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Pregnancy, Cholestasis

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Pregnancy, Cholestasis

Basics

Description

Defect in biliary excretion of steroid metabolites may result in saturation of hepatic transporters and injure the canalicular membrane leading to cholestasis.

Mainly noninvasive testing to make diagnosis

Liver biopsy rarely necessary for diagnosis

Goals of treatment are improvement of maternal symptoms and fetal outcomes.

Several medications have been used to treat pruritus with no significant improvement in biochemical profile or fetal outcome (e.g.antihistamines benzodiazepines, phenobarbital).

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]

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]

646.70 Liver and biliary tract disorders in pregnancy, unspecified as to episode of care or not applicable

O26.619 Liver and biliary tract disord in pregnancy, unsp trimester

  • Typically a benign cholestatic disorder in the mother
  • Associated with fetal complicationsMeconium stainingPreterm deliveryIntrapartum fetal distressIntrauterine fetal demise
  • Resolves promptly after delivery
  • Meconium staining
  • Preterm delivery
  • Intrapartum fetal distress
  • Intrauterine fetal demise

Epidemiology

  • Cases reported from all over the world; however, significant geographic variations exist in incidence and prevalence.
  • Occurs in women of all ages
  • Incidence varies by country and ethnicityRare 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 affectedSecond highest incidence reported in Sweden (2% of births)
  • Incidence also varies by season.Highest rates reported in November
  • 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)
  • Native Araucanian Indians of Chile most affected
  • Highest rates reported in November
  • Less than 1% in North America, UK, Asia, and Australia
  • 1 " “1.5% in Scandinavia
  • 15.6% in Chile " “BoliviaPrevalence may be decreasing in Chile for unclear reasons.
  • 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
  • Genetic predisposition suggested by high incidence of disease in certain ethnic groupsThe 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.
  • 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.
  • MDR3 codes for a canalicular phospholipid transporter.
  • Heterozygosity for MDR3 gene defect may predispose women to disease development.

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

Etiology

  • Likely multifactorialEnvironmental factorsLow serum selenium levels in affected women may account for geographic and seasonal variation.Estrogen effectsEstrogen 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 effectsAffected 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
  • Environmental factorsLow serum selenium levels in affected women may account for geographic and seasonal variation.
  • Estrogen effectsEstrogen 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 effectsAffected 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
  • Low serum selenium levels in affected women may account for geographic and seasonal variation.
  • 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.
  • 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.

Diagnosis

  • Diagnosis relies on clinical history, including the timing of gestation, and laboratory studies.
  • Primary symptom is severe pruritus.Mostly involves hands and feetMay extend to trunk, extremities, eyelids, and rarely the oral cavityWorse at nightCan cause sleep deprivation leading to psychological distress
  • JaundiceOccurs in only 10 " “20% of casesDevelops after onset of pruritus
  • Nausea/vomiting
  • SteatorrheaMay be subclinical
  • Anorexia
  • Poor weight gain
  • Mostly involves hands and feetMay extend to trunk, extremities, eyelids, and rarely the oral cavity
  • Worse at nightCan cause sleep deprivation leading to psychological distress
  • May extend to trunk, extremities, eyelids, and rarely the oral cavity
  • Can cause sleep deprivation leading to psychological distress
  • Occurs in only 10 " “20% of cases
  • Develops after onset of pruritus
  • May be subclinical

History

  • Inquire about nature of pruritusTime of onsetUsually begins during the second or third trimesters but cases have been reported in first trimesterDistributionIntolerability
  • Has been associated with suicidal ideation
  • Obtain family history
  • Obtain medication history
  • Time of onsetUsually begins during the second or third trimesters but cases have been reported in first trimester
  • Distribution
  • Intolerability
  • Usually begins during the second or third trimesters but cases have been reported in first trimester

Physical Exam

  • Generally benign
  • Skin examMay see evidence of excoriationJaundice, if present, is mild.
  • May see evidence of excoriation
  • Jaundice, if present, is mild.

Tests

  • Most sensitive abnormality is elevated fasting serum bile acids.May be elevated 10 " “25-fold in affected womenRisk of fetal complications highest when bile acids are ≥40 Ž Όmol/LConjugated 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 normalIf elevated, usually does not exceed 6 times the upper limit of normal (ULN)
  • Transaminases elevatedMay be 2 " “10 times above the ULN
  • Alkaline phosphatase levels difficult to interpretPhysiologically increased due to placental production to 2 " “3 times above the ULN
  • GGT normal or modestly elevated
  • PT normal or elevatedIf 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).
  • May be elevated 10 " “25-fold in affected womenRisk of fetal complications highest when bile acids are ≥40 Ž 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.
  • Risk of fetal complications highest when bile acids are ≥40 Ž Όmol/L
  • Affected women have marked elevation of the cholic/chenodeoxycholic acid ratio compared to pregnant women without ICP.
  • If elevated, usually does not exceed 6 times the upper limit of normal (ULN)
  • May be 2 " “10 times above the ULN
  • Physiologically increased due to placental production to 2 " “3 times above the ULN
  • If elevated, due to vitamin K deficiency rather than hepatic dysfunction
  • Bland cholestasisBile plugs in hepatocytes and canaliculi without surrounding inflammationNo signs of biliary obstructionOccurs predominantly in centrilobular regions
  • Portal tracts normal
  • Bile plugs in hepatocytes and canaliculi without surrounding inflammation
  • No signs of biliary obstruction
  • Occurs predominantly in centrilobular regions

Differential Diagnosis

  • Viral hepatitisConsider when transaminases >1,000
  • Biliary obstruction
  • Primary biliary cirrhosis
  • Primary sclerosing cholangitis
  • Drug-induced hepatotoxicity
  • Benign recurrent intrahepatic cholestasis
  • Consider when transaminases >1,000

Treatment

Medication

  • UDCA (1)[A]Modifies bile acid pool and displaces toxic bile acids from hepatic membranesRecommended dose is 15 mg/kg/day divided in 2 doses.FDA category B
  • 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
  • Cholestyramine (2)[A]Binds bile acids in the intestine and increases bile acid excretion in fecesImproves pruritus but does not improve biochemical profile or fetal outcomeProlonged 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 itchingRecommended dose is 25 " “50 mg/day.FDA category C
  • 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
  • Antihistamine that helps relieving itching
  • Recommended dose is 25 " “50 mg/day.
  • FDA category C

Additional Treatment

  • Manage aggressively to decrease poor fetal outcomes (1)[B]Close fetal surveillanceMedication to lower bile acidsDelivery 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].
  • Close fetal surveillance
  • Medication to lower bile acids
  • Delivery after fetal lung maturity
  • 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].
  • Patients should be delivered by 38 weeks, or if cholestasis is severe by 36 weeks if fetal lung maturity can be achieved (1)[C].
  • Bilirubin or transaminases elevated above expected rangeRefer to gastroenterology to evaluate for other causes of LFT abnormalities in pregnancy
  • Refer to gastroenterology to evaluate for other causes of LFT abnormalities in pregnancy
  • Obstetric managementMust be prepared to terminate pregnancy in severe cases to prevent intrauterine deathCan give antenatal steroids to promote fetal lung maturity
  • Must be prepared to terminate pregnancy in severe cases to prevent intrauterine deathCan give antenatal steroids to promote fetal lung maturity
  • 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 levelsMore studies needed
  • Has been shown in some studies to decrease pruritus, bile acids level, and aminotransferase levels
  • More studies needed

Surgery

  • Cesarean sectionRecommended in cases of fetal distress, heavy meconium staining of amniotic fluid
  • Recommended in cases of fetal distress, heavy meconium staining of amniotic fluid

In-Patient Considerations

  • Evaluate for fetal distress and fetal lung maturityNonstress testAmniocentesis
  • Nonstress test
  • Amniocentesis
  • Fetal distress requiring emergent delivery
  • Maternal coagulopathy requiring administration of IV vitamin K or fresh frozen plasma
  • May be mild to moderately dehydrated due to associated nausea and vomitingAdminister normal saline as needed
  • Administer normal saline as needed
  • Maternal symptoms resolved
  • Fetal stability
  • Successful delivery

Ongoing Care

Follow-Up Recommendations

  • Monitor patient every 2 " “4 weeksAssess severity of symptomsFollow fasting serum bile acid levelsAssess psychological well-beingBe aware that suicide has been reported in severe cases
  • Monitor fetus weekly especially near termWeekly nonstress test (NST)
  • Check LFTs several months after delivery to screen for underlying liver disease
  • Assess severity of symptoms
  • Follow fasting serum bile acid levels
  • Assess psychological well-beingBe aware that suicide has been reported in severe cases
  • Be aware that suicide has been reported in severe cases
  • Weekly nonstress test (NST)

Prognosis

  • No long-term sequelae in most womenSymptoms 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.
  • Symptoms and lab abnormalities resolve 1 " “2 weeks after delivery.

Complications

  • Postpartum hemorrhageDue to malabsorption of fat-soluble vitamins especially when cholestyramine usedGive prophylactic vitamin K to all patients
  • Cholelithiasis2.7-fold risk of postpartum gallstone formation in primiparous women
  • Due to malabsorption of fat-soluble vitamins especially when cholestyramine usedGive prophylactic vitamin K to all patients
  • Give prophylactic vitamin K to all patients
  • 2.7-fold risk of postpartum gallstone formation in primiparous women

References

Additional Reading

Codes

ICD9

ICD10

SNOMED

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