Liver disease in pregnancy

This article briefly discusses gestational physiologic changes and thereafter reviews liver diseases during pregnancy, which are divided into 3 main categories. The first category includes conditions that are unique to pregnancy and generally resolve with the termination of pregnancy, the second category includes liver diseases that are not unique to the pregnant population but occur commonly or are severely affected by pregnancy, and the third category includes diseases that occur coincidentally with pregnancy and in patients with underlying chronic liver disease, with cirrhosis, or after liver transplant who become pregnant.     

Pregnancy-related liver diseases

Liver diseases related to pregnancy may be associated with preeclampsia (liver dysfunction related to preeclampsia; hemolysis, elevated liver enzymes, and low platelets with or without preeclampsia [HELLP syndrome]; and acute fatty liver of pregnancy) or may not involve preeclampsia (hyperemesis gravidarum and intrahepatic cholestasis of pregnancy). Liver diseases associated with pregnancy have unique presentations, but it can be difficult differentiating these from liver diseases that occur coincidentally with pregnancy. Recently, advances have been made in the disease mechanism and intervention of pregnancy-related liver diseases. Early diagnosis and delivery remains the key element in managing the liver diseases associated with preeclampsia, but emerging data suggest that incorporating advance supportive management into current strategies can improve both maternal and fetal outcomes.     

Liver disease in pregnancy

Abnormal liver tests occur in 3%-5% of pregnancies, with many potential causes, including coincidental liver disease (most commonly viral hepatitis or gallstones) and underlying chronic liver disease. However, most liver dysfunction in pregnancy is pregnancy-related and caused by 1 of the 5 liver diseases unique to the pregnant state: these fall into 2 main categories depending on their association with or without preeclampsia. The preeclampsia-associated liver diseases are preeclampsia itself, the hemolysis (H), elevated liver tests (EL), and low platelet count (LP) (HELLP) syndrome, and acute fatty liver of pregnancy. Hyperemesis gravidarum and intrahepatic cholestasis of pregnancy have no relationship to preeclampsia. Although still enigmatic, there have been recent interesting advances in understanding of these unique pregnancy-related liver diseases. Hyperemesis gravidarum is intractable, dehydrating vomiting in the first trimester of pregnancy; 50% of patients with this condition have liver dysfunction. Intrahepatic cholestasis of pregnancy is pruritus and elevated bile acids in the second half of pregnancy, accompanied by high levels of aminotransferases and mild jaundice. Maternal management is symptomatic with ursodeoxycholic acid; for the fetus, however, this is a high-risk pregnancy requiring close fetal monitoring and early delivery. Severe preeclampsia itself is the commonest cause of hepatic tenderness and liver dysfunction in pregnancy, and 2%-12% of cases are further complicated by hemolysis (H), elevated liver tests (EL), and low platelet count (LP)-the HELLP syndrome. Immediate delivery is the only definitive therapy, but many maternal complications can occur, including abruptio placentae, renal failure, subcapsular hematomas, and hepatic rupture. Acute fatty liver of pregnancy is a sudden catastrophic illness occurring almost exclusively in the third trimester; microvesicular fatty infiltration of hepatocytes causes acute liver failure with coagulopathy and encephalopathy. Early diagnosis and immediate delivery are essential for maternal and fetal survival.     

Liver disease in pregnancy

Liver diseases in pregnancy may be categorized into liver disorders that occur only in the setting of pregnancy and liver diseases that occur coincidentally with pregnancy. Hyperemesis gravidarum, preeclampsia/eclampsia, syndrome of hemolysis, elevated liver tests and low platelets （HELLP）, acute fatty liver of pregnancy, and intrahepatic cholestasis of pregnancy are pregnancy-specific disorders that may cause elevations in liver tests and hepatic dysfunction. Chronic liver diseases, including cholestatic liver disease, autoimmune hepatitis, Wilson disease, and viral hepatitis may also be seen in pregnancy. Management of liver disease in pregnancy requires collaboration between obstetricians and gastroenterologists/hepatologists. Treatment of pregnancy-specific liver disorders usually involves delivery of the fetus and supportive care, whereas management of chronic liver disease in pregnancy is directed toward optimizing control of the liver disorder. Cirrhosis in the setting of pregnancy is less commonly observed but offers unique challenges for patients and practitioners. This article reviews the epidemiology, pathophysiology, diagnosis, and management of liver diseases seen in pregnancy.     

The spectrum and treatment of gastrointestinal disorders during pregnancy

Gastrointestinal symptoms are extremely common during pregnancy. Increased levels of female sex hormones cause or contribute to symptoms such as heartburn, nausea, vomiting and constipation. If these symptoms do not respond adequately to lifestyle and dietary changes, drug therapy is often warranted to improve quality of life and to prevent complications. Physicians, therefore, need to be familiar with the low-risk treatment options available. Treatment of chronic conditions such as IBD or chronic liver disease during pregnancy can be demanding. In women with IBD, maintenance of adequate disease control during pregnancy is crucial. Most IBD drugs can be used during pregnancy, but the benefits and risks of specific drugs should be discussed with the patient. Liver diseases can be coincidental or pregnancy-specific. Pregnancy-specific liver diseases include not only benign disorders such as intrahepatic cholestasis of pregnancy, but also pre-eclampsia, eclampsia and HELLP syndrome (hemolytic anemia, elevated liver enzymes and low platelet count). Accordingly, the spectrum of therapeutic measures ranges from expectant management to urgent induction of delivery. During pregnancy, lamuvidine therapy for chronic hepatitis B can be continued; however, interferon and ribavirin therapy for chronic hepatitis C is contraindicated. This Review provides an overview of the spectrum and therapy of motility disturbances that occur during pregnancy, and discusses pregnancy-specific aspects of IBD and liver diseases.     

Liver Diseases Unique to Pregnancy

Severe liver diseases occur in less than 0.1% of pregnancies. Accurate diagnosis and appropriate therapy are essential to the health and survival of both the mother and fetus. Because of their low incidence and the fact that most pregnant women are cared for primarily by their obstetricians, gastroenterologists only infrequently encounter these diseases. This review is intended to update the practicing gastroenterologist on the complex spectrum of liver diseases unique to pregnancy.     

Liver disease in pregnancy

Development of liver diseases during pregnancy is not uncommon. They are caused by either a disorder that is unique to pregnancy or an acute or chronic liver disease that already exists or coincidentally develops as a comorbidity of pregnancy. Liver diseases unique to pregnancy include hyperemesis gravidarum; hypertensive disorders of pregnancy, such as pre‐eclampsia/eclampsia; hemolysis, elevated liver enzymes, and low platelet count syndrome; intrahepatic cholestasis of pregnancy; and acute fatty liver of pregnancy. Chronic liver diseases that affect pregnancy, or are affected by pregnancy, mainly include autoimmune liver diseases and non‐alcoholic fatty liver disease. Prompt diagnosis and management of liver diseases in pregnancy, while very challenging, is extremely important, as they might cause adverse maternal and fetal outcomes. Therefore, a multidisciplinary, collaborative approach involving both hepatologists and obstetricians is required. In this review article, the up‐to‐date epidemiology, etiology, clinical features, and outcomes of liver diseases in pregnancy are discussed, to promote a deeper understanding among physicians, and subsequently improved outcomes.     

Pregnancy-related liver diseases

Opinion statement  

Liver disease in pregnancy

Liver dysfunction during pregnancy can be caused by conditions that are specific to pregnancy or by liver diseases that are not related to pregnancy itself. This review attempts to summarize the epidemiology, pathophysiology, and management of the different pregnancy-related liver diseases, and to review different liver diseases not related to pregnancy and how they may affect or be effected by pregnancy. Some of the liver diseases specific to pregnancy can cause significant morbidity and mortality both to the mother and to the fetus, while most of the liver diseases not specific to pregnancy do not have a deleterious effect on the pregnancy itself.     

Hepatic vascular involvement related to pregnancy, oral contraceptives, and estrogen replacement therapy

Both pregnancy and oral contraception (mainly when estrogen is included) may precipitate the development of Budd-Chiari syndrome in patients with underlying thrombophilia. By contrast, there is little evidence for such a role of pregnancy and oral contraception in women with portal vein thrombosis. In pregnant women, special modalities for anticoagulation are required, whereas the management of portal hypertension can be similar to that recommended in other diseases and settings. Hereditary hemorrhagic telangiectasia may deteriorate during pregnancy and improve after delivery. Hepatic sinusoidal dilatation and hepatic peliosis are classic complications of long-term use of oral contraceptives. The impact of pregnancy or oral contraceptives on the natural history on hemangioma and focal nodular hyperplasia appears to be limited. Preeclampsia, a liver disease unique to pregnancy, may be complicated by life-threatening liver vascular involvement, especially when the syndrome of hemolysis, elevated liver enzymes, and low platelet count (HELLP syndrome) is present.     

Liver diseases in pregnancy: Diseases unique to pregnancy

Pregnancy is a special clinical state with several normal physiological changes that influence body organs including the liver.Liver disease can cause significant morbidity and mortality in both pregnant women and their infants.This review summarizes liver diseases that are unique to pregnancy.We discuss clinical conditions that are seen only in pregnant women and involve the liver;from Hyperemesis Gravidarum that happens in 1out of 200 pregnancies and Intrahepatic Cholestasis of Pregnancy(0.5%-1.5%prevalence),to the more frequent condition of preeclampsia(10%prevalence)and its severe form;hemolysis,elevated liver enzymes,and a low platelet count syndrome(12%of pregnancies with preeclampsia),to the rare entity of Acute Fatty Liver of Pregnancy(incidence of 1 per 7270 to 13000deliveries).Although pathogeneses behind the development of these aliments are not fully understood,theories have been proposed.Some propose the special physiological changes that accompany pregnancy as a precipitant.Others suggest a constellation of factors including both the mother and her fetus that come together to trigger those unique conditions.Reaching a timely and accurate diagnosis of such conditions can be challenging.The timing of the condition in relation toward which trimester it starts at is a key.Accurate diagnosis can be made using specific clinical findings and blood tests.Some entities have well-defined criteria that help not only in making the diagnosis,but also in classifying the disease according to its severity.Management of these conditions range from simple medical remedies to measures such as immediate termination of the pregnancy.In specific conditions,it is prudent to have expert obstetric and medical specialists teaming up to help improve the outcomes.     

Liver disease in pregnancy: Medical aspects and their implications for mother and child

Liver disease during pregnancy is more common than expected and may require specialized intervention. It is important to determine if changes in liver physiology may develop into liver disease, to assure early diagnosis. For adequate surveillance of mother-fetus health outcome, liver disease during pregnancy might require intervention from a hepatologist. Liver diseases have a prevalence of at least 3% of all pregnancies in developed countries, and they are classified into two main categories: related to pregnancy; and those non- related that are present de novo or are preexisting chronic liver diseases. In this review we describe and discuss the main characteristics of those liver diseases associated with pregnancy and only some frequent pre-existing and co-incidental in pregnancy are considered.In addition to the literature review, we compiled the data of liver disease occurring during pregnancies attended at the National Institute of Perinatology in Mexico City in a three-year period.In our tertiary referral women hospital, liver disease was present in 11.24 % of all pregnancies. Associated liver disease was found in 10.8% of all pregnancies, mainly those related to pre-eclampsia (9.9% of pregnancies). Only 0.56% was due to liver disease that was co-incidental or preexisting; the acute or chronic hepatitis C virus was the most frequent in this group (0.12%).When managing pregnancy in referral hospitals in Latin America, it is important to discard liver alterations early for adequate follow up of the disease and to prevent adverse consequences for the mother and child.     

Liver diseases unique to pregnancy: a 2010 update

Liver disorders occurring during pregnancy may be specifically pregnancy-related, or may be due to an intercurrent or chronic liver disease, which may present in anyone, pregnant or not. This review focuses on the liver diseases unique to pregnancy. Hyperemesis gravidarum, which occurs during early pregnancy, may be associated with liver dysfunction. Intrahepatic cholestasis of pregnancy typically occurs during the second or third trimester. Pruritus and the associated biological signs of cholestasis improve rapidly after delivery. Mutations in gene encoding biliary transporters, especially ABCB4 encoding the multidrug resistance 3 protein, have been found to be associated with this complex disease. Ursodeoxycholic acid is currently the most effective medical treatment in improving pruritus and liver tests. Pre-eclampsia, which presents in late pregnancy frequently involves the liver, and HELLP syndrome (Hemolysis-Elevated Liver enzymes-Low Platelets) is a life-threatening complication. Prognosis of acute fatty liver of pregnancy has been radically transformed by early delivery, and clinicians must have a high index of suspicion for this condition when a woman presents nausea or vomiting, epigastric pain, jaundice, or polyuria-polydipsia during the third trimester. Acute fatty liver of pregnancy has been found to be associated with a defect of long-chain 3-hydroxyacyl coenzyme A dehydrogenase in the fetus, and mothers and their offspring should undergo DNA testing at least for the main associated genetic mutation (c.1528G>C).     

A delay in the HELLP syndrome diagnosis

HELLP syndrome is a serious obstetrical complication that tends to occur in the second half of pregnancy that complicates six promiles of pregnancies. The term HELLP syndrome is derived from the beginning letters of the English words indicating laboratory changes, which is occurs as a specific illness in pregnancy. There is hemolysis, elevated liver enzymes and a decreased platelet count. It can present itself with preeclampsia or without it. The most serious complications are disseminated intravascular coagulation, liver rupture or various organ failures. The pathogenesis at the moment is not completely known. The basic approach to care is delivery at the earliest possible term. HELLP syndrome generally arises in the second or third trimester of pregnancy, but can also occur after delivery. It has typical signs, which can also arise due to other liver diseases, but more frequently in diseases of the gall bladder, which in pregnancy given the physiological changes in the body of the pregnant women is also predisposed. In this context, woman with this problem can seek out other physicians than obstetricians. In our case, we wanted to refer to the needs of early diagnosis of this frequently diagnosed illness, since in the case of late diagnosis and a woman not sent to the obstetrical department can lead to a serious life threatening state for the mother and child.     

Gallstone disease and pancreatitis in pregnancy.

Controversy exists over whether pregnancy is a risk factor for gallstone formation; however, changes in hepatobiliary function do occur during pregnancy to create a lithogenic environment; these changes include gallbladder stasis and secretion of bile with increased amounts of cholesterol and decreased amounts of chenodeoxycholic acid. In women with existing gallstones, pregnancy may bring out symptoms, including pain and even acute cholecystitis. This may be more common during the postpartum period than during pregnancy itself; however, the overall occurrence of symptomatic biliary disease in association with pregnancy is low. The effects of pregnancy, if any, on pancreatic exocrine function are undefined. Acute pancreatitis can occur during pregnancy but does not appear to do so with either increased or, alternatively, decreased frequency. The concept of pancreatitis caused by pregnancy per se is not valid, although in susceptible women with lipid disorders, hypertriglyceridemia can occur and serve as an etiologic factor. Gallstones are a common cause of pancreatitis, but in contrast to nonpregnant women, alcohol is unusual as a cause. Although the presentation of both acute cholecystitis and acute pancreatitis may be similar to that in the nonpregnant state, the differential diagnosis of both these disorders is expanded because of unique pregnancy-related conditions and the shift of abdominal viscera by the enlarging uterus. The diagnosis is clinical and supported with conventional laboratory studies and ultrasound; management is supportive and in most patients successful. Cholecystectomy is seldom necessary during pregnancy, either for acute cholecystitis or gallstone pancreatitis, but can be safely performed if necessary after the first trimester. Endoscopic papillotomy and stone removal for choledocholithiasis are possible during pregnancy and may be the treatment of choice for this unusual condition. Specific enteral or parenteral nutrition may be necessary in women with pancreatitis associated with hypertriglyceridemia.     

Liver diseases unique to pregnancy

Liver injury and dysfunction in a pregnant woman may be caused by intrinsic features of the pregnancy itself, disorders that are coincidental with pregnancy or pre-existing liver disease that is exacerbated by pregnancy. The clinical setting, gestational age and standard liver biochemistry testing are useful tools in helping to establish a diagnosis. Prompt recognition of the signs of liver disease in pregnant patients leads to timely management and may save the life of both mother and baby. This review summarises the incidence, risk factors, pathogenesis, clinical presentation, diagnosis, treatment and outcome of those liver diseases unique to pregnancy.     

Clinical course and management of acute and chronic viral hepatitis during pregnancy

Pregnancy is a para‐physiologic condition, which usually evolves without any complications in the majority of women, even if in some circumstances moderate or severe clinical problems can also occur. Among complications occurring during the second and the third trimester very important are those considered as concurrent to pregnancy such as hyperemesis gravidarum, intrahepatic cholestasis of pregnancy, HELLP syndrome and acute fatty liver of pregnancy. The liver diseases concurrent to pregnancy typically occur at specific times during the gestation and they may lead to significant maternal and foetal morbidity and mortality. Commonly, delivery of the foetus, even preterm, usually terminates the progression of these disorders. All chronic liver diseases, such as chronic viral hepatitis, autoimmune hepatitis, Wilson's disease, and cirrhosis of different aetiologies may cause liver damage, independently from pregnancy. In this review we will also comment the clinical implications of pregnancies occurring in women who received a orthotopic liver transplantation (OLT) Therefore, the management of immunosuppressive therapy before and after the delivery in women who received liver transplant is becoming a relevant clinical issue. Finally, we will focus on acute and chronic viral hepatitis occurring during pregnancy, on management of advanced liver disease and we will review the literature on the challenging issue regarding pregnancy and OLT.     

Pregnancy and chronic hepatitis B virus infection

The combination of chronic hepatitis B virus (HBV) infection and pregnancy presents unique management questions. Aspects of care that need to be considered include effects of hepatitis B on pregnancy, effects of pregnancy itself on the course of hepatitis B infection, treatment of hepatitis B during pregnancy and prevention of mother-to-infant transmission. Chronic HBV infection is usually mild in pregnant women, but may flare shortly after delivery. Effect of HBV infection on pregnancy outcomes are generally favorable, but may depend on severity of liver disease. Mother-to-infant transmission can be minimized by current immunoprophylaxis strategies, however, high levels of viremia in mothers may be a factor in the small but reproducible failure rate of current immunoprophylaxis strategies. Use of antivirals during pregnancy needs to be individualized. Careful planning and management of pregnancy must be done among patients with chronic HBV infection.     

Liver diseases in pregnancy: Diseases not unique to pregnancy

Pregnancy is a special clinical state with several normal physiological changes that influence body organs including the liver.Liver disease can cause significant morbidity and mortality in both pregnant women and their infants.Few challenges arise in reaching an accurate diagnosis in light of such physiological changes.Laboratory test results should be carefully interpreted and the knowledge of what normal changes to expect is prudent to avoid clinical misjudgment.Other challenges entail the methods of treatment and their safety for both the mother and the baby.This review summarizes liver diseases that are not unique to pregnancy.We focus on viral hepatitis and its mode of transmission,diagnosis,effect on the pregnancy,the mother,the infant,treatment,and breast-feeding.Autoimmune hepatitis,primary biliary cirrhosis,primary sclerosing cholangitis,Wilson’s disease,Budd Chiari and portal vein thrombosis in pregnancy are also discussed.Pregnancy is rare in patients with cirrhosis because of the metabolic and hormonal changes associated with cirrhosis.Variceal bleeding can happen in up to 38%of cirrhotic pregnant women.Management of portal hypertension during pregnancy is discussed.Pregnancy increases the pathogenicity leading to an increase in the rate of gallstones.We discuss some of the interventions for gallstones in pregnancy if symptoms arise.Finally,we provide an overview of some of the options in managing hepatic adenomas and hepatocellular carcinoma during pregnancy.     

Pregnancy and autoimmune connective tissue diseases

Autoimmune connective tissue diseases predominantly affect women and often occur during the reproductive years. Thus, specialized issues in pregnancy planning and management are commonly encountered in this patient population. This chapter provides a current overview of pregnancy as a risk factor for onset of autoimmune disease, considerations related to the course of pregnancy in several autoimmune connective tissue diseases, and disease management and medication issues before pregnancy, during pregnancy, and in the postpartum period. A major theme that has emerged across these inflammatory diseases is that active maternal disease during pregnancy is associated with adverse pregnancy outcomes, and that maternal and fetal health can be optimized when conception is planned during times of inactive disease and through maintaining treatment regimens compatible with pregnancy.