妊娠期肝内胆汁淤积症对HBV感染孕妇妊娠不良结局的影响

熊霞鹂; 朱云霞; 魏宏; 赵志强; 孟君; 邹怀宾; 段钟平

doi:10.3969/j.issn.1001-5256.2022.08.009

妊娠期肝内胆汁淤积症对HBV感染孕妇妊娠不良结局的影响

DOI: 10.3969/j.issn.1001-5256.2022.08.009

a.
首都医科大学附属北京佑安医院产科, 北京 100069
b.
首都医科大学附属北京佑安医院疑难肝病及人工肝中心, 北京 100069

基金项目:

国家科技重大专项“艾滋病和病毒性肝炎等重大传染病防治” (2017ZX10201201-001-001);

国家科技重大专项“艾滋病和病毒性肝炎等重大传染病防治” (2017ZX10201201-002-002);

国家科技重大专项“艾滋病和病毒性肝炎等重大传染病防治” (2017ZX10201201-002-009);

北京市属医院科研培育计划项目 (PX2020067)

伦理学声明：本研究方案于2020年9月9日经由首都医科大学附属北京佑安医院伦理委员会审批，批号：京佑科伦字[2020]11号。

利益冲突声明：本研究不存在研究者、伦理委员会成员、受试者监护人以及与公开研究成果有关的利益冲突。

作者贡献声明：段钟平、邹怀宾、朱云霞、熊霞鹂负责课题设计，资料分析，撰写论文；魏宏、赵志强、孟君、熊霞鹂参与收集数据，修改论文；段钟平、朱云霞负责拟定写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
段钟平, duan@ccmu.edu.cn

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出版历程
- 收稿日期: 2022-05-13
- 录用日期: 2022-06-16
- 出版日期: 2022-08-20

Influence of intrahepatic cholestasis of pregnancy on adverse pregnancy outcomes of HBV-infected pregnant women

a.
Department of Obstetrics, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
b.
Intractable Hepatic Diseases and Artificial Liver Treatment & Training Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China

Research funding:

National Science and Technology Key Project on "Major Infectious Diseases such as HIV/AIDS, Viral Hepatitis Prevention and Treatment" (2017ZX10201201-001-001);

National Science and Technology Key Project on "Major Infectious Diseases such as HIV/AIDS, Viral Hepatitis Prevention and Treatment" (2017ZX10201201-002-002);

National Science and Technology Key Project on "Major Infectious Diseases such as HIV/AIDS, Viral Hepatitis Prevention and Treatment" (2017ZX10201201-002-009);

Beijing Municipal Hospital Scientific Research and Cultivation Program (PX2020067)

More Information

Corresponding author: DUAN Zhongping, duan@ccmu.edu.cn(ORCID: 0000-0002-5927-5979)

摘要

摘要: 目的探讨妊娠期肝内胆汁淤积症(ICP)对HBV感染孕妇不良妊娠结局的影响。方法回顾性选取2018年3月—2021年3月首都医科大学附属北京佑安医院收治的232例慢性HBV感染孕妇。按照孕期是否存在ICP，分为单纯HBV感染组(n=100)和HBV+ICP组(n=132)；根据ICP严重程度将HBV+ICP组进一步分为HBV+轻度ICP组(n=86)和HBV+重度ICP组(n=46)。比较各组妊娠期母体并发症发生率情况，如早产、胎膜早破、妊娠期糖尿病、妊娠期高血压疾病、产后出血(PPH)发生率情况；以及分别比较各组胎儿/新生儿不良结局情况，如胎死宫内、新生儿窒息、羊水Ⅲ度污染(AFⅢ)、新生儿呼吸窘迫综合征、小于胎龄儿(SGA)、转入新生儿重症监护病房、肺炎以及HBV母婴传播(MTCT)发生情况。计量资料多组间比较采用单因素方差分析；计数资料组间比较采用χ²检验、连续校正χ²检验或Fisher精确概率法。结果 HBV+ICP组孕妇在孕晚期母体并发症方面，早产、PPH发生率较单纯HBV感染组增加，差异均有统计学意义(χ²值分别为4.169、5.448，P值分别为0.041、0.020)；HBV+ICP组孕妇所分娩新生儿在不良妊娠结局方面，新生儿窒息、AFⅢ及SGA发生率较单纯HBV感染组均增加，差异有统计学意义(χ²值分别为5.448、16.567、11.053，P值分别为0.020、＜0.001、0.002)。HBV+重度ICP组孕妇所分娩新生儿在不良妊娠结局方面，AFⅢ及SGA发生率较HBV+轻度ICP组增加，差异均有统计学意义(χ²值分别为4.200、4.511，P值分别为0.040、0.034)。结论 HBV感染合并ICP孕妇母体及新生儿不良妊娠结局的发生率相较于单纯HBV感染明显升高，且ICP程度越重，新生儿分娩不良结局发生率越高，但ICP对HBV-MTCT未见影响。
- 乙型肝炎病毒 /
- 胆汁淤积，肝内 /
- 妊娠
Abstract: Objective To investigate the influence of intrahepatic cholestasis of pregnancy (ICP) on adverse pregnancy outcomes of hepatitis B virus (HBV)-infected pregnant women. Methods A retrospective analysis was performed for 232 pregnant women with chronic HBV infection who were admitted to Beijing YouAn Hospital, Capital Medical University, from March 2018 to March 2021. According to the presence or absence of ICP, the patients were divided into HBV infection group with 100 patients and HBV+ICP group with 132 patients; according to the severity of ICP, the patients in the HBV+ICP group were further divided into HBV+mild ICP group with 86 patients and HBV+severe ICP group with 46 patients. The above groups were compared in terms of the incidence rates of maternal complications during pregnancy, such as premature delivery, premature rupture of membranes, gestational diabetes mellitus, hypertensive disorder complicating pregnancy, and postpartum hemorrhage (PPH), as well as the adverse outcomes of fetus/neonate, such as intrauterine fetal death, neonatal asphyxia, amniotic fluid pollution degree Ⅲ(AFⅢ), neonatal respiratory distress syndrome, small-for-gestational-age (SGA), admission to the neonatal intensive care unit, pneumonia, and mother-to-child transmission (MTCT) of HBV. A one-way analysis of variance was used for comparison between multiple groups; the chi-square test, the chi-square test with continuity correction or the Fisher's exact test was used for comparison of categorical data between multiple groups. Results Compared with the HBV infection group in terms of maternal complications in late pregnancy, the HBV+ICP group had significantly higher incidence rates of premature delivery and PPH (χ²=4.169 and 5.448, P=0.041 and 0.020), and in terms of the adverse outcomes of neonates, the HBV+ICP group had significantly higher incidence rates of neonatal asphyxia, AFⅢ, and SGA than the HBV infection group (χ²=5.448, 16.567, and 11.053, P=0.020, P < 0.001, and P=0.002). In terms of the adverse outcomes of neonates, the HBV+severe ICP group had significantly higher incidence rates of AFⅢ and SGA than the HBV+mild ICP group (χ²=4.200 and 4.511, P=0.040 and 0.034). Conclusion Compared with the pregnant women with HBV infection alone, the pregnant women with HBV infection and ICP have significantly higher incidence rates of adverse pregnancy outcomes in mothers and neonates, and the incidence rate of adverse outcomes in neonates increases with the increase in the severity of ICP. However, ICP has no influence on HBV MTCT.
- Hepatitis B Virus /
- Cholestasis, Intrahepatic /
- Pregnancy

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表 1 单纯HBV感染组与HBV+轻/重度ICP组孕妇一般资料比较

Table 1. Comparison of general data between pregnant women with HBV infection alone and pregnant women with HBV infection + mild/severe ICP

组别	例数	孕妇年龄 (岁)	孕前BMI (kg/m²)	初产妇 [例(%)]	自然受孕 [例(%)]	孕期母婴阻断 [例(%)]	HBeAg阳性 [例(%)]	分娩前 ALT (U/L)	分娩前 HBV DNA (Ig IU/mL)
单纯HBV感染组	100	30.17±5.32	23.35±3.86	79(79.00)	91(91.00)	39(39.00)	31(31.00)	25.00±6.71	2.00±1.30
HBV+轻度ICP组	86	29.11±4.55	22.12±3.51	70(81.40)	78(90.70)	31(36.05)	24(27.91)	29.00±8.31	1.80±1.45
HBV+重度ICP组	46	28.79±6.06	23.91±2.99	37(80.43)	43(93.48)	20(43.48)	16(34.78)	30.00±5.32	2.00±1.21
统计值		F=1.131	F=2.228	χ²=4.932	χ²=2.763	χ²=1.552	χ²=4.610	F=5.371	F=2.514
P值		0.612	0.375	0.091	0.261	0.471	0.100	0.063	0.310

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表 2 单纯HBV感染组与HBV+ICP组孕妇母儿妊娠结局指标比较

Table 2. Comparison of pregnancy outcome indicators between pregnant women with HBV infection alone and those with HBV infection + ICP

指标	单纯HBV感染组 (n=100)	HBV+ICP组 (n=132)	χ²值	P值
母体并发症[例(%)]
早产	6(6.00)	19(14.39)	4.169	0.041
GDM	15(15.00)	19(14.39)	0.017	0.897
HDCP	4(4.00)	5(3.79)	0.000	1.000
PROM	12(12.00)	14(10.61)	0.111	0.739
PPH	4(4.00)	17(12.88)	5.448	0.020
新生儿不良结局[例(%)]
胎死宫内	1(1.00)	3(2.27)	0.052	0.819
新生儿窒息	4(4.00)	17(12.88)	5.448	0.020
AFⅢ	11(11.00)	45(34.09)	16.567	＜0.001
NRDS	1(1.00)	8(6.06)	2.668	0.102
SGA	3(3.00)	22(16.67)	11.053	0.002
NICU入院	1(1.00)	8(6.06)	2.668	0.102
肺炎	2(2.00)	7(5.30)	0.897	0.344
MTCT	1(1.00)	1(0.76)		1.000

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表 3 HBV+轻/重度ICP组孕妇母儿妊娠结局指标比较

Table 3. Comparison of maternal and perinatal outcomes in HBV + mild/severe ICP group

指标	HBV+轻度ICP组 (n=86)	HBV+重度ICP组 (n=46)	χ²值	P值
母体并发症[例(%)]
早产	10(11.63)	9(19.57)	1.532	0.216
GDM	12(13.95)	7(15.22)	0.010	0.920
HDCP	0	5(10.87)
PROM	9(10.47)	5(10.87)	0.000	1.000
PPH	9(10.47)	8(17.39)	1.281	0.258
新生儿不良结局[例(%)]
胎死宫内	2(2.33)	1(2.17)	0.000	1.000
新生儿窒息	9(10.47)	8(17.39)	1.281	0.258
AFⅢ	24(27.91)	21(45.65)	4.200	0.040
NRDS	5(5.81)	3(6.52)	0.000	1.000
SGA	10(11.63)	12(26.09)	4.511	0.034
NICU入院	4(4.65)	4(8.70)	0.297	0.586
肺炎	4(4.65)	3(6.52)	0.000	1.000
MTCT	1(1.16)	0		0.394

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参考文献(23)

[1]	Obstetrics Subgroup, Chinese Society of Obstetrics and Gynecology, Chinese Medical Association. Guidelines for the management of intrahepatic cholestasis of pregnancy (2015)[J]. J Clin Hepatol, 2015, 31(10): 1575-1578. DOI: 10.3969/j.issn.1001-5256.2015.10.003. 中华医学会妇产科学分会产科学组. 妊娠期肝内胆汁淤积症诊疗指南(2015)[J]. 临床肝胆病杂志, 2015, 31(10): 1575-1578. DOI: 10.3969/j.issn.1001-5256.2015.10.003.
[2]	XIN X, WANG Y, CHENG J, et al. Seroepidemiological survey of hepatitis B virus infection among 764, 460 women of childbearing age in rural China: A cross-sectional study[J]. J Clin Virol, 2016, 81: 47-52. DOI: 10.1016/j.jcv.2016.05.014.
[3]	KUNTZ M, KUNTZ HD. Hepatology textbook and atlas[M]. Berlin, Heidelberg: Springer, 2008.
[4]	CHEN YC, ZHANG YM, ZHANG HS, et al. Effects of viral load of HBV-infected pregnant women on the humoral immune status and neonatal HBV infection rate[J]. Int J Virol, 2022, 29(1): 49-53. DOI: 10.3760/cma.j.issn.1673-4092.2022.01.010. 陈月婵, 张艳敏, 张红升, 等. HBV感染孕妇病毒载量对体液免疫状态及新生儿HBV感染率的影响[J]. 国际病毒学杂志, 2022, 29(1): 49-53. DOI: 10.3760/cma.j.issn.1673-4092.2022.01.010.
[5]	CHEN Y, TIAN Z. HBV-induced immune imbalance in the development of HCC[J]. Front Immunol, 2019, 10: 2048. DOI: 10.3389/fimmu.2019.02048.
[6]	Chinese Society of Infectious Diseases, Chinese Medical Association, Chinese Society of Hepatology, Chinese Medical Association. Guidelines for the prevention and treatment of chronic hepatitis B (version 2019)[J]. J Clin Hepatol, 2019, 35(12): 2648-2669. DOI: 10.3969/j.issn.1001-5256.2019.12.007. 中华医学会感染病学分会, 中华医学会肝病学分会. 慢性乙型肝炎防治指南(2019年版)[J]. 临床肝胆病杂志, 2019, 35(12): 2648-2669. DOI: 10.3969/j.issn.1001-5256.2019.12.007.
[7]	SHEN JC, LENG XJ, ZHANG Y, et al. Interpretation of managing HBV in pregnancy. Prevention, prophylaxis, treatment and follow-up[J]. J Clin Hepatol, 2016, 32(6): 1060-1068. DOI: 10.3969/j.issn.1001-5256.2016.06.008. 申姣春, 冷雪君, 张莹, 等. 《妊娠期HBV的阻断、预防、治疗和随访管理》解读[J]. 临床肝胆病杂志, 2016, 32(6): 1060-1068. DOI: 10.3969/j.issn.1001-5256.2016.06.008.
[8]	PIECHOTA J, JELSKI W. Intrahepatic cholestasis in pregnancy: Review of the literature[J]. J Clin Med, 2020, 9(5): 1361. DOI: 10.3390/jcm9051361.
[9]	LIU Y, MA C, JIA H, et al. Knowledge, attitudes, and practices regarding hepatitis B vaccination among hospital-based doctors and nurses in China: Results of a multi-site survey[J]. Vaccine, 2018, 36(17): 2307-2313. DOI: 10.1016/j.vaccine.2018.03.018.
[10]	YULE CS, HOLCOMB DS, KRAUS AC, et al. Cholestasis: A prospective study of perinatal outcomes and time to symptom improvement[J]. Am J Perinatol, 2021, 38(5): 414-420. DOI: 10.1055/s-0040-1717076.
[11]	GERMAIN AM, KATO S, CARVAJAL JA, et al. Bile acids increase response and expression of human myometrial oxytocin receptor[J]. Am J Obstet Gynecol, 2003, 189(2): 577-582. DOI: 10.1067/s0002-9378(03)00545-3.
[12]	KONDRACKIENE J, KUPCINSKAS L. Intrahepatic cholestasis of pregnancy-current achievements and unsolved problems[J]. World J Gastroenterol, 2008, 14(38): 5781-5788. DOI: 10.3748/wjg.14.5781.
[13]	ARTHUIS C, DIGUISTO C, LORPHELIN H, et al. Perinatal outcomes of intrahepatic cholestasis during pregnancy: An 8-year case-control study[J]. PLoS One, 2020, 15(2): e0228213. DOI: 10.1371/journal.pone.0228213.
[14]	WU K, WANG H, LI S, et al. Maternal hepatitis B infection status and adverse pregnancy outcomes: a retrospective cohort analysis[J]. Arch Gynecol Obstet, 2020, 302(3): 595-602. DOI: 10.1007/s00404-020-05630-2.
[15]	ROY A, PREMKUMAR M, MISHRA S, et al. Role of ursodeoxycholic acid on maternal serum bile acids and perinatal outcomes in intrahepatic cholestasis of pregnancy[J]. Eur J Gastroenterol Hepatol, 2021, 33(4): 571-576. DOI: 10.1097/MEG.0000000000001954.
[16]	ZHANG C, WEI H, ZHU YX. Adverse pregnancy outcomes and mother-to-child transmission in patients with hepatitis B virus infection and intrahepatic cholestasis of pregnancy[J]. Ginekol Pol, 2021. DOI: 10.5603/GP.a2021.0110. [Online ahead of print]
[17]	ABU-HAYYEH S, PAPACLEOVOULOU G, LÖVGREN-SANDBLOM A, et al. Intrahepatic cholestasis of pregnancy levels of sulfated progesterone metabolites inhibit farnesoid X receptor resulting in a cholestatic phenotype[J]. Hepatology, 2013, 57(2): 716-726. DOI: 10.1002/hep.26055.
[18]	BATSRY L, ZLOTO K, KALTER A, et al. Perinatal outcomes of intrahepatic cholestasis of pregnancy in twin versus singleton pregnancies: is plurality associated with adverse outcomes?[J]. Arch Gynecol Obstet, 2019, 300(4): 881-887. DOI: 10.1007/s00404-019-05247-0.
[19]	LEE RH, KWOK KM, INGLES S, et al. Pregnancy outcomes during an era of aggressive management for intrahepatic cholestasis of pregnancy[J]. Am J Perinatol, 2008, 25(6): 341-345. DOI: 10.1055/s-2008-1078756.
[20]	ROOK M, VARGAS J, CAUGHEY A, et al. Fetal outcomes in pregnancies complicated by intrahepatic cholestasis of pregnancy in a Northern California cohort[J]. PLoS One, 2012, 7(3): e28343. DOI: 10.1371/journal.pone.0028343.
[21]	KREMER AE, WOLF K, STÄNDER S. Intrahepatic cholestasis of pregnancy: Rare but important[J]. Hautarzt, 2017, 68(2): 95-102. DOI: 10.1007/s00105-016-3923-y.
[22]	ZECCA E, de LUCA D, BARONI S, et al. Bile acid-induced lung injury in newborn infants: a bronchoalveolar lavage fluid study[J]. Pediatrics, 2008, 121(1): e146-e149. DOI: 10.1542/peds.2007-1220.
[23]	FUNK AL, LU Y, YOSHIDA K, et al. Efficacy and safety of antiviral prophylaxis during pregnancy to prevent mother-to-child transmission of hepatitis B virus: a systematic review and meta-analysis[J]. Lancet Infect Dis, 2021, 21(1): 70-84. DOI: 10.1016/S1473-3099(20)30586-7.