1. CHOLESTASIS OF PREGNANCY Sean Heinz

2. 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

3. 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.

4. 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.

5. 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

7.  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).

8. 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)

9. 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

10. 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…”

11. 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

12. 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

13. 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

14. 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.

15. 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.

16. Drug Therapy Vitamin K  Dose 10 mg daily orally or weekly IV - to prevent the increase in PPH and haemolytic disease of the newborn.

17. The role of Vitamin K  Coag factors II, VII, IX, X (manufacture)  Mandatory with prolonged PT.  Should be started from 32 weeks onwards.

18. 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

19. 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 μ mol/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

20. 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.

21. 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.