RARE DISEASE
Intrahepatic cholestasis of pregnancy
Intrahepatic cholestasis of pregnancy
Intrahepatic cholestasis of pregnancy
Synonyms: Gravidic intrahepatic cholestasis, Pregnancy-related cholestasis, Recurrent intrahepatic cholestasis of pregnancy
Synonyms: Gravidic intrahepatic cholestasis, Pregnancy-related cholestasis, Recurrent intrahepatic cholestasis of pregnancy
Synonyms: Gravidic intrahepatic cholestasis, Pregnancy-related cholestasis, Recurrent intrahepatic cholestasis of pregnancy
Drug discovery
0
drugs
With orphan designations
Overview
Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder characterized by pruritus and elevated serum bile acids, typically presenting in the third trimester. Driven by hormonal, genetic, and environmental factors, ICP increases risks of preterm labor (30–60%), fetal distress, and stillbirth (3% with bile acids ≥100 µmol/L). Management focuses on ursodeoxycholic acid, fetal monitoring, and timed delivery [1][5][7][12][15].
Burden
Maternal: Severe pruritus (99%), gestational diabetes (25.7%), preeclampsia, postpartum hemorrhage [2][6][15]
Fetal/neonatal: Preterm birth (44.5%), meconium aspiration, respiratory distress, stillbirth risk escalating with bile acids [5][7][15]
Long-term: Maternal hepatobiliary/cardiovascular risks, offspring metabolic/immune dysregulation [6][8][15]
Therapies
First-line: Ursodeoxycholic acid (10–15 mg/kg/day) to reduce pruritus and improve liver function [3][7][10][16]
Monitoring: Serial bile acid levels, liver function tests, and fetal surveillance (e.g., NSTs) [3][7][12]
Delivery: Timed at 36–39 weeks based on bile acid severity (≥100 µmol/L warrants ≤36 weeks) [3][7][12][15]
Categories: rare gynecological and obstetric diseases, rare hepatic diseases
Research Papers
666 drug discovery papers about Intrahepatic cholestasis of pregnancy, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
666 drug discovery papers about Intrahepatic cholestasis of pregnancy, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-01 | Nanocellulose Alleviates Intrahepatic Cholestasis of Pregnancy via Gut Microbiota‐Mediated Bile Acid Homeostasis (Adv. Sci. 45/2026)
Cellulose Nanofibers This cover illustration highlights a promising gut microbiota-targeted strategy for intrahepatic cholestasis of pregnancy (ICP). Dietary cellulose nanofibers (CNF) enrich beneficial microbes and modulate gut-liver farnesoid X receptor (FXR) signaling. This cascade reduces maternal systemic bile acid burdens and improves offspring survival, identifying CNF as a biosafe, translationally viable intervention for managing gestational bile acid disorders. More details can be found in the Research Article by Yuhao Zhang, Xiaojing Dong, Ting-Li Han, and co-workers (DOI: 10.1002/advs.202518337).
2026-07-29 | MOTS-c attenuates placental vascular endothelial cell apoptosis in intrahepatic cholestasis of pregnancy by inhibiting K33-linked deubiquitination of BACH1
Intrahepatic cholestasis of pregnancy (ICP) is a gestational liver disorder characterized by impaired placental vascular architecture, leading to placental dysfunction and fetal growth restriction. Our prior work demonstrated that the transcription repressor BACH1 modulates SLC25A51 expression to regulate placental injury under ICP conditions. MOTS-c, a mitochondria-originated peptide, participates in vascular homeostasis, yet its biological functions within the placental vasculature during ICP have not been fully characterized. Clinical analyses revealed significantly reduced MOTS-c protein levels in both maternal serum and placental tissues from ICP patients. In a cholic acid-induced murine model of ICP, MOTS-c administration promoted placental angiogenesis and inhibited apoptosis of placental vascular endothelial cells. These protective effects were recapitulated in vitro , where MOTS-c attenuated oxidative stress and apoptosis in human umbilical vein endothelial cells (HUVECs) exposed to taurocholic acid. Mechanistically, biotinylated MOTS-c pull-down coupled with mass spectrometry identified BACH1 as a direct binding partner; subsequent functional validation demonstrated that MOTS-c binds competitively to the D560 residue of BACH1, thereby displacing the deubiquitinase USP7 and promoting K33-linked polyubiquitination and proteasomal degradation of BACH1. Consequently, MOTS-c-mediated BACH1 depletion relieves transcriptional repression of SLC25A51, enhancing mitochondrial NAD + import, biogenesis, and redox resilience. Importantly, BACH1 overexpression abolished MOTS-c–induced protection in HUVECs, confirming the functional dependency of MOTS-c on this axis. In vivo , MOTS-c treatment in CA-induced ICP mice significantly improved key offspring developmental parameters-including birth weight, placental efficiency, and neonatal survival. Collectively, these findings establish MOTS-c as a placenta-targeted endogenous regulator that ameliorates ICP-associated placental vascular pathology and adverse perinatal outcomes via modulation of the BACH1/SLC25A51 signaling axis.
2026-07-24 | Adult-Onset BAAT p.Glu401Asp Mutation Linking Intrahepatic Cholestasis of Pregnancy to FXR-SREBP Dysregulation.
Intrahepatic cholestasis of pregnancy (ICP) affects 0.5-5.6 % of pregnancies and involves bile acid transport defects (ABCB11, ABCB4, ATP8B1). BAAT mutations classically cause neonatal familial hypercholanemia type 3 (FHCA3), with five previously identified pathogenic variants in the catalytic domains. We report a rare adult-onset homozygous BAAT missense mutation (c.1203G>T; p.Glu401Asp) in a 41-year-old Indian woman with third-trimester ICP, postpartum-persistent hypercholanemia, and severe hypertriglyceridemia. This novel BAAT substitution occurs at codon 401 (C-terminal, non-catalytic), yielding conflicting in silico predictions (CADD: 22.5 pathogenic vs. REVEL: 0.211 benign). However, classified as a Variant of Uncertain Significance, its homozygosity and phenotypic correlation support plausibility, pending family segregation, bile acid profiling, or functional assays. Proposedly unconjugated primary bile acids impair ileal FXR activation, thereby disrupting FGF19-SHP-mediated repression of SREBP-1c lipogenesis, a process compounded by insulin resistance. This case represents a rare adult BAAT-ICP association and BAAT-related FXR-SREBP dysregulation, expanding the low-GGT cholestasis spectrum per EASL guidelines. Glycocholic acid and FXR agonists may offer targeted therapies.
2026-07-22 | Mechanistic Basis and Translational Potential of Traditional Chinese Medicine in the Treatment of Cholestasis: A Narrative Review.
Cholestasis results from impaired bile formation, secretion, or flow and contributes to heterogeneous hepatobiliary disorders, including primary biliary cholangitis, primary sclerosing cholangitis, intrahepatic cholestasis of pregnancy, cholestatic drug-induced liver injury, and cholestasis-associated fibrosis. Persistent bile acid retention drives hepatocyte and cholangiocyte injury, immune activation, gut-liver axis disruption, and fibrogenesis. Traditional Chinese medicine (TCM) has been investigated as a multi-component therapeutic approach, but its evidence strength and translational readiness remain uncertain. To synthesize mechanistic, clinical, and translational evidence on TCM-based interventions for cholestasis and identify evidence gaps relevant to future development. PubMed, Web of Science Core Collection, CNKI, Wanfang, VIP, and SinoMed were searched for publications from 1 January 2016 to 25 January 2026, supplemented by backward citation chasing. A sensitivity search of CNKI, Wanfang, VIP, and SinoMed was performed to reduce language bias. Eligible studies were mapped by cholestatic condition or model, intervention type, study design, mechanistic domain, clinical relevance, and evidence strength. Eighty studies were included in the core evidence set. The evidence base was dominated by preclinical animal, in vitro, omics, pharmacokinetic, quality-control, and toxicology studies, with limited mature clinical evidence. Recurrent mechanisms involved FXR-centered bile acid homeostasis, transporter regulation, inflammatory and immune pathways, oxidative stress and regulated cell death, fibrogenic signaling, and gut-liver axis modulation. Clinical evidence was most developed for intrahepatic cholestasis of pregnancy, where adjunctive TCM plus ursodeoxycholic acid was associated with improvements in bile acids and pruritus. However, heterogeneity in formula composition, trial quality, endpoint selection, and safety reporting limits inference, particularly for maternal-fetal outcomes. Evidence for other cholestatic indications remains limited or largely preclinical. TCM provides pathway-linked therapeutic hypotheses and candidate compounds for cholestasis, but high-confidence translation requires standardized products, exposure-response characterization, causal target validation, robust safety and herb-drug interaction assessment, and adequately powered disease-specific trials using clinically meaningful endpoints.
2026-07-03 | Maternal and neonatal outcomes of intrahepatic cholestasis of pregnancy in twin pregnancies: a systematic review and meta-analysis.
Intrahepatic cholestasis of pregnancy (ICP) is linked with adverse perinatal outcomes; however, its impact in twin pregnancies remains unclear. This systematic review and meta-analysis aimed to evaluate maternal and neonatal outcomes in twin pregnancies complicated by ICP. A comprehensive search of PubMed, Embase, Web of Science, and Scopus was conducted from inception to 14 February 2026. Cohort studies comparing twin pregnancies with and without ICP were included. Random-effects meta-analyses were performed to assess maternal and neonatal outcomes reported by at least three studies. Seven retrospective cohort studies were included. ICP in twin pregnancies was associated with increased risk of cesarean delivery, preeclampsia, and gestational diabetes mellitus. Preterm birth (PTB) <37 weeks was significantly increased with ICP in both crude and adjusted analysis. Mean gestational age was significantly reduced, and birthweight was lower in ICP. ICP was strongly associated with meconium-stained amniotic fluid and increased neonatal intensive care unit (NICU) admission. However, no significant association was noted between ICP and stillbirth, small-for-gestational age and postpartum hemorrhage. ICP in twin pregnancies is associated with PTB and increased maternal and neonatal morbidity. Current evidence is derived mostly from crude data and from a limited number of studies with high inter-study heterogeneity.
2026-08-01 | Nanocellulose Alleviates Intrahepatic Cholestasis of Pregnancy via Gut Microbiota‐Mediated Bile Acid Homeostasis (Adv. Sci. 45/2026)
Cellulose Nanofibers This cover illustration highlights a promising gut microbiota-targeted strategy for intrahepatic cholestasis of pregnancy (ICP). Dietary cellulose nanofibers (CNF) enrich beneficial microbes and modulate gut-liver farnesoid X receptor (FXR) signaling. This cascade reduces maternal systemic bile acid burdens and improves offspring survival, identifying CNF as a biosafe, translationally viable intervention for managing gestational bile acid disorders. More details can be found in the Research Article by Yuhao Zhang, Xiaojing Dong, Ting-Li Han, and co-workers (DOI: 10.1002/advs.202518337).
2026-07-29 | MOTS-c attenuates placental vascular endothelial cell apoptosis in intrahepatic cholestasis of pregnancy by inhibiting K33-linked deubiquitination of BACH1
Intrahepatic cholestasis of pregnancy (ICP) is a gestational liver disorder characterized by impaired placental vascular architecture, leading to placental dysfunction and fetal growth restriction. Our prior work demonstrated that the transcription repressor BACH1 modulates SLC25A51 expression to regulate placental injury under ICP conditions. MOTS-c, a mitochondria-originated peptide, participates in vascular homeostasis, yet its biological functions within the placental vasculature during ICP have not been fully characterized. Clinical analyses revealed significantly reduced MOTS-c protein levels in both maternal serum and placental tissues from ICP patients. In a cholic acid-induced murine model of ICP, MOTS-c administration promoted placental angiogenesis and inhibited apoptosis of placental vascular endothelial cells. These protective effects were recapitulated in vitro , where MOTS-c attenuated oxidative stress and apoptosis in human umbilical vein endothelial cells (HUVECs) exposed to taurocholic acid. Mechanistically, biotinylated MOTS-c pull-down coupled with mass spectrometry identified BACH1 as a direct binding partner; subsequent functional validation demonstrated that MOTS-c binds competitively to the D560 residue of BACH1, thereby displacing the deubiquitinase USP7 and promoting K33-linked polyubiquitination and proteasomal degradation of BACH1. Consequently, MOTS-c-mediated BACH1 depletion relieves transcriptional repression of SLC25A51, enhancing mitochondrial NAD + import, biogenesis, and redox resilience. Importantly, BACH1 overexpression abolished MOTS-c–induced protection in HUVECs, confirming the functional dependency of MOTS-c on this axis. In vivo , MOTS-c treatment in CA-induced ICP mice significantly improved key offspring developmental parameters-including birth weight, placental efficiency, and neonatal survival. Collectively, these findings establish MOTS-c as a placenta-targeted endogenous regulator that ameliorates ICP-associated placental vascular pathology and adverse perinatal outcomes via modulation of the BACH1/SLC25A51 signaling axis.
2026-07-24 | Adult-Onset BAAT p.Glu401Asp Mutation Linking Intrahepatic Cholestasis of Pregnancy to FXR-SREBP Dysregulation.
Intrahepatic cholestasis of pregnancy (ICP) affects 0.5-5.6 % of pregnancies and involves bile acid transport defects (ABCB11, ABCB4, ATP8B1). BAAT mutations classically cause neonatal familial hypercholanemia type 3 (FHCA3), with five previously identified pathogenic variants in the catalytic domains. We report a rare adult-onset homozygous BAAT missense mutation (c.1203G>T; p.Glu401Asp) in a 41-year-old Indian woman with third-trimester ICP, postpartum-persistent hypercholanemia, and severe hypertriglyceridemia. This novel BAAT substitution occurs at codon 401 (C-terminal, non-catalytic), yielding conflicting in silico predictions (CADD: 22.5 pathogenic vs. REVEL: 0.211 benign). However, classified as a Variant of Uncertain Significance, its homozygosity and phenotypic correlation support plausibility, pending family segregation, bile acid profiling, or functional assays. Proposedly unconjugated primary bile acids impair ileal FXR activation, thereby disrupting FGF19-SHP-mediated repression of SREBP-1c lipogenesis, a process compounded by insulin resistance. This case represents a rare adult BAAT-ICP association and BAAT-related FXR-SREBP dysregulation, expanding the low-GGT cholestasis spectrum per EASL guidelines. Glycocholic acid and FXR agonists may offer targeted therapies.
2026-07-22 | Mechanistic Basis and Translational Potential of Traditional Chinese Medicine in the Treatment of Cholestasis: A Narrative Review.
Cholestasis results from impaired bile formation, secretion, or flow and contributes to heterogeneous hepatobiliary disorders, including primary biliary cholangitis, primary sclerosing cholangitis, intrahepatic cholestasis of pregnancy, cholestatic drug-induced liver injury, and cholestasis-associated fibrosis. Persistent bile acid retention drives hepatocyte and cholangiocyte injury, immune activation, gut-liver axis disruption, and fibrogenesis. Traditional Chinese medicine (TCM) has been investigated as a multi-component therapeutic approach, but its evidence strength and translational readiness remain uncertain. To synthesize mechanistic, clinical, and translational evidence on TCM-based interventions for cholestasis and identify evidence gaps relevant to future development. PubMed, Web of Science Core Collection, CNKI, Wanfang, VIP, and SinoMed were searched for publications from 1 January 2016 to 25 January 2026, supplemented by backward citation chasing. A sensitivity search of CNKI, Wanfang, VIP, and SinoMed was performed to reduce language bias. Eligible studies were mapped by cholestatic condition or model, intervention type, study design, mechanistic domain, clinical relevance, and evidence strength. Eighty studies were included in the core evidence set. The evidence base was dominated by preclinical animal, in vitro, omics, pharmacokinetic, quality-control, and toxicology studies, with limited mature clinical evidence. Recurrent mechanisms involved FXR-centered bile acid homeostasis, transporter regulation, inflammatory and immune pathways, oxidative stress and regulated cell death, fibrogenic signaling, and gut-liver axis modulation. Clinical evidence was most developed for intrahepatic cholestasis of pregnancy, where adjunctive TCM plus ursodeoxycholic acid was associated with improvements in bile acids and pruritus. However, heterogeneity in formula composition, trial quality, endpoint selection, and safety reporting limits inference, particularly for maternal-fetal outcomes. Evidence for other cholestatic indications remains limited or largely preclinical. TCM provides pathway-linked therapeutic hypotheses and candidate compounds for cholestasis, but high-confidence translation requires standardized products, exposure-response characterization, causal target validation, robust safety and herb-drug interaction assessment, and adequately powered disease-specific trials using clinically meaningful endpoints.
2026-07-03 | Maternal and neonatal outcomes of intrahepatic cholestasis of pregnancy in twin pregnancies: a systematic review and meta-analysis.
Intrahepatic cholestasis of pregnancy (ICP) is linked with adverse perinatal outcomes; however, its impact in twin pregnancies remains unclear. This systematic review and meta-analysis aimed to evaluate maternal and neonatal outcomes in twin pregnancies complicated by ICP. A comprehensive search of PubMed, Embase, Web of Science, and Scopus was conducted from inception to 14 February 2026. Cohort studies comparing twin pregnancies with and without ICP were included. Random-effects meta-analyses were performed to assess maternal and neonatal outcomes reported by at least three studies. Seven retrospective cohort studies were included. ICP in twin pregnancies was associated with increased risk of cesarean delivery, preeclampsia, and gestational diabetes mellitus. Preterm birth (PTB) <37 weeks was significantly increased with ICP in both crude and adjusted analysis. Mean gestational age was significantly reduced, and birthweight was lower in ICP. ICP was strongly associated with meconium-stained amniotic fluid and increased neonatal intensive care unit (NICU) admission. However, no significant association was noted between ICP and stillbirth, small-for-gestational age and postpartum hemorrhage. ICP in twin pregnancies is associated with PTB and increased maternal and neonatal morbidity. Current evidence is derived mostly from crude data and from a limited number of studies with high inter-study heterogeneity.
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