Pregnancy and liver disease

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Chapter 48 PREGNANCY AND LIVER DISEASE

• During pregnancy expect a 10%–60% drop in serum albumin and a 2–4-fold increase in alkaline phosphatase.

• The transaminases and clotting times remain unchanged.

• Think of cholestasis of pregnancy in a woman who develops an itch mid to late pregnancy.

• Cholestasis of pregnancy is characterised by a rise in the bile acids, without evidence of biliary obstruction on imaging.

• Minor liver function test (LFT) changes can occur in severe hyperemesis gravidarum during the first trimester.

• Development of nausea, LFT abnormalities or right upper quadrant pain in late pregnancy could indicate serious liver problems, such as fatty liver of pregnancy.

• The timing of LFT abnormalities during pregnancy is the best guide to diagnosis, with most pregnancy-related disorders occurring in the third trimester.

• The risk of cholelithiasis increases during pregnancy and postpartum.

ABNORMAL LIVER FUNCTION TESTS IN PREGNANCY

Screening tests for women presenting with abnormal liver function tests (LFTs) in pregnancy should include serology for hepatitis A, B, C, Epstein-Barr virus (EBV), cytomegalovirus (CMV) and herpes simplex virus (HSV) as well as an upper abdominal ultrasound to exclude biliary disorders.

Determine the stage of pregnancy, and whether there is anything in the history to indicate a liver disorder. A pregnancy-related liver disorder should be considered in the event of any relevant past history, or history of medications or in the presence of features of pre-eclampsia.

NORMAL PHYSIOLOGICAL CHANGES IN PREGNANCY

Normal physiological changes in pregnancy are shown in Table 48.1. The mother’s blood volume increases by 40%, and her total body water increases by 20%. This is reflected in a 10%–60% fall in serum albumin and also a fall in haemoglobin. Up to 50% of women develop spider naevi and palmar erythema during pregnancy, which is thought to be due to the increasing levels of oestrogen. This reverses quickly post delivery. Serum alkaline phosphatase increases 2–4-fold in the third trimester (placental) and gamma-glutamyltranspeptidase decreases slightly. No change is observed in the aminotransferases (alanine aminotransferase and aspartate aminotransferase) or the prothrombin time. A rise in the transaminases should lead to further investigation.

TABLE 48.1 Normal changes in liver function tests during pregnancy

Blood test	Change during pregnancy
Alkaline phosphatase	Increases 2–4-fold (placenta)
Gamma-glutamyl transpeptidase	No change or slightly decreases
Aspartate aminotransferase	No change
Alanine aminotransferase	No change
Bilirubin	No change or slightly increases
Bile salts	No change
Albumin	Decreases by 10%–60%
Globulin	Increases
Caeruloplasmin	Increases
Prothrombin time	No change
Cholesterol	2-fold increase
Triglycerides	2–3-fold increase

Up to 3% of pregnancies are complicated by abnormal LFTs at term. The best guide in determining the cause of abnormal LFTs is the timing of the problem during pregnancy (Figure 48.1). The differential diagnoses include:

• Liver diseases unique to pregnancy—generally occur in the third trimester (Table 48.2)

• Liver diseases occurring concomitantly—can occur anytime during pregnancy (Table 48.3)

• Preexisting chronic liver problems (Table 48.4).

FIGURE 48.1 Abnormal liver function tests in pregnancy.

TABLE 48.2 Liver diseases unique to pregnancy

TABLE 48.3 Liver disease occurring concomitantly during pregnancy

TABLE 48.4 Liver disease existing before pregnancy

Pregnancy is associated with an increased rate of gallstone formation. Hence cholecystitis and cholelithiasis need to be excluded in any pregnant woman presenting with right upper quadrant pain, nausea and abnormal LFTs. The differential diagnosis of right upper quadrant pain (Table 48.5) in late pregnancy includes pregnancy-related liver problems, such as liver involvement in pre-eclampsia, even hepatic infarction or rupture. It should be remembered that the gravid uterus pushes up the appendix, and appendicitis in late pregnancy can present with right upper quadrant pain.

TABLE 48.5 Differential diagnosis for right upper quadrant pain in the third trimester of pregnancy

Diagnosis	Incidence during pregnancy
Pyelonephritis	1%–2%
Cholelithiasis/cholecystitis	3%–5% have biliary sludge
Acute appendicitis	1/1500
Pancreatitis	1/1439
AFLP	1/10,000–1/15,000
Pre-eclampsia + liver involvement	<1%
HELLP syndrome	0.1%
Hepatic haematoma/rupture	1/45,000
Acute viral hepatitis	Same as in the general population
Acute Budd-Chiari syndrome	Rare

AFLP = Acute fatty liver of pregnancy; HELLP = haemolysis elevated liver enzymes and low platelet syndrome.

LIVER DISEASES UNIQUE TO PREGNANCY

Hyperemesis gravidarum

Hyperemesis gravidarum or extreme morning sickness is not a liver disease. However, one-quarter of women hospitalised for this condition have elevated aminotransferase levels. The condition classically occurs in the first trimester and resolves by about week 20, and is usually worse in twin pregnancies and during a first pregnancy. The LFT abnormalities improve on fluid and electrolyte management.

Cholestasis of pregnancy

Cholestasis of pregnancy is the most common liver disease unique to pregnancy. The incidence is about 1/500 pregnancies (0.2%) in Australia. A higher prevalence is seen in Scandinavia and South America (14% risk in Chile). The condition is characterised by pruritus, and an increase in the serum bile acid, and is usually seen in the third trimester. Women present with an itch, without any skin lesions (apart from scratch marks). There may be a history of mothers or sisters with the same problem, and it may have occurred in previous pregnancies. The itch normally goes within days after delivery.

Investigations

An itch is the only symptom; there should be no pain. Check for skin lesions as well as fasting bile acids, LFTs and an upper abdominal ultrasound (to exclude cholelithiasis). Make sure the expectant mother is not taking any drugs or herbs that could cause hepatotoxicity. Take a careful history, because any preexisting liver problem or hepatotoxic drug reaction will become more cholestatic during pregnancy. In addition, any form of cholestasis will cause an increase in serum bile acids. Rarely, thyrotoxicosis or primary biliary cirrhosis can present with an itch during pregnancy. These can be excluded by thyroid function tests and anti-mitochondrial antibody screening, respectively (especially if the problem doesn’t resolve postpartum). The hallmark of the condition is normalisation of symptoms and LFT abnormalities within a few weeks post delivery. A liver biopsy is not necessary for the diagnosis, but histology would show intracanalicular cholestasis without inflammation, or liver damage.

The pathogenesis is not understood. Membrane layers of the hepatocytes and the bile canaliculi become slightly leaky during a normal pregnancy (an effect of oestrogen), and this is more pronounced in women with a family history. Genetic deficiencies of canalicular transport proteins are associated with this condition.

Risks to the mother

Apart from a severe itch, cholestasis of pregnancy does not affect the mother (excluding the increased risk of a postpartum haemorrhage). Some women develop LFT abnormalities—the bilirubin may rise to 100 μmol/L and serum aminotransferases increase to 2–10 times the upper limit of normal—but there is no associated increased risk of liver failure. There is a 70% chance of recurrence during a subsequent pregnancy.

Risks to the baby

There is a five-fold increase in the risk of preterm labour and stillbirth. Fetal monitoring does not predict the babies at risk, as there is no problem with placental blood flow. The fetal risk is not understood; high bile acids appear toxic to the baby, and cause myometrial irritability. When the total bile acids are 40 μmol/L or greater, fetal complications can occur. Women with this condition will usually have an induced delivery at 38 weeks, to decrease the fetal risk.

Treatment

Women in whom cholestasis of pregnancy occurs earlier than week 36 of pregnancy or who have high levels of bile acids should be offered treatment. The number of reported pregnant women on drug treatment for cholestasis of pregnancy is small. However studies have shown that ursodeoxycholic acid used at a dosage of 15–25 μg/kg/day in divided doses can improve both the mother’s itch and the fetal outcome. Oral dexamethasone at 12 mg daily for 10 days has been used as salvage treatment. Other treatments, such as antihistamines, are not effective. Vitamin K supplements are necessary.

Pre-eclampsia and the HELLP syndrome

Pre-eclampsia occurs in 5%–10% of pregnancies. It occurs particularly with first pregnancies during the third trimester. About 10% of women with pre-eclampsia have minor LFT abnormalities. Pre-eclampsia is characterised by hypertension, oedema and proteinuria. Women with LFT abnormalities have a more severe form of pre-eclampsia.

The aetiology of pre-eclampsia is unknown. It is thought to relate to placental ischaemia, causing abnormal endothelial reactivity, and activation of the coagulation cascade, predisposing to fibrin deposition in small blood vessels. The clinical manifestations of the disease relate to which organs are involved (brain, kidney, liver or all of these).

Women with liver involvement may present with right upper quadrant pain or nausea in late pregnancy, along with other pre-eclamptic features. The transaminases are increased up to five-fold. Massive transaminase rises indicate hepatic infarction or rupture. Close monitoring and expedient delivery is required.

The haemolysis elevated liver enzymes and low platelet (HELLP) syndrome occurs in 0.2%–0.6% of all pregnancies, and in about 20% of women with severe pre-eclampsia. One-fifth of cases occur postpartum. Usually women present after week 32 with anorexia, nausea, right upper quadrant pain and/or bleeding from gums and intravenous access sites. The platelet count is 100,000 × 10⁹/L or less. The blood film is consistent with microangiopathic haemolytic anaemia. Aminotransferases are elevated (>70U/L), lactate dehydrogenase >600 U/L and bilirubin slightly raised. The prothrombin time may be normal unless complicated by disseminated intravascular coagulation (DIC). The symptoms can be non-specific, and the condition may not be diagnosed until blood tests are done for pre-eclampsia. Characteristically, these women have rapid weight gain. If the diagnosis is suspected and the LFTs are unremarkable, they should be repeated in 4–6 hours, as things can change quickly.

The liver problem in the HELLP syndrome is the same as with pre-eclampsia, with microvascular blood vessel changes in the liver, leading to vasospasm and endothelial damage. This can cause hepatic infarcts. Microvascular ischaemia is exacerbated by thrombosis from DIC, worsening the problem. The histology demonstrates small vessel thrombosis and areas of haemorrhage and ischaemia. Some consider the HELLP syndrome a variant of pre-eclampsia, but it occurs in older multiparous women typically, and occasionally postpartum.

As with pre-eclampsia, the management is expedient delivery. If the condition occurs before 34 weeks’ gestation, the mother needs to be monitored in an intensive care setting with intravenous dexamethasone for fetal lung maturity, and delivery as soon as practicable. The mother should be receiving magnesium sulfate, antihypertensives and blood products as required. As there is a risk of developing a hepatic haematoma, the liver needs to be imaged.

The differential diagnoses of liver involvement with pre-eclampsia and the HELLP syndrome include acute viral hepatitis, autoimmune thrombocytopenia and systemic lupus erythematosis, as well as acute fatty liver of pregnancy. Other possible diagnoses include thrombotic thrombocytopenic purpura, and haemolytic uraemic syndrome. There is an uncommon association between these liver problems and fetal fatty acid oxidation defects (see next section).

Acute fatty liver of pregnancy

Acute fatty liver of pregnancy (AFLP) occurs between 1/6659 and 1/113,000 pregnancies, typically in late pregnancy. Symptoms include malaise, vomiting and abdominal pain. Jaundice and signs of hepatic encephalopathy may be evident. Coagulopathy, moderately elevated aminotransferases (500 U/L or below) and renal dysfunction are common. The uric acid is increased. Severe hepatic dysfunction is manifest by profound hypoglycaemia and high ammonia levels. DIC is almost universal, and the condition may progress to fulminant liver failure with death of the mother and the baby.

It can be difficult to differentiate AFLP and the HELLP syndrome, as a percentage of those with AFLP have pre-eclamptic features. The mechanism of the disease is different; AFLP is a severe metabolic disorder. The differentiation is more of an academic exercise, as the management is the same: expedient delivery. It is important to differentiate a severe pregnancy-related liver problem and fulminant viral hepatitis in the third trimester, as the clinical picture can be indistinguishable. Expedient delivery will not help the latter. Pre-eclamptic features favour a pregnancy-related problem, coexistent diabetes insipidus favours AFLP. Transaminases in the thousands favour viral hepatitis. Urgent viral serology is needed.

The pathogenesis of AFLP is unclear. The oxidative stress of pregnancy may cause defective mitochondrial fatty acid oxidation. Although liver biopsy is rarely done, this would show microvesicular steatosis. If a biopsy is needed to establish a diagnosis, a frozen section should be taken, with a histopathologist on standby to do special staining using Oil red O. Without this, the steatosis may not be appreciated.

After the delivery, the mother should make a full recovery without any long-term sequelae, although this may take up to a month. The condition was thought not to recur, but there are reports of an associated mitochondrial fatty acid oxidation enzyme deficiency in both mother and baby in some cases. These women are at risk of a recurrence during subsequent pregnancies (see below).

Fatty acid oxidation enzyme deficiency and severe maternal liver disease

About 20% of babies born to mothers with acute fatty liver of pregnancy have a homozygous deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD). This enzyme is needed for fatty acid oxidation at the mitochondria to produce glucose during periods of fasting. These babies are at risk of sudden death from hypoglycaemia, and develop severe microvesicular steatosis in the liver, heart and skeletal muscles, dying within months.

Mothers heterozygous for LCHAD do not have abnormal fatty acid metabolism. However, when the mother carries a fetus that cannot metabolise long chain fatty acids, these accumulate in the placenta, and spill over into the maternal circulation. Triglycerides (fatty acids) accumulate in the mother’s hepatocyte mitochondria, leading to impaired function.

This problem does not explain most cases of AFLP. However, genetic counselling should be offered, and affected babies identified and given glucose at birth. Affected babies can be identified prenatally in subsequent pregnancies. There is also an association between LCHAD deficiency and the HELLP syndrome.

Hepatic haematoma and rupture

A rare but life-threatening problem occurring in the third trimester. It can occur with severe pre-eclampsia, the HELLP syndrome and AFLP. Other causes such as with cocaine use, liver neoplasm (e.g. enlarging adenomas) and liver abscess have been described. Hepatic haematomas generally occur in the right lobe, and can present with right upper quadrant pain, malaise and abnormal LFTs. A rupture will present, or progress into shock. This is a surgical emergency with high mortality. It is important to consider the diagnosis and image the liver. Women with less severe forms of HELLP, or AFLP earlier in pregnancy, being monitored in ICU should be imaged frequently.

LIVER DISEASES OCCURRING CONCOMITANTLY DURING PREGNANCY

Liver disorders that occur at the same time as the pregnancy are those most likely to be seen in the community.

Acute viral hepatitis

Acute viral hepatitis can occur any time during pregnancy. Most cases are due to hepatitis A virus (HAV) infection, but occasionally hepatitis B or C viruses will be the cause. Epstein–Barr virus and cytomegalovirus (CMV) can cause a mild hepatitis (but are associated with congenital defects). Rarely, hepatitis is seen with herpes simplex virus (HSV) and herpes zoster virus infections. Herpes simplex hepatitis can be severe in pregnancy; a rash will be seen and treatment with intravenous aciclovir is recommended. A history of intravenous drug use, recent travel or illnesses in other family members supports a diagnosis of viral hepatitis. Skin lesions (such as herpes) and stigmata of chronic liver disease may be apparent on examination. Depending on the clinical situation, the following tests might be ordered: HAV IgM, HbsAb (hepatitis B surface antigen), HCVAb (hepatitis C antibodies) as well as EBV IgM and CMV IgM, and perhaps HSV IgM.

Hepatitis E has a high association with fulminant hepatitis in the third trimester of pregnancy and should be considered in women returning from regions where it is seen, such as the Indian subcontinent.

Hepatic adenomas and focal nodular hyperplasia

Hepatic adenomas and focal nodular hyperplasia are both rare, occurring in 1/1,000,000 women. They are usually asymptomatic and may be picked up on a routine ultrasound. If diagnosed before conception, it is recommended that they be removed if they are greater than 6 cm in diameter, as they may increase in size during pregnancy and then spontaneously rupture. Some clinicians recommend symptomatic or larger lesions be removed during the second trimester.

Alcohol problems

Most young women with alcohol problems have insignificant liver problems and a normal fertility. Part of the alcohol counselling should include the risks of alcohol on a subsequent pregnancy and the potential of a baby developing fetal alcohol syndrome. Contraceptives need to be offered to women of child-bearing age with high-risk alcohol intakes.

A subset of this group will have more advanced liver disease or cirrhosis (see next section).

Budd-Chiari syndrome

Pregnancy heightens a procoagulant status. Pregnant women with a thrombophilic condition are at risk of hepatic vein thrombosis (Budd-Chiari syndrome), and will present with an enlarged tender liver and ascites. The condition is diagnosed by Doppler ultrasound. Budd-Chiari syndrome has a poor outcome and affected women need to be managed in a specialty unit. Fortunately, the condition is rare.

Cholelithiasis/cholecystitis and pancreatitis

The bile becomes more lithogenic during pregnancy, with gallstones being present in 12% of pregnancies. The risk of biliary and pancreatic problems increases during pregnancy and immediately postpartum. Cholelithiasis/cholecystitis and pancreatitis need to be excluded in any pregnant woman presenting with right upper quadrant or epigastric pain and/or abnormal liver function tests. Check the liver function tests, serum amylase and lipase, and perform an ultrasound. If imaging is required, nuclear magnetic resonance would be the next choice.

The management of acute cholelithiasis/cholecystitis and pancreatitis is supportive, however about one-third do not settle and require intervention. Uncontrolled sepsis or acidosis is associated with a poor fetal outcome. Should the mother require endoscopic biliary treatment, aspiration techniques at biliary cannulation with very little screening is suggested. The woman should be imaged, rather than taking pictures, and images should not be magnified, to decrease radiation exposure to the fetus. More fetal X-ray protection is used. The patient should be intubated in later pregnancy, as pregnancy causes gastric stasis, which carries a risk of aspiration. Endoscopic sphincterotomy and/or biliary stenting usually manages the acute problem, so that cholecystectomy can be left until after delivery. Laparoscopic cholecystectomy can be safely performed in the second trimester, and there are cases reporting successful procedures performed safely during the third trimester. Fetal monitoring should be done intraoperatively, and quick-induction anaesthetic techniques used. The woman should be positioned with a 30-degree pelvic tilt on the theatre table during the third trimester. This is to prevent the gravid uterus blocking pelvic blood flow, which could cause placental insufficiency.

Gallstone pancreatitis is rare, but is associated with a poor fetal outcome if the woman becomes acidotic. There is a 70% recurrence rate of pancreatitis during the pregnancy, so endoscopic treatment is justified.

Preexisting chronic liver disease

Most women with chronic liver disease are not of childbearing age. In addition, women with chronic liver disease have a lower fertility rate due to the liver disease. The woman’s history is very important, as it is difficult to diagnose chronic liver disease in late pregnancy based on clinical features alone.

Cirrhosis

Pregnant women with cirrhosis have an increased risk of hepatic decompensation and preterm delivery, and need to be closely monitored during pregnancy. If the mother has portal hypertension, a gastroscopy is recommended to screen for oesophageal varices. If there are oesophageal varices, prophylactic banding and/or non-selective beta-blockers may be recommended, depending on their size and risk of haemorrhage. However, there are reported cases of beta-blockers affecting the growth of the long bones. Women with non-cirrhotic portal hypertension have a normal fertility, but risk a complicated pregnancy, and should be counselled, preferably before conception.

Haemorrhage is the most likely adverse outcome. Ascites is rare during pregnancy, and should alert a search for a complication, such as a portal or hepatic vein block.

Chronic hepatitis B

Hepatitis B serology, HBsAg (hepatitis B virus [HBV] surface antigen) is part of routine antenatal screening in most countries. If the HBsAg is positive, check for markers of viral replication (HBV e antigen, HBV DNA). Liver function tests should be checked for evidence of more advanced liver disease and, if present, clotting factors and so forth should be undertaken as part of the work-up of chronic liver disease. Lamivudine has been used during the third trimester in women with a high viral load, to decrease the chance of vertical transmission. The mother should be followed up postpartum, to see if antiviral therapy is needed. As most cases of HBV infection are the result of congenital infection, other family members (e.g. siblings) need to be screened.

These women need to be identified antenatally, because of the high risk of HBV vertical transmission, with chronic hepatitis B developing in the offspring. The baby should receive vaccination and hyperimmune gamma globulin (hepatitis B immunoglobulin) at birth and follow-up vaccinations. The risk of vertical transmission drops to 5% in vaccinated babies.

Chronic hepatitis C virus

Women with chronic hepatitis C usually give a history of previous intravenous drug use, and routine antenatal screening generally includes hepatitis C serology (hepatitis C virus [HCV] antibody test).

The LFTs and HCV RNA status should be checked in women who are positive for HCV antibody (that is, anti-HCV positive). There is a 5% risk of vertical transmission in women who are HCV RNA positive. This rate is possibly influenced by the mode of delivery, but as yet there are no recommendations for preferred mode of delivery. Breastfeeding, however, appears to be safe. The risk of vertical transmission relates to maternal viral load, and increases three-fold if the mother is coinfected with human immunodeficiency virus (HIV). This high rate decreases wth antiretroviral drug therapy.

The liver enzymes in patients with hepatitis C decrease during pregnancy, so these women need to be tested after delivery to get a more representative picture of the condition and its effect on the liver.

The usual treatment for hepatitis C, pegylated interferon and ribavirin, are contraindicated in pregnancy, and a hepatitis C vaccine has not yet been developed. These women should be followed up after finishing breastfeeding, and offered antiviral therapy, if appropriate.

Autoimmune chronic active hepatitis and Wilson’s disease

Both autoimmune chronic active hepatitis and Wilson’s disease (also called hepatolenticular degeneration) can occur in young women who want to have families. Pregnancy should be timed and the severity of liver disease assessed. Immunosuppressive drugs (corticosteroids and/or azathioprine) should be maintained in those with autoimmune chronic active hepatitis, and chelating agents (D-penicillamine) in those with Wilson’s disease.

Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are the most common causes of LFT abnormalities in the general community. As obesity rates rise, so does the incidence of associated liver problems. Liver histology in NAFLD and NASH shows macrovesicular fat, with or without an inflammatory reaction and increased fibrosis. These histological changes are similar to the histology seen with alcohol damage. Whereas the histological features with acute fatty liver of pregnancy are distinct (microvesicular steatosis), NAFLD and NASH remain stable throughout pregnancy and postpartum. The aminotransferases and gamma-glutamyl transpeptidase are minimally elevated. An ultrasound may show a hyperechoic liver consistent with fatty infiltration in the liver. Cirrhosis is unlikely to be seen in this age group. Affected women may give a family history of maturity onset diabetes, and have a higher body mass index. They are more likely to be older and have an increased risk of hypertension, diabetes and cholelithiasis.

The problem occurs in an overweight pregnant woman during the third trimester, where abnormal LFTs are identified on the first set of LFTs ordered. Check for echodensity changes in the liver on ultrasound, and if there is a personal or family history of insulin resistance. The woman needs to be monitored, as often it is difficult to differentiate this NASH from the beginning of a more serious pregnancy-related liver problem.

SUMMARY

The normal physiological changes in the LFTs during pregnancy are reviewed. LFTs are unchanged apart from a drop in the albumin and a rise in the alkaline phosphatase.

Liver diseases unique to pregnancy usually occur during the third trimester, the most common being cholestasis of pregnancy. This occurs in roughly 1% of pregnancies, and is characterised by the development of an itch in an otherwise asymptomatic woman. LFTs may be abnormal, and bile acids increased. Other disorders unique to pregnancy are life-threatening, and are associated with subtle constitutional symptoms and the development of pre-eclamptic features. The level of LFT abnormalities can underestimate the severity of the condition, and close monitoring in a high dependency setting and/or immediate delivery is/are required.

Other conditions occurring concurrently with the pregnancy, such as acute viral hepatitis, need to be excluded by appropriate serology. Likewise, cholelithiasis should be excluded by imaging.

Preexisting liver disorders, such as chronic hepatitis B or C, and autoimmune chronic active hepatitis, will be picked up by the history and appropriate serology. Those with unsuspected cirrhosis, alcoholic liver disease, or non alcoholic steatohepatitis can be a diagnostic problem, particularly if the first set of LFTs is done in the third trimester.

FURTHER READING

Benjaminov FS, Heathcote J. Liver disease in pregnancy. Am J Gastroenterol. 2004;99:2479-2488.

Doshi S, Zucker SD. Liver emergencies during pregnancy. Gastroenterol Clin N Am. 2003;32:1213-1227.

Glantz A, Marschall HU, Mattsson LA. Intrahepatic cholestasis of pregnancy: relationships between bile acid levels and fetal complication rates. Hepatology. 2004;40:467-474.

Guntupalli SR, Steingrub J. Hepatic disease and pregnancy: an overview of diagnosis and management. Crit Care Med. 2005;33:S332-S339.

Kaaja RJ, Greer IA. Manifestations of chronic disease during pregnancy. JAMA. 2005;294:2751-2757.

Tham TC, Vandervoort J, Wong RC, et al. Safety of ERCP during pregnancy. Am J Gastroenterol. 2003;98:308-311.

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