Intrahepatic cholestasis of pregnancy (ICP) in depth: pathomechanisms, clinical management and evidence-based practice
Intrahepatic cholestasis of pregnancy (ICP) is a liver disease characterized by pruritus and elevated bile acids in mid- to late-gestation, which can lead to severe perinatal complications. The following is a systematic description of the clinical management of ICP from five dimensions: pathophysiologic mechanisms, diagnostic criteria, risk stratification, treatment strategies and fetal monitoring.
I. Pathophysiologic mechanism and risk factors
Hormone metabolism imbalance
Elevated estrogen levels inhibit hepatocyte membrane transport proteins (e.g., BSEP, MDR3), resulting in impaired bile acid excretion (normal bile acid excretion <10 μmol/L); Progesterone metabolites (e.g., allopregnanolone) enhance the hepatotoxic effects of estrogen, inducing bile acid reflux into the blood (total bile acid TBA >10 μmol/L is abnormal).
Genetic susceptibility
Mutations in the ABCB11 gene (encoding the BSEP protein) cause familial ICP with a 60-90% risk of recurrence;
Preterm birth rate is increased 3-fold in those with defects in the MDR3 gene (ABCB4) (NEJM study data).
Environmental and Nutritional Factors
Elevated winter morbidity associated with selenium deficiency (4-fold increased risk of ICP with serum selenium <70 μg/L); High-fat diet exacerbates cholestasis (30% increase in TBA with saturated fatty acid intake >13% of total calories).
II. Clinical manifestations and diagnostic criteria
Symptomatic features
Pruritic pattern:
First on palms and metatarsals (70% of cases), worsening at night (cortisol circadian rhythm effect);
No primary lesions, but may be accompanied by scratching (itch score VAS ≥ 7 needs to be alerted to ICP).
Jaundice: incidence 20-25%, scleral yellowing seen with total bilirubin >1.2 mg/dL.
Laboratory diagnosis
Core indicators: fasting serum total bile acids (TBA) ≥10 μmol/L (sensitivity 95%);
Auxiliary indicators: ALT>40 U/L (elevated in 70% of cases), AST/ALT ratio <1.2;
Differential diagnosis: exclude viral hepatitis (anti-HAV IgM negative), acute fatty liver of pregnancy (platelets <100×10^9/L).
III. Perinatal risk stratification and early warning
Fetal Adverse Outcome Prediction Models
TBA threshold:
TBA 40-99 μmol/L: 1.5% risk of stillbirth;
TBA ≥100 μmol/L: stillbirth risk increased to 6.8% (Lancet study data).
Gestational week association: 3-fold increased incidence of fetal distress with TBA ≥40 μmol/L after 34 weeks of gestation.
Placental pathologic changes
Narrowing of the intervillous space due to bile acid deposition (30-50% reduction in the chorionic gap);
Increased apoptosis of syncytiotrophoblasts and 40% decrease in placental perfusion (ultrasound Doppler S/D ratio >3.0).
IV. Treatment strategy and drug selection
First-line treatment options
Ursodeoxycholic acid (UDCA):
Dose: 15 mg/kg/d orally in three divided doses (e.g., 900 mg daily in 60 kg patients);
Mechanism: activation of FXR nuclear receptors promotes bile acid efflux and reduces TBA by 50-70% (confirmed in GUT study);
Safety: FDA pregnancy category B, does not cross the placental barrier.
Adjuvant Therapy
Bile acid-lowering combination: 25% improvement in pruritus relief with SAM-e (1600 mg/d) in combination with UDCA;
Symptomatic management:
Nocturnal pruritus: loratadine 10 mg orally at bedtime (pregnancy category B);
Skin care: menthol lotion (0.5-2%) cold compresses to reduce VAS score by 2-3 points.
Nutritional interventions
Vitamin K1 10 mg/d intramuscularly (necessary to prevent postpartum hemorrhage and for PT prolongation >15 seconds);
High selenium diet (Brazil nuts, oysters) to raise serum selenium levels to 100-120 μg/L.
V. Fetal monitoring and timing of termination of pregnancy
Monitoring program
Fetal movement count: <10 movements/2 hours requires immediate NST; Fetal heart rate monitoring: NST twice weekly from 32 weeks of gestation (abnormality defined as baseline variation <5 bpm for 40 minutes); Ultrasound evaluation: weekly BPP (amniotic fluid index 95th percentile suggestive of hypoxia). Labor and Delivery Decision Making Termination indications: TBA ≥40 μmol/L: Elective induction of labor is recommended at 36-37 weeks of gestation; TBA ≥100 μmol/L or fetal growth restriction: immediate termination of pregnancy (ACOG guidelines). Mode of delivery: Vaginal delivery preferred (continuous CTG monitoring during labor); Indication for cesarean section: acute fetal distress (fetal heart rate <100 bpm for 3 minutes). VI. Postpartum management and recurrence prevention Maternal recovery Review of TBA 48 hours postpartum (reduced to normal in 90% of cases); Polyene phosphatidylcholine 456 mg tid orally for those with abnormal liver function (ALT>100 U/L).
Long-term risks
Increased risk of cirrhosis (OR=3.2), 6 months postpartum liver fibrosis scan (FibroScan) recommended;
Recurrence rate of 60-70% with another pregnancy, pre-pregnancy testing for ABC gene mutations is required.
Summarize
The management of ICP should follow the principle of “early diagnosis, strict monitoring and timely termination”. Through standardized treatment of UDCA, intensive fetal monitoring and precise timing of delivery, perinatal mortality can be reduced from 3.5% to 0.7%. Clinicians should be alert to complaints of nocturnal itching and implement preconception genetic counseling for high-risk groups (multiple births, history of ICP) in order to achieve optimal outcomes for mother and child safety.
