Hepatitis B virus infection and intrahepatic cholestasis of pregnancy: a birth cohort study in Lanzhou, China

doi:10.21203/rs.3.rs-3903110/v1

Background: Intrahepatic cholestasis of pregnancy (ICP) has been confirmed to have a clear influence on pregnancy outcome. This study is aimed at investigating the correlation between hepatitis B virus (HBV) infection and ICP, and confirming whether HBV infection may aggravate the adverse fetal or maternal outcomes of ICP.

Methods: A birth cohort study was conducted from 2010–2012 at Gansu Provincial Maternity & Child Care Hospital in Lanzhou, China. A total of 10,536 pregnant women without chronic hepatopathy were enrolled. HBV infection was defined by the presence of hepatitis B virus antigens (HBsAg) positive.

Results: 259 (2.46%) women were diagnosed with ICP and it was observed that maternal HBV infection increased the risk of ICP (OR:1.95, 95%CI:1.17-3.24). Compared to non-ICP with HBV negative women, ICP with HBV positive women were more likely to have postpartum hemorrhage (PPH) (p=0.019), caesarean section(p<0.0001), and preterm birth(p<0.0001). When ICP was combined with HBV infection, after adjusting for influencing factors, the risk of PPH was increased compared with ICP with HBV negative (OR: 6.65, 95%CI: 1.30-33.95), non-ICP with HBV positive (OR: 11.16, 95%CI: 1.83-68.18), or non-ICP with HBV negative (OR: 10.12, 95%CI: 2.72-37.67).

Conclusions: Our study supports the hypothesis that HBV infection increases the risk of ICP. Furthermore, it indicates that ICP combined with HBV infection substantially increases PPH risk.

Intrahepatic cholestasis of pregnancy

Hepatitis B virus infection

Risk

Outcomes

Postpartum hemorrhage

China

Intrahepatic cholestasis of pregnancy (ICP) is a liver disease, which is unique to the peripartum period, characterized by pruritus and an increase in serum bile acids (BA). It is diagnosed after exclusion of other liver causes of cholestasis [1]. The incidence of ICP has been reported varying from 0.2–5.6% among different populations [2–5]. A reported incidence of ICP in the Chinese obstetrical population was 1.1% [6].

The etiology of ICP is not yet fully understood, but likely results from a combination of genetic, pregnancy hormones and their metabolites, and environmental factors[7, 8]. While the symptoms and biochemical abnormalities of ICP resolve rapidly after delivery, they can result in adverse fetal outcomes, such as spontaneous preterm birth, meconium staining amniotic fluid (MSAF), stillbirth, and low (< 7) 5-minute Apgar score [9, 10].

Hepatitis B virus (HBV) infection is both a serious infection and a major risk factor for death from cirrhosis and liver cancer. There are more than 240 million chronically HBV infected people worldwide[11]. Among the Chinese obstetrical population, the HBV infection rate was found to be 3.35% [6]. Individuals with HBV infection or asymptomatic Hepatitis B virus antigens carriers can experience adverse effects, namely, an autoimmune response which causes hepatic cell damage [12, 13]. As estrogen levels increase during pregnancy, progesterone metabolites may activate the bile salt export pump (BSEP) or farnesoid X receptor (FXR) trans-inhibition in a pregnant woman with genetic susceptibility[14, 15]. Abnormal BA homeostasis ultimately leads to hepatic cell damage and plays a role in ICP development. Furthermore, BA increases HBV transcription and gene expression in the 1.2-mer HBV replicon-transfected human hepatocyte cell lines [16]. Eventually, the accumulation of BA may place an extra burden on the liver in HBV infected patients that continues after pregnancy. So far, little is known about whether HBV infection will increase the risk of ICP.

The question of whether ICP entails an increased risk for adverse pregnancy outcomes was first raised in 1976 by Reid et al [17] with several subsequent studies further evaluating this question. However, only one case-control study observed an association between ICP and concomitant HBV infection and adverse perinatal outcome. But, it did not include potential complicating maternal diseases during pregnancy or after delivery[12].In consideration of the few studies about the association between HBV infection and ICP, and whether HBV infection may aggravate both adverse fetal and maternal outcomes of ICP, we analyzed data collected in a birth cohort study in Lanzhou, China. This study was conducted with the goal of systemically estimating the risk of ICP in patients with HBV infection. We also wanted to examine whether HBV infection may trigger or aggravate the adverse pregnancy outcomes of ICP.

A birth cohort study was conducted in 2010–2012 at Gansu Provincial Maternity and Child Care Hospital (refs). All pregnant women who came to the hospital for delivery with gestational age ⩾ 20 weeks, had no mental illness and were aged 18 years or older were considered eligible for this study. Eligible women were informed about the study upon arrival at the hospital for delivery. Among the 14,359 eligible women, 3,712 refused to participate and 105 women did not complete in-person interviews. Finally, 10,542 (73.4%) women completed their in-person interviews using a standardized and structured questionnaire after obtaining written consent. The questionnaire collected information on demographic factors, smoking and alcohol consumption, reproductive, family, and medical history. Information on birth outcomes and pregnancy complications were abstracted from medical records. All study procedures were approved by the Human Investigation Committees at Gansu Provincial Maternity and Child Care Hospital.

ICP was diagnosed on the basis of a clinical diagnostic criteria. It included the onset of pruritus during late pregnancy without skin or medical conditions known to be associated with it and increases in serum total BA and glycocholic acid. The criteria also included abnormal liver function accompanied by a slight increase in alanine transaminase(ALT) with or without jaundice. All symptoms had to persist up to the time of delivery and disappear after delivery. HBV infected women were identified as those who tested HBsAg positive after arrival at the hospital for delivery. Postpartum hemorrhage (PPH) was diagnosed as a > 500 ml blood loss during vaginal delivery or a > 1000 ml blood loss during cesarean delivery within the 24 hours following birth.

STATISTICAL ANALYSIS

After excluding women who had hepatitis C virus infection and chronic or serious liver diseases, the final sample size was 10,536. Among those, 259 (2.46%) women were diagnosed with ICP, 374 (3.55%) women were infected with HBV and 384 (3.64%) women were diagnosed with PPH.

Firstly, distributions of selected characteristics between the ICP and control group were compared using χ2-tests. Unconditional logistic regression models were used to estimate the association between HBV infection and the risk of ICP. Adjustments for family monthly income per capita (< 3000, ⩾ 3000 RMB), weight gain during pregnancy (⩽15, 15–18.4, ⩾18.5 kg), history of ICP (yes/no), family history of ICP (yes/no), multiple birth (yes/no), abortion history (yes/no), and preeclampsia (yes/no) were made. Additional adjustments for age, maternal employment, education level, pre-pregnancy body mass index (BMI), active and passive smoking, alcohol consumption, natural pregnancy, oral contraceptives use, parity, gender, and gestational diabetes did not result in material changes of the observed associations, and thus they were not included in the final models.

Secondly, differential pregnancy outcomes between ICP with HBV negative and non-ICP with HBV negative, as well as ICP with HBV positive and non-ICP with HBV negative were compared using χ2-tests. The associations between ICP with/without HBV infection and PPH were compared using χ2-tests. Unconditional logistic regression models were used to estimate the risk of PPH in ICP patients with/without HBV infection, adjusting for maternal age, weight gain during pregnancy, parity, gender, placenta previa, macrosomia, multiple birth, anemia, and blood system disease. Additional adjustment for pre-pregnant BMI, family monthly income per capita, smoking during pregnancy, alcohol consumption during pregnancy, gestational hypertension, preeclampsia, placenta abruption, and stillbirth did not result in material changes of the observed associations, and thus they were not included in the final model.

All analyses were performed using SAS, version 9.3 (SAS Institute, Inc., Cary, NC, USA).

Among the 10,536 pregnant women, 259 were diagnosed with ICP (Table 1). Compared with women who did not suffer from ICP, women with ICP were more likely to have lower family income, experience less than 15 kg of weight gain during pregnancy, and be HBV positive. Women with ICP were also more likely to have a history of ICP, family history of ICP, multiple birth, no abortion history and maternal preeclampsia. The distributions of age, education level, pre-pregnancy BMI, smoking, alcohol consumption, natural pregnancy, oral contraceptive use, parity, gender and maternal diabetes were similar between women with or without ICP.

The risk factors of ICP are presented with crude and adjusted odds ratios (OR) and 95% confidence intervals (CI) (Table 2). After adjusting for influencing factors, the risk factors associated with ICP were; HBV positive (OR:1.95,95%CI:1.17–3.24), history of ICP (OR:9.66,95%CI:2.93–31.83), family history of ICP (OR:4.34,95% CI:1.40-13.43), multiple birth (OR:3.01,95%CI:1.92–4.72), and maternal preeclampsia (OR:3.04,95%CI:2.00-4.61).Weight gain during pregnancy greater than 15 kg (OR:0.60,95%CI:0.44–0.83 for 15-18.5kg; OR:0.53,95%CI: -0.39-0.72 for > 18kg) and abortion history (OR:0.62,95%CI:0.40–0.96) were shown to reduce the risk of ICP.

Table 3 displays the fetal outcomes. We selected fetal outcomes of non-ICP with HBV negative as the control group, with which to separately compare the fetal outcomes of ICP with HBV negative and ICP with HBV positive. There were no significant differences in the proportions of birth defect, stillbirth, fetal distress, neonatal asphyxia, low Apgar score (< 7) 1 minute, hyperbilirubinemia, and intrauterine growth retardation (IUGR) between the two groups. The proportion of low birth weight (p < 0.0001) was higher in ICP with HBV negative than non-ICP with HBV negative.

Maternal outcomes are shown in Table 4. We selected maternal outcomes of non-ICP with HBV negative as the control group, with which to separately compare the maternal outcomes of ICP with HBV negative and ICP with HBV positive with. The proportions of preeclampsia (p < 0.0001), caesarean section (p < 0.0001), preterm birth (p < 0.0001), and MSAF (p < 0.0001) were higher in ICP with HBV negative than in non-ICP with HBV negative. The proportion of premature rupture of fetal membrane (p < 0.0001) was lower in ICP with HBV negative than in non-ICP with HBV negative. The proportions of caesarean section (p = 0.027) and preterm birth (p = 0.022) were higher in ICP with HBV positive than in non-ICP with HBV negative. It was revealed that the proportion of PPH (p = 0.019) was higher in ICP with HBV positive than in non-ICP with HBV negative. This difference was not observed when ICP with HBV negative was compared with non-ICP with HBV negative.

Associations between ICP combined with HBV infection and PPH are displayed in Table 5. The proportion of PPH in ICP women was higher than in non-ICP women (p = 0.03). The proportion of PPH in ICP with HBV positive was higher than in ICP with HBV negative (p = 0.021), non-ICP with HBV positive (p = 0.029) or non-ICP with HBV negative (p = 0.014).

ICP women had an increased risk of PPH compared with non-ICP (OR: 1.77, 95%CI: 1.06–2.97) (Table 6). However, the corresponding risk was not observed after adjustment. When ICP was combined with HBV infection, the risk of PPH increased when compared with ICP with HBV negative (OR: 6.65, 95%CI: 1.30-33.95), non-ICP with HBV positive (OR: 11.16, 95%CI: 1.83–68.18), or non-ICP with HBV negative (OR: 10.12, 95%CI: 2.72–37.67).

Table 1

Distribution of Selected Characteristics between ICP group and non-ICP group (N = 10536)
Characteristics	Non-ICP(n = 10277)		ICP (n = 259)		P-value^a
Characteristics	n	%	n	%
Maternal age(years)
<25	1646	16.02	49	18.92	0.20
25–29	4909	47.77	110	42.47
⩾30	3722	36.22	100	38.61
Maternal employment					0.67
No	5019	48.84	123	47.49
Yes	5258	51.16	136	52.51
Maternal education level
<College	4075	39.65	110	42.47	0.51
⩾College	6014	58.52	146	56.37
Missing	188	1.83	3	1.16
Family monthly income per capita(RMB)
< 3000	5213	50.72	158	61.00	0.0007
⩾3000	4068	39.58	90	34.75
Missing	996	9.69	11	4.25
Pre-pregnancy body mass index					0.05
< 18.5	2086	20.30	69	26.64
18.5–23.9	6734	65.52	154	59.46
⩾24	1097	10.67	30	11.58
Missing	360	3.50	6	2.32
Weight gain during pregnancy
< 15kg	3087	30.04	111	42.86	0.0002
15-18.4kg	2958	28.78	62	23.94
⩾18.5kg	3785	36.83	77	29.73
Missing	447	4.35	9	3.47
Smoking (passive and active) during pregnancy
No	8275	80.52	201	77.61	0.24
Yes	2002	19.48	58	22.39
Alcohol consumption during pregnancy
No	10258	99.82	19	95.00	0.46
Yes	19	0.18	1	5.00
Maternal HBV infection
No	9920	96.53	242	93.44	0.008
Yes	357	3.47	17	6.56
History of ICP (Missing 713)
No	10264	99.87	255	98.46	< 0.0001
Yes	13	0.13	4	1.54
Family history of ICP (Missing 645)
No	9623	93.66	239	92.28	0.0008
Yes	27	0.26	4	1.54
Missing	624	6.07	16	6.18
Multiple birth
No	9979	97.10	234	90.35	< 0.0001
Yes	298	2.90	25	9.65
Natural Pregnancy
No	375	3.65	8	3.09	0.48
Yes	7225	70.30	191	73.75
Missing	2677	26.05	60	23.17
Taken oral contraceptives
No	9512	97.51	243	97.95	0.44
Yes	765	2.49	16	2.05
Abortion history
No	8927	92.56	236	93.82	0.045
Yes	1350	7.44	23	6.18
Parity
Primipara	7379	71.80	192	74.13	0.41
Multipara	2898	28.20	67	25.87
Gender (Missing 36)
Male	5405	52.59	141	54.44	0.83
Female	4837	47.07	117	45.17
Missing	35	0.34	1	0.39
Gestational diabetes
No	10176	99.02	254	98.07	0.19
Yes	101	0.98	5	1.93
Preeclampsia
No	9891	96.24	229	88.42	< 0.0001
Yes	386	3.76	30	11.58

Table 2

Risk factors associated with ICP (N = 10536)
Characteristics	Crude OR (95%CI)		P-value^a	Adjusted OR (95%CI)		P-value^a
Family monthly income per capita(RMB)
< 3000	1		0.001	1		0.0067
⩾3000	0.73	(0.56–0.95)		0.81	(0.62–1.06)
Missing	0.36	(0.20–0.67)		0.37	(0.20–1.69)
Weight gain during pregnancy
< 15kg	1		0.0002	1		< 0.0001
15-18.5kg	0.58	(0.43–0.80)		0.60	(0.44–0.83)
⩾18.5kg	0.57	(0.42–0.76)		0.53	(0.39–0.72)
Missing	0.56	(0.28–1.11)		0.51	(0.25–1.02)
Maternal HBV infection
No	1		0.0092	1		0.01
Yes	1.95	(1.18–3.23)		1.95	(1.17–3.24)
History of ICP
No	1		< 0.0001	1		0.0002
Yes	12.38	(4.01–38.23)		9.66	(2.93–31.83)
Family history of ICP
No	1		0.0042	1		0.035
Yes	5.96	(2.07–17.18)		4.34	(1.40-13.43)
Missing	1.03	(0.62–1.72)		1.19	(0.71–2.01)
Multiple birth
No	1		< 0.0001	1		< 0.0001
Yes	3.58	(2.33–5.49)		3.01	(1.92–4.72)
Abortion history
No	1		0.047	1		0.041
Yes	0.65	(0.42–0.99)		0.62	(0.40–0.96)
Preeclampsia
No	1		< 0.0001	1		< 0.0001
Yes	3.56	(2.64–4.98)		3.04	(2.00-4.61)

Table 3

The fetal outcomes of ICP with HBV- vs. ICP with HBV+, and ICP with HBV + vs. non-ICP with HBV-
Fetal outcome	ICP with HBV- 240	Non-ICP with HBV- 9922	P-value^a	ICP with HBV+ 19	Non-ICP with HBV- 9922	P-value^a
Fetal outcome	n(%)	n(%)	P-value^a	n(%)	n(%)	P-value^a
Birth defect	4(1.67)	261(2.63)	0.35	1(5.26)	261(2.63)	0.40
Stillbirth	2(0.83)	50(0.50)	0.22	0	50(0.50)	0.22
Fetal distress	40(16.67)	1437(14.48)	0.37	3(1.79)	1437(14.48)	0.71
Low birth weight	49(20.42)	919(9.26)	< 0.0001	3(15.79)	919(9.26)	0.23
Neonatal asphyxia	4(1.67)	213(2.15)	0.60	0	213(2.15)	0.54
Low Apgar score(< 7) 1 min	10(4.18)	743(7.49)	0.052	1(5.26)	743(7.49)	0.054
Hyperbilirubinemia	12(5.00)	367(3.70)	0.18	1(5.26)	367(3.70)	0.18
Intrauterine growth retardation	3(1.25)	69(0.70)	0.15	0	69(0.70)	0.73

Table 4

The maternal outcomes of ICP with HBV- vs. non-ICP with HBV-, and ICP with HBV + vs. non-ICP with HBV-
Maternal outcome	ICP with HBV- 240	Non-ICP with HBV- 9922	P-value^a	ICP with HBV+ 19	Non-ICP with HBV- 9922	P-value^a
Maternal outcome	n(%)	n(%)	P-value^a	n(%)	n(%)	P-value^a
Gestational diabetes	5(2.08)	97(0.98)	0.093	0	97(0.98)	0.68
Preeclampsia	30(12.50)	373(3.76)	< 0.0001	0	373(3.76)	0.42
Postpartum hemorrhage	12(5.00)	355(3.58)	0.14	4(21.05)	355(3.58)	0.019
Caesarean section	199(82.91)	3772(38.02)	< 0.0001	11(57.89)	3772(38.02)	0.027
Preterm birth	92(38.33)	1149(11.58)	< 0.0001	5(26.32)	1149(11.58)	0.022
Premature rupture of fetal membrane	18(7.50)	1428(14.39)	0.0022	1(5.26)	1428(14.39)	0.32
Meconium stained amniotic fluid	73(30.17)	1670(16.83)	< 0.0001	4(23.53)	1670(16.83)	0.46
Placental abruption	2(0.83)	88(0.89)	0.92	0	88(0.89)	0.69

Table 5

Chi-square test on associations between ICP with/without HBV infection and postpartum hemorrhage
	Total(n)	Postpartum hemorrhage(n)	%	χ2	P-value^a
ICP/non-ICP	259/10277	16/368	6.18/3.58	4.85	0.03
HBV+/HBV-	374/10162	16/368	4.28/3.62	0.44	0.51
ICP with HBV-/non-ICP with HBV-	240/9922	12/356	5.00/3.59	2.18	0.14
non-ICP with HBV+/non-ICP with HBV-	355/9922	12/356	3.38/3.59	0.039	0.95
ICP with HBV+/ICP with HBV-	19/240	4/12	21.05/5.00	5.30	0.021
ICP with HBV+/non-ICP with HBV+	19/355	4/12	21.05/3.38	4.73	0.029
ICP with HBV+/non-ICP with HBV-	19/9922	4/356	21.05/3.59	6.05	0.014

Table 6

Multiple Regression Analysis on associations between ICP with/without HBV infection and postpartum hemorrhage
	Total(n)	Postpartum hemorrhage(n)	Crude OR (95%CI)		P-value^a	Adjusted OR(95%CI)		P-value^a
non-ICP	10277	368	1			1
ICP	259	16	1.77	(1.06–2.97)	0.029	1.62	(0.92–2.86)	0.094
HBV-	10162	368	1			1
HBV+	374	16	1.19	(0.71–1.98)	0.51	1.49	(0.88–2.53)	0.14
non-ICP with HBV-	9922	356	1			1
ICP with HBV-	240	12	1.53	(0.87–2.70)	0.14	1.35	(0.72–2.52)	0.35
non-ICP with HBV-	9922	356	1			1
non-ICP with HBV+	355	12	1.02	(0.58–1.79)	0.95	1.25	(0.70–2.25)	0.45
ICP with HBV-	240	12	1			1
ICP with HBV+	19	4	5.07	(1.46–17.62)	0.011	6.65	(1.30-33.95)	0.023
non-ICP with HBV+	355	12	1			1
ICP with HBV+	19	4	5.67	(1.45–22.19)	0.013	11.16	(1.83–68.18)	0.0009
non-ICP with HBV-	9922	356	1			1
ICP with HBV+	19	4	5.77	(1.65–20.18)	0.006	10.12	(2.72–37.67)	0.0006

Adjusted for maternal age, weight gain during pregnancy, parity, gender, placenta previa, macrosomia, multiple birth, anemia, blood system disease, HBV infection(first class)and ICP(second class).

In this study, we found that HBV infection increased the risk of ICP. We also found that when ICP and HBV infection occurred simultaneously, the risk of PPH increased.

HBsAg is the main clinical marker indicating acute or chronic HBV infection and prevalence. In addition, endemicity of HBV infection is defined by the presence of HBsAg[11]. China has relatively high rates of chronic HBV infection and an immense absolute number of people living with the virus. HBV infection and ICP can affect the development of liver disease, but their relationship with the development of pregnancy complications is not yet known. After adjusting for confounding factors maternal age ICP in a previous pregnancy, family history of ICP, multiple birth, and preeclampsia. we confirmed many previous conclusions[9, 18, 24, 25], but not all. We did not find ICP to be associated with advanced maternal age, gestational diabetes, consumption of oral contraceptive pill, or IVF. However, we found that a maternal weight gain during pregnancy of greater than 15 kg and an abortion history will decrease the risk of ICP, which had not been previously reported. Moreover, for the first time, we propose that HBV infection may approximately double the risk of ICP.

Twenty-six original studies have observed an association between ICP and adverse pregnancy outcomes. Five prospective cohort studies, published in the last decade, have observed obstetrical outcomes, such as preterm delivery, MSAF, induction of labor [9, 10, 26–28], and maternal diseases, such as gestational diabetes and preeclampsia[9]. These studies also observed fetal outcomes including low (< 7) 5 minute Apgar score, large for gestational age, neonatal asphyxia, neonatal unit admission, stillbirth, and low birth weight[9, 10, 26, 28]. A case control study demonstrated that HBV infection combined with ICP caused higher rates of PROM, MSAF, Cesarean section, fetal distress, and low infant Apgar scores (4–7) compared with the control group[12]. However, the risk of adverse outcomes were not estimated since confounders were not controlled and maternal diseases during pregnancy and after delivery were not examined. To the best of our knowledge, this is the first birth cohort study on the pregnancy outcomes of ICP combined with HBV infection.

In our study, we selected pregnancy outcomes, which have been previously related to ICP, to observe their relevance. It should be noted that ICP combined with HBV increased the proportion of PPH compared with non-ICP with HBV negative. However, this difference was not observed when ICP with HBV negative was compared to non-ICP with HBV negative. We hypothesized that ICP combined with HBV infection to aggravate the adverse pregnancy outcomes of PPH. To confirm their associations, we did further analysis. After adjustment, the risk of PPH was increased 5.65 times, 10.16 times, and 9.12 times when ICP had concomitant HBV infection compared with ICP with HBV negative, non-ICP with HBV positive, and non-ICP with HBV negative, respectively. Moreover, this increased risk did not appear when ICP or HBV infection independently existed when compared with non-ICP with HBV negative.

Obstetric hemorrhage is the leading cause of maternal mortality worldwide with the vast majority of cases being PPH[29]. The World Health Organization estimated worldwide deaths from obstetric hemorrhage at 78,000 women, accounting for 27% of all maternal deaths in 2013[30]. Shemer et al [31] confirmed that onset of labor among women with ICP and intended vaginal delivery during gestational weeks 37–39 both have a high risk of blood loss of > 1000 ml. However, one Swiss study from Furrer et al[32] showed that postpartum blood loss does not differ between the ICP and control groups. When we excluded HBV infected woman from our study group, we also drew the same conclusion that the proportion of PPH does not differ between the ICP and control groups(Table 5). This consistent conclusion might result from the lower HBV infection in Switzerland[11].

A recent study of the coagulation parameters of 319 women did not find coagulation abnormalities in pregnant patients with ICP[33]. However, in a small study of 70 ICP patients, Kenyon et al [34]found that the percent of PPH was increased in patients without vitamin K supplementation. Despite this, few papers have reported routine parenteral vitamin K administration[17]. Vitamin K plays a key role in the physiological process of blood coagulation. Only one national guideline deals with ICP and a possible benefit from vitamin K supplementation in the presence of malabsorption[32]. A future question that could be asked is; whether ICP may lead to malabsorption of vitamin K and subsequent PPH development?

According to recent studies, the major concerns for women with HBV infection are both maternal-neonatal virus transmission[35–37] and the effects of HBV infection on pregnancy outcomes, such as miscarriage[13], large for gestational age, macrosomia[38], premature birth[39]. Chen et al ’s study[37] found that ICP may lead to an increased risk of maternal-neonatal transmission of HBV. Moreover, a study from Tse et al[40] found that HBsAg carriers have an increased risk of antepartum hemorrhage and intraventricular hemorrhage. The liver has a vital function in the regulation of blood coagulation. Furthermore, hepatocyte injury or necrotization impairs coagulation factor production. However, no evidence has confirmed that asymptomatic HBV could result in coagulation impairment or PPH. Further studies are needed to explore the mechanism of HBV infection and ICP. Future studies will also need to investigate the interaction of HBV infection combined with ICP and adverse hepatic cell damage which could lead to coagulation impairment or PPH.

In conclusion, our study supports the hypothesis that HBV infection will increase the risk of ICP and indicates that ICP combined with HBV infection may substantially increase the risk of PPH. Careful surveillance of high-risk pregnancies is quite essential.

Ethics approval and consent to participate：

The study procedures were established, according to the ethical guidelines of the Helsinki Declaration and were approved by the Human Ethics Committee of Gansu Provincial Maternity and Child Care Hospital. Written informed consent was obtained from individual or guardian participants.

Consent for publication：

No conflict of interest exits in the submission of this manuscript, and manuscript is approved by all authors for publication.

Availability of data and materials

The data can be obtained on request from the corresponding author.

Competing interests

The authors declare that they have no competing interests.

Funding

Not applicable

Authors' contributions

Wei Li wrote the main manuscript text. Zhaoyan Meng gave the suggestion for the research method and conclusion. Zhenqiang Da and Yue Zhao made the data analysis. Fang Wang and Tao Yang prepared the figures and tables. Qing Liu made a comprehensive summary. All authors reviewed the manuscript.

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No competing interests reported.

Hepatitis B virus infection and intrahepatic cholestasis of pregnancy: a birth cohort study in Lanzhou, China

Status:

Version 1

Abstract

BACKGROUND

METHODS

STATISTICAL ANALYSIS

RESULTS

DISCUSSION

CONCLUSIONS

Declarations

References

Additional Declarations

Status:

Version 1