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, EBV, 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)- 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

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 death

USS/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/kgNo 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.