Liver disease in pregnancy.

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Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2015) 1e13

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Liver disease in pregnancy Victoria Geenes, MBBS, PhD, Catherine Williamson, MBChB, MD, Professor of Women's Health * Women's Health Academic Centre, King's College London, London, UK

Keywords: liver disease pregnancy cholestasis hepatitis

Liver disease in pregnancy, either pre-existing or pregnancy specific, can be associated with a significant risk of maternal and fetal morbidity and mortality. Here, we review the presentation, management and perinatal outcomes of common causes of liver disease. © 2015 Published by Elsevier Ltd.

Introduction The liver plays several important roles, including metabolism and excretion of endobiotics, such as cholesterol and bilirubin, and xenobiotics. It also synthesizes several important proteins, for example clotting factors and albumin, and influences bile acid and cholesterol metabolism. The liver moves in normal pregnancy to a more superior and posterior position, but there is little change in liver size in human pregnancy. The normal range of liver function tests alters in normal pregnancy [1], and several clinical signs that are considered to be pathological in non-pregnant individuals are not of concern in pregnancy. Examples include palmar erythema and the presence of spider naevi. Hepatic disorders in pregnancy may result from pre-existing liver disease or they can be the result of pregnancy-specific disorders. Liver abnormalities as a result of hypertensive disorders are summarized in Table 1.

* Corresponding author. Women's Health Academic Centre, King's College London, 2nd Floor Hodgkin Building, Guy's Hospital Campus, London SE1 1UL, UK. Tel.: þ44 (0) 207 848 6350. E-mail address: [email protected] (C. Williamson). http://dx.doi.org/10.1016/j.bpobgyn.2015.04.003 1521-6934/© 2015 Published by Elsevier Ltd.

Please cite this article in press as: Geenes V, Williamson C, Liver disease in pregnancy, Best Practice & Research Clinical Obstetrics and Gynaecology (2015), http://dx.doi.org/10.1016/j.bpobgyn.2015.04.003


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V. Geenes, C. Williamson / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2015) 1e13

Table 1 Abnormalities in liver function tests as a result of hypertensive disorders of pregnancy. Distinguishing feature

Pre-eclampsia

HELLP syndrome

Typical gestational week at onset Symptoms and signs

>20 weeks Headache Visual disturbance Abdominal/epigastric pain Nausea and vomiting Polyuria/polydipsia Oedema Raised blood pressure Brisk reflexes/clonus Proteinuria

36 (25e38)

[ [ [ N N

[[ [ [ [ N

N Y [ [

Y YY [ [

Liver function tests ALT AST gGT Bilirubin Bile acids Other tests Haemoglobin Platelets Creatinine Urate

* The haemolysis, elevated liver enzymes and low platelets syndrome.

Pre-existing liver disease Infectious liver disease Hepatitis A Hepatitis A is an acute viral hepatitis caused by a small non-enveloped RNA virus. The infection is typically acquired via faeco-oral transmission, usually through the ingestion of infected food. Infection with hepatitis A typically causes a self-limiting icteric illness, and it is not associated with chronic infection. It has an incubation period of 2e7 weeks. Acute presentation of hepatitis A infection in pregnancy is similar to that in non-pregnant women, with a mild prodromal illness followed by the onset of dark urine, pale stools jaundice and hepatomegaly. Transaminases are elevated by 10e100 times. Most symptoms and signs resolve within 3 weeks. Although hepatitis A infection is not a cause of major maternal or neonatal morbidity, it can rarely be transmitted from mother to child, and vaccination is therefore appropriate for women at a risk of infection. In utero transmission of hepatitis A infection in the first trimester is reported to cause fetal meconium peritonitis, and in the third trimester it may result in asymptomatic neonatal infection and/or self-limiting neonatal cholestasis [2e4]. Acute infection in the third trimester is associated with a risk of preterm labour [5]. Hepatitis A infection is not transmitted via breast milk, and women should be advised that they can breastfeed. Treatment is supportive. Hepatitis B Hepatitis B is a small double-stranded DNA virus, with eight known serotypes. In adults in lowprevalence areas, the major routes of transmission are via unprotected sex and intravenous drug use. However, the predominant route of transmission worldwide is from mother to child, and acquisition of the virus during the perinatal period is associated with the highest risk of chronic infection. It is estimated that between 30% and 50% of chronic hepatitis B virus (HBV) infections are acquired during the perinatal period. During pregnancy, hepatitis B may present as an acute or chronic infection. All women should be screened for the virus at booking and again in late pregnancy if at an ongoing high risk of infection. This is achieved by testing the surface antigen (HBsAg) status. If the HBsAg is negative but the woman is at a high risk of acquiring the infection during pregnancy, anti-HBsAg should also be Please cite this article in press as: Geenes V, Williamson C, Liver disease in pregnancy, Best Practice & Research Clinical Obstetrics and Gynaecology (2015), http://dx.doi.org/10.1016/j.bpobgyn.2015.04.003



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tested. If this is negative, women should be offered vaccination, which is generally given after the first trimester as, although it is not a live vaccine, there are limited safety data. The course of both acute and chronic HBV infection is unchanged by pregnancy, and HBV is not a cause of congenital malformations, pregnancy loss or stillbirth. As discussed above, HBV can be transmitted from mother to child and both in utero transplacental and direct transmission at delivery are possible. There is no evidence that delivery by elective caesarean section prevents transmission, and this is therefore not routinely offered. Although the HBV is contained in breast milk, breastfeeding does not appear to increase the risk of transmission of the virus above the risk associated with the pregnancy and delivery itself. Given that blood contains the highest concentrations of virus of any body fluid, women are often advised that a pragmatic approach is to suspend breastfeeding if they develop cracked nipples or mastitis. All babies born to women with HBV infection should receive active and passive immunization with HBV vaccine and HBV immunoglobulin, respectively. Effective vaccination programs have resulted in a marked reduction in HBV-associated hepatocellular carcinoma rates in children. For women presenting with acute HBV infection during pregnancy, treatment is largely supportive. Up to 95% of women spontaneously recover from the acute illness, but nucleoside analogues can be used in those with fulminant HBV or protracted severe infection. There is limited evidence for the use of antivirals in pregnant women with chronic HBV, and treatment is generally deferred until after delivery. There is no evidence that this delay significantly alters the course of infection. Hepatitis C Hepatitis C is an RNA virus with six known genotypes, each of which has thousands of subtypes. Hepatitis C virus (HCV) is a blood-borne virus that causes chronic infection, and this can lead to cirrhosis and hepatocellular carcinoma. In adults, it is most commonly acquired via intravenous drug use, although a sizeable proportion of pregnant women are not aware of the mode of infection. Motherto-child transmission is the most common route for acquisition in infants and children, with transmission rates of between 3.6% and 6.2% [6,7]. The risk of mother-to-child transmission is increased by up to three times in women with HIV co-infection. Other risk factors that increase transmission are HCV viraemia, prolonged rupture of membranes (>6 h) and intrapartum exposure to maternal blood from perineal lacerations [7e10]. HCV can be found in breast milk, but this is not a route of transmission and breastfeeding is not contraindicated. HCV can present acutely during pregnancy, or it can be a chronic infection. Universal screening of pregnant women for HCV is not currently performed, and testing should be guided by the presence of risk factors for infection. The course of infection is unchanged by pregnancy, but women with HCV have higher rates of intrahepatic cholestasis of pregnancy (ICP), which may temporarily worsen their liver function [11]. HCV is not a cause of congenital malformations, pregnancy loss or stillbirth. All babies born to women with HCV should have HCV antibodies tested at around 16 months of age, by which time the infant should have developed its own antibodies and maternal antibodies will have cleared. Alternatively, nucleic acids can be tested on two occasions between 2 and 6 years of age. Antiviral treatment for HCV infection in pregnancy is currently contraindicated due to the teratogenicity of the drugs. During labour, fetal monitoring with scalp electrodes and prolonged rupture of membranes (>6 h) should be avoided, especially in women with high viral loads, as they may increase the risk of transmission. There is no evidence that planned delivery by caesarean section reduces the risk of transmission and therefore this is currently not recommended. Hepatitis E Hepatitis E is an RNA virus. Most reported epidemics are associated with seasonal rains and flooding in endemic areas leading to the suggestion that it is a waterborne virus. Hepatitis E virus (HEV) usually causes an acute self-limiting hepatitis, but pregnant women are both more susceptible to infection and more likely to suffer fulminant hepatic failure. Mortality rates from acute HEV infection in pregnancy have been reported to be as high as 26% [12]. Mother-to-child transmission of HEV can be both in utero and direct. There are case reports of transmission following infection in the third trimester leading to neonatal hepatic necrosis and death, but also of infants recovering from in utero infection [12,13]. Breastfeeding does not increase the risk of transmission. Unlike HBV and HCV, HEV does not cause Please cite this article in press as: Geenes V, Williamson C, Liver disease in pregnancy, Best Practice & Research Clinical Obstetrics and Gynaecology (2015), http://dx.doi.org/10.1016/j.bpobgyn.2015.04.003


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chronic infection. Infection during pregnancy is associated with high rates of preterm delivery, but there is no evidence for congenital malformations. Treatment of HEV is largely supportive, and postexposure immunoglobulin treatment does not reduce disease incidence. Inflammatory liver disease Autoimmune hepatitis Autoimmune hepatitis (AIH) is a cause of chronic hepatitis characterized by hepatocellular inflammation and necrosis, which may progress to cirrhosis. AIH may present as acute hepatitis, chronic hepatitis or cirrhosis. The symptoms of AIH include fatigue, myalgia, pruritus, nausea, anorexia, amenorrhoea and upper abdominal pain. It predominantly affects women (3:1 female to male preponderance) and has two peaks of presentation (10e30 and 40e50 years). Older studies of AIH in women reported high rates of reduced fertility secondary to amenorrhoea. However, with successful immunosuppressive therapy, pregnancy is becoming more common, and up to 6% of cases present during pregnancy [14]. AIH can be classified into three types depending on the autoantibodies present. Type I is the most common type, affecting people of any age. It is characterized by antinuclear antibodies (ANAs, 70%) or anti-smooth muscle antibodies (SMAs, 57%). Type II most commonly affects children and young women, and it is also a more severe phenotype with more frequent relapses and a greater risk of concurrent extrahepatic autoimmune disease. It is characterized by anti-liver kidney microsomal antibodies (LKM1, 3e4%) and seronegativity for ANA and SMA. Finally, type III occurs in 30% of patients, and it is not associated with any of the conventional antibodies. It is characterized by anti-soluble liver antigen and anti-liver pancreas antibodies. All women with AIH should undergo preconception counselling, and the importance of continuing their immunosuppressive treatment should be emphasized. Azathioprine is not associated with adverse outcomes during pregnancy or with breastfeeding. Women should also be screened for anti-Ro and anti-La antibodies, and for gastro-oesophageal varices. If varices are present, they should be offered banding of the varices prior to conception. Poorly controlled AIH is associated with high rates of adverse perinatal outcomes. Between 1966 and 2004, there were 17 case reports and series describing 101 pregnancies from 58 women with AIH reported in the literature [15]. In these cases, there were 47 disease flares (35 (74%) occurring during pregnancy and 12 (26%) in the post-partum period) and five cases with clinical improvement during pregnancy. Of the remaining cases, the disease remained stable in 45 pregnancies and no data are available from four. There were two maternal deaths, 19 intrauterine fetal deaths (mostly before 20 weeks of gestation) and four perinatal deaths. These findings have been consolidated by several further case reports and small case series [14,16e18]. The largest individual case series reported outcomes in 81 pregnancies from 53 women (of whom 41% had cirrhosis), and it also examined some of the factors influencing the risk of adverse outcomes. In this series, the live birth rate was 73% with a preterm delivery rate of 20% and a special care baby unit (SCBU) admission rate of 6%. Both the risk of preterm delivery and admission to SCBU increased in women with cirrhosis. A flare of disease was observed in 33% of women, and serious maternal complications (defined as death or liver transplant within 12 months of delivery, or decompensation of liver disease within 3 months of delivery) were reported in 11%. Factors influencing the outcome of a pregnancy in AIH are suggested to include the age at diagnosis of AIH, poor compliance with treatment, relapse within 12 months prior to conception and the presence of cirrhosis. Maternal therapy with either immunosuppressants or steroids had no significant impact on the live-birth rate, termination rate, miscarriage rate or gestational age at delivery, but the risk of flare was lower in women who continued their immunosuppressive treatment [19]. It is imperative that women of reproductive age with AIH attend pre-pregnancy counselling, as this is likely to ensure they understand the merits of continuing treatment. One study reported that only 48% women with AIH attended pre-pregnancy counselling [18], and it is hoped this proportion will increase with improved education. Primary sclerosing cholangitis Primary sclerosing cholangitis (PSC) is a disease affecting both the intrahepatic and extrahepatic bile ducts. Recurrent episodes of cholangitis result in progressive scarring and obstruction of the bile Please cite this article in press as: Geenes V, Williamson C, Liver disease in pregnancy, Best Practice & Research Clinical Obstetrics and Gynaecology (2015), http://dx.doi.org/10.1016/j.bpobgyn.2015.04.003



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ducts leading to cholestasis. It is associated with cirrhosis and liver failure. The symptoms of PSC include chronic fatigue, jaundice, pruritus and malabsorption with steatorrhoea. It may also be associated with inflammatory bowel disease (IBD). PSC typically presents in those aged 20e30 years, but it may be diagnosed in childhood. Although the condition affects predominantly males (2:1 male to female preponderance), women of childbearing age are affected. The aetiology of PSC is unclear, but it may involve autoimmunity. Eight percent of those affected have positive tests for perinuclear antineutrophil cytoplasmic antibodies (pANCAs), with a smaller proportion (20e50%) also being positive for ANAs or anti-SMAs. It should be noted, however, that none of these antibodies are specific for PSC. The hypothesis of an autoimmune aetiology is supported by the finding that up to 70% of those with PSC also have ulcerative colitis. PSC is commonly treated with ursodeoxycholic acid (UDCA) despite a lack of definitive evidence of improved survival. Other pharmacological treatments used with varying success include antihistamines, cholestyramine and rifampicin, naltrexone for pruritus, antibiotics for episodes of cholangitis and vitamin supplementation (A, D, E and K) to counteract the effects of malabsorption. Sclerosed bile ducts may be stented. Liver transplantation is curative, and it is indicated in cases with recurrent cholangitis, refractory jaundice and decompensated cirrhosis, and for the complications of portal hypertension. However, PSC may recur in the transplanted liver. Cholangiocarcinoma develops in up to 15% of cases. Until recently, there were very few case reports of pregnancy outcomes in women with PSC [20,21]. One study reported the outcomes of 17 women with 21 live births [22]. Of these, five women had worsening liver function during pregnancy, and eight in the post-partum period. Liver function was reported to remain more stable in women treated with UDCA. Four women had first-trimester pregnancy loss, and all of these women had concurrent IBD. Two babies were born prematurely. Fifteen of the women continued treatment with UDCA during the pregnancy, and two continued azathioprine. Neither drug was reported to be associated with adverse outcomes. There are also reports of more marked adverse outcomes, including the need for maternal endoscopic retrograde pancreatography (ERCP) and stenting, fetal distress and preterm delivery [23,24]. These studies have been superseded by a large cohort study from Sweden reporting the outcomes of 229 singleton pregnancies between 1987 and 2009 [25]. In this series, PSC was associated with an increased risk of preterm delivery (both spontaneous and iatrogenic) and delivery by caesarean section (predominantly elective caesarean section), but not with any significant change in the incidence of low Apgar score, birthweight, stillbirth or neonatal death. Furthermore, PSC was not associated with a significant risk of congenital abnormalities. The risks of preterm delivery and caesarean section were found to be independent of IBD status. Unfortunately, this study was not able to assess the influence of treatment on outcomes. Immunoglobulin G4-related disease Immunoglobulin G4 (IgG4)-related disease is an increasingly recognized immune-mediated condition that may affect one or more organs. It describes a collection of disorders that were previously thought to be unrelated, but that share common clinical and histological features, including swelling of the involved organ, IgG4-positive plasma cell-enriched lymphoplasmacytic infiltrate and a variable degree of fibrosis. Sixty to seventy percent of those affected also have raised serum IgG4 levels. Presentation is variable, and it includes IgG4-related sclerosing cholangitis. This is clinically distinct from PSC, and it can be distinguished on the basis of typical liver biopsy features. It rarely occurs in the absence of pancreatitis and it characteristically responds to treatment with steroids. To date, there are no reports of IgG4-related sclerosing cholangitis in the literature, but it is an important diagnosis to consider. Primary biliary cirrhosis Primary biliary cirrhosis (PBC) is an autoimmune disease of the liver characterized by slow progressive destruction of the small bile ducts, leading to scarring and eventual cirrhosis. The symptoms of PBC are similar to those of PSC. It predominantly affects women (9:1 female to male preponderance), and typically presents in middle age, but it may be diagnosed in younger women or even present during pregnancy. It is more common in those with a family history of PBC and it has a reported incidence of up to one in 3000 people in the UK. Up to 80% of those affected by PBC have additional extrahepatic autoimmune diseases such as thyroid disease, coeliac disease, AIH, rheumatoid arthritis or Please cite this article in press as: Geenes V, Williamson C, Liver disease in pregnancy, Best Practice & Research Clinical Obstetrics and Gynaecology (2015), http://dx.doi.org/10.1016/j.bpobgyn.2015.04.003


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€gren's syndrome. Antimitochondrial antibodies (AMAs) are positive in 90e95% of those with PBC, Sjo and they have a specificity of 98%. ANAs are also positive in approximately 35% of cases. PBC is commonly treated with UDCA, which slows the progression of the disease and is particularly effective in early disease. Some studies also suggest beneficial effects on mortality. Immunosuppressive agents, including methotrexate, ciclosporin and azathioprine, have been used in case reports, but they are not currently recommended for use outside of randomized controlled trials. Other pharmacological treatments used to control symptoms include cholestyramine, rifampicin and naltrexone for pruritus; modafinil for fatigue; and vitamin supplementation (A, D, E and K) to counteract the effects of malabsorption. Liver transplant is indicated in cirrhosis, but the reported recurrence rate is 18% at 5 years. The natural history of the disease, and the fact that PBC is most commonly diagnosed in women aged between 35 and 55 years, means that there are few reports of the outcomes of pregnancy in these women. There is no clear consensus of the effect of PBC on pregnancy outcomes, with several reports suggesting that it is associated with worsening of maternal liver function and an increased risk of adverse outcomes, including intrauterine fetal death and others showing no deterioration in maternal liver function or symptoms during pregnancy [26e29]. Series in which most women are treated with UDCA report better fetal and maternal outcomes [30]. Biliary atresia Biliary atresia is a congenital or acquired inflammatory disease of the bile ducts that leads to progressive cholestasis. The congenital form of the disease presents in infancy as prolonged neonatal jaundice with steatorrhoea and hepatomegaly, which may be visible. The blocked or absent common bile duct results in progressive cholestasis, characterized by elevated liver enzymes and a conjugated hyperbilirubinaemia. It is more common in girls than boys, and also in Asians than white Europeans. The aetiology of biliary atresia is unknown, and it is likely to be multifactorial. The treatment involves the surgical reconstruction of the biliary tract (Kasai procedure), which, although not curative, delays the need for liver transplantation. Pregnancy in women with biliary atresia and native livers has been reported. Most women in the literature have had a worsening of their liver function during pregnancy that has recovered post partum [31,32], although there are cases of prolonged cholestasis requiring urgent post-partum liver transplantation [33]. Women with portal hypertension and oesophageal varices appear to have an increased risk of variceal bleeding during pregnancy [32,34,35]. On the whole, the perinatal outcomes are favourable in the small numbers reported, and there is no suggestion of congenital abnormality in babies born to women with biliary atresia. There is one case report of a termination of pregnancy due to deteriorating liver function and another of intrauterine death in a woman with cholangitis and portal hypertension [31].

Metabolic liver disease Hereditary haemochromatosis Haemochromatosis is multi-system disorder secondary to iron overload. It is most commonly caused by mutations in the HFE (haemochromatosis) gene. Clinical presentation of haemochromatosis is variable, and it may be asymptomatic in the early stages of iron overload. Symptoms include fatigue, arthralgia and loss of libido. Chronic iron overload can result in cirrhosis and hepatocellular carcinoma, dilated cardiomyopathy or cardiac conduction disturbances, pancreatic dysfunction or diabetes, hypogonadism, non-inflammatory osteoarthritis and bronzing of the skin. Women are somewhat protected from the development of clinical haemochromatosis by menstruation. The risks of pregnancy in women with haemochromatosis predominantly relate to end-organ dysfunction, and iron overload itself is not known to be related to adverse perinatal outcomes. Specific issues are glycaemic control at the time of conception and during pregnancy, and the association with congenital abnormalities and adverse outcomes. The presence of cardiomyopathy or cirrhosis has well-documented implications. There are no haemochromatosis-specific treatments for these conditions, and they should be managed accordingly. Please cite this article in press as: Geenes V, Williamson C, Liver disease in pregnancy, Best Practice & Research Clinical Obstetrics and Gynaecology (2015), http://dx.doi.org/10.1016/j.bpobgyn.2015.04.003



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Wilson's disease Wilson's disease is a rare autosomal recessive disorder that results in the accumulation of copper. It is a multi-system disease, but it predominantly affects liver and brain leading to cirrhosis, liver failure and neurologic and psychiatric symptoms. Fertility is commonly reduced and infertility may be a presenting feature. It is also associated with increased miscarriage rates. The diagnosis of Wilson's disease is based on abnormal liver function tests, low serum copper and ceruloplasmin levels, raised urinary copper levels and the presence of KaysereFleischer rings. Treatment is aimed at reducing absorption and increasing elimination of copper, usually with D-penicillamine, trientine and zinc. Dpenicillamine and trientine are both reported to cause teratogenicity when used in the treatment of cystinuria, and this is thought to relate to fetal copper deficiency. However, as the doses used in the treatment of Wilson's disease are lower, women should undergo preconception counselling and be advised to continue treatment as there are reports of deterioration in liver function, haemolysis and death in women who have stopped treatment [36]. With good control, perinatal outcomes are reported to be good. There are no specific considerations for labour and delivery relating to Wilson's disease, and infants typically have normal levels of serum copper and ceruloplasmin even if maternal disease control has been poor during pregnancy. Breastfeeding is not contraindicated. Vascular liver disease BuddeChiari syndrome This is a rare veno-occlusive syndrome, most commonly caused by thrombosis of the hepatic veins or distal inferior vena cava. It is more common in women than men, and it may be associated with hereditary thrombophilia. Reports suggest that up to 15% of cases are associated with pregnancy, either due to a new diagnosis or due to pre-existing disease. Oral contraceptive use has also been identified as a risk factor. The presentation of BuddeChiari syndrome, both during pregnancy and outside of pregnancy, depends on the rate of onset and the pattern of venous obstruction, but it typically involves the gradual onset of ascites, abdominal pain and distension and tender hepatomegaly over a period of months. Pregnant women with acute major venous obstruction will deteriorate rapidly with portal hypertension, variceal bleeding and fulminant hepatic failure. Liver enzymes are typically only modestly raised, but there is a marked rise in alkaline phosphatase compared to normal pregnancy. Diagnosis is based on the Doppler ultrasound finding of diminished or absent flow. Magnetic resonance imaging (MRI) may also be used. Women with a patent portal vein and without obstruction of the inferior vena cava may benefit from insertion of a portacaval shunt to improve portal hypertension and ascites. Many women will not be stable enough to undergo this procedure surgically, but there are reports of successful pregnancy outcomes following transjugular intrahepatic portosystemic shunting procedures. All women with BuddeChiari syndrome should have a thrombophilia screen, and thromboprophylaxis should be prescribed during pregnancy. Most women with BuddeChiari syndrome in pregnancy will have the disease diagnosed prior to conception, and the prognosis in this group depends upon the presence of oesophageal varices. There is a high risk of bleeding if they have not had sclerotherapy or banding prior to pregnancy, and this is considerably reduced with previous treatment (see below). Treatment with b-blockers or proton pump inhibitors is not contraindicated in pregnancy, and it should be considered. Other Progressive familial intrahepatic cholestasis and benign recurrent intrahepatic cholestasis Progressive familial intrahepatic cholestasis (PFIC) and benign recurrent intrahepatic cholestasis (BRIC) are inherited cholestatic disorders. Although both conditions belong to a spectrum of cholestatic liver disease, there are some important differences. PFIC describes severe cholestatic disease that typically presents in the first year of life, with jaundice, pruritus, an enlarged liver and failure to thrive. There are three subtypes of PFIC, which are determined by the genetic defect, and more specific symptoms depend on the subtype. PFIC type 1 (also known as Byler's disease) is due to mutations in the ATP8B1 (FIC1) gene. It is a systemic disease and, in addition to liver disease, patients may have hearing difficulties and pancreatitis. PFIC 2 is due to mutations in ABCB11 (BSEP) and is a liver-specific Please cite this article in press as: Geenes V, Williamson C, Liver disease in pregnancy, Best Practice & Research Clinical Obstetrics and Gynaecology (2015), http://dx.doi.org/10.1016/j.bpobgyn.2015.04.003


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condition. It tends to be more severe and progressive. PFIC 3 is due to mutations in ABCB4 (MDR3); in contrast to PFIC 1 and PFIC 2, it is characterized by high levels of serum gamma-glutamyl transferase (GGT). The more severe form of PFIC 3 may progress to cirrhosis and liver failure within the first few years of life. Mutations in ATP8B1, ABCB4 and ABCB11 cause a spectrum of disease phenotypes, depending upon the specific mutation. This is most extensively described for ABCB4 where the disease varies from severe PFIC3 to low phospholipid gallstones, drug-induced cholestasis or ICP, and these latter presentations are usually diagnosed in adulthood. Some women with BRIC develop ICP during pregnancy (see below). Alagille syndrome Alagille syndrome is a multi-system inherited disorder characterized by chronic cholestasis due to biliary hypoplasia, and it is associated with cardiovascular, renal, eye or vertebral defects. Patients with Alagille syndrome have distinctive facial features including a broad, prominent forehead, deep-set eyes and a small chin. It affects approximately one in 100,000 children. The aetiology is not fully understood, but it has an autosomal dominant inheritance pattern and 70e90% of patients have mutations of JAG-1. Treatment of Alagille syndrome includes phenobarbitone, rifampicin and cholestyramine for pruritus and vitamin supplementation. There are very few case reports of pregnancy in women with Alagille syndrome, but they suggest that there may be a higher risk of adverse pregnancy outcomes including first-trimester miscarriage, preterm labour, intrauterine growth restriction and hydrops and neonatal death [37e40]. In the majority of these case reports, the adverse outcomes are associated with the inheritance of Alagille syndrome by the fetus. However, there are two case reports of successful outcomes, and at least one of these was associated with an infant with a positive JAG-1 mutation [40,41]. Cirrhosis and portal hypertension Cirrhosis is defined as permanent scarring of the liver as a result of continuous long-term damage. It is the final common pathway of many different liver pathologies, but the majority of cases in the UK are the result of excessive alcohol consumption and hepatitis C infection. Early cirrhosis may be asymptomatic, but as the liver becomes more scarred symptoms can include reduced appetite, nausea and pruritus. Later on, affected women may develop jaundice, steatorrhoea and ascites. Cirrhosis may be associated with portal hypertension, oesophageal varices and hypersplenism. There are a few reports of pregnancy in women with cirrhosis, and the majority of them relate to alcoholic liver disease or viral hepatitis. Studies have suggested that there are higher rates of both maternal and neonatal mortality in women with cirrhosis, and women with portal hypertension and oesophageal varices appear to be at higher risk [42e46]. Up to 78% of those with pre-existing oesophageal varices will have a variceal bleed during pregnancy, most commonly in the second or third trimester [47]. Other maternal complications include higher rates of anaemia, post-partum haemorrhage, pre-eclampsia, placental abruption and maternal death [44,46]. Fetal complications are reported to include miscarriage, preterm delivery and intrauterine growth restriction [42e44,46]. Management of cirrhosis largely relates to treatment of the underlying pathology. There is no consensus on the optimal treatment for variceal bleeding; however, prognosis is better if women are treated, ideally prior to conception, but this should also be considered in a woman with a new diagnosis in pregnancy. Endoscopy, sclerotherapy and ligation banding appear to be safe, but there are no randomized controlled trials. Furthermore, there are limited data regarding the best method of delivering women with cirrhosis. There are concerns over women labouring as the process involves repeated Valsalva manoeuvres, which raises intra-abdominal pressure and therefore increases the risk of variceal rupture [47]. Although the most common cause of portal hypertension is cirrhosis, non-cirrhotic portal hypertension is seen in patients without any underlying liver disease. Causes of non-cirrhotic portal hypertension include BuddeChiari syndrome and extrahepatic obstruction (Table 2). Women with noncirrhotic portal hypertension tend to be younger, and they are therefore more likely to be of childbearing age than those with cirrhotic portal hypertension. They rarely have abnormal liver function tests prior to pregnancy, and the fertility rates are reported to be the same as controls [48]. Pregnancy outcomes in women with non-cirrhotic portal hypertension are likely to be influenced by the Please cite this article in press as: Geenes V, Williamson C, Liver disease in pregnancy, Best Practice & Research Clinical Obstetrics and Gynaecology (2015), http://dx.doi.org/10.1016/j.bpobgyn.2015.04.003



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Table 2 Causes of cirrhotic and non-cirrhotic portal hypertension. Cirrhotic portal hypertension

Non-cirrhotic portal hypertension

Autoimmune hepatitis Viral hepatitis Primary biliary cirrhosis Primary sclerosing cholangitis Biliary atresia Alcohol Non-alcoholic steatohepatitis Hereditary haemochromatosis Wilson's disease Drugs Amiodarone Methotrexate

Portal vein thrombosis BuddeChiari syndrome Sinusoidal obstruction syndromea Schistosomiasis Sarcoidosis Congenital hepatic fibrosis Idiopathic portal hypertension Obliterative portal venopathy Chemical (vinyl chloride) Drugs (azathioprine, didanosine, stavudine) Immune-mediated (thyroiditis, lupus) Prothrombotic conditions

a

Also known as veno-occlusive disease.

underlying aetiology, and they include increased rates of fetal loss and the risk of variceal bleeding [49,50]. However, the overall prognosis is generally better than for those with cirrhotic portal hypertension, particularly if the underlying disease is diagnosed and treated prior to pregnancy. Liver transplantation Perinatal outcomes in women with liver transplants are generally reported to be good, and these are improved if pregnancy is delayed for at least 1 year after the transplant, or after an episode of rejection [51]. The overall live-birth rate is reported to be 70e90%. However, there is an increased risk of maternal complications, and particularly of hypertensive disorders and pre-eclampsia. There are also high incidences of preterm birth and low-birthweight babies. Pregnancy does not appear to affect graft survival or outcome, despite episodes of rejection being reported in between 2% and 17% of women. Episodes of rejection during pregnancy can be managed as they would be outside of pregnancy, that is, with appropriate investigations and, if necessary, a change in the immunosuppressive regimen.

Pregnancy-specific liver disease Intrahepatic cholestasis of pregnancy ICP affects approximately 0.7% of pregnant women in the UK, making it the most common pregnancy-specific cause of hepatic impairment. It typically presents with maternal pruritus in the third trimester, and it is characterized by raised maternal serum bile acid levels. The pruritus most commonly affects the palms of the hands and the soles of the feet, but it may be reported anywhere. Symptoms of cholestasis (dark urine, pale stools and steatorrhoea) may also be present, but clinical jaundice is rare. The aetiology of ICP is complex, and it is thought to relate to the cholestatic effects of reproductive hormones in genetically susceptible women [52]. The diagnosis of ICP is one of exclusion and other causes of hepatic impairment, including gallstones, viral hepatitis and PBC/PSC, should be excluded. Serum bile acids levels are the most sensitive and specific biochemical markers for ICP, and they should be raised to make the diagnosis. Elevated levels of transaminases (alanine transaminase (ALT) and aspartate transaminase (AST)) are supportive of the diagnosis of ICP. A coagulation profile should also be requested, as there is a theoretical risk of deranged clotting secondary to malabsorption of vitamin K. The symptoms and biochemical abnormalities of ICP typically resolve rapidly following delivery. Liver function tests and serum bile acid levels should be checked approximately 6e8 weeks following delivery to ensure that they have normalized. ICP is associated with an increased risk of adverse perinatal outcomes [53e55]. The largest prospective study of perinatal outcomes in ICP to date reported that women with serum bile acid levels >40 mmol/L were at an increased risk of preterm delivery (both spontaneous and iatrogenic), admission to the neonatal unit and stillbirth. Furthermore, there was a higher incidence of meconium staining of the amniotic fluid, and this also had a tendency Please cite this article in press as: Geenes V, Williamson C, Liver disease in pregnancy, Best Practice & Research Clinical Obstetrics and Gynaecology (2015), http://dx.doi.org/10.1016/j.bpobgyn.2015.04.003


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to occur at earlier gestational weeks. These findings are supported by those of several smaller studies. The perinatal outcomes associated with ICP in women whose serum bile acid level does not exceed 40 mmol/L is less clear. However, the data appear to be reassuring as the largest study of this subgroup of women reported that there was no difference in the rate of spontaneous preterm delivery, meconium staining of the amniotic fluid or asphyxial events [54]. Older studies of ICP, with higher rates of stillbirths, suggested that there was clustering of stillbirths around 38 weeks of gestation [56]. Therefore, many centres have adopted policies of active management, including regular blood tests and fetal monitoring, and they aim to deliver around 37 weeks to reduce the risk of stillbirth. However, it should be noted that these practices are not evidence based, and although regular cardiotocography may provide some reassurance for both the woman and clinician, there are several reports of normal fetal heart tracings in the hours preceding fetal death [52]. UDCA is commonly used to treat ICP, and it has recently been shown to result in a significant reduction in pruritus, ALT and bilirubin in the largest randomized controlled trial to date [57]. In this trial, there was no reduction in serum bile acid levels; however, a meta-analysis of nine smaller trials suggested that UDCA treatment did have beneficial effects on serum bile acid levels and therefore further trials are warranted [58]. Other drugs including cholestyramine, S-adenosyl L-methionine and dexamethasone are less effective than UDCA at reducing pruritus or improving liver function, and they have therefore been superseded by UDCA [52]. There is a high risk of recurrence of ICP in subsequent pregnancies (up to 80% in some studies), and a subgroup of women also report recurrent symptoms with their menstrual cycle. Some women develop signs and symptoms of cholestasis when taking the oral contraceptive pill, and it is recommended that they do not use oestrogen-containing preparations. Recent studies have reported that women with a history of ICP have higher rates of hepatobiliary disease and metabolic syndrome later in life [11]. Acute fatty liver of pregnancy Acute fatty liver of pregnancy (AFLP) is a rare cause of acute liver failure that occurs almost exclusively in the third trimester, but it may also present following delivery [59]. It affects approximately one in 7000e16,000 pregnancies and it is characterized by microvesicular steatosis, hepatic failure and encephalopathy. It is thought to be more common in nulliparous women and in multiple pregnancy. An association between AFLP and fetal homozygosity for long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) deficiency has been reported in several studies. The mothers of babies with LCHAD are obligate heterozygotes for LCHAD deficiency, and therefore they have a reduced capacity to oxidize long-chain fatty acids in the liver and placenta, which combined with the fetal deficiency leads to an accumulation of hepatotoxic metabolites in the maternal liver. AFLP typically presents with a history of vomiting, reduced appetite, abdominal pain (mid-epigastric or right upper quadrant), headache and jaundice. Some women also have a low-grade fever. Other presenting features may include hyperlactaemia, hypoglycaemia, hypertension, proteinuria, ascites and bleeding. The ‘Swansea criteria’ for diagnosis are present in almost all cases, and it may be useful to distinguish AFLP from the HELLP syndrome (haemolysis, elevated liver enzymes and low platelets syndrome) (Table 3).

Table 3 Swansea criteria for acute fatty liver of pregnancy. Six or more of the following in the absence of an alternative cause should be present to make the diagnosis. Symptoms and signs

Laboratory abnormalitiesa

Other

Vomiting Abdominal pain Polydipsia/polyuria Encephalopathy

Elevated bilirubin (>14 mmol/L) Hypoglycaemia (340 mmol/L) Leucocytosis (>11 109/L) Elevated transaminases (ALT or AST, >42 IU/L) Elevated ammonia (>47 mmol/L) Renal impairment (creatinine > 150 mmol/L) Coagulopathy (PT > 14 s or APTT > 34 s)

Ascites or bright liver on ultrasound scan Microvesicular steatosis on liver biopsy

ALT, alanine transaminase; AST, aspartate transaminase; PT, prothrombin time; APTT, activated partial thromboplastin time. a Numbers in brackets are the ranges used in Knight et al. [59].




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AFLP is associated with a high risk of both maternal and fetal mortality (1.8e18% and 9e23%, respectively), and early recognition and diagnosis are essential [59]. The mother should be stabilized and then the baby delivered immediately. Most deliveries are by caesarean section, but there is no specific contraindication to vaginal delivery if this can be achieved rapidly. However, epidural and spinal anaesthesia are contraindicated due to the associated coagulopathy. The postnatal course is variable. Liver function tests and coagulopathy typically improve within 2e3 days, but they may continue to deteriorate. In the case of continued deterioration or the development of liver failure, women should be transferred to a specialist liver unit to be considered for transplantation. Recovery is usually complete with no signs of chronic liver disease. There is an increased risk of recurrence in women with LCHAD mutations. All babies born to women with AFLP should be tested for defects of fatty acid oxidation. Summary There is a spectrum of hepatic disorders in pregnancy. The important common symptoms and signs that indicate underlying pathology are pruritus, nausea, vomiting and jaundice. If liver disease is suspected, prompt diagnosis and intervention with appropriate management may reduce maternal and fetal morbidity and mortality. Conflict of interest None to declare.

Practice points The new appearance of palmar erythema and spider naevi may be normal in pregnancy. Indications for investigation of underlying liver disease include new onset of vomiting in the third trimester, jaundice, pruritus, polyuria and polydipsia. The ‘Swansea criteria’ are valuable for the diagnosis of acute fatty liver of pregnancy. Hepatitis E has a worse course in pregnancy than in non-pregnant individuals. Azathioprine is considered safe in pregnancy and lactation. Pregnancy-specific reference ranges for liver function tests should be used.

Research agenda Prospective cohort studies of rare liver diseases in pregnancy to enable evidence-based guidelines to be written. Randomized controlled trials to evaluate the effectiveness of ursodeoxycholic acid in pregnancy and in improving perinatal outcomes. Studies to evaluate the safety of drugs commonly used in liver disease during lactation.

Q2

References *[1] Walker I, Chappell LC, Williamson C. Abnormal liver function tests in pregnancy. BMJ 2013;347:f6055. [2] Renge RL, Dani VS, Chitambar SD, et al. Vertical transmission of hepatitis A. Indian J Pediatr 2002;69:535e6. [3] Urganci N, Arapoglu M, Akyildiz B, et al. Neonatal cholestasis resulting from vertical transmission of hepatitis A infection. Pediatr Infect Dis J 2003;22:381e2.



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Q3


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Pregnancy and vascular liver disease.

Echinococcal disease of the liver in pregnancy.

ACG Clinical Guideline: Liver Disease and Pregnancy.

Liver diseases in pregnancy: liver transplantation in pregnancy.

Pregnancy in primary liver carcinoma.

Liver diseases in pregnancy: diseases not unique to pregnancy.

Liver diseases in pregnancy: diseases unique to pregnancy.

Thyroid disease in pregnancy.

Respiratory disease in pregnancy.

Skin disease in pregnancy.

Coronary disease in pregnancy.

Respiratory disease in pregnancy.

Renal disease in pregnancy.

Heart disease in pregnancy.

Cardiac disease in pregnancy.

Cardiac disease in pregnancy.

Respiratory disease in pregnancy.

Autoimmune disease in pregnancy.

[Acute fatty liver of pregnancy].

Abnormal liver function tests in pregnancy.

[Twin pregnancy after liver transplantation].

A Spotty Liver of Pregnancy.

Plasma vitamin D-binding globulin in vitamin D deficiency, pregnancy and chronic liver disease.

Heart disease in pregnancy: ischaemic heart disease.