Jaundice in Pregnancy

Approximately 3-5% of pregnant women have abnormal liver function tests and jaundice in pregnancy, whilst relatively rare, has potentially serious consequences for maternal and fetal health.¹ It can be caused by pregnancy or occur intercurrently. Causes of jaundice specific to pregnancy include:^1,2

• Pre-eclampsia associated with HELLP syndrome (haemolysis, elevated liver enzymes and low platelet count)
• Acute fatty liver of pregnancy
• Hyperemesis gravidarum
• Intrahepatic cholestasis of pregnancy

This is the commonest cause of jaundice in pregnancy with infections due to hepatitis viruses A, B, C, D and E.
The incidence of hepatitis in pregnancy varies greatly around the world: in developed countries, the incidence is around 0.1%, whilst in developing countries it can range from 3-20% or higher.
The course of most viral hepatitis infections (A, B, C, D) is unaltered by pregnancy - the exception is hepatitis E where pregnant women who contract the disease exhibit fatality rates of 10-20%.

Hepatitis A

• Transmission occurs via contaminated food or water or by faecal-oral contact.
• After incubation period of 15-50 days, flu-like symptoms develop with weakness, fatigue, fever, anorexia, joint pain and headaches. This is followed by jaundice, dark urine, light stools and right-upper-quadrant tenderness.
• The disease usually lasts 2-3 weeks with death in <1% of patients and no chronic form.
• Acutely, ALT and AST are elevated with IgM antibody detectable in serum (remains for 3-6 months followed by IgG antibodies that last for life).
• Isolate infected patient to prevent spread.
• Symptomatic treatment includes maintenance of adequate hydration and nutrition.
• Pregnant women exposed to the virus can be given immune globulin within 2 weeks of exposure together with vaccine.
• It is not clear if the virus is transmitted from mother to baby but if the illness has occurred in the last month of pregnancy, the neonate should receive immune globulin.

Hepatitis B

• This is the commonest cause of acute viral hepatitis in pregnancy and can occur in acute, subclinical or chronic form.
• Symptoms are similar to those of Hepatitis A but associated complications of serum sickness, nephritis, essential mixed cryoglobulinaemia and aplastic anaemia are more frequent.
• Symptomatic treatment includes maintenance of adequate hydration and nutrition. Transmission is sexual or via IV drug use, acupuncture, tattooing and blood products.
• HB_sAg (viral surface antigen) appears soon after onset of infection, reaches a maximum early in the disease and becomes undetectable in most cases a few weeks after recover. If it persists after 6 months, patients are chronic carriers. Hb_eAg is detectable in serum soon after HB_sAg and then disappears within approximately 2 weeks with the appearance of its antibody Hb_eAb. The presence of HB_eAg is associated with a very high risk of neonatal infection.
• All women should now be offered Hepatitis B screening as part of routine antenatal screening.
• Infants of HB_sAg positive women should receive hepatitis B immune globulin immunoprophylaxis at birth and hepatitis B vaccine at one week, one month and six months old. This regime reduces the incidence of hepatitis B vertical transmission to less than 3%.
• The prevalence of neonatal infection depends on the time during gestation that maternal infection takes place: rare in first trimester, 6% in second trimester and 67% of those in the third trimester.

Hepatitis C

• Transmission is similar to Hepatitis B but infection is usually sub-clinical, so jaundice is often not present.
• No therapy has been shown to influence the neonatal transmission of hepatitis C virus.
• Interferon should not be used during pregnancy because of possible adverse effects on the fetus.

Hepatitis D

Develops as a co-infection with hepatitis B. When present, it increases the incidence of acute hepatic failure.

Hepatitis E⁵

• This is rare in the developed world, but in developing countries where it is more common, it is responsible for high level of fulminant hepatic failure and mortality in pregnant women.
• In India, it appears to be associated with a higher maternal mortality rate and worse obstetric and fetal outcomes compared to other causes of acute viral hepatitis in pregnancy.⁶
• It is a waterborne virus spreading through faecal-oral transmission. Outbreaks occur after flooding.

Epidemiology

This may affect as many as 6% of pregnant women but jaundice occurs only in about 1 in 20 of these women. Pregnancy alters bile composition and gall bladder emptying slows in the second trimester increasing the risk of gall stones.
Individual risk factors are multiparity and previous gallbladder disease.

Presentation

Symptoms are similar in pregnant and nonpregnant women:

• Pain in the right-upper-quadrant or epigastrium, peaking at 12-24 hours.
• Pain may radiate towards the back. and there may be epigastric or right upper-quadrant tenderness. Murphy's sign (right-sided tenderness at tip of 9th costal cartilage as patient breathes in) is much less common in pregnancy.

Management

Obstructive jaundice requires surgical intervention usually via laparoscopic cholecystectomy. Uncomplicated cholecystectomy is safer in first and second trimesters with fetal loss of approximately 4%.⁷

Chronic liver disease in pregnancy is associated with an increased risk of fetal loss. In patients with primary biliary cirrhosis (PBC), ursodeoxycholic acid can be safely continued. Cholestasis may worsen during pregnancy with PBC. Infants of patients with marked hyperbilirubinaemia during pregnancy may require exchange transfusion at birth.

This can present with an acute attack and serum bilirubin increase is dependant upon type of disease, presence of antinuclear, small muscle, liver-kidney microsomes antibodies or antibodies to soluble liver antigen/liver pancreas antibodies. Azathioprine treatment has been used during pregnancy. There is generally a favourable prognosis for both mother and baby.

Hepatic dysfunction with pre-eclampsia has long been recognised but more recently it has been strongly associated with HELLP syndrome which complicates 3-10% pre-eclamptic pregnancies.

Presentation

Typically, patients complain of nausea and vomiting and epigastric/right upper quadrant pain. Jaundice occurs in those who develop haemolysis.

Investigations

Biochemical changes associated with HELLP include:

• Elevated bilirubin and LDH
• Moderately elevated liver transaminases
• Decreased platelet count
• Rising serum creatinine (if associated renal failure)

Lab abnormalities peak 1-2 days postpartum and then return to normal within 3-11 days.

Management

The most effective treatment for HELLP is prompt delivery. There is currently insufficient evidence to support the use of adjunctive steroids to reduce maternal and perinatal mortality and major morbidity.^9,10

Complications

Maternal mortality associated with HELLP is 2%. Perinatal mortality rate is 33%. The most serious complications are:

• DIC
• Renal failure
• Placental abruption
• Pulmonary oedema
• Subcapsular haematoma
• Liver rupture

Risk of recurrence in future pregnancies is 3-4%.

Epidemiology

• A rare disease affecting <1 in 10,000 pregnancies.
• Risk factors include first pregnancies, pre-eclampsia, twin pregnancies and male fetuses.
• It may be associated with a mutant gene producing a defect in mitochondrial fatty acid oxidation.

Presentation

This usually presents acutely with nausea, vomiting and abdominal pain, fevers, headache and pruritus, beginning typically at about 35 week's gestation but can occur much earlier. It may also appear immediately after delivery.
Jaundice appears soon after onset of symptoms and can become intense in a large proportion of patients. Fulminant liver failure may follow.

Investigations

• The white cell count is often elevated. There may also be neutrophilia and thrombocytopenia.
• Liver transaminases are moderately high.
• Raised serum bilirubin.
• Abnormal clotting with coagulopathy (prolongation of prothrombin and partial thromboplastin times with depression of fibrinogen levels).

Biopsy would be diagnostic but coagulation problems often preclude it. CT/MRI may show reduced attenuation in the liver.

Management

Consider early delivery as after delivery, the condition resolves usually with complete recovery. Supportive ITU care is frequently required.

Complications

Acute fatty liver of pregnancy is a life-threatening condition with an 18% maternal and 23% fetal mortality rate (up to 85% if associated with pre-eclampsia).
Serious complications include:

• DIC and GI bleeding
• Hepatic coma
• Renal failure
• Pancreatitis
• Hypoglycaemia

This is a reversible form of cholestasis complicating about 0.5-1.8% pregnancies, developing in the last trimester and usually resolving rapidly after delivery.

Epidemiology

• Increased prevalence in certain populations (e.g. Chile) and family clusters.
• Dominant inheritance is likely.
• May represent a pre-existing subclinical defect in a bile transport system which is unmasked in pregnancy by the effect of high levels of circulating hormones during the last trimester. This is supported by the fact that women with a history of ICP are prone to cholestasis induced by oral contraceptives and vice versa.

Presentation

Symptoms are pruritus alone(80%) or with jaundice(20%).

Investigations

Serum bile salts are increased, minimal or no transaminase elevation, mild to moderate steatorrhoea.

Management

Medical treatment of ICP is controversial. Ursodeoxycholic acid is used where pruritus is severe and provides safe and effective relief.
Close fetal surveillance is necessary prior to and during delivery.

Complications

There is no increased risk to the mother but an increased risk of preterm delivery, fetal distress and increased perinatal mortality rate (1-3.5%).
ICP recurs in 60-70% of subsequent pregnancies.