Metabolomic Profile of Umbilical Cord Blood Plasma from Early and Late Intrauterine Growth Restricted (IUGR) Neonates with and without Signs of Brain Vasodilation

Abstract

ObjectivesTo characterize via NMR spectroscopy the full spectrum of metabolic changes in umbilical vein blood plasma of newborns diagnosed with different clinical forms of intrauterine growth restriction (IUGR).Methods23 early IUGR cases and matched 23 adequate-for-gestational-age (AGA) controls and 56 late IUGR cases with 56 matched AGAs were included in this study. Early IUGR was defined as a birth weight <10th centile, abnormal umbilical artery (UA) Doppler and delivery <35 weeks. Late IUGR was defined as a birth weight <10th centile with normal UA Doppler and delivery >35 weeks. This group was subdivided in 18 vasodilated (VD) and 38 non-VD late IUGR fetuses. All AGA patients had a birth weight >10th centile. 1H nuclear magnetic resonance (NMR) metabolomics of the blood samples collected from the umbilical vein at delivery was obtained. Multivariate statistical analysis identified several metabolites that allowed the discrimination between the different IUGR subgroups, and their comparative levels were quantified from the NMR data. ResultsThe NMR-based analysis showed increased unsaturated lipids and VLDL levels in both early and late IUGR samples, decreased glucose and increased acetone levels in early IUGR. Non-significant trends for decreased glucose and increased acetone levels were present in late IUGR, which followed a severity gradient when the VD and non-VD subgroups were considered. Regarding amino acids and derivatives, early IUGR showed significantly increased glutamine and creatine levels, whereas the amounts of phenylalanine and tyrosine were decreased in early and late-VD IUGR samples. Valine and leucine were decreased in late IUGR samples. Choline levels were decreased in all clinical subforms of IUGR.ConclusionsIUGR is not associated with a unique metabolic profile, but important changes are present in different clinical subsets used in research and clinical practice. These results may help in characterizing comprehensively specific alterations underlying different IUGR subsets.

Proton Magnetic Resonance Spectroscopy Assessment of Fetal Brain Metabolism in Late-Onset ‘Small for Gestational Age' versus ‘Intrauterine Growth Restriction' Fetuses

“…The findings of the present study challenge the notion that SGA fetuses without signs of severity are merely constitutionally small. This notion goes in line with recent studies showing that SGA fetuses without high-risk factors present changes in their brain sulcation, umbilical blood metabolomic profile and cardiovascular profile [7,8,12]. However, our results do not contribute to clarify the pathogenesis of fetal smallness in this subgroup.…”

“…Thus, small fetuses with abnormal uterine artery Doppler ultrasound [4], birth weight below the 3rd centile [5] or signs of brain redistribution [3] are associated with poorer perinatal outcome. It has been speculated whether those SGA fetuses without signs of poor perinatal outcome showed merely milder forms of the same disease, were constitutionally small fetuses or represented another pathogenic pathway leading to abnormally low fetal growth [8,12,13]. The findings of the present study challenge the notion that SGA fetuses without signs of severity are merely constitutionally small.…”

“…However, our results do not contribute to clarify the pathogenesis of fetal smallness in this subgroup. A recent study conducting metabolomic analyses in fetal cord blood identified changes in the levels of several amino acids, such as phenylalanine, tyrosine and glutamine, that were specific to either late-onset IUGR or SGA fetuses [8]. These results support the hypothesis that there might be pathogenic differences among clinical forms of small fetuses and provide grounds for future studies focusing on brain metabolomics to characterize in more detail which metabolic patterns are associated with the differences observed in these clinical presentations.…”

“…However, it is unclear whether these fetuses are ‘constitutional' SGA or represent other forms of growth restriction. For instance, despite normal perinatal outcomes, small fetuses with normal brain and uterine Doppler sonography still present long-term differences as compared with normally grown fetuses, such as cardiovascular and metabolic programming [7,8], neurological deficits [9,10,11] and neurostructural changes [12,13,14]. Therefore, there is a need to improve the characterization and understanding of the different phenotypes under the common diagnosis of ‘fetal smallness'.…”

Clinical Metabolomics in Neonatology: From Metabolites to Diseases

“…On the contrary, methionine produces high concentrations of Sadenosyl-methionine, which is one of the essential amino acids with antioxidant activity and it exerts a very important role in preventing abnormal fat accumulation in the liver. Taking into account the perinatal data, in some metabolomics studies performed on umbilical cord blood there are reduced levels of choline and betaine in low birth weight or IUGR neonates compared to controls [32][33][34]. These differences in metabolic profile seem to characterize alterations in fetal energy and antioxidant defense as a signature of preterm birth or reduced growth.…”