Familial clustering of intrahepatic cholestasis of pregnancy: A nationwide population-based study in Denmark.

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.

The impact of maternal intrahepatic cholestasis during pregnancy on the growth trajectory of offspring: a population-based nested case‒control cohort study.

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.

The severity of intrahepatic cholestasis during pregnancy increases risks of adverse outcomes beyond stillbirth: evidence from 15,826 patients.

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.

Gestational diabetes complicated with preterm birth: a retrospective cohort study.

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.

History of Cholestasis Is Not Associated with Worsening Outcomes in Subsequent Pregnancy with Cholestasis.

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..

Intrahepatic cholestasis of pregnancy and its association with preeclampsia and gestational diabetes: a retrospective analysis.

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.

Intrahepatic Cholestasis of Pregnancy during COVID-19 Pandemic.

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.

[Correlation between hepatitis B virus infection and adverse pregnancy outcomes-a systematic review and meta-analysis].

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.

Risk of stillbirth in United States patients with diagnosed intrahepatic cholestasis of pregnancy.

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.

Childhood Cholestatic Liver Diseases that Persist Into Adulthood: Lessons for the Adult Gastroenterologist.

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.

The impact of intrahepatic cholestasis on pregnancy outcomes: a retrospective cohort study.

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/m2 (aOR = 0.446), 25 m2 < maternal BMI < 29.9 kg/m2 (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.

Body mass index implications in intrahepatic cholestasis of pregnancy and placental histopathological alterations.

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.

Platelet counts affect the association between hyperhomocysteinemia and pregnancy complications.

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.

Beyond stillbirth: association of intrahepatic cholestasis of pregnancy severity and adverse outcomes.

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.

The impact of assisted reproductive technology in twin pregnancies complicated by intrahepatic cholestasis: a five-year retrospective study.

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.

Perinatal outcomes associated with ICP in twin pregnancies were worse than singletons: an almost 5-year retrospective cohort study.

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.

Intrahepatic Cholestasis of Pregnancy: Natural History and Current Management.

Intrahepatic cholestasis of pregnancy (ICP) is a common disorder in the second half of pregnancy characterized by pruritus and elevated serum bile acids (BAs) with spontaneous resolution after delivery. ICP carries a risk of adverse effects on the fetus which correlates with the degree of BA elevation. ICP occurs in genetically susceptible women as the reproductive hormones increase during pregnancy. Ursodeoxycholic acid is still considered the first-line treatment for ICP though it is of unproven benefit in preventing adverse effects on the fetus. Fetal complications, such as stillbirth, increase with gestational age, so preterm delivery is generally performed in cases of severe ICP, defined as BA levels above 40 µmol/L. ICP may recur in future pregnancies and is associated with an increased risk for future hepatobiliary, immune mediated, and cardiovascular diseases. Children born of mothers with ICP have normal development but may have a risk for subsequent metabolic disease.

Outcomes of Pregnant Women With Cirrhosis and Their Infants in a Population-Based Study.

BACKGROUND & AIMS: The incidence of cirrhosis is increasing among women of childbearing age. Contemporary outcomes of pregnant women with cirrhosis and their infants, as well as liver-related complications, have not been described in North America, to our knowledge. We investigated the association between cirrhosis and perinatal outcomes and evaluated perinatal liver-related events. METHODS: We performed a retrospective cohort study using population-based administrative health care data from Ontario, Canada (2000-2017). We identified pregnant women with compensated cirrhosis (n = 2022) using validated case definitions and routine mother-infant linkage; the women were matched to 10,110 pregnant women in the general population (1:5) based on birth year and socioeconomic status. Maternal and infant outcomes up to 6 weeks postpartum and liver-related complications up to 1 year postpartum were evaluated by using multivariate log-binomial regression. RESULTS: After we adjusted for demographic and metabolic risk factors, cirrhosis was independently associated with intrahepatic cholestasis of pregnancy (relative risk [RR], 10.64; 95% confidence interval [CI], 7.49-15.12), induction of labor (RR, 1.15; 95% CI, 1.03-1.28), puerperal infections (RR, 1.32; 95% CI, 1.02-1.70), preterm birth (RR, 1.60; 95% CI, 1.35-1.89), infants who were large for gestational age (RR, 1.24; 95% CI, 1.05-1.46), and neonatal respiratory distress (RR, 1.20; 95% CI, 1.02-1.42). Fewer than 2% of pregnant women with cirrhosis had liver-related complications, but these occurred in a significantly higher proportion of women with a history of hepatic decompensation (13%) than women with compensated cirrhosis (1.2%) (P < .001). CONCLUSIONS: In a population-based study, we found that cirrhosis is an independent risk factor for adverse perinatal outcomes. However, liver-related complications are rare. Multidisciplinary teams are needed to coordinate care for pregnant women with cirrhosis during pregnancy and postpartum to optimize outcomes.

A nomogram based on combining systemic and hepatic inflammation markers for predicting microscopic bile duct tumour thrombus in hepatocellular carcinoma.

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.

Differentiated timing of induction for women with intrahepatic cholestasis of pregnancy-A historical cohort study.

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.