A prospective cohort study of the value of maternal plasma concentrations of angiogenic and anti-angiogenic factors in early pregnancy and midtrimester in the identification of patients destined to develop preeclampsia

Figures & data

Table I.  Demographic and clinical characteristics of the population.

	Preeclampsia (n = 62)	Normal pregnancy/other complications (n = 1560)	p
Maternal age (year)	23 (20–27)	26 (22–31)	0.007
Height (cm)	158 (153–163)	156 (153–161)	0.2
Weight (kg)	64 (57–74)	60 (53–68)	0.004
Pre-pregnancy BMI (kg/m^2)	25.7 (23.7–29)	24.3 (21.9–27.4)	0.006
Obesity (BMI >30)	20 (12/60)	14.1 (210/1488)	0.2
Nulliparity (%)	61.3 (38/62)	39.7 (619/1560)	0.001
Previous preeclampsia (%)	12.9 (8/62)	2.6 (41/1560)	<0.001
Smoking (%)	6.5 (4/62)	11.3 (177/1560)	0.2
Gestational age at first sample (week)	11.9 (10.4–13.1)	12.1 (10.7–13.4)	0.2
Gestational age at second sample (week)	22.9 (21.4–23.9)	22.4 (21.1–23.7)	0.4
Gestational age at delivery (week)	38.3 (36.3–39.3)	39.4 (38.6–40.3)	<0.001
Delivery <37 weeks (%)	29 (18/62)	5.4 (84/1560)	<0.001
Birth weight (g)	3025 (2365–3470)	3380 (3080–3690)	<0.001
SGA neonate (%)	29 (18/62)	12.4 (194–1559)	<0.001
Storage time first sample (year)	2.3 (1.7–2.9)	2.3 (1.7–2.8)	0.8
Storage time second sample (year)	2.1 (1.4–2.7)	2.1 (1.5–2.6)	0.9

The results are expressed as percentage (proportion) or median (inter-quartile range).

BMI, body mass index; SGA, small-for-gestational age.

Table II.  Maternal plasma concentrations of sVEGFR-1, PlGF, sEng, and their ratios, deltas and slopes in early pregnancy and midtrimester of patients who subsequently developed preeclampsia.

Analyte	Preeclampsia (n = 62)	Normal pregnancy/other complications (n = 1560)	p
Early pregnancy
sVEGFR-1 pg/ml	1426.3 (597.9–4546.5)	1725.8 (48.6–13575.1)	0.02
PlGF pg/ml	23.5 (0.0–77.1)	33.8 (0.0–451.9)	<0.001
sEng ng/ml	7.4 (4.1–13.3)	7.1 (3.3–26.9)	0.04
PlGF/sVEGFR-1	0.016 (0.0–0.06)	0.018 (0.0–0.47)	0.01
PlGF/sEng	3.1 (0.0–10.5)	4.6 (0.0–60)	<0.001
PlGF/sEng × sVEGFR-1	0.0019 (0.0–0.01)	0.0025 (0.0–0.06)	0.004
PlGF/sEng + sVEGFR-1	0.0025 (0.0–0.008)	0.0036 (0.0–0.05)	<0.001
Midtrimester
sVEGFR-1 pg/ml	1637.4 (325.1–17768.9)	1612.1 (245–10595.5)	0.5
PlGF pg/ml	213.9 (0.0–969.6)	329.8 (22.3–2894.4)	<0.001
sEng ng/ml	6.9 (3–47)	5.9 (2.4–29.6)	<0.001
PlGF/sVEGFR-1	0.17 (0.0–1)	0.21 (0.008–4.6)	0.006
PlGF/sEng	36.9 (0.0–157.8)	55.5 (1.2–354.9)	<0.001
PlGF/sEng × sVEGFR-1	0.025 (0.0–0.2)	0.036 (0.0–0.9)	<0.001
PlGF/sEng + sVEGFR-1	0.028 (0.0–0.1)	0.042 (0.001–0.3)	<0.001
Delta sVEGFR-1	157.4 (−1053 to 16476.6)	−129.8 (−12093.3 to 4120.4)	0.003
Delta PlGF	181.1 (0.0–902.3)	290.7 (−72.9 to 2798.6)	<0.001
Delta sEng	−0.8 (−4.9 to 41.5)	−1.2 (−14.2 to 18.8)	0.02
Delta PlGF/sVEGFR-1	0.16 (−0.05 to 1)	0.18 (−0.04 to 4.4)	0.01
Delta PlGF/sEng	34.1 (−2 to 147.3)	49.8 (−8.4 to 340.8)	<0.001
Delta PlGF/sEng × sVEGFR-1	0.023 (−0.01 to 0.2)	0.032 (−0.005 to 0.9)	0.001
Delta PlGF/sEng + sVEGFR-1	0.025 (−0.002 to 0.1)	0.038 (−0.007 to 0.3)	<0.001
Slope sVEGFR-1	14.4 (−109.4 to 1109)	−13.3 (−1019.9 to 379.7)	0.003
Slope PlGF	18.1 (0.0–96.1)	28.5 (−6.2 to 321.2)	<0.001
Slope sEng	−0.07 (−0.6 to 2.8)	−0.12 (−1.3 to 1.8)	0.01
Slope PlGF/sVEGFR-1	0.014 (−0.005 to 0.09)	0.018 (−0.004 to 0.4)	0.002
Slope PlGF/sEng	2.9 (−0.2 to 15.9)	5 (−0.7 to 39.1)	<0.001
Slope PlGF/sEng × sVEGFR-1	0.0021 (−0.001 to 0.02)	0.0032 (0.0–0.09)	<0.001
Slope PlGF/sEng + sVEGFR-1	0.0024 (0.0–0.01)	0.0038 (−0.001 to 0.03)	<0.001

The results are expressed as median (range).

Table III.  Predictive accuracy of maternal plasma concentrations of PlGF, sVEGFR-1, sEng, and their ratios, deltas and slopes in early pregnancy and midtrimester for the diagnosis of preeclampsia.

Analyte	AUC	ROC curve (p-value)	Cutoff	Sensitivity (%)	Specificity (%)	Positive predictive value (%)	Negative predictive value (%)	Positive likelihood ratio (95% CI)	Negative likelihood ratio (95% CI)
Early pregnancy
sVEGFR-1 pg/ml	0.587	0.02	≤1405.41	50	68	5.8	97.2	1.6 (1.2–2.0)	0.7 (0.6–0.9)
PlGF pg/ml	0.647	<0.001	≤28.04	62.9	60.4	5.9	97.6	1.6 (1.3–1.9)	0.6 (0.4–0.8)
sEng ng/ml	0.579	0.04	≥8.59	40.3	79	7.1	97.1	1.9 (1.4–2.6)	0.8 (0.6–0.9)
PlGF/sVEGFR-1	0.592	0.01	≤0.033	93.5	22.2	4.6	98.9	1.2 (1.1–1.3)	0.3 (0.1–0.7)
PlGF/sEng	0.662	<0.001	≤6.69	93.5	31	5.1	99.2	1.3 (1.2–1.4)	0.2 (0.1–0.5)
PlGF/sEng × sVEGFR-1	0.608	0.004	≤0.0022	59.7	56.6	5.2	97.2	1.4 (1.1–1.7)	0.7 (0.5–0.9)
PlGF/sEng + sVEGFR-1	0.649	<0.001	≤0.0035	67.7	53.7	5.5	97.7	1.5 (1.2–1.7)	0.6 (0.4–0.8)
Midtrimester
PlGF pg/ml	0.650	<0.001	≤215.04	51.6	76.4	8	97.5	2.2 (1.7–2.7)	0.6 (0.5–0.8)
sEng ng/ml	0.680	<0.001	≥6.7	58.1	73.3	8	97.8	2.2 (1.7–2.6)	0.6 (0.4–0.7)
PlGF/sVEGFR-1	0.602	0.006	≤0.12	40.3	78.5	6.9	97.1	1.9 (1.3–2.5)	0.8 (0.6–0.9)
PlGF/sEng	0.681	<0.001	≤48.28	69.4	60.6	6.5	98	1.8 (1.4–2.0)	0.5 (0.3–0.7)
PlGF/sEng × sVEGFR-1	0.631	<0.001	≤0.019	43.5	77.8	7.2	97.2	2.0 (1.4–2.6)	0.7 (0.6–0.9)
PlGF/sEng + sVEGFR-1	0.664	<0.001	≤0.025	48.4	81.9	9.6	97.6	2.7 (2.0–3.4)	0.6 (0.5–0.8)
Delta sVEGFR-1	0.610	0.003	≥176.62	50	68.7	6	97.2	1.6 (1.2–2.0)	0.7 (0.6–0.9)
Delta PlGF	0.635	<0.001	≤183.25	51.6	76.4	8	97.5	2.2 (1.7–2.7)	0.6 (0.5–0.8)
Delta sEng	0.591	0.02	≥−0.53	48.4	74	6.9	97.3	1.9 (1.4–2.4)	0.7 (0.5–0.9)
Delta PlGF/sVEGFR-1	0.594	0.01	≤0.039	19.4	97.2	21.8	96.8	7.0 (3.9–12.3)	0.8 (0.7–0.9)
Delta PlGF/sEng	0.667	<0.001	≤27.88	45.2	82.5	9.3	97.4	2.6 (1.9–3.4)	0.7 (0.5–0.8)
Delta PlGF/sEng × sVEGFR-1	0.622	0.001	≤0.019	46.8	71.8	6.2	97.1	1.7 (1.2–2.1)	0.7 (0.6–0.9)
Delta PlGF/sEng + sVEGFR-1	0.650	<0.001	≤0.024	50	77.9	8.2	97.5	2.3 (1.7–2.9)	0.6 (0.5–0.8)
Slope sVEGFR-1	0.611	0.003	≥13.51	51.6	66.5	5.8	97.2	1.5 (1.2–1.9)	0.7 (0.5–0.9)
Slope PlGF	0.660	<0.001	≤18.14	51.6	77.1	8.2	97.6	2.3 (1.7–2.8)	0.6 (0.5–0.8)
Slope sEng	0.592	0.01	≥−0.055	50	72.6	6.8	97.3	1.8 (1.4–2.3)	0.7 (0.5–0.9)
Slope PlGF/sVEGFR-1	0.613	0.002	≤0.0089	38.7	82.6	8.1	97.1	2.2 (1.6–3.0)	0.7 (0.6–0.9)
Slope PlGF/sEng	0.691	<0.001	≤2.9	51.6	80.8	9.6	97.7	2.7 (2.0–3.4)	0.6 (0.5–0.8)
Slope PlGF/sEng × sVEGFR-1	0.642	<0.001	≤0.0034	75.8	46.7	5.3	98	1.4 (1.2–1.6)	0.5 (0.3–0.8)
Slope PlGF/sEng + sVEGFR-1	0.677	<0.001	≤0.0026	56.5	74.5	8.1	97.7	2.2 (1.7–2.7)	0.6 (0.4–0.8)

Prevalence of preeclampsia: 3.8% (62/1622).

AUC, area under the curve; ROC, receiver operating characteristic.

Table IV.  Logistic regression analysis of maternal plasma concentrations of sVEGFR-1, PlGF, sEng, and their ratios, deltas and slopes in early pregnancy and midtrimester, for the prediction of preeclampsia after adjusting for maternal age, previous preeclampsia, pre-pregnancy BMI, nulliparity, smoking status, gestational age at venipuncture, and storage time.

Analyte	Cutoff	Odds Ratio	95% C.I.	p
Early pregnancy
sVEGFR-1 pg/mL	≤1405.41	2.2	1.3–3.8	0.003
PlGF pg/mL	≤28.04	2.3	1.3–3.9	0.003
sEng ng/mL	≥8.59	3.1	1.7–5.4	<0.001
PlGF/sVEGFR-1	≤0.033	3.7	1.3–10.3	0.01
PlGF/sEng	≤6.69	5.8	2.1–16.1	0.001
PlGF/sEng × sVEGFR-1	≤0.0022	1.8	1.03–3.0	0.04
PlGF/sEng + sVEGFR-1	≤0.0035	2.1	1.2–3.6	0.01
Midtrimester
PlGF pg/mL	≤215.04	3.8	2.2–6.7	<0.001
sEng ng/mL	≥6.7	4.6	2.6–8.0	<0.001
PlGF/sVEGFR-1	≤0.12	2.0	1.1–3.4	0.02
PlGF/sEng	≤48.28	3.9	2.1–7.0	<0.001
PlGF/sEng × sVEGFR-1	≤0.019	2.2	1.2–3.7	0.006
PlGF/sEng + sVEGFR-1	≤0.025	4.5	2.6–7.8	<0.001
Delta sVEGFR-1	≥176.62	1.9	1.1–3.2	0.02
Delta PlGF	≤183.25	3.2	1.9–5.5	<0.001
Delta sEng	≥−0.53	2.7	1.6–4.5	<0.001
Delta PlGF/sVEGFR-1	≤0.039	6.7	3.2–14.1	<0.001
Delta PlGF/sEng	≤27.88	3.8	2.2–6.5	<0.001
Delta PlGF/sEng × sVEGFR-1	≤0.019	1.8	1.1–3.1	0.03
Delta PlGF/sEng + sVEGFR-1	≤0.024	3.3	2.0–5.7	<0.001
Slope sVEGFR-1	≥13.51	1.8	1.1–3.1	0.03
Slope PlGF	≤18.14	3.1	1.8–5.3	<0.001
Slope sEng	≥−0.055	2.7	1.6–4.6	<0.001
Slope PlGF/sVEGFR-1	≤0.0089	2.4	1.4–4.2	0.002
Slope PlGF/sEng	≤2.9	4.1	2.4–7.1	<0.001
Slope PlGF/sEng × sVEGFR-1	≤0.0034	2.4	1.3–4.4	0.005
Slope PlGF/sEng + sVEGFR-1	≤0.0026	3.5	2.1–6.1	<0.001

CI, confidence interval.

Table V.  Maternal plasma concentrations of sVEGFR-1, PlGF, sEng, and their ratios, deltas and slopes in early pregnancy and midtrimester of patients who subsequently developed early-onset preeclampsia.

Analyte	Early-onset preeclampsia (n = 9)	Normal pregnancy/other complications (n = 1613)	p
Early pregnancy
sVEGFR-1 pg/mL	1307.7 (597.9–4546.5)	1719.2 (48.6–13575.1)	0.3
PlGF pg/mL	16.9 (0.0–44.1)	33.4 (0.0–451.9)	0.01
sEng ng/mL	8.6 (4.7–11.4)	7.1 (3.3–26.9)	0.3
PlGF/sVEGFR-1	0.012 (0.0–0.06)	0.018 (0.0–0.5)	0.08
PlGF/sEng	2.0 (0.0–6.3)	4.6 (0.0–60)	0.01
PlGF/sEng × sVEGFR-1	0.0015 (0.0–0.01)	0.0025 (0.0–0.06)	0.07
PlGF/sEng + sVEGFR-1	0.0017 (0.0–0.006)	0.0036 (0.0–0.05)	0.02
Midtrimester
sVEGFR-1 pg/mL	4162.3 (1536–17768.9)	1610.7 (245–10595.5)	<0.001
PlGF pg/mL	42.1 (0.0–126.3)	329.1 (22.3–2894.4)	<0.001
sEng ng/mL	14.9 (7.9–47)	5.9 (2.4–29.6)	<0.001
PlGF/sVEGFR-1	0.01 (0.0–0.08)	0.2 (0.008–4.6)	<0.001
PlGF/sEng	4.4 (0.0–13.3)	55.0 (1.2–354.9)	<0.001
PlGF/sEng × sVEGFR-1	0.001 (0.0–0.009)	0.04 (0.0003–0.9)	<0.001
PlGF/sEng + sVEGFR-1	0.003 (0.0–0.01)	0.04 (0.001–0.3)	<0.001
Delta sVEGFR-1	3170.9 (177.5–16476.6)	−129.5 (−12093.3 to 4120.4)	<0.001
Delta PlGF	21.0 (0.0–104.9)	288.9 (−72.9 to 2798.6)	<0.001
Delta sEng	9.1 (−1 to 41.5)	−1.2 (−14.2 to 18.8)	<0.001
Delta PlGF/sVEGFR-1	0.0 (−0.05 to 0.07)	0.2 (−0.04 to 4.4)	<0.001
Delta PlGF/sEng	0.0 (−2 to 10.9)	49.1 (−8.4 to 340.8)	<0.001
Delta PlGF/sEng × sVEGFR-1	0.0 (−0.01 to 0.007)	0.03 (−0.005 to 0.9)	<0.001
Delta PlGF/sEng + sVEGFR-1	0.0 (−0.002 to 0.009)	0.04 (−0.007 to 0.3)	<0.001
Slope sVEGFR-1	352.3 (15.3–1109)	−13.2 (−1019.9 to 379.7)	<0.001
Slope PlGF	2.1 (0.0–9.1)	28.2 (−6.2 to 321.2)	<0.001
Slope sEng	0.9 (−0.1 to 2.8)	−0.1 (−1.3 to 1.8)	<0.001
Slope PlGF/sVEGFR-1	0.0 (−0.005 to 0.006)	0.02 (−0.004 to 0.4)	<0.001
Slope PlGF/sEng	0.0 (−0.2 to 1)	4.9 (−0.7 to 39.1)	<0.001
Slope PlGF/sEng × sVEGFR-1	0.0 (−0.0009 to 0.0006)	0.003 (−0.0004 to 0.09)	<0.001
Slope PlGF/sEng + sVEGFR-1	0.0 (−0.0002 to 0.0008)	0.004 (−0.0006 to 0.03)	<0.001

Values are expressed as median (range).

Table VI.  Predictive accuracy of maternal plasma concentrations of PlGF, sVEGFR-1, sEng, and their ratios, deltas and slopes in early pregnancy and midtrimester for the diagnosis of early-onset preeclampsia.

Analyte	AUC	ROC curve (p-value)	Cutoff	Sensitivity (%)	Specificity (%)	Positive predictive value (%)	Negative predictive value (%)	Positive likelihood ratio (95% CI)	Negative likelihood ratio (95% CI)
Early pregnancy
PlGF pg/mL	0.741	0.012	≤22.93	77.8	69.7	1.4	99.8	2.6 (1.5–3.1)	0.3 (0.09–0.8)
PlGF/sEng	0.745	0.011	≤2.91	77.8	71.5	1.5	99.8	2.7 (1.6–3.3)	0.3 (0.09–0.8)
PlGF/sEng + sVEGFR-1	0.733	0.016	≤0.0023	77.8	72.7	1.6	99.8	2.9 (1.7–3.4)	0.3 (0.09–0.8)
Midtrimester
sVEGFR-1 pg/mL	0.865	<0.001	≥3460.4	66.7	93.2	5.2	99.8	9.8 (5.1–13.1)	0.4 (0.1–0.7)
PlGF pg/mL	0.994	<0.001	≤126.42	100	95.8	11.8	100	24.1 (16.4–24.1)	0.0 (0.0–0.3)
sEng ng/mL	0.973	<0.001	≥7.85	100	89.8	5.2	100	9.8 (6.8–9.8)	0.0 (0.0–0.3)
PlGF/sVEGFR-1	0.987	<0.001	≤0.082	100	89.1	4.9	100	9.2 (6.3–9.2)	0.0 (0.0–0.3)
PlGF/sEng	0.997	<0.001	≤13.44	100	98.3	24.3	100	57.6 (37.6–57.6)	0.0 (0.0–0.3)
PlGF/sEng × sVEGFR-1	0.993	<0.001	≤0.0087	100	95.3	10.6	100	21.2 (14.5–21.2)	0.0 (0.0–0.3)
PlGF/sEng + sVEGFR-1	0.997	<0.001	≤0.012	100	98	22	100	50.4 (33.2–50.4)	0.0 (0.0–0.3)
Delta sVEGFR-1	0.922	<0.001	≥176.62	100	68.3	1.7	100	3.2 (2.2–3.2)	0.0 (0.0–0.4)
Delta PlGF	0.993	<0.001	≤104.98	100	94.9	9.9	100	19.7 (13.4–19.7)	0.0 (0.0–0.3)
Delta sEng	0.949	<0.001	≥0.82	88.9	96.5	12.3	99.9	25.2 (15.4–28.1)	0.1 (0.02–0.4)
Delta PlGF/sVEGFR-1	0.988	<0.001	≤0.067	100	90.5	5.5	100	10.5 (7.2–10.5)	0.0 (0.0–0.3)
Delta PlGF/sEng	0.997	<0.001	≤10.95	100	98.2	23.7	100	55.6 (36.4–55.6)	0.0 (0.0–0.3)
Delta PlGF/sEng × sVEGFR-1	0.994	<0.001	≤0.0069	100	96	12.2	100	24.8 (16.9–24.8)	0.0 (0.0–0.3)
Delta PlGF/sEng + sVEGFR-1	0.997	<0.001	≤0.0094	100	97.9	20.9	100	47.4 (31.4–47.4)	0.0 (0.0–0.3)
Slope sVEGFR-1	0.931	<0.001	≥45.67	88.9	81.2	2.6	99.9	4.7 (3.0–5.2)	0.1 (0.03–0.5)
Slope PlGF	0.995	<0.001	≤9.19	100	97	15.5	100	32.9 (22.1–32.9)	0.0 (0.0–0.3)
Slope sEng	0.933	<0.001	≥0.071	88.9	95.9	10.8	99.9	21.7 (13.4–24.3)	0.1 (0.02–0.4)
Slope PlGF/sVEGFR-1	0.990	<0.001	≤0.0058	100	92.6	7	100	13.6 (9.3–13.6)	0.0 (0.0–0.3)
Slope PlGF/sEng	0.998	<0.001	≤0.94	100	98.9	33.3	100	89.6 (56.4–89.6)	0.0 (0.0–0.3)
Slope PlGF/sEng × sVEGFR-1	0.995	<0.001	≤0.00059	100	97	15.5	100	32.9 (22.1–32.9)	0.0 (0.0–0.3)
Slope PlGF/sEng + sVEGFR-1	0.997	<0.001	≤0.00081	100	98.6	28.1	100	70.1 (45.1–70.1)	0.0 (0.0–0.3)

Prevalence of early-onset preeclampsia: 0.6% (9/1622).

AUC, area under the curve; ROC, receiver operating characteristic.