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.

Systematic review and meta-analysis: Evaluating the influence of intrahepatic cholestasis of pregnancy on obstetric and neonatal outcomes.

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.

The Incidence of Intrahepatic Cholestasis of Pregnancy and its Maternal, Fetal, and Neonatal Adverse Outcomes: A Systematic Review and Meta-Analysis.

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.

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.

The correlation between serum total bile acid and adverse perinatal outcomes in pregnant women with intrahepatic cholestasis of pregnancy (ICP) and non-ICP hypercholanemia of pregnancy.

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.

If someone doesn't have ICP but does have moderate-to-severe hepatitis and TBA levels of 100 µmol/L or more, they should be treated more aggressively, and their pregnancies should be terminated earlier (before 34 weeks) than what is usually done for ICP.

Risk-stratified management strategies for intrahepatic cholestasis of pregnancy: A tertiary center population review over nearly 5 years.

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.

A Chinese longitudinal maternity cohort study (2013-2021) on intrahepatic cholestasis phenotypes: Risk associations from environmental exposure to adverse pregnancy outcomes.

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 PM2.5, O3, 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.

Maternal and neonatal outcomes in patients with hepatitis C and intrahepatic cholestasis of pregnancy: The sum of the parts.

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.

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.

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.

Intrahepatic cholestasis of pregnancy and fetal cardiac dysfunction: a systematic review and meta-analysis.

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.

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.

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.

Factors associated with intrahepatic cholestasis of pregnancy and its influence on maternal and infant outcomes.

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.

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.

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.

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.