction (FGR) convey the highest risk of perinatal mortality and morbidity, as well as increasing the chance of developing chronic disease in later life. Identifying early in pregnancy the unfavourable maternal conditions that can predict poor birth outcomes could help their prevention and management. Here we used an exploratory metabolic profiling approach (metabolomics) to investigate the association between birth outcomes and metabolites in maternal urine collected early in pregnancy as part of the prospective mother–child cohort Rhea study. Metabolomic techniques can simultaneously capture information about genotype and its interaction with the accumulated exposures experienced by an individual from their diet, environment, physical activity or disease (the exposome). As metabolic syndrome has previously been shown to be associated with PB in this cohort, we sought to gain further insight into PB-linked metabolic phenotypes and to define new predictive biomarkers.

Methods

Our study was a case–control study nested within the Rhea cohort. Major metabolites (n = 34) in maternal urine samples collected at the end of the first trimester (n = 438) were measured using proton nuclear magnetic resonance spectroscopy. In addition to PB, we used FGR in weight and small for gestational age as study endpoints.

Results

We observed significant associations between FGR and decreased urinary acetate (interquartile odds ratio (IOR) = 0.18 CI 0.04 to 0.60), formate (IOR = 0.24 CI 0.07 to 0.71), tyrosine (IOR = 0.27 CI 0.08 to 0.81) and trimethylamine (IOR = 0.14 CI 0.04 to 0.40) adjusting for maternal education, maternal age, parity, and smoking during pregnancy. These metabolites were inversely correlated with blood insulin. Women with clinically induced PB (IPB) had a significant increase in a glycoprotein N-acetyl resonance (IOR = 5.84 CI 1.44 to 39.50). This resonance was positively correlated with body mass index, and stratified analysis confirmed that N-acetyl glycoprotein and IPB were significantly associated in overweight and obese women only. Spontaneous PB cases were associated with elevated urinary lysine (IOR = 2.79 CI 1.20 to 6.98) and lower formate levels (IOR = 0.42 CI 0.19 to 0.94).

Conclusions

Urinary metabolites measured at the end of the first trimester are associated with increased risk of negative birth outcomes, and provide novel information about the possible mechanisms leading to adverse pregnancies in the Rhea cohort. This study emphasizes the potential of metabolic profiling of urine as a means to identify novel non-invasive biomarkers of PB and FGR risk.

Keywords:
Fetal growth restriction (FGR); Intrauterine growth restriction (IUGR); Small for gestational age (SGA); Preterm birth (PB); NMR; Metabonomics; Metabolomics; In utero environment; Exposome