Table 1.

Previously Published Studies Reporting Extracellular miRNA Biomarkers for Prediction or Diagnosis of Pre-eclampsia

Study and Population Origin	Biofluid	exRNA Isolation Method	exRNA Measurement Method	N; GA Sample Collection	Time Frame	Sensitivity, Specificity, AUC	miRNA PE > Control	miRNA PE < Control
Yang et al.33 China	serum	mirVana (Ambion)	small RNA-seq (SOLiD, Applied Biosystems)	5 (4 pree [2 mild, 2 severe], 1 control)	third trimester, after diagnosis	–,–,–	hsa-miR-521, 520h, 517c-3p, 519d, 520 g, 517b-3p, 542-3p, 136, 518e, 125b, 125a-5p, 519a, 29a, let-7f-3p, 7a-3p	hsa-miR-223, 1260, 320c, 185, 1272, let-7f-5p, 7d-5p
Wu et al.31 China (Han)	plasma	mirVana PARIS (Ambion)	miRNA microarray, 821 miRNAs (Agilent)	9 (5 severe PE, 4 normal)	37 and 40 weeks, after diagnosis	–,–,–, p < 0.05, fold-change R≥2	miR-574–5p, 26a,151-3p, 130a, 181a, 130b, 30d, 145, 103, 425, 221, 342-3p, and 24	miR-144 and 16
Hromadnikova et al.20 Czech Republic	plasma	mirVana (Ambion)	qRT-PCR, 7 C19MC miRNAs	168 (24 mild PE, 39 severe PE, 27 FGR, 23 ghtn, 55 normal)	after diagnosis	–,–,–	hsa-miR-516–5p, 517-5p, 520-5p, 525-5p, 526a
Li et al.22 China	plasma	mirVanaTM miRNA Isolation Kit (Ambion)	discovery: small RNAseq (SOLiD, Applied Biosystems) validation: qRT-PCR	discovery: 4 mild PE, 4 severe PE, 4 normal. validation: 16 mild PE, 22 severe PE, 32 normal.	34–37 weeks, after diagnosis	–,–,–	miR-141 and miR-29a (mild PE versus control)	miR-144 (mild PE and severe PE versus control)
Luque et al.23 Barcelona	serum	miRNeasy Mini kit (QIAGEN)	TaqMan OpenArray Human MicroRNA Panel, 754 miRNAs, (Applied Biosystems)	31 PE, 44 normal	11–136 weeks, asymptomatic	–,–,–	miRNAs: miR-192, 143, and −125b	miR-127, −942, −126*, and −221, did not validate
Xu et al.32 China	placenta and plasma	not given	placenta: mammalian miRNA chip array, 435 human miRNAs (V2.0, Capitalbio). Plasma: TaqMan qPCR.	53 (20 severe PE, 33 normal)	15–18 and 35– 38 weeks, asymptomatic	–,–,–	miR-210	miR-18a, miR-19b1, and miR-92a1
Stubert et al.28 Germany	serum	QIAamp Circulating Nucleic Acid Kit (QIAGEN)	TaqMan Low Density Array Human MicroRNA Card Set v3.0, 754 miRNAs (Applied Biosystems)	26 (13 HELLP, 13 controls)	28–41 weeks, at diagnosis	miR-122e: AUC = 0.82	miR-122, miR-758, and miR-133a (>2-fold)	miR-573, miR-766, and miR-409-3p
Ura et al.30 Italy	sera	mirVana PARIS with 23 acidphenol/chloroform extraction	TaqMan Low Density Array Human MicroRNA Card Set v3.0, 754 miRNAs (Applied Biosystems)	48 (24 severe PE, 24 control)	12–14 weeks, asymptomatic	validated miR- 1233, miR-520a, miR-210, miR-14	miR-1233; miR-650; miR-520a; miR-215; miR-210; miR-25; miR-518b; miR-193a-3p; miR-32; miR-204; miR-296-5p; miR-15	miR-126; miR-335; miR-144; miR-204; miR-668; miR-376a; miR-15b
Yang et al.34 China	plasma and placenta	TRIzol	small RNA-seq (SOLiD, Applied Biosystems)	5 (2 mild PE, 2 severe PE, 1 control)	244–283 days, at diagnosis (plasma) and delivery (placenta)	–,–,–	miR-126, miR-126*, miR-130a, miR-135b, miR-142-3p, miR-149, miR-188-5p, miR-18a, miR-18b, miR-203, miR-205, miR-224, miR-27a, miR-29a, miR-301a, miR-517c, miR-518-3p, miR-518e, miR-519d and miR-93
Miura et al.25 Japan	plasma	mirVana (Ambion)	qRT-PCR of 10 C19MC miRNAs	40 (20 cases [severe]: 20 controls)	27–34 weeks, after diagnosis	–,–,–	hsa-miR-518b, 1323, 516b, 516a-5p, 525-5p, 515-5p, 520h, 520a-5p, 519d, 526b
Jairajpuri et al.21 Bahrain	plasma	miRNeasy (QIAGEN)	custom miScript miRNA PCR array, 84 miRNAs (QIAGEN)	22 (15 cases [7 mild, 8 severe]: 7 controls)	third trimester, 8 severe]: 7 controls	–,–,–	hsa-miR-215, 155, 650, 210, 21, 518b, 29a	hsa-miR-15b, 144, 18a, 19b1
Yoffe et al.35 UK	plasma	miRNeasy (QIAGEN)	small RNA-seq (TruSeq, Illumina)	75 (35 cases [early onset]: 40 controls)	pre-symptomatic, 11 weeks 0 days to 13 weeks 6 days	0.72, 0.8, 0.86	hsa-miR-4433b, 221, hsa-let-7g	hsa-miR-182, 10b, 25, 99b, 143, 151a, 191, 146b, 486
Salomon et al.27 Chile	plasma	miRNeasy Mini Kit (QIAGEN) from exosomes isolated by density gradient ultracentrifugation	small RNA-seq (TruSeq, Illumina)	47 (15 PE, 32 control)	11–14 weeks, 22– 24 weeks, 32–36 weeks	–,–,–, p < 0.05	hsa-miR-486–5p, 423-5p, 451a, 107, 15a-5p, 335-5p, 92a-3p, 103a-3p	hsa-miR-126–3p
Gunel et al.18 Turkey	plasma, placenta	mirVana miRNA Isolation kit (Ambion) plasma	G4870A SurePrint G3 Human v16 miRNA 8 × 60 K Microarray, 1368 miRNAs (Agilent)	36 (18 severe PE at Human v16 miRNA 8 × 60 K Microarray, 1368 miRNAs (Agilent)	32–40 weeks, at delivery and diagnosis	–,–,–	hsa-miR-877*, hsa-miR-118	hsa-miR-1539, hsa-let-7b*, hsa-miR-191*, hsa-miR-23c, hsa-miR-33b*, hsamiR-425*, hsa-miR-4313, hsa-miR-550a, hsa-miR-933, hsa -miR-7f-1*
Gan et al.17 China	plasma, urine cells	Trizol LS reagent (Invitrogen)	qRT-PCR, miR-210, miR-155, miR-125b-5p, miR-125a-5p	40 (20 PE, 20 control)	20–34 weeks, at diagnosis	miR-210: AUC = 0.750; miR-155: AUC = 0.703	miR-210 and miR-155 in plasma
Timofeeva et al.29 Russia	plasma	miRNeasy (QIAGEN)	small RNA-seq (NEBNext, NEB) on 12 cases from cohort 1; qRT-PCR on cohort 2	cohort 1– 54 (28 cases [16 early onset, 12 late onset]: 26 controls [10 < 34 weeks, 16 > 37 weeks]); at delivery. cohort 2–16 (6 cases: 10 controls); 11–13, 24–26, 30–32 weeks.		hsa-miR-423–5p: Sensitivity = 0.875; Specificity = 0.80; AUC = 0.844	hsa-miR-423–5p, Sensitivity = 0.875; Specificity = 0.80; AUC = 0.844
Hromadnikova et al.19 Czech Republic	plasma	mirVana (Ambion)	qRT-PCR of 6 C19MC miRNAs	97 (39 cases [21 pre-eclampsia, 18 IUGR]: 58 controls)	10–13 weeks	hsa-miR-517–5p: preeclampsia,18 IUGR]: 58 controls)	hsa-miR-517–5p, 518b, 520h
Martinez-Fierro et al.24 Mexico	serum	miRNeasy Mini Kit (QIAGEN	TaqMan Low Density Array Human MicroRNA Card Set v2.0, focused on 51 C19MC miRNAs (Applied Biosystems)	34 (16 PE, 18 control)	12, 16, and/or 20 weeks, asymptomatic, longitudinal	–,–,–, p < 0.05	hsa-miR-520c-3p (16 weeks); hsa-miR-512-3p, 518f-3p,520d-3p (20 weeks)
Motawi et al.26 Egypt	plasma	miRNeasy Mini Kit (QIAGEN) from exosomes isolated by ultracentrifugation	TaqMan miRNA qPCR of hsa-miR-136, 494, and 495	200 (100 PE [23 < 20 weeks, 77 > 20 weeks], 100 control [20 < 20 weeks], 80 > 20 weeks)	at diagnosis	<20 weeks: hsa-miR- 136 0.95, 1.00, 1.000; hsamiR- 494 0.86, 0.95, 0.868; hsamiR- 495 0.90,0.83, 0.940,p > 0.05	<20 weeks and >20 weeks: hsa-miR- 136, 494 and 495

List of nineteen previously published studies with key characteristics and findings. Column “Sensitivity, Specificity, AUC” lists information where available; “–,–,–” is listed for studies that did not report sensitivity, specificity, or AUC. See also Tables S1 and S2.