Intrahepatic cholestasis of pregnancy is the most common pregnancy-related liver disease, manifesting typically during the third trimester of pregnancy with pruritus and elevated serum bile acids. This condition is associated with increased fetal morbidity and mortality, and its pathogenesis is still incompletely understood, but is most likely multifactorial, involving ethnicity, genetics, hormones and environmental factors. Available evidence covering the pathophysiology of both maternal and fetal manifestations, and potential new areas of interest such as microbiota and the environment, have been reviewed, as well as available biomarkers that can be used particularly with regard to genetics, multiomics and the possible use of machine learning algorithms to predict intrahepatic cholestasis of pregnancy. Ursodeoxycholic acid is still the mainstay of therapy with limited alternative options; however, a new class of drugs inhibiting intestinal bile acid transport might be on the horizon. Intrahepatic cholestasis of pregnancy is still not completely understood, warranting a critical appraisal of its epidemiology, pathogenesis, diagnosis and management.© 2025. Springer Nature Limited.

Intrahepatic cholestasis of pregnancy (ICP) can be a source of significant distress for both pregnant women and the fetus, impairing the quality of life and well-being of pregnant women, leading to psychological disorders among pregnant women with severe or recurrent ICP, and causing life-threatening complications among fetuses. Regrettably, our current understanding of ICP globally is limited, lacking a comprehensive estimation of its incidence. Therefore, in this systematic review and meta-analysis, we aimed to investigate the global and regional incidence of ICP and identify factors that account for its variety across studies.A comprehensive search strategy was implemented across PubMed, Scopus, and Web of Science databases. To stabilize the variance, the Freeman-Tukey double arcsine transformation was employed. Subgroup analyses were conducted based on continent, publication type, study design and timing, regional classifications, developmental status, and World Bank income grouping. A multivariate meta-regression analysis was performed to estimate the effects of the continuous moderators on the effect size.A total of 42,972,872 pregnant women were analyzed from 302 studies. The overall pooled incidence [95% confidence interval] of ICP was 2.9% [2.5, 3.3]. Studies with larger sample sizes tended to provide significantly lower estimates of ICP incidence: 1.6% [1.3, 2] vs 4.7% [3.9, 5.5]. Asia had the highest incidence of ICP among the continents, whereas Oceania had the lowest. Countries that were classified as developed and with higher income had a lower incidence of ICP than those classified as developing and low and middle income.The findings of this study will provide valuable insights into the current knowledge regarding the association of the quality of public health and socioeconomic variations with the incidence of ICP on a global scale.© 2025. The Author(s).

Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disease specific to pregnancy. The cardinal symptom of pruritus and a concomitant elevated level of bile acids in the serum and/or alanine aminotransferase (ALT) are suggestive for the diagnosis. Overall, the maternal prognosis is good. The fetal outcome depends on the bile acid level. ICP is associated with increased risks for adverse perinatal outcomes, including preterm delivery, meconium-stained amniotic fluid, and stillbirth. Acute fetal asphyxia and not chronic uteroplacental dysfunction leads to stillbirth. Therefore, predictive fetal monitoring is not possible. While medication with ursodeoxycholic acid (UDCA) improves pruritus, it has not been shown to affect fetal outcome. The indication for induction of labour depends on bile acid levels and gestational age. There is a high risk of recurrence in subsequent pregnancies.

To determine the optimal total serum bile acid (TSBA) threshold and sampling time for accurate intrahepatic cholestasis of pregnancy (ICP) diagnosis.

Current guidelines recommend viral, autoimmune, coagulation and liver ultrasound testing in intrahepatic cholestasis of pregnancy to exclude alternative diagnoses.

To review the management and outcomes of Intrahepatic Cholestasis of Pregnancy (ICP) in South Australia (SA) over the past decade.Retrospective cohort review.Public clinics at two teaching hospitals in SA.All pregnancies associated with ICP (defined as pruritus with serum bile acids≥10μmol/L) managed 2001-2010.Identification of subjects (laboratory database), detailed chart-review to ascertain demographics, maternal/perinatal outcomes and associated pregnancy comorbidities, analysis of mild/severe disease cohorts, comparison with normal population data, using Student's t-test or Mann-Whitney U test as appropriate for continuous variables, and Pearson's chi-square test or Fisher's exact test for categorical variables. Unadjusted odds ratios (OR) with 95% confidence intervals (95% CI) were calculated in comparison with the general pregnant population for clinically significant outcomes.320 women (359 pregnancies) were diagnosed with ICP over the 10-years: incidence 0.6%/year. Within the cohort, the incidences of gestational diabetes (12.5%; OR 3.06, 95% CI 2.23-4.18), pre-eclampsia (10.3%; OR 75.84, 95% CI 52.91-178.70), and spontaneous preterm labour (23.1%; OR 2.05, 95% CI 1.41-2.98) were much higher than in the general SA pregnant population. Pregnancies with severe ICP (serum bile acids≥40μmol/L) had ICP diagnosed earlier (231 vs 248 days, P<0.001), and ended earlier (256 vs 260 days, P<0.001) with lower birthweights (2827g vs 3093g, P <0.001) than those with mild ICP. Neonates of severe ICP mothers were more likely to require special-care-nursery admission, but perinatal complication rates did not differ. There were no stillbirths.This large Australian retrospective cohort study confirms generally favourable outcomes associated with ICP, mild or severe, with no stillbirths, likely secondary to proactive medical management. A high proportion of pregnancies were also affected by gestational diabetes, pre-eclampsia, and/or spontaneous pre-term labour compared with the general population.Copyright © 2017 Elsevier B.V. All rights reserved.

OBJECTIVES. Neonatal respiratory distress syndrome is associated with intrahepatic cholestasis of pregnancy, and bile acids may play a major role in neonatal bile acid pneumonia. Our aim was to demonstrate the bile acid presence in the bronchoalveolar lavage fluid of neonates affected by respiratory distress syndrome who were born from intrahepatic cholestasis of pregnancy and to investigate bile acid mechanisms of action in acute lung injury.

Intrahepatic cholestasis of pregnancy (ICP) is complicated by spontaneous preterm labor, fetal anoxia and unexplained fetal death. We aim to evaluate the mechanisms by which raised fetal bile acids cause placental abnormalities and fetal cardiac pathology.The study was performed using placental samples taken from ICP pregnancies, placental explant culture, neonatal and adult cardiomyocytes, and murine and human embryonic stem cell-derived cardiomyocytes.Maternal cholestasis causes a placental phenotype with histological abnormalities. This can be evaluated using placental explant cultures. Taurocholate, the principal bile acid raised in the fetal compartment in ICP, causes abnormal cardiomyocyte contraction, rhythm and desynchronization of calcium dynamics. To extend our observations that the muscarinic M2 receptor plays a role in bile acid-induced arrhythmia in cardiomyocytes, we are developing a model containing mixed cell populations to represent the fetal and maternal hearts. This will be used to evaluate the underlying mechanisms to explain fetal arrhythmia in the presence of cholestasis.Bile acids signal via a spectrum of pathways in the placenta and the fetal heart.Copyright © 2011 S. Karger AG, Basel.

Intrahepatic cholestasis of pregnancy (ICP) is a rare complication of late pregnancy associated with a high rate of premature delivery, antepartum fetal death and fetal hypoxia. Since the principal biochemical feature of ICP is a marked elevation of maternal serum bile acid levels, a role of these substances in the pathophysiology of fetal complications has been suggested. In this study, the effect of bile acids on isolated human placental chorionic veins is described. High concentrations of bile acids, especially cholic acid, have a dose-dependent vasoconstrictive effect, which suggests that these substances could exert a detrimental effect on the fetus by increasing the resistance in chorionic veins through a vasospasm of the placental chorionic surface. An abrupt reduction of the oxygenated blood flow at the level of the placental chorionic plate may cause an acute impairment of the fetal perfusion and oxygenation, leading to fetal asphyxia. This is the first report that provides experimental evidence of the possible role of bile acids in those mechanisms that trigger fetal asphyxia in pregnancies complicated by ICP.

To describe perinatal outcomes of twin pregnancies complicated by intrahepatic cholestasis of pregnancy (ICP).We conducted a retrospective cohort study of women delivered at a large tertiary obstetric center in Shanghai, China from January 2006 to May 2014. Delivery data were abstracted from medical records of all twin gestations delivered at the hospital.A total of 129/1922(6.7%) twin and 1190/92 273 singleton (1.3%) pregnancies were complicated by ICP. An increased risk of stillbirth among twin pregnancies was observed (3.9% and 0.8% in the ICP and non-ICP groups, respectively; aOR 5.75, 95% CI 2.00-16.6). Stillbirths with ICP and twins occurred between 33 and 35 weeks gestation compared to 36-38 weeks gestation among singletons. ICP in twins was also associated with an increased risk of preterm birth (<37 weeks) with an aOR of 4.17 (95% CI 2.47-7.04) and an aOR of 1.89 (95% CI 1.26-2.85) for delivery <35 weeks. Twin pregnancies complicated by ICP also had increased meconium staining of amniotic fluid and lower birth weight.Twin pregnancies with ICP have significantly increased risks of adverse perinatal outcomes including stillbirth and preterm birth. Stillbirth occurs at an earlier gestational age in twin gestation compared to singletons, suggesting that earlier scheduled delivery should be considered in these women.

To evaluate whether a particular group of women with intrahepatic cholestasis of pregnancy (ICP), based on their presenting characteristics, would benefit from treatment with ursodeoxycholic acid (UDCA).

To evaluate enzymatic total serum bile acid quantification as a monitoring strategy for women with intrahepatic cholestasis of pregnancy (ICP) treated with ursodeoxycholic acid (UDCA).

Intrahepatic cholestasis of pregnancy is associated with an increased risk of fetal death. The mechanism of death is unknown.The first case involved a young primipara with pruritus and a bile acid concentration of 79 mumol/dL. While undergoing fetal heart rate monitoring, the fetus had a prolonged deceleration resulting in intrauterine death. The second case involved a young multipara with cholestasis who received ursodeoxycholic acid. Her bile acid concentration improved to13 micromol/dL. At 34 weeks of gestation, she had uterine contractions with prolonged decelerations resulting in delivery of her fetus with Apgar scores of 0, 0, and 5 at 1, 5, and 10 minutes, respectively.Fetal death from intrahepatic cholestasis of pregnancy can be abrupt and not reliably predicted by the characteristics of the fetal heart rate tracing.

The objective of this study is to examine perinatal outcomes associated with cholestasis of pregnancy according to bile acid level and antenatal testing practice.Retrospective cohort study of women with symptoms and bile acid testing from 2005 to 2014. Women were stratified by bile acid level: no cholestasis (<10 μmol/L), mild (10-39 μmol/L), moderate (40-99 μmol/L), and severe (≥100 μmol/L). The primary outcome was composite neonatal morbidity (hypoxic ischemic encephalopathy, severe intraventricular hemorrhage, bronchopulmonary dysplasia, necrotizing enterocolitis, or death).785 women were included; 487 had cholestasis (347 mild, 108 moderate, 32 severe) and 298 did not. After controlling for gestational age (GA), severe cholestasis was associated with the composite neonatal outcome (aRR 5.6, 95% CI 1.3-23.5) and meconium-stained fluid (aRR 4.82, 95%CI 1.6-14.2). Bile acid levels were not correlated with the frequency of testing (p = .50). Women who underwent twice weekly testing were delivered earlier (p = .016) than women tested less frequently, but the difference in GA was ≤4 d. Abnormal testing prompting delivery was uncommon. Among women with cholestasis, there were three stillbirths. One of these women was undergoing antenatal testing, which was normal 1 d prior to the fetal demise.Severe cholestasis is associated with neonatal morbidity which antenatal testing may not predict.

Intrahepatic cholestasis of pregnancy, characterised by maternal pruritus and increased serum bile acid concentrations, is associated with increased rates of stillbirth, preterm birth, and neonatal unit admission. Ursodeoxycholic acid is widely used as a treatment without an adequate evidence base. We aimed to evaluate whether ursodeoxycholic acid reduces adverse perinatal outcomes in women with intrahepatic cholestasis of pregnancy.We did a double-blind, multicentre, randomised placebo-controlled trial at 33 hospital maternity units in England and Wales. We recruited women with intrahepatic cholestasis of pregnancy, who were aged 18 years or older and with a gestational age between 20 weeks and 40 weeks and 6 days, with a singleton or twin pregnancy and no known lethal fetal anomaly. Participants were randomly assigned 1:1 to ursodeoxycholic acid or placebo, given as two oral tablets a day at an equivalent dose of 500 mg twice a day. The dose could be increased or decreased at the clinician's discretion, to a maximum of four tablets and a minimum of one tablet a day. We recommended that treatment should be continued from enrolment until the infant's birth. The primary outcome was a composite of perinatal death (in-utero fetal death after randomisation or known neonatal death up to 7 days after birth), preterm delivery (<37 weeks' gestation), or neonatal unit admission for at least 4 h (from birth until hospital discharge). Each infant was counted once within this composite. All analyses were done according to the intention-to-treat principle. The trial was prospectively registered with the ISRCTN registry, number 91918806.Between Dec 23, 2015, and Aug 7, 2018, 605 women were enrolled and randomly allocated to receive ursodeoxycholic acid (n=305) or placebo (n=300). The primary outcome analysis included 304 women and 322 infants in the ursodeoxycholic acid group, and 300 women and 318 infants in the placebo group (consent to use data was withdrawn for 1 woman and 2 infants). The primary composite outcome occurred in 74 (23%) of 322 infants in the ursodeoxycholic acid group and 85 (27%) of 318 infants in the placebo group (adjusted risk ratio 0·85 [95% CI 0·62-1·15]). Two serious adverse events were reported in the ursodeoxycholic acid group and six serious adverse events were reported in the placebo group; no serious adverse events were regarded as being related to treatment.Treatment with ursodeoxycholic acid does not reduce adverse perinatal outcomes in women with intrahepatic cholestasis of pregnancy. Therefore, its routine use for this condition should be reconsidered.National Institute for Health Research Efficacy and Mechanism Evaluation Programme.Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

The benefits of ursodeoxycholic acid (UDCA) use for treating intra-hepatic cholestasis of pregnancy (ICP) remain uncertain. A 2010 Cochrane Review of randomized control trials was unable to recommend either for or against the use of UDCA in treating ICP. We conducted a meta-analysis of the literature, including both non-randomized studies (NRSs) and RCTs. The objective of the study was to determine if patients included in NRSs were comparable to those in RCTs, and to determine whether the inclusion of NRSs could strengthen the available evidence and guide clinical practice on UDCA use in women with ICP.We searched Medline (Ovid), Embase (Ovid), EMB Reviews, Cinahl (Ebsco), and Web of Knowledge (Thomson Reuters) for articles published from 1966 to June 2012.We included all eligible RCTs of UDCA versus placebo or other treatments, and all NRSs comparing UDCA with any other treatment in women with ICP.We included 11 RCTs (n = 625 pregnancies) and six NRSs (n = 211 pregnancies). The women included in RCTs and NRSs were comparable, but study quality was poorer for NRSs. Overall, women treated with UDCA had decreased pruritus in 73% of RCTs and in 100% of NRSs with available data. Liver function tests were improved in 82% of RCTs and in 100% of NRSs with available data. UDCA use did not affect the Caesarean section rate, but was associated with less prematurity, less use of neonatal intensive care units (data available in only 3/17 studies), and trends towards increased birth weight and decreased meconium staining. There were 0/356 stillbirths with UDCA and 3/399 stillbirths with comparator.UDCA treatment should be recommended for women with ICP to reduce adverse maternal and fetal outcomes.

Intrahepatic cholestasis of pregnancy is an incompletely understood disease that poses significant fetal risks, including stillbirth. Treatment of intrahepatic cholestasis of pregnancy is aimed at relieving maternal symptoms and improving fetal outcomes.A 21-year-old gravid woman, 3 para 0111, presented at 27 2/7 weeks of gestation with severe intrahepatic cholestasis of pregnancy. Her clinical course was refractory to first-line therapy with ursodiol, and she was started on rifampin with rapid improvement of symptoms and transaminitis. Despite maternal improvement, she was delivered at 31 weeks of gestation for persistent nonreassuring fetal status.Rifampin may be an effective adjunctive therapy for intrahepatic cholestasis of pregnancy refractory to ursodiol alone. Additional research is needed to assess short-term and long-term maternal and newborn outcomes, because fetal deterioration still occurred in spite of maternal improvement.

We examined the morbidities from delivery at earlier gestational ages versus intrauterine fetal demise (IUFD) for women with intrahepatic cholestasis of pregnancy (ICP) to determine the optimal gestational age for delivery.A decision-analytic model was created to compare delivery at 35 through 38 weeks gestation for different delivery strategies: (1) empiric steroids; (2) steroids if fetal lung maturity (FLM) negative; (3) wait a week and retest if FLM negative; or (4) deliver immediately. Literature review identified 18 studies that estimated IUFD in ICP; we used the mean rate, 1.74%, and assumed a uniform distribution from 34 to 40 weeks gestation. Large cohort data was used to calculate neonatal morbidity rates at each gestational age. Maternal and neonatal quality-adjusted life years (QALYs) were combined. Univariate sensitivity and Monte Carlo analyses were performed to test for robustness.Immediate delivery at 36 weeks without FLM testing and steroid administration was the optimal strategy as compared to delivery at 36 weeks with steroids (+47 QALYs) and as compared to immediate delivery at 35 weeks (+210 QALYs). Our results were robust up to a 30% increase in the rate of IUFD.Immediate delivery at 36 weeks in women with ICP is the optimal delivery strategy.

Preterm delivery represents the major cause of neonatal morbidity and mortality. Respiratory morbidity\nis the primary cause of early neonatal mortality and disability. The administration of antenatal corticosteroids,\nin cases of imminent preterm delivery, can enhance fetal lung maturation and reduce the incidence of\nrespiratory distress syndrome, leading to improved neonatal outcomes. The scope of this narrative review was\nto synthesize available evidence on the efficacy and safety of corticosteroids' administration during antenatal\nperiod, in cases of anticipated preterm delivery. Hence, for those cases, a single course of antenatal corticosteroids\nfrom 24 up to 34 gestational weeks should be offered. Betamethasone and dexamethasone are the most\nwidely used drugs, with similar effectiveness and a recommended dosage of 24mg in divided doses, over a 24-\nhour period. However, there is an ongoing debate regarding the gestational age of administration. Some obstetric\nsocieties recommend their administration even at 22 weeks of gestation. Conflicting is also their usefulness\nin late preterm cases (between 34 and 37 weeks) or in cases of elective cesarean delivery at term. The use of\nrepeated courses of corticosteroids may be considered in specific cases, however, concerns on the long-term\noutcomes of repeated courses beyond 34 gestational weeks have been raised.

To evaluate postpartum blood loss in women with treated intrahepatic cholestasis of pregnancy.In a retrospective case-control study, 15,083 deliveries including 348 women with intrahepatic cholestasis of pregnancy (2.3%) were analyzed from 2004 to 2014. To adjust for differences in baseline characteristics, a propensity analysis was performed and women in the control group were matched to the women in the intrahepatic cholestasis of pregnancy group in a 5:1 ratio. Blood loss was analyzed by estimated blood loss and Δ hemoglobin (Hb, difference between prepartum and postpartum Hb). A subgroup analysis regarding severity of intrahepatic cholestasis of pregnancy based on maximum bile acid level (mild [less than 40 micromoles/L], moderate [40-99 micromoles/L], and severe intrahepatic cholestasis of pregnancy [100 micromoles/L or greater]) was performed. Differences in estimated blood loss, ΔHb, and meconium staining between subgroups were analyzed. A Spearman rank correlation was performed to evaluate the association of bile acid levels and blood loss within subgroups.Estimated blood loss (median 400 [300-600] mL compared with 400 [300-600] mL, P=.22), ΔHb (14.0 [5.0-22.0] compared with 12.0 [4.0-21.0] g/L, P=.09), meconium staining (14.5% compared with 11.4%, P=.12), and number of stillbirths after 26 weeks of gestation (0.6% compared with 1.8%, P=.10) were not significantly different in the study compared with the control group. In moderate and severe intrahepatic cholestasis of pregnancy, meconium staining was observed significantly more often compared with that in a control group (23.0% and 32.3% compared with 11.4%, P<.01). There was no correlation between estimated blood loss or ΔHb and severity of intrahepatic cholestasis of pregnancy.In our cohort of women with intrahepatic cholestasis of pregnancy who are treated with ursodeoxycholic acid and have planned delivery (induction of labor or planned cesarean delivery) at 38 weeks of gestation, no differences in postpartum blood loss were seen.

Reported recurrence rates of intrahepatic cholestasis of pregnancy (ICP) range from 40% to 90% based on prior literature, but data remain limited. In a retrospective cohort, we aimed to evaluate the rate of ICP recurrence and risk factors associated with recurrence. Among 104 patients with ICP in an index pregnancy, 46 experienced recurrence (44%) of ICP in subsequent pregnancy. A peak total bile acid (TBA) level greater than 40 micromoles/L in the index pregnancy was significantly associated with ICP recurrence; shorter interpregnancy intervals were associated with lower risk. These findings contribute to the literature on the risk of ICP recurrence in a modern, racially diverse cohort and highlight elevated TBA level as a predictor of recurrence.