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Liver and gastrointestinal diseases in pregnancy 

Liver and gastrointestinal diseases in pregnancy

Liver and gastrointestinal diseases in pregnancy

Alexander Gimson

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Liver and gastrointestinal diseases unique to pregnancy

Hyperemesis gravidarum—a condition of unknown cause where severe vomiting can lead to volume depletion, ketonuria, electrolyte disturbances, and nutritional deficiency. Management is supportive.

Intrahepatic cholestasis of pregnancy—a common cause of jaundice in pregnancy, presenting in the second or third trimester, usually with pruritus. Serum bilirubin and aminotransferases may be elevated, with no significant rise in alkaline phosphatase (beyond the normal elevation expected in pregnancy) or γ‎-glutamyl transpeptidase. Serum bile acids increase 3- to 100-fold. The cause is unknown, but there is marked geographical variation. Treatment is symptomatic with the bile salt ursodeoxycholic acid, and most obstetric physicians recommend delivery at 38 weeks to prevent late fetal complications.

Acute fatty liver of pregnancy—a rare complication that usually arises between 34 and 36 weeks of gestation. Often associated with features of pre-eclampsia, with peripheral oedema, hypertension and proteinuria, and occasionally the HELLP syndrome (haemolysis, elevated liver enzymes and low platelet count). Some cases may be due to abnormalities of mitochondrial fatty acid oxidation. The most important component of management is early delivery of the fetus.

In association with hypertension—abnormalities of liver blood tests have been described in three clinical syndromes associated with high blood pressure in pregnancy: (1) pre-eclampsia/eclampsia—see Chapter 14.4. (2) HELLP syndrome—diagnosis requires haemolysis with a characteristic peripheral blood smear, serum lactate dehydrogenase 600 U/litre or more, serum aspartate aminotransferase 70 U/litre or more, and platelet count less than 100 × 109/litre. Usually presents in the second or third trimester. Maternal complications and perinatal mortality are common. Management of the coexisting pre-eclampsia is crucial, with seizure prophylaxis using magnesium sulphate and blood pressure control. Aside from signs of significant fetal distress, indications for urgent delivery include persistent severe right upper quadrant or shoulder tip pain, often associated with hypotension and thrombocytopenia, which indicate possible liver haematoma or impending rupture. (3) Spontaneous hepatic rupture.

Differential diagnosis of liver diseases associated with pregnancy—it can be difficult to distinguish acute fatty liver of pregnancy, pre-eclampsia, and HELLP syndrome. The size of the liver, degree of hyperbilirubinaemia, abnormalities on peripheral blood film, presence of hypoglycaemia, and disseminated intravascular coagulation are the most discriminatory features.

Other liver and gastrointestinal diseases in pregnancy

When dealing with a pregnant woman with liver disease it is important to remember that pregnancy does not protect against conditions that are common in those who are not pregnant. Acute viral hepatitis is the most common cause of jaundice during pregnancy: the outcome is the same as in patients who are not pregnant, with the notable exception of hepatitis E (20% mortality in pregnancy).


This chapter discusses gastrointestinal and liver diseases specific to pregnancy, those occurring with increased frequency during pregnancy, and those already present at conception or arising coincidentally during the course of pregnancy (Table 14.9.1). Liver or gastrointestinal dysfunction is present in fewer than 5% of pregnancies in Europe and the United States of America, but their recognition and management is important because increased maternal and fetal morbidity and mortality may result without prompt intervention.

Table 14.9.1 Liver diseases during pregnancy

Diseases specific to pregnancy

Hyperemesis gravidarum

Intrahepatic cholestasis of pregnancy

Acute fatty liver of pregnancy

Hypertension-associated liver diseases of pregnancy

Diseases where pregnancy increases frequency or severity of presentation

Budd–Chiari syndrome—increased frequency, possibly related to low antithrombin III levels

Acute cholecystitis—increased risk of gallstones/complications

Acute viral hepatitis E—increased frequency of acute liver failure in the third trimester

Hepatic tumours—vascular hepatic tumours may enlarge and rupture

Variceal haemorrhage—more common in non-cirrhotic portal hypertension

Liver diseases manifesting during but unrelated to pregnancy

Acute viral hepatitis A, B, cytomegalovirus, Epstein–Barr virus

Chronic liver diseases

Drug hepatotoxicity

There are significant physiological changes in hepatic function during pregnancy. The increased circulating blood volume and cardiac output are not associated with any changes in hepatic blood flow, but there is increased azygous flow that results rarely in the formation of small oesophageal varices. Gallbladder motility is reduced and bile lithogenicity increased due to increased hepatic cholesterol synthesis and excretion into bile. Minor but important changes in laboratory blood tests occur due to haemodilution or alteration in hepatic synthesis (Table 14.9.2).

Table 14.9.2 Effects of pregnancy on laboratory blood tests



Trimester with maximum change






Bile salts




γ‎-Glutamyl transpeptidase


Alkaline phosphatase



Increased bone/placental isoenzyme




Dilution, reduced synthesis








Increased hepatic synthesis




Increased hepatic synthesis

Increased gastric myoelectric activity may be manifest as nausea and vomiting, but there are few other significant changes in gastrointestinal function during normal pregnancy.

Liver diseases specific to pregnancy

Hyperemesis gravidarum

Although nausea and vomiting may occur in up to 75% of pregnancies, severe vomiting leading to dehydration, ketonuria, electrolyte disturbances, and nutritional deficiency is rare, developing in 2 to 16 of every 1000 pregnancies. Nutritional deficiency has been so severe as to progress to Wernicke’s encephalopathy and changes in serum sodium may precipitate osmotic demyelination (central pontine myelinolysis). This is more common in younger women, in obesity, and in those with pre-existing diabetes or gastrointestinal disorders; recent surveys do not suggest any relationship with parity or gravidity. Elevated transaminases, by two- to threefold, occur in 50% of cases, with a minor rise in alkaline phosphatase and bilirubin in 10%. Liver histology shows few abnormalities or hepatic steatosis only. The aetiology is unclear and may be multifactorial: positive helicobacter serology has been reported in up to 90% of cases, and changes in thyroid function are present in 50%. An elevated free thyroxin (T4) with suppressed thyroid-stimulating hormone (TSH) correlates with elevated human chorionic gonadotrophin (hCG) levels in these patients, raising the possibility that gestational thyrotoxicosis may also have role in pathogenesis. In some cases psychological factors are also important.

Management, which may require hospitalization, is symptomatic and includes rehydration and correction of nutritional deficiencies. Psychological support is crucial. Treatment of symptomatic gastro-oesophageal reflux is important and antiemetics are required, with metoclopramide and promethazine as effective as newer 5-HT3 antagonists. There are uncontrolled reports and a single controlled trial demonstrating benefit with corticosteroids. In rare cases there may be recurrence in subsequent pregnancies.

Intrahepatic cholestasis of pregnancy

This cholestatic disorder of the second and third trimesters is the most common cause of jaundice during pregnancy, after acute viral hepatitis. Initially starting with pruritus, jaundice follows after 1 to 4 weeks in 20 to 60% of cases, associated with pale stools and dark urine. Diagnosis is by history and the classic biochemical features of an elevated bilirubin (<100 µmol/litre) and increased aminotransferases (rarely >250 IU/litre), with no significant rise in alkaline phosphatase (beyond the normal elevation expected in pregnancy) or γ‎-glutamyl transpeptidase. Serum bile acids increase 3- to 100-fold, those factors with the highest predictive diagnostic value being total bile acid concentration of more than 11.0 µmol/litre and a cholic/chenodeoxycholic acid ratio of more than 1.5 with a cholic acid percentage over 42. In a large cohort study fetal complications were most common in those cases with bile acid level greater than 40 µmol/l. An ultrasound scan is necessary to exclude choledocholithiasis, and further imaging of the bile duct with magnetic resonance cholangiopancreatography will occasionally be needed. A liver biopsy is not required for diagnosis, but shows a canalicular cholestasis with no hepatocellular necrosis.

The epidemiology of intrahepatic cholestasis of pregnancy is interesting, with marked geographical variation. The highest incidence, over 10%, has been recorded in Arauncanian Indians in Chile, with 2 to 3% in Sweden and 0.1% in Canada. It is rare in Afro-Caribbeans. It is more common in women with a history of contraceptive pill induced jaundice (50%) and those with benign recurrent intrahepatic cholestasis who have multiple gestations, and it may be more common in women who are positive for hepatitis C virus antibodies. In France it has been associated with use of progesterone in early pregnancy.

The aetiology is unknown, but one hypothesis suggests enhanced sensitivity of components of the bile salt excretion apparatus to oestrogen: pregnancy impairs sulphation of both monohydroxy bile salts and oestrogen, which may enhance the cholestatic potential of both compounds. Family studies have suggested a dominant mode of transmission in a few kindreds. Mutations in the MDR3 gene (ABCB4) that encodes an ATP-dependent transporter of phosphatidylcholine across the canalicular membrane occur more commonly in those with the severe form of the disease.

Intrahepatic cholestasis of pregnancy is associated with an increased incidence of fetal prematurity (fivefold increase), fetal distress, stillbirths, and meconium staining of amniotic fluid (1.5-fold increase), but perinatal mortality is normal with modern management. Reports of maternal morbidity from postpartum haemorrhage relate to vitamin K deficiency and are not a feature of recent series.

Treatment is symptomatic, with the bile salt ursodeoxycholic acid (10–15 mg/kg per day) the treatment of choice and better than S-adenosylmethionine. Ursodeoxycholic acid relieves pruritus, reduces bile salt levels in maternal serum, and may reduce the frequency of fetal complications. Both bile salt sequestration with cholestyramine and dexamethasone have given variable results. Vitamin K should be given before delivery.

Most authors recommend elective delivery at 38 weeks to prevent late fetal complications, and this has been shown to improve fetal outcome. More recently there have been suggestions that a policy of careful observation and induction of labour only for fetal distress may be used in those with lower bile acid levels, but there is anxiety that classical markers of fetal distress may not be adequate in this setting.

Intrahepatic cholestasis of pregnancy recurs in up to 60 to 80% of subsequent pregnancies and is associated with a late increased incidence of gallstones. Oral contraceptives should be used with caution, although early reports of liver abnormalities were predominantly with high-dose pills and combined low-dose preparations may cause fewer problems.

Acute fatty liver of pregnancy

Acute fatty liver of pregnancy, a microvesicular steatosis during the last trimester of pregnancy, was first adequately described by Sheehan in 1940. Occurring in 1 in 14 000 pregnancies between the 34th and 36th weeks, it is more common in primigravidae, with male fetuses, and with twin pregnancies. Up to 40% may have associated features of pre-eclampsia, with peripheral oedema, hypertension, and proteinuria, and occasionally the HELLP syndrome (haemolysis, elevated liver enzymes and low platelet count; see below). Acute fatty liver of pregnancy occurs only rarely before the third trimester, but postpartum presentations are well recorded. Initial symptoms are of headache, fatigue, nausea, and vomiting with abdominal discomfort. In severe cases jaundice develops within 14 days. This may progress to manifest all the features of acute liver failure, including coma, renal failure and death. However, less severe cases are now described more commonly, with recent series reporting a 10 to 20% fetal and maternal mortality.

The cause of many cases of acute fatty liver of pregnancy may be a fetal–maternal interaction resulting from abnormalities of mitochondrial fatty acid oxidation, more commonly with long than medium or short chain defects. A mutation involving substitution of glutamine for glutamic acid at amino acid residue 474 of the α‎ subunit of long-chain 3-hydroxyacyl-CoA dehydrogenase, an enzyme that forms one component of a trifunctional protein catalysing the last three steps in the β‎-oxidation of fatty acids within mitochondria, has been found in up to 20% of pregnancies in this condition. Up to 80% of heterozygote mothers carrying fetuses with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency may develop either acute fatty liver of pregnancy or HELLP syndrome. Mitochondrial oxidation of fatty acids is already impaired during pregnancy, mediated by oestrogen and progesterone, and long-chain 3-hydroxyacyl metabolites produced by the fetus can accumulate and be toxic to the liver. Because presentation of children with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency may occur late after birth, with nonketotic hypoglycaemia and sudden infant death, the early identification and treatment of such cases is important. For this reason diagnostic molecular testing is recommended on all mothers and offspring of acute fatty liver of pregnancy and HELLP pregnancies.

The important differential diagnosis is between acute viral hepatitis with liver failure, acute fatty liver of pregnancy, and hypertension-associated liver dysfunction of pregnancy. The presence of features of pre-eclampsia in up to 40% may make this distinction difficult. In acute fatty liver of pregnancy transaminases are elevated to less than 500 IU/litre, in contrast to viral hepatitis where values are usually higher. Hypoglycaemia is more common in acute fatty liver of pregnancy than in pre-eclampsia, and a blood film commonly showing neutrophilia, normoblasts, thrombocytopenia, target cells and giant platelets may also help to make the diagnosis of acute fatty liver of pregnancy. Prothrombin and partial thromboplastin times are prolonged with low antithrombin III levels. Although hepatic steatosis in acute fatty liver of pregnancy may be detected by ultrasonography, CT scanning is more sensitive with attenuation values less than half normal and less than spleen, the reverse of normal. Hyperuricaemia is present in 80%, but is not pathognomonic as this may also be found in pre-eclampsia.

Despite all these biochemical and radiological tests, and because differentiation of acute fatty liver of pregnancy from acute viral hepatitis and hypertension-associated liver diseases is important in assessing the prognosis for future pregnancies, a liver biopsy may be necessary to distinguish between these three diagnoses. Histology demonstrates a microvesicular fat deposition with rare hepatocyte necrosis and minimal inflammation, a pattern similar to that seen in Reye’s syndrome, tetracycline and sodium valproate hepatotoxicity, Jamaican vomiting sickness due to a toxin in unripe ackee fruit, some urea cycle enzyme deficiencies, and defects in mitochondrial fatty acid oxidation.

Other obstetric causes of renal failure that are associated with minor changes in liver blood tests rarely need to be considered. These include thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome. The former is particularly associated with neurological signs, including epileptic fits, without evidence of disseminated intravascular coagulation, whereas haemolytic uraemic syndrome may occur postpartum and with microangiopathic anaemia.

After the diagnosis of acute fatty liver of pregnancy has been established, the most important component of management is early delivery of the fetus. A policy of careful monitoring has been proposed for the mildest cases, but extreme caution is required as deterioration can be sudden and unpredictable. Vaginal delivery can be tried first, but caesarean section will usually require general anaesthesia as a spinal anaesthetic in the presence of coagulation deficits is dangerous. Hypoglycaemia is prevented by intravenous dextrose infusion; aggressive correction of coagulation abnormalities with fresh frozen plasma, cryoprecipitate, and antithrombin III has also been recommended. Liver transplantation has been used (very rarely) for cases failing to respond to early delivery and intensive care.

The risk of recurrence of acute fatty liver of pregnancy is very low, the few recorded cases most probably being due to associated recurrent metabolic defects in the fetus.

Hypertension-associated liver diseases of pregnancy

Hypertension occurs in up to 8% of pregnancies and is the most common cause of maternal mortality in developed countries. Abnormalities of liver blood tests have been described in three clinical syndromes associated with hypertension in pregnancy: pre-eclampsia/eclampsia, spontaneous hepatic rupture, and the HELLP syndrome.


Pre-eclampsia is discussed in detail in Chapter 14.4. There are abnormalities of liver biochemistry in up to 25% of mild cases and up to 80% of those with severe disease, i.e. those with renal impairment, visual disturbance, headache, fits, and the onset of eclampsia. The usual abnormality is a rise in transaminases, with jaundice occurring only in the most severe cases. The alanine aminotransferase levels are usually less than 150 IU/litre, lower than in acute fatty liver of pregnancy, and bilirubin is less than 100 µmol/litre. Changes in coagulation parameters, with elevated d-dimers, reflect the intravascular activation and consumption of clotting factors. Antithrombin III levels are low. Liver histology in the early stages shows few changes except for deposition of fibrinogen within sinusoids and the space of Disse. Blockage of sinusoids by fibrin may progress to frank infarction of hepatic parenchyma, when the low levels of coagulation factors may then predispose to haemorrhage into these infarcted areas. This combination of infarcts and associated haemorrhage, often covert and without apparent clinical consequence, may be demonstrated on ultrasound or CT scan of the liver.

The management of liver dysfunction in this context is that for pre-eclampsia, with correction of hypertension and coagulation defects, early delivery being the most important aspect. Anticonvulsant prophylaxis must be considered. Very close fetal monitoring is important. Liver biochemistry improves after delivery, but a late cholestatic phase with rise in alkaline phosphatase and γ‎-glutamyl transpeptidase is common.

Spontaneous hepatic rupture

Spontaneous rupture of the liver is fortunately rare, occurring in 1 in 100 000 deliveries. In 80% of cases liver haematomas, segmental or larger infarcts, and rupture occur in patients with severe pre-eclampsia and eclampsia: the remainder occur in association with acute fatty liver of pregnancy, or underlying hepatic adenomata, hepatocellular carcinoma, haemangioma, choriocarcinoma, or liver abscess.

The classical presentation is with right upper quadrant pain, nausea, vomiting and hypotension in an older woman with severe pre-eclampsia during the third trimester. Right upper quadrant tenderness may be associated with frank peritonism where rupture into the peritoneum has occurred. The diagnosis can be confirmed by ultrasonography or CT scanning. Treatment is conservative if possible, starting with angiography and hepatic artery embolization, proceeding to laparotomy, use of collagen meshes, and hepatic artery ligation if necessary. Successful orthotopic liver transplantation has been performed, but associated coagulation abnormalities are difficult to manage. The baby should be delivered by caesarean section. Successful subsequent pregnancies are recorded, as is recurrent haemorrhage, hence careful monitoring of any future pregnancy is necessary.

Haemolysis, elevated liver enzymes, and low platelet count (HELLP syndrome)

Weinstein first described a syndrome of haemolysis, elevated liver enzymes, and a low platelet count in patients with severe pre-eclampsia or eclampsia. HELLP syndrome occurs in 10% of pregnancies with severe pre-eclampsia. Strict criteria should be used for the diagnosis: haemolysis with a characteristic peripheral blood smear, serum lactate dehydrogenase 600 U/litre or more, serum aspartate aminotransferase 70 U/litre or more, and platelet count less than 100 × 109/litre. An abnormal peripheral blood smear with fractured red blood cells (schistocytes, echinocytes, spherostomatocytes) is sensitive but not specific for HELLP, and the elevated serum lactate dehydrogenase is simply another indicator of haemolysis. Some cases display only one or two of the above criteria and have been labelled as having partial HELLP: these have been shown to follow a less severe clinical course. HELLP syndrome has also been classified (by Martin and colleagues) according to platelet count: in class 1 the platelet count is 50 × 109/litre or less, in class 2 it is 50 to 100 × 109/litre, and in class 3 more than 100 × 109/litre, which is equivalent to partial HELLP.

The reason why some cases with severe pre-eclampsia progress to HELLP syndrome is not clear. The haemolysis is clearly related to intravascular deposition of thrombin and mechanical fracture of red cells, and there is fibrin deposition obstructing hepatic sinusoids, but the factors causing particular damage to the hepatic microcirculation are unknown. Overt disseminated intravascular coagulation is not usually a major component: when defined as hypofibrinogenaemia (<300 mg/dl) and elevated d-dimers (>40 µg/ml) it occurred in 21% of a series of 442 cases. Compared with other cases with severe pre-eclampsia, those with HELLP syndrome tend to be older, white, and multiparous. HELLP may be more common in mothers heterozygous for thrombophilic states.

Symptoms usually start in the second or third trimester, with 15% starting prior to 26 weeks and 30% only developing symptoms after delivery. HELLP syndrome has protean manifestations but universal early symptoms include malaise and fatigue, followed by nausea, vomiting, and headache shortly thereafter (Table 14.9.3). Epigastric and right upper quadrant pain are ominous signs, particularly when accompanied by right shoulder tip pain. Weight gain and peripheral oedema are found in 50%, with diastolic blood pressure 90 mmHg or more in all but a small minority.

Table 14.9.3 Clinical features and complications of hypertension-associated liver diseases

HELLP syndrome


Martin et al. (1999)

Sibai et al. (1993)

Audibert et al. (1996)

Martin et al. (1999)

Symptoms (%)











Epigastric/abdominal pain





Maternal complications (%)





  • Haematological/

  • DIC















  • Neurological/

  • Ophthalmic










Obstetric complications (%)






Placental abruption





Perinatal mortality/1000 births



DIC, disseminated intravascular coagulation.

The fall in platelet count and rise in transaminases usually reach their nadir in the first 2 days postpartum. Aspartate aminotransferase and lactate dehydrogenase are elevated in unison, along with other markers of hepatocellular or sinusoidal cell dysfunction, glutathione-S-transferase and hyaluronic acid.

Maternal complications associated with HELLP syndrome occur in up to 50% of cases. Blood transfusion to correct hypovolaemia, anaemia, or coagulopathy is required in 50%, with features of disseminated intravascular coagulation in 25%, and pleural effusions or pulmonary oedema in 15 to 20%. Renal failure due to acute tubular necrosis may occur in 3 to 8%. Obstetric complications are also associated with the degree of fall in platelet counts, with placental abruption (16%) and wound haematomas after caesarean section the most prevalent. Eclampsia is approximately two to three times more common in patients with class 1 HELLP than in those with milder varieties, and consistent with this the maternal mortality was 1.5% in a large series, with a perinatal mortality in Martin et al.’s tertiary referral practice of 119/1000 infants. Overall perinatal mortality is strongly related to time of delivery, with rates as high as 30% in some series, although this may be due to case selection. Mortality was 9.5% in a large series assessing class 1, 2, and 3 cases. Preterm infants born before 32 weeks from mothers with HELLP syndrome had a higher frequency of severe intraventricular haemorrhage than other preterm infants. Birth weights tend to be lower in severe HELLP than in pre-eclampsia alone.

Preterm patients with HELLP syndrome should be treated at a referral centre with appropriate obstetric, anaesthetic, and haematological support. Management of the coexisting pre-eclampsia is crucial, with seizure prophylaxis using magnesium sulphate and blood pressure control with labetolol, ketanserin, or hydrallazine if blood pressure is more than 160/105 mmHg. Antenatal corticosteroids enhance fetal lung maturity if the pregnancy is of less than 32 weeks gestation. Careful fluid resuscitation is required to prevent volume overload, particularly in the presence of renal impairment, as is very close fetal monitoring.

Aside from signs of significant fetal distress, indications for urgent delivery include persistent severe right upper quadrant or shoulder tip pain, often associated with hypotension and thrombocytopenia, which indicate possible liver haematoma or impending rupture. Early delivery, at the safest time for mother and fetus, is strongly recommended in the absence of treatment that unequivocally improves the haematological abnormalities and both maternal and fetal outcome. Although arguments have been put forward for a more conservative approach in patients with mild disease—with careful monitoring of coagulation profiles, fetal growth and well-being, and with the timing of delivery depending on clinical judgement—this management strategy is not without risk and has not been examined in a randomized controlled trial.

Attempts have been made to improve the outcome of HELLP with medical management alone in an effort to buy time to enhance fetal maturity and to improve the mother’s clinical condition prior to delivery. Although plasma volume expansion, antithrombotic agents, plasma exchange and corticosteroids have all been advocated, no therapies have been shown to allow safe deferral of delivery and improve outcome. In one study dexamethasone given before delivery resulted in a modest prolongation of pregnancy, whereas two other trials showed significant improvements in haematological and biochemical parameters when this was given postpartum. In a trial of invasive haemodynamic monitoring, plasma volume expansion and afterload reduction, laboratory parameters improved with prolongation of gestation by 21 days, but no significant change in perinatal mortality.

Recurrence of HELLP syndrome in subsequent pregnancies is uncommon: it recurred in only 5% of a series of 139 normotensive women after an index pregnancy with HELLP syndrome, despite 25% developing pre-eclampsia. In hypertensive cases a further pregnancy was associated with pre-eclampsia in 70% and HELLP syndrome in 8%.

Differential diagnosis of jaundice during pregnancy

Many patients with acute fatty liver of pregnancy have signs of pre-eclampsia and such cases may be part of a clinical syndrome that includes hypertension-associated liver diseases. Evidence for this possibility includes the finding of microvesicular hepatic steatosis in cases with pre-eclampsia; indeed one study found fat deposition by special staining in all 41 cases examined. Histological evidence of both pre-eclampsia and acute fatty liver of pregnancy has also been demonstrated in some cases, and pregnancies associated with pre-eclampsia have been followed in the next by HELLP syndrome. Despite this there are usually features in the clinical history or laboratory findings (Table 14.9.4) that allow discrimination between these diagnoses. The size of the liver, degree of hyperbilirubinaemia, abnormalities on peripheral blood film, presence of hypoglycaemia, and disseminated intravascular coagulation are the most discriminatory tests. The differential diagnosis of jaundice and abnormal liver blood tests differs in the three trimesters of pregnancy (Table 14.9.5).

Table 14.9.4 Clinical features and laboratory variables in acute fatty liver of pregnancy, HELLP syndrome, and pre-eclampsia

Acute fatty liver of pregnancy


Severe pre-eclampsia


1/13 000



Clinical features

Nausea/vomiting (70%)

Malaise/lethargy (90%)

Oedema (80%)


RUQ pain (65%)

Nausea/vomiting (35%)

Weight gain (75%)

Small liver

Oedema/weight gain (60%)

RUQ tenderness


RUQ tenderness (80%)

Mental status changes

Encephalopathy later

Hypertension (80%)

Hypertension 40%

Liver normal size



Bilirubin <100 µmol/litre

Bilirubin variable

Bilirubin >100 µmol/litre

ALT 150 IU/litre

ALT 150–200 IU/litre (unless infarction)

ALT 300 IU/litre

Hypoglycaemia rare

DIC 7%


DIC 25%

DIC 75%

Maternal mortality




Fetal mortality




Very rare



ALT, serum alanine aminotransferase; DIC, disseminated intravascular coagulation; RUQ, right upper quadrant.

Table 14.9.5 Differential diagnosis of abnormal liver blood tests during pregnancy



Clinical features, diagnostic criteria, and investigations

First trimester

Acute viral hepatitis

As general population

IgM anti-HAV, IgM anti-HBc, IgM anti-HEV CMV PCR, EBV serology, IgM anti-herpes simplex



RUQ pain, fever, gallstones/dilated common bile duct on USS/MRCP for choledocholithiasis

Drug-induced hepatotoxicity


Drug history

Hyperemesis gravidarum


Young, overweight, multiple births. ALT <200 IU/litre. Low TSH in 50%

Intrahepatic cholestasis of pregnancy


Pruritus. ALT <300 IU/l, bilirubin <100 µmol/litre, bile acids × 30–100

Second trimester

Acute viral hepatitis

As general population

As for first trimester



As for first trimester

Drug hepatotoxicity


As for first trimester

Intrahepatic cholestasis of pregnancy


As for first trimester



Lethargy (90%), weight gain, hypertension. Bilirubin <100 µmol/litre, ALT 150–300 IU/litre unless infarction. Hypoglycaemia rare, DIC 7%

HELLP syndromea


RUQ pain, vomiting, haemolysis (LDH >600 IU/litre, blood film), ALT >70 IU/litre, platelets <100, bilirubin <100 µmol/litre, ALT 150–300 IU/litre unless infarction. Hypoglycaemia rare, DIC 25%

Third trimester

Intrahepatic cholestasis of pregnancy


As for first trimester



As for second trimester

Hepatic rupture


RUQ/shoulder tip pain, low blood pressure/peritonism. CT, angiography

HELLP syndrome


As for second trimester

Acute fatty liver of pregnancy


Nausea/vomiting (70%), RUQ pain (65%), small liver, hypertension (40%), encephalopathy later, leucocytosis. Bilirubin >100 µmol/litre, ALT 300 IU/litre. Hypoglycaemia, DIC 75%. USS

Acute viral hepatitis

As general population

As for first trimester



As for first trimester

Drug hepatotoxicity


As for first trimester

a Rare in this trimester.

ALT, serum alanine aminotransferase; CMV, cytomegalovirus; DIC, disseminated intravascular coagulation; EBV, Epstein–Barr virus; HAV, hepatitis A virus; HEV, hepatitis E virus; LDH, serum lactate dehydrogenase; MCRP, magnetic resonance cholangiopancreatography; PCR, polymerase chain reaction; RUQ, right upper quadrant; TSH, thyroid-stimulating hormone; USS, ultrasound scan.

Liver diseases that are commoner in pregnancy

Budd–Chiari syndrome

Thrombosis in one or more hepatic veins has an increased prevalence during pregnancy and in those on the oral contraceptive pill. This relates to low antithrombin III levels and may be more common in those with an underlying procoagulant state or presence of antiphospholipid antibodies. Right upper quadrant pain, hepatomegaly and maternal ascites should suggest the diagnosis, with confirmation by ultrasonography or hepatic venous angiography. Although hepatic venous balloon dilatation or insertion of a transjugular intrahepatic stent shunt has been recommended for Budd–Chiari syndrome, there are few data on their use during pregnancy. Maternal mortality remains very high.


Gallbladder sludge and gallstones develop in 31% and 9% of pregnancies respectively, although most resolve thereafter. Prior use of oral contraceptives, increased cholesterol synthesis, reduced cholesterol carriage in bile, and impaired gallbladder motility all account for the increased lithogenicity of bile. Symptomatic gallstone disease should be managed in the usual way. Magnetic resonance cholangiopancreatography (MRCP) can accurately detect common bile duct stones without exposing the fetus to radiation, with endoscopic sphincterotomy and/or stent placement reserved for those in whom they are detected. In most cases surgery can be deferred until after delivery.

Other hepatological conditions in pregnancy

Viral hepatitis

Acute viral hepatitis is the most common cause of jaundice during pregnancy (Table 14.9.5), with no specific change to presentation, clinical course or outcome for acute hepatitis A, B, cytomegalovirus, or Epstein–Barr virus infection.

Transmission of virus from a mother with acute hepatitis B to her child occurs in 50% of cases, rising to 70% when hepatitis starts in the third trimester. Transmission of virus from mothers with chronic hepatitis B carriage is less common, but depends on the level of viral replication. The rate is at least 90% in those who are hepatitis B virus DNA positive, and who are usually hepatitis B e antigen positive, as is most common in East Asians. Following vertical transmission up to 80% of offspring become chronic HBsAg carriers. Transmission of hepatitis B can be effectively interrupted by use of hepatitis B immunoglobulin at birth, with hepatitis B virus vaccination within 7 days and at 1, 2, and 12 months.

Transmission of hepatitis C from chronic carriers occurs in up to 8% of cases, being higher in those with high maternal viral load. Hepatitis C virus antibody seroconversion of infants following transmission may take 6 to 12 months to appear, but detection of hepatitis C virus RNA by polymerase chaine reaction allows detection of transmission sooner.

Acute hepatitis E is due to an RNA virus and occurs, often in waterborne epidemics, predominantly in the Middle East and East Asia. In pregnancy it is associated with a mortality of up to 20% due to development of acute liver failure during the third trimester, but transmission to offspring has not been recorded.

Liver tumour during pregnancy

The first presentations of focal nodular hyperplasia, hepatic adenoma, hepatocellular carcinoma, and cholangiocarcinoma have all been reported during pregnancy. Adenomas, in some cases related to prior oral contraceptive use, may undergo vascular engorgement during pregnancy and rupture has been reported. Secondary tumours, including hepatic choriocarcinoma and ovarian teratomas, may also rupture.

Pregnancy during chronic liver disease

Most patients with established cirrhosis are infertile, but a few remain fertile, although with a high rate of prematurity, low-birthweight babies, and stillbirths. There is little evidence that pregnancy results in deterioration in liver dysfunction in patients with cirrhosis, and improvement of inflammatory activity occurs in some cases of autoimmune chronic active liver disease. There is no increased rate of relapse after delivery. Patients with treated Wilson’s disease are able to conceive and successful pregnancies whilst taking d-penicillamine or trientine have been reported.

Variceal haemorrhage

Changes in splanchnic haemodynamics, increased cardiac output and azygous blood flow, and an increase in circulating blood volume have all been suggested as risk factors for variceal bleeding during pregnancy. Evidence for this remains controversial, although recent large series of patients with noncirrhotic portal hypertension report a haemorrhage rate of 13%. Treatment of variceal bleeding during pregnancy should be by conventional endoscopic techniques, with use of transjugular intrahepatic stent shunts or surgical shunts reserved for rescue therapy.

Pregnancy following orthotopic liver transplantation

Fertility returns quickly following liver transplantation. Pregnancy does not alter the risks of cellular rejection, but immunosuppressive drug toxicity needs to be carefully monitored. Azathioprine may cause neonatal pancytopenia, and ciclosporin A is associated with a 40% incidence of hypertension, which may be lower with tacrolimus.

Pregnancy during gastrointestinal disease

Only a few gastrointestinal diseases occur with altered frequency during pregnancy.

Gastro-oesophageal reflux

Symptomatic gastro-oesophageal reflux is present at some stage in up to 80% of pregnancies. It is mainly due to a reduced lower oesophageal sphincter pressure rather than elevated intra-abdominal pressure from a gravid uterus. Treatment with antacid is recommended, with avoidance of H2 antagonists or proton pump inhibitors unless symptoms and complications of gastro-oesophageal reflux outweigh potential drug toxicity. Acid–pepsin reflux combined with vomiting in early pregnancy may precipitate haematemesis, occasionally with a Mallory–Weiss tear, for which management should be as in the nonpregnant state. Upper gastrointestinal endoscopy is a safe procedure during pregnancy.

Inflammatory bowel disease

Stable inactive ulcerative colitis and Crohn’s disease do not affect fertilityand are not associated with increased fetal risk; disease control is not impeded by pregnancy. There are few data on the effect of drug therapy on fertility, although sperm counts may be reduced in men on salazopyrine. The risk of relapse of inflammatory bowel disease during pregnancy has been assessed at between 30 and 50%, but this is no higher than comparable nonpregnant control groups. Folate and iron supplementation are recommended, with regular monitoring of nutritional status.

Active inflammatory bowel disease is associated with involuntary infertility, and when very severe it is prudent to recommend deferring any attempt to conceive. Increased fetal loss may occur when active inflammatory bowel disease is first manifest during pregnancy, with recent reports suggesting that the site of disease activity (colonic or small bowel) does not affect outcome. Most studies have demonstrated that corticosteroids, sulphasalazine, and 5-aminosalicylic acid preparations are safe to use during pregnancy. Colonoscopy, in expert hands, can be performed during pregnancy without risk, although it is often possible to defer this procedure.

Acute appendicitis

Acute appendicitis, the most common nonobstetric emergency requiring surgery, occurs in 1 in 2500 to 1 in 3500 pregnancies. It is not clear if reports of a more aggressive clinical course reflect delays in diagnosis or reporting bias. Clinical management is similar to that of the nonpregnant case: surgery must not be deferred, as the frequency of prematurity and perinatal mortality may be increased if perforation occurs.

Coeliac disease

Women with untreated coeliac disease have a markedly increased risk of abortion and low birthweight babies, which can be reversed following institution of a gluten-free diet. Screening for coeliac disease should be considered in women with a previous history of abortion or unfavourable pregnancy outcomes.

Further reading

Audibert F, et al. (1996). Clinical utility of strict criteria for the HELLP syndrome. Am J Obstet Gynecol, 175, 460–4.Find this resource:

Geenes V, Williamson C (2009). Intrahepatic cholestasis of pregnancy. World J of Gastroenterol, 15(17), 2049–66.Find this resource:

Hay JE (2008). Liver Disease in pregnancy. Hepatology, 47, 1067–76.Find this resource:

Ibdah JA, et al. (1999). A fetal fatty-acid oxidation disorder as a cause of liver disease in pregnant women. N Engl J Med, 340, 1723–31.Find this resource:

Knox T, Olans L (1996). Liver disease in pregnancy. N Engl J Med, 335, 569–76.Find this resource:

Kochhar R, et al. (1999). Pregnancy and its outcome in patients with noncirrhotic portal hypertension. Digest Dis Sci, 44, 1356–61.Find this resource:

Korelitz BI (1992). Inflammatory bowel disease and pregnancy. Gastroenterol Clin North Am, 27, 213–24.Find this resource:

Martin JN, et al. (1999). The spectrum of severe preeclampsia: comparative analysis by HELLP (hemolysis, elevated liver enzyme levels, and low platelet count) syndrome classification. Am J Obstet Gynecol, 180, 1373–84.Find this resource:

Martinelli P, et al. (2000). Coeliac disease and unfavourable outcome of pregnancy. Gut, 46, 332–5.Find this resource:

Mayberry J, Weterman IT (1986). European survey of fertility and pregnancy in women with Crohn’s disease; a case control study by the European Collaborative group. Gut, 27, 821–5.Find this resource:

Modigliani R, (1997). Drug therapy for ulcerative colitis during pregnancy. Eur J Gastroenterol Hepatol, 9, 854–7.Find this resource:

Nicastri P, et al. (1998). A randomised placebo-controlled trial of ursodeoxycholic acid and S-adenosylmethionine in the treatment of intrahepatic cholestasis of pregnancy. Br J Obstet Gynaecol, 105, 1205–7.Find this resource:

Palma J, et al. (1997). Ursodeoxycholic acid in the treatment of cholestasis of pregnancy: a randomized, double-blind study controlled with placebo. J Hepatol, 27, 1022–8.Find this resource:

Sibai BM, et al. (1993). Maternal morbidity and mortality in 442 pregnancies with hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome). Am J Obstet Gynecol, 169, 1000–1006.Find this resource: