Basics
Description
- Typically a benign cholestatic disorder in the mother
- Associated with fetal complications
- Meconium staining
- Preterm delivery
- Intrapartum fetal distress
- Intrauterine fetal demise
- Resolves promptly after delivery
Epidemiology
- Cases reported from all over the world; however, significant geographic variations exist in incidence and prevalence.
- Occurs in women of all ages
Incidence
- Incidence varies by country and ethnicity
- Rare in North America, Asia, and Australia (<1% of births)
- Highest incidence reported in Chile " Bolivia (6 " 27% of births)
- Native Araucanian Indians of Chile most affected
- Second highest incidence reported in Sweden (2% of births)
- Incidence also varies by season.
- Highest rates reported in November
Prevalence
- Less than 1% in North America, UK, Asia, and Australia
- 1 " 1.5% in Scandinavia
- 15.6% in Chile " Bolivia
- Prevalence may be decreasing in Chile for unclear reasons.
Risk Factors
- Multiparity
- Advanced maternal age
- Twin gestation
- Personal history of cholestasis on oral contraceptives
- Family history of cholestasis of pregnancy
Genetics
- Genetic predisposition suggested by high incidence of disease in certain ethnic groups
- The ABCB4 (adenosine triphosphate-binding cassette, subfamily B, member 4) gene encoding the multidrug resistance 3 (MDR3) protein has been implicated.
- MDR3 codes for a canalicular phospholipid transporter.
- Heterozygosity for MDR3 gene defect may predispose women to disease development.
- Genes encoding other canalicular transporters or their regulators may also be involved.
General Prevention
- Ursodeoxycholic acid (UDCA) to modify bile acid pool and decrease distribution of bile acids in fetal circulation
- Delivery when fetal maturity has been achieved to avoid late fetal death
Pathophysiology
Defect in biliary excretion of steroid metabolites may result in saturation of hepatic transporters and injure the canalicular membrane leading to cholestasis.
Etiology
- Likely multifactorial
- Environmental factors
- Low serum selenium levels in affected women may account for geographic and seasonal variation.
- Estrogen effects
- Estrogen is known to produce cholestasis in experimental and clinical conditions.
- Affected women may have exaggerated response to the high levels of estrogen during pregnancy.
- Progesterone effects
- Affected women have elevated levels of progesterone metabolites which may saturate hepatic transport systems.
- Exogenous progesterone given to delay premature delivery found to trigger disease development.
- Genetic defects
Diagnosis
- Diagnosis relies on clinical history, including the timing of gestation, and laboratory studies.
- Primary symptom is severe pruritus.
- Mostly involves hands and feet
- May extend to trunk, extremities, eyelids, and rarely the oral cavity
- Worse at night
- Can cause sleep deprivation leading to psychological distress
- Jaundice
- Occurs in only 10 " 20% of cases
- Develops after onset of pruritus
- Nausea/vomiting
- Steatorrhea
- Anorexia
- Poor weight gain
History
- Inquire about nature of pruritus
- Time of onset
- Usually begins during the second or third trimesters but cases have been reported in first trimester
- Distribution
- Intolerability
- Has been associated with suicidal ideation
- Obtain family history
- Obtain medication history
Physical Exam
- Generally benign
- Skin exam
- May see evidence of excoriation
- Jaundice, if present, is mild.
Tests
Mainly noninvasive testing to make diagnosis
Lab
- Most sensitive abnormality is elevated fasting serum bile acids.
- May be elevated 10 " 25-fold in affected women
- Risk of fetal complications highest when bile acids are ≥40 Όmol/L
- Conjugated bile acids, especially cholic acid, are elevated.
- Affected women have marked elevation of the cholic/chenodeoxycholic acid ratio compared to pregnant women without ICP.
- Bilirubin usually normal
- If elevated, usually does not exceed 6 times the upper limit of normal (ULN)
- Transaminases elevated
- May be 2 " 10 times above the ULN
- Alkaline phosphatase levels difficult to interpret
- Physiologically increased due to placental production to 2 " 3 times above the ULN
- GGT normal or modestly elevated
- PT normal or elevated
- If elevated, due to vitamin K deficiency rather than hepatic dysfunction
- Women with suspected cholestasis of pregnancy should be screened for chronic hepatitis (especially hepatitis C).
Surgery
Liver biopsy rarely necessary for diagnosis
Pathological Findings
- Bland cholestasis
- Bile plugs in hepatocytes and canaliculi without surrounding inflammation
- No signs of biliary obstruction
- Occurs predominantly in centrilobular regions
- Portal tracts normal
Differential Diagnosis
- Viral hepatitis
- Consider when transaminases >1,000
- Biliary obstruction
- Primary biliary cirrhosis
- Primary sclerosing cholangitis
- Drug-induced hepatotoxicity
- Benign recurrent intrahepatic cholestasis
Treatment
Goals of treatment are improvement of maternal symptoms and fetal outcomes.
Medication
Several medications have been used to treat pruritus with no significant improvement in biochemical profile or fetal outcome (e.g.antihistamines benzodiazepines, phenobarbital).
First Line
- UDCA (1)[A]
- Modifies bile acid pool and displaces toxic bile acids from hepatic membranes
- Recommended dose is 15 mg/kg/day divided in 2 doses.
- FDA category B
Second Line
- Cholestyramine (2)[A]
- Binds bile acids in the intestine and increases bile acid excretion in feces
- Improves pruritus but does not improve biochemical profile or fetal outcome
- Prolonged use can cause vitamin K malabsorption and worsen coagulopathy.
- Recommended dose is 8 " 16 g/day.
- FDA category C
- Hydroxyzine (2)[B]
- Antihistamine that helps relieving itching
- Recommended dose is 25 " 50 mg/day.
- FDA category C
Additional Treatment
General Measures
- Manage aggressively to decrease poor fetal outcomes (1)[B]
- Close fetal surveillance
- Medication to lower bile acids
- Delivery after fetal lung maturity
- Delivery is curative.
- Timing of delivery depends on severity of maternal symptoms, gestational age, and presence of fetal distress.
- Patients should be delivered by 38 weeks, or if cholestasis is severe by 36 weeks if fetal lung maturity can be achieved (1)[C].
Issues for Referral
- Bilirubin or transaminases elevated above expected range
- Refer to gastroenterology to evaluate for other causes of LFT abnormalities in pregnancy
Additional Therapies
- Obstetric management
- Must be prepared to terminate pregnancy in severe cases to prevent intrauterine death
- Can give antenatal steroids to promote fetal lung maturity
Complementary and Alternative Medicine
- S-adenosyl methionine (SAMe) (2)[C]
- Has been shown in some studies to decrease pruritus, bile acids level, and aminotransferase levels
- More studies needed
Surgery
- Cesarean section
- Recommended in cases of fetal distress, heavy meconium staining of amniotic fluid
In-Patient Considerations
Initial-Stabilization
- Evaluate for fetal distress and fetal lung maturity
- Nonstress test
- Amniocentesis
Admission Criteria
- Fetal distress requiring emergent delivery
- Maternal coagulopathy requiring administration of IV vitamin K or fresh frozen plasma
IV Fluids
- May be mild to moderately dehydrated due to associated nausea and vomiting
- Administer normal saline as needed
Discharge Criteria
- Maternal symptoms resolved
- Fetal stability
- Successful delivery
Ongoing Care
Follow-Up Recommendations
Patient Monitoring
- Monitor patient every 2 " 4 weeks
- Assess severity of symptoms
- Follow fasting serum bile acid levels
- Assess psychological well-being
- Be aware that suicide has been reported in severe cases
- Monitor fetus weekly especially near term
- Weekly nonstress test (NST)
- Check LFTs several months after delivery to screen for underlying liver disease
Prognosis
- No long-term sequelae in most women
- Symptoms and lab abnormalities resolve 1 " 2 weeks after delivery.
- Recurrence common in subsequent pregnancies (40 " 60%)
- Some women have underlying liver disease (e.g., hepatitis C, nonalcoholic fatty liver disease) for which they need follow-up.
Complications
- Postpartum hemorrhage
- Due to malabsorption of fat-soluble vitamins especially when cholestyramine used
- Give prophylactic vitamin K to all patients
- Cholelithiasis
- 2.7-fold risk of postpartum gallstone formation in primiparous women
References
1Sandhu BS, Sanyal AJ. Pregnancy and liver disease. Gastroenterol Clin N Am. 2003;32:407 " 436. [View Abstract]2Riely CA, Bacq Y. Intrahepatic cholestasis of pregnancy. Clin Liver Dis. 2004;8:167 " 176. [View Abstract]
Additional Reading
1Benjaminov FS, Heathcote J. Liver disease in pregnancy. Am J Gastroenterol. 2004;99:2479 " 2488. [View Abstract]2Doshi S, Zucker SD. Liver emergencies during pregnancy. Gastroenterol Clin N Am. 2003;32:1213 " 1227. [View Abstract]3Glantz A, Marschall H-U, Mattson L-A. Intrahepatic cholestasis of pregnancy: Relationships between bile acid levels and fetal complication rates. Hepatology. 2004;40:467 " 474. [View Abstract]4Riely CA, Davila R. Pregnancy related hepatic and gastrointestinal disorders. In: Feldman M, ed. Sleisenger & Fordtran 's gastrointestinal and liver disease, 7th ed. St. Louis: WB Saunders, 2002:1448 " 1449.5Ropponen A, Sund R, Riikonen S. Intrahepatic cholestasis of pregnancy as an indicator of liver and biliary diseases: A population-based study. Hepatology. 2006;43:723 " 728. [View Abstract]6Wakim-Fleming J, Zein NN. The liver in pregnancy: Disease vs benign changes. Cleveland Clin J Med. 2005;72:713 " 727. [View Abstract]
Codes
ICD9
646.70 Liver and biliary tract disorders in pregnancy, unspecified as to episode of care or not applicable
ICD10
O26.619 Liver and biliary tract disord in pregnancy, unsp trimester
SNOMED
235888006 cholestasis of pregnancy (disorder)
Clinical Pearls
- Disorder of second and third trimesters of pregnancy
- Prompt diagnosis and treatment improves maternal symptoms and fetal outcomes.
- Likely to recur with subsequent pregnancies