The pathophysiology of intrahepatic cholestasis of pregnancy.

This chapter on the gastrointestinal and hepatic systems in pregnancy focusses on those conditions that are frequent and troublesome (gastro-oesophageal reflux and constipation), distressing (hyperemesis gravidarum) or potentially fatal (obstetric cholestasis, acute fatty liver of pregnancy and HELLP (haemolysis, elevated liver enzymes, low platelets) syndrome). It also highlights the clinical challenge obstetricians may face in managing rare conditions such as the Budd-Chiari syndrome, liver transplantation, primary biliary cirrhosis and Wilson disease. The clinical presentation of liver and gastrointestinal dysfunction in pregnancy is not specific, and certain 'abnormalities' may represent physiological changes of pregnancy. Diagnosis and management are often difficult because of atypical symptoms, a reluctance to use invasive investigations and concerns about the teratogenicity of the medications. The best available evidence to manage these conditions is discussed in the chapter.

Gastrointestinal and liver disease in pregnancy.

Background Intrahepatic cholestasis of pregnancy is a pregnancy-specific liver disorder, possibly associated with an increased risk of severe fetal adverse events. Total serum bile acids (TSBA) concentration, alone or in combination with serum aminotransferases, have been the most often used biomarkers for the diagnosis of intrahepatic cholestasis of pregnancy in clinical practice. Serum bile acid profile, composed of primary or secondary, conjugated or non-conjugated bile acids, may provide more specific disease information. Objectives To assess and compare, independently or in combination, the diagnostic accuracy of total serum bile acids or serum bile acids profile, or both, for the diagnosis of intrahepatic cholestasis of pregnancy in pregnant women, presenting with pruritus. To define the optimal cut-off values for components of serum bile acid profile; to investigate possible sources of heterogeneity. Search methods We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Hepato-Biliary Group Diagnostic Test Accuracy Studies Register, the Cochrane Library, MEDLINE Ovid, Embase Ovid, Science Citation Index Expanded, Conference Proceedings Citation Index - Science, BIOSIS, CINAHL, two Chinese databases (CKNI, VIP), Latin American and Caribbean Health Sciences Literature (LILACS), Scientific Electronic Library Online (SciELO), Evidence Search: Health and Social Care by the National Institute for Health and Care Excellence (NICE), the World Health Organization (WHO) Reproductive Health Library (RHL), and the Turning Research into Practice database (TRIP). The most recent date of search was 6 May 2019. We identified additional references by handsearching the references of articles, meta-analyses, and evidence-based guidelines retrieved from the computerised databases, on-line trial registries, and grey literature through OpenSIGLE, National Technical Information Service (NTIS), ProQuest Dissertations & Thesis Database, and Index to Theses in Great Britain and Ireland. Selection criteria Prospective or retrospective diagnostic case-control or cross-sectional studies, irrespective of publication date, format, and language, which evaluated the diagnostic accuracy of total serum bile acids (TSBA) or components of serum bile acid profile for the diagnosis of intrahepatic cholestasis of pregnancy in pregnant women of any age or ethnicity, in any clinical setting, symptomatic for pruritus. Data collection and analysis We selected studies by reading titles, abstracts, or full texts, and assessing their fulfilment of our inclusion criteria. We emailed primary authors to request missing data or individual participant data. Having extracted data from each included study, we built the two-by-two tables for each primary study and for all the index tests considered. We estimated sensitivity and specificity with their 95% confidence intervals (CI). We presented data in coupled forest plots, showing sensitivities and specificities of each study, and we plotted the studies in the Receiver Operating Characteristic (ROC) space. We performed meta-analyses adopting the hierarchical summary ROC model (HSROC) or the bivariate model to meta-analyse the data. We made indirect comparisons of the considered index tests by adding the index tests as covariates to the bivariate or HSROC models. We performed heterogeneity analysis and sensitivity analysis on studies assessing TSBA accuracy. We used Review Manager 5 (RevMan 5) and SAS statistical software, release 9.4 (SAS Institute Inc., Cary, NC, USA), to perform all statistical analyses. We used QUADAS-2 domains to assess the risk of bias of the included studies. Main results Our search yielded 5073 references, but at the end of our selection process, only 16 studies fulfilled the review inclusion criteria. Nine of these provided individual participant data. We analysed only data concerning TSBA, cholic acid (CA), glycocholic acid (GCA), chenodeoxycholic acid (CDCA), and CA/CDCA because the remaining planned index tests were assessed in few studies. Only one study had low risk of bias in all four QUADAS-2 domains. The most biased domains were the patient sampling and the reference standard domains. When considering all studies with a cut-off of 10 μmol/L, TSBA overall sensitivity ranged from 0.72 to 0.98 and specificity ranged from 0.81 to 0.97. After a sensitivity analysis excluding case-control studies, TSBA sensitivity ranged from 0.48 to 0.66 and specificity from 0.52 to 0.99. After a sensitivity analysis excluding studies in which TSBA was part of the reference standard, TSBA sensitivity ranged from 0.49 to 0.65 and specificity from 0.53 to 0.99. We found the estimates of the overall accuracy for some serum bile acid components (CA, GCA, CDCA, and CA/CDCA) to be imprecise, with the CI for sensitivity and specificity very wide or impossible to calculate. Indirect comparisons between serum bile acid profile components and TSBA were not statistically significant. None of the heterogeneity analysis performed was statistically significant, except for the timing of assessment of TSBA (onset of symptoms, peak value among multiple assessments, delivery) but without clinically relevant results. We could not analyse the diagnostic accuracy of combinations of index tests because none of the included studies carried them out, and because of the small number of included studies. Authors' conclusions The overall high risk of bias, the existing concern regarding applicability of the results in clinical practice, and the great heterogeneity of the results in the included studies prevents us from making recommendations and reaching definitive conclusions at the present time. Thus, we do not find any compelling evidence to recommend or refute the routine use of any of these tests in clinical practice. So far, the diagnostic accuracy of TSBA for intrahepatic cholestasis of pregnancy might have been overestimated. There were too few studies to permit a precise estimate of the accuracy of serum bile acid profile components. Further primary clinical research is mandatory. We need both further phase II and phase III diagnostic studies.

Total serum bile acids or serum bile acid profile, or both, for the diagnosis of intrahepatic cholestasis of pregnancy

Intrahepatic cholestasis of pregnancy (ICP), also known as obstetric cholestasis, causes maternal pruritus and liver impairment, and may be complicated by spontaneous preterm labour, fetal asphyxial events and intrauterine death. Our understanding of the aetiology of this disease has expanded significantly in the last decade due to a better understanding of the role played by genetic factors. In particular, advances in our knowledge of bile homeostasis has led to the identification of genes that play a considerable role in susceptibility to ICP. In this review we consider these advances and discuss the disease in the context of bile synthesis and metabolism, focusing on the genetic discoveries that have shed light on the molecular aetiology and pathophysiology of the condition.

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The molecular genetics of intrahepatic cholestasis of pregnancy.

With increasing adoption of laparoscopic surgery in gynaecology,there has been a corresponding rise in the types and rates ofcomplications reported. This article sets out to classify complica-tions associated with laparoscopy according to the phases of thesurgery; assess the incidence, the mechanisms, the presentations;and recommend methods for preventing and dealing withcomplications in laparoscopic surgery. Its aim is to promotea culture of risk management based on the development of strat-egies to improve patient safety and outcome. 2009 Elsevier Ltd. All rights reserved.

Best Practice & Research Clinical Obstetrics and Gynaecology

Objective To study the perinatal outcomes of intrahepatic cholestasis of pregnancy (ICP). Methods The clinical data of 1210 cases of ICP in recent ten years were retrospectively analyzed. Results The incidence rates of perinatal outcomes of ICP were as follows: 19.0% (230/1210) for threatened premature labor, 24.0% (290/1210) for premature delivery; 23.2% (281/1210) for meconium stained amniotic fluid, 7.1% (86/1210) for neonatal asphyxia, 22.5 per thousand (27/1210) for perinatal mortality, 85.9% (1039/1210) for cesarean section, 0.9% (11/1210) for fetal growth restriction (FGR), 1.4% (17/1210) for postpartum hemorrhage, and 8.1% (101/1210) for preeclampsia. Threatened premature labor occurred beyond the gestation gestation period of 32 weeks in 88.7% (204/230) of the patients, and the fetal death rate in threatened premature labor was 46.7% (7/15). Premature delivery occurred after 34 weeks of gestation in 96.2% of the patients (279/290) 89.7% (260/290) of which were caused by cesarean section because of abnormal fetal monitoring. 41.3% of the cases with meconium stained amniotic fluid (116/281) occurred before the onset of labor. Fetal death accounted for 56% (15/27) of perinatal death, 80% (12/15) of which happened after the gestation week of 35 (36.5 +/- 1.2) with normal fetal heart rate monitoring. 95% (19/20) of the fetal death and stillbirth occurred after threatened premature labor and occasional uterine contractions, or at the early stage of labor. Conclusion The rates of FGR, postpartum hemorrhage, and preeclampsia in ICP are almost the same as those of the normal pregnancy. Routine fetal heart rate monitoring methods cannot predict fetal death. The important measures to decrease the perinatal mortality include paying attention to fetal monitoring when threatened premature labor, occasional uterine contractions and prenatal meconium occur, and at the early stage of labor, and management of threatened premature labor and timely intervention of pregnancy (at the gestation period of 34 - 37 weeks).

[Perinatal outcomes of intrahepatic cholestasis of pregnancy: analysis of 1210 cases].

Objective To study the clinical features and diagnosis of intrahepatic cholestasis of pregnancy (ICP). Methods During the last 10 years 1241 cases of ICP stayed in our hospital. Their clinical data were retrospectively reviewed. Results 5.2% of all the maternity patients had ICP. It occurred more in winter and 3.5% of ICP occurred in multiple pregnancies. The recurrence rate of ICP was 30.2%. On the average, it occurred at gestational week 32.6. Skin pruritus was the characteristic manifestation and the presenting symptom in 1201 patients (96.8%). The other presenting features included elevated serum ALT and AST (2.3%), jaundice (8 patients), diarrhea (3 patients), deep yellow urine (2 patients) and right upper abdominal pain (1 patient). The serum transaminases levels were elevated, of which 60% were between 50-200 IU/L. Serum total bile acid (TBA) levels were elevated in 82.4% of the patients and bilirubin levels in 33.4%. The elevated bilirubin levels were 30 to 90 micromol/L in 85% of those patients with this condition, and it was never higher than 170 micromol/L. Conclusion The basic diagnostic points of ICP are pruritus and abnormal liver function characterized by increased transaminases and TBA. Therefore paying attention to typical pruritus and other atypical features such as elevated serum transaminases, jaundice, diarrhea, deep yellow urine and right upper abdominal pain during antenatal care is important for an early diagnosis of ICP.

A clinical analysis of intrahepatic cholestasis of pregnancy in 1241 cases

Objective To explore the relationship between human leukocyte antigen-DQA1 (HLA-DQA1) allele gene polymorphism and intrahepatic cholestasis of pregnancy (ICP). Methods Forty-five patients with ICP, eighteen ICP families, forty-five normal pregnant women and eighteen normal control families were tested for HLA-DQA1 allele gene polymorphism by polymerase chain reaction with sequence-specific primer (PCR-SSP) method. [WTHZ]Results The frequency of HLA-DQA1*0301 in normal pregnant women was markedly higher than that in the ICP group (P0.05). No significant differences were observed between the frequencies of other detected HLA-DQA1 alleles in both groups. The analysis of feto-maternal or couples sharing of the HLA-DQA1 alleles showed that no significant differences were observed between the two groups. Conclusion The above findings suggest that there is no significant association between the genetic polymorphisms in HLA-DQA1 and ICP in Chengdu district; HLA-DQA1*0301 may be a protective gene against ICP. It may prevent the development of ICP.

[Association of genetic polymorphisms in human leukocyte antigen-DQA1 with intrahepatic cholestasis of pregnancy in Chengdu district].

OBJECTIVE: To study the mechanism of ceramide-induced cellular signal transduction and its effect on renal injury. METHODS: Sixty male Sprague-Dawley rats were randomly assigned to four groups (n = 15): control group, sham operation group, experiment group one and experiment group two. Except the control and the sham operation group, the other two experiment groups underwent the common bile duct bound to form the rat model of obstructive jaundice. The renal glomerular mesangial cells (GMC) were cultured primarily. After GMC were given different stimulating factors, we performed the measurement of the PLD activity and the GMC apoptosis analyzed by flow cytometry. RESULTS: The biological activity of PC-PLD was significantly decreased by TNF-alpha and ceramide (P< 0.05). On the other hand, the GMC apoptosis was induced by TNF-alpha and ceramide (P <0. 05). However, other opposite results were obtained in addition of ceramide inhibitor to GMC. CONCLUSION: TNF-alpha can induce the ceramide increase in GMC, which is significant to effect on the kidney injury of the rats with obstructive jaundice, by the means of inducing GMC apoptosis and decreasing the activity of PC-PLD.

The mechanism and significance of cellular signal transduction in kidney glomerular mesangial cells of rat with obstructive jaundice

Objecitve To study the indication,efficacy,and safety of double-balloon catheter for cervical ripening and labor induction in term pregnant women.Methods A total of 586 pregnant women using double-balloon catheters from May 2011 to October 2012 were divided into three groups according to their initial Bishop scores: group 1(Bishop score ≤3,n=155),group 2(Bishop score 4-5,n=223) and group 3(Bishop score ≥6,n=208).The control group(Bishop score≥6,n=112) were directly given low-dose of oxytocin through continuous intravenous infusion for labor induction.Results ① The effective rate of cervical ripening and the success rate of vaginal delivery in group 1,2 and 3 were gradually increased,with significantly differences among the three groups.The rate and the duration of oxytocin infusion were gradually decreased in group 1,2 and 3,also with significantly differences.② The success rate of vaginal delivery in group 3 was significantly higher than that in control group.The average total labor stage of group 3 was significantly shorter than that of control group.The complications of mothers and fetus showed no significant difference between the two groups.Conclusion The efficacy of double-balloon catheter for cervical ripening and labor induction was closely associated with the Bishop score.It is suitable in pregnant women with higher Bishop score.

Bing Peng

Papers

[Perinatal outcomes of intrahepatic cholestasis of pregnancy: analysis of 1210 cases].

A clinical analysis of intrahepatic cholestasis of pregnancy in 1241 cases

[Association of genetic polymorphisms in human leukocyte antigen-DQA1 with intrahepatic cholestasis of pregnancy in Chengdu district].

The mechanism and significance of cellular signal transduction in kidney glomerular mesangial cells of rat with obstructive jaundice

[Efficacy of double-balloon catheter for cervical ripening and labor induction].