Characteristics of Included Patients
Table 1 shows clinical characteristics of the 329 pregnant women. Among patients with PE, 170 patients measured 24-hour proteinuria, and divided them into 3 groups according to the quantitative level of 24hour urine protein (A vs. B vs. C). Group A was defined as proteinuria < 0.3g/24 hours (n=53, mean 24-hour proteinuria = 136.27 ± 89.39 mg/24h), group B was defined as 0.3 to 2 g/24 hours (n=64, mean 24-hour proteinuria = 884.29 ± 538.33 mg/24h) and group C was defined as urinary protein excretion exceeding 2 g in 24 hours (n=53, mean 24-hour proteinuria = 6246.13 ± 5099.54 mg/24h).
Between non-PE and PE groups, the maternal age and cesarean section rate were higher in PE group than non-PE group (p < 0.001). Laboratory findings such as SBP and DBP at admission, ALT, AST, uric acid and creatinine level in PE group were higher than those in non-PE group (p < 0.001), the levels of albumin was lower than those in non-PE group (P < 0.001).
Among three subgroups, C group had a shorter gestational age at delivery than A and B group(p < 0.001). Laboratory findings such as SBP, DBP, uric acid and creatinine were found higher in C group than A and B group (p < 0.001). We also found that the higher level of proteinuria was, the lower level of albumin (p < 0.001). The other clinical characteristics such as age, nulliparaty, mode of delivery were not significantly different among three groups.
Table1:Characteristics of included women
|
Non-PE
|
PE
|
p value
|
Subgroups
|
p value
|
A
|
B
|
C
|
number
|
54
|
275
|
-
|
53
|
64
|
53
|
-
|
Clinical characteristics
|
|
|
|
|
|
|
|
Mean age
|
27.61±4.52
|
30.16±5.53
|
<0.001
|
31.70±5.51
|
30.27±6.00
|
31.28±5.12
|
0.180
|
Gestation week
|
37.96±3.71
|
36.65±3.68
|
0.012
|
37.19±2.20
|
37.31±2.87
|
34.53±4.19ab
|
<0.001
|
Mode of delivery
|
|
|
|
|
|
|
|
Spontaneously
|
38
|
24
|
<0.001
|
6
|
1
|
1
|
0.038
|
Caesarean section
|
14
|
232
|
|
46
|
59
|
42
|
|
Laboratory findings
|
|
|
|
|
|
|
|
SBP,mmHg
|
113.46±9.67
|
146.34±18.24
|
<0.001
|
140.76±14.23
|
143.67±17.72
|
155.40±19.53ab
|
<0.001
|
DBP,mmHg
|
70.5±8.53
|
95.44±13.68
|
<0.001
|
91.30±9.83
|
93.60±13.10
|
104.15±14.42ab
|
<0.001
|
ALT, U/L
|
14.58±13.34
|
34.59±64.46
|
<0.001
|
37.79±93.46
|
24.51±25.83
|
43.62±78.85
|
0.055
|
AST, U/L
|
18.37±6.89
|
35.82±49.85
|
<0.001
|
35.70±67.53
|
30.01±40.16
|
43.63±64.72
|
0.191
|
Albumin,g/L
|
37.44±4.55
|
34.15±4.92
|
<0.001
|
36.63±3.62
|
34.23±4.38a
|
31.38±4.52ab
|
<0.001
|
Uric acid, μmol/L
|
315.72±67.35
|
424.38±108.67
|
<0.001
|
352.09±82.85
|
419.66±119.40a
|
460.14±99.80a
|
<0.001
|
Creatinine, μmol/L
|
45.22±6.23
|
62.53±46.85
|
<0.001
|
46.44±8.46
|
58.53±18.95
|
72.52±41.09ab
|
<0.001
|
24-hour urine collection, mg/24h
|
-
|
-
|
-
|
136.27±89.39
|
884.29±538.33
|
6246.13±5099.54ab
|
<0.001
|
ALT, Alanine aminotransferase; AST, Aspartate aminotransferase; DBP, Diastolic Blood Pressure; SBP: Systolic Blood Pressure; A: 24-hour urinary protein < 0.3 g; B: 24-hour urinary protein 0.3~2g; C: 24-hour urinary protein ≧ 2g; a compared with A group,p < 0.05; b compared with B group, p < 0.05.
Comparison of Adverse Pregnancy Outcomes In Pregnant Women
Table 2 shows the adverse pregnancy outcomes. The frequencies of adverse outcomes (both maternal and fetal complications included) were 27.78% in non-PE group and 51.27% in PE group (p = 0.001). For patients with different proteinuria level, the frequency of adverse pregnancy outcomes was 41.5% in group A, 45.3% in group B and 77.4% in group C (p < 0.001), it seems that the higher degree of proteinuria, the higher chance of adverse outcomes.
The number of maternal complications in PE group (92/275, 33.5%) was more than that in non-PE group (2/54,3.7%), (P < 0.001). Compared with non-PE group, PE group had a higher incidence in hypoproteinemia (p = 0.006), organ dysfunction (p = 0.041), retinal detachment (p = 0.047). Other maternal outcomes such as pleural and peritoneal effusion, eclampsia, DIC, postpartum hemorrhage, hemorrhagic anemia, placental abruption, maternal death, has no significant difference compared with normal pregnancy group (p > 0.05).
In PE subgroups, The induction rate was different among 3 groups (p = 0.006). The incidences of hypoproteinemia, organ dysfunction were significantly different among three groups(A: 5.7%; B: 12.5%; C: 35.8%; p < 0.001 for hypoproteinemia; A: 5.7%; B: 0%; C: 13.2%; p = 0.010 for organ dysfunction). No significant differences were observed in other maternal complications, such as placental abruption, retinal detachment. No pregnant women died in the three groups.
Table2:Comparison of maternal complications
|
Non-PE
|
PE
|
p value
|
subgroups
|
p value
|
A
|
B
|
C
|
number
|
54
|
275
|
|
53
|
64
|
53
|
|
Mode of delivery
|
|
|
|
|
|
|
|
Spontaneously
|
38
|
24
|
<0.001
|
6
|
1
|
1
|
0.038
|
Caesarean section
|
14
|
232
|
|
46
|
59
|
42
|
|
Induction
|
2
|
19
|
0.378
|
1
|
4
|
10
|
0.006
|
Total adverse
outcomes
|
15
|
145
|
0.001
|
22
|
29
|
41
|
<0.001
|
adverse maternal outcomes
|
2
|
92
|
<0.001
|
11
|
21
|
26
|
0.009
|
Retinal disease
|
0
|
19
|
0.047
|
1
|
2
|
3
|
0.561
|
Hypoproteinemia
|
1
|
44
|
0.006
|
3
|
8
|
19
|
<0.001
|
Organ dysfunction
|
0
|
20
|
0.041
|
3
|
0
|
7
|
0.010
|
Maternal death
|
0
|
1
|
0.657
|
0
|
0
|
0
|
-
|
Organ dysfunction* : including heart,liver ,renal dysfunction, pleural effusio and peritoneal effusion
Comparison of Adverse Fetal Outcomes among Groups
Adverse fetal outcomes are shown in Table 3. The number of adverse fetal outcomes is different in five groups (non-PE group: 13/54 vs. PE group: 124/275, p = 0.004; group A: 16/53 vs. group B: 19/64 vs. group C: 36/53, p < 0.001).
Between non-PE and PE group, PE group had higher frequencies in premature (p = 0.010), FGA (p = 0.024), light for date infant (p = 0.014), and oligohydramnios(p = 0.012). In another three subgroups, only the rate of premature (p = 0.009), stillbirth ( p = 0.001) and birth weight (p = 0.001) have significant difference. Though it seems that group C had more fetal complications, the incidence not increased by 24-hour proteinuria degree.
Table3:Adverse fetal outcomes
|
Non-PE
|
PE
|
p value
|
subgroups
|
p value
|
A
|
B
|
C
|
Number
|
54
|
275
|
-
|
53
|
64
|
53
|
-
|
Total adverse fetal outcomes
|
13
|
124
|
0.004
|
16
|
19
|
36
|
<0.001
|
Premature(<37week)
|
3
|
56
|
0.010
|
15
|
7
|
18
|
0.009
|
FGR
|
0
|
24
|
0.024
|
3
|
5
|
6
|
0.563
|
Low birth weight*
|
0
|
28
|
0.014
|
6
|
4
|
4
|
0.596
|
Oligohydramnios
|
0
|
29
|
0.012
|
6
|
8
|
3
|
0.437
|
Stillbirth
|
1
|
16
|
0.229
|
0
|
3
|
9
|
0.002
|
Birth weight, g
|
3157.46±494.72
|
2878.16±709.86
|
0.008
|
2872.02±559.15
|
3010.25±607.36
|
2444.76±871.95
|
0.001
|
Low birth weight*: including light for date infant and premature low birth weight infants; FGR: Fetal Growth Restriction;A: 24-hour urinary protein < 0.3g ; B:24-hour urinary protein 0.3~2g; C:24-hour urinary protein ≧ 2g
Correlation Analysis of Risk Factors of Adverse Pregnancy Outcome
In order to further determine the impact of proteinuria and other factors on pregnancy outcomes in patients with PE, a correlation test and binary logistics regression analysis were used in the multivariate analysis to compare parameters with P < 0.05 in the univariate analysis, as shown in Table 4 and Table 5. Albumin, uric acid, creatinine, gestational weeks and proteinuria were associated with maternal complications in preeclampsia pregnant women (albumin: r = -0.405, p < 0.001; uric acid: r = 0.304, p < 0.001; creatinine r = 0.235, p = 0.003; gestational weeks: r = -0.236, p = 0.003; proteinuria: r = 0.239, p = 0.002). The factors highly related to the adverse fetal outcome were gestational weeks (r = -0.463, p < 0.001) and proteinuria (r = 0.336, p < 0.001). Incorporate meaningful indicators of correlation analysis into multivariate logistic analysis, the predictive indicators with statistically significant differences obtained by multivariate regression analysis are albumin, urine acid. Proteinuria is negatively correlated with gestational week ( r = -0.309, p < 0.001) and albumin (r = -0.360, p < 0.001), suggesting that 24-hour proteinuria may have an indirect predictive value for adverse outcomes.
Table4.Correlation test between various diagnostic indicators and adverse outcomes
|
|
Gestational weeks
|
24-hour urine protein (mg/24h)
|
SBP
|
DBP
|
Albumin
|
Urine acid
|
Creatinine
|
r
|
Maternal complications
|
-0.236
|
0.239
|
0.057
|
0.026
|
-0.405
|
0.304
|
0.235
|
p
|
0.003
|
0.002
|
0.256
|
0.381
|
<0.001
|
<0.001
|
0.003
|
r
|
Fetal complications
|
-0.463
|
0.345
|
0.244
|
0.328
|
-0.296
|
0.228
|
0.145
|
p
|
<0.001
|
<0.001
|
0.002
|
<0.001
|
<0.001
|
0.004
|
0.048
|
r
|
24h proteinuria
|
-0.309
|
1
|
0.226
|
0.290
|
-0.360
|
0.197
|
0.166
|
p
|
<0.001
|
-
|
0.004
|
<0.001
|
<0.001
|
0.020
|
0.052
|
Table5:Multivariate logistic model predicting adverse outcomes of preeclampsia
|
|
B
|
|
Standard deviation
|
|
WALD
|
|
Sig.
|
|
OR (95CI%)
|
|
|
|
Adverse maternal outcomes
|
|
|
|
|
|
|
albumin
Urine acid
proteinuria
creatinine
Gestational week
constant
|
-0.157
|
.052
|
9.163
|
.002
|
.855(0.773-0.946)
|
|
0.004
|
.002
|
3.978
|
.046
|
1.004(1.000-1.009)
|
|
0.000
|
.000
|
0.178
|
.673
|
1.000(1.000-1.000)
|
|
-0.002
|
.009
|
0.040
|
.841
|
0.998(0.980-1.016)
|
|
-0.079
|
.056
|
1.956
|
.162
|
0.924(0.828-1.032)
|
|
5.871
|
2.955
|
3.946
|
.047
|
354.479
|
|
Adverse fetal outcomes
|
|
|
|
|
|
|
Nulliparaty
|
-0.163
|
.452
|
0.129
|
0.719
|
0.850(0.351-2.061)
|
|
Gestational week
|
-0.111
|
.066
|
2.854
|
.091
|
.895(0.787-1.018)
|
|
proteinuria
|
0.000
|
.000
|
0.395
|
.530
|
1.000(1.000-1.000)
|
|
SBP
|
0.013
|
.019
|
0.513
|
.474
|
1.013(0.977-1.051)
|
|
DBP
|
-0.041
|
.027
|
2.337
|
.126
|
.960(0.911-1.012)
|
|
albumin
|
-0.162
|
.054
|
9.120
|
.003
|
.851(0.766-0.945)
|
|
Urine acid
|
0.005
|
.002
|
4.544
|
.033
|
1.005(1.000-1.009)
|
|
creatinine
|
-0.002
|
.010
|
0.041
|
.839
|
0.998(0.979-1.017)
|
|
ALT
|
-0.001
|
.003
|
0.135
|
.714
|
0.999(0.992-1.006)
|
|
constant
|
9.087
|
4.186
|
4.713
|
.030
|
8842.119
|
|
DBP: Diastolic Blood Pressure; SBP: Systolic Blood Pressure; ALT, Alanine aminotransferase; AST, Aspartate aminotransferase.
The Best 24-hour Urine Protein Cutoff Value in Preeclampsia to Determine Adverse Outcomes
In studying the relationship between 24-hour proteinuria and adverse outcomes in women with preeclampsia, we found there were differences in the incidence of hypoalbuminemia, organ dysfunction, premature delivery and stillbirth in different level of 24-hour proteinuria, so we explore the potential diagnostic value of 24-hour proteinuria to predict adverse outcomes. Table 6 and Figure 1(1a to 1d) show the best 24-hour proteinuria cutoff values based on ROC curves. The cutoff value to determine adverse outcomes was 872.09 mg/24h, its corresponding area under the ROC curve (AUC) was 0.698 (p < 0.001) and odds ratios (95% confidence interval, CI) was 5.03 (2.60-9.74). The cutoff value to determine hypoproteinemia was 1935 mg/24h, the AUC was 0.740 (p < 0.001) and ORs (95% CIs) was 6.7 (2.6-17.4). The cutoff value to determine stillbirth, premature and intrauterine distress were 3965.0 mg/24h, 984.75 mg/24h and 1503.85 mg/24h, those AUC were 0.816, 0.618 and 0.745 (p < 0.001, p = 0.034 and p = 0.003, respectively) and ORs (95%CIs) were 12.46 (3.46-44.88), 2.48 (1.15-5.37) and 10.02 (2.14-46.80), respectively. Although univariate analysis showed that there was a difference in the incidence of organ dysfunction among urinary protein subgroups, the cutoff value obtained by ROC curve was not significant.
Table6:Relationship between 24hour urine protein cutoff value based on ROC curve and pregnant outcomes.
|
24hour urine protein cutoff value(mg/24h)
|
Se
|
Sp
|
OR
|
95% CI of
OR
|
Youden
index
|
AUC
|
Standa-rd error
|
P
|
95%CI
|
Adverse outcomes
|
872.09
|
0.63
|
0.76
|
5.03
|
2.60-9.74
|
0.386
|
0.698
|
0.041
|
<0.001
|
0.618-0.777
|
hypoproteinemia
|
1935
|
0.72
|
0.74
|
6.7
|
2.6-17.4
|
0.46
|
0.740
|
0.057
|
<0.001
|
0.629-0.851
|
Stillbirth
|
3965.0
|
0.67
|
0.86
|
12.46
|
3.46-44.88
|
0.529
|
0.816
|
0.048
|
<0.001
|
0.722-0.910
|
Premature
|
984.75
|
0.62
|
0.60
|
2.48
|
1.15-5.37
|
0.224
|
0.618
|
0.054
|
0.034
|
0.511-0.724
|
Intrauterine distress
|
1503.85
|
0.85
|
0.66
|
10.02
|
2.14-46.80
|
0.492
|
0.745
|
0.055
|
0.003
|
0.638-0.853
|
Se, Sensitivity; Sp, Speciality; OR, Odds Ratio; CI: Confidence Interval; AUC: Area Under Curve.