Metabolomics of Pregnancy Complications: Emerging Application of Maternal Hair
Table 1
Examples of metabolomics studies associated with preeclampsia (EO-PE: early-onset preeclampsia, LO-EP: late-onset preeclampsia, and PE: preeclampsia).
Sample specimen
Participants (n)
Outcomes
Analytical platforms
Metabolites
Statistical analysis
References
Serum
80 (20 EO-PE, 20 LO-PE)
EO-PE, LO-PE, controls for both
FTIR spectroscopy, H1 NMR
FTIR results: carbohydrate, protein and lipid region sign. Different in EO-PE, H1 NMR model included: ↑Glutamate, choline, alanine, lactate ↓ arginine, citrate
Study 2: data mining and modeling techniques it gave rise of a model containing 14 metabolites (5-Hydroxytryptophan, Monosaccharide(s), Decanoylcarnitine, Methylglutaric acid and/or adipic acid, Oleic acid, Docosahexaenoic acid and/or Docosatetraenoic acid, -Butyrolactone and/or oxolan-3-one, 2-Oxovaleric acid and/or oxo-methylbutanoic acid, Acetoacetic acid, Hexadecenoyl- eicosatetraenoyl-sn- glycerol, Di-(octadecadienoyl)-sn- glycerol, Sphingosine 1-phosphate, Sphinganine 1-phosphate, Vitamin D3 derivatives) to be a robust model to predict PE with AUC of >0.9
Study 2: P<0.05, robust predictive model of 14 metabolites: AUC of >0.9
Placenta (first trimester)
Study 1: 12 (terminated pregnancy); study 2: 17 (6 PE)
Late PE, controls
GC-TOF-MS, UPLC-LTQ Orbitrap-MS
classes which are significantly different between term PE and normal term pregnancies: acyl glycerides, phospholipids, fatty acids and related metabolites, amino acids related metabolites, vitamin D-related metabolites, isoprenoids, and steroids
1st analysis (late onset PE vs controls): 17 metabolites significant different, of which Glycerol, carnitine, methylhistidine, acetone most important to discriminate based on VIP. 2nd analysis (Late onset vs early onset PE): glycerol, acetate, trimethylamine and succinate most important to discriminate based on VIP analysis
P<0.05, complex model (metabolites/maternal demographic info): 76.6% sensitivity at 100% specificity, simplified model: 60% sensitivity at 96.6% specificity
Model 1: metabolites (glutamine, pyruvate, propylene glycol, trimethylamine, hydroxybutyrate) in combination with maternal characteristics (weight and medical disorder) and Model 2: metabolites (glutamine, pyruvate, propylene glycol, trimethylamine, hydroxybutyrate, carnitine, hydroxy isovalerate) in combination with uterine artery PI.
P<0.005, model 1: estimated detection rate is 75.9%, model 2: estimated detection rate is 82.6%
Metabolite-only model: glycerol, 3-hydroxyisovalerate, 2-hydroxybutyrate, acetone, and citrate; combined logistic regression model: glycerol, 3-hydroxyisovalerate, arginine, and UtPI data
Metabolite only model: O.835 of AUC; combined logistic regression model (metabolite plus uterine Doppler pulsatility index): 0.916 of AUC for early PE detection in validation group
Hydroxyhexanoylcarnitine, phenylalanine, glutamate, alanine, were significantly higher in PE cases compared to controls and adjusted by BMI, ethnicity and pregestational diabetes,
P<0.05, individual metabolites AUC of 0.77-0.80, combined metabolites AUC of 0.82 for all PE cases and 0.85 for EO-PE cases
Urine: by PLS-DA: ↑choline and creatinine level, ↓ glycine levels in PE aces vs healthy pregnancies, women with early onset PE had ↑Trimethylamine-N-oxide, creatinine, ↓choline and creatinine compared to late onset PE; Serum: lipid content PE cases>normal pregnancies>nonpregnant women. Distribution of lipoproteins was also different between groups with PE cases most ↑ levels from VLDL and LDL and ↓ levels of HDL, PE cases had significantly ↓ levels of histidine compared to healthy pregnancy.
P<0.05 (PCA) and P<0.001 (PLS-DA), 95% significance of the predictive model
↑ levels of creatinine, glycine, 4-deoxythreonic acid, α-hydroxyisobutyrate, histidine and dimethylamine, ↓ levels of hippurate, lactate and proline betaine in the urine of women which developed preeclampsia. Women who developed gestational hypertension had an additional ↓ of citrate level in urine. In serum samples: ↑ lipid levels in both hypertensive groups. ↓ levels of phosphatidylcholines, glucose, lactate, and alanine.
P<0.05,Urine: 51.3% sensitivity for PE and 40% gestational hypertension, Serum: 15% sensitivity for PE and 33% gestational hypertension