Maternal plasma concentrations of angiogenic/anti-angiogenic factors are of prognostic value in patients presenting to the obstetrical triage area with the suspicion of preeclampsia

Figures & data

Table I.  Demographic and clinical characteristics of the study population.

	No PE, may become mild PE at term (n = 19)	Mild PE and stable until term delivery (n = 15)	Mild PE became severe PE requiring preterm delivery (n = 26)	Severe PE (n = 27)	p
Age (years)	26 ± 6.5	28 ± 7.7	24 ± 5.1	27 ± 6.7	0.2
African–American	17 (89.5%)	14 (93.3%)	23 (88.5%)	24 (88.9%)	0.9
Nulliparous	6 (31.6%)	6 (40%)	13 (50%)	12 (55.6%)	0.7
Smoking	4 (21.1%)	7 (46.7%)	4 (15.4%)	6 (22.2%)	0.1
BMI (Kg/m^2)	38.6 ± 10.3	36.9 ± 10.7	33.6 ± 8	6.8 ± 12.6	0.5
Previous preeclampsia	2 (10.5%)	1 (6.7%)	7 (26.9%)	6 (22.2%)	0.3
Chronic hypertension	9 (47.3%)	5 (33.3%)	7 (26.9%)	13 (48.1%)	0.2
Pre-gestational diabetes	--	3 (20%)	--	1 (3.7%)	0.02
GA at blood sampling (weeks)
Mean ± SD	31 ± 4.8	34 ± 3.2	31 ± 3.5	31 ± 3.5	0.2
Median (inter-quartile range)	33 (26–35)	33 (32–36)	32.5 (27–33)	31.8 (29–35)
GA <34 weeks	10 (52.6%)	8 (53.3%)	21 (80.8%)	20 (74.1%)
Average blood pressure in the triage area
Systolic (mmHg)	134 ± 15	144 ± 112	152 ± 20	165 ± 22	<0.001
Diastolic (mmHg)	79 ± 11	85 ± 12	94 ± 11	96 ± 11	<0.001
Diagnosis in the triage area
No hypertensive disease	5 (26.3%)	--	1 (3.8%)	--	<0.001
Gestational hypertension	5 (26.3%)	1 (6.7%)	3 (11.5%)	--
Chronic hypertension	9 (47.7%)	2 (13.3%)	4 (15.4%)	--
Chronic hypertension with superimposed preeclampsia	--	3 (20%)	3 (11.5%)	13 (48.1%)
Mild preeclampsia	--	9 (60%)	15 (57.7%)	--
Severe preeclampsia	--	--	--	14 (51.9%)
Diagnosis at delivery
No hypertensive disease	3 (15.8%)	--	--	--	<0.001
Gestational hypertension	4 (21.1%)	--	--	--
Chronic hypertension	7 (36.8%)	--	--	--
Chronic hypertension with superimposed preeclampsia	2 (10.5%)	5 (33.3%)	7 (26.9%)	13 (48.1%)
Mild preeclampsia	2 (10.5%)	7 (46.7%)	--	--
Severe preeclampsia	1 (5.3%)	3 (20%)	19 (73.1%)	14 (51.9%)

Table II.  Obstetrical and neonatal outcomes of the study population.

	No PE may becomePE at term (n = 19)	Mild PE and stable until term delivery (n = 15)	Mild PE became severe PE requiring preterm delivery (n = 26)	Severe PE (n = 27)	p
Obstetrical outcomes
Interval to delivery (days)
Mean + SD	43 ± 37	25 ± 24	17 ± 18	6 ± 14	<0.001
Median (inter-quartile range)	33 (13–62)	21 (5–36)	10 (6–19)	3 (2–5)
Labor
Spontaneously	4 (21.1%)	3 (20%)	1 (3.8%)	1 (3.7%)	0.03
Induced	13 (68.4%)	4 (26.7%)	16 (61.5%)	14 (51.9%)
No labor	2 (10.5%)	8 (53.3%)	9 (34.6%)	12 (44.4%)
Delivery
Cesarean delivery	7 (36.8%)	11 (73.3%)	15 (57.7%)	19 (70.4%)	0.2
Induced for preeclampsia (either at term or preterm)	4 (21.1%)	10 (66.7%)	25 (96.2%)	26 (96.3%)	<0.001
Maternal complications
Abruption	1 (5.3%)	--	--	4 (14.8%)	0.08
Pulmonary edema	--	--	2 (7.7%)	2 (7.7%)	0.4
HELLP	--	--	1 (3.8%)	1 (3.7%)	0.7
Eclampsia	--	--	1 (3.8%)	1 (3.8%)	0.7
Neonatal outcomes
GA at delivery (weeks)
Mean ± SD	37 ± 2.3	37 ± 1.5	33 ± 2.9	32 ± 3.4	<0.001
Median (inter-quartile range)	38 (36–39)	37 (37–38)	34 (32–35)	32 (30–36)
Delivery <34 weeks	2 (10.5%)	1 (6.7%)	10 (38.5%)	17 (63%)
Delivery <37 weeks	5 (26.3%)	3 (20%)	26 (100%)	25 (92.6%)
Birth weight (grams)	3120 ± 637	2627 ± 665	1907 ± 714	1566 ± 630	<0.001
<10%	1 (5.3%)	8 (53.3%)	9 (34.6%)	15 (55.6%)
<5%	1 (5.3%)	4 (26.7%)	5 (19.2%)	7 (25.9%)
Apgar at 5 minutes <7	--	1 (6.7%)	1 (3.8%)	5 (18.5%)	0.09

Table III.  Demographic and clinical characteristics of uncomplicated pregnant women whose samples were used to construct the reference range (n = 180)

Age (years)	23 ± 4
African-American	149 (82.8%)
Nulliparous	63 (35%)
Smoking	24 (13.3%)
BMI (Kg/m^2)	27.7 ± 6.8
GA at 1st US (weeks)	12.6 ± 4.1
GA at delivery (weeks)	39.6 ± 1.0
Birth weight (grams)	3350 ± 304

Figure 1.  Plasma concentration of sVEGFR-1 in Multiple of Median (MoM) unit. The mean MoM plasma concentration of sVEGFR-1 was significantly higher in patients with mild preeclampsia who subsequently developed severe preeclampsia than those who remained stable until term (p = 0.002). Comparisons among groups were performed after logarithmic transformation.

Figure 2.  Plasma concentration of sEng in Multiple of Median (MoM) unit. The mean MoM plasma concentration of sEng was significantly higher in patients with mild preeclampsia who subsequently developed severe preeclampsia than those who remained stable until term (p = 0.008). Comparisons among groups were performed after logarithmic transformation.

Figure 3.  Plasma concentration of PlGF in Multiple of Median (MoM) unit. The mean MoM plasma concentration of PlGF was significantly lower in patients with mild preeclampsia who subsequently developed severe preeclampsia than those who remained stable until term (p = 0.005). Comparisons among groups were performed after logarithmic transformation.

Figure 4.  Plasma concentration of sVEGFR-2 in Multiple of Median (MoM) unit. The mean MoM plasma concentration of sVEGFR-2 was significantly lower in patients with mild preeclampsia who subsequently developed severe preeclampsia than those who remained stable until term (p = 0.001). Comparisons among groups were performed after logarithmic transformation.

Figure 5.  Plasma concentration of PlGF/sVEGFR-1 ratio in Multiple of Median (MoM) unit. The mean MoM plasma concentration of PlGF/sVEGFR-1 ratio was significantly lower in patients with mild preeclampsia who subsequently developed severe preeclampsia than those who remained stable until term (p < 0.001). Comparisons among groups were performed after logarithmic transformation.

Figure 6.  Plasma concentration of PlGF/sEng ratio in Multiple of Median (MoM) unit. The mean MoM plasma concentration of PlGF/sEng ratio was significantly lower in patients with mild preeclampsia who subsequently developed severe preeclampsia than those who remained stable until term (p = 0.002). Comparisons among groups were performed after logarithmic transformation.

Table IV.  Diagnostic performance of plasma concentrations of angiogenic/anti-angiogenic factors for the identification of patients who subsequently develop severe preeclampsia (Group III and IV).

	Cut-off (MoM) derived from ROC	AUC (95% CI)	Sensitivity (%)	Specificity(%)	Likelihood Ratio of a positive test	Posterior probability(95% CI)	Likelihood Ratio of a negative test	Posterior probability(95% CI)
sVEGFR-1	≥3.46	84 (76–93)	81 (43/53)	79 (27/34)	3.9 (2.0–7.7)	86% (76–92)	0.24 (0.13–0.43)	27% (17–40)
sEng	≥2.693	87 (79–95)	81 (43/53)	88 (30/34)	6.9 (2.7–17)	91% (81–96)	0.21 (0.12–0.38)	25% (16–37)
PlGF	≤0.396	87 (79–95)	94 (50/53)	71 (24/34)	3.2 (1.9–5.4)	83% (75–89)	0.08 (0.03-0.25)	11% (4-28)
sVEGFR-2	≤0.74	81 (71–91)	74 (39/53)	79 (24/34)	3.6 (1.8–7.1)	85% (74–92)	0.33 (0.21–0.54)	34% (25–46)
PlGF/sVEGFR-1	≤0.05	88 (81–96)	74 (39/53)	91 (31/34)	8.3 (2.8–25)	93% (81–97)	0.29 (0.18–0.46)	31% (22–42)
PlGF/sEng	≤0.07	90 (83–97)	76 (40/53)	91 (31/34)	8.6 (2.9–25)	93% (82–97)	0.27 (0.17–0.44)	30% (21–41)

Prevalence of severe preeclampsia requiring preterm delivery = 60.9% (53/87).

Figure 7.  Plasma concentrations of sVEGFR-1 (ng/ml) in patients from each study group plotted against a reference range (2.5th, 5th, 50th, 95th, and 97.5th percentile) derived from quantile regression of 1046 samples obtained from 180 uncomplicated pregnant women.

Figure 8.  Plasma concentrations of sEng (ng/ml) in patients from each study group plotted against a reference range (2.5th, 5th, 50th, 95th, and 97.5th percentile) derived from quantile regression of 1046 samples obtained from 180 uncomplicated pregnant women.

Figure 9.  Plasma concentrations of PlGF (ng/ml) in patients from each study group plotted against a reference range (2.5th, 5th, 50th, 95th, and 97.5th percentile) derived from quantile regression of 1046 samples obtained from 180 uncomplicated pregnant women.

Figure 10.  Plasma concentrations of sVEGFR-2 (ng/ml) in patients from each study group plotted against a reference range (2.5th, 5th, 50th, 95th, and 97.5th percentile) derived from quantile regression of 1046 samples obtained from 180 uncomplicated pregnant women.

Figure 11.  Plasma concentrations of PIGF/sVEGFR-1 ratio in patients from each study group plotted against a reference range (2.5th, 5th, 50th, 95th, and 97.5th percentile) derived from quantile regression of 1046 samples obtained from 180 uncomplicated pregnant women.

Figure 12.  Plasma concentrations of PlGF/sEng ratio in patients from each study group plotted against a reference range (2.5th, 5th, 50th, 95th, and 97.5th percentile) derived from quantile regression of 1046 samples obtained from 180 uncomplicated pregnant women.

Table V.  Diagnostic performance of plasma concentrations of angiogenic/anti-angiogenic factors in patients who presented at <34 weeks for the identification of those who subsequently delivered within 14 days due to preeclampsia.

GA at blood sampling <34 weeks	Cut-off (MoM) derived from ROC	AUC (95% CI)	Sensitivity (%)	Specificity (%)	Likelihood Ratio of a positive test (95% CI)	Posterior probability (95% CI)	Likelihood Ratio of a negative test (95% CI)	Posterior probability (95% CI)
sVEGFR-1	≥3.97	86 (76–96)	93 (25/27)	75 (24/32)	3.70 (2.0–6.8)	76% (63–85)	0.10 (0.03–0.38)	8% (2–24)
sEng	≥2.96	84 (74–95)	96 (26/27)	75 (24/32)	3.85 (2.1–7.1)	76% (64–86)	0.05 (0.01–0.34)	4% (1–22)
PlGF	≤0.152	85 (75–95)	82 (22/27)	84 (27/32)	5.21 (2.29–12)	81% (66–91)	0.22 (0.10–0.49)	16% (8–29)
sVEGFR-2	≤0.74	82 (72–93)	82 (22/27)	72 (23/32)	2.90 (1.6–5.2)	71% (58–81)	0.26 (0.11–0.59)	18% (9–33)
PlGF/sVEGFR-1	≤0.033	88 (79–97)	93 (25/27)	78 (25/32)	4.23 (2.2–8.2)	78% (65–87)	0.09 (0.02-0.36)	7% (2–23)
PlGF/sEng	≤0.05	87 (77–96)	85 (23/27)	84 (27/32)	5.45 (2.4–12)	82% (67–91)	0.18 (0.07–0.44)	13% (6–27)

Prevalence of patients who subsequently delivered within 14 days due to severe preeclampsia = 45.8% (27/59).

Figure 13.  Survival curve of patients who had plasma concentration of PlGF/sVEGFR-1 ratio ≤ 0.033 MoM and >0.033 MoM. This cut-off was associated with a shorter interval-to-delivery due to preeclampsia [PlGF/sVEGFR-1 > 0.033 MoM: n = 27, censored 5; median survival 41 days, interquartile range (IQR) 22–85 days vs. PlGF/sVEGFR-1 ≤ 0.033 MoM: n = 32, censored 3, median survival 6 days, IQR 3-10 days; p < 0.001; hazard ratio = 6 (95% CI 2.5–14.6)].

Figure 14.  Plasma concentrations of PIGF/sVEGFR-1 ratio in patients from each study group plotted against a reference range (2.5th, 5th, 50th, 95th, and 97.5th percentile) and the cut-offs (dash line) according to the 3-zone classification.

Figure 15.  Plasma concentrations of PlGF/sEng ratio in patients from each study group plotted against a reference range (2.5th, 5th, 50th, 95th, and 97.5th percentile) and the cut-offs (dash line) according to the 3-zone classification.

Table VI.  Rate of preterm delivery in patients presenting to the obstetrical triage area at <34 weeks with a diagnosis of “suspected preeclampsia” according to the 3-zone classification of plasma angiogenic/anti-angiogenic factor concentrations.

Preterm delivery	Prevalence % (n/N)	PlGF/sVEGFR-1 (MoM)			PlGF/sEng (MoM)
		≥0.35 (n = 16)	0.051–0.35 (n = 10)	≤0.05 (n = 33)	≥0.30 (n = 16)	0.071–0.30 (n = 10)	≤0.07 (n = 33)
Delivery <34 weeks	50.8% (30/59)	6.3% (1/16)	30.0% (3/10)	78.8% (26/33)	6.3% (1/16)	36.4% (4/10)	75.8% (25/33)
Delivery <34 weeks due to PE	44% (26/59)	0 (0/16)	30.0% (3/10)	69.7% (23/33)	0 (0/16)	30.0% (3/10)	69.7% (23/33)
Delivery within 14 days	52.5% (31/59)	6.3% (1/16)	20.0% (2/10)	84.8% (28/33)	6.3% (1/16)	40.0% (4/10)	78.8% (26/33)
Delivery within 14 days due to PE	45.8% (27/59)	0 (0/16)	20.0% (2/10)	75.8% (25/33)	0 (0/16)	30.0% (3/10)	72.7% (24/33)
Delivery within 7 days	39% (23/59)	6.3% (1/16)	20.0% (2/10)	60.6% (20/33)	6.3% (1/16)	40.0% (4/10)	54.5% (18/33)
Delivery within 7 days due to PE	33.9% (20/59)	0 (0/16)	20.0% (2/10)	54.5% (18/33)	0 (0/16)	30.0% (3/10)	51.5% (17/33)

PE: preeclampsia; MoM: multiple of the medians

Table VII.  Disposition of patients with “suspected preeclampsia” before 34 weeks of gestation from the triage area according to the 3-zone classification of plasma angiogenic/anti-angiogenic factor concentrations.

	PlGF/sVEGFR-1 (MoM)			PlGF/sEng (MoM)
	≥0.35 (n = 16)	0.051–0.35 (n = 10)	≤0.05 (n = 33)	≥0.30 (n = 16)	0.071–0.30 (n = 10)	≤0.07 (n = 33)
Home	8 (50%)	2 (20%)	2 (6.1%)	8 (53.3%)	2 (18.2%)	2 (6.1%)
Hospitalized	8 (50%)	8 (80%)	31 (93.9%)	8 (50%)	8 (80%)	31 (93.9%)

p < 0.005 for both PlGF/sVEGFR-1 and PlGF/sEng.

Table VIII.  Obstetrical characteristics and plasma concentrations of PlGF/sVEGFR-1 and PlGF/sEng ratio in patients with severe maternal complications.

Complications	Group	Diagnosis in triage	Diagnosis at delivery	Gestational age at blood Draw (weeks)	Gestational age at delivery (weeks)	Birth weight (grams)	%	PlGF/sVEGFR-1 (MoM)	PlGF/sEng (MoM)	Apgar at 1/5 minute	Interval to delivery (days)
Placental Abruption	I	GHTN	GHTN	26.3	38.3	3265	50	0.667	0.983	9/9	85
Placental Abruption	IV	CHTN +SPE	CHTN +SPE	27.9	28.3	810	11.2	0.001	0.002	7/9	3
Placental abruption	IV	CHTN +SPE	CHTN +SPE	30.1	30.3	1120	12.5	0.006	0.006	0/0	1
Placental abruption	IV	CHTN +SPE	CHTN +SPE	30.4	30.7	1250	22	0.001	0.001	6/8	2
Placental abruption	IV	Severe PE	Severe PE	32.1	32.9	1585	15.1	0.011	0.040	5/6	5
HELLP	III	Mild PE	Severe PE	27.6	28.4	715	6.8	0.001	0.001	3/6	6
HELLP	IV	Severe PE	Severe PE	31.6	31.7	1660	33.9	0.003	0.003	6/7	1
Pulmonary edema	III	CHTN +SPE	CHTN +SPE	26.3	28.9	941	24.4	0.062	0.064	5/8	18
Pulmonary edema	III	Mild PE	Severe PE	25.7	26.6	750	28.2	0.005	0.014	6/7	6
Pulmonary edema	IV	Severe PE	Severe PE	32.1	32.9	1585	15.1	0.011	0.040	5/6	5
Pulmonary edema	IV	Severe PE	Severe PE	35.7	36	2235	7	0.032	0.054	6/8	2
Eclampsia	III	Mild PE	Severe PE	36.6	36.6	3125	58.7	0.116	0.232	6/8	0
Eclampsia	IV	Severe PE	Severe PE	36.9	37.1	1670	1	0.005	0.005	7/8	2

PE, preeclampsia; GHTN, gestational hypertension; CHTN, chronic hypertension; SPE, superimposed preeclampsia; %, percentile.