Intrahepatic Cholestasis of Pregnancy

Contributor: Andy Lane, MD

Updated: 10/09/21

Definition: unexplained pruritus and elevated bile acids (BA) with resolution after delivery

Background:

• Incidence:3 – 0.5% of pregnancies in the US (5% in Hispanic women)
• Etiology: likely a combination of genetic susceptibility, hormonal factors, and environmental factors
• Risk Factors: hx ICP, FHx, multifetal gestations, IVF, AMA, pre-existing liver disease (including Hep C)
• Recurrence: 50%
• Pathophysiology:
  • Transport of bile acids from the liver → gallbladder → intestine for excretion is interrupted → compensatory transport of bile acids to the blood → ↑ bile acids → pruritus
  • Bile acids are cytotoxic, transported across the placenta, and can accumulate in the fetal compartment
• Pregnancy complications: SPTB (15-44%), meconium (25-45%), NRFHT (5-15%), IUFD (1.2%)
  • BA > 40 = ↑ risk of IUFD (1.5%), PTB, neonatal asphyxia, RDS, meconium-stained amniotic fluid
  • BA > 100 = ↑↑↑ risk of IUFD (10-15%)

Differential Diagnosis:

• Pregnancy related causes of ↑ transaminases – pre-e, HELLP, AFLP
• Pregnancy related cause of pruritus – pruritus gravidarum (most common), ICP, atopic eruption of pregnancy, polymorphic eruption of pregnancy, pemphigoid gestationis
  • Pruritus affects 23% of pregnancies
• Causes of pruritis w/o a rash – medication side effect, Hep A/B/C/liver disease, gallstones, tumors of the hepatobiliary tract, chronic renal failure, hypo/hyperthyroidism, HIV, malabsorption, parasitosis, Hodgkin disease, leukemia, non-Hodgkin lymphoma, polycythemia vera, MS, psychiatric disease (anxiety, depression, OCD)
• Causes of ↑ BA – medication side effect (Phenergan, Compazine, ampicillin, Bactrim), primary biliary or sclerosing cholangitis, obstructive bile duct lesion, liver tumor, EBV/CMV infection, autoimmune hepatitis, cirrhosis, Crohn disease

Diagnosis:

• Otherwise-unexplained pruritus AND elevated bile acids (> 10 mmol/L)
  • Random (non-fasting) samples are acceptable
  • If results are borderline (ex. 11) and the clinical presentation does not suggest ICP, may consider (not required) repeating while fasting and also assessing for other causes in the differential
    • Do not start Actigall
    • If repeat level is still elevated and an alternative diagnosis can’t be made, then the patient should be diagnosed with ICP
  • Presumptive diagnosis may be made at > 37w0d with high clinical suspicion, ↑ LFTs, normal BA
    • ↑ LFTs and pruritus can predate ↑ bile acids by as much as 3 weeks

Signs/Symptoms:

• Common – severe/intolerable pruritus, typically after 30 weeks, typically worse at night, typically widespread with most severe symptoms in the palms of the hands and soles of feet
• Less common – mild jaundice (14-25%), insomnia, fatigue, anorexia, malaise, weight loss, epigastric discomfort, steatorrhea (fatty stool), gallstones, cholecystitis, Vit K def, dark urine

Physical Exam:

• Scratch marks and excoriations, but no primary lesions
• Jaundice (14-25%)

Labs: bile acids and CMP with ↑ transaminases (60%, usually < 2x ULN), ↑ alk phos (25%, up to 4x), ↑ bilirubin (25%, total and direct bilirubin))

Medical Management

• Actigall (ursodeoxycholic acid, ursodiol)
  • Actigall is the treatment of choice as it relieves pruritus, ↓ BA and LFTs, and has no known fetal/neonatal toxicity
  • Conflicting data concerning protection against stillbirth
  • If started empirically, ↑ bile acid and transaminase levels may never be detected
  • Mechanism of action: hydrophilic bile acid → inhibits intestinal absorption of other bile acids, ↑ hepatocyte excretory function and choleretic activity, stabilizes hepatic cell membranes, dilutes toxic bile acids in enterohepatic circulation, may also allow for transport of bile acids out of the fetal compartment
  • Dose: 300 mg TID up to total of 2g/day
  • Adverse effects (<25%): HA, diarrhea, constipation
  • Compared to placebo: ↓ pruritus, bile acids, transaminases, PTB
  • Compared to other medications: ↓ pruritus (61% have improvement, 42% have resolution, 1-2 wks), ↓ bile acids (3-4 wks), ↓ transaminases
• Hydroxyzine
  • Central and peripheral histamine-1 antagonist
  • Improves tolerance to persistent itching (through sedation)
  • Dose: 25-100 mg q 6 hrs PRN
• Over the Counter
  • Calamine lotion or aqueous cream w/ menthol (ex. Gold Bond medicated lotion)

Antenatal Fetal Testing:

• The efficacy of antepartum testing to prevent stillbirth is unknown
  • Mechanism of IUFD thought to be a sudden event, rather than a chronic placental process
  • Early delivery is the only known evidence-based intervention that ↓ the risk of stillbirth
• We recommend daily kick counts and antenatal testing based on standard of care at most institutions
  • Bile acids < 40 – weekly testing (NST, BPP, or modified BPP) starting at 32 weeks
  • Bile acids > 40 – 2x weekly testing started by 28 weeks
    • Individualize after counseling, starting gestational age can be as early as viability

Delivery Timing: See chart below.

Late Preterm Corticosteroids

• Consider with planned deliveries at 34+0 – 36+6 weeks if patient has not previously received them and there are no contraindications.
• Do not delay an indicated delivery for late preterm corticosteroid administration

Postpartum:

• Pruritus usually disappears within several days
• Check BA and CMP at postpartum visit if there are continued symptoms and refer to GI if abnormal
• Contraception
  • Combination OCPs may cause a recurrence of cholestasis outside of pregnancy; however, CDC states that using OCPs is appropriate if absence of history of ICP related to OCP use

Before starting OCPs, confirm resolution and counsel on prompt discontinuation if symptoms develop

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References

1. SMFM Consults Series #53: Intrahepatic cholestasis of pregnancy. 2021.
2. ACOG Committee Opinion #818: Medically Indicated Late-Preterm and Early-Term Deliveries. 2021.
3. Maternal-Fetal Evidence Based Guidelines. 3rd ed. Chapter 10: Intrahepatic cholestasis of pregnancy.
4. Creasy and Resnik’s Maternal-Fetal Medicine. 7th ed. Chapter 63: Diseases of the liver, biliary system, and pancreas.
5. Geenes V, et al. Association of severe intrahepatic cholestasis of pregnancy with adverse pregnancy outcomes: a prospective population-based case-control study. Hepatology. 2014; 59(4): 1482-91.
6. Browers L, et al. Intrahepatic cholestasis of pregnancy: maternal and fetal outcomes associated with elevated bilce acid levels. AJOG. 2015; 212(1): 100e1-7.
7. Kawakita T, et al. Predictors of adverse neonatal outcomes in intrahepatic cholestasis of pregnancy. AJOG. 2015; 213(4):570 e1-8.
8. Kenyon AP, et al. Pruritus in pregnancy: a study of anatomical distribution and prevalence in relation to the development of obstetric cholestasis. Obstetric Med. 2010; 3(1):25-9.