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BackgroundIntrahepatic cholestasis of pregnancy is associated with adverse perinatal outcomes, but the association with the concentration of specific biochemical markers is unclear. We aimed to quantify the adverse perinatal effects of intrahepatic cholestasis of pregnancy in women with increased serum bile acid concentrations and determine whether elevated bile acid concentrations were associated with the risk of stillbirth and preterm birth.MethodsWe did a systematic review by searching PubMed, Web of Science, and Embase databases for studies published from database inception to June 1, 2018, reporting perinatal outcomes for women with intrahepatic cholestasis of pregnancy when serum bile acid concentrations were available. Inclusion criteria were studies defining intrahepatic cholestasis of pregnancy based upon pruritus and elevated serum bile acid concentrations, with or without raised liver aminotransferase concentrations. Eligible studies were case-control, cohort, and population-based studies, and randomised controlled trials, with at least 30 participants, and that reported bile acid concentrations and perinatal outcomes. Studies at potential higher risk of reporter bias were excluded, including case reports, studies not comprising cohorts, or successive cases seen in a unit; we also excluded studies with high risk of bias from groups selected (eg, a subgroup of babies with poor outcomes were explicitly excluded), conference abstracts, and Letters to the Editor without clear peer review. We also included unpublished data from two UK hospitals. We did a random effects meta-analysis to determine risk of adverse perinatal outcomes. Aggregate data for maternal and perinatal outcomes were extracted from case-control studies, and individual patient data (IPD) were requested from study authors for all types of study (as no control group was required for the IPD analysis) to assess associations between biochemical markers and adverse outcomes using logistic and stepwise logistic regression. This study is registered with PROSPERO, number CRD42017069134.FindingsWe assessed 109 full-text articles, of which 23 studies were eligible for the aggregate data meta-analysis (5557 intrahepatic cholestasis of pregnancy cases and 165 136 controls), and 27 provided IPD (5269 intrahepatic cholestasis of pregnancy cases). Stillbirth occurred in 45 (0·83%) of 4936 intrahepatic cholestasis of pregnancy cases and 519 (0·32%) of 163 947 control pregnancies (odds ratio [OR] 1·46 [95% CI 0·73-2·89]; I2=59·8%). In singleton pregnancies, stillbirth was associated with maximum total bile acid concentration (area under the receiver operating characteristic curve [ROC AUC]) 0·83 [95% CI 0·74-0·92]), but not alanine aminotransferase (ROC AUC 0·46 [0·35-0·57]). For singleton pregnancies, the prevalence of stillbirth was three (0·13%; 95% CI 0·02-0·38) of 2310 intrahepatic cholestasis of pregnancy cases in women with serum total bile acids of less than 40 μmol/L versus four (0·28%; 0·08-0·72) of 1412 cases with total bile acids of 40-99 μmol/L (hazard ratio [HR] 2·35 [95% CI 0·52-10·50]; p=0·26), and versus 18 (3·44%; 2·05-5·37) of 524 cases for bile acids of 100 μmol/L or more (HR 30·50 [8·83-105·30]; p

Objective: The aim of this study was to determine whether the institution of a modern management strategy affected pregnancy outcomes for intrahepatic cholestasis of pregnancy (ICP).Methods: We performed a retrospective cohort study of women diagnosed with ICP at one hospital from 2005 to 2013. A new management protocol for ICP was instituted in 2009 for women with total bile acids >40 μmol/L at <36 weeks. This strategy included inpatient admission, continuous fetal heart rate monitoring, with delivery between 36 and 37 weeks. We compared maternal and neonatal outcomes prior and subsequent to the institution of this protocol.Results: We identified 186 singleton gestations with bile acids >40 μmol/L and diagnosis <36 weeks. Patient demographics were similar between the groups, with the exception of greater maternal age and gestational diabetes in the newer cohort. The newer cohort demonstrated a significant reduction in the incidence of stillbirth 0% versus 3.4%, p= 0.035). There was no difference in the age at delivery, cesarean delivery rates or NICU admissions.Conclusion: Application of our management strategy for ICP reduced the stillbirth rate without adversely affecting other maternal and neonatal outcomes. [ABSTRACT FROM AUTHOR]

Introduction: Intrahepatic cholestasis of pregnancy (ICP) affects 0.2-2% of pregnant women. While the maternal clinical course of ICP is usually benign, the fetal effects can be severe spanning from spontaneous preterm birth to fetal demise to long term effects on the health of the progeny. ICP is characterized by high maternal serum levels of bile acids and placental and hepatic bile acids accumulation. Intrahepatic cholestasis, in the non-pregnant state, has been also linked to alterations of the mitochondrial activity attributed to high oxidative stress rates driven by high intracellular bile acids concentrations. Here we explored the hypothesis that elevated bile acid levels of ICP modify the placental mitochondrial activity.Methods: By using a set of 12 ICP and 12 control placenta samples, we assessed the expression of all 13 mitochondrial-encoded protein-coding genes and the mitochondrial DNA (mtDNA) relative abundance by real-time PCR. We also assessed the oxidative stress status by measuring DNA damage by ELISA.Results: We determined that: 1) the expression of MT-ND4L (+53% - p < 0.01), MT-ND4 (-19%-0.05 < p ≤ 0.01), MT-ND5 (+40% - p < 0.01), MT-CYTB (+35% - p < 0.01) is associated with ICP; 2) the mtDNA relative abundance is not associated with ICP (0.098 in ICP vs 0.118 in controls - p > 0.05); 3) the oxidative stress status is associated with ICP (4403.9 pM 8-oxo-dG/μg DNA in ICP vs 3809.8 pM 8-oxo-dG/μg DNA in controls - p < 0.01).Discussion: This preliminary study suggests that mitochondria in placenta respond to high oxidative stress to modify their gene expression which may play an important role in the pathophysiology of ICP. [ABSTRACT FROM AUTHOR]