Jaundice in Pregnancy

Introduction

Abnormal liver function is found in around 3% of pregnancies, and jaundice in far fewer. The clinical difficulty is that the differential spans conditions that resolve spontaneously after delivery and conditions that kill both mother and fetus within hours, and the early symptoms of both are nausea, malaise and vague upper abdominal discomfort.

A workable approach is to ask three questions in order. Is this a normal physiological change in pregnancy? If not, is it one of the four pregnancy-specific liver diseases? If not, is it a coincidental or pre-existing liver disorder that happens to be presenting now? The gestation narrows the differential considerably, because the pregnancy-specific conditions occur in characteristic windows.

Liver function in normal pregnancy

Clinical signs are equally treacherous. Spider naevi and palmar erythema occur in a large proportion of normal pregnancies because of high circulating oestrogen, and mean nothing on their own. The liver is displaced upwards by the gravid uterus, so a palpable liver edge below the costal margin in the third trimester is genuinely abnormal.¹

The pregnancy-specific liver diseases

Intrahepatic cholestasis of pregnancy

Intrahepatic cholestasis of pregnancy, still widely called obstetric cholestasis, affects around 0.7% of UK pregnancies and is more common in women of South Asian origin. It results from a genetically predisposed sensitivity of the biliary transport proteins to the high oestrogen and progesterone concentrations of late pregnancy, causing impaired bile acid excretion and their accumulation in the maternal circulation.

Clinical features

• Pruritus without a rash - the cardinal symptom, characteristically worst on the palms and soles and at night, and often severe enough to prevent sleep
• Excoriations from scratching may be present, but any primary rash points to a different diagnosis such as polymorphic eruption of pregnancy or pemphigoid gestationis
• Dark urine and pale stools in more marked cases
• Frank jaundice occurs in fewer than 10%
• Steatorrhoea, and rarely vitamin K deficiency with a prolonged prothrombin time
• The mother is systemically well: no fever, no hypertension, no encephalopathy

Diagnosis

Diagnosis requires pruritus with raised serum bile acids, once other causes have been excluded. RCOG now grades severity by the peak random total bile acid concentration, because that is what predicts perinatal risk: mild disease is 19-39 micromol/L, moderate 40-99 micromol/L and severe 100 micromol/L or above. Transaminases are raised in around 60% of cases. Other causes of abnormal liver function should be excluded with a viral hepatitis screen, liver autoantibodies and a liver ultrasound.²

Management

• Symptomatic relief: emollients such as aqueous cream with menthol, cool clothing, loose cotton, and sedating antihistamines such as chlorphenamine at night
• Ursodeoxycholic acid should not be offered for the purpose of improving perinatal outcomes; the PITCHES trial found no reduction in stillbirth, preterm birth or neonatal unit admission. It may be used for pruritus, with the woman understanding the modest effect
• Vitamin K only where the prothrombin time is prolonged or there is steatorrhoea, not routinely
• Repeat bile acids and liver function weekly to identify progression to the severe category
• Cardiotocography and ultrasound do not predict stillbirth in this condition and should not be used to provide false reassurance
• Check liver function and bile acids at least 4 weeks after birth; persistent abnormality requires investigation for underlying liver disease

Symptoms resolve rapidly after delivery. The recurrence rate in a subsequent pregnancy is high, of the order of 45-90%, and women should be told this at the postnatal review. There is an association with later hepatobiliary disease, including gallstones and hepatitis C, which is worth mentioning to the GP.

Pre-eclampsia and HELLP syndrome

Hepatic involvement in pre-eclampsia arises from the same endothelial injury that produces the renal and cerebral features. Fibrin deposition in the hepatic sinusoids causes ischaemia, periportal necrosis and stretching of Glisson's capsule, which is felt as epigastric or right upper quadrant pain. HELLP syndrome, comprising haemolysis, elevated liver enzymes and low platelets, complicates 10-20% of severe pre-eclampsia and can occur with surprisingly modest hypertension.

Acute fatty liver of pregnancy

Acute fatty liver of pregnancy is rare, occurring in roughly 1 in 10,000 to 1 in 20,000 pregnancies, but it is a genuine obstetric emergency with mortality that was historically catastrophic and remains appreciable. It is characterised by microvesicular fatty infiltration of hepatocytes with acute liver failure.

A proportion of cases are associated with an inherited fetal defect of mitochondrial fatty acid oxidation, most often long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency. The heterozygous mother cannot metabolise the accumulating long-chain fatty acid intermediates produced by the homozygous fetus, and these are hepatotoxic. This is why the neonate should be screened for fatty acid oxidation disorders after a maternal case.⁵

Presentation and diagnosis

• A prodrome of malaise, anorexia, nausea, vomiting, abdominal pain and polydipsia over days to weeks in the third trimester
• Progressive jaundice, then hypoglycaemia, coagulopathy, encephalopathy and acute kidney injury
• Around half have coexisting pre-eclampsia, which complicates the distinction from HELLP
• Bloods show raised transaminases (usually 300-1000 IU/L), raised bilirubin, marked hypoglycaemia, raised urate, leucocytosis, raised ammonia, and a coagulopathy with prolonged prothrombin time and low fibrinogen
• Diagnosis uses the Swansea criteria: six or more of fourteen clinical, laboratory and imaging features in the absence of another explanation
• Ultrasound and CT are insensitive; liver biopsy is diagnostic but rarely appropriate given the coagulopathy

Management

Management is supportive stabilisation followed by prompt delivery, which is the only intervention that halts the process. Correct hypoglycaemia with concentrated glucose infusion, correct coagulopathy with fresh frozen plasma, cryoprecipitate and vitamin K, and manage in a level 2 or 3 critical care environment with hepatology and intensive care input. A minority progress to fulminant hepatic failure requiring transplantation. Maternal mortality has fallen from historical figures above 70% to under 10% with early recognition, and hepatic recovery in survivors is usually complete.⁵

Coincidental and pre-existing liver disease

• Viral hepatitis - hepatitis A, B and C behave much as outside pregnancy. Hepatitis E is the exception, carrying a mortality of up to 20% when acquired in the third trimester; ask about travel. Disseminated herpes simplex hepatitis is rare but fulminant and treatable with aciclovir
• Gallstone disease - pregnancy increases biliary sludge and stone formation through progesterone-mediated gallbladder hypomotility; cholecystitis and choledocholithiasis present as they do outside pregnancy and ERCP can be performed with fetal shielding
• Drug-induced liver injury - consider methyldopa, antibiotics, antiepileptics and paracetamol overdose
• Budd-Chiari syndrome - pregnancy is prothrombotic; presents with ascites, hepatomegaly and abdominal pain
• Sepsis - a cholestatic picture is common in severe sepsis of any source
• Autoimmune hepatitis and primary biliary cholangitis - may flare in pregnancy or in the puerperium
• Cirrhosis with portal hypertension - variceal bleeding risk is greatest in the second trimester as plasma volume expands, and in the second stage of labour

Assessment

The history should establish the gestation, the presence and character of any itch, whether there is a rash, the site and nature of any pain, systemic symptoms, drug and herbal use, alcohol, travel, and risk factors for viral hepatitis. Examine for scratch marks, jaundice, right upper quadrant tenderness, hepatomegaly, stigmata of chronic liver disease, asterixis and encephalopathy, and measure the blood pressure and dipstick the urine in every case.

• Liver function tests interpreted against pregnancy-specific ranges, plus random total bile acids
• Full blood count and blood film, looking for thrombocytopenia and red cell fragments
• Coagulation screen with fibrinogen
• Urea, electrolytes, creatinine and urate
• Capillary and laboratory glucose - hypoglycaemia points strongly to acute fatty liver
• Urinary protein:creatinine ratio and blood pressure to detect pre-eclampsia
• Hepatitis A, B, C and E serology, Epstein-Barr virus and cytomegalovirus serology
• Liver autoantibodies, immunoglobulins, caeruloplasmin where chronic disease is suspected
• Liver and biliary ultrasound

Red flags

Prognosis

Intrahepatic cholestasis resolves completely after birth in almost all cases, and with bile-acid-guided timing of delivery the perinatal outcome is good. Persistent abnormality of liver function beyond four weeks postnatally is not part of the condition and warrants hepatological investigation.

HELLP syndrome typically worsens for 24-48 hours after birth before improving, and most women recover fully; the risks are of haemorrhage, acute kidney injury and hepatic complications during that window. Acute fatty liver of pregnancy carries the worst prognosis of the group, but with early recognition, prompt delivery and critical care support, maternal survival now exceeds 90% and the liver usually recovers without long-term sequelae. Recurrence is uncommon but has been reported, particularly in families with an identified fatty acid oxidation defect, so the neonate should be tested and the family counselled.^2,5