The extension cohort included only a subset of women who met our inclusion criteria (N=541), as previously described (Figure 1).
Demographics
The women in the extension cohort (compared with those in the original fullPIERS development cohort) were different in a number of ways (Table 2). In general, women admitted with preeclampsia in the original fullPIERS cohort were known to be managed expectantly, whereas those admitted in the extension cohort settings (mostly in the USA) were more likely to be delivered; this was also evident in the shorter admission-to-delivery interval. On average, the women in the extension cohort were younger with lower blood pressure measurements and presenting with earlier-onset of preeclampsia than the women in the fullPIERS cohort. They were also more likely to be multiparous, smokers, and receive magnesium sulfate; have a shorter admission-to-delivery interval with early-onset preeclampsia (gestational age [GA] <34 weeks); and have babies with lower birth weight, compared with the fullPIERS cohort. There were no meaningful differences in the proportions of multifetal pregnancies or treatment with antihypertensive medication. Adverse maternal outcomes occurred in 8.1% of women within 48 hours of admission, 9.6% within seven days of admission, and 10.5% at any time during admission.
Table 2. Maternal characteristics for the fullPIERS Development cohort vs Extension cohort, (n (%) or median (interquartile range))
Characteristics
|
fullPIERS cohort (development)
(2,023 women)
|
Extension cohort
(541 women)
|
P value
|
Demographics & pregnancy charaCteristics
|
|
|
|
Maternal age at EDD (year)
|
31 [27, 36]
|
30 [24, 34]
|
<0.001
|
Parity ≥1
|
581 (28·7%)
|
219 (40.4%)
|
<0.001
|
Gestational age at eligibility (week)
|
36 [33, 38·3]
|
33.0 [29.7, 35.9]
|
<0.001
|
Gestational age at eligibility <34 weeks, N
|
636 (31.4%)
|
307 (56.7%)
|
<0.001
|
Multiple pregnancy
|
192 (9·5%)
|
43 (8.0%)
|
0.2468
|
Smoking in this pregnancy
|
249 (12·3%)
|
118 (21.8%)
|
<0.001
|
Interventions during admission
|
|
|
|
Corticosteroids, GA onset <34
|
440/636 (69.2%)
|
128/307 (41.7%)
|
<0.001
|
Antihypertensive therapy
|
1381 (68·3%)
|
384 (71.0%)
|
0.054
|
MgSO4
|
690 (34·1%)
|
410 (75.8%)
|
<0.001
|
Pregnancy outcomes
|
|
|
|
Admission-To-Delivery Interval, <34⁺⁰ Weeks (Days), mean (SD)
|
10.9 (11)
|
5.0 (8)
|
<0.001
|
Gestational age at delivery (week), median (IQR)
|
36.9 [34·1, 38·6]
|
33.9 [30.5, 36.4]
|
<0.001
|
Stillbirth
|
20 (1.0%)
|
10 (1.9%)
|
0.2489
|
Neonatal death
|
26 (1·3%)
|
12 (2.2%)
|
0.0989
|
ADVERSE MATERNAL OUTCOME
(N women)
|
|
|
|
Within 48h
|
106 (5.2%)
|
44 (8.1%)
|
0.023
|
Within 7 days
|
203 (10.0%)
|
52 (9.6%)
|
0.067
|
At anytime
|
261 (12.9%)
|
57 (10.5%)
|
0.243
|
Abbreviations: EDD – Estimated date of delivery, GA – Gestational age, MgSO4 – Magnesium sulphate, SD – standard deviation, IQR – interquartile range
PlGF was classified as low (<100 pg/ml) in 485 women (89.6%) (Table 3). Low maternal PlGF concentrations were more likely among women with earlier onset of preeclampsia, higher blood pressure, and babies with lower birth weight. Low PlGF was present in almost all women who went on to experience adverse maternal (N= 53/57, 93.0%) at any time during admission.
Table 3. Maternal characteristics for Normal vs Low PlGF values in the Extension data, (n (%) or median (interquartile range))
Characteristics
|
Low PlGF
(< 100 pg/ml),
n (%) or median (IQR),
(n=485)
|
Normal PlGF
(≥100 pg/ml),
n (%) or median (IQR),
(n=56)
|
Demographics & pregnancy charateristics
|
|
|
Maternal age at EDD (year)
|
30 [24, 34]
|
29 [26, 34]
|
Parity ≥1
|
192 (39.6%)
|
27 (48.2%)
|
Gestational age at eligibility (week)
|
32.6 [29.6, 35.7]
|
35.2 [33.4, 36.8]
|
Gestational age at eligibility <35 weeks, N
|
329 (67.8%)
|
26 (46.4%)
|
Multiple pregnancy
|
40 (8.2%)
|
3 (5.4%)
|
Smoking in this pregnancy
|
101 (20.8%)
|
17 (30.4%)
|
CLINICAL MEASURES
|
|
|
Systolic BP (mm Hg)
|
144 [135, 155]
|
136 [126, 150]
|
Diastolic BP (mm Hg)
|
86 [78, 94]
|
80 [74, 91]
|
Uric acid
|
375 [315, 435]
|
297 [256, 351]
|
Lowest platelet count (×109 per L)
|
199 [154, 243]
|
226 [160, 251]
|
Highest AST/ALT (U/L)
|
24 [19, 37]
|
18 [16, 24]
|
Creatinine
|
62 [53, 71]
|
53 [44, 62]
|
Interventions during admission
|
|
|
Corticosteroids, GA onset <35
|
127/329 (38.6%)
|
7/26 (26.9%)
|
Antihypertensive therapy
|
348 (71.8%)
|
36 (64.3%)
|
MgSO4
|
376 (77.5%)
|
34 (60.7%)
|
Pregnancy outcomes
|
|
|
Admission-To-Delivery Interval (Days)
|
2 [1, 4]
|
2 [1, 7]
|
Gestational age at delivery (week)
|
33.3 [30·1, 36.3]
|
36.1 [34.7, 37.3]
|
Stillbirth
|
10 (2.1%)
|
0
|
Neonatal death
|
12 (2.5%)
|
0
|
MATERNAL OUTCOME (N women)
|
|
|
Within 48h
|
41 (8.5%)
|
3 (5.4%)
|
Within 7 days
|
49 (10.1%)
|
3 (5.4%)
|
At anytime
|
53 (10.9%)
|
4 (7.1%)
|
PlGF measurement-To-adverse maternal outcome Interval (at any time, Days)
|
3 [2, 6]
Mean = 4
|
3 [1, 5]
Mean = 2
|
Abbreviations: AST (aspartate aminotransferase), BP (blood pressure), EDD (estimated date of delivery), MgSO4 (magnesium sulphate)
Prediction of adverse maternal outcomes after adding PlGF to fullPIERS
In our analyses, the original fullPIERS model (AUROC 0.67 [95% CI 0.58-0.76]) and PlGF alone (AUROC 0.60 [95% CI 0.52-0.67]) showed poor discriminatory performance for prediction of adverse maternal outcomes within 48 hours of admission in the extension cohort (Figure 2). Addition of PlGF to fullPIERS neither altered the odds of an adverse maternal outcome (OR 0.98 [95% CI 0.99-1.00]) for every percentile increase in PlGF (Table 1), nor discriminatory performance (AUROC 0.67 [95% CI 0.59-0.75]) (Figure 2).
With addition of PlGF to fullPIERS, using a threshold of ≥10% for the calculated predicted probabilities, there were eight upward movements of women with adverse maternal outcomes into the high-risk category and two fewer cases without adverse maternal outcomes in the highest-risk category compared with the classification using the original model (Table 4). The overall improvement in specificity was 11.9%, with a decrease of 18.4% in sensitivity using the extended model. Thus, the NRI was -8.7, indicating no overall improvement in reclassification of risks. The discrimination slope for the extended model (fullPIERS plus PlGF) was 0.03, compared with 0.09 for the original model (Figure 3). The IDI was -0.06, also indicating no meaningful improvement in discrimination.
Table 4. Reclassification Table for Extended Model with PlGF (fullPIERS plus PlGF)
fullPIERS Model without PlGF
|
Predicted probability
|
Women with events
|
Women without events
|
Total
|
0 to 9%
|
37
|
475
|
512
|
≥ 10%
|
7
|
22
|
29
|
Total
|
44
|
497
|
541
|
fullPIERS model with PlGF
|
Predicted probability
|
Women with events
|
Women without events
|
Total
|
0 to 9%
|
29
|
416
|
445
|
≥ 10%
|
15
|
81
|
96
|
Total
|
44
|
497
|
541
|
Net reclassification index (NRI) calculation
Original fullPIERS model
Sensitivity = 37/44*100 = 84.1%; Specificity = 22/497*100 = 4.4%
fullPIERS model + PlGF (extended fullPIERS model)
Sensitivity = 29/44*100 = 65.9%; Specificity =81/497*100 = 16.3%
Improved sensitivity = 65.9% - 84.3% = -18.4%; Improved specificity = 16.3% - 4.4% = 11.9%
NRI = Improved sensitivity + Improved specificity = -18.4% + 9.7% = -8.7%