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To conduct a comprehensive bibliometric analysis of research published on intrahepatic cholestasis of pregnancy (ICP) and explore the related frontiers and critical issues concerning it, we searched the Web of Science Core Collection for ICP-related publications from the beginning of 2001 until August of 2023. CiteSpace and VOSviewer were utilized to evaluate the contribution and co-occurrence relationships of various countries and regions, institutes and so on to identify new frontiers and currently exciting topics. Our bibliometric analysis scrutinized 933 articles from 59 countries/regions. China has generated the largest number of publications (31.6% of the total), whereas Germany ranked first when it came to citations per publication. The Imperial College London ranked first with respect to publication output on ICP and betweenness centrality. The Journal of Maternal-Fetal & Neonatal Medicine was the journal with the highest plurality of papers. Authors such as Williamson, Beuers, Ulrich, and Shao were the most influential. Pregnancy, ursodeoxycholic acid, and ICP were principally noted in publications. Cluster analysis of the references that correlated with the 933 publications showed that they clustered into mortality, ABCB11, BSEP, MRP2, bile acid, and intrahepatic cholestasis. ICP is associated with adverse clinical outcomes for both the mother and fetus. This study provides a critical analysis of the current status and future research trends regarding ICP. It can serve as a useful reference, allowing researchers to conduct in-depth investigations into this promising field., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Intrahepatic cholestasis of pregnancy (ICP) poses significant risks to maternal and neonatal health. Our study at Jiangxi Provincial Maternal and Child Health Hospital analyzed clinical and biochemical markers in singleton pregnancies diagnosed with ICP from October 2016 to December 2022. This research, supported by a systematic review and meta-analysis of existing studies, highlights the increasing incidence of ICP and its association with elevated levels of total bile acids, transaminases, and bilirubin. Our findings indicate a marked increase in the risk of preterm birth, cesarean delivery, and neonatal asphyxia as the severity of ICP escalates. This underscores the need for vigilant monitoring and management of affected pregnancies. By confirming the relationship between biochemical marker abnormalities and adverse pregnancy outcomes, our study advocates for enhanced clinical strategies and paves the way for future research aimed at improving prevention, diagnosis, and treatment methods for ICP.

Objective: To delineate the clinical characteristics of preterm birth (PTB) in the context of gestational diabetes mellitus (GDM)., Methods: A retrospective cohort study was conducted, including 14,314 pregnant women with GDM who delivered at Fujian Provincial Maternity and Children's Hospital from January 1, 2018, to December 31, 2021. PTB was stratified into late PTB (34-36 weeks of gestation) and early PTB (< 34 weeks) and pregnancy complications were analyzed., Results: Compared to the term birth (TB) cohort, a higher prevalence of premature rupture of membranes, hypertensive diseases of pregnancy (HDP), intrahepatic cholestasis of pregnancy (ICP), anemia and cervical insufficiency was observed in the PTB cohort. Notably, early PTB increased the incidence of HDP, ICP, anemia and cervical insufficiency compared to late PTB. In the early stages of pregnancy, early PTB was characterized by elevated triglyceride (TG) levels and decreased high-density lipoprotein cholesterol (HDL-C) levels compared to late PTB. In the late pregnancy stages, early PTB was associated with increased white blood cell (WBC) and neutrophil counts. No disparities were observed in 75 g oral glucose tolerance test (OGTT) between early and late PTB., Conclusion: Enhanced surveillance and management of GDM, particularly in the presence of HDP, ICP and anemia, are imperative to mitigate the risk of PTB. The lipid profile may serve as a predictive tool for early PTB in the early stages of pregnancy, warranting further studies., (© 2024. The Author(s).)

Objective:  Intrahepatic cholestasis of pregnancy is associated with adverse pregnancy outcomes including intrauterine fetal demise, spontaneous preterm labor, and meconium-stained amniotic fluid. Studies have yet to determine if patients with a history of pregnancy complicated by cholestasis had an association with more severe adverse outcomes in a subsequent pregnancy complicated by cholestasis., Study Design:  Retrospective cohort study of multiparous, singleton, nonanomalous live gestations complicated by cholestasis at Elmhurst Hospital Center from 2005 to 2019. We compared rates of adverse outcomes in multiparous pregnancies complicated by cholestasis with versus without prior cholestasis. Our primary outcome was rates of spontaneous preterm labor. Our secondary outcomes included rates of iatrogenic preterm birth, meconium-stained amniotic fluid, cesarean delivery for nonreassuring fetal heart tracing. Chi-square and multivariate regression tests were used to determine the strength of association. In all analyses, a p -value less than 0.05 and 95% confidence interval not crossing 1.00 indicated statistical significance. Mount Sinai Icahn School of Medicine Institutional Review Board approval was obtained for this project., Results:  Of the 795 multiparous pregnancies complicated by cholestasis, 618 (77.7%) had no prior history of cholestasis and 177 (23.3%) had prior history of cholestasis. Multiparous pregnancies with history of cholestasis had higher rates of prior preterm birth, earlier gestational age at diagnosis and delivery, and were more likely to receive ursodeoxycholic acid therapy. Pregnancies with history of cholestasis were not associated with spontaneous preterm labor in subsequent pregnancies with cholestasis, but history of cholestasis was associated with iatrogenic preterm birth and neonatal intensive care unit (NICU) admission. After adjusting for confounders, the association with iatrogenic preterm birth and NICU admission were no longer statistically significant. There was no significant association between history of cholestasis and other adverse obstetric outcomes., Conclusion:  Findings suggests that history of prior cholestasis is not associated with worsening outcomes in subsequent pregnancies complicated by cholestasis., Key Points: · Prior cholestasis may not alter risk in subsequent pregnancies.. · Unclear relationship between cholestasis and hepatobiliary disease.. · Studies needed to develop cholestasis screening protocol.., Competing Interests: None declared., (Thieme. All rights reserved.)

Objectives: To determine the prevalence of proteinuria in patients diagnosed with intrahepatic cholestasis of pregnancy (IHCP), and the association between the presence of proteinuria and adverse pregnancy outcomes., Methods: This was a retrospective cohort study. The study included all pregnant patients between July 2014 and January 2022, at gestational age > 24weeks who had been diagnosed with IHCP and had completed a 24-hour protein collection. High order multifetal gestations were excluded. Patients were divided into 3 groups:1. IHCP without proteinuria (Non-proteinuric group);2. IHCP with proteinuria and normal blood pressure (Isolated proteinuria group), and 3. IHCP with proteinuria and elevated blood pressure (IHCP with preeclampsia (PET)). Primary outcome was defined as a composite maternal-fetal outcome including: preterm labor <34 weeks, arterial cord blood ph<7.1, rate of Cesarean delivery due to non-reassuring fetal monitoring. Parametric and non-parametric statistical methods were used for analysis., Results: A total of 272 met all inclusion criteria and were included, 94 patients (34.5%) had proteinuria; of them, 67 (24.6%) had isolated proteinuria and 27 (9.9%) had PET. Demographic parameters were comparable among the groups. Patients with PET had higher rates of in-vitro fertilization (IVF) treatments, twin gestation and elevated serum creatinine and urea levels. The rate of composite adverse pregnancy outcome was higher in patients with PET compared with patients with and without proteinuria (14/27 (51.9%) vs. 18/67 (26.9%) vs. 49/178 (27.5%), respectively, p = 0.03)., Conclusions: Approximately 35% of patients with IHCP have proteinuria. The presence of PET, rather than isolated proteinuria, is associated with adverse pregnancy outcome., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Watad et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: The association between excessive serum total bile acid (TBA) and adverse perinatal outcomes in individuals with non-intrahepatic cholestasis of pregnancy (non-ICP) hypercholanemia has not been determined, and it is unclear if this link is similar to that observed in patients with ICP., Objective: To examine the adverse perinatal outcomes in two specific subcategories: those with ICP and those with non-ICP, including individuals with liver disease and asymptomatic hypercholanemia of pregnancy (AHP), at different levels of TBA. Investigate the correlation between TBA levels and adverse perinatal outcomes of ICP, liver disease, and AHP., Methods: From 2013 to 2021, pregnant women with excessive TBA levels were taken from the electronic medical record database of our hospital and categorized into three groups: ICP ( n  = 160), liver disease ( n  = 164), and AHP ( n  = 650). This was done as part of a retrospective cohort research project. Multivariable regression and subgroup analyses were performed to examine the association between TBA levels and adverse perinatal outcomes in each group., Results: The study found no significant differences in adverse perinatal outcomes between the ICP and liver disease groups at different TBA levels. However, at moderate TBA levels, both groups had a higher risk of adverse perinatal outcomes than the AHP group ( p  < 0.017). Among liver disease cases with TBA ≥ 100µmol/L, three cases of perinatal deaths (6.67%) associated with moderate-to-severe acute hepatitis occurred between 27 and 33 weeks of gestation. A 59% higher chance of perinatal death was found for every 10 µmol/L rise in TBA, even after significant variables and confounders were taken into account (adjusted odds ratio (aOR) = 1.59; 95% confidence interval (CI): 1.06-2.40; p  = 0.03)., Conclusions: If a pregnant woman has moderate-to-severe liver disease and TBA ≥ 100µmol/L, preterm termination of pregnancy (before 34 weeks) may be considered.

Background: What kinds of fetal adverse outcomes beyond stillbirth directly correlate to the severity of intrahepatic cholestasis during pregnancy (ICP) remained tangled. Herein, we conducted a retrospective cohort study and a dose-response meta-analysis to speculate the association between the severity of ICP and its adverse outcomes., Methods: We retrospectively collected a cohort of ICP patients from electronic records from Guangzhou Women and Children's Medical Center between Jan 1st, 2018, and Dec 31st, 2022. Also, we searched PubMed, Cochrane, Embase, Scopus, and Web of Science to extract prior studies for meta-analysis. The Kruskal-Wallis test, a one-way or two-way variants analysis (ANOVA), and multi-variant regression are utilized for cohort study. One stage model, restricted cubic spline analysis, and fixed-effect model are applied for dose-response meta-analysis. The data analysis was performed using the R programme., Results: Our cohort included 1,289 pregnant individuals, including 385 mild ICP cases, 601 low moderate ICP cases, 282 high moderate ICP cases, and 21 severe ICP cases. The high moderate bile acid levels were correlated to preterm birth [RR = 2.14, 95%CI 1.27 to 3.62), P < 0.01], and preterm premature rupture of membranes [RR = 0.34, 95%CI 0.19 to 0.62), P < 0.01]. We added our cases to cases reported by other studies included in the meta-analysis. There were 15,826 patients included in dose-response meta-analysis. The severity of ICP was associated with increased risks of stillbirth, spontaneous preterm birth, iatrogenic preterm birth, preterm birth, admission to neonatal intensive care unit, and meconium-stained fluid (P < 0.05)., Conclusions: Our study shows the correlation between the severity of ICP and the ascending risks of stillbirth, preterm birth, and meconium-stained fluid, providing new threshold TBA levels., Prospero Registration Number: CRD42023472634., (© 2024. The Author(s).)

Purpose: To evaluate maternal and neonatal outcomes in patients with intrahepatic cholestasis of pregnancy (ICP)., Methods: Patients who gave birth in our hospital between January 2018 and March 2022 were retrospectively reviewed from the hospital database and patient file records. The study comprised 1686 patients, 54 in the ICP group and 1632 controls. Patients who had ICP after 20 weeks of gestation and were monitored and delivered at our facility were enrolled. Maternal demographic and obstetric characteristics data were examined. Perinatal outcomes were also assessed. Logistic regression analysis was used to determine adverse maternal outcomes., Results: The mean age was 29 years. ART, GDM, and preeclampsia were significantly higher in the ICP group. The mean serum bile acid level was 19.3 ± 3 μmol/L in the ICP group. There was a higher risk of GDM and pre-eclampsia in women with ICP compared with those without and a significant association between ICP and adverse perinatal outcomes. There was a statistically significant relation between the presence of ICP and spontaneous preterm delivery, iatrogenic preterm delivery, 5th-minute Apgar scores < 7, and NICU requirement. No significant relationship was found between the presence of ICP and SGA and meconium. There was a significant relationship between the presence of ICP, mode of delivery, and PPH (p < 0.05). Those with ICP had a lower gestational week and birth weight, and higher rates of cesarean delivery and PPH., Conclusion: ICP should prompt close monitoring and management to mitigate the potential exacerbation of adverse outcomes, including preeclampsia, GDM, and preterm birth., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To explore the relationships between gestational hepatitis B virus (HBV) infection, antiviral therapy, and pregnancy outcomes., Methods: We retrospectively selected hepatitis B surface antigen (HBsAg)-positive pregnant women hospitalized for delivery at Fujian Medical University Affiliated Hospital from October 1, 2016 to October 1, 2020. The control group included randomly selected healthy pregnant women hospitalized for delivery during the same time., Results: Overall, 1115 participants were enrolled and grouped into control (n = 380) and HBsAg-positive groups (n = 735), which were further divided into groups I (n = 407; low viral load), II (n = 207; high viral load without antiviral therapy), and III (n = 121; high viral load with antiviral therapy). Pregnant women with HBV were positively correlated with the incidence of intrahepatic cholestasis of pregnancy (ICP) (adjusted odds ratio [aOR] 5.1, 95% confidence interval [CI] 2.62-9.92, P < 0.001), neonatal jaundice (aOR 10.56, 95% CI 4.49-24.83, P < 0.001), and neonatal asphyxia (aOR 5.03, 95% CI 1.46-17.27, P = 0.01). Aspartate aminotransferase (AST) greater than the upper limit of normal (ULN) was an independent risk factor for increased ICP incidence (aOR 3.49, 95% CI 1.26-9.67, P = 0.019). Antiviral therapy considerably reduced HBV DNA and improved liver function. High viral load and antiviral therapy did not correlate significantly with adverse pregnancy outcomes (P < 0.05)., Conclusion: Pregnant women with HBV have significantly elevated incidence of ICP, neonatal jaundice, and neonatal asphyxia not significantly correlated with viral load. AST greater than ULN independently increases the risk of ICP. Antiviral therapy effectively reduces viral replication and improves liver function without increasing the risk of adverse outcomes., (© 2024 International Federation of Gynecology and Obstetrics.)

Objective: To systematically evaluate the effect of hepatitis B virus (HBV) infection on the risk of adverse pregnancy outcomes. Methods: We searched PubMed, Embase, Web of Science, and Cochrane databases. Two researchers independently screened the literature, extracted data, and evaluated the quality. Meta-analysis and cumulative meta-analysis were performed using R4.4.1 software. Fixed/random effects models were used to analyze heterogeneous and non-heterogeneous results. Heterogeneous modifiers were identified by subgroup analysis. Funnel plots and Peters' test were used to analyze potential publication bias. Results: A total of 48 studies involving 92 836 HBsAg-positive pregnant women and 7 123 292 HBsAg-negative pregnant women were included. In terms of adverse pregnancy outcomes, HBV infection was significantly correlated with the occurrence of gestational diabetes mellitus [odds ratio ( OR )=1.34, 95% confidence interval ( CI ): 1.17-1.53] and intrahepatic cholestasis ( OR =2.48, 95% CI : 1.88-3.29), with statistically significant differences. In terms of adverse neonatal outcomes, HBV infection was significantly correlated with the occurrence of neonatal asphyxia ( OR =1.49, 95% CI : 1.20-1.86) and preterm birth ( OR =1.22, 95% CI : 1.12-1.33), with statistically significant differences. In addition, the cumulative meta-analysis demonstrated that the risk of gestational diabetes mellitus and preterm birth both tended to be stable in pregnant women with HBV infection following 2009 and 2010, respectively. The supplementary questions answered for repeated studies had limited significance. Conclusion: Intrahepatic cholestasis, gestational diabetes mellitus, neonatal asphyxia, and preterm birth occurrence risk can be raised with HBV infection in pregnant women.

Background: Intrahepatic cholestasis of pregnancy (ICP) is associated with an increased risk of adverse fetal outcomes, yet its influence on offspring growth remains unclear. Our study dynamically tracks growth rates in children from ICP and healthy mothers and investigates the link between maternal liver function and developmental abnormalities in offspring., Method: Our case‒control study involved 97 women with ICP and 152 with uncomplicated pregnancies nested in a cohort of their offspring, including 50 from the ICP group and 87 from the uncomplicated pregnancy group. We collected pediatric growth and development data, with a maximum follow-up duration of 36 months. Stratified analyses of children's height, weight, and head circumference were conducted, and Spearman's rank correlation was applied to examine the relationships between maternal serological markers and pediatric growth metrics., Result: Maternal liver and renal functions, along with serum lipid profiles, significantly differed between the ICP and normal groups. In the ICP group, the offspring showed elevated alanine aminotransferase (ALT), direct bilirubin (DBIT), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B (APOB) levels. Notably, the length-for-age z score (LAZ), weight-for-age z score (WAZ), and head circumference-for-age z score (HCZ) were lower in ICP offspring compared with those from normal pregnancies within the 1- to 12-month age range (P < 0.05). However, no significant differences in LAZ, weight-for-length z score (WLZ), BMI-for-age z score (BAZ), or HCZ were observed between groups in the 13- to 36-month age range. Maternal maximum lactate dehydrogenase (LDH) and total bile acids (TBA) levels during pregnancy were inversely correlated with LAZ and WAZ in the first year. Furthermore, offspring of mothers with ICP exhibited a greater incidence of stunting (24% vs. 6.9%, P = 0.004) and abnormal HCZ (14% vs. 3.7%, P = 0.034)., Conclusions: Growth disparities in offspring of ICP-affected pregnancies were most significant within the 1- to 12-month age range. During this period, maximum maternal LDH and TBA levels were negatively correlated with LAZ and WAZ values of offspring. The observation of similar growth rates between ICP and control group offspring from 13 to 36 months suggested catch-up growth in the ICP group., (© 2024. The Author(s).)

Background: Intrahepatic cholestasis of pregnancy (ICP) is a serious liver conditions that negatively impacts obstetric and neonatal outcomes. Elevated levels of bile acid, particularly glycine conjugate, may compromise blood flow and cause functional hypoxia-ischemia., Aims: This meta-analysis aims to assess the association between ICP and key pregnancy outcomes including emergency caesarian sections (C-sections), preeclampsia, hemorrhage, preterm birth, small for gestational age, admission rate to neonatal intensive care union (NICU), gestational age, and stillbirth., Materials and Methods: Literature search across five databases (PubMed, Embase, Web of Science) was done to detect relevant studies published up until June 2023. Meta-analysis of the identified studies was done using a random-effects model, and the results presented as Odds ratio (OR)., Results: A literature search identified 662 studies. Of them, 21 met the inclusion criteria. There was a significant association between ICP and odds of C-section (OR: 1.42, p <0.001), preeclampsia (OR: 2.64, p <0.001), NICU admission (OR: 2.1, p <0.001), and pre-term birth (OR: 2.64, p <0.001). ICP was not associated with postpartum hemmorhage (OR: 1.31, p = 0.13), small for gestational age (OR: 0.87, p = 0.07), stillbirth (OR: 1.49, p = 0.29)., Conclusions: Our results confirm the adverse effects of ICP on co-existing pregnancy complications, obstetric and neonatal outcomes. ICP in associated with severe complications including increased rates of preeclampsia, emergency C-sections, preterm births, l gestational periods and higher rates of NICU admissions. These results may assist healthcare professionals in formulating comprehensive care guidelines for expectant mothers and newborns., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Huang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Intrahepatic cholestasis of pregnancy (ICP) is a problem with an increasing incidence and negative maternal, fetal, and neonatal consequences. This problem is becoming increasingly important. This systematic review and meta-analysis aimed to determine the incidence of ICP and its adverse maternal, fetal, and neonatal adverse outcomes based on primary research studies., Methods: This systematic review and meta-analysis used Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines and was conducted between June and September 2023 using the following keywords: obstetric cholestasis OR intrahepatic cholestasis AND pregnancy OR pregnant OR prenatal OR antenatal OR perinatal OR maternal OR fetal OR neonatal. Quality assessment of the studies was performed using the Critical Appraisal Checklists developed by the JBI Institute. Data were synthesized using meta-analysis methods., Results: The analysis included 10 studies published between 2013 and 2023. The meta-analysis showed that the incidence of ICP was 1.7% (odds ratio [OR], 0.021; 95% CI, 0.012-0.027), whereas maternal, fetal, and neonatal adverse outcomes included cesarean birth (OR, 2.938; 95% CI, 1.467-5.881), preterm birth or preterm prelabor rupture of membranes (OR, 4.241; 95% CI, 1.996-9.009), hypertensive disorders of pregnancy (OR, 3.715; 95% CI, 1.545-8.929), maternal infection (OR, 3.301; 95% CI, 2.917-3.737), neonatal intensive care unit admission (OR, 2.715; 95% CI, 1.458-5.056), birth weight less than or equal to 2500 g (OR, 2.518; 95% CI, 1.296-4.892), and small for gestational age (OR, 1.915; 95% CI, 1.424-2.573)., Discussion: This systematic review and meta-analysis revealed that ICP has a high incidence and several maternal, fetal, and neonatal adverse outcomes. Therefore, midwives and other health professionals must be aware of these outcomes and provide appropriate care to pregnant individuals with ICP., (© 2024 by the American College of Nurse‐Midwives.)

Objective: To evaluate the relationship between intrahepatic cholestasis of pregnancy (ICP) and coronavirus disease 2019 (COVID-19)., Study Design: We performed a retrospective cohort study of pregnant women undergoing induction of labor (IOL) at a single institution between May 2020 to January 2021. Primary exposure was diagnosis of intrahepatic cholestasis of pregnancy (ICP). The primary outcome was the prevalence of COVID-19 as determined by reverse-transcriptase polymerase chain reaction testing on nasopharyngeal swabs for SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) on routine admission testing. Secondary outcomes were abnormal laboratory values and adverse fetal outcomes. Logistic regression with log link analysis was performed comparing patients undergoing IOL for ICP compared with IOL for all other indications. The moderating effect of ethnicity was assessed by the interaction between ethnicity and ICP in a logistic regression model. The Wilcoxon rank-sum test and Fisher's exact test were performed for the secondary outcome analyses., Results: Over the course of the study, 596 patients underwent IOL: 24 for ICP and 572 for other indications. The overall prevalence of COVID-19 positivity in the cohort was 5.5% (33 of 596). Those with ICP were more likely to test positive for COVID-19 compared with those with other IOL indications (29.2 vs. 4.5%, RR = 6.4, 95% CI: 2.8-12.5, p  < 0.001). All patients with ICP who tested positive for COVID-19 were Hispanic. To analyze the moderating effect of ethnicity, the results of the logistic model found the interaction between ethnicity and ICP to not be significant ( p  = 0.991). In patients with ICP, the median AST (aspartate aminotransferase) was higher than those with COVID-19 ( p  = 0.0182). There were no adverse fetal outcomes in the ICP group., Conclusion: In this single-site retrospective cohort study, we demonstrated an increased prevalence of COVID-19 in those with ICP in general and among Hispanic patients specifically. Despite this difference, there was no increased risk of adverse fetal outcomes., Key Points: · There is an increased prevalence of COVID-19 among Hispanic patients with ICP.. · The median AST of COVID-19-positive patients was significantly higher than COVID-19-negative patients.. · There was no increased risk of adverse fetal outcomes in with COVID-19 and ICP.., Competing Interests: None declared., (Thieme. All rights reserved.)

Background and Objectives : Intrahepatic cholestasis of pregnancy (ICP) stands as one of the most prevalent concerns in maternal-fetal medicine, presenting a significant risk to fetal health and often associated with liver dysfunction. Concurrently, the coronavirus-19 (COVID-19) infection can lead to hepatic cell injury through both direct and indirect pathways. Hypothetically, these two conditions may coincide, influencing each other. This study aimed to comparatively assess the incidence and severity of ICP before and during the COVID-19 pandemic. Methods : A retrospective cohort study was conducted, comparing the incidence and severity of ICP between January 2018 and February 2020 (pre-COVID-19 period) and March 2020 to March 2022 (COVID-19 period) across two hospitals, encompassing 7799 deliveries. The diagnosis of ICP was established using the ICD-10 code and defined as total bile acids (BA) levels ≥ 10 μmol/L. Statistical analysis included descriptive statistics, Chi-square and Mann-Whitney U tests, as well as multiple or logistic regression analysis. Results : A total of 226 cases of ICP were identified. The incidence of mild cholestasis (BA < 40 μmol/L) was lower during the pandemic compared to before (3% before versus 2%, p < 0.05), while the incidence of moderate and severe ICP remained unchanged (0.6% before vs. 0.4%, p = 0.2). Overall, the total incidence of ICP was lower during the pandemic (3.6% before versus 2.4%, p = 0.01). No significant differences were observed in severity (as defined by BA and liver function test levels), rates of caesarean section, or neonatal birth weights. Conclusions : During the COVID-19 pandemic, the total incidence of ICP appeared to be lower. However, this reduction was primarily observed in cases of mild ICP, potentially indicating challenges in detection or reduced access to medical services during this period. The incidence of moderate and severe ICP remained unchanged, suggesting that these forms of the condition were unaffected by the pandemic's circumstances.

Intrahepatic cholestasis of pregnancy (ICP) is an idiopathic disease that occurs during mid-to-late pregnancy and is associated with various adverse pregnancy outcomes, including intrauterine fetal demise. However, since the underlying cause of ICP remains unclear, there is an ongoing debate on the phenotyping criteria used in the diagnostic process. Here, we identified single- and multi-symptomatic ICP (ICP-S and ICP-M) in 104,221 Chinese females from the ZEBRA maternity cohort, with the objective of exploring the risk implications of the two phenotypes on pregnancy outcomes and from environmental exposures. We employed multivariate binary logistic regression to estimate confounder-adjusted odds ratios and found that ICP-M was more strongly associated with preterm birth and low birth weight compared to ICP-S. Throughout pregnancy, incremental exposure to PM 2.5 , O 3 , and greenness could alter ICP risks by 17.3%, 12.5%, and -2.3%, respectively, with more substantial associations observed with ICP-M than with ICP-S. The major scientific advancements lie in the elucidation of synergistic risk interactions between pollutants and the protective antagonistic effects of greenness, as well as highlighting the risk impact of preconceptional environmental exposures. Our study, conducted in the context of the "three-child policy" in China, provides epidemiological evidence for policy-making to safeguard maternal and neonatal health., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Intrahepatic cholestasis of pregnancy (ICP) is associated with an increased risk of adverse perinatal outcomes, resulting in a higher risk of perinatal morbidity and mortality., Methods: The authors conducted a retrospective study of 2385 singletons with ICP who underwent risk-stratified management strategies. To explore the risks of perinatal outcomes of ICP, subgroup analyses were performed using different total bile acid (TBA) levels., Results: In this study, there was only one stillbirth and one neonatal death. Among the study cohort, 2299 patients had ICP with a TBA level ≥10 μmol/L and 86 had ICP with a TBA level <10 μmol/L. The 2299 patients with ICP (TBA level ≥ 10 μmol/L) were divided into three groups: mild ICP (n = 1803), severe ICP (n = 400), and extremely severe ICP (n = 96). Increased TBA concentration was associated with an increased incidence of preterm birth, newborn asphyxia, neonatal intensive care unit hospitalization, meconium-stained amniotic fluid, and low birth weight in the three groups (P < 0.05). Furthermore, severe and extremely severe ICP with hypotonic absonant uterine contraction had a significant effect on neonatal asphyxia (odds ratio, 5.06 [95% confidence interval, 1.09-23.37]; P < 0.05) and meconium-stained amniotic fluid (odds ratio, 2.37 [95% confidence interval, 1.43-3.93]; P < 0.05)., Conclusions: Hypotonic absonant uterine contractions could be high-risk stressors for severe and extremely severe ICP; hence, proper prenatal care is recommended. Risk-stratified management strategies for ICP are critical to obtaining better maternal-fetal outcomes., (© 2023 International Federation of Gynecology and Obstetrics.)

Objective: Hepatitis C virus and intrahepatic cholestasis of pregnancy (ICP) are well-known independent risk factors for adverse outcomes in pregnancy. In addition, it is well-established that there is an association between Hepatitis C and ICP. This study's objective was to describe the impact of having both Hepatitis C and ICP on maternal and obstetric outcomes compared to patients having either Hepatitis C or ICP., Methods: We conducted a retrospective cohort study of the Nationwide Readmissions Database, an all-payor sample of discharges from approximately 60% of US hospitalizations. Deliveries at 24-42+ weeks between 10/2015 and 12/2020 were included. Diagnosis of Hepatitis C and ICP, and outcomes related to severe maternal morbidity were identified using International Classification of Disease-10 codes. Patients were categorized based on Hepatitis C and ICP status. Weighted logistic and negative binomial regression analyses were used to evaluate the association between Hepatitis C and ICP status and outcomes, adjusting for patient and hospital characteristics. The primary outcome was any severe maternal morbidity; secondary outcomes included acute respiratory distress syndrome, acute kidney injury, sepsis, gestational diabetes, cesarean delivery, preterm birth, and hospital length of stay. We modeled interaction terms between ICP and Hepatitis C to assess whether there was a greater or lesser effect from having both conditions on outcomes than we would expect from additive combination of the individual components (i.e., synergy or antagonism)., Results: A total of 10,040,850 deliveries between 24-42+ weeks were identified. Of these, 45,368 had Hepatitis C only; 84,582 had ICP only; and 1,967 had both Hepatitis C and ICP. Patients with both Hepatitis C and ICP had 1.5-fold higher odds of developing severe maternal morbidity compared to having neither. There was an also an increased odds of severe maternal morbidity in patients with both Hepatitis C and ICP compared to patients with only Hepatitis C or ICP. Having both was also associated with higher odds of preterm birth and length of stay compared to having only Hepatitis C, only ICP, or neither (preterm birth: aOR 5.09, 95% CI 4.87-5.33 vs. neither; length of stay: 46% mean increase, 95% CI 35-58% vs. neither). Associations were additive-no significant interactions between hepatitis C and cholestasis were found on rates of severe maternal morbidity, acute respiratory distress syndrome, acute kidney injury, sepsis, cesarean section, or preterm birth (all p>0.05), and was minimal for gestational diabetes and length of stay., Conclusion: Hepatitis C and ICP are independent, additive risk factors for adverse maternal and obstetric outcomes. Despite physiologic plausibility, no evidence of a synergistic effect of these two diagnoses on outcomes was noted. These data may be useful in counseling patients regarding their increased risk of adverse outcomes when ICP presents in association with Hepatitis C versus ICP alone., Competing Interests: The authors report no conflict of interest., (Copyright: © 2023 Goins et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Intrahepatic cholestasis of pregnancy is associated with a 4- to 10-fold increase in the risk of stillbirth in the absence of intervention, leading to recommendations for antenatal assessment, ursodiol use, and often preterm or early term delivery., Objective: This study aimed to determine whether current management strategies for intrahepatic cholestasis of pregnancy mitigate the elevated risk of stillbirth at a population level., Study Design: This was a retrospective cohort study using the 2015-2020 National Readmissions Database, an administrative database developed by the United States Agency for Healthcare Research and Quality. Our study identified delivery hospitalizations, gestational age at delivery, occurrence of intrahepatic cholestasis of pregnancy and stillbirth, and comorbid conditions using the International Classification of Diseases diagnosis and procedure codes. Moreover, this study compared the timing of delivery and stillbirth rates of pregnant patients with intrahepatic cholestasis of pregnancy vs those without intrahepatic cholestasis of pregnancy at the time of delivery hospitalization., Results: This study identified a cohort of 9,987,705 delivery hospitalizations in the National Readmissions Database, corresponding to a weighted national estimate of 18,609,207 births. Of these births, 152,040 (0.8%) were noted to have an intrahepatic cholestasis of pregnancy diagnosis. Patients with an intrahepatic cholestasis of pregnancy diagnosis were older, with small differences in comorbidities, such as a higher rate of gestational diabetes mellitus, than patients without an intrahepatic cholestasis of pregnancy diagnosis at delivery hospitalization. The overall rates of stillbirth were lower among those with intrahepatic cholestasis of pregnancy than among those without intrahepatic cholestasis of pregnancy (252 vs 386 per 100,000 deliveries; risk difference, 133 fewer per 100,000 deliveries; 95% confidence interval, 98-170), a finding that persisted after adjustment for insurance status, socioeconomic factors, and comorbid conditions (risk difference, 160 fewer stillbirths per 100,000 deliveries; 95% confidence interval, 127-194). Furthermore, although patients with intrahepatic cholestasis of pregnancy were more likely to deliver before term than those without intrahepatic cholestasis of pregnancy (30.1% vs 9.3%; P<.001), increased rates of stillbirth were not noted at any point after stratification of the cohort by gestational age at delivery., Conclusion: Patients with intrahepatic cholestasis of pregnancy diagnosis codes delivered earlier than those without intrahepatic cholestasis of pregnancy diagnosis codes, but the percentage of births affected by stillbirth was lower, even when stratifying for gestational age at birth. These results may provide reassurance to patients receiving an intrahepatic cholestasis of pregnancy diagnosis that current management does mitigate stillbirth risk in intrahepatic cholestasis of pregnancy., (Copyright © 2023. Published by Elsevier Inc.)

Objective: Intrahepatic cholestasis of pregnancy is associated with adverse perinatal outcomes. Fetal cardiac dysfunction may be 1 part of the pathophysiology of pregnancies complicated by intrahepatic cholestasis of pregnancy. This systematic review and meta-analysis aimed to evaluate the association between intrahepatic cholestasis of pregnancy and fetal cardiac dysfunction., Data Sources: Systematic searches were performed on the databases of Medline, Embase, and Cochrane Library (up to March 2, 2023) for studies evaluating fetal cardiac function in pregnancies complicated by intrahepatic cholestasis of pregnancy in addition to the reference lists of included studies., Study Eligibility Criteria: Studies were eligible for inclusion if they assessed the fetal cardiac function by fetal echocardiography in women with intrahepatic cholestasis of pregnancy (mild or severe) and compared with fetuses of healthy pregnant women. The studies published in English were included., Methods: The quality of the retrieved studies was assessed using the Newcastle-Ottawa Scale. Data on fetal myocardial performance index, E wave/A wave peak velocities ratio, and PR interval were pooled for the meta-analysis using random-effects models. The results were presented as weighted mean differences and 95% confidence intervals. This meta-analysis was registered with the International Prospective Register of Systematic Reviews (registration number: CRD42022334801)., Results: A total of 14 studies were included in this qualitative analysis. Of note, 10 studies that reported data on fetal myocardial performance index, E wave/A wave peak velocities ratio, and PR interval were included in the quantitative analysis and showed a significant association between intrahepatic cholestasis of pregnancy and fetal cardiac dysfunction. Significantly higher fetal left ventricular myocardial performance index values (weighted mean difference, 0.10; 95% confidence interval, 0.04-0.16) and longer fetal PR intervals (weighted mean difference, 10.10 ms; 95% confidence interval, 7.34-12.86) were revealed in pregnancies complicated by intrahepatic cholestasis of pregnancy. Compared with the situation in pregnancies complicated by mild intrahepatic cholestasis of pregnancy, PR intervals were even longer in pregnancies complicated by severe intrahepatic cholestasis of pregnancy (weighted mean difference, 5.98 ms; 95% confidence interval, 0.20-11.77). There was no significant difference in fetal E wave/A wave peak velocities ratio between the group with intrahepatic cholestasis of pregnancy and the healthy pregnant group (weighted mean difference, 0.01; 95% confidence interval, -0.03 to 0.05)., Conclusion: Our findings supported the idea that intrahepatic cholestasis of pregnancy is associated with overall impaired fetal myocardial performance and impaired fetal cardiac conduction system. However, current evidence about the association between fetal cardiac dysfunction and intrahepatic cholestasis of pregnancy-induced stillbirth is lacking. Further studies are needed to reveal the relationship between fetal cardiac dysfunction and adverse perinatal outcomes in pregnancies complicated by intrahepatic cholestasis of pregnancy., (Copyright © 2023. Published by Elsevier Inc.)

Children with cholestatic liver diseases are increasingly living into adulthood, thanks to innovations in medical and surgical therapies. The excellent outcomes observed in pediatric liver transplantation for diseases, such as biliary atresia, have transformed the life trajectory of children born with once-fatal liver diseases. The evolution of molecular genetic testing, has helped expedite the diagnosis of other cholestatic disorders, improving the clinical management, disease prognosis, and family planning for inherited disorders, such as progressive familial intrahepatic cholestasis and bile acid synthesis disorders. The expanding list of therapeutics, including bile acids and the newer ileal bile acid transport inhibitors, has also helped slow the progression of disease and improve the quality of life for certain diseases, like Alagille syndrome. More and more children with cholestatic disorders are expected to require care from adult providers familiar with the natural history and potential complications of these childhood diseases. The aim of this review is to bridge the gap between pediatric and adult care in children with cholestatic disorders. The present review addresses the epidemiology, clinical features, diagnostic testing, treatment, prognosis, and transplant outcomes of 4 hallmark childhood cholestatic liver diseases: biliary atresia, Alagille syndrome, progressive familial intrahepatic cholestasis, and bile acid synthesis disorders., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Aims: Genetics plays a role in the pathogenesis of intrahepatic cholestasis of pregnancy (ICP); however, empirical evidence on familial clustering of ICP is scarce. We aimed to assess the extent of familial recurrence of ICP., Approach and Results: This population-based cohort study included all 668,461 primiparous women who gave birth between 1995 and 2018 in Denmark. Women diagnosed with ICP were included to the index cohort. Kinship with index women was determined with the Danish Civil Registration System. Log-binomial regression was used to calculate the relative recurrence risk (RRR) of ICP in relatives of index women. A total of 6722 (1.0%) primiparous women were diagnosed with ICP. In co-twins (n=57), first-degree (n=2279), second-degree (n=1373), and third-degree (n=1758) relatives of the index women, the incidence of ICP reached 5.3%, 2.6%, 0.7%, and 1.4%, respectively, corresponding to adjusted RRRs of 4.82 (95% CI, 1.60-14.48), 2.54 (1.98-3.26), 0.81 (0.44-1.51), and 1.15 (0.77-1.71), respectively. The first-degree relatives of women who had recurrent ICP or first-trimester ICP seemed to be at higher risks [RRR, 4.30 (2.85-6.48), 3.04 (1.93-4.77), respectively]. A minor increased risk was observed in nonbiological relatives [RRR, 1.35 (1.05-1.73); n=4274, including women's full-brothers' partner and women's husbands' full sisters]., Conclusions: Co-twins and first-degree relatives of ICP patients were at ~5- and ~2.5-fold increased risk of ICP, respectively. No increased risk was observed in second-degree and third-degree relatives. Recurrent ICP and first-trimester ICP might indicate a higher degree of family clustering. Further investigation is needed to investigate the increased risk of ICP in nonbiological relatives., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Background: The joint effect of platelet and other modifiers on the risk of pregnancy complications is unknown. This study investigated whether platelet count (PC) and total homocysteine (tHcy) level have a synergistic effect on the incidence of pregnancy complications in a Chinese population., Methods: Total 11,553 consecutive pregnant women who received whole blood cell and biochemical tests at the time of admission for labor in Changzhou Maternal and Child Health Care Hospital were analyzed. The primary outcome was the prevalence of pregnancy complications: gestational diabetes mellitus (GDM), intrahepatic cholestasis of pregnancy (ICP), pre-eclampsia (PE), and pregnancy induced hypertension (PIH)., Results: The prevalence of GDM, ICP, PE, and PIH was 8.4%, 6.2%, 3.4%, and 2.1%, respectively. The highest rate of ICP (28.6%) was observed in women with high tHcy (> 15 μmol/L) and low PC (quartile 1); and the lowest rate of GDM (0.6%) was found in women with high tHcy and high PC (quartiles 2 to 4). In low PC group, the prevalence of ICP in women with high tHcy was significantly higher than that in women with low tHcy (≤ 15 μmol/L) (28.6% vs. 8.4%), representing an absolute risk increment of 20.2% and a relative risk increment of 3.3-fold (OR: 3.34; 95% CI: 1.55, 7.17; P = 0.002), whereas no joint effect was observed among high PC group., Conclusions: Among Chinese pregnant women, one subgroup (high tHcy and low PC) has the highest risk of ICP and another (high tHcy and high PC) has the lowest risk of GDM; tHcy and platelet could be used as indicators to identify the women with high risk of ICP or low risk of GDM., (© 2023. The Author(s).)

Background: This study analyzed the pregnancy outcomes of patients with intrahepatic cholestasis of pregnancy (ICP) in Hangzhou, China., Methods: Cases of pregnant women monitored by antepartum testing at Hangzhou Women's Hospital from January 2018 to December 2020 were reviewed. Subjects were classified into two groups according to whether they had ICP: 688 cases of ICP were assigned to an exposure group while 38,556 cases of non-ICP were assigned to a non-exposed group. Univariate analysis was performed on qualitative or quantitative data using the Chi-Squared test or Mann-Whitney U test, and the adjusted odds ratio (aOR) and 95% confidence interval (CI) of the two groups of related variables were calculated by multivariate binary logistic regression analysis., Results: The incidence rate of ICP was 1.75%. Pregnant women with hepatitis B virus were correlated with ICP. Hepatitis B carriers (aOR = 3.873), preeclampsia (PE, aOR = 3.712), thrombocytopenia (aOR = 1.992), gestational hypertension (GH, aOR = 1.627), hyperlipidemia (aOR = 1.602) and gestational diabetes mellitus (GDM, aOR = 1.265) were all risk factors for ICP. In contrast, Body Mass Index (BMI) ≥ 30 kg/m 2 (aOR = 0.446), 25 m 2 < maternal BMI < 29.9 kg/m 2 (aOR = 0.699) and parity ≥ 1 (aOR = 0.722) were protective factors for ICP. Pregnant women in the ICP group had an increased risk of gestation days < 259 days (aOR = 4.574) and cesarean delivery (aOR = 1.930) after ICP, and a decreased risk of longer gestational days (aOR = 0.105), premature rupture of membranes (aOR = 0.384) and fetal macrosomia (aOR = 0.551)., Conclusions: By analyzing a Chinese population with ICP, we identified that pregnant women who are hepatitis B carriers or with PE, thrombocytopenia, GH, hyperlipidemia, and GDM are at higher risk of ICP. Moreover, ICP is associated with adverse pregnancy outcomes; in particular, ICP may increase the incidence of shorter gestational days and non-vaginal delivery methods such as cesarean section but reduce the incidence of premature rupture of membranes and fetal macrosomia., (© 2023. The Author(s).)

The aim of this study was to investigate the clinical features and risk factors of intrahepatic cholestasis of pregnancy (ICP) and its effect on pregnancy outcomes. The data from 300 pregnant women with ICP and 300 pregnant women without ICP admitted from July 2015 to December 2016 at Changsha Maternal and Child Health Hospital were collected. The factors associated with ICP were examined. The family history of ICP, twin pregnancies, number of births, hypertensive disorder of pregnancy (HDP), gestational diabetes, hyperlipidemia, hepatitis virus infection, and in vitro fertilization and embryo transfer, differed significantly between the 2 groups (all P < .05). The multivariable analysis showed that body mass index at delivery, number of births, HDP, gestational diabetes, hyperlipidemia, and hepatitis virus infection were associated with ICP (all P < .05). The incidence of abnormal amniotic fluid and premature births in the ICP group were significantly higher than in the control group (all P < .05). ICP is associated with BMI at delivery, number of births, HDP, gestational diabetes, hyperlipidemia, and hepatitis virus infection. ICP greatly influences pregnancy outcomes., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction and Objectives: Intrahepatic cholestasis is a frequent disease during pregnancy. It is unknown if liver function alterations produce specific placental lesions. The aim of this study was to evaluate placental histopathological changes in patients with intrahepatic cholestasis of pregnancy (ICP), and to explore correlations between the placental histopathology and hepatic function alteration or patient comorbidities, and body mass index., Patients and Methods: A retrospective cohort study included women with ICP, most of them showing comorbidities such as overweight/obesity, preeclampsia and gestational diabetes. They were attended at the National Institute of Perinatology in Mexico City for three years. Placental histopathological alterations were evaluated according to the Amsterdam Placental Workshop Group Consensus Statement. Data was analyzed using Graph-Pad Prism 5., Results: The results indicated that the placenta of ICP patients showed many histopathological alterations; however, no correlations were observed between the increase in bile acids or liver functional parameters and specific placental lesions. The most frequent comorbidities found in ICP patients were obesity, overweight and preeclampsia. Surprisingly, high percentage of ICP patients did not respond to UDCA treatment independently of the BMI group to which they belonged., Conclusion: The data suggest that ICP contribute to placental lesions. In addition, in patients with normal weight, an increase of chorangiosis and a reduced accelerated villous maturation without syncytial knots were observed in comparison with overweight and obese patients. It is necessary to improve the medical strategies in the treatment and liver disfunction surveillance of ICP patients., Competing Interests: Conflicts of interest None., (Copyright © 2022 Fundación Clínica Médica Sur, A.C. Published by Elsevier España, S.L.U. All rights reserved.)

Introduction: Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-associated hepatic disorder characterized by pruritus in the setting of elevated serum bile acids (BA). Risk factors for the disease include preexisting hepatobiliary disease, personal or family history of ICP, and advanced maternal age. Recent data suggests that patients with severe ICP (BA ≥100 μmol/L) have a higher risk of adverse pregnancy outcomes including stillbirth., Material and Methods: This was a retrospective cohort study of patients diagnosed with ICP between 2012 and 2019 at a tertiary referral center. ICP was defined as symptomatic pruritus combined with serum BA >10 μmol/L. Maternal characteristics and outcomes were abstracted from electronic medical records. Baseline characteristics were compared between patients with mild (BA <40 μmol/L), moderate (BA 40-99 μmol/L) and severe (BA ≥100 μmol/L) ICP. Obstetrics and neonatal outcomes for patients in each category were then analyzed. Shapiro-Wilk test was used to test for normality for continuous variables, and ANOVA, Kruskal-Wallis, Chi-squared or Fisher's exact tests were used as appropriate. A p -value <.05 was considered statistically significant., Results: 438 patients were included in the analysis. Individuals with pregestational diabetes ( p  < .01), history of ICP ( p  < .01), prior cholecystectomy ( p  < .01), and tobacco use ( p  < .05) were more likely to have severe disease. When compared to individuals with moderate and mild disease, individuals with severe disease were more likely to be diagnosed earlier (29w1d vs 34w1d vs 34w1d, p  < .05), have gestational diabetes (50% vs 6% vs 13%, p  < .01), hypertensive disorders of pregnancy (42% vs 10% vs 15%, p  = .02), and abnormal aspartate aminotransferase (91% vs 65% vs 27%, p  < .01) and alanine aminotransferase levels (91% vs 60% vs 26%, p  < .01). There were no differences in preterm labor, meconium-stained amniotic fluid, or neonatal respiratory distress syndrome and no stillbirths in this cohort., Conclusions: In patients with ICP, those with pregestational diabetes, history of ICP, prior cholecystectomy, and tobacco use are more likely to develop severe disease. Given the adverse outcomes associated with severe disease, serial BA measurements to monitor for development of severe disease may be warranted in this population.

Objective: To determine the obstetrical outcomes of women delivered for the diagnosis of intrahepatic cholestasis of pregnancy (ICP)., Methods: Retrospective study of singleton pregnancies diagnosed with ICP between 1 May 2014 and 31 December 2017. Population was analyzed based on bile acids: normal (<10 µmol/L), mild (10 to 40 µmol/L), moderate-severe (>40 µmol/L), and not obtained. Receiver operating characteristic curves established critical values for aspartate aminotransferase (AST) and alanine aminotransferase (ALT) to predict elevated bile acids. Statistical analyses included χ 2 for categorical variables and ANOVA for continuous variables. All tests used a 2-sided α level of significance of .05., Results: Bile acids were normal in 39 (45.9%) women, 30 (35.3%) had mild cholestasis, 10 (11.8%) had moderate-severe cholestasis and not obtained for six (7%) women. Gestational diabetes was more common in mild cholestasis ( p = .03). There were no differences in demographics, clinical presentation, obstetric interventions and neonatal outcomes. Bile acids took 5-6 days to result. Rate of labor inductions was high in all groups. Postpartum complications occurred in four women in the normal group and in one woman in the mild cholestasis group. Five (12.8%) neonates in the normal group, six (20%) in the mild group, and one (10%) in the severe group were admitted to the NICU. There was no fetal asphyxia, no 5-minute Apgar score <7, and no perinatal deaths. An AST of 27.5 IU/L ( p  = .002) with sensitivity of 81% and specificity of 76%, and an ALT of 26.7 IU/L ( p  = .004) with sensitivity of 78% and specificity of 68% predicted elevated bile acids. Improving the sensitivity of AST and ALT to 95%, the ROC curve identified an AST of 62 IU/L with a specificity, positive and negative predictive values of 32, 58 and 86%, respectively; and an ALT of 106 IU/L with a specificity, positive and negative predictive values of 27, 57 and 83%, respectively., Conclusions: ICP should not be presumed in patients with pruritus. This practice may lead to early term delivery and associated complications.

Purpose: To compare the clinical characteristics of pregnant women and perinatal outcomes with or without recurrent severe intrahepatic cholestasis of pregnancy (sICP), and identify possible factors associated with disease recurrence., Methods: A retrospective study of 164,603 deliveries was performed to identify pregnant women diagnosed with sICP in the previous pregnancy from January 2012 to December 2020. Eligible patients were divided into two subgroups according to the status of disease recurrence in the second pregnancy: recurrent severe ICP (r-sICP) and non-recurrent severe ICP (nr-sICP). Demographics, clinical characteristics, maternal and perinatal outcomes, and potential factors linked to disease recurrence were analyzed., Results: Totally 118 patients were enrolled and respectively classified into the r-sICP group ( n  = 63) and the nr-sICP group ( n  = 55). The proportion of hepatitis B virus (HBV) infection (HBsAg+, HBeAg+, HBcAb+) and early-onset ICP (<28 weeks) in the r-sICP group in the previous pregnancy were higher than those in the nr-sICP group. In the second delivery, neonatal outcomes in the r-sICP group were worse than those in the nr-sICP group. Logistic regression analysis of predictive factors for disease recurrence in the second delivery revealed that the combination of HBV infection and early-onset ICP in the previous delivery had the steepest receiver-operating characteristic (ROC) curve value 0.720 (95%CI: 0.629-0.812)., Conclusion: Patients with sICP displayed a higher recurrence rate in the second pregnancy. Being <28 weeks at the time of ICP diagnosis and having HBV infection in the previous delivery appear to be independent predictive factors for disease recurrence of sICP.

Background: Intrahepatic cholestasis of pregnancy (ICP) is associated with an increased risk of adverse perinatal outcomes leading to high perinatal morbidity and mortality. However, few studies have examined twin pregnancies complicated by ICP. To assess the perinatal outcomes of twin pregnancies with ICP, a retrospective cohort study was conducted., Methods: A total of 633 twin pregnancies and 1267 singleton pregnancies with ICP were included. In addition, a correlation study was performed on the matched total bile acid (TBA) levels from maternal serum, fetal umbilical venous blood, and amniotic fluid of 33 twin pregnancies from twin groups., Results: When compared to singletons, twin pregnancies with ICP had a higher risk of cesarean section (CS) (96.4% vs. 76.1%), preterm birth (PTB) (82.6% vs. 19.7%), fetal distress (2.0% vs. 1.3%), and neonatal intensive care unit (NICU) admission (23.6% vs. 5.1%), which was significantly related to increasing TBA levels (P < 0.05). In twin pregnancies with TBA ≥100 μmol/L, the incidences of CS, PTB, fetal distress, neonatal asphyxia, and meconium-stained amniotic fluid were 94.4, 100, 11.1, 5.6, and 36.1%, respectively. Furthermore, the maximum maternal TBA levels were positively correlated with TBA levels in the amniotic fluid (r = 0.61, P < 0.05) and umbilical cord blood (r = 0.44, P < 0.05), and a similar correlation was found for maternal TBA levels at delivery. TBA levels in umbilical cord blood and amniotic fluid also had a significant and positive correlation (r = 0.52, P < 0.05)., Conclusions: Twin pregnancies with ICP had a higher risk for adverse perinatal outcomes than singletons, which was associated with higher TBA levels. TBA can be transported through the placenta and is involved in uterus-placenta-fetal circulation., (© 2022. The Author(s).)

Variants in ATP8B1, ABCB11, and ABCB4 underlie the most prevalent forms of progressive familial intrahepatic cholestasis. We aim to describe variants in these genes in a cohort of patients with adult-onset liver disease, and explore a genotype-phenotype correlation. Patients with onset of liver disease aged above 18 who underwent sequencing of cholestasis genes for clinical purposes over a 5-year period were identified. Bioinformatic analysis of variants was performed. Liver histology was evaluated in patients with variants. Of the 356 patients tested, at least one variant was identified in 101 (28.4%): 46 ABCB4, 35 ABCB11, and 28 ATP8B1. Patients with ABCB4 variants had chronic liver disease (71.7%) and pregnancy-associated liver dysfunction (75%), with a younger age of onset in more severe genotypes (p = 0.046). ABCB11 variants presented with pregnancy-associated liver dysfunction (82.4%) and acute/episodic cholestasis (40%), with no association between age of onset and genotype severity. ATP8B1 variants were associated with chronic liver disease (75%); however, they were commonly seen in patients with an alternate etiology of liver disease and variants were of low predicted pathogenicity. In adults with suspected genetic cholestasis, variants in cholestasis genes were frequently identified and were likely to contribute to the development of liver disease, particularly ABCB4 and ABCB11. Variants were often in heterozygous state, and they should no longer be considered recessive Mendelian traits. Sequencing cholestasis genes in selected patients with adult-onset disease should be considered, with interpretation in close collaboration with histopathologists and geneticists., (© 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Background: Intrahepatic cholestasis of pregnancy is associated with adverse pregnancy outcomes, including sudden fetal cardiac arrhythmias, resulting in stillbirth. This association has been correlated with the total bile acid levels, which are a marker for disease severity. Studies are yet to determine if intrahepatic cholestasis of pregnancy severity is also associated with increased rates of other adverse neonatal outcomes., Objective: This study aimed to determine whether pregnancies complicated by intrahepatic cholestasis of pregnancy show a bile acid severity-based relationship with other adverse obstetrical outcomes beyond stillbirth alone., Study Design: This was a retrospective cohort study of singleton, nonanomalous gestations complicated by intrahepatic cholestasis of pregnancy at the Elmhurst Hospital Center from 2005 to 2019. Severity was defined by the peak total bile acid levels (μmol/L): mild (10-19), low moderate (20-39), high moderate (40-99), and severe (>100). We examined the rates of spontaneous preterm labor, fetal growth restriction, preterm prelabor rupture of membranes, iatrogenic preterm birth, meconium-stained amniotic fluid, cesarean delivery for nonreassuring fetal heart tracing, umbilical artery pH, neonatal intensive care unit admission, and neonatal birthweight. The chi-square, Fisher exact, Student t, Mann-Whitney, and multivariate regression tests were used to determine the association of intrahepatic cholestasis of pregnancy severity and adverse neonatal outcomes. In all analyses, mild severity was used as the base comparator. A P value of <.05 and 95% confidence interval not crossing 1.00 indicated statistical significance., Results: Of the 1202 pregnancies complicated by intrahepatic cholestasis of pregnancy, 306 (25.5%) were mild, 449 were low moderate (37.4%), 327 were high moderate (27.2%), and 120 were severe (10.0%). After adjusting for confounders, progressive intrahepatic cholestasis of pregnancy severity was associated with an increased risk of spontaneous preterm labor (low moderate adjusted odds ratio, 1.60; 95% confidence interval, 0.76-3.38; high moderate adjusted odds ratio, 3.49; 95% confidence interval, 1.69-7.22; severe adjusted odds ratio, 6.58; 95% confidence interval, 2.97-14.55), iatrogenic preterm birth (low moderate adjusted odds ratio, 1.54; 95% confidence interval, 0.95-2.52; high moderate adjusted odds ratio, 3.11; 95% confidence interval, 1.91-5.06; severe adjusted odds ratio, 4.94; 95% confidence interval, 2.81-8.71), and meconium-stained amniotic fluid (low moderate adjusted odds ratio, 1.33; 95% confidence interval, 0.75-2.36; high moderate adjusted odds ratio, 2.63; 95% confidence interval, 1.48-4.65; severe adjusted odds ratio, 3.91; 95% confidence interval, 1.98-7.69). There was no significant association between intrahepatic cholestasis of pregnancy severity and other adverse outcomes., Conclusion: The findings suggest that intrahepatic cholestasis of pregnancy disease severity is associated with an increased risk of spontaneous preterm labor, iatrogenic preterm birth, and meconium-stained amniotic fluid. These findings provide valuable insight toward patient anticipatory counseling., (Copyright © 2022 Elsevier Inc. All rights reserved.)

To examine the association of fetal fraction with a wide spectrum of pregnancy-related complications among Chinese population, we carried out a single-institution retrospective cohort study of women with negative Noninvasive prenatal testing (NIPT) results and singleton pregnancies between May 2018 and May 2020. Indicators of pregnancy-related complications were examined individually, including preterm birth, low birth weight, hypertensive disorders of pregnancy, gestational diabetes, oligohydramnios and intrahepatic cholestasis. We evaluated disease odds ratios (ORs) and 95% confidence intervals (CIs), after controlling for potential confounders including body mass index (BMI), maternal age and gestational week at NIPT. A total of 3534 women were included in our analyses. Women with fetal fraction<15.15% had increased risk of gestational hypertension (OR 4.41, CI [1.65, 12.45]) and oligohydramnios (OR 2.26, CI [1.33, 3.80]) compared to women with fetal fraction≥15.15%. No significant associations with fetal fraction were found for preterm birth, low birth weight, gestational diabetes, and intrahepatic cholestasis. In Summary, fetal fraction is inversely associated with the risk of gestational hypertension and oligohydramnios., Competing Interests: YZ, KZ, and XM are employees of GenomCan Inc.. DZ is an employee of Chengdu CapitalBio Technology Co., Ltd.. The remaining authors do not have any conflicts of interest to disclose. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Introduction: Intrahepatic cholestasis of pregnancy has been consistently associated with a higher incidence of adverse pregnancy outcomes. Previous studies mainly focused on the effects of intrahepatic cholestasis of pregnancy on pregnant mothers and fetuses, and few studies reported the postpartum growth and development of fetuses in pregnant women with intrahepatic cholestasis of pregnancy. The aim of this study was to investigate impact of maternal serum total bile acid levels on maternal and neonatal outcomes as well as child growth and food allergy., Material and Methods: A retrospective longitudinal cohort investigation was carried out among 751 pregnant women with intrahepatic cholestasis of pregnancy at 30-32 weeks of gestation from the Longitudinal Intrahepatic Cholestasis of Pregnancy Study (LoICPS). Data on the characteristics of the mothers and neonates were collected. Infant growth data and food sensitivities were also collected., Results: In our cohort, the average maternal serum total bile acid level was 35.09±30.02 μmol/L, with 58.8% of mothers suffering from mild intrahepatic cholestasis of pregnancy and 29.2% suffering from severe intrahepatic cholestasis of pregnancy. Positive correlations were found between maternal serum total bile acid levels and twin pregnancy (beta-value: 11.55, 95% CI: 2.89 - 20.20. P = 0.009) and meconium stained amniotic fluid (beta-value: 14.64, 95% CI: 9.41 - 19.87. P < 0.001). In addition, the infants of mothers with severe intrahepatic cholestasis of pregnancy were more likely to be allergic to foods at 6 months., Conclusions: This study suggested that despite pregnant women with intrahepatic cholestasis of pregnancy taking ursodeoxycholic acid tablets and cesarean section before expected date of childbirth, the perinatal outcome of newborns partially improving, the incidence of infantile food allergy was still increased., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Intrahepatic cholestasis of pregnancy is one of the common complications during pregnancy, and ursodeoxycholic acid has been recommended as the first-line drug. However, if the assisted reproductive technology may increase adverse perinatal outcomes of twin pregnancies complicated by intrahepatic cholestasis is disputed, we aimed to investigate perinatal outcomes between twin pregnancies by assisted reproductive technology versus spontaneous conception, based on these women accepted ursodeoxycholic acid treatment., Methods: From January 2014 to January 2019, we retrospectively analysed the clinical data of twin pregnant women with intrahepatic cholestasis, excluding those who did not receive ursodeoxycholic acid treatment. In total, 864 women were included, among whom 500 conceived by assisted reproductive technology and 364 conceived by spontaneous conception. The primary assessment for perinatal outcomes included premature birth, meconium-stained amniotic fluid, low Apgar score, neonatal intensive care unit and still birth, and secondary indicators were serum bile acid and liver enzymes level during medication, so we also finished subgroup analysis based on different elevated bile acid level and drug usage. The statistical analysis was performed by SPSS 22.0., Results: The study demonstrated that compared to spontaneous conception, assisted reproductive technology conceived twin pregnancies diagnosed as intrahepatic cholestasis earlier (p = 0.003), and lower birth weight (p = 0.001), less incidence of preterm delivery (p = 0.000) and neonatal intensive care unit admission (p = 0.001), but the rate of meconium-stained amniotic fluid, low Apgar score and still birth have no statistic differences. Moreover, the subgroup analysis showed no significant difference in elevated bile acid levels and medication between assisted reproductive technology and spontaneous conception groups., Conclusions: The assisted reproductive technology may increase the risk of early-onset intrahepatic cholestasis in twin pregnancies, but it does not seem to increase adverse effects on bile acid levels and perinatal outcomes. Regardless of ursodeoxycholic acid used alone or combination, the effect of bile acid reduction and improving perinatal outcomes in twin pregnancies is limited. Our conclusions still need more prospective randomized controlled studies to confirm., (© 2022. The Author(s).)

Pruritus in pregnancy is a common and burdensome symptom that may be a first sign of a pregnancy-specific pruritic disease (atopic eruption of pregnancy, polymorphic eruption of pregnancy, pemphigoid gestationis, and intrahepatic cholestasis in pregnancy) or a dermatosis coinciding with pregnancy by chance. Despite its high prevalence, pruritus is often underrated by physicians, and data regarding the safety profiles of drugs for pruritus are very limited. In this review, we illustrate the epidemiology, possible pathophysiology, clinical characteristics, and diagnostic workup of various pregnancy-related diseases and discuss antipruritic treatments. The prevalence of pruritus in pregnancy demonstrates the importance of symptom recognition and the need for an holistic approach, taking into account both the potential benefits for the patient and the potential risks to the fetus., (© 2022. The Author(s).)

Objective: To explore the clinical features, fetal outcomes and serum bile acids (BAs) metabolism in asymptomatic hypercholanemia of pregnancy (AHP), as well as the comparison with those in intrahepatic cholestasis of pregnancy (ICP) and normal pregnancies., Methods: A study containing 676 pregnant women was performed to investigate the clinical informations, routine biochemical features and obstetric outcomes of AHP by the comparison with ICP and normal pregnancies. Within the study subjects, 203 pregnant women received prospective determination for 55 serum individual BAs based on a validated UPLC-QTOF-MS/MS method. The differences in clinical features and serum BAs metabolism among the three groups were then investigated., Results: The risk of adverse fetal outcomes in AHP (28.3%) was significantly higher than that in normal pregnancies (8.9%, p < 0.001), but lower than that in ICP group (52.1%, p < 0.001). Multivariate statistics analysis indicated a distinctive serum BAs metabolic profiling among the three groups (PLS-DA, R 2 Y = 0.580, Q 2  = 0.537). Levels of serum BAs especially for deoxycholic acid species were found remarkably elevated in AHP as compared to those in ICP., Conclusions: AHP group had distinguished clinical features and serum BAs metabolism as compared to ICP group and normal pregnancies., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: To ascertain the most effective approach in pregnancies complicated by mild intrahepatic cholestasis of pregnancy (mICP) by evaluating rates of adverse perinatal outcomes (APOs) and pathological placental findings., Methods: A total of 89 pregnancies complicated by mICP (defined as total serum bile acids (TSBAs) levels <40 µmol/L) were included. One-drug (ursodeoxycholic acid [UDCA]) ( n = 49, 55.1%) and combined (UDCA plus S-adenosyl methionine (SAMe)) ( n = 40, 44.9%) therapies were compared., Results: No differences were found in demographic, obstetric, and placental characteristics. In UDCA plus SAMe group, premature delivery was a common clinical decision (14.3 versus 25%, p -value = .201), with increased rates of instrumental vaginal delivery (VD; 28.6 versus 40%, p -value = .522), but similar cesarean section (CS) rates (26.5 versus 25%, p -value = .498). Mean placental weight was comparable (UDCA, mean 595.7 g, SD 213.1 g versus UDCA plus SAMe, mean 586.4 g, SD 102.9 g, p -value = .875). A total of 110 lesions were identified, 64 in 25 placentas of patients assigned to the UDCA and 46 in 15 placentas of patients managed by UDCA plus SAMe. Placental findings attributable to maternal malperfusion were found in 41/25 and 32/15 cases treated by UCDA and UDCA plus SAMe (165 versus 213%, p -value = .774), pathological fetal vascular supply in 17/25 and 8/15 placentas (68 versus 53%, p- value = .777), and inflammatory lesions in 6/25 and 6/15 cases (24 versus 40%, p -value = .757)., Conclusions: Pregnancies complicated by mICP and managed by UDCA alone present similar APO rates and placental histopathology if compared with those treated by UDCA plus SAMe, failing to recognize advantages in the combined therapy. Further prospective studies and data sharing from ongoing RTCs could drive changes in therapeutic plan.

Objectives: This article aimed to explore the relationship between hepatitis B virus infection (HBV) and intrahepatic cholestasis in pregnancy (ICP)., Material and Methods: We conducted a retrospective study at the Beijing Youan Hospital in China between January 1, 2010 and November 31, 2016. In total, 217 pregnancies were identified and retrospectively studied. Characteristics, pregnant outcomes and the rate of mother-to-child transmission (MTCT) of HBV were compared between groups., Results: Elevate of total bile acid occurred mainly during the second and third trimester among HBV with ICP (HBV + ICP) patients. The rate of preterm birth occurred more frequently in HBV + ICP patients than both ICP and HBV patients (p < 0.05). Furthermore HBV + ICP patients had a higher percentage of cesarean section, postpartum hemorrhage Apgar < 7 at 1/5 min, AFIII and LBWI rate than HBV patients (p > 0.05) but did not have an increased incidence of fetal loss or birth defect when compared with that in HBV and ICP patients (p > 0.05)., Conclusions: HBV + ICP patients have adverse pregnant outcomes and as a high occurrence in the second and third trimesters of pregnancy monitoring should be enhanced at this time.

Purpose: Applying machine-learning models to clinical and laboratory features of women with intrahepatic cholestasis of pregnancy (ICP) and creating algorithm to identify these patients without bile acid measurements., Methods: This retrospective study included 336 pregnant women with a chief complaint of pruritis without rash during the second/third trimesters. Data extracted included: demographics, obstetric, clinical and laboratory features. The primary outcome was an elevated bile acid measurement  ≥ 10 µmol/L, regardless of liver enzyme levels. We used different machine-learning models and statistical regression to predict elevated bile acid levels., Results: Among 336 women who complained about pruritis, 167 had bile acids  ≥ 10 µmol/L and 169 had normal levels. Women with elevated bile acids were older than those with normal levels (p = 0.001), higher parity (p = 0.001), and higher glutamic oxaloacetic transaminase ( GOT) (p = 0.001) and glutamic-pyruvic transaminase (GPT) levels (p = 0.001). Using machine-learning models, the XGB Classifier model was the most accurate (area under the curve (AUC), 0.9) followed by the K-neighbors model (AUC, 0.86); and then the Support Vector Classification (SVC) model (AUC, 0.82). The model with the lowest predicative ability was the logistic regression (AUC, 0.72). The maximum sensitivity of the XGB model was 86% and specificity 75%. The best predictive parameters of the XGB model were elevated GOT (Importance 0.17), elevated GPT (Importance 0.16), family history of bile disease (0.16) and previous pregnancy with ICP (0.13)., Conclusion: Machine-learning models using clinical data may predict ICP more accurately than logistic regression does. Using detection algorithms derived from these techniques may improve identification of ICP, especially when bile acid testing is not available., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Aim: Single pregnancy patients with intrahepatic cholestasis of pregnancy (ICP) were divided into two groups according to the conception method, as spontaneous and in vitro fertilization (IVF). We aim to compare the maternal, laboratory and perinatal characteristics of both groups., Materials and Method: The records of 10,929 patients who gave birth in the center between October 2011 and July 2019 were analyzed retrospectively from the data processing system records. Maternal, laboratory and perinatal characteristics of 109 single pregnancies (spontaneous n : 91; IVF n : 18) diagnosed with ICP were compared., Findings: The maternal demographic data of both groups were similar ( p : .05). In both groups, gestational week, gestational age at birth, birth weight, neonatal intensive care admission rate, meconium-stained amniotic fluid, umbilical cord pH, the 5-minute APGAR score, and the presence of pregnancy complications were similar ( p  > .05)., Result: Although ICP is reported with a higher incidence in IVF pregnancies, ICP findings and prognosis are similar to those of spontaneous pregnancies.

Background: Progressive familial intrahepatic cholestasis is a rare, heterogeneous group of liver disorders of autosomal recessive inheritance, characterised by an early onset of cholestasis with pruritus and malabsorption, which rapidly progresses, eventually culminating in liver failure. For children and their parents, PFIC is an extremely distressing disease. Significant pruritus can lead to severe cutaneous mutilation and may affect many activities of daily living through loss of sleep, irritability, poor attention, and impaired school performance., Methods: Databases including MEDLINE and Embase were searched for publications on PFIC prevalence, incidence or natural history, and the economic burden or health-related quality of life of patients with PFIC. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed., Results: Three systematic reviews and twenty-two studies were eligible for inclusion for the epidemiology of PFIC including a total of 2603 patients. Study periods ranged from 3 to 33 years. Local population prevalence of PFIC was reported in three studies, ranging from 9.0 to 12.0% of children admitted with cholestasis, acute liver failure, or splenomegaly. The most detailed data come from the NAPPED study where native liver survival of >15 years is predicted in PFIC2 patients with a serum bile  acid concentration below 102 µmol/L following bile diversion surgery. Burden of disease was mainly reported through health-related quality of life (HRQL), rates of surgery and survival. Rates of biliary diversion and liver transplant varied widely depending on study period, sample size and PFIC type, with many patients have multiple surgeries and progressing to liver transplant. This renders data unsuitable for comparison., Conclusion: Using robust and transparent methods, this systematic review summarises our current knowledge of PFIC. The epidemiological overview is highly mixed and dependent on presentation and PFIC subtype. Only two studies reported HRQL and mortality results were variable across different subtypes. Lack of data and extensive heterogeneity severely limit understanding across this disease area, particularly variation around and within subtypes.

Objective: Intrahepatic Cholestasis of Pregnancy (ICP) is a rare pregnancy specific disorder. Genetic variants of ABCB4 gene increase ICP risk. This study was conducted to determine frequency of ICP cases presented at a tertiary care hospital in Rawalpindi, Pakistan and to screen for genetic variants of exon 6 and 14 of ABCB4 gene in ICP cases., Methods: This analytical study included ICP patients presenting at Department of Gynaecology and Obstetrics, Holy Family Hospital Rawalpindi, from February 2017 to May 2017. Sanger's sequencing was performed using genomic DNA extracted from blood samples of patients and controls., Results: Twenty pregnant women out of 1150 (1.74%) had ICP and were enrolled during study period. Overall (19/20) 95% patients had pruritus and among them (8/20) 40%, (4/20) 20% and (2/20) 10% had a history of miscarriages, stillbirths and familial ICP respectively. Genetic analysis revealed an already reported variant i.e., c.504C>T in exon 6 in thirteen patients and a novel variant i.e., c.1686A>G in exon 14 in five patients. Both variants were not present in controls. In silico analysis suggested that both variants might affect pre-mRNA splicing of ABCB4 transcript., Conclusions: ICP had a frequency of 1.74% among pregnant women. Identification of a novel heterozygous variant in five patients and an already reported variant in thirteen patients reaffirms genetic heterogeneity and role of ABCB4 in ICP etiology.

Aim: Intrahepatic cholestasis of pregnancy (ICP) is associated with safe maternal outcomes but perinatal outcomes have been variable. We assessed clinical factors and impact of bile acid levels on maternal and neonatal outcomes in ICP., Methods: Patients with ICP (defined as pruritus with serum bile acids ≥ 10 mmol/l) were included prospectively with an assessment of risk factors, modes of delivery as well as maternal and neonatal outcomes. Mild and severe ICP were diagnosed when serum bile acid was always <40 mmol/l and ≥40 mmol/l, respectively. Patients with gestational pruritus served as controls., Results: Out of 643 patients, 375 patients (mean age 29 ± 7.6 years, 45.8% primigravida) met inclusion criteria. Pregnancy-induced hypertension [PIH: 10.5%; odds ratio (OR): 4.8; 95% confidence interval (CI): 2.4-8.5; P = 0.0014], gestational diabetes (GDM: 12.5%; OR: 2.6; 95% CI: 2.3-4.1; P = 0.045) and spontaneous preterm labor (15.1%; OR: 2.5; 95% CI: 1.2-3.5; P = 0.040) were higher in patients with ICP. Ursodeoxycholic acid (UDCA) (median dose 900 mg; 600-1800 mg) ameliorated symptoms of cholestasis, bile acid levels and liver aminotransferases in 79% cases. When compared with patients with mild ICP, patients with severe ICP presented at a lower gestational period (26 vs. 32 weeks, P = 0.036), required frequent induction (12.5%; OR: 3.2; 95% CI: 2.1-5.6; P = 0.045) and had increased fetal distress (15%; OR: 1.9; 95% CI: 1.3-4.9; P = 0.048).Overall eight stillbirths were recorded., Conclusion: Severe ICP is associated with a higher incidence of GDM and PIH, risk of pre-term labor, elective induction and stillbirths. UDCA remains a first-line agent in treating ICP., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Although intrahepatic cholestasis of pregnancy (ICP) remains poorly understood, there are several perinatal complications associated with this condition. This study aimed to examine perinatal outcomes of women with ICP, evaluate outcomes according to severity of disease, and monitor time to symptom improvement following diagnosis., Study Design: It involves a prospective, observational study of women with ICP at a single institution. Women with new-onset pruritus without rash were referred to a high-risk obstetrics clinic and evaluated with fasting total bile acids (TBA). Laboratory-confirmed ICP was defined as fasting TBA ≥10 µmol/L. Following diagnosis, a standardized protocol was utilized, including treatment with ursodeoxycholic acid (UDCA). Perinatal outcomes were compared amongst those with and without ICP, and to the general population. Women with ICP were further analyzed based on maximum TBA: 10 to 39, 40 to 99, and ≥100 µmol/L. A Kaplan-Meier survival curve was used to analyze time to symptom improvement., Results: A total of 404 patients were evaluated and 212 (52%) were diagnosed with ICP. The mean gestational age at diagnosis was 34.1 ± 3.3 weeks. When comparing those with ICP to those not confirmed, and to the general population, there were no differences in age, parity, mode of delivery, preeclampsia, or stillbirth ( p  > 0.05). Preterm birth was significantly associated with ICP ( p  < 0.01). This relationship was significant across increasing severity of TBA ( p  < 0.01) and persisted when examining rates of spontaneous preterm birth ( p  < 0.01). All women with fasting TBA ≥40 µmol/L delivered preterm due to premature rupture of membranes or spontaneous labor. Time to symptom improvement after diagnosis was over 2 weeks on average; however, this time increased with worsening severity of disease., Conclusion: Despite treatment with UDCA, women with ICP are at increased risk for spontaneous preterm birth, and this risk significantly increased with severity of disease. Although not significant, a trend exists between increasing time to symptom improvement and worsening severity of disease., Key Points: · Preterm birth is significantly increased in patients diagnosed with intrahepatic cholestasis of pregnancy.. · The risk of preterm birth in women with ICP increases across increasing strata of disease.. · Following initiation of treatment in patients with ICP, symptom improvement takes more than 2 weeks.., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: Bile duct invasion is a relatively rare event and is not well characterised in hepatocellular carcinoma (HCC). It remains very difficult to diagnose HCC with bile duct tumour thrombus (BDTT) before surgery. Increasing evidence has revealed that inflammation plays a critical role in tumorigenesis. This study aimed to develop nomograms based on systemic and hepatic inflammation markers to predict microscopic BDTT (micro-BDTT) before surgery in HCC., Methods: A total of 723 HCC patients who underwent hepatectomy as initial therapy between January 2012 and June 2020 were included in the study. Logistic regression analysis was used to identify independent risk factors for micro-BDTT. The nomograms were constructed using significant predictors, including α-fetoprotein (AFP), alkaline phosphatase (ALP), direct bilirubin (DB), prognostic nutritional index (PNI), and γ-glutamyl transferase (γ-GT)/alanine aminotransferase (ALT). The prediction accuracies of the nomograms were evaluated using the area under the receiver operating characteristic (ROC) curve., Results: AFP, ALP, DB, PNI, and γ-GT/ALT were independent risk factors for predicting micro-BDTT (P = 0.036, P = 0.004, P = 0.013, P = 0.012, and P = 0.006, respectively), which were assembled into the nomograms. The area under the ROC curve of the nomograms combining PNI and γ-GT/ALT for predicting micro-BDTT was 0.804 (95% confidence interval [CI]: 0.730-0.878). The sensitivity and specificity values when used in predicting micro-BDTT before surgery were 0.739 (95% CI: 0.612-0.866) and 0.781 (95% CI: 0.750-0.813), respectively., Conclusions: The nomogram based on combining systemic and hepatic inflammation markers is suitable for predicting micro-BDTT before surgery in HCC patients, leading to a rational therapeutic choice for HCC.

Introduction: Our study aims to evaluate the perinatal outcomes in twin pregnancies diagnosed with intrahepatic cholestasis of pregnancy (ICP) and to compare these with normal healthy twin pregnancies for perinatal outcomes. The second outcome of the study was to determine whether in vitro fertilization-embryo transfer (IVF-ET) affects the perinatal outcome in ICP patients., Materials and Methods: In this study, 59 ICP and 641 healthy twin pregnancies were compared for perinatal outcomes retrospectively. According to the mode of conception, the twin pregnancies with ICP were divided into 2 groups. The twin pregnancies with ICP who were conceived with IVF were referred to as the IVF-ET group. The twin pregnancies with ICP who were conceived spontaneously or by ovulation induction and intrauterine insemination (IUI) were referred to as the non-IVF-ET group., Results: Twin pregnancies with ICP give birth significantly earlier than normal twin pregnancies (p ˂ 0.001). The diagnosis of ICP occurred significantly earlier in the IVF-ET pregnancy with ICP than in the non-IVF-ET group. In twin pregnancies with IVF-ET, patients delivered significantly earlier than in the non-IVF-ET group (p=0.002). Twin pregnancies with ICP were found to have significantly higher rates of meconium-stained amniotic fluid, postnatal intubation, and admission to the neonatal intensive care unit (NICU) than healthy twin pregnancies., Conclusions: ICP is a risk factor for preterm delivery in twin pregnancies. In addition, ICP develops earlier and more frequently in twin pregnancies from IVF-ET than in those from non-IVF twin pregnancies, and the disease may be more serious., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Progressive familial intrahepatic is a heterogeneous group of rare autosomal recessive liver disorders. Neonatal onset is characteristic of the PFIC 1 and PFIC 2, which result from mutations in genes respectivelyATP8B1 and ABCB11. Four Tunisian patients, three of them with PFIC 2 and one with PFIC1, were described. They all had typical clinical and biological features. However, they all had newly reported mutations. The same mutation was found in the patients with PFIC2, which could facilitate the diagnosis in Tunisian patients suspected in the future. The patient diagnosed with PFIC1 had also a newly described mutation, with a probable phenotypic particularity that is congenital hypothyroidism. Advances are being made to establish a molecular diagnosis in neonatal onset cholestasis. Indeed, next generation sequencing gene panels (NGSGP) potentially decrease the need for invasive procedures in these patients, enable early initiation of treatment and adequate genetic counseling.

Introduction: Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disease characterized by pruritus and abnormal liver function tests and it has been associated with intrauterine fetal distress and stillbirth. We compared two guidelines of the management of ICP: one mandating induction at 38 weeks of gestation (Rigshospitalet and Hvidovre Hospital before 2012) and another separating ICP into mild and severe forms, and only women with severe ICP were recommended for induction at 38 weeks (Hvidovre Hospital after 2012)., Material and Methods: We performed a historical cohort study at two Copenhagen Hospitals from 2004 to 2015. We included 62 937 women with singleton deliveries at Rigshospitalet and 71 015 at Hvidovre Hospital, of whom 971 women (1.5%) and 998 women (1.4%) were diagnosed with ICP at Rigshospitalet and Hvidovre Hospital, respectively. Data were retrieved from a local medical database. For the analysis of induction and comparison of obstetrical outcomes we only included pregnancies with an ICP diagnosis and excluded women with other medical conditions that could mandate induction. Main outcome measures were induction and cesarean section rates, asphyxia and stillbirth., Results: We found no changes in the rate of spontaneous labor, cesarean section and induction over the years at Rigshospitalet (P = .17) and Hvidovre Hospital (P = .38). For women with intended vaginal delivery we found no change in the final mode of delivery over the years at Rigshospitalet (P = .28) and Hvidovre Hospital (P = .57)., Conclusions: The two approaches to the management of mild ICP regarding the timing of induction are comparable. Women with mild ICP and their clinicians should be encouraged to engage in shared decision-making when discussing timing of induction., (© 2020 Nordic Federation of Societies of Obstetrics and Gynecology (NFOG). Published by John Wiley & Sons Ltd.)