Obstetric Cholestasis and Acute Fatty Liver of Pregnancy

Question 1

Definition of obstetric cholestasis

Answer 1

Also known as intrahepatic cholestasis of pregnancy (ICP). A pruritic condition (in the absence of a primary skin condition) during pregnancy caused by impaired bile flow and resulting in abnormal bile acid concentrations. Onset of symptoms is most common in the third trimester, but can be earlier in pregnancy

Question 2

What is the prevalence of obstetric cholestasis in the UK

Answer 2

• Prevalence is influenced by genetic and environmental aspects
• In the UK, ICP affects 0.7% of pregnancies in multi-ethnic populations, 1.2-1.5% of women of Indian-Asian or Pakistani-Asian origin

Question 3

What is the pathophysiology of obstetric cholestasis

Answer 3

• The pathophysiology is incompletely understood, but thought to involve genetic susceptibility, hormonal and environmental factors
• Bile acid concentrations are not associated with intensity of itching

Question 4

Classification of obstetric cholestasis

Answer 4

• Gestational pruritis- itching and peak bile acid concentrations < 19micromol/L
• Mild ICP- itching and raised peak bile acid concentrations 19-39micromol/L
• Moderate ICP- itching and raised peak bile acid concentration 40-99micromol/L
• Severe ICP- itching and raised peak bile acid concentration >100micromol/L

Question 5

Risk factors for obstetric cholestasis

Answer 5

Previous hepatitis C infection, FHx of obstetric cholestasis (particularly in mother and/or sister)

Question 6

Presentation of obstetric cholestasis

Answer 6

• Itching (pruritis) is the main symptoms, particularly affecting the palms of the hands and soles of the feet
• Other symptoms are related to cholestasis and outflow obstruction in the bile ducts: Fatigue, Dark urine, Pale, greasy stools and jaundice
• Importantly, there is NO RASH associated with obstetric cholestasis- a rash points towards an alternative diagnosis such as polymorphic eruption of pregnancy or pemphigoid gestationis
• Foetal morbidity likely occurs secondary to the limited ability of foetal liver to remove bile acids from the blood and vasoconstricting effects of bile acid on human placental chorionic veins

Question 7

Other possible causes of pruritis and deranged LFTs

Answer 7

• Gallstones, Acute fatty liver, AI hepatitis, Viral hepatitis, DRUG REACTIONS, allergic reactions, urticaria

Question 8

How can obstetric cholestasis be diagnosed

Answer 8

• Should be considered in women who have itching in skin of normal appearance and raised peak random total bile acid conc. of 19micromol/L or more. Diagnosis more likely if symptoms resolve after birth
• Other causes of itching should be excluded

Question 9

Investigations for obstetric cholestasis

Answer 9

• Bile acids (see thresholds above)
• LFTs- using pregnancy specific ranges
  Mainly AST and GGT- it is normal for alkaline phosphatase (ALP) to rise in pregnancy, this is because the placenta produces ALP (rise in ALP without other abnormal LFT results therefore does not suggest liver pathology)
  Raised bilirubin
  If diagnosed, measure weekly until delivery
• Coagulation profile
• Consider hepatitis screen
• Once obstetric cholestasis is diagnosed it is reasonable to measure LFTs weekly until delivery. Postnatally LFTs should be deferred for at least 10 days

Question 10

Complications of obstetric cholestasis

Answer 10

• Stillbirth- in hospital settings, the current additional risk of stillbirth in obstetric cholestasis is likely to be small- risk of stillbirth only increases above population rate once serum BA concentration rises above 100 micromol/L
• Increased incidence of premature birth, especially iatrogenic
  6.5% of women with bile acids below 40 micromol/L (373/2264), 19.1% of women with bile acids 40–99 micromol (261/1368), and 30.5% of women with bile acids 100 micromol/L or more (157/514)
• Increased likelihood of meconium passage
• Baby is at increased likelihood of receiving neonatal care
• Increased risk of developing pre-eclampsia or gestational diabetes
• NOT associated with changes in foetal growth

Question 11

How can pregnancy outcomes be predicted in women with ostetric cholestasis

Answer 11

Poor outcomes cannot currently be predicted by biochemical results and delivery decisions should not be based on results alone. No specific antenatal foetal monitoring should be recommended (CTG and USS are unreliable), continuous foetal monitoring in labour should be offered (>100 micromol/L)

Question 12

Conservative management of ostetric cholestasis

Answer 12

• Advise women that there are no treatments that improve pregnancy outcomes (or raised bile acid concentrations) and treatments to improve maternal itching are of limited benefit
• Requires consultant-led, team-based care and give birth in a hospital unit

Conservative measures:
* Wear cool, loose cotton clothing
* Soak in a cool bath
* Apply ice packs for short periods over affected areas
* Topical emollients- Menthol 0.5% with aqueous cream

Question 13

Medical management of obstetric cholestasis

Answer 13

• Sedating antihistamines (eg. chlorphenamine) – improves sleep (sedative), but no impact on pruritus
• Ursodeoxycholic acid – improves pruritus and LFTs but no protection against still birth
• Vitamin K- considered ONLY if there appears to be reduced absorption of dietary fats and/ or there is evidence of abnormal PT in coagulation studies

Question 14

How is timing of birth affected by obstetric cholestasis

Answer 14

• Consider option of planned birth by 40 weeks gestation or ongoing antenatal care in women with mild ICP (peak bile acids 19-39 micromol/L) and no other risk factors
• Consider planned birth at 38-39 weeks gestation in women with moderate ICP with peak BAs 40-99 micromol/L and no other risk factors
• Consider planned birth at 35-36 weeks in women with severe ICP (>100)
• The presence of co-morbidities (gestational diabetes, pre-eclampsia, multifetal pregnancy) appear to increase the risk of stillbirth and may influence decision-making around timing of planned birth
• Mode of birth is based on usually obstetric practice for that woman

Question 15

How should women with obstetric cholestasis be followed up

Answer 15

• For women who have uncomplicated ICP, follow-up should be arranged at least 4 weeks after birth to confirm resolution of ICP. Advise them that they should anticipate itching and raised maternal bile acid concentrations to resolve after birth
• For women with ICP and previous cholestasis secondary to combined hormonal (oestrogen-containing) contraception, advise them to use progestogen-only or non-hormonal methods
• Advise women with a history of ICP that they have an increased chance of recurrence of ICP in subsequent pregnancies
• Perform a baseline liver function test and bile acid concentration with booking blood investigations

Question 16

How should women be advised on the risk of stillbirth due to ICP

Answer 16

Question 17

Definition of acute fatty liver of pregnancy

Answer 17

A rare disorder that is a medical and obstetric emergency, which can lead to liver failure due to micro-vesicular fatty infiltration of hepatocytes (and resultant acute hepatitis). It most commonly occurs in the third trimester.

Question 18

Incidence of acute fatty liver of pregnancy

Answer 18

• Incidence: 1/7000 to 1/16,000 pregnancies

Question 19

Risk factors for acute fatty liver of pregnancy

Answer 19

Genetic, nulliparity, older maternal age, male foetus, obesity and twin pregnancy

Question 20

Pathophysiology of acute fatty liver of pregnanyc

Answer 20

• Results from impaired processing of fatty acids in the placenta
• This is the result of a genetic condition in the foetus which impairs fatty acid metabolism- the most common cause is long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency in the foetus- AUTOSOMAL RECESSIVE
• The mode of inheritance means the mother will also have one defective copy of the gene
• The LCAD enzyme is important in fatty acid oxidation- utilisation of fatty acids as fuel
• As a result fatty acids enter the maternal circulation and accumulate in the liver.
• The mother’s defective copy of the gene also contributes to the accumulation of FAs which ultimately lead to inflammation and liver failure

Question 21

Presentation of acute fatty liver of pregnancy

Answer 21

Often have vague clinical features associated with hepatitis including:
* General malaise and fatigue, nausea and vomiting, jaundice, abdominal pain, anorexia (lack of appetite), ascites
* The Swansea diagnostic criteria are used to aid diagnosis (6 features in the absence of another explanation)

Question 22

Investigations for acute fatty liver of pregnancy

Answer 22

• Liver function tests will show elevated liver enzymes (ALT and AST)
• U&Es may indicate renal dysfunction
• PT (coagulopathy in the absence of thrombocytopenia), serum uric acid and bilirubin (derangement is a sign of severe disease)
• May see profound hypoglycaemia (suggested to be a poor diagnostic marker)

Question 23

Management of acute fatty liver of pregnancy

Answer 23

• Obstetric emergency- require prompt delivery of the baby (expedite delivery). Should be attempted as soon as maternal condition is stable OR as soon as possible if maternal condition is deteriorating
• Most patients will recover after delivery (may take around 4 weeks)

Supportive care:
* Admit to ITU - if at high risk of multi organ failure and death
* Continue maternal and foetal monitoring
* Correct coagulopathy, electrolytes and hypoglycaemia (FFP and vitamin K with 50% dextrose)
* N-acetyl cysteine and plasmapheresis sometimes used
* Treat acute liver failure - consider liver transplant
* Screen the baby for LCHAD deficiency