10 Michael A. Heneghan1 and Catherine Williamson2 1 Institute of Liver Studies, King’s College Hospital, London, UK 2 King’s College London, Guys Campus, London, UK In pregnancy, physiological changes occur that mimic the changes seen in decompensated chronic liver disease and cirrhosis. These changes peak in the second trimester. Blood volume increases by 50% yet blood flow to the liver remains constant and typically the liver is not palpable during the pregnancy. Examination changes of telangiectasia, spider angiomas and palmar erythema are normal, and may be confused with the presence of cirrhosis. There is an increased tendency to bile lithogenicity and there is an increased incidence of gallstone formation as a consequence [1,2]. Similarly, the contractility of the gallbladder is reduced. These findings are all related to increasing oestrogen. In a normal pregnancy, plasma volume results in a fall in many serum markers including albumin levels. Alkaline phosphatase activity increases due to placental secretion. Aminotransferase levels (alanine aminotransferase, ALT, and aspartate aminotransferase, AST), bilirubin and gamma‐glutamyl transpeptidase (GGT) all remain normal throughout pregnancy. When abnormalities exist in these parameters, further investigation is warranted. Liver histology typically is normal. Table 10.1 summarizes the laboratory changes occurring in pregnancy. Table 10.1 Liver function test results in normal pregnancy. Source: adapted from Girling et al. [1] and Walker et al. [19]. ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma‐glutamyl transpeptidase. Imaging of the liver is a frequent requirement. Ultrasound is the safest modality but should further imaging be required, magnetic resonance imaging (MRI) without contrast is safe. Gadolinium‐enhanced MRI should be avoided unless essential due to transplacental transfer and the unknown effects on the fetus, although increasing evidence suggests that in the third trimester it is possible to do this safely. Computed tomography (CT) and endoscopic retrograde cholangiopancreatography (ERCP) can also be used during pregnancy. However, precautions should be taken to shield the fetus from radiation or to provide dosimetry estimates if significant exposure is likely. The presence of liver enlargement is always an abnormal finding in pregnancy, and hepatomegaly if identified may signify an infiltrative process ranging from acute fatty liver of pregnancy in the correct context to viral hepatitis, or even an infiltrative process such as lymphoma or cancer. Since pregnancy itself is a procoagulant state, consideration also needs to be given to outflow obstruction of the hepatic veins in the form of Budd–Chiari syndrome. Jaundice and scleral icterus are abnormal findings and always warrant further evaluation. It is very rare that a liver biopsy is actually needed in the management of patients with liver disease in pregnancy. It is unusual for a liver biopsy to influence the timing or decision to proceed with delivery. However, liver biopsy can be undertaken if clinically indicated. The typical biochemical features of pregnancy‐specific liver diseases are summarized in Table 10.2. Table 10.2 Characteristic timings and diagnostic laboratory features in the liver diseases unique to pregnancy. HELLP, haemolysis, elevated liver enzymes and low platelets; ALT, alanine aminotransferase; AST, aspartate aminotransferase; LDH, lactate dehydrogenase. Nausea and vomiting are common in pregnancy. However, exact estimates vary in relation to the prevalence of hyperemesis gravidarum (HG). Reports range from 0.3 to 2% of all pregnancies, typically within the first trimester [3,4]. Under‐reporting of symptoms may in fact account for the variation in incidence in the literature. One of the most frequently used definitions of HG is intractable vomiting, resulting in ketosis, dehydration and weight loss of 5% or greater of body weight. The aetiology remains unclear but a combination of abnormal gastric motility, hormonal factors and changes in the autonomic nervous system are all thought to play a key role. Risk factors include increased body mass index (BMI), psychiatric illness, molar pregnancy, pre‐existing diabetes and multiple pregnancies whilst hyperthyroidism is identified in an estimated 60% of cases [5–8]. Higher serum concentrations of human chorionic gonadotrophin (hCG) may stimulate the thyroid in pregnancy, accounting for this finding [8]. HG typically occurs from the fourth week of gestation, resolving by week 18. Although AST and ALT may be elevated by as much as 20 times the upper limit of normal, this is rare, as is jaundice. Dehydration can contribute to raised serum urea and creatinine levels, and there may be associated hypophosphataemia, hypomagnesaemia and hypokalaemia. Abnormalities in biochemistry typically resolve on resolution of vomiting. Failure to resolve abnormalities in liver biochemistry should alert the physician to alternative diagnoses such as viral hepatitis. Liver biopsy is not indicated, but if performed shows non‐specific changes. Persistence of symptoms beyond 18 weeks should warrant consideration of a gastroscopy to exclude mechanical obstruction. Overall management of HG is supportive and includes intravenous rehydration, antiemetics and gradual reintroduction of oral intake. Vitamin supplementation, especially thiamine, is mandatory to prevent Wernicke’s encephalopathy. Most patients will require 5–8 days of hospital admission, but relapse is common. Recurrence in subsequent pregnancies is also common. Attention should be given to the development of refeeding syndrome for patients that have a protracted clinical course. Pre‐eclampsia, HELLP (haemolysis, elevated liver enzymes, and low platelets) syndrome, acute fatty liver of pregnancy (AFLP), and liver rupture are separate but similar conditions that usually occur during the third trimester and after delivery. Often associated with hypertension, elevated liver enzymes are common. Low platelets may occur irrespective of the presentation and these conditions typically recover following delivery. In some situations, progressive disease may occur with multisystem organ failure and in the extreme maternal death. HELLP syndrome is most often considered a variant of severe pre‐eclampsia since hypertension and proteinuria are generally accompanying features. To complicate matters, there may also be overlap clinically and biochemically between AFLP and pre‐eclampsia, and up to 50% of patients with AFLP will have pre‐eclampsia [9,10]. It is essential for the clinician to recognize and differentiate the overlap syndromes from unrelated conditions which do not improve after delivery. For severe cases, a multidisciplinary team approach is warranted. Disorders of fatty acid oxidation play a key role in the aetiology of AFLP, HELLP syndrome and pre‐eclampsia. In the presence of oxygen, fatty acids are metabolized to carbon dioxide and water, and approximately 40% of the free energy produced in this process is conserved as adenosine triphosphate (ATP), whereas the remainder is released as heat within the mitochondrion. An enzyme that plays a central role in this pathway is long‐chain 3‐hydroxyacyl‐coenzyme A dehydrogenase (LCHAD) [11,12]. It is part of an enzyme complex that constitutes the mitochondrial trifunctional protein (MTP), located on the inner mitochondrial membrane. In LCHAD deficiency, there is accumulation of long‐chain hydroxyl‐acylcarnitines, free plasma hydroxyl‐long‐chain fatty acids, and dicarboxylic acids, which results in cell toxicity. Defects in the trifunctional protein are inherited as autosomal recessive conditions and cause non‐ketotic hypoglycaemia and hepatic encephalopathy in early infancy that may progress to coma and death if untreated [12]. They can also cause cardiomyopathy, peripheral neuropathy, myopathy and sudden death, although the latter clinical features are not characteristically seen in isolated LCHAD deficiency [12]. It is important to diagnose MTP disorders because the clinical complications can be avoided with dietary manipulation. An increased prevalence of AFLP, HELLP syndrome and severe pre‐eclampsia has been identified among heterozygous mothers of children who are homozygous for LCHAD deficiency [11–13]. A subsequent study of 27 pregnancies complicated by AFLP demonstrated that five women had fetuses with MTP mutations and that at least one copy of the common E474Q mutation was present in each case [14]. The study authors recommended that the neonates of women whose pregnancies are complicated by AFLP should be screened for MTP disorders or for the E474Q mutation. Routine screening of offspring of women whose pregnancies are complicated by HELLP syndrome is not recommended since MTP disorders are not common in the fetuses [14–16]. Outwith mitochondrial β‐oxidation defects, other defects such as short‐chain and medium‐chain defects have been described in AFLP; in a series of 50 infants whose mothers had severe liver disease, long‐chain defects were 50 times more likely than in controls and defects in short‐chain and medium‐chain pathways were 12 times more likely to be present [17]. AFLP is a rare, potentially life‐threatening, pregnancy‐related disease that affects 1 in 7000 to 1 in 16 000 pregnancies [18]. It is more likely to occur in a first pregnancy, multiple pregnancies, and pregnancies carrying a male fetus [18,19]. In two case series of 32 and 16 affected women admitted to tertiary centres, the maternal mortality rate was 12.5% [9]. Perinatal mortality rates are reported as approximately 10% in the latest series, [9,10,20], although other series report higher mortality possibly related to premature delivery [17]. The pathogenesis of AFLP is not completely understood. It is clear that fatty acid oxidation disorders contribute to approximately 20% of cases of AFLP [14]. In these cases, it is likely that the heterozygous mother has a reduced hepatic ability to metabolize long‐chain fatty acids. Although there is sufficient capacity in the non‐pregnant state, when a heterozygous woman becomes pregnant, her liver is required to metabolize fatty acids from the placenta as well as her own circulation. Accumulation of fatty acids and the increased metabolite load likely results in hepatotoxicity. This may be further compounded by the alterations in lipid metabolism that occur in normal pregnancy. AFLP typically manifests in the third trimester with symptoms of nausea and anorexia. Other later symptoms include vomiting and abdominal pain whereas polydipsia and polyuria may also occur. Liver function tests should be requested for any pregnant woman reporting these symptoms because rapid diagnosis of an acute fatty liver allows stabilization of the patient and rapid delivery. It is often difficult to differentiate AFLP from HELLP syndrome. Patients with AFLP more commonly have high levels of bilirubin, creatinine, uric acid and neutrophils; a prolonged prothrombin time (PT); acidosis; and hypoglycaemia. Patients frequently exhibit disseminated intravascular coagulation. Although levels of liver transaminases can be markedly increased, this can be variable. Moreover, the level of ALT or AST does not reflect disease severity since hepatocytes cannot release transaminases if they have already been destroyed by severe injury. Diagnostic criteria for AFLP have been created and are summarized in Table 10.3. Table 10.3 Swansea criteria for the diagnosis of acute fatty liver of pregnancy. Source: adapted from Ch’ng et al. [21]. ALT, alanine aminotransferase; AST, aspartate aminotransferase; APTT activated partial thromboplastin time. Imaging modalities that have been used to diagnose AFLP include liver ultrasound, MRI and CT. Liver biopsy may be used to obtain a definitive diagnosis using an oil red stain, although delivery should not be delayed to facilitate biopsy. It is also pertinent to consider alternative diagnoses even in patients with suspected AFLP. In a series of 32 patients, six had an additional diagnosis, two patients having malignancy, one alcohol‐induced fatty liver, another veno‐occlusive disease with antiphospholipid syndrome, and another acute viral hepatitis A infection [9]. Poisoning with acetaminophen can produce a clinical presentation that is hard to distinguish from AFLP and should always be considered in the context of an AST or ALT level above 1000 IU/L. Women with AFLP should be managed by a multidisciplinary team that includes obstetricians, hepatologists, anaesthetists, obstetric physicians, neonatologists and intensivists. In severe disease, the mother should be cared for in an intensive care unit (ITU). Biochemical and haematological monitoring is critical. It is essential to monitor the international normalized ratio (INR) or PT and other markers of coagulopathy. Similarly, plasma glucose levels, platelets, creatinine, liver function test results, and arterial blood gases including lactate are appropriate. Fresh‐frozen plasma should be given as required. Women often require large amounts of glucose intravenously to correct hypoglycaemia. If multisystem failure develops, it may be necessary to use dialysis and support with mechanical ventilation. N‐Acetylcysteine is often used by liver units to treat AFLP, and we advocate its use. Patients with AFLP should be assessed regularly for encephalopathy. It is advisable to consult with a liver unit specialist at the time of presentation of patients who have severe AFLP, hypoglycaemia and/or encephalopathy for advice on detailed management of fulminant liver failure and because assessment of suitability for liver transplantation may be necessary. In a study of 56 admissions to a liver failure unit in the UK, the presence of encephalopathy in conjunction with the presence of an elevated blood lactate level was highly associated with a poor prognosis and a need for liver transplantation [20]. The most important management strategy is delivery of the infant. The decision about the mode of delivery is often complex because the mother is likely to have a coagulopathy. Although vaginal delivery reduces the risk of haemorrhage, induction of labour often takes longer and prompt delivery can improve the maternal outcome. Regional anaesthesia should be avoided or used with caution and in conjunction with close monitoring. Blood tests should be performed frequently to ensure that coagulopathy is rapidly corrected in the days after delivery. AFLP does not commonly recur in subsequent pregnancies, although there are recurrent cases reported in the literature. In women who are heterozygous for disorders of fatty acid oxidation, it may be possible to establish whether the fetus is affected, and this can indicate the magnitude of the mother’s risk. Mothers who deliver an affected fetus have a greater chance of recurrence. For heterozygous mothers who do not have affected fetuses and for others who do not have a fatty acid oxidation disorder, the recurrence risk is lower. However, the disease has potentially disastrous consequences, and women who have had one affected pregnancy should be managed in an obstetric clinic specializing in high‐risk pregnancies. Liver involvement often occurs in the context of severe pre‐eclampsia. Although severe hypertension may be absent in women with HELLP syndrome, in most instances there is some degree of accompanying hypertension that helps to differentiate this disorder from other diseases. Similarly, as discussed earlier, there may be overlap between HELLP syndrome and AFLP yet isolated serum AST/ALT elevations in severe pre‐eclampsia rarely exceed 500 IU/L. Bilirubin levels rise in women with the HELLP syndrome, partly as a consequence of liver damage and partly in response to haemolysis, but bilirubin levels are usually higher in AFLP [14]. Hepatic failure with encephalopathy and coagulopathy are uncommon in pre‐eclampsia and should prompt consideration of a different diagnosis, including fatty liver and other causes of hepatic dysfunction. Table 10.4 summarizes classification systems for HELLP syndrome. Table 10.4 Classification systems used in HELLP syndrome. Hepatic involvement occurs in approximately 10% of women with severe pre‐eclampsia [22]. The presence of right upper quadrant pain usually signifies liver involvement. Increased AST/ALT levels may occur several hours after the onset of pain and, where performed, liver biopsy shows periportal haemorrhage, sinusoidal fibrin deposition and cellular necrosis [23]. However, in practice, liver biopsy is rarely warranted. Women with pre‐eclampsia and liver involvement should usually undergo prompt delivery, with steroids administered as protocol to promote fetal lung maturity. Laboratory values improve within 1 week of delivery, but may persist for weeks. Because HELLP syndrome may develop during the postpartum period in 20% of cases, liver function testing and imaging should be undertaken if abdominal pain, thrombocytopenia or other clinical features suggesting pre‐eclampsia occur after delivery. Rupture of the liver during pregnancy is a rare but often catastrophic event, with substantial risk for fetal and maternal death [20,24]. The majority of cases during pregnancy occur with pre‐eclampsia or HELLP syndrome [25]. Liver rupture occurs in only a small proportion of women with pre‐eclampsia, 4 of 442 (<1%) in one series [26]. Hepatic haematoma and rupture may rarely also occur after uncomplicated pregnancy, in association with biliary disease, infection, aneurysm and hepatic neoplasm [26–29]. Although the pathogenesis of hepatic rupture remains unclear, subcapsular haemorrhage is a common finding at post‐mortem in cases of pre‐eclampsia. Hypertension may not be present, and the presence of severe right upper quadrant pain and hypotension should trigger thoughts on this outcome. Other symptoms include nausea, vomiting, shoulder pain and headache. Haemoperitoneum produces peritoneal signs and hypovolaemic shock. Diagnostic imaging is required to establish a diagnosis [30]. CT or MRI is the preferred technique for visualizing liver haematomas. Paracentesis and the finding of blood may occasionally be helpful. Laboratory evaluation of women with subcapsular haematoma or rupture reveals thrombocytopenia, hypofibrinogenaemia or INR/PT. Anaemia and haemolysis are typically present, and levels of bilirubin, lactate dehydrogenase and liver transaminases are elevated. The differential diagnosis for unruptured liver haematoma includes AFLP, placental abruption with coagulopathy, thrombotic thrombocytopenic purpura, and cholangitis with sepsis. An intact haematoma without rupture may be managed conservatively, particularly if the patient is haemodynamically stable [30]. Patients should be managed in ITU, with serial imaging studies to define the extent of the subcapsular haemorrhage, its progression and whether leaking has occurred. Management options for hepatic rupture include embolization of the hepatic artery, hepatic resection, hepatic artery ligation, and exploration with digital compression of the hepatic artery and portal vein to temporarily arrest the haemorrhage (i.e. Pringle manoeuvre). Surgical exploration and evacuation of haematoma and temporary packing of the liver is often appropriate. Fluid replacement, multiple transfusions and correction of coagulopathy are necessary components in conjunction with an attempt to control the hepatic bleeding. In a patient who is relatively stable, angiography may be attempted while making preparations for potential laparotomy. Mortality rates approach 50% in cases of liver rupture. In a series of seven cases, the four survivors were managed with packing and drainage [24]. The three women undergoing hepatic lobectomy did not survive. In another series of 10 patients, nine were treated surgically with a combination of stitching of the lesion, omental patching, hepatic artery embolization, and ligation. The tenth patient was dead on arrival at hospital. Five patients were treated with hepatic artery ligation and all survived [31]. Evaluation of the literature suggests that patients who receive arterial embolization, whether performed with or without a laparotomy, have a better prognosis than patients managed by other strategies in isolation. Death is often caused by massive blood loss and coagulopathy. Patients who survive commonly experience respiratory insufficiency from adult respiratory distress syndrome or pulmonary oedema and acute liver failure. Hospital stay is significantly prolonged [22]. Infarction involving many areas of liver parenchyma may be a feature of severe pre‐eclampsia or HELLP syndrome [32]. Presenting signs usually include abdominal pain and fever. CT demonstrates clearly demarcated areas of poor vascularization involving many liver segments. Histological evaluation of these areas demonstrates haemorrhage and leucocyte infiltration in areas adjacent to haemorrhage. In the setting of HELLP syndrome, many adjacent areas of periportal haemorrhage most likely form these infarcted segments. Improvement after delivery can be expected, even in the face of laboratory evidence of severe liver inflammation. Intrahepatic cholestasis of pregnancy (ICP), also called obstetric cholestasis, is the commonest liver‐specific disorder in pregnancy [33]. It affects approximately 1 in 140 women in the UK, but there is geographical variability in prevalence, with higher rates in women from South America, particularly Chile, and Asia. The condition is more rarely seen in women of African/Caribbean origin. The aetiology of ICP has a genetic component, with a 17‐fold increase of developing the disease in parous first‐degree relatives. Mutations have been identified in biliary transporters, most commonly in ABCB11/BSEP and ABCB4/MDR3, which transport bile acids and phosphatidylcholine from the hepatocyte into bile, respectively [34]. There is evidence that raised reproductive hormones in pregnancy impact the normal pathways of bile acid homeostasis resulting in the development of cholestasis, and this is likely to be more severe in genetically predisposed women. The commonest presenting symptom of ICP is pruritus. This has varying severity but can be sufficiently severe to result in marked excoriations (Fig. 10.1) and sleep deprivation. Most women develop pruritus in the third trimester, but ICP can present as early as 8 weeks’ gestation. Women commonly also complain of dark urine and approximately 25% have pale stools secondary to steatorrhoea. If ICP is suspected, the liver function tests and serum bile acids should be checked. The condition is characterized by raised serum bile acids, and most women also have elevated liver transaminases. Approximately 10% have raised bilirubin concentrations, consistent with jaundice being a relatively rare symptom. Those with severe disease may have abnormal coagulation with a prolonged PT. Fig. 10.1 Typical appearance of excoriations on skin in a woman with severe pruritus in ICP. Reproduced with permission of ICP Support. The largest population studies in ICP, one in Sweden [35] and one in the UK [36], both demonstrated increased risk of adverse pregnancy outcomes in pregnancies in which the maternal serum bile acid concentration is 40 µmol/L or greater. The risk of spontaneous and preterm labour, stillbirth, meconium‐stained amniotic fluid and prolonged admission to the neonatal unit were increased in these pregnancies. Both studies also demonstrated that the risk of an adverse outcome was greater as the maternal serum bile acid concentration became higher. Although liver transaminases were also raised in most cases, there was a less clear‐cut relationship with adverse outcome compared with bile acids. The rise in serum bile acids can occur several weeks after onset of symptoms, and therefore it is advisable to continue to measure the serum bile acids weekly in women with ICP, including after making the diagnosis as otherwise severe cases (bile acids ≥40 µmol/L) may be missed. ICP is a diagnosis of exclusion, and therefore other hepatic disorders must be discounted. Women should have blood tests to exclude hepatitis C and autoimmune hepatitis and an ultrasound scan to ensure they do not have gallstones. The drug with the best evidence to support its use is ursodeoxycholic acid (UDCA). Most studies demonstrate that UDCA treatment improves maternal pruritus and improves biochemical derangements [37]. There are currently no completed trials to establish whether UDCA treatment can reduce the frequency of adverse pregnancy outcome in ICP, although one meta‐analysis [38] and a pilot trial of UDCA versus placebo [39] suggested that some adverse outcomes may be less frequent in ICP pregnancies in which the mother was treated. Specifically, the meta‐analysis combined the data from eight trials of UDCA versus another treatment (placebo or another drug, e.g. cholestyramine, dexamethasone or S‐adenosyl‐methionine), and included data from 207 UDCA‐treated and 70 placebo‐treated ICP cases. This study reported reduced rates of all preterm labour (including iatrogenic), fetal distress and duration of admission to the neonatal unit [38]. The UDCA versus placebo pilot trial, although underpowered to investigate an effect on pregnancy outcome, did show reduced rates of meconium‐stained liquor and a trend for reduction in neonatal unit admission and preterm labour in UDCA‐treated women [39]. A large randomized controlled trial is currently underway with the aim of establishing whether UDCA treatment reduces adverse pregnancy outcome in ICP. As most stillbirths have been shown to occur at later gestational weeks, it has been proposed that induction of labour at 37–38 weeks’ gestation may reduce the risk of fetal death. There are no prospective studies to support or refute this practice. Several studies have recently evaluated the merits of elective delivery with the aim of reducing the risk of stillbirth in ICP, and all concluded that elective delivery at 36 weeks’ gestation is associated with reduced risk. Specifically, a retrospective cohort study of 1 604 386 singleton pregnancies in California between 34 and 36 weeks’ gestation with and without ICP demonstrated an increased risk of stillbirth in ICP at each gestational age from 34 weeks after adjusting for race, maternal age, hypertension, diabetes mellitus, parity and limited perinatal care [40]. This study also reported that the risk of mortality associated with delivery is lower than the risk of expectant management from 36 weeks’ gestation. This was supported by retrospective reports of pregnancy outcomes in centres adopting a strategy of delivery at 36 or 37 weeks [41,42], and by the findings of a team that used a decision‐analytic model to compare different decision strategies, which concluded that the optimal strategy for ICP pregnancies is immediate delivery at 36 weeks, without fetal lung maturity testing or steroid administration [43]. The pruritus and hepatic impairment usually resolve within a small number of weeks after delivery. Women should be advised that ICP has a high recurrence risk in subsequent pregnancies and they are at increased risk of hepatobiliary disease in later life, in particular gallstones. They should also be aware that they have an increased risk of cholestasis if they take the combined oral contraceptive pill. However, progesterone‐containing contraception can be used. Viral hepatitis is the commonest cause of jaundice in pregnancy worldwide. Presentation, clinical features and general outcome for hepatitis A virus, hepatitis B virus (HBV), hepatitis C virus (HCV), cytomegalovirus or Epstein–Barr virus infection in pregnancy is similar to that in the non‐pregnant state [44]. HBV can present in an acute or chronic form. For patients with acute hepatitis B, transmission of the virus to the child occurs in 50% of cases, with 70% of children infected if acute HBV infection occurs in the third trimester. For patients with chronic HBV, transmission of virus is dependent on the degree of viral replication and the quantity of HBV DNA detectable in the serum of the mother. Transmission rates above 90% have been reported from mothers who are HBV DNA positive and these are typically hepatitis B E antigen positive (HBeAg+). Vaccination programmes throughout Southeast Asia and in the developed world have reduced transmission rates dramatically. Following vertical transmission, up to 80% of children become chronic carriers. Two strategies exist to reduce transmission rates. Firstly, the use of antiviral therapy such as tenofovir disoproxil fumarate (245 mg daily) that decreases HBV DNA level in the third trimester for appropriate patients reduces viral load and vertical transmission. Secondly, the use of hepatitis B immunoglobulin with hepatitis B vaccination in the neonate within 7 days of birth and at 1, 2 and 12 months of age also reduces the transmission rate significantly. Chronic HCV infection in chronic carriers occurs in 8% of cases. Vertical transmission is highest in those patients with higher viral loads. Mother‐to‐child transmission of HCV has become the leading cause of paediatric infection, at an approximate rate of 5%, with maternal HIV co‐infection a significant risk factor for mother‐to‐child transmission. However, anti‐HIV therapy during pregnancy can reduce the transmission rate of both viruses. A high maternal viral load is an important but unpreventable risk factor since no anti‐HCV treatment can currently be administered in pregnancy. With obstetric procedures such as amniocentesis or internal fetal monitoring that could expose the fetus to maternal blood, caution should be undertaken, although evidence is lacking on the real risk of single obstetric practices. Mode of delivery and type of feeding do not represent significant risk factors for mother‐to‐child transmission. Therefore, there is no reason to offer elective caesarean section or discourage breastfeeding in HCV‐infected patients. Antibody conversion of infants following transmission may take 6–12 months, although measurement of HCV RNA levels will allow for early diagnosis. Hepatitis E virus is problematic in pregnancy, typically occurring in epidemic form in Southeast Asia, the Indian subcontinent and the Middle East. The development of acute liver failure in the second and third trimester can be associated with a mortality of up to 20%. Many patients with chronic liver disease and cirrhosis are infertile. However, patients with autoimmune liver diseases such as autoimmune hepatitis, primary sclerosing cholangitis and primary biliary cirrhosis may become pregnant. Patients with autoimmune hepatitis should be maintained on baseline immunosuppression throughout pregnancy (azathioprine with or without prednisolone). For patients treated with mycophenolate mofetil before pregnancy, they should be converted to an alternative immunosuppressant such as azathioprine, tacrolimus or cyclosporin prior to planned pregnancy. A 20–25% risk of flare in autoimmune hepatitis occurs following delivery in the first 3 months post partum, and this is reduced if immunosuppressive treatment is maintained. Since varices develop even in normal pregnancy as a consequence of changes in cardiac output, azygos blood flow, increased circulating blood volume and changes in splanchnic haemodynamics, an increased risk of variceal bleeding in cirrhotic patients can be anticipated. Patients with established cirrhosis should be screened for varices in the second trimester. This is to facilitate and guide appropriate peripartum care. The presence of small varices in otherwise well‐compensated cirrhotic patients should not preclude a vaginal delivery. However, close monitoring in pregnancy is warranted. For patients with non‐cirrhotic portal hypertension, a bleeding rate in pregnancy of 13% has been reported. In cirrhotic patients contemplating pregnancy, pre‐pregnancy screening and appropriate treatment of large varices should be undertaken. Propranolol is not contraindicated in pregnancy and episodes of variceal bleeding should be treated with normal endoscopic approaches including endoscopic band ligation or histoacryl glue, whereas transjugular intrahepatic shunts should be reserved for rescue therapy and field endoscopic treatment. There are limited safety data for vasoconstrictors such as terlipressin, but they may be used in women with life‐threatening haemorrhage in pregnancy. Successful pregnancy following liver transplantation has been widely reported and fertility will return typically within 6 months of transplant. Best outcomes are reported for pregnancies undertaken more than 1 year after the transplant operation since it reduces the risk of acute cellular rejection and other infective complications. Tacrolimus, cyclosporin, azathioprine and corticosteroid therapy are widely and safely used in pregnancy. Specific complications in pregnancy related to a higher prevalence of hypertension/pre‐eclampsia and preterm delivery have been reported. Patients on mycophenolate should be converted to an alternative immunosuppressant prior to pursuing pregnancy.
Liver and Endocrine Diseases in Pregnancy
LIVER DISEASE IN PREGNANCY
Normal physiological changes in pregnancy
Test
Not pregnant
First trimester
Second trimester
Third trimester
AST (IU/L)
7–40
10–28
11–29
11–30
ALT (IU/L)
0–40
6–32
6–32
6–32
Bilirubin (µmol/L)
0–17
4–16
3–13
3–14
GGT (IU/L)
11–50
5–37
5–43
5–41
Alkaline phosphatase (IU/L)
30–130
32–100
43–135
130–418
Bile acids (µmol/L)
0–9
0–9
0–9
0–9
Investigation of liver disease in pregnancy
Approach to the patient with suspected liver disease in pregnancy
Pregnancy‐related liver disease
Disease
Trimester
Diagnostics
Hyperemesis gravidarum
1, 2
↑ Bilirubin (×5)
↑ ALT/AST (×2–4)
Intrahepatic cholestasis of pregnancy
2, 3
↑ ALT/AST (×6)
↑ Bile acids
Pre‐eclampsia
2, 3
↑ Bilirubin (×2–5)
↑ ALT/AST (×10–50)
↑ Platelets
HELLP syndrome
2, 3
↑ ALT/AST (×10–20)
↑ LDH
↑ Platelets
↑ Urate
Acute fatty liver of pregnancy
2, 3
↑ Bilirubin (×5–10)
↑ ALT/AST (×5–10), rarely >20×
Hyperemesis gravidarum
Clinical features, diagnosis and management
Management
Overlap syndromes with liver dysfunction
Fatty acid oxidation pathways
Acute fatty liver of pregnancy
Pathogenesis
Diagnosis
Six or more criteria required in the absence of another cause:
Management
Prevention
Pre‐eclampsia and HELLP syndrome
Liver rupture and infarction
Epidemiology
Pathogenesis and clinical features
Diagnosis
Management
Liver infarction
Intrahepatic cholestasis of pregnancy
Pathogenesis
Diagnosis
Management
Liver diseases incidental to pregnancy
Viral hepatitis in pregnancy
Hepatitis B virus
Hepatitis C virus
Hepatitis E virus
Pregnancy in patients with cirrhosis
Pregnancy following liver transplantation
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