瘙痒与妊娠期肝内胆汁淤积症临床预后的关系及风险预测

doi:10.3969/j.issn.1004-583X.2023.05.003

摘要/Abstract

摘要：

目的比较伴或不伴瘙痒症状的妊娠期肝内胆汁淤积症(intrahepatic cholestasis of pregnancy,ICP)患者的不同临床特征,评估瘙痒在妊娠期胆汁淤积症中的意义。方法 359例ICP患者,根据有无瘙痒症状,发病孕周和血清总胆汁酸(total bile acid,TBA)浓度进行分组,随机选取同期产检正常的孕妇设为对照组。评估瘙痒和TBA水平与围产期结局的关系。结果 ICP发生率约1.1%,其中无症状者居多(71.03%)。伴或不伴瘙痒症状的ICP患者肝功能指标、妊娠期糖尿病、新生儿低体重和早产、剖宫产率较对照组增高(P <0.05),3组分娩前脐血流均在正常范围内,ICP组,尤其是有症状ICP组,脐血流值都在正常范围的上限(P<0.05)。轻度、无症状ICP的剖宫产率、早产率在所有分组中最低(P <0.05)。瘙痒症状和TBA浓度与围产期发病率呈正相关,其中 TBA≥40 μmol/L尤为显著。结论瘙痒不应成为ICP诊断的先决条件,无论有无瘙痒,ICP均增加围产期发病率,但瘙痒和TBA≥40 μmol/L是围产期发病的危险因素。无症状ICP多表现为轻型ICP,但均可无预警发生胎死宫内。因此,妊娠期应定期检查TBA和肝功能,以防止无症状患者漏诊。

关键词: 胆汁淤积,肝内, 孕妇, 瘙痒症, 胆汁酸类, 围产期

Abstract:

Objective To compare the clinical characteristics of intrahepatic cholestasis of pregnancy (ICP) with or without pruritus and to evaluate the significance of pruritus in ICP. Methods A total of 359 ICP patients were divided into different groups according to the presence or absence of pruritus, the onset of gestational age and the total bile acid (TBA) levels. Pregnant women with normal birth examination during the same period were randomly selected as the control group. The correlation of pruritus and TBA levels with perinatal morbidity was evaluated. Results The incidence of ICP was about 1.1%, and most of them were asymptomatic (71.03%). Liver function, gestational diabetes mellitus (GDM), low birth weight, preterm birth and cesarean section rate were significantly higher in ICP patients with or without pruritus than those in the control group (P <0.05). The cord blood flow before delivery was within the normal range in all three recruited pregnant women. In ICP group, especially in symptomatic ICP group, the cord blood flow values were within the upper limit of the normal range (P <0.05). Pregnant women with mild and asymptomatic ICP had the lowest rates of cesarean section and preterm birth (P<0.05). Pruritus and TBA level were positively correlated with perinatal morbidity, especially when TBA≥40 μmol/L. Conclusion Pruritus should not be a prerequisite for the diagnosis of ICP. Regardless of the presence or absence of pruritus, ICP increases perinatal morbidity, but pruritus and TBA≥40 μmol/L are risk factors for perinatal morbidity. Cases of asymptomatic ICP are mostly mild, but intrauterine fetal death can occur without warning. Therefore, TBA and liver function should be regularly monitored during pregnancy to prevent missed diagnosis in asymptomatic ICP patients.

Key words: cholestasis, intrahepatic, pregnant women, pruritus, bile acids, perinatal period

中图分类号:

R575

张源, 周娟, 黎文香, 刘金香, 汤小湄, 罗惠娟. 瘙痒与妊娠期肝内胆汁淤积症临床预后的关系及风险预测[J]. 临床荟萃, 2023, 38(5): 405-411.

Zhang Yuan, Zhou Juan, Li Wenxiang, Liu Jinxiang, Tang Xiaomei, Luo Huijuan. Correlation between pruritus and the prognosis of intrahepatic cholestasis of pregnancy and prediction of its risks[J]. Clinical Focus, 2023, 38(5): 405-411.

导出引用管理器 EndNote|Ris|BibTeX

链接本文: https://huicui.hebmu.edu.cn/CN/10.3969/j.issn.1004-583X.2023.05.003

https://huicui.hebmu.edu.cn/CN/Y2023/V38/I5/405

图/表 5

参考文献 35

[1]	Arrese M, Macias RI, Briz O, et al. Molecular pathogenesis of intrahepatic cholestasis of pregnancy[J]. Expert Rev Mol Med, 2008, 10: e9. doi: 10.1017/S1462399408000628 URL
[2]	Lammert F, Marschall HU, Matern S. Intrahepatic cholestasis of pregnancy[J]. Curr Treat Options Gastroenterol, 2003, 6(2): 123-132. pmid: 12628071
[3]	Geenes V, Williamson C. Intrahepatic cholestasis of pregnancy[J]. World J Gastroenterol, 2009, 15(17): 2049-2066. doi: 10.3748/wjg.15.2049 URL
[4]	Glantz A, Marschall HU, Mattsson LA. Intrahepatic cholestasis of pregnancy: Relationships between bile acid levels and fetal complication rates[J]. Hepatology, 2004, 40(2): 467-474. doi: 10.1002/hep.20336 pmid: 15368452
[5]	Pascual MJ, Serrano MA, El-Mir MY, et al. Relationship between asymptomatic hypercholanaemia of pregnancy and progesterone metabolism[J]. Clin Sci (Lond), 2002, 102(5): 587-593. doi: 10.1042/cs1020587 URL
[6]	Feng D, He W. Asymptomatic elevated total serum bile acids representing an unusual form of intrahepatic cholestasis of pregnancy[J]. Int J Gynaecol Obstet, 2016, 134(3): 343-344. doi: 10.1016/j.ijgo.2016.04.004 pmid: 27481015
[7]	Lunzer M, Barnes P, Byth K, et al. Serum bile acid concentrations during pregnancy and their relationship to obstetric cholestasis[J]. Gastroenterology, 1986, 91(4): 825-829. pmid: 3743960
[8]	Castaño G, Lucangioli S, Sookoian S, et al. Bile acid profiles by capillary electrophoresis in intrahepatic cholestasis of pregnancy[J]. Clin Sci (Lond), 2006, 110(4): 459-465. doi: 10.1042/CS20050302 URL
[9]	Obstetrics Subgroup, Chinese Society of Obstetrics and Gynecology, Chinese Medical Association. Guidelines for diagnosis and treatment of intrahepatic cholestasis of pregnancy (2015)[J]. Zhonghua Fu Chan Ke Za Zhi, 2015, 50(7): 481-485.
[10]	Whittington JR, Allen LR, Ennen CS, et al. Relationship between maternal serum bile acid levels and fetal cardiac troponin-I levels in asymptomatic pregnant patients at term: A cross-sectional observational study[J]. Cureus, 2019, 11(8): e5508.
[11]	Alemi F, Kwon E, Poole DP, et al. The TGR5 receptor mediates bile acid-induced itch and analgesia[J]. J Clin Invest, 2013, 123(4): 1513-1530. doi: 10.1172/JCI64551 pmid: 23524965
[12]	Kondrackiene J, Beuers U, Zalinkevicius R, et al. Predictors of premature delivery in patients with intrahepatic cholestasis of pregnancy[J]. World J Gastroenterol, 2007, 13(46): 6226-6230. doi: 10.3748/wjg.v13.i46.6226 URL
[13]	Lee NM, Brady CW. Liver disease in pregnancy[J]. World J Gastroenterol, 2009, 15(8): 897-906. doi: 10.3748/wjg.15.897 URL
[14]	Mullally BA, Hansen WF. Intrahepatic cholestasis of pregnancy: Review of the literature[J]. Obstet Gynecol Surv, 2002, 57(1): 47-52. doi: 10.1097/00006254-200201000-00023 pmid: 11773831
[15]	Hepburn IS, Schade RR. Pregnancy-associated liver disorders[J]. Dig Dis Sci, 2008, 53(9): 2334-2358. doi: 10.1007/s10620-007-0167-9 URL
[16]	Angueira AR, Ludvik AE, Reddy TE, et al. New insights into gestational glucose metabolism: Lessons learned from 21st century approaches[J]. Diabetes, 2015, 64(2): 327-334. doi: 10.2337/db14-0877 pmid: 25614666
[17]	Men·zyk T, Bator M, Derra A, et al. The role of metabolic disorders in the pathogenesis of intrahepatic cholestasis of pregnancy[J]. Clin Exp Hepatol, 2018, 4(4): 217-223. doi: 10.5114/ceh.2018.80122 URL
[18]	Liu C, Gao J, Liu J, et al. Intrahepatic cholestasis of pregnancy is associated with an increased risk of gestational diabetes and preeclampsia[J]. Ann Transl Med, 2020, 8(23): 1574. doi: 10.21037/atm-20-4879 pmid: 33437773
[19]	Jain R, Suri V, Chopra S, et al. Obstetric cholestasis: Outcome with active management[J]. J Obstet Gynaecol Res, 2013, 39(5): 953-959. doi: 10.1111/jog.12005 URL
[20]	Lo JO, Shaffer BL, Allen AJ, et al. Intrahepatic cholestasis of pregnancy and timing of delivery[J]. J Matern Fetal Neonatal Med, 2015, 28(18): 2254-2258. doi: 10.3109/14767058.2014.984605 pmid: 25371372
[21]	Puljic A, Kim E, Page J, et al. The risk of infant and fetal death by each additional week of expectant management in intrahepatic cholestasis of pregnancy by gestational age[J]. Am J Obstet Gynecol, 2015, 212(5): 667.
[22]	Arthur C, Mahomed K. Intrahepatic cholestasis of pregnancy: Diagnosis and management; a survey of royal Australian and New Zealand college of obstetrics and gynaecology fellows[J]. Aust N Z J Obstet Gynaecol, 2014, 54(3): 263-267. doi: 10.1111/ajo.12178 pmid: 24506294
[23]	Nichols AA. Cholestasis of pregnancy: A review of the evidence[J]. J Perinat Neonatal Nurs, 2005, 19(3): 217-225.
[24]	Mays JK. The active management of intrahepatic cholestasis of pregnancy[J]. Curr Opin Obstet Gynecol, 2010, 22(2): 100-103. doi: 10.1097/GCO.0b013e328337238d URL
[25]	Floreani A, Gervasi MT. New insights on intrahepatic cholestasis of pregnancy[J]. Clin Liver Dis, 2016, 20(1): 177-189. doi: 10.1016/j.cld.2015.08.010 pmid: 26593298
[26]	Mozurkewich E, Chilimigras J, Koepke E, et al. Indications for induction of labour: A best-evidence review[J]. BJOG, 2009, 116(5): 626-636. doi: 10.1111/j.1471-0528.2008.02065.x URL
[27]	Menezes EV, Yakoob MY, Soomro T, et al. Reducing stillbirths: Prevention and management of medical disorders and infections during pregnancy[J]. BMC Pregnancy Childbirth, 2009, 9 Suppl 1(Suppl 1): S4.
[28]	Henderson CE, Shah RR, Gottimukkala S, et al. Primum non nocere: How active management became modus operandi for intrahepatic cholestasis of pregnancy[J]. Am J Obstet Gynecol, 2014, 211(3): 189-196. doi: 10.1016/j.ajog.2014.03.058 pmid: 24704063
[29]	Girling JC, Dow E, Smith JH. Liver function tests in pre-eclampsia: Importance of comparison with a reference range derived for normal pregnancy[J]. Br J Obstet Gynaecol, 1997, 104(2): 246-250. pmid: 9070148
[30]	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): e146-149. doi: 10.1542/peds.2007-1220 URL
[31]	Vasavan T, Deepak S, Jayawardane IA, et al. Fetal cardiac dysfunction in intrahepatic cholestasis of pregnancy is associated with elevated serum bile acid concentrations[J]. J Hepatol, 2021, 74(5): 1087-1096. doi: 10.1016/j.jhep.2020.11.038 URL
[32]	Madazli R, Yuksel MA, Oncul M, et al. Pregnancy outcomes and prognostic factors in patients with intrahepatic cholestasis of pregnancy[J]. J Obstet Gynaecol, 2015, 35(4): 358-361. doi: 10.3109/01443615.2014.968102 pmid: 25384180
[33]	Estiú MC, Frailuna MA, Otero C, et al. Relationship between early onset severe intrahepatic cholestasis of pregnancy and higher risk of meconium-stained fluid[J]. PLoS One, 2017, 12(4): e0176504.
[34]	Piechota J, Jelski W. Intrahepatic cholestasis in pregnancy: Review of the literature[J]. J Clin Med, 2020, 9(5): 1361. doi: 10.3390/jcm9051361 URL
[35]	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 URL

项目	对照组 (n=200)	有症状ICP组 (n=104)	无症状ICP组 (n=255)	P值
年龄(岁)	30.0(27.0, 33.0)	29.0(27.0, 33.7)	30.0(27.0, 33.0)	0.887
孕次(次)	2.0(1.0, 2.0)	2.0(1.0, 3.0)	2.0(1.0, 3.0)^*	0.035
分娩次数(次)	1.0(1.0, 2.0)	1.0(1.0, 2.0)	2.0(1.0, 2.0)^*	0.013
BMI(kg/m²)	26.2(24.1, 28.1)	25.1(23.3, 27.6)^*	25.7(23.5, 27.2)	0.025
胆汁酸异常时胎龄(周)	-	34.3(30.0, 37.0)	33.0(24.4, 37.3)	0.254
TBA(μmol/L)	3.8(2.7, 4.5)	23.8(15.0, 43.2)^*	21.4(14.5, 31.3)^*	<0.01
ALT(IU/L)	12.5(9.0, 14.0)	46.5(15.3, 159.3)^*	14.0(10.0, 16.0)^*#	<0.01
AST(IU/L)	18.0(15.0, 20.0)	50.5(21.3, 104.3)^*	18.0(15.0, 20.0)^#	<0.01
TBIL(μmol/L)	8.2(6.5, 9.0)	12.3(7.7, 15.5)^*	8.5(7.0, 8.6)^*#	<0.01
GC(μmol/L)	2.8(2.2, 3.7)	18.2(7.9, 35.8)^*	13.2(7.7, 22.6)^*	<0.01
GDM[例(%)]	23(11.5)	26(25.0)^*	58(22.8)^*	0.002
脐血流量
S/D	2.1(1.9, 2.3)	2.4(2.1, 2.7)^*	2.2(2.0, 2.5)^*#	<0.01
PI	0.7(0.7, 0.9)	0.8(0.7, 1.0)^*	0.8(0.7, 0.9)^#	0.002
RI	0.5(0.5, 0.6)	0.6(0.5, 0.6)^*	0.6(0.5, 0.6)	0.012
早产[例(%)]	6(3.0)	30(28.8)^*	47(18.4)^*#	<0.01
医源性早产	0	15(14.4)^*	16 (6.3)^*#	<0.01
自发性早产	6(3.0)	15(14.4)^*	31(12.2)^*	0.001
分娩时胎龄(周)	39.4(38.6, 40.2)	37.6(36.4, 38.5)^*	38.3(37.2, 39.1)^*#	<0.01
分娩方式[例(%)]
剖宫产	40(20.0)	71(68.3)^*	123 (48.2)^*#	<0.01
阴道助产	8(4.0)	2(1.9)	6(2.4)	0.912
正常分娩	152(76.0)	31(29.8)^*	126 (49.4)^*#	<0.01
新生儿体重(g)	3250(2950, 3450)	3000(2650, 3200)^*	3000(2700, 3300)^*	<0.01
新生儿性别(女)[例(%)]	96(48.0)	45(43.3)	124(48.6)	0.639
胎儿宫内窘迫[例(%)]	31(15.5)	18(17.3)	44(17.2)	0.853
羊水异常[例(%)]	14(7.0)	21(20.2)^*	26(10.2)^#	0.002
MSAF	11(5.5)	17(16.4)^*	24(9.4)	0.008
羊水过少	3(1.5)	4(3.8)	2(0.8)	0.110
新生儿窒息[例(%)]	3(1.5)	4(3.8)	12(4.7)	0.164

项目	对照组 (n=200)	有症状ICP组 (n=104)	无症状ICP组 (n=255)	P值
年龄(岁)	30.0(27.0, 33.0)	29.0(27.0, 33.7)	30.0(27.0, 33.0)	0.887
孕次(次)	2.0(1.0, 2.0)	2.0(1.0, 3.0)	2.0(1.0, 3.0)^*	0.035
分娩次数(次)	1.0(1.0, 2.0)	1.0(1.0, 2.0)	2.0(1.0, 2.0)^*	0.013
BMI(kg/m²)	26.2(24.1, 28.1)	25.1(23.3, 27.6)^*	25.7(23.5, 27.2)	0.025
胆汁酸异常时胎龄(周)	-	34.3(30.0, 37.0)	33.0(24.4, 37.3)	0.254
TBA(μmol/L)	3.8(2.7, 4.5)	23.8(15.0, 43.2)^*	21.4(14.5, 31.3)^*	<0.01
ALT(IU/L)	12.5(9.0, 14.0)	46.5(15.3, 159.3)^*	14.0(10.0, 16.0)^*#	<0.01
AST(IU/L)	18.0(15.0, 20.0)	50.5(21.3, 104.3)^*	18.0(15.0, 20.0)^#	<0.01
TBIL(μmol/L)	8.2(6.5, 9.0)	12.3(7.7, 15.5)^*	8.5(7.0, 8.6)^*#	<0.01
GC(μmol/L)	2.8(2.2, 3.7)	18.2(7.9, 35.8)^*	13.2(7.7, 22.6)^*	<0.01
GDM[例(%)]	23(11.5)	26(25.0)^*	58(22.8)^*	0.002
脐血流量
S/D	2.1(1.9, 2.3)	2.4(2.1, 2.7)^*	2.2(2.0, 2.5)^*#	<0.01
PI	0.7(0.7, 0.9)	0.8(0.7, 1.0)^*	0.8(0.7, 0.9)^#	0.002
RI	0.5(0.5, 0.6)	0.6(0.5, 0.6)^*	0.6(0.5, 0.6)	0.012
早产[例(%)]	6(3.0)	30(28.8)^*	47(18.4)^*#	<0.01
医源性早产	0	15(14.4)^*	16 (6.3)^*#	<0.01
自发性早产	6(3.0)	15(14.4)^*	31(12.2)^*	0.001
分娩时胎龄(周)	39.4(38.6, 40.2)	37.6(36.4, 38.5)^*	38.3(37.2, 39.1)^*#	<0.01
分娩方式[例(%)]
剖宫产	40(20.0)	71(68.3)^*	123 (48.2)^*#	<0.01
阴道助产	8(4.0)	2(1.9)	6(2.4)	0.912
正常分娩	152(76.0)	31(29.8)^*	126 (49.4)^*#	<0.01
新生儿体重(g)	3250(2950, 3450)	3000(2650, 3200)^*	3000(2700, 3300)^*	<0.01
新生儿性别(女)[例(%)]	96(48.0)	45(43.3)	124(48.6)	0.639
胎儿宫内窘迫[例(%)]	31(15.5)	18(17.3)	44(17.2)	0.853
羊水异常[例(%)]	14(7.0)	21(20.2)^*	26(10.2)^#	0.002
MSAF	11(5.5)	17(16.4)^*	24(9.4)	0.008
羊水过少	3(1.5)	4(3.8)	2(0.8)	0.110
新生儿窒息[例(%)]	3(1.5)	4(3.8)	12(4.7)	0.164

项目	有症状ICP组		无症状ICP组		P值
项目	轻度(n=67)	重度(n =37)	轻度(n=196)	重度(n=59)	P值
早发型	12(17.9)	7(18.9)	45(23.0)	29(49.2)^*#△	<0.01
迟发型	55(82.1)	30(81.1)	151(76.3)	30(50.9)
分娩方式
剖宫产	46(68.7)	27(75.7)	89(45.4)^*#	39(66.1)^△	<0.01
阴道分娩	21(31.3)	10(27.0)	107(54.6)	20(33.9)
早产	15(22.4)	16(43.2)^*	25(12.8)^#	21(35.6)^△	<0.01
医源性早产	6(9.0)	10(27.0)^*	6(3.1)^#	10(17.0)^△	<0.01
自发性早产	9(13.4)	6(16.2)	19(9.7)	11(18.6)	0.266
胎儿宫内死亡	0	1(2.7)	1(0.5)	0	0.285
胎儿窘迫	13(5.2)	4(10.8)	35(17.9)	6(10.2)	0.350
羊水异常	12(17.9)	10(27.0)	20(10.2)^#	6(10.2)^#	0.025
MSAF	9(13.4)	8(21.6)	19(9.7)	5(8.5)	0.161
羊水过少	3(4.5)	2(5.4)	1(0.5)	1(1.7)	0.082
新生儿窒息	4(6.0)	0	8(4.1)	4(6.8)	0.400
胎儿宫内死亡	0	1(2.7)	1(0.5)	0	0.285

项目	有症状ICP组		无症状ICP组		P值
项目	轻度(n=67)	重度(n =37)	轻度(n=196)	重度(n=59)	P值
早发型	12(17.9)	7(18.9)	45(23.0)	29(49.2)^*#△	<0.01
迟发型	55(82.1)	30(81.1)	151(76.3)	30(50.9)
分娩方式
剖宫产	46(68.7)	27(75.7)	89(45.4)^*#	39(66.1)^△	<0.01
阴道分娩	21(31.3)	10(27.0)	107(54.6)	20(33.9)
早产	15(22.4)	16(43.2)^*	25(12.8)^#	21(35.6)^△	<0.01
医源性早产	6(9.0)	10(27.0)^*	6(3.1)^#	10(17.0)^△	<0.01
自发性早产	9(13.4)	6(16.2)	19(9.7)	11(18.6)	0.266
胎儿宫内死亡	0	1(2.7)	1(0.5)	0	0.285
胎儿窘迫	13(5.2)	4(10.8)	35(17.9)	6(10.2)	0.350
羊水异常	12(17.9)	10(27.0)	20(10.2)^#	6(10.2)^#	0.025
MSAF	9(13.4)	8(21.6)	19(9.7)	5(8.5)	0.161
羊水过少	3(4.5)	2(5.4)	1(0.5)	1(1.7)	0.082
新生儿窒息	4(6.0)	0	8(4.1)	4(6.8)	0.400
胎儿宫内死亡	0	1(2.7)	1(0.5)	0	0.285

TBA (μmol/L)	有症状ICP围产期发病率				无症状ICP围产期发病率
	OR值	P值	95%CI		OR值	P值	95%CI
	OR值	P值	下限	上限	OR值	P值	下限	上限
10~19.999	7.710	<0.01	3.370	17.638	2.934	<0.01	1.827	4.712
20~29.999	4.681	0.001	1.853	11.829	3.755	<0.01	2.135	6.606
30~39.999	7.710	0.11	1.594	37.303	1.589	0.249	0.723	3.495
≥40	12.047	<0.01	4.031	36.004	6.302	<0.01	2.824	14.067