Download Cholestasis of Pregnancy

CHOLESTASIS OF
PREGNANCY
Sean Heinz
Epidemiology
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Prevalence varies throughout the world
 Influenced
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by genetic and environmental factors
0.7% in multiethnic populations
Highest rates in South America, especially Chile and
among Indigenous South Americans (5%
prevalence)
Overall, incidence appears to be increasing (?
attributable to increased awareness and therefore
increased case ascertainment (esp mild cases))
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Mortality actually declining
Aetiology and Pathogenesis
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Multifactorial pathogenesis – incompletely understood
Cholestatic effect of oestrogen – mechanism unclear
May disrupt membrane transport mechanisms in the hepatocytes and bile ducts 
altered cholesterol:phospholipid ratio)
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Most commonly presents in the third trimester
Resembles a condition caused by taking the OCP
More common in twin pregnancies (increased sensitivity to oestrogen)
Symptoms quickly resolve after delivery
No evidence of placental insufficiency/fetal growth restriction/oligo not
features. UA dopplers not different
Genetics: family history in 33-50%; suggestions of autosomal
dominant inheritance pattern
45-90% recurrence, increased risk in multiple pregnancy, Hep C,
cholelithiasis.
Clinical Features
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Main symptom: severe pruritis, usually in third
trimester
 Typically
develops on soles of feet and palms of hands,
spreading to the trunk and limbs; worse at night
 Cause of pruritis unknown
 One theory has implicated the deposition of bile acids
and subsequent histamine release
 Absence of rash (excoriations may be present)
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Other signs: dark urine, pale stools, anorexia,
steatorrhoea and, rarely, jaundice.
Associated risks
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Maternal – disrupted absorption of fat-soluble vitamins (vitamin K) 
depletion of vitamin K-dependent clotting factors  increased rate of PPH
(if prolonged PT, 5-10mg OD water-soluble vit k)
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Sleep deprivation/intense puritis (affects 23% preg.)
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Only possible “rash” is dermatographia artefacta/excoriations
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NOT Eczema/Atopic eruption of pregnancy/PUPPPs/Pemphigoid Gestationis
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Foetal – increased risk of:
Intrauterine death, especially after 37 weeks (undetermined risk, likely
to be small)
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5-10/1000 (perinatal mortality)
Spontaneous preterm delivery (4-12%, only slightly higher than
general)/iatrogenic preterm birth (7-25%)
Intrapartum events – passage of meconium (25%, more common with
severe (BA>40)) and intrapartum fetal distress (12-22%)
Intracranial hemorrhage, secondary to vitamin K deficiency
The mechanisms of foetal implications are unclear
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One theory postulates a direct toxic effect from bile acids crossing the placenta and
disrupting fetal physiology (bile acids may have a direct vasospastic effect on the
placental circulation).
Differentials
1) Gall stones with extrahepatic obstruction.
2) Acute or chronic viral hepatitis (Hepatitis A, B, C, EBV, CMV)
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Requires thorough Hx incl. drug hx.
3) Autoimmune liver disorders : Chronic active hepatitis ( Antismooth muscle antibody), Primary Biliary Cirrhosis (antimitochondrial antibodies), sclerosing cholangitis (ANA)
Early Cholestasis4) Preeclampsia
5) Acute fatty liver of pregnancy (AFLP)
Diagnosis
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Risk factors:
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History of similar in previous pregnancies,
 Family history
 Associated problems while taking the COCP
Typical history
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Exclude other gastrointestinal and hepatic diseases (preexisting liver disease, intravenous drug or alcohol abuse,
medication use like methyldopa, other risk factors for viral
hepatitis):
Liver Ultrasound
- Fasting blood sugar
Viral screen
- LFT
Autoimmune screen
- Bile acids +- PT/coags
RCOG Green Top Guideline
“…when otherwise unexplained pruritus occurs in
pregnancy and abnormal liver function tests (LFTs) and/or
raised bile acids occur in the pregnant woman and both
resolve after delivery (check LFT prior to 6/52 FU).
Pruritus that involves the palms and soles of the feet is
particularly suggestive…”
Investigations
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LFTs
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Pregnancy specific ranges
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For AST/ALT/GGT/Bili upper limit of normal is
20% lower than non-pregnant range
Increase in transaminases (ALT and AST) by 2-4
times
Mild increase in bilirubin
Increase in fasting bile acid levels
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“Majority of studies and
clinical practice use random
levels”- despite bile levels can
rise after meal
Mild 10 - 20 umol/l (micmol)
Severe > 40 umol/l
Normal levels do not exclude diagnosis
Foetal compromise (preterm delivery, asphyxial events, meconium
staining of fluid and membranes) increase by 1–2% for each
additional umol/l > 10 umol/l; with significant increase of
adverse outcomes at levels > 40umol/l
Investigations
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Exclude other causes of cholestasis (US to exclude
gallstones, hepatitis serology, screen for autoimmune
liver diseases)
Symptoms may precede abnormal biochemistry (by
about a fortnight) – women with persisting pruritis
and normal biochemistry should have LFTs repeated
every 1-2 weeks
Monitoring and Foetal surveillance
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Traditionally –
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Consultant-led team based care birthing in hospital
At least twice-weekly CTG monitoring, CFM in labour (offered)
Weekly AFI and umbilical artery Doppler waveform studies
Weekly LFTs until delivery (coagulation screen if abnormal)
Two-weekly foetal welfare / growth scans
However, difficult to predict cases of foetal compromise based
on monitoring/investigations (often found to be normal on
retrospective review of poor outcomes)
Insufficient data available to inform decisions about best
monitoring and intervention to prevent foetal death
USS/CTG not reliable methods to prevent fetal death in OC
Drug Therapy
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Mild cases: antihistamines and emollients for symptomatic relief
 Safe,
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but efficacy unknown
Severe cases: Ursodeoxycholic acid (UDCA)
Category B: 8-12mg/kg in two daily divided doses –
decreases concentrations of potentially toxic endogenous bile
acids, replacing it with a benign exogenous bile acid  Improves symptoms and biochemistry (esp if BA>40)
 No evidence for improves perinatal morbidity or mortality
Women to be informed of lack of evidence
If unresponsive: Increase dose to 25mg/kg
No evidence of adverse foetal or maternal effects available even
use for more than 8 weeks.
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Drug Therapy
Dexamethasone:
 Suppresses foetomaternal oestrogen production.
 Dose: 12mg/day can relieve pruritus, reduce
transaminases & bile acids.
 Can be used as second line drug, 70%
improvement.
 Consider adverse foetomaternal effects from such
high dose.
Drug Therapy
Vitamin K
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Dose 10 mg daily orally or weekly IV - to
prevent the increase in PPH and haemolytic
disease of the newborn.
The role of Vitamin K
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Coag factors II, VII, IX, X (manufacture)
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Mandatory with prolonged PT.
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Should be started from 32 weeks onwards.
Delivery Planning
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Deliver at 37-38 weeks of gestation (earlier if maternal or foetal
well-being compromised)
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Discussion re: delivery risks (prematurity, resp distress, failed IOL) vs
uncertain fetal risk of cont preg.; even stronger if severe derang.
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Risk of admission to NICU after elective LSCS @37/40~10%, @38/40~5%,
@39/40~1%
One study (n=352) found that over 90% of intra-uterine deaths occurred
after 37 weeks
Spontaneous premature delivery is more likely if pruritus starts earlier.
Williamson C, Hems LM, Goulis DG, Walker I, Chambers J, Donaldson O, et al. Clinical outcome in a
series of cases of obstetric cholestasis identified via a patient support group. BJOG 2004;111:676–
81
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Close monitoring due to increased rate of adverse intrapartum
events
Active management of the third stage due to increased risk of
PPH
Can you predict adverse foetal
outcome?
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Relationships between bile acid levels and fetal complication
rates: A prospective cohort study in Sweden over 3 years among
>45,000 women showed
-- Probability of foetal complications increase by 1- 2% per
additional micromol of bile acid level rise over 10micromol/l.
-- Complementary analyses showed that fetal complications did not
arise until bile acid levels were ≥40 μmol/L. Gallstone disease
and a family history of ICP were significantly (P < .001) more
prevalent in the group of ICP patients with higher bile acid levels
Glantz A, Marschall HU, Mattsson LA. Intrahepatic cholestasis of
pregnancy: relationships between bile acid levels and fetal
complication rates. Hepatology 2004;40:467–74
Can you predict adverse foetal outcome?
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Bile acids cause vasoconstriction (dose dependent) on
isolated human placental chorionic veins which may
cause abrupt disruption of oxygenated blood flow to
foetus explaining stillbirth.
Foetal vessel dopplers (umbilical, uterine or cerebral
arteries) can not predict foetal compromise
The risk of a given complication of OC is higher if it
happened in previous pregnancy.
Repeated amniocentesis to detect meconium may
predict foetal compromise but practically not feasible.
Postnatal
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Symptoms and biochemistry usually resolve soon
after delivery, check LFT postpartum (6/52).
High risk of recurrence in subsequent pregnancies
(estimated 45-90%)
Avoid use of the COCP (avoid estrogen)
Persistence of abnormal LFT should raise suspicion
of causes other than OC.