Shotgun metabolomic profiles in maternal urine identify potential mass spectral markers of abnormal fetal biochemistry – dihydrouracil and progesterone in the metabolism of Down syndrome

In Down syndrome (DS) in particular, the precise cellular mechanisms linking genotype to phenotype is not straightforward despite a clear mapping of the genetic cause. Metabolomic profiling might be more revealing in understanding molecular–cellular mechanisms of inborn errors of metabolism/syndromes than genomics alone and also result in new prenatal screening approaches. The urinary metabolome of 122 maternal urine from women with and without an aneuploid pregnancy (predominantly Down syndrome) were compared by both zwitterionic hydrophilic interaction chromatography (ZIC‐HILIC) and reversed‐phase liquid chromatography (RPLC) coupled to hybrid ion trap time of flight mass spectral analysis. ZIC‐HILIC mass spectrometry resolved 10‐fold more unique molecular ions than RPLC mass spectrometry, of which molecules corresponding to ions of m/z 114.07 and m/z 314.20 showed maternal urinary level changes that significantly coincided with the presence of a DS fetus. The ion of m/z 314.20 was identified as progesterone and m/z 114.07 as dihydrouracil. A metabolomics profiling‐based maternal urinary screening test modelled from this separation data would detect approximately 87 and 60.87% (using HILIC‐MS and RPLC‐MS, respectively) of all DS pregnancies between 9 and 23 weeks of gestation with no false positives. Copyright © 2014 John Wiley & Sons, Ltd.