Jaundice in pregnancy

Jaundice in pregnancy, whilst relatively rare, affecting less than 5% of pregnancies globally,¹ has potentially serious consequences for maternal and fetal health. It is responsible for 12% of maternal deaths globally.²It can be caused by pregnancy or occur intercurrently. Causes of jaundice specific to pregnancy include:

• 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.

The presenting clinical features of liver disease in pregnancy are often nonspecific and consist of jaundice, nausea, vomiting and abdominal pain. All liver diseases occurring during pregnancy can lead to increased maternal and fetal morbidity and mortality.³

Viral hepatitis⁴

Viral hepatitis is the most common cause of jaundice in pregnancy worldwide with infections due to hepatitis A, hepatitis B, hepatitis C, hepatitis D and hepatitis E viruses.

The incidence of hepatitis in pregnancy varies greatly around the world; in MEDCs the incidence is around 0.1%, whilst in LEDCs it can range from 3-20% or higher.

• Hepatitis A is most prevalent in low- and middle-income countries. 1:1,000 pregnant women are infected with acute hepatitis A virus (HAV). The disease is mostly self-limited, with mortality of 0.3% to 0.6%. It has been associated with premature rupture of membranes, placental separation, vaginal bleeding and premature contractions. Fetal ascites and meconium peritonitis have been reported though are very rare.

• Hepatitis B affects more than 250 million individuals worldwide and is the most common cause of chronic hepatitis worldwide. Sixty-five million women of childbearing age are infected with chronic hepatitis B virus (HBV). About 800,000 to 1.4 million people are infected with HBV in the USA. There is a 0.7% to 0.9% prevalence of chronic HBV infection among pregnant women in the USA. Chronic HBV in pregnancy increases the risks of progression to cirrhosis.

• Hepatitis C virus (HCV) affects more than 170 million people worldwide. About 8% of pregnant women are infected with HCV. The estimated prevalence of antenatal HCV infection in the USA is 1% to 2.5%.

• Hepatitis D virus (HDV) affects 15-20 million people worldwide with HBV carriers. New studies estimate the prevalence of hepatitis D to be closer to 62-72 million. The prevalence of HDV in the USA is estimated to range from 2% to 50%, depending on the patient population. The prevalence of HDV in a study in Pakistan revealed an estimated 20.63% in pregnant women with chronic HBV infection.

• Hepatitis E virus (HEV) affects about 20.1 million new infections. HEV infection is prevalent in low- and middle-income countries. The course of most viral hepatitis infections is unaltered by pregnancy - the exception is hepatitis E, where pregnant women who contract the disease exhibit fatality rates of 10-20%.

Treatment of viral hepatitis in pregnancy

Hepatitis A

See the separate Hepatitis A article for further information.

• Isolate the infected patient to prevent spread.

• Symptomatic treatment includes maintenance of adequate hydration and nutrition.

• Pregnant women exposed to the virus can be given immunoglobulin within two weeks of exposure, together with vaccine.

• Neonate should receive HAV immunoglobulin within 48 hours of birth if the infection occurred in the third trimester.⁴

• There are no contra-indications to breastfeeding.

Hepatitis B

See the separate Hepatitis B article for further information.

• This is the most common cause of acute viral hepatitis in pregnancy and can occur in acute, subclinical or chronic form.

• The presence of HBeAg 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.

• Antiviral treatment may be offered during pregnancy.⁵

• Infants of HBsAg-positive women should receive hepatitis B immune globulin immunoprophylaxis at birth and hepatitis B vaccine at 1 week, 1 month and 6 months of age. 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 the first trimester, 6% in the second trimester and 67% of those in the third trimester.

Hepatitis C⁴

See the separate Hepatitis C article for further information.

• No therapy has been shown to influence the neonatal transmission of HCV.

• Caesarean section to reduce the risks of intra-partum transmission is not currently recommended.

• Treatment has historically been delayed till after the pregnancy but new evidence is developing which considers the option of treating during pregnancy. ⁶

• There is no contra-indication to breastfeeding.

Hepatitis D⁴

This develops as a co-infection with hepatitis B. When present, it increases the incidence of acute hepatic failure. The incidence has significantly decreased.

Hepatitis E⁴

• This is rare in MEDCs but, in LEDCs (where it is more common), it is responsible for a 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 with other causes of acute viral hepatitis in pregnancy.

• The HEV recombinant vaccine has been shown to be effective in reducing transmission but has not been trialled in pregnant women so safety and efficacy is unknown.

Cholelithiasis in pregnancy

The prevalence of gallstones in pregnancy is around 3.6% globally but is highest in the United States at about 6.8%,⁷with some evidence that it is present in 12% of pregnancies in the United States. ⁸ Symptomatic gallstone disease occurs in approximately 1 in 100 pregnancies.⁸

Pregnancy alters bile composition and gallbladder emptying slows in the second trimester, increasing the risk of gallstones.

Individual risk factors are multiparity, high BMI, increasing age and previous gallbladder disease.⁷

Presentation

Symptoms are similar in pregnant and non-pregnant 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 the tip of the 9th costal cartilage as the patient breathes in) is much less common in pregnancy.

Management

Obstructive jaundice may require surgical intervention, usually via laparoscopic cholecystectomy, after a clear discussion of pros and cons. Risks of fetal death appears to be low (less than 1 in 200). ⁹Delays to surgery increase the risks of preterm delivery, longer hospital stays and readmissions.⁸

Chronic liver disease

Chronic liver disease in pregnancy is associated with an increased risk of fetal loss though these risks are lower than previously. A successful outcome would now be expected in women with stable disease.¹⁰

In patients with primary biliary cirrhosis (PBC), ursodeoxycholic acid can be safely continued during pregnancy and breastfeeding.¹⁰Cholestasis may worsen during pregnancy with PBC.¹¹

Infants of patients with marked hyperbilirubinaemia during pregnancy may require exchange transfusion at birth.

A post-partum flare of PBC is common, occurring in 60% of women.¹⁰

Autoimmune hepatitis

Autoimmune hepatitis (AIH) in pregnancy is associated with an increased risk of fetal complications and maternal complications. Women with known AIH are advised to delay their pregnancy until their disease is stable. 20% of women with AIH will experience a flare during pregnancy and this is associated with significant complications.¹²

Corticosteroids with azathioprine treatment have been shown to be safe and effective during pregnancy. Current advice is also that they be continued during breastfeeding. Other medications usually used in AIH are contra-indicated in pregnancy.¹²

Pre-eclamptic liver disease and HELLP

See the separate HELLP syndrome article for further details.

This complicates 3-10% of pre-eclamptic pregnancies and the risk of recurrence in future pregnancies is 3-4%.

The most effective treatment for HELLP is prompt delivery.

Acute fatty liver of pregnancy¹³

Epidemiology

• It is a rare condition with a prevalence of between 1 in 7,000 and 1 in 20,000 pregnancies.

• Acute fatty liver of pregnancy (AFLP) tends to occur in late pregnancy.

• 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 and infants born to mothers with AFLP should be screened for defects in this system.

Presentation

Although there are some known pre-disposing factors, acute fatty liver in pregnancy is not predictable or preventable.¹⁴It usually presents acutely with nausea, vomiting, anorexia and abdominal pain, fevers, headache and pruritus, beginning typically at about 35 weeks of 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 scanning may show reduced attenuation in the liver.

The "Swansea criteria" have been shown to be a valid method of assessing the likelihood of symptoms being related to AFLP.¹⁵

Management

Immediate delivery is the only treatment. There is no evidence of success of expectant management.¹⁴ Following delivery, normalisation of LFTs and symptoms is expected within 7-10 days.

Complications

AFLP is a life-threatening condition. To date, there are no reports of spontaneous remission of AFL prior to delivery of the infant. The characteristic course is progression to acute liver failure within one or two weeks, which is characterised by increasing jaundice, hypoglycaemia, development of coagulopathy, ascites/pleural effusions, encephalopathy and acute kidney failure in up to 90% of affected women.

With improved recognition of the condition and improved access to rapid delivery, the maternal death rate has dropped from 75% to 5% in the last few years.¹⁴

Intrahepatic cholestasis of pregnancy

Intrahepatic cholestasis is defined as pruritus with elevated serum bile acids occurring in the second half of pregnancy, which resolves after delivery. This is the most common cause of jaundice in pregnancy in the UK.

See also the separate Obstetric cholestasis article.

Epidemiology

ICP incidence rate is between 0.2% to 2% of pregnancies.¹⁶ It is more common in South American and northern European continents. Research has described ICP in 0.2% to 0.3% of pregnancies in the USA.

Presentation

The main symptom is pruritus, especially of the palms and soles, which is followed by generalised symptoms. This usually occurs from week 25 of gestation.

Jaundice is uncommon. However, when present, it arises 2-4 weeks after the onset of pruritus.

Investigations

• Aminotransferase activity can be increased by 20 times the normal level.

• Raised gamma-glutamyltransferase activity is unusual but is indicative of MDR3 mutation or underlying liver disease unrelated to pregnancy. The key diagnostic test is a fasting serum bile acid concentration of greater than 10 mmol/L.

Management

Ursodeoxycholic acid is the mainstay of medical management.

Complications

Maternal morbidity results from pruritus and insomnia. The importance of this disorder is the effects on the fetus which can lead to prematurity, perinatal death, fetal distress and stillbirth. ICP often recurs in subsequent pregnancies.¹⁷