Metabolic Changes in Urine during and after Pregnancy in a Large, Multiethnic Population-Based Cohort Study of Gestational Diabetes

Abstract

This study aims to identify novel markers for gestational diabetes (GDM) in the biochemical profile of maternal urine using NMR metabolomics. It also catalogs the general effects of pregnancy and delivery on the urine profile. Urine samples were collected at three time points (visit V1: gestational week 8–20; V2: week 28±2; V3∶10–16 weeks post partum) from participants in the STORK Groruddalen program, a prospective, multiethnic cohort study of 823 healthy, pregnant women in Oslo, Norway, and analyzed using 1H-NMR spectroscopy. Metabolites were identified and quantified where possible. PCA, PLS-DA and univariate statistics were applied and found substantial differences between the time points, dominated by a steady increase of urinary lactose concentrations, and an increase during pregnancy and subsequent dramatic reduction of several unidentified NMR signals between 0.5 and 1.1 ppm. Multivariate methods could not reliably identify GDM cases based on the WHO or graded criteria based on IADPSG definitions, indicating that the pattern of urinary metabolites above micromolar concentrations is not influenced strongly and consistently enough by the disease. However, univariate analysis suggests elevated mean citrate concentrations with increasing hyperglycemia. Multivariate classification with respect to ethnic background produced weak but statistically significant models. These results suggest that although NMR-based metabolomics can monitor changes in the urinary excretion profile of pregnant women, it may not be a prudent choice for the study of GDM.

A systematic review of metabolite profiling in gestational diabetes mellitus

“…In addition, the GDM diagnostic criteria used varied among the studies. Two studies specified using O’Sullivan and Mahan criteria [19, 20], seven studies used Carpenter–Coustan criteria [21-27]; three studies referenced the World Health Organization [28-30], one study referenced the Fourth International Gestational Diabetes Workshop criteria, and four studies did not specify the GDM diagnostic criteria used [31-34]. …”

“…One study used amniotic fluid only [31], eight used maternal plasma only [19, 20, 22, 23, 25, 26, 29, 35], three used maternal serum only [21, 24, 30], two used maternal urine only [28, 34], one used both amniotic fluid and urine [33], and one used both maternal urine and plasma [32]. Three studies examined metabolite profiles in the setting of other prenatal disorders [28, 33, 34]; however, only data on women with GDM without these potential confounders were abstracted from these studies.…”

“…Three studies examined metabolite profiles in the setting of other prenatal disorders [28, 33, 34]; however, only data on women with GDM without these potential confounders were abstracted from these studies. The analytical platforms used for metabolite detection included ion exchange chromatography [19], amino acid analyser [20], fluorescence polarisation immunoassay [21, 22], HPLC/dual wavelength spectrophotometry [23], Immunolite 2000 assay [24], ELISA-based assay [29, 30], HPLC/fluorescence spectroscopy [25], ultra-performance LC-MS [33], GC-MS [27] and 1 H NMR spectroscopy [28, 31, 32, 34]. The methodologies, metabolites and regulation pattern (‘upregulated’, ‘downregulated’ or ‘unchanged/not statistically significantly different’) in each study are summarised in Table 1.…”

“…Diaz et al [32] reported upregulated levels of 3-hydroxyisovalerate, N -methylnicotinamide and 2-hydroxyisobutyrate with lower levels of trimethylamine N -oxide and betaine in the second trimester, but these results were not observed by Sachse et al [28] when examining maternal urine levels in the third trimester. Pappa et al [35] observed lower levels of fasting acylcarnitine esters and higher levels of fasting β-hydroxybutyrate in maternal plasma of women with GDM at 30-33 weeks’ gestational age and suggested that there may be a shift from gluconeogenesis to ketone body production as the predominant energy source in GDM.…”

Metabolic profiles of placenta in preeclampsia using HR-MAS MRS metabolomics

“…In paper I, even with the small sample size, reproducible results could be found compared to similar studies. 77,142,201 In paper II, although there were relatively few hypertensive cases, the large number of normotensive pregnancies established a robust baseline to which the hypertensive groups could be compared. Sample collection is labor intensive and it is di cult to obtain su cient samples for high powered metabolomic studies.…”