The correlation between serum total bile acid and adverse perinatal outcomes in pregnant women with intrahepatic cholestasis of pregnancy (ICP) and non-ICP hypercholanemia of pregnancy

Figures & data

Figure 1. Flowchart of the Study Population.

TBA: total bile acid; ICP: intrahepatic cholestasis of pregnancy; AHP: asymptomatic hypercholanemia of pregnancy.

Table 1. Maternal demographics within the study population.

Baseline demographic	Total population	ICP	Non-ICP		p value
			Liver disease	AHP
	(n = 974)	(n = 160)	(n = 164)	(n = 650)
Maternal age	30.28 ± 4.71	29.29 ± 4.63	30.15 ± 4.97	30.56 ± 4.63	< 0.01
Middle school degree or less	155 (15.91)	31 (19.37)	28 (17.07)	96 (14.77)	0.42
Primigravida	372 (38.19)	71 (44.38)	56 (34.15)	245 (37.69)	0.15
Multigravida	602 (61.81)	89 (55.62)	108 (65.85)	405 (62.31)
Primiparous	586 (60.16)	103 (64.38)	100 (60.98)	383 (58.92)	0.44
Multiparous	388 (39.84)	57 (35.62)	64 (39.02)	267 (41.08)
Hepatitis virus carrier	284(29.16)	47(29.38)	93(56.71)	144(22.15)	< 0.01
Hepatitis B virus carrier	275 (28.23)	46 (28.75)	87 (53.05)	142 (21.85)
Hepatitis C virus carrier	7 (0.72)	1 (0.62)	5 (3.05)	1 (0.15)
Hepatitis E virus carrier	1 (0.10)	0 (0)	1 (0.61)	0 (0)
Hepatitis A virus carrier	1 (0.10)	0 (0)	0 (0)	1 (0.15)
Gallstones	22 (2.26)	5 (3.12)	5 (3.05)	12 (1.85)	0.42
Cholecystitis	95 (9.75)	26 (16.25)	29 (17.68)	40 (6.15)	< 0.01
Cholecystic polypus	66 (6.78)	12 (7.50)	15 (9.15)	39 (6)	0.33
Fatty liver	118 (12.11)	17 (10.62)	38 (23.17)	63 (9.69)	< 0.01
Cirrhosis	8 (0.82)	3 (1.88)	4 (2.44)	1 (0.15)	< 0.01
Abnormal hepatobiliary ultrasound (simple)^a	141 (14.48)	32 (20)	24 (14.63)	85 (13.08)	0.08
Autoimmune diseases	9 (0.92)	0 (0)	4 (2.44)	5 (0.77)	0.06
History of hyperbileacidemia	66 (6.78)	6 (3.75)	6 (3.66)	54 (8.31)	0.03
Hypercholanemia (special)^b	208 (21.36)	44 (27.50)	164 (100)	0 (0)	< 0.01
Pruritus	160 (16.43)	160 (100)	0 (0)	0 (0)	< 0.01
Twin pregnancies	53(5.44)	11 (6.88)	13(7.93)	29(4.46)	0.15
In-vitro fertilization	49(5.03)	9(5.62)	11(6.71)	29(4.46)	0.47
Hypertensive disorders of pregnancy	60(6.16)	1(0.62)	18(10.98)	41(6.31)	< 0.01
GDM or PGDM	167(17.15)	23(14.40)	32(19.51)	112(17.23)	0.57
AST^c	21.00	52.50	77.50	18.00	< 0.01
	(16.00, 45.50)	(20.00, 152.50)	(39.20, 192.50)	(15.00, 23.00)
ALT^d	16.00	83.00	120.50	12.00	< 0.01
	(11.00, 54.20)	(13.20, 243.00)	(46.00, 316.00)	(9.20, 18.00)
GGT^e	12.00	25.00	32.00	9.00	< 0.01
	(8.00, 29.50)	(12.00, 49.80)	(21.00, 53.50)	(7.00, 14.00)
TBA	41.90	60.00	67.90	33.80	< 0.01
	(26.30, 62.30)	(38.70, 90.20)	(50.00, 105.70)	(22.70, 50.30)
10 µmol/L ≤ TBA < 40 µmol/L (mild hypercholanemia)	462 (47.43)	44 (27.50)	19 (11.59)	399 (61.38)	< 0.01
40 µmol/L ≤ TBA < 100 µmol/L (moderate hypercholanemia)	410 (42.09)	82 (51.25)	100 (60.98)	228 (35.08)	< 0.01
TBA ≥ 100 µmol/L (severe hypercholanemia)	102 (10.47)	34 (21.25)	45 (27.44)	23 (3.54)	< 0.01

ICP: intrahepatic cholestasis of pregnancy; AHP: asymptomatic hypercholanemia of pregnancy; GDM: gestational diabetes mellitus; PGDM: pregestational diabetes mellitus; AST: aspartate aminotransferase; ALT: alanine aminotransferase; GGT: γ-glutamyl transpeptidase; TBA: serum total bile acid.

Continuous variables are shown as mean ± SD, or median interquartile range.

Categorical variables are presented as numbers (percentages).

p < 0.017 compared to ICP.

^a Hepatobiliary ultrasound abnormalities without clearly associated liver pathologies.

^b Hypercholanemia was combined with elevated liver enzymes and hepatic disease. In the liver disease group, hypercholanemia was caused by hepatic disease, while there was no clear correlation between hypercholanemia and hepatic disease in the other two groups.

^c Data is missing for 78 (8.00%) patients.

^d Data is missing for 144 (14.8%) patients.

^e Data is missing for 359 (36.9%) patients.

Table 2. Perinatal outcomes in pregnant women with ICP, liver disease, or AHP at different levels of TBA.

Perinatal outcomes	Study population					Mild hypercholanemia					Moderate hypercholanemia					Severe hypercholanemia
	Total population	ICP	Non-ICP		p value	Total population	ICP	Non-ICP		p value	Total population	ICP	Non-ICP		p value	Total population	ICP	Non-ICP		p value
			Liver disease	AHP				Liver disease	AHP				Liver disease	AHP				Liver disease	AHP
	(n = 974)	(n = 160)	(n = 164)	(n = 650)		(n = 462)	(n = 44)	(n = 19)	(n = 399)		(n = 410)	(n = 82)	(n = 100)	(n = 228)		(n = 102)	(n = 34)	(n = 45)	(n = 23)
Gestational age at diagnosis, weeks	30.42 ± 8.17	30.96 ± 6.69	30.85 ± 8.15	30.17 ± 8.50	0.42	31.98 ± 7.86	32.53 ± 6.45	31.96 ± 8.78	31.93 ± 7.97	0.89	29.25 ± 8.18	30.32 ± 7.05	31.37 ± 8.25	27.93 ± 8.30	< 0.01	28.02 ± 8.23	30.49 ± 5.92	29.24 ± 7.60	21.97 ± 9.58	< 0.01
Gestational age at delivery^b, weeks	37.17 ± 2.31	36.18 ± 2.29	36.12 ± 2.69	37.68 ± 2.03	< 0.01	38.10 ± 1.85	37.62 ± 1.60	37.44 ± 2.48	38.18 ± 1.83	0.05	36.83 ± 2.04	36.29 ± 1.84	36.73 ± 2.31	37.06 ± 1.96	0.01	34.39 ± 2.59	34.07 ± 2.50	34.22 ± 2.66	35.20 ± 2.53	0.23
Preterm birth^bf	328 (33.68)	84 (52.50)	91 (55.49)	153 (23.54)	< 0.01	67 (14.50)	8 (18.18)	5 (26.32)	54 (13.53)	0.20	182 (44.39)	49 (59.76)	50 (50)	83 (36.40)	< 0.01	79 (77.45)	27 (79.41)	36 (80)	16 (69.57)	0.59
Full-term birth	646 (66.32)	76 (47.50)	73 (44.51)	497 (76.46)		395 (85.50)	36 (81.82)	14 (73.68)	345 (86.47)		228 (55.61)	33 (40.24)	50 (50)	145 (63.60)		23 (22.55)	7 (20.59)	9 (20)	7 (30.43)
Early preterm birth^b	95 (9.75)	29 (18.12)	36 (21.95)	30 (4.62)	< 0.01	15 (3.25)	2 (4.55)	2 (10.53)	11 (2.76)	0.11	30 (7.32)	10 (12.20)	8 (8)	12 (5.26)	0.11	50 (49.02)	17 (50)	26 (57.78)	7 (30.43)	0.10
Spontaneous preterm birth	34 (3.49)	6 (3.75)	5 (3.05)	23 (3.54)	0.94	13 (2.81)	1 (2.27)	1 (5.26)	11 (2.76)	0.51	16 (3.90)	3 (3.66)	2 (2)	11 (4.82)	0.57	8 (7.84)	2 (5.88)	4 (8.89)	2 (8.70)	0.90
Cesarean section^bf	677 (69.51)	129 (80.62)	144 (87.80)	404 (62.15)	< 0.01	254 (54.98)	28 (63.64)	11 (57.89)	215 (53.88)	0.45	331 (80.73)	70 (85.37)	92 (92)	169 (74.12)	< 0.01	92 (90.20)	31 (91.18)	41 (91.11)	20 (86.96)	0.84
Vaginal birth	297 (30.49)	31 (19.38)	20 (12.20)	246 (37.85)		208 (45.02)	16 (36.36)	8 (42.11)	184 (46.12)		79 (19.27)	12 (14.63)	8 (8)	59 (25.88)		10 (9.80)	3 (8.82)	4 (8.89)	3 (13.04)
Iatrogenic preterm labor because of TBA^bf	228 (23.41)	69 (43.12)	71 (43.29)	88 (13.54)	< 0.01	16 (3.46)	3 (6.82)	2 (10.53)	11 (2.76)	0.05	145 (35.37)	42 (51.22)	39 (39)	64 (28.07)	< 0.01	67 (65.69)	24 (70.59)	30 (66.67)	13 (56.52)	0.54
NST fetal distress	62 (6.37)	5 (3.12)	6 (3.66)	51 (7.85)	0.03	49 (10.61)	3 (6.82)	3 (15.79)	43 (10.78)	0.54	10 (2.44)	1 (1.22)	2 (2)	7 (3.07)	0.75	3 (2.94)	1 (2.94)	1 (2.22)	1 (4.35)	1.00
Meconium-stained amniotic fluid^bf	147 (15.09)	33 (20.62)	41 (25)	73 (11.23)	< 0.01	50 (10.82)	4 (9.09)	3 (15.79)	43 (10.78)	0.66	65 (15.85)	17 (20.73)	23 (23)	25 (10.96)	< 0.01	32 (31.37)	12 (35.29)	15 (33.33)	5 (21.74)	0.52
Low Apgar score^b	32 (3.29)	5 (3.12)	12 (7.32)	15 (2.31)	< 0.01	15 (3.25)	1 (2.27)	3 (15.79)	11 (2.76)	0.02	9 (2.20)	2 (2.44)	3 (3)	4 (1.75)	0.67	8 (7.84)	2 (5.88)	6 (13.33)	0 (0)	0.18
Neonatology department admission^bf	427 (43.84)	96 (60)	100 (60.98)	231 (35.54)	< 0.01	154 (33.33)	19 (43.18)	8 (42.11)	127 (31.83)	0.23	197 (48.05)	49 (59.76)	61 (61)	87 (38.16)	< 0.01	76 (74.51)	28 (82.35)	31 (68.89)	17 (73.91)	0.40
Rooming-in	547 (56.16)	64 (40)	64 (39.02)	419 (64.46)		308 (66.67)	25 (56.82)	11 (57.89)	272 (68.17)		213 (51.95)	33 (40.24)	39 (39)	141 (61.84)		26 (25.49)	6 (17.65)	14 (31.11)	6 (26.09)
Perinatal death	4 (0.41)	0 (0)	3 (1.83)	1 (0.15)	0.04	0	0	0	0	–	1 (0.24)	0 (0)	0 (0)	1 (0.44)	–	3 (2.94)	0 (0)	3 (6.67)	0 (0)	0.34

ICP: intrahepatic cholestasis of pregnancy; AHP: asymptomatic hypercholanemia of pregnancy; CI: confidence interval; NST: non-stress test; TBA: serum total bile acid.

Continuous variables are shown as the mean ± SD.

Categorical variables are presented as numbers (percentages).

p < 0.017 compared to ICP.

^aindicates statistically significant differences between the ICP and liver groups in the total study population.

^bindicates statistically significant differences between the ICP and AHP groups in the total study population.

^cindicates statistically significant differences between the ICP and liver groups in the study population with mild hypercholanemia.

^dindicates statistically significant differences between the ICP and AHP groups in the study population with mild hypercholanemia.

^eindicates statistically significant differences between the ICP and liver groups in the study population with moderate hypercholanemia.

^findicates statistically significant differences between the ICP and AHP groups in the study population with moderate hypercholanemia.

^gindicates statistically significant differences between the ICP and liver groups in the study population with severe hypercholanemia.

^hindicates statistically significant differences between the ICP and AHP groups in the study population with severe hyperchola.

Figure 2. Forest plots of logistic regression analyses of adverse outcomes for the foetus for every 10 μmol/L rise in TBA of ICP, liver disease, and AHP.

CI: confidence interval; ICP: intrahepatic cholestasis of pregnancy; TBA: serum total bile acid; AHP: asymptomatic hypercholanemia of pregnancy.

*: adjustment for maternal age, primigravida, primiparous, twin pregnancies, abnormal hetpatic ultrasound, autoimmune disease, and history of hyperbileacidemia. Significance levels: p < 0.05.

Data availability statement

Upon reasonable request, the corresponding author will provide the dataset.