The demographic characteristics and laboratory measurements of pregnant women
According to maternal serum TBA levels, 11120 pregnant women (94.15%) were control, 563 (4.77%) mild ICP, and 128 (1.08%) severe ICP in this cohort (Table 1). The demographic characteristics of pregnant women were preseaed in Table 1. No subjects were drinking or smoking throughout pregnancy. No significant differences on pre-pregnancy body mass index (BMI), parity and gravidity were observed among three groups. There was also no significant difference on gestational diabetes mellitus among three groups (Table 1). The incidences of gestational hypertension and preeclampsia were significantly higher in pregnant women with mild and severe ICP than controls (Table 1). Maternal serum TBA concentrations, serum aspartate transaminase concentrations, alanine transaminase concentrations, and serum total bilirubin concentrations were significantly higher in pregnant women with mild ICP and severe ICP as compared with controls (Table 2). Moreover, serum TBA concentrations, serum aspartate transaminase concentrations, alanine transaminase concentrations, and serum total bilirubin concentrations were significantly higher in pregnant women with severe ICP than those with mild ICP (Table 2).
Table 1 Maternal demographic characteristics
Demographic variables
|
Control
|
Mild ICP
|
Severe ICP
|
P-value
|
Pregnant women [n (%)]
|
11120 (94.15)
|
563 (4.77)
|
128 (1.08)
|
|
Maternal age (years, mean ± SD)
|
28.2±5.6
|
28.4±5.1
|
28.9±4.5
|
|
<25 [n (%)]
25-34 [n (%)]
≥35 [n (%)]
|
1636 (14.71)
8227 (73.98)
1257 (11.30)
|
121 (21.49)
371 (65.90)
71 (12.61)
|
37 (28.91)
71 (55.47)
20 (15.63)
|
<0.001
|
Maternal BMI [kg/m2, n (%)]
|
21.0±2.9
|
21.0±3.1
|
20.6±3.4
|
|
<18.5 [n (%)]
18.5-22.9 [n (%)]
23.0-27.4 [n (%)]
|
1916 (17.23)
6875 (61.83)
2003 (18.01)
|
113 (20.07)
328 (58.26)
102 (18.12)
|
29 (22.66)
79 (61.72)
15 (11.72)
|
0.159
|
≥27.5 [n (%)]
|
326 (2.93)
|
20 (3.55)
|
5 (3.90)
|
Maternal education (years)
|
|
|
|
|
≤9 (Junior school)
10-15 (High school)
≥16 (University)
|
3527 (31.72)
3457 (31.09)
3669 (32.99)
|
298 (52.93)
149 (26.47)
107 (19.00)
|
74 (57.81)
31 (24.22)
15 (11.72)
|
<0.001
|
Data missing
|
467 (4.20)
|
9 (1.60)
|
8 (6.25)
|
Mode of delivery [n (%)]
|
|
|
|
|
Vaginal delivery
Cesarean delivery
|
6276 (56.44)
4844 (43.56)
|
342 (60.75)
221 (39.25)
|
81 (63.28)
47 (36.72)
|
0.042
|
Parity [n(%)]
|
|
|
|
|
1
≥2
|
8288 (74.53)
2832 (25.47)
|
418 (74.25)
145 (25.75)
|
89 (69.53)
39 (30.47)
|
0.432
|
Gravidity
|
|
|
|
|
1
|
5931 (53.34)
|
297 (52.75)
|
61 (47.66)
|
0.428
|
≥2
|
5189 (46.66)
|
266 (47.25)
|
67 (52.34)
|
Gestational diabetes mellitus [n(%)]
|
|
|
|
|
Yes
|
922 (8.29)
|
55 (9.77)
|
12 (9.38)
|
0.429
|
No
|
10198 (91.71)
|
508 (90.23)
|
116 (90.62)
|
Gestational hypertension [n(%)]
|
|
|
|
|
Yes
|
614 (3.18)
|
74 (4.62)
|
8 (6.25)
|
0.029
|
No
|
10766 (96.82)
|
537 (95.38)
|
120 (93.75)
|
Preeclampsia [n(%)]
|
|
|
|
|
Yes
|
614 (5.52)
|
74 (13.14)
|
18 (14.06)
|
<0.001
|
No
|
10506 (94.48)
|
489 (86.86)
|
110 (85.94)
|
Table 2 Laboratory measurements within the study population
Demographic variables
|
Control
(mean ± SD)
|
Mild ICP
(mean ± SD)
|
Severe ICP
(mean ± SD)
|
Ptrend
|
Total bile acid (TBA), μmol/L
|
3.35±1.98
|
17.19±7.06
|
62.56±23.01
|
<0.001
|
Aspartate transaminase, IU/L
|
23.1±25.1
|
93.2±128.8
|
168.7±167.0
|
<0.001
|
Alanine transaminase, IU/L
|
18.3±30.4
|
110.2±152.6
|
189.3±171.4
|
<0.001
|
Total bilirubin, μmol/L
|
8.04±7.70
|
12.60±11.41
|
33.92±68.66
|
<0.001
|
Direct bilirubin, μmol/L
|
6.19±2.84
|
7.52±5.18
|
24.39±33.80
|
<0.001
|
Indirect bilirubin, μmol/L
|
1.85±2.41
|
4.08±5.81
|
9.53±10.30
|
<0.001
|
Birth sizes among different groups
The correlation between maternal serum TBA levels and birth sizes were analyzed. There were inverse correlations between maternal serum TBA levels and birth weight (r=-0.173, P<0.001), birth length (r=-0.139, P<0.001), head circumference (r=-0.136, P<0.001) and chest circumference (r=-0.151, P<0.001). Subjects were divided into three groups according to maternal serum TBA levels. Birth weight was compared among three groups. As shown in Figure 1A, birth weight was significantly decreased in mild ICP and severe ICP groups as compared with control group. Moreover, birth weight was significantly lower in pregnant women with severe ICP than pregnant women with mild ICP (Figure 1A). Stratification analyses based on neonates' gender was used to further compare birth weight among three groups. Results also showed that birth weight in both boys and girls were lower in the mild ICP and severe ICP groups than in the control group, whereas were the lowest in the severe ICP group (Figure 1A). Birth length, head circumference and chest circumference were then compared among three groups. As shown in Figure 1B-D, birth length, head circumference and chest circumference were significantly lower in the mild ICP and severe ICP groups than in the control group, and were the lowest in the severe ICP group. Stratification analyses based on neonates' gender was used to further compare birth length, head circumference and chest circumference among three groups. As shown in Figure 1B-D, birth length, head circumference and chest circumference in both boys and girls were lower in the mild ICP and severe ICP groups than in the control group, and were the lowest in the severe ICP group.
Association between ICP and the risk of SGA infants
The association between ICP and the risk of SGA infants was analyzed. As shown in Table 3, 24.51% neonates were SGA infants among subjects with mild ICP (RR: 4.07; 95%CI: 3.32, 4.99) and 39.06% among subjects with severe ICP (RR: 8.03; 95%CI: 5.59, 11.54), higher than 7.39% among controls. After adjustment for maternal age, pre-pregnancy BMI, maternal education, parity, gestational diabetes mellitus, gestational hypertension and preeclampsia, RRs for SGA infants were 3.44 (2.72, 4.34) among subjects with mild ICP and 6.54 (4.27, 10.02) among subjects with severe ICP using multiple logistic regression model. Stratification analyses based on neonates' gender was used to further explore the association between ICP and the risk of SGA infants using multiple logistic regression models. For boys, 25.00% neonates were SGA infants among subjects with mild ICP (RR: 4.69; 95%CI: 3.54, 6.19) and 34.72% among subjects with severe ICP (RR: 7.48; 95%CI: 4.55, 12.28), significantly higher than 6.64% among controls (Table 3). After adjustment for maternal age, pre-pregnancy BMI, maternal education parity, gestational diabetes mellitus, gestational hypertension and preeclampsia, RRs for SGA infants were 4.03 (2.92, 5.55) among subjects with mild ICP and 5.04 (2.83, 8.97) among subjects with severe ICP (Table 3). For girls, 23.94% neonates were SGA infants among subjects with mild ICP (RR: 3.50; 95%CI: 2.59, 4.74) and 44.64% among subjects with severe ICP (RR: 8.97; 95%CI: 5.25, 15.34), significantly higher than 8.25% among controls (Table 3). After adjustment for maternal age, pre-pregnancy BMI, maternal education parity, gestational diabetes mellitus, gestational hypertension and preeclampsia, RRs for SGA infants were 2.94 (2.08, 4.15) among subjects with mild ICP and 9.94 (5.21, 18.93) among subjects with severe ICP (Table 3).
Table 3 Crude and adjusted RRs for SGA in different groups
Demographic variables
|
Control
(n=11120)
|
Mild ICP
(n=563)
|
Severe ICP
(n=128)
|
SGA [n (%)]
|
822 (7.39)
|
138 (24.51)
|
50 (39.06)
|
Crude RR (95% CI)
|
1.00
|
4.07 (3.32, 4.99)**
|
8.03 (5.59, 11.54)**
|
Adjusted RR (95% CI) 1
|
1.00
|
3.44 (2.72, 4.34)**
|
6.54 (4.27, 10.02)**
|
Stratification analyses based on neonates' gender
|
Boys (n)
|
5917
|
304
|
72
|
SGA [n (%)]
|
393 (6.64)
|
76 (25.00)
|
25 (34.72)
|
Crude RR (95% CI)
|
1.00
|
4.69 (3.54, 6.19)**
|
7.48 (4.55, 12.28)**
|
Adjusted RR (95% CI) 1
|
1.00
|
4.03 (2.92, 5.55)**
|
5.04 (2.83, 8.97)**
|
Girls (n)
|
5203
|
259
|
56
|
SGA [n (%)]
|
429 (8.25)
|
62 (23.94)
|
25 (44.64)
|
Crude RR (95% CI)
|
1.00
|
3.50 (2.59, 4.74)**
|
8.97 (5.25, 15.34)**
|
Adjusted RR (95% CI) 1
|
1.00
|
2.94 (2.08, 4.15)**
|
9.94 (5.21, 18.93)**
|
1Adjustment for maternal age, pre-pregnancy BMI, maternal education, parity, gestational diabetes mellitus, gestational hypertension and preeclampsia.
**P<0.01 as compared with control.
Correlation between maternal serum TBA levels and birth sizes
Linear regression was used to explore the correlation between maternal serum TBA levels and birth weight. As shown in Figure 2A, for crude models, each 1μmol/L increase in maternal serum TBA levels was associated with a 14.6g (95%CI: -16.1, -13.1) decrease in birth weight among all subjects, 46.1g (95%CI: -51.9, -40.3) decrease in birth weight among controls, 21.9g (95%CI: -30.8, -13.0) decrease in birth weight among subjects with mild ICP, and 4.0g (95%CI: -9.3, 1.3) decrease in birth weight among subjects with severe ICP, respectively. After adjustment for maternal age, pre-pregnancy BMI, maternal education parity, gestational diabetes mellitus, gestational hypertension and preeclampsia, each 1μmol/L increase in maternal serum TBA levels was associated with a 11.1g (95%CI: -12.8, -9.4) decrease in birth weight among all subjects, 35.1g (95%CI: -41.2, -29.0) decrease in birth weight among controls, 19.1g (95%CI: -26.6, -11.6) decrease in birth weight among subjects with mild ICP, and 4.9g (95%CI: -11.3, 1.5) decrease in birth weight among subjects with severe ICP, respectively (Figure 2A). Stratification analyses based on neonates' gender was used to further explore the correlation between maternal serum TBA levels and birth weight using linear regression models. As shown in Figure 2A, an inverse correlation was observed between maternal serum TBA levels and birth weight in both boys and girls. The correlation between maternal serum TBA levels and birth length, head circumference and chest circumference were then analyzed based on linear regression models. After adjustment for maternal age, pre-pregnancy BMI, maternal education parity, gestational diabetes mellitus, gestational hypertension and preeclampsia, the birth length decreased by 0.045cm (95%CI: -0.054, -0.036) among all subjects, by 0.130cm (95%CI: -0.162, -0.098) among controls, by 0.064cm (95%CI: -0.105, -0.023) among subjects with mild ICP and by 0.047cm (95%CI: -0.086, -0.008) among subjects with severe ICP for each 1μmol/L increase of serum TBA levels, respectively (Figure 2B). The head circumference decreased by 0.034cm (95%CI: -0.040, -0.028) among all subjects, by 0.070cm (95%CI: -0.092, -0.048) among controls, by 0.067cm (95%CI: -0.098, -0.036) among subjects with mild ICP and by 0.012cm (95%CI: -0.040, 0.016) among subjects with severe ICP for each 1μmol/L increase of TBA levels, respectively (Figure 2C). The chest circumference decreased by 0.041cm (95%CI: -0.048, -0.034) among all subjects, by 0.121cm (95%CI: -0.147, -0.095) among controls, by 0.091cm (95%CI: -0.124, -0.058) among subjects with mild ICP and by 0.025cm (95%CI: -0.056, 0.006) among subjects with severe ICP for each 1μmol/L increase of TBA levels, respectively (Figure 2D). Stratification analyses based on neonates' gender was used to further explore the correlation between maternal serum TBA levels and birth length, head circumference and chest circumference. As shown in Figure 2B-D, inverse correlations were observed between maternal serum TBA levels and birth length, head circumference and chest circumference in both boys and girls.