Cholestasis of Pregnancy - PowerPoint Presentation

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Cholestasis of Pregnancy

Sean Heinz

Epidemiology

Prevalence varies throughout the world

Influenced 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))

Mortality actually declining

Aetiology and Pathogenesis

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

)

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

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)

Other signs: dark urine, pale stools, anorexia,

steatorrhoea

and, rarely, jaundice.

Associated risks

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)

Sleep deprivation/intense

puritis

(affects 23%

preg

.)

Only possible “rash” is

dermatographia

artefacta

/excoriations

NOT Eczema/Atopic eruption of pregnancy/PUPPPs/

Pemphigoid

Gestationis

Foetal

–

increased risk of:

Intrauterine death, especially after 37 weeks (undetermined risk, likely to be small)

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

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,

E

BV, CMV)

Requires thorough

Hx

incl. drug

hx

.

3) Autoimmune liver disorders : Chronic active hepatitis ( Anti-smooth muscle antibody), Primary Biliary Cirrhosis (anti-mitochondrial antibodies),

sclerosing

cholangitis (ANA)

Early Cholestasis-

4) Preeclampsia

5) Acute fatty liver of pregnancy (AFLP)

Diagnosis

Risk factors:

History of similar in previous pregnancies,

Family history

Associated problems while taking the COCP

Typical history

Exclude other gastrointestinal and hepatic diseases (pre-existing 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

LFTs

Pregnancy specific ranges

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

“Majority of studies and clinical practice use random levels”- despite bile levels can rise after meal

Mild 10 - 20

umol

/l (

micmol

)

S

evere

> 40

umol/lNormal 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

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

Traditionally

–

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 deathUSS/CTG not reliable methods to prevent fetal death in OC

Drug Therapy

Mild cases: antihistamines and emollients for symptomatic relief

Safe, 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.

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

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

Coag

factors II, VII, IX, X (manufacture)

Mandatory with prolonged PT.

Should be started from 32 weeks onwards.

Delivery Planning

Deliver at 37-38 weeks of gestation (earlier if maternal or

foetal

well-being compromised)

Discussion re: delivery risks (prematurity,

resp

distress, failed IOL) vs uncertain fetal risk of

cont

preg

.; even stronger if severe

derang

.

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

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?

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?

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

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.