Blood laboratory testing for early prediction of preeclampsia: chasing the finish line or at the starting blocks?

Figures & data

Table 1. Diagnostic performance of blood circulating biomarkers for early prediction of PE (<20th GW).

Biomarker	Physiological function	Alteration in women who developed PE compared to HC	Main res ults about performance for prediction of PE
VEGF-A	Angiogenic	↑	• AUC: 0.73; SE: 45%; SP: 90%; PPV: n.r.; NPV: n.r.; LR+: n.r.; LR-: n.r. OR: n.r. (32)
PlGF	Angiogenic	↓	• AUC 0.64, SE: 26%; SP: 90%; PPV: n.r.; NPV: n.r.; LR+: n.r.; LR-: n.r.; OR: n.r. (32)  • AUC: 0.57; SE: 52.9%; SP: 60%; PPV: 7.5%; NPV: 95.4%; LR+: n.r.; LR-: n.r.; O.R.:n.r. (45)  •  (early PE): AUC: n.r.; SE: 65%; SP: 90%; PPV: n.r.; NPV: n.r.; LR+: n.r.; LR-: n.r.; O.R.:n.r. (25)  • AUC: 0.831; SE: 73%; SP: 80%; PPV: n.r.; NPV: n.r.; LR+: n.r.; LR-: n.r.; O.R.: n.r. (24)  •  (late PE): AUC: 0.703; SE: 61.5%; SP: 90%; PPV: n.r.; NPV: n.r.; LR+: n.r.; LR-: n.r.; O.R.:n.r. (19)  • AUC: 0.61; SE: 32%; SP: 80%; PPV: n.r.; NPV: n.r.; LR+: n.r.; LR-: n.r.; O.R.:n.r. (18)
sFlt-1/PlGF ratio	Angiogenic-anti-angiogenic balance	↑	• AUC: 0.74; SE: 40%; SP: 90%; PPV: n.r.; NPV: n.r.; LR+: n.r.; LR-: n.r. OR: n.r. (32)
PAPP-A	Immunological	↓	• Adj-OR: 1.54; SE: 13%; SP: 90%; PPV: 3%; NPV: 98%; LR+: n.r.; LR-: n.r. (48)  • AUC: 0.77; SE: 58%; SP: 80%; PPV: n.r.; NPV: n.r.; LR+: n.r.; LR-: n.r. OR: n.r. (26)  • AUC: 0.64; SE: 32%; SP: 80%; PPV: n.r.; NPV: n.r.; LR+: n.r.; LR-: n.r. OR: n.r. (22)  • (early PE): AUC: n.r.; SE: 58.3%; SP: 90%; PPV: n.r.; NPV: n.r.; LR+: n.r.; LR-: n.r.; O.R.:n.r. (25)  • (late PE): AUC: 0.613; SE: 15.4%; SP: 90%; PPV: n.r.; NPV: n.r.; LR+: n.r.; LR-: n.r.; O.R.:n.r. (19)  • AUC: 0.54; SE: 23%; SP: 80%; PPV: n.r.; NPV: n.r.; LR+: n.r.; LR-: n.r.; O.R.:n.r. (18)
Inhibin-A	Endocrine	↑	• AUC: 0.715; SE: 60% SP: 84% PPV: n.r.; NPV: n.r.; LR+: n.r.; LR-: n.r. Adj-OR: 3.06 (52)  • AUC: 0.64; SE: 28%; SP: 95%; PPV: n.r.; NPV: n.r.; LR+: n.r.; LR-: n.r. (60)  • AUC: n.r.; SE: 85,7%; SP: 98.7%; PPV: 85.7%; NPV: 98.5%; LR+: n.r.; LR-: n.r. OR: n.r. (61)  • OR: n.r.; SE: 33%; SP: n.r.; PPV: n.r.; PPV: n.r.; NPV: n.r.; LR+: 6.8; LR-: n.r. (62)  •  (early PE): AUC: n.r.; SE: 56.7%; SP: 90%; PPV: n.r.; NPV: n.r.; LR+: n.r.; LR-: n.r.; O.R.:n.r. (25)  • AUC: 0.796; SE: 53%; SP: 80%; PPV: n.r.; NPV: n.r.; LR+: n.r.; LR-: n.r.; O.R.: n.r. (24)  • AUC: n.r.; SE: 28%; SP: 88%; PPV: n.r.; NPV: n.r.; LR+: 2.3; LR-: n.r.; O.R.: n.r. (51)
Activin-A	Endocrine	↑	• AUC: 0.59; SE: 15%; SP: 95%; PPV: n.r.; NPV: n.r.; LR+: n.r.; LR-: n.r.; OR: n.r. (60)  • (early PE): AUC: n.r.; SE: 53%; SP: 90%; PPV: n.r.; NPV: n.r.; LR+: n.r.; LR-: n.r.; OR: n.r. (25)  • AUC: 0.823; SE: 61%; SP: 80%; PPV: n.r.; NPV: n.r.; LR+: n.r.; LR-: n.r.; O.R.: n.r. (24)  • AUC: n.r.; SE: 41%; SP: 89%; PPV: n.r.; NPV: n.r.; LR+: 3.8; LR-: n.r.; O.R.: n.r. (51)
PP13	Immunological	↓	• AUC: 0.74; SE: 49%; SP: 80%; PPV: n.r.; NPV: n.r.; LR+: n.r.; LR-: n.r. OR: n.r. (32)  • AUC: 0.91; SE: 79%; SP: 90%, PPV: n.r.; NPV: n.r.; LR+: n.r.; LR-: n.r.; OR: 32.1; (58)  • AUCadj: 0.72; SE: 15.5% SP: 95%; PPV: 7.7%; NPV: 97.6%; LR+:3.1; LR-: 0.9; OR: 3.5 (59)  • (early PE): AUC: n.r.; SE: 51.9%; SP: 90%; PPV: n.r.; NPV: n.r.; LR+: n.r.; LR-: n.r.; O.R.:n.r. (25)  • AUC: 0.51; SE: 21%; SP: 80%; PPV: n.r.; NPV: n.r.; LR+: n.r.; LR-: n.r.; O.R.:n.r. (18)
Cytokines	Inflammatory	↑ or =	• IL-2 AUC: n.r.; SE: 81.3%, SP: 81.3%, PPV: n.r.; NPV: n.r.; LR+: n.r.; LR-: n.r.; OR: n.r.; (71)  • TNF-α: AUC: n.r. SE: 75%, SP: 75%, PPV: n.r.; NPV: n.r.; LR+: n.r.; LR-: n.r.; OR: n.r. (71)  • Panel of cytokines: AUC: n.r.; SE: 68%, SP: 80%; PPV: n.r.; NPV: n.r.; LR+: n.r.; LR-: n.r.; OR: n.r.; classification accuracy: 74%, (80)
Chemerin	Inflammatory	↑	• OR: 1.011, AUC: 0.845, SE: 87.8%; SP: 75.7%; PPV: n.r.; NPV: n.r.; LR+: n.r.; LR-: n.r.; OR: n.r. (78)
Hs-CRP	Inflammatory	↑	• SE: 78.1%; SP: 72.1%; PPV: 25%; NPV: 96.5%; LR+: n.r.; LR-: n.r.; OR: n.r. (84)
P-selectin	Pro-coagulant	↑	• AUC: 0.93; SE: 80%; SP: 91.2%; PPV: 84.2%; NPV: 88.6%; LR+: n.r.; LR-: n.r.; OR: n.r.; (96)  • (early PE): AUC: n.r.; SE: 50.5%; SP: 90%; PPV: n.r.; NPV: n.r.; LR+: n.r.; LR-: n.r.; O.R.:n.r. (98)  • (late PE): AUC: 0.658; SE: 30.8%; SP: 90%; PPV: n.r.; NPV: n.r.; LR+: n.r.; LR-: n.r.; O.R.:n.r. (19)  • Panel including P-selectin (at a 3% prevalence of PE): OAPR: 10%, SE: 66%; SP: 90%; LR+: n.r.; LR-: n.r.; OR: n.r.; (97)
MPV	–	↑	• AUC: 0.67; SE: 67%; SP: 64%; PPV: n.r.; NPV: n.r.; LR+: n.r.; LR-: n.r.; OR: n.r.; (88)

GW: gestational week; VEGF-A: vascular endothelial growth factor; PlGF: placental growth factor; sFlt-1: soluble fms-like tyrosine kinase-1; TNF: tumor necrosis factor; IL: interleukin; HC: healthy controls; Hs-CRP: high-sensitivity C-reactive protein; PAPP-A: Pregnancy-Associated Plasma Protein-A; PE: preeclampsia; PP13: placental protein 13; MPV: mean platelet volume; FPR: false-positive rate; OR: odds ratio; OAPR: odds of being affected given a positive results; n.r.: not reported.

Table 2. Estimated positive predicted values according to a hypothesized prevalence of PE of 1, 2, 5, 10, and 20%, in the screened population.

		Postulated prevalence of PE in the population screened
First author (Ref.)	Marker	1%	2%	5%	10%	20%
Odibo (32)	VEGF	4.3	8.4	19.1	33.3	52.9
Odibo (32)	PlGF	2.6	5.0	12.0	22.4	39.4
McElrath (43)	PlGF	1.3	2.6	6.5	12.8	24.9
Widmer (44)	PlGF	1.1	2.2	5.6	11.1	22.0
Akolekar (25)	PlGF	6.2	11.7	25.5	41.9	61.9
Yu (24)	PlGF	3.6	6.9	16.1	28.9	47.7
Youssef (19)	PlGF	5.8	11.2	24.5	40.6	60.6
Myatt (18)	PlGF	1.6	3.2	7.8	15.1	28.6
Odibo (32)	sFlt-1/PlGF	3.9	7.5	17.4	30.8	50.0
Spencer (47)	PAPP-A	1.3	2.6	6.4	12.6	24.5
Odibo (32)	PAPP-A	2.8	5.6	13.2	24.4	42.0
Poon (23)	PAPP-A	1.9	3.8	9.2	17.6	32.4
Goetzinger (22)	PAPP-A	1.6	3.2	7.8	15.1	28.6
Akolekar (25)	PAPP-A	5.5	10.6	23.4	39.2	59.2
Youssef (19)	PAPP-A	1.5	3.0	7.5	14.6	27.8
Myatt (18)	PAPP-A	1.1	2.3	5.7	11.3	22.3
Ree (52)	Inhibin-A	3.6	7.1	16.5	29.4	48.4
Spencer (60)	Inhibin-A	5.4	10.3	22.8	38.4	58.3
El-Gharib (61)	Inhibin-A	40.0	57.4	77.6	88.0	94.3
Akolekar (25)	Inhibin-A	5.4	10.4	23.0	38.7	58.6
Yu (24)	Inhibin-A	2.6	5.1	12.2	22.7	39.8
Muttukrishna (51)	Inhibin-A	2.3	4.5	10.9	20.6	36.8
Spencer (60)	Activin-A	2.9	5.8	13.6	25.0	42.9
Akolekar (25)	Activin-A	5.1	9.8	21.8	37.1	57.0
Yu (24)	Activin-A	3.0	5.9	13.8	25.3	43.3
Muttukrishna (51)	Activin-A	3.6	7.1	16.4	29.3	48.2
Odibo (32)	PP13	2.4	4.8	11.4	21.4	38.0
Chafetz (58)	PP13	7.4	13.9	29.4	46.7	66.4
Schneuer (59)	PP13	3.0	6.0	14.0	25.6	43.7
Akolekar (25)	PP13	5.0	9.6	21.5	36.6	56.5
Myatt (18)	PP13	1.0	2.1	5.2	10.4	20.8
Hamai (71)	IL-2	4.2	8.1	18.6	32.6	52.1
Hamai (71)	TNF-alfa	2.9	5.8	13.6	25.0	42.9
Tangerås (80)	Panel of cytokines	3.3	6.5	15.2	27.4	45.9
Xu (82)	Chemerin	3.5	6.9	16.0	28.6	47.5
Kashanian (84)	Hs-CRP	2.7	5.4	12.8	23.7	41.2
Bosio (96)	P-selectin	8.4	15.6	32.4	50.3	69.4
Akolekar (98)	P-selectin	4.9	9.3	21.0	35.9	55.8
Youssef (19)	P-selectin	3.0	5.9	13.9	25.5	43.5
Banzola (97)	Panel with P-selectin	6.3	11.9	25.8	42.3	62.3
Michelson (89)	MPV	1.8	3.7	8.9	17.1	31.8

VEGF-A: vascular endothelial growth factor; PlGF: placental growth factor; sFlt-1: soluble fms-like tyrosine kinase-1; TNF: tumor necrosis factor; IL: interleukin; Hs-CRP: high-sensitivity C-reactive protein; PAPP-A: Pregnancy-Associated Plasma Protein-A; PE: preeclampsia; PP13: placental protein 13; MPV: mean platelet volume; FPR: false-positive rate; OR: odds ratio; OAPR: odds of being affected given a positive results.

Table 3. Circulating miRs expression for prediction of PE at early stage of gestation (<20th GW).

Target miRs	Population size	Gestational weeks of blood sampling	Main results	References
754 miRs (human microRNA panel V3.0; Applied Biosystems Inc, Norwalk, CT, USA)	24 PE 24 HC	12–14 GW	- miR-1233, miR-650, miR-520a, miR-215, miR-210, miR-25, miR-518b, miR-193a-3p, miR-32, miR-204, miR-296-5p, and miR-152 resulted upregulated in PE patients in comparison to HC  - miR-126; miR-335; miR-144; miR-204; miR-668; miR-376a; miR-15b resulted downregulated in PE patients in comparison to HC  - miR-1233, miR-520a, miR-210, miR-144 were successively validated in PE serum sample by qRT-PCR  - miR-1233 displayed the greater differential expression between PE and HC	(114)
miR-152 miR-182 miR-183 miR-210 miR-1 miR-328 miR-363 miR-377 miR-500 miR-584	32 PE 32 HC	12–14 GWs	- No significant differences between PE and HC were found regarding the first-trimester levels of the circulating miRs	(133)
miR-34c miR-372 miR-135b miR-518b miR-512-5p miR-515-5p miR-224 miR-516-5p miR-517* miR-136 miR-518f* miR-519a miR-519d miR-519e miR-520a* miR-520h miR-524-5p miR-525 miR-526a miR-526b	23 PE 10 HC	12–16 GWs	- miR-516-5p, miR-517*, miR-518b, miR-520a*, miR-520h, miR-525 and miR-526a showed the best diagnostic potential based on the following criteria: Detection rate of 100% in term placenta samples; Detection rate of ≥67% in maternal plasma throughout gestation; No detection in nonpregnant individuals	(138)
754 miRs (TaqMan^® OpenArray^® Human MicroRNA Panel; Applied Biosystems, Foster City, CA, USA)	31 PE 44 HC	11–14 GWs	- No significant differences between PE and HC were found regarding the first-trimester levels of the circulating miRs	(139)
754 miRs (TaqMan^® OpenArray^® Human MicroRNA Panel; Applied Biosystems/Life Technologies, Paisley, UK)	18 PE 18 HC	16th GW	- The only miR found to be differentially expressed at 16th GW was miR-23a∗, which was found to be downregulated in PE in comparison to HC	(140)

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