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	P<0.001, 95% CI	[40]
Plasma	Cohort 1: 40 (20 PE); cohort 2: 174 (87 PE) [167]	Preeclampsia and controls	UPLC-LTQ Orbitrap-MS	Alanine, 2-Hydroxy-3-methyl-butanoic acid, 2-Ethyl-3-hydroxypropionic acid, 2-Oxoglutaric acid, Glutamic acid, Xylitol or ribitol, Uric acid, Creatinine	P<0.01	[168]
Plasma (15+/- 1 weeks of gestation)	120 (discovery, 60 PE)	PE and controls	UPLC-MS	Study 1: 45 unique metabolites divided into 11 clear metabolite classes: amino acids, carbohydrates, carnitines, Eicosanoids, fatty acids, keto or hydroxy acids, lipids, phospholipids, porphyrins, phosphatidylserine, and steroids.	study 1: P<0.05	[169]
	79 (validation, 39 PE)			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	P<0.05	[170]
Serum (11(+0)-13(+6) weeks of gestation)	119 (30 LO-PE, 30 EO-PE)	LO-PE, EO-PE, controls	NMR	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	[171]
Plasma (11-13 weeks)	90 (30 EO-PE)	EO-PE, controls	NMR	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%	[172]
Serum (11(+0)-13(+6) weeks of gestation)	Discovery: 95 (30 EO-PE); Validation: 63 (20 EO-PE)	EO-PE, controls	NMR	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	[173]
Serum (11-14 weeks of gestation)	82 (41 PE)	PE and controls	LC-MS/MS	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	[174]
Urine, Serum at time of diagnosis	30 (10 PE, 10 controls, 10 non-pregnant)	PE and controls (pregnant and non-pregnant)	NMR	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	[175]
Urine, serum (first trimester)	599 (26 PE, 21 gest. Hypertension)	PE, gestational hypertension, controls	NMR	↑ 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	[176]
Serum(8(+0)-13(+6) weeks of gestation)	667 (68 EO-PE, 99 LO-PE)	EO-PE, LO-PE, controls	UPLC-MS/MS, LC-MS	EO-PE vs controls: taurine and asparagine; LO-PE vs controls: glycylglycine		[41]