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Pregnancy and Liver Disease
Chapter
22
Pregnancy and Liver Disease Christine J. Bruno, MD, and Roshan Shrestha, MD
NORMAL ANATOMICAL aND PHYSIOLOGIC CHANGES DURING PREGNANCY 1. What are the structural and functional hepatic adaptations during pregnancy? Liver size and histology do not change. Maternal blood volume and cardiac output increase significantly, without a corresponding increase in hepatic blood flow, with a net decrease in fractional blood flow to the liver. An enlarging uterus makes venous return via the inferior vena cava progressively more difficult toward term. Blood is shunted via the azygous system with possible development of esophageal varices. 2. Does liver function change during pregnancy? Hepatic function remains normal during pregnancy, but the normal range of laboratory values changes because of hormonal changes and an increase in blood volume with subsequent hemodilution. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyl transpeptidase (GGTP), bilirubin, and prothrombin remain within normal limits. Total alkaline phosphatase (AP) is elevated. The placenta is the major source of AP; levels return to normal within 20 days after delivery. Estrogen increases the synthesis of fibrinogen, as well as other coagulation proteins (factors VII, VIII, IX, and X). Attributed also to estrogen’s effects are significant increases in serum concentrations of major lipid classes (triglycerides, cholesterol, and low- and very-low-density lipoproteins). These levels may be twice the normal limit of nonpregnant women of the same age. Serum albumin decreases slightly, contributing to the approximately 20% decline in serum protein concentration. Plasma concentrations of other serum proteins (ceruloplasmin, corticosteroids, testosterone, serum binding protein for thyroxine), as well as vitamin D and folate, also increase during pregnancy. DISEASES DURING PREGNANCY
• Coincident occurrence of liver disease (viral hepatitis, alcoholic hepatitis, gallstone disease, autoimmune hepatitis) • Intrahepatic cholestasis of pregnancy (IHCP) • Acute fatty liver of pregnancy (AFLP) • Hemolysis, elevated liver enzymes, and low platelet count (HELLP syndrome) 3. Can gestational age differentiate between different liver diseases in pregnancy? Most definitely. Hyperemesis gravidarum presents in the first trimester of pregnancy. Patients have severe nausea and vomiting, and about one-half have associated elevations of bilirubin, AST, or ALT. Cholestasis of pregnancy, viral hepatitis, and abnormal liver chemistries due to cholelithiasis may present at any point in gestation, from the first to the third trimester. AFLP and preeclamptic liver disease (HELLP, hepatic infarct, and hepatic rupture) are specifically encountered in the third trimester of pregnancy. Both herpes simplex virus and hepatitis E virus are exacerbated in pregnancy and usually present in the third trimester. The presentation may be a mild elevation in transaminases or severe hepatic failure. Budd-Chiari syndrome presents from the second half of pregnancy to 3 months postpartum. COINCIDENT OCCURreNCE 4. Can we assume the presence of chronic liver disease in a pregnant patient with angiomas and palmar erythema on physical examination and small esophageal varices detected endoscopically? No. Spider angiomas and palmar erythema are common and appear in about two-thirds of pregnant women without liver disease. Small esophageal varices are present in approximately 50% of healthy pregnant women without liver disease because of the increased flow in the azygous system. 5. What is the most common cause of jaundice in pregnancy? Viral hepatitis.
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6. How severe is the course of viral hepatitis acquired during pregnancy? • Hepatitis A, B, and C run a similar course in pregnant and nonpregnant patients. • Hepatitis E runs a different course in pregnancy. It is fulminant in up to 20% of patients, compared with less than 1% of nonpregnant women. The fatality rate is 1.5% during the first trimester, 8.5% during the second trimester, and up to 21% during the third trimester compared with 0.5% to 4% in nonpregnant women. Fetal complications and neonatal deaths are increased if infection is acquired in the third trimester of pregnancy. • Herpes simplex hepatitis can be fulminant in pregnancy and associated with high mortality rates. Patients present in the third trimester with fever, systemic symptoms, and possibly vesicular cutaneous rash. Associated pneumonitis or encephalitis may be present. Liver biopsy is characteristic, showing necrosis and inclusion bodies in viable hepatocytes, along with few or no inflammatory infiltrates. Response to acyclovir therapy is prompt; there is no need for immediate delivery of the baby. 7. What signs and symptoms suggest the diagnosis of Budd-Chiari syndrome? The clinical triad of sudden onset of abdominal pain, hepatomegaly, and ascites, near term or shortly after delivery. Ascitic fluid shows a high protein content in about one-half of cases. Biopsy typically shows centrilobular hemorrhage and necrosis, along with sinusoidal dilation and erythrocyte extravasation into the space of Disse. Hepatic scintigraphy and computed tomography (CT) typically show compensatory hypertrophy of the caudate lobe due to its separate drainage into the inferior vena cava. Doppler analysis of portal and hepatic vessels and magnetic resonance imaging (MRI) establish hepatic vein occlusion. 8. Is the serum ceruloplasmin level a good diagnostic marker in pregnant women at term who are suspected of having Wilson disease? No. Ceruloplasmin levels increase gradually during pregnancy, reaching the maximum at term. Because of this, a patient with Wilson disease who usually has a low level of ceruloplasmin may have it increase misleadingly into the normal range (greater than 20 mg/dL) during pregnancy. 9. Can we maintain a woman with Wilson disease on therapy during pregnancy? Absolutely. Therapy must continue during pregnancy; otherwise, the mother is at risk for hemolytic episodes associated with fulminant hepatic failure. Agents approved by the U.S. Food and Drug Administration are D-penicillamine, trientine, and zinc. Evidence indicates that penicillamine and trientine (tissue copper-chelating agents) are teratogenic in animal studies, and there are reports of penicillamine effects in humans, including cutis laxis syndrome or micrognathia, low-set ears, and other abnormalities. According to the current consensus, penicillamine and trientine are safe in doses of 0.75 to 1 g/day during the first two trimesters; the dosage should be reduced to 0.5 g/day during the last trimester and in nursing mothers. Zinc therapy is an attractive alternative with a different mechanism of action; it induces synthesis of metallothionein, which sequesters copper in enterocytes, blocking its absorption. No teratogenic effects have been reported in animals or humans. The recommended doses are 50 mg 3 times/day for patients with 24-hour urinary copper values greater than 0.1 mg and 25 mg 3 times/day for patients with lower urinary copper values. Close monitoring of urinary copper and zinc levels is suggested; the zinc dose should be adjusted accordingly. INTRAHEPATIC CHOLESTASIS OF PREGNANCY (IHCP) 10. What is the most common liver disorder unique to pregnancy? Intrahepatic cholestasis of pregnancy (IHCP). 11. What is the major clinical manifestation of IHCP? Severe pruritus with onset in the second or, more commonly, third trimester (more than 70% of cases). 12. What biochemical changes are noted in IHCP? Serum bile acids, often measured as cholylglycine, increase by 10- to 100-fold. Serum levels of AP rise by 7- to 10-fold, along with a modest rise in serum levels of 5′-nucleotidase (confirming the hepatic source of AP). AST, ALT, and direct bilirubin also rise. No evidence of hemolysis is found. GGTP is usually normal, as is prothrombin time (PT), unless cholestyramine treatment leads to malabsorption. 13. What is the expected clinical and biochemical course after delivery for patients with IHCP? Pruritus should improve promptly after delivery (within 24 hours). Jaundice is rare and, if present, may persist for days. Biochemical abnormalities may persist for months.
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14. What is a possible cause for abnormal bleeding in a postpartum woman previously diagnosed with IHCP? What is the treatment? Malabsorption of liposoluble vitamins, including vitamin K, especially in patients treated with cholestyramine for pruritus. The international normalized ratio (INR) corrects with parenteral administration of vitamin K. 15. What is the effect of IHCP on the fetus? Fetal distress requiring cesarean section develops in about 30% to 60% of cases. Prematurity occurs in about 50% of cases and fetal death in up to 9% of affected pregnancies. All of these effects are more likely if the disorder begins early in pregnancy. 16. What is the therapy for IHCP? Alleviating pruritus is the main goal. Therapeutic agents include:
• Ursodeoxycholic acid, ≈15 mg/kg/day; up to 24 mg/kg/day studied with good results • Cholestyramine, 4 g 4 or 5 times/day (bile acid–binding resin) • Hydroxyzine hydrochloride (Atarax) or pamoate (Vistaril) (antihistamines); Atarax 25-50 mg every 6 hours as needed, Vistaril 15-30 mg every 6 hours as needed
• Phenobarbital, 100 mg/day (choleretic and centrally acting sedative) • Phototherapy with ultraviolet B light as directed by a dermatologist Vitamin K before delivery is highly recommended to minimize the risk of postpartum hemorrhage. Mother and fetus should be observed closely. Elective induction is recommended at 36 weeks (severe cases) or 38 weeks (average cases) if the fetal lungs have matured. 17. Can IHCP recur? Yes. About 40% to 70% of subsequent pregnancies show evidence of mild intrahepatic cholestasis. The same pattern can be seen with use of estrogen-containing contraceptives. 18. What atypical signs and symptoms make the diagnosis of IHCP doubtful? Fever, hepatosplenomegaly, pain, jaundice preceding or without pruritus, and pruritus after delivery or before 21 weeks of pregnancy, especially with a singleton pregnancy, should prompt the search for an alternate diagnosis. 19. What biochemical changes suggest an alternate diagnosis? • Normal AST and ALT levels • Elevated AP and GGTP (i.e., biliary disease) • Predominantly unconjugated hyperbilirubinemia (i.e., hemolysis) ACUTE FATTY LIVER OF PREGNANCY 20. What are the clinical and laboratory features of AFLP? AFLP is a rare disorder with an incidence of 1 in 13,000 to 1 in 16,000 pregnancies. Onset occurs in the second half of pregnancy, usually during the third trimester, although occasionally postpartum onset is reported. Clinical manifestations include nausea and vomiting, jaundice, malaise, thirst, and altered mental status. Severe cases progress rapidly to hypoglycemia, disseminated intravascular coagulation (DIC), renal insufficiency, coma, and death. Signs of coexistent preeclampsia may be present, such as moderately increased arterial blood pressure, proteinuria, and hyperuricemia. Laboratory abnormalities consist of moderate AST/ALT elevations (usually less than 1000), conjugated hyperbilirubinemia, elevated PT, fibrin split products, and D-dimers, along with low platelet count, elevated levels of ammonia and serum uric acid, and leukocytosis. Hypoglycemia is a sign of extreme severity; blood glucose levels must be monitored closely. 21. How do we diagnose and treat AFLP? High clinical suspicion is crucial for early recognition and appropriate management. AFLP is suggested by hepatic failure at or near term or shortly after delivery in the absence of risk factors or serology suggesting viral hepatitis. Thirst, a symptom of underlying vasopressin-resistant diabetes insipidus, is characteristic to AFLP or HELLP syndrome. Liver biopsy, if feasible, is diagnostic in the appropriate clinical context. Treatment consists of admission to hospital, close monitoring by a multidisciplinary team (hepatologist, maternal-fetal medicine specialist, intensive care specialist) and immediate delivery. Recovery is usually complete, although it may be delayed in patients with significant clinical complications before delivery (e.g., DIC, renal failure, infections). 22. Is biopsy pathognomonic for AFLP? Biopsy is confirmatory but not pathognomonic or indispensable in making the diagnosis. Histology is characterized by microvesicular fatty infiltration, mostly in centrilobular zones. In general, lobular and trabecular architecture is
Chapter 22 Pregnancy and Liver Disease
preserved, and inflammatory infiltrates and cell necrosis are mild, if present at all. AFLP is a systemic disorder. Similar fatty changes have been noted in pancreatic acinar cells and tubular epithelial cells of the kidneys. The same prominent microvesicular steatosis is seen in other conditions such as Reye syndrome, sodium valproate toxicity, Jamaican vomiting sickness, and congenital defects of urea cycle enzymes or beta-oxidation of fatty acids. 23. Describe the pathogenesis of AFLP. Pathogenesis remains somewhat unclear. AFLP seems to be a fetal-maternal interaction. In some cases the fetus has an isolated deficiency of long chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), which leads to a disorder of mitochondrial fatty acid oxidation. The inheritance pattern is recessive and involves a mutation from glutamic acid to glutamine at amino acid residue 474 (Glu474Gln) on at least one allele. It is hypothesized that in the presence of this mutation in homozygous or compound heterozygote fetuses, long-chain fatty acid metabolites produced by the fetus or placenta accumulate in the mother and are highly toxic to the maternal liver. The mother is phenotypically normal; her genotype does not correlate with development of AFLP. 24. What is the outcome of a child whose mother has AFLP? Previously reported fetal mortality rates of 75% to 90% have been significantly reduced by better awareness, earlier diagnosis, availability of neonatal intensive care units, and institution of close monitoring and dietary treatment through childhood. In pregnancies associated with LCHAD defects, children present at a mean age of 7.6 months (range, 0 to 60 months) with acute hepatic dysfunction (incidence of 79%). They may experience hypoketotic hypoglycemia, hypotonia, hepatomegaly, hepatic encephalopathy, high transaminase levels, and fatty liver. The condition may progress rapidly to coma and death. Frequent feedings of a low-fat diet in which the fats are medium-chain triglycerides prevent hypoketotic hypoglycemic liver dysfunction. According to recent studies, 67% of children treated with dietary modification are alive, and most attend school. 25. Does AFLP recur in subsequent pregnancies? In the cases associated with LCHAD defects, the disorder is recessive, affecting one in four fetuses. The rate of recurrence of maternal liver disease is 15% to 25%. 26. Is genetic testing indicated in women diagnosed with AFLP? All women with AFLP, as well as their partners and children, should be advised to undergo molecular diagnostic testing. Testing for Glu474Gln only in the mother is not sufficient to rule out LCHAD deficiency in the fetus or other family members. HEMOLYSIS, ELEVATED LIVER ENZYMES, AND LOW PLATELETS (HELLP) 27. What is the spectrum of liver involvement in preeclampsia? Liver involvement in preeclampsia ranges from subclinical, with biopsy evidence of fibrinogen deposition along hepatic sinusoids, to several possibly severe disorders. In patients with HELLP syndrome, the chief complaint is abdominal pain, which usually presents in the second half of gestation but may occur up to 7 days after delivery (almost 30% of affected women). Hepatic infarction is another rare manifestation of liver involvement in preeclampsia. Patients present in the third trimester or early after delivery with unexplained fever, leukocytosis, abdominal or chest pain, and extremely elevated aminotransferases (greater than 3000). The diagnosis depends on visualization of hepatic infarcts on CT contrast images or MRI. Subcapsular hematomas and hepatic rupture are life-threatening complications with high morbidity and mortality rates. A high index of suspicion and early CT imaging allow diagnosis and prompt intervention. 28. How common is HELLP syndrome? The incidence of HELLP syndrome is 0.2% to 0.6% in all pregnancies and 4% to 12% in preeclamptic patients. The incidence is higher in multiparous, white, and older women, but the mean age of occurrence is around 25 years. 29. Describe the incidence and prognosis of spontaneous intrahepatic hemorrhage. Spontaneous intrahepatic and subcapsular hemorrhage occurs in about 1% to 2% of patients with preeclampsia, with an estimated incidence of 1 in 45,000 live births. Prognosis improves with awareness, early diagnosis by imaging studies, and aggressive surgical management. Recent reported maternal mortality rates range from 33% to 49%. Fetal mortality remains high (≈60%). 30. What findings typically lead to the diagnosis of HELLP syndrome? Diagnosis relies on typical laboratory evidence of liver involvement with associated thrombocytopenia. Not all patients have clinical hypertension or proteinuria at presentation. Liver test abnormalities are hepatocellular. Liver function is
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normal. Thrombocytopenia is present, usually less than 100,000/mm3. Hemolysis is mild, with microangiopathic findings on peripheral smear. Biopsy is characteristic but may be extremely risky and is not needed for diagnosis. It shows periportal hemorrhage, fibrin deposition, and necrosis, possibly with steatosis and/or deposition of fibrinogen along sinusoids with focal parenchymal necrosis. A normal biopsy does not exclude the diagnosis, because involvement may be patchy. 31. What is the treatment for severe preeclamptic liver disease? The initial priority is to stabilize the mother, by administering intravenous fluids, correcting any concurrent coagulopathy, administering magnesium for seizure prophylaxis, and treating severe hypertension. Early hepatic imaging is indicated to rule out infarcts or hematomas. Fetal functional status should be determined. Fetal outcome is related mostly to gestational age. Beyond 34 weeks of gestation with evidence of fetal lung maturity, delivery is the recommended therapy. If fetal lungs are immature, the fetus can be delivered 48 hours after administration of two doses of steroids. Termination of pregnancy should be attempted immediately with evidence of fetal or maternal distress. In cases of ruptured subcapsular hematoma, massive transfusions and immediate surgical intervention are required. In cases where surgical intervention is not possible and there are of signs and symptoms of acute liver failure liver, transplantation should be considered for survival. 32. Does HELLP recur in subsequent pregnancies? Possibly. Studies report recurrence risks as low as 3.4% and as high as 25%. 33. What information helps to differentiate AFLP from HELLP? At presentation, AFLP and HELLP may be difficult to differentiate. Hypertension is usually but not invariably associated with HELLP syndrome. Patients with HELLP have mild, predominantly unconjugated hyperbilirubinemia due to hemolysis, along with severe thrombocytopenia, but no laboratory values suggestive of hepatic failure. Laboratory abnormalities are significantly more severe in AFLP; evidence of hepatic synthetic failure manifests as prolonged PT and significant hypoglycemia in advanced stages. Fibrinogen is low, and ammonia is elevated. Biopsy shows microvesicular steatosis, predominantly in the central zone, in patients with AFLP, whereas patients with HELLP show predominantly periportal fibrin deposition, necrosis, and hemorrhage. 34. Is prospective screening necessary in pregnancies complicated by AFLP or HELLP? From 15% to 20% of pregnancies complicated by AFLP and less than 2% of pregnancies complicated by HELLP syndrome are associated with fetal LCHAD deficiency. Newborns should be screened prospectively at birth in all pregnancies complicated by AFLP. Homozygosity and heterozygosity for the Glu474Gln would indicate the need for avoidance of prolonged fasting and replacement of dietary long-chain fatty acids with medium-chain fatty acids. Parents and physicians should be educated in the risk of metabolic crises and sudden death and instructed in the need for early intervention with intravenous glucose during episodes of vomiting, lethargy, and even minor illnesses. Recent results do not justify routine screening of newborns in pregnancies complicated by HELLP syndrome. Molecular diagnostic testing should, however, be considered in women with recurrent HELLP syndrome in multiple pregnancies. CARE OF PATIENTS WITH PREEXISTING LIVER DISEASE BEFORE
• • • • •
AND
DURING PREGNANCY
Contraception Management of underlying liver disease Management of portal hypertension Management in the setting of transplantation Prevention of vertical transmission
CONTRACEPTION 35. What methods of contraception are available for patients with liver disease? Patients with advanced or untreated liver disease commonly experience amenorrhea and infertility. If clinical improvement leads to restoration of fertility, multiple methods of contraception are available, including barrier methods and intrauterine devices. Tubal ligation may be used in women who have completed their families. Estrogen-based contraceptive agents are generally contraindicated, especially for patients with acute liver disease, but progestin contraceptives are safe alternatives. Combination contraceptives are absolutely contraindicated in patients with cholestatic jaundice of pregnancy or jaundice with prior use, and World Health Organization is listing them as category 4 type of drugs for patients with decompensated cirrhosis of any etiology. Numerous formulations and delivery systems are available.
Chapter 22 Pregnancy and Liver Disease
MANAGEMENT OF UNDERLYING LIVER DISEASE 36. How should patients with preexisting liver disease be managed if pregnancy occurs? Patients are best managed by a multidisciplinary team that includes a maternal-fetal medicine specialist, perinatologist, and hepatologist. They have an increased risk for maternal complications along with a higher incidence of fetal wastage and prematurity. In general, patients should be maintained on the previous therapy that was successful in controlling liver disease and restoring fertility. Women with autoimmune hepatitis should be continued on corticosteroids alone or in combination with azathioprine, which is not teratogenic at the usual dose. Patients with Wilson disease should be continued on the anticopper agent. Patients with portal hypertension should have a baseline endoscopy. If they have never bled and medium or large varices are present, they are at increased risk for variceal hemorrhage during pregnancy. Primary prophylaxis with a nonselective beta blocker or isosorbide mononitrate should be instituted. The fetus should be monitored for bradycardia or growth retardation if the mother is maintained on beta blockers. Variceal bleeding is safely managed with variceal band ligation or sclerotherapy. Octreotide in customary doses is safe in pregnancy. Performing surgical portacaval shunts for patients with well-preserved liver function is possible. Placement of a transjugular intrahepatic portosystemic shunt and splenectomy (in patients with massive splenomegaly, varices, and thrombocytopenia) also have been reported. MANAGEMENT OF PORTAL HYPERTENSION 37. What are the effects of pregnancy on the mother with portal hypertension? The morbidity rate is 30% to 50% because of possible onset of hepatic encephalopathy, spontaneous bacterial peritonitis, and progressive liver failure. The incidence of variceal hemorrhage is 19% to 45%, especially in the second trimester and during labor. Postpartum hemorrhage is seen in 7% to 10% of women, most frequently in those with cirrhotic portal hypertension; thrombocytopenia plays a major role. The mortality rate of these complications is 4% to 7% in noncirrhotic and 10% to 18% in cirrhotic patients with portal hypertension. Data regarding this topic originate mostly from case series and prospectively acquired data are few. 38. What is the effect of maternal portal hypertension on pregnancy? Spontaneous abortion rates for patients with cirrhosis range from 15% to 20%. Most cases occur in the first trimester. Of interest, patients with extrahepatic portal hypertension and patients with well-compensated cirrhosis who underwent surgical shunting before conception have abortion rates similar to the general population. The incidence of premature termination of pregnancy in the second and third trimesters is similar in all of the above groups. Fetal mortality rates are around 50% if the mother requires emergent surgical intervention for variceal hemorrhage. Perinatal mortality rates in cirrhotic mothers are as high as 11% to 18% because of premature delivery, stillbirth, and neonatal death, but they are similar to those for the general population in noncirrhotic patients with portal hypertension and patients who underwent previous portal surgical decompressive procedures. MANAGEMENT IN THE SETTING OF ORTHOTOPIC LIVER TRANSPLANTATION 39. When can a liver transplant recipient actively seek conception? At least a 1-year waiting period is advisable. Case reports suggest that conception close to the transplant date may result in increased maternal and fetal morbidity and mortality. Contraception should be instituted before resuming sexual relations, preferably with barrier methods. 40. Is pregnancy possible after liver transplantation? Pregnancy will become possible once normal menstrual cycles resume. In women with chronic liver disease, most pretransplant amenorrhea resolves in approximately 3 to 10 months following liver transplantation. 41. What are the possible complications of pregnancies occurring after liver transplantation? Hypertensive complications, preterm delivery, infection and fetal growth restriction. Immunosuppressive agents used such as cyclosporine and tacrolimus cause hypertension and renal insufficiency, as well as impairment of placental amino acid transport systems, leading to fetal growth restriction. Cytomegalovirus (CMV) infection can cause congenital anomalies and liver disease if the mother was infected early in the pregnancy. Risk for CMV infection is greatest immediately after transplant or in case of increased immunosuppression due to rejection episodes. Rejection is a rare complication; only about 10% of the reported pregnancies have been complicated by biopsy-proved rejection.
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42. What is recommended in the management of a pregnancy occurring post liver transplantation? Management as high-risk pregnancy by a specialist in maternal-fetal medicine is preferred. Immunosuppression should be continued with close monitoring of blood levels. Abnormal liver function tests should be evaluated aggressively. Percutaneous liver biopsy is not contraindicated but should be performed under ultrasound guidance. Monitoring for maternal and fetal CMV infection is indicated. Quantitative CMV immunoglobulins or detection of CMV viremia and viruria in the mother are adequate tests, and even amniotic fluid analysis could be used if there is suspicion of fetal infection. Deliveries should be via cesarean section if there are active herpes simplex lesions present. Prophylactic antibiotics should be used for deliveries in general. 43. What are pregnancy safety data regarding maintenance immunosuppressive agents used in orthotopic liver transplantation (OLT)? • Category B (no evidence of risk in humans): prednisone • Category C (risks cannot be ruled out): cyclosporine, tacrolimus (FK506), rapamycin (Sirolimus), OKT3, antithymocyte globulin, antilymphocyte globulin • Category D (evidence of risk): azathioprine • Category D with black box warning (high risk: mutagenic/teratogenic): mycophenolate mofetil (CellCept, Myfortic). It is advised that anyone pregnant or wishing to become pregnant be changed to azathioprine. 44. Is breastfeeding permitted after delivery in a liver transplant recipient? At this time, it is believed that breastfeeding should be discouraged. A woman administered immunosuppressive drugs should not breast feed. Calcineurin inhibitors could cause immunosuppression and nephrotoxicity, and no recommendation can be made at this time regarding azathioprine-based regimens because there is extremely limited experience. Manufacturer recommends against breastfeeding in mothers administered interferon therapy, ribavirin, ganciclovir, or lamivudine. No specific recommendation can be made regarding foscarnet. No data are available regarding ursodeoxycholic acid excretion in breast milk. 45. Are immunosuppressive agents safe during pregnancy? Corticosteroids, azathioprine, cyclosporine, tacrolimus, and OKT3 have no apparent teratogenic potential. All may contribute to low birth weights and fetal prematurity. Tacrolimus crosses the placenta and may contribute to transient perinatal hyperkalemia and mild, reversible renal impairment. There are no reports of allograft loss as a result of pregnancy in the tacrolimus-treated group of 35 patients at the University of Pittsburgh. The Philadelphia-based cyclosporine registry reports an allograft rejection rate of 17% and a graft loss rate of 5.7% in 35 patients taking cyclosporine during gestation and post partem period. PREVENTION OF VERTICAL TRANSMISSION 46. How may vertical transmission of viral hepatitis A be prevented? Maternal infection with the hepatitis A virus (HAV) is not associated with fetal wastage or teratogenic effects. Vertical transmission of HAV is rare. There are no restrictions concerning breastfeeding. Passive immunization with immunoglobulin for urgent postexposure prophylaxis, and HAV vaccine is safe and recommended in pregnant women at risk for acquiring the disease, such as women traveling to endemic areas. 47. How may vertical transmission of viral hepatitis B be prevented? The hepatitis B virus (HBV) may be transmitted vertically. If the mother acquires HBV in the first trimester of pregnancy, there is a 10% risk that the infant will test positive for hepatitis B surface antigen (HBsAg) at birth. The percentage dramatically increases to 80% to 90% if the acute maternal infection develops during the third trimester. In mothers who have chronic hepatitis B and test positive for the hepatitis Be antigen (HBeAg), 90% of neonates develop chronic hepatitis B without prophylaxis. If the mother has HBeAg- and HBeAb-negative chronic hepatitis B, 40% of neonates develop chronic hepatitis B infection without prophylaxis. The rate decreases to less than 5% if the mother is HBeAg negative and HBeAb positive. Antepartum serum HBsAg testing is mandatory. Neonates of HBsAg-positive mothers or HBsAg status–unknown mothers are treated with HBV human hyperimmune globulin (HBIG), 0.5 mL intramuscularly, at delivery. At the same time, they are given the first dose of HBV vaccine. The second dose is administered at 1 month of age, and the third dose at 6 months of age. If the mother is HBsAg negative, the child should be vaccinated only with the three-dose regimen, with the first inoculation at birth. The regimen is about 85% effective in preventing chronic hepatitis B in neonates and is ineffective in cases of hematogenous transplacental transmission, which are seen in about 15% of pregnancies as a result of small placental tears. Active and passive immunization at birth reduces also possibility of viral transmission by breastfeeding. Hepatitis B vaccination is safe in pregnant women. Lamivudine administered in the last month of pregnancy was recently shown to be safe and efficacious in decreasing risk of vertical transmission. Telbivudine has similar safety profile during pregnancy in animal studies.
Chapter 22 Pregnancy and Liver Disease
48. What about vertical transmission of viral hepatitis C? The risk of perinatal transmission is approximately 2% for infants of anti-HCV seropositive women. When a pregnant woman is HCV RNA positive at delivery, this risk increases to 4% to 7%. Higher HCV RNA levels appear to be associated with a greater risk. Levels of RNA of 1 million copies/mL are reportedly associated with vertical transmission rates as high as 50%. HCV transmission increases up to 20% in women coinfected with HCV and HIV. There are currently no data to determine whether antiviral therapy reduces perinatal transmission. Immunoglobulin therapy is ineffective. Rate of infection is similar among first- and second-born children. 49. Is it possible to prevent vertical transmission of viral hepatitis D and G? Perinatal transmission of the hepatitis D virus (HDV) is rare. There are no documented cases of vertical transmission of HDV in the United States. No clinical data about hepatitis G infection during pregnancy are available, and no studies of vertical transmission have been done. Due to the lack of data on HDV, recommendations regarding breastfeeding are unknown. 50. Are HCV-infected women allowed to breastfeed? HCV-infected women should be told that hepatitis C transmission via breastfeeding has not been documented. Current available studies show that the average rate of infection is 4%, similarly for breastfed and bottle-fed infants. According to the Centers for Disease Control and Prevention (CDC) and to a 1997 consensus statement from the National Institutes of Health (NIH), “Breastfeeding is not contraindicated for HCV-positive mothers,” and “the maternal to baby transmission of HCV infection through breast milk has not been documented.” Risk of transmission by breastfeeding was not found to be significant unless coinfection with HIV was present. 51. Does the mode of delivery influence hepatitis C transmission? Current data are limited but indicate that infection rates are similar in infants delivered vaginally and cesarean-delivered infants. There are no prospective studies evaluating the use of elective cesarean section for the prevention of mother-toinfant transmission of HCV. However, avoiding fetal scalp monitoring and prolonged labor after rupture of membranes may reduce the risk of transmission to the infant. 52. How can perinatal HCV infection be diagnosed? Infants passively acquire maternal antibodies that can persist for months. Anti-HCV antibodies after 15 months of age or positive HCV-RNA, which can be detected as early as 1 or 2 months, are diagnostic of perinatal transmission of HCV. A recent NIH consensus conference recommends that infants born to HCV-positive mothers be tested for HCV infection by HCV-RNA tests on two occasions between the ages of 2 and 6 months and/or have tests for anti-HCV after 15 months of age. Positive anti-HCV in infants prior to 15 months of age may be due to transplacental transfer of maternal anti-HCV antibody.
WE BSI TE S http://www.aasld.org http://www.liverfoundation.org
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Chapter 22 Pregnancy and Liver Disease 14. Reinus JF, Leikin EL. Viral hepatitis in pregnancy. Clin Liver Dis 1999;3:115–31. 15. Riely CA. Contraception and pregnancy after liver transplantation. Liver Transpl 2001;7(Suppl. 1):S74–6. 16. Riely CA, Fallon HJ. Liver diseases. In: Burrow GN, Duffy TP, editors. Medical Complications During Pregnancy. 5th ed Philadelphia: WB Saunders; 1999. p. 269–94. 17. Rinaldo P, Raymond K, Al-Odaib A, et al. Clinical and biochemical features of fatty acid oxidation disorders. Curr Opin Pediatr 1998;10:615–21. 18. Sandhu BS, Sanyal AJ. Pregnancy and liver disease. Gastroenterol Clin North Am 2003;32:407–36. 19. Sheikh RA, Yasmeen S, Pauly MP, et al. Spontaneous intrahepatic hemorrhage and hepatic rupture in the HELLP syndrome. J Clin Gastroenterol 1999;28:323–8. 20. Van Nunen AB, De Man RA, Heijtink RA, et al. Lamivudine in the last 4 weeks of pregnancy to prevent perinatal transmission in highly viremic chronic hepatitis B patients. J Hepatol 2000;32:1040–1. 21. World Health Organization. Hepatitis B and breastfeeding. J Int Assoc Physicians AIDS Care 1998;4:20–1. 22. Yang Z, Yamada J, Zhao Y, et al. Prospective screening for pediatric mitochondrial trifunctional protein defects in pregnancies complicated by liver disease. JAMA 2002;288:2163–6. 23. Zanetti AR, Ferroni P, Magliano EM, et al. Perinatal transmission of the hepatitis B virus and of the HBV-associated delta agent from mothers to offspring in Northern Italy. J Med Virol 1982;9:139–48.
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Pregnancy and Liver Disease Christine J. Bruno, MD, and Roshan Shrestha, MD
NORMAL ANATOMICAL aND PHYSIOLOGIC CHANGES DURING PREGNANCY 1. What are the structural and functional hepatic adaptations during pregnancy? Liver size and histology do not change. Maternal blood volume and cardiac output increase significantly, without a corresponding increase in hepatic blood flow, with a net decrease in fractional blood flow to the liver. An enlarging uterus makes venous return via the inferior vena cava progressively more difficult toward term. Blood is shunted via the azygous system with possible development of esophageal varices. 2. Does liver function change during pregnancy? Hepatic function remains normal during pregnancy, but the normal range of laboratory values changes because of hormonal changes and an increase in blood volume with subsequent hemodilution. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyl transpeptidase (GGTP), bilirubin, and prothrombin remain within normal limits. Total alkaline phosphatase (AP) is elevated. The placenta is the major source of AP; levels return to normal within 20 days after delivery. Estrogen increases the synthesis of fibrinogen, as well as other coagulation proteins (factors VII, VIII, IX, and X). Attributed also to estrogen’s effects are significant increases in serum concentrations of major lipid classes (triglycerides, cholesterol, and low- and very-low-density lipoproteins). These levels may be twice the normal limit of nonpregnant women of the same age. Serum albumin decreases slightly, contributing to the approximately 20% decline in serum protein concentration. Plasma concentrations of other serum proteins (ceruloplasmin, corticosteroids, testosterone, serum binding protein for thyroxine), as well as vitamin D and folate, also increase during pregnancy. DISEASES DURING PREGNANCY
• Coincident occurrence of liver disease (viral hepatitis, alcoholic hepatitis, gallstone disease, autoimmune hepatitis) • Intrahepatic cholestasis of pregnancy (IHCP) • Acute fatty liver of pregnancy (AFLP) • Hemolysis, elevated liver enzymes, and low platelet count (HELLP syndrome) 3. Can gestational age differentiate between different liver diseases in pregnancy? Most definitely. Hyperemesis gravidarum presents in the first trimester of pregnancy. Patients have severe nausea and vomiting, and about one-half have associated elevations of bilirubin, AST, or ALT. Cholestasis of pregnancy, viral hepatitis, and abnormal liver chemistries due to cholelithiasis may present at any point in gestation, from the first to the third trimester. AFLP and preeclamptic liver disease (HELLP, hepatic infarct, and hepatic rupture) are specifically encountered in the third trimester of pregnancy. Both herpes simplex virus and hepatitis E virus are exacerbated in pregnancy and usually present in the third trimester. The presentation may be a mild elevation in transaminases or severe hepatic failure. Budd-Chiari syndrome presents from the second half of pregnancy to 3 months postpartum. COINCIDENT OCCURreNCE 4. Can we assume the presence of chronic liver disease in a pregnant patient with angiomas and palmar erythema on physical examination and small esophageal varices detected endoscopically? No. Spider angiomas and palmar erythema are common and appear in about two-thirds of pregnant women without liver disease. Small esophageal varices are present in approximately 50% of healthy pregnant women without liver disease because of the increased flow in the azygous system. 5. What is the most common cause of jaundice in pregnancy? Viral hepatitis.
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6. How severe is the course of viral hepatitis acquired during pregnancy? • Hepatitis A, B, and C run a similar course in pregnant and nonpregnant patients. • Hepatitis E runs a different course in pregnancy. It is fulminant in up to 20% of patients, compared with less than 1% of nonpregnant women. The fatality rate is 1.5% during the first trimester, 8.5% during the second trimester, and up to 21% during the third trimester compared with 0.5% to 4% in nonpregnant women. Fetal complications and neonatal deaths are increased if infection is acquired in the third trimester of pregnancy. • Herpes simplex hepatitis can be fulminant in pregnancy and associated with high mortality rates. Patients present in the third trimester with fever, systemic symptoms, and possibly vesicular cutaneous rash. Associated pneumonitis or encephalitis may be present. Liver biopsy is characteristic, showing necrosis and inclusion bodies in viable hepatocytes, along with few or no inflammatory infiltrates. Response to acyclovir therapy is prompt; there is no need for immediate delivery of the baby. 7. What signs and symptoms suggest the diagnosis of Budd-Chiari syndrome? The clinical triad of sudden onset of abdominal pain, hepatomegaly, and ascites, near term or shortly after delivery. Ascitic fluid shows a high protein content in about one-half of cases. Biopsy typically shows centrilobular hemorrhage and necrosis, along with sinusoidal dilation and erythrocyte extravasation into the space of Disse. Hepatic scintigraphy and computed tomography (CT) typically show compensatory hypertrophy of the caudate lobe due to its separate drainage into the inferior vena cava. Doppler analysis of portal and hepatic vessels and magnetic resonance imaging (MRI) establish hepatic vein occlusion. 8. Is the serum ceruloplasmin level a good diagnostic marker in pregnant women at term who are suspected of having Wilson disease? No. Ceruloplasmin levels increase gradually during pregnancy, reaching the maximum at term. Because of this, a patient with Wilson disease who usually has a low level of ceruloplasmin may have it increase misleadingly into the normal range (greater than 20 mg/dL) during pregnancy. 9. Can we maintain a woman with Wilson disease on therapy during pregnancy? Absolutely. Therapy must continue during pregnancy; otherwise, the mother is at risk for hemolytic episodes associated with fulminant hepatic failure. Agents approved by the U.S. Food and Drug Administration are D-penicillamine, trientine, and zinc. Evidence indicates that penicillamine and trientine (tissue copper-chelating agents) are teratogenic in animal studies, and there are reports of penicillamine effects in humans, including cutis laxis syndrome or micrognathia, low-set ears, and other abnormalities. According to the current consensus, penicillamine and trientine are safe in doses of 0.75 to 1 g/day during the first two trimesters; the dosage should be reduced to 0.5 g/day during the last trimester and in nursing mothers. Zinc therapy is an attractive alternative with a different mechanism of action; it induces synthesis of metallothionein, which sequesters copper in enterocytes, blocking its absorption. No teratogenic effects have been reported in animals or humans. The recommended doses are 50 mg 3 times/day for patients with 24-hour urinary copper values greater than 0.1 mg and 25 mg 3 times/day for patients with lower urinary copper values. Close monitoring of urinary copper and zinc levels is suggested; the zinc dose should be adjusted accordingly. INTRAHEPATIC CHOLESTASIS OF PREGNANCY (IHCP) 10. What is the most common liver disorder unique to pregnancy? Intrahepatic cholestasis of pregnancy (IHCP). 11. What is the major clinical manifestation of IHCP? Severe pruritus with onset in the second or, more commonly, third trimester (more than 70% of cases). 12. What biochemical changes are noted in IHCP? Serum bile acids, often measured as cholylglycine, increase by 10- to 100-fold. Serum levels of AP rise by 7- to 10-fold, along with a modest rise in serum levels of 5′-nucleotidase (confirming the hepatic source of AP). AST, ALT, and direct bilirubin also rise. No evidence of hemolysis is found. GGTP is usually normal, as is prothrombin time (PT), unless cholestyramine treatment leads to malabsorption. 13. What is the expected clinical and biochemical course after delivery for patients with IHCP? Pruritus should improve promptly after delivery (within 24 hours). Jaundice is rare and, if present, may persist for days. Biochemical abnormalities may persist for months.
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14. What is a possible cause for abnormal bleeding in a postpartum woman previously diagnosed with IHCP? What is the treatment? Malabsorption of liposoluble vitamins, including vitamin K, especially in patients treated with cholestyramine for pruritus. The international normalized ratio (INR) corrects with parenteral administration of vitamin K. 15. What is the effect of IHCP on the fetus? Fetal distress requiring cesarean section develops in about 30% to 60% of cases. Prematurity occurs in about 50% of cases and fetal death in up to 9% of affected pregnancies. All of these effects are more likely if the disorder begins early in pregnancy. 16. What is the therapy for IHCP? Alleviating pruritus is the main goal. Therapeutic agents include:
• Ursodeoxycholic acid, ≈15 mg/kg/day; up to 24 mg/kg/day studied with good results • Cholestyramine, 4 g 4 or 5 times/day (bile acid–binding resin) • Hydroxyzine hydrochloride (Atarax) or pamoate (Vistaril) (antihistamines); Atarax 25-50 mg every 6 hours as needed, Vistaril 15-30 mg every 6 hours as needed
• Phenobarbital, 100 mg/day (choleretic and centrally acting sedative) • Phototherapy with ultraviolet B light as directed by a dermatologist Vitamin K before delivery is highly recommended to minimize the risk of postpartum hemorrhage. Mother and fetus should be observed closely. Elective induction is recommended at 36 weeks (severe cases) or 38 weeks (average cases) if the fetal lungs have matured. 17. Can IHCP recur? Yes. About 40% to 70% of subsequent pregnancies show evidence of mild intrahepatic cholestasis. The same pattern can be seen with use of estrogen-containing contraceptives. 18. What atypical signs and symptoms make the diagnosis of IHCP doubtful? Fever, hepatosplenomegaly, pain, jaundice preceding or without pruritus, and pruritus after delivery or before 21 weeks of pregnancy, especially with a singleton pregnancy, should prompt the search for an alternate diagnosis. 19. What biochemical changes suggest an alternate diagnosis? • Normal AST and ALT levels • Elevated AP and GGTP (i.e., biliary disease) • Predominantly unconjugated hyperbilirubinemia (i.e., hemolysis) ACUTE FATTY LIVER OF PREGNANCY 20. What are the clinical and laboratory features of AFLP? AFLP is a rare disorder with an incidence of 1 in 13,000 to 1 in 16,000 pregnancies. Onset occurs in the second half of pregnancy, usually during the third trimester, although occasionally postpartum onset is reported. Clinical manifestations include nausea and vomiting, jaundice, malaise, thirst, and altered mental status. Severe cases progress rapidly to hypoglycemia, disseminated intravascular coagulation (DIC), renal insufficiency, coma, and death. Signs of coexistent preeclampsia may be present, such as moderately increased arterial blood pressure, proteinuria, and hyperuricemia. Laboratory abnormalities consist of moderate AST/ALT elevations (usually less than 1000), conjugated hyperbilirubinemia, elevated PT, fibrin split products, and D-dimers, along with low platelet count, elevated levels of ammonia and serum uric acid, and leukocytosis. Hypoglycemia is a sign of extreme severity; blood glucose levels must be monitored closely. 21. How do we diagnose and treat AFLP? High clinical suspicion is crucial for early recognition and appropriate management. AFLP is suggested by hepatic failure at or near term or shortly after delivery in the absence of risk factors or serology suggesting viral hepatitis. Thirst, a symptom of underlying vasopressin-resistant diabetes insipidus, is characteristic to AFLP or HELLP syndrome. Liver biopsy, if feasible, is diagnostic in the appropriate clinical context. Treatment consists of admission to hospital, close monitoring by a multidisciplinary team (hepatologist, maternal-fetal medicine specialist, intensive care specialist) and immediate delivery. Recovery is usually complete, although it may be delayed in patients with significant clinical complications before delivery (e.g., DIC, renal failure, infections). 22. Is biopsy pathognomonic for AFLP? Biopsy is confirmatory but not pathognomonic or indispensable in making the diagnosis. Histology is characterized by microvesicular fatty infiltration, mostly in centrilobular zones. In general, lobular and trabecular architecture is
Chapter 22 Pregnancy and Liver Disease
preserved, and inflammatory infiltrates and cell necrosis are mild, if present at all. AFLP is a systemic disorder. Similar fatty changes have been noted in pancreatic acinar cells and tubular epithelial cells of the kidneys. The same prominent microvesicular steatosis is seen in other conditions such as Reye syndrome, sodium valproate toxicity, Jamaican vomiting sickness, and congenital defects of urea cycle enzymes or beta-oxidation of fatty acids. 23. Describe the pathogenesis of AFLP. Pathogenesis remains somewhat unclear. AFLP seems to be a fetal-maternal interaction. In some cases the fetus has an isolated deficiency of long chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), which leads to a disorder of mitochondrial fatty acid oxidation. The inheritance pattern is recessive and involves a mutation from glutamic acid to glutamine at amino acid residue 474 (Glu474Gln) on at least one allele. It is hypothesized that in the presence of this mutation in homozygous or compound heterozygote fetuses, long-chain fatty acid metabolites produced by the fetus or placenta accumulate in the mother and are highly toxic to the maternal liver. The mother is phenotypically normal; her genotype does not correlate with development of AFLP. 24. What is the outcome of a child whose mother has AFLP? Previously reported fetal mortality rates of 75% to 90% have been significantly reduced by better awareness, earlier diagnosis, availability of neonatal intensive care units, and institution of close monitoring and dietary treatment through childhood. In pregnancies associated with LCHAD defects, children present at a mean age of 7.6 months (range, 0 to 60 months) with acute hepatic dysfunction (incidence of 79%). They may experience hypoketotic hypoglycemia, hypotonia, hepatomegaly, hepatic encephalopathy, high transaminase levels, and fatty liver. The condition may progress rapidly to coma and death. Frequent feedings of a low-fat diet in which the fats are medium-chain triglycerides prevent hypoketotic hypoglycemic liver dysfunction. According to recent studies, 67% of children treated with dietary modification are alive, and most attend school. 25. Does AFLP recur in subsequent pregnancies? In the cases associated with LCHAD defects, the disorder is recessive, affecting one in four fetuses. The rate of recurrence of maternal liver disease is 15% to 25%. 26. Is genetic testing indicated in women diagnosed with AFLP? All women with AFLP, as well as their partners and children, should be advised to undergo molecular diagnostic testing. Testing for Glu474Gln only in the mother is not sufficient to rule out LCHAD deficiency in the fetus or other family members. HEMOLYSIS, ELEVATED LIVER ENZYMES, AND LOW PLATELETS (HELLP) 27. What is the spectrum of liver involvement in preeclampsia? Liver involvement in preeclampsia ranges from subclinical, with biopsy evidence of fibrinogen deposition along hepatic sinusoids, to several possibly severe disorders. In patients with HELLP syndrome, the chief complaint is abdominal pain, which usually presents in the second half of gestation but may occur up to 7 days after delivery (almost 30% of affected women). Hepatic infarction is another rare manifestation of liver involvement in preeclampsia. Patients present in the third trimester or early after delivery with unexplained fever, leukocytosis, abdominal or chest pain, and extremely elevated aminotransferases (greater than 3000). The diagnosis depends on visualization of hepatic infarcts on CT contrast images or MRI. Subcapsular hematomas and hepatic rupture are life-threatening complications with high morbidity and mortality rates. A high index of suspicion and early CT imaging allow diagnosis and prompt intervention. 28. How common is HELLP syndrome? The incidence of HELLP syndrome is 0.2% to 0.6% in all pregnancies and 4% to 12% in preeclamptic patients. The incidence is higher in multiparous, white, and older women, but the mean age of occurrence is around 25 years. 29. Describe the incidence and prognosis of spontaneous intrahepatic hemorrhage. Spontaneous intrahepatic and subcapsular hemorrhage occurs in about 1% to 2% of patients with preeclampsia, with an estimated incidence of 1 in 45,000 live births. Prognosis improves with awareness, early diagnosis by imaging studies, and aggressive surgical management. Recent reported maternal mortality rates range from 33% to 49%. Fetal mortality remains high (≈60%). 30. What findings typically lead to the diagnosis of HELLP syndrome? Diagnosis relies on typical laboratory evidence of liver involvement with associated thrombocytopenia. Not all patients have clinical hypertension or proteinuria at presentation. Liver test abnormalities are hepatocellular. Liver function is
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normal. Thrombocytopenia is present, usually less than 100,000/mm3. Hemolysis is mild, with microangiopathic findings on peripheral smear. Biopsy is characteristic but may be extremely risky and is not needed for diagnosis. It shows periportal hemorrhage, fibrin deposition, and necrosis, possibly with steatosis and/or deposition of fibrinogen along sinusoids with focal parenchymal necrosis. A normal biopsy does not exclude the diagnosis, because involvement may be patchy. 31. What is the treatment for severe preeclamptic liver disease? The initial priority is to stabilize the mother, by administering intravenous fluids, correcting any concurrent coagulopathy, administering magnesium for seizure prophylaxis, and treating severe hypertension. Early hepatic imaging is indicated to rule out infarcts or hematomas. Fetal functional status should be determined. Fetal outcome is related mostly to gestational age. Beyond 34 weeks of gestation with evidence of fetal lung maturity, delivery is the recommended therapy. If fetal lungs are immature, the fetus can be delivered 48 hours after administration of two doses of steroids. Termination of pregnancy should be attempted immediately with evidence of fetal or maternal distress. In cases of ruptured subcapsular hematoma, massive transfusions and immediate surgical intervention are required. In cases where surgical intervention is not possible and there are of signs and symptoms of acute liver failure liver, transplantation should be considered for survival. 32. Does HELLP recur in subsequent pregnancies? Possibly. Studies report recurrence risks as low as 3.4% and as high as 25%. 33. What information helps to differentiate AFLP from HELLP? At presentation, AFLP and HELLP may be difficult to differentiate. Hypertension is usually but not invariably associated with HELLP syndrome. Patients with HELLP have mild, predominantly unconjugated hyperbilirubinemia due to hemolysis, along with severe thrombocytopenia, but no laboratory values suggestive of hepatic failure. Laboratory abnormalities are significantly more severe in AFLP; evidence of hepatic synthetic failure manifests as prolonged PT and significant hypoglycemia in advanced stages. Fibrinogen is low, and ammonia is elevated. Biopsy shows microvesicular steatosis, predominantly in the central zone, in patients with AFLP, whereas patients with HELLP show predominantly periportal fibrin deposition, necrosis, and hemorrhage. 34. Is prospective screening necessary in pregnancies complicated by AFLP or HELLP? From 15% to 20% of pregnancies complicated by AFLP and less than 2% of pregnancies complicated by HELLP syndrome are associated with fetal LCHAD deficiency. Newborns should be screened prospectively at birth in all pregnancies complicated by AFLP. Homozygosity and heterozygosity for the Glu474Gln would indicate the need for avoidance of prolonged fasting and replacement of dietary long-chain fatty acids with medium-chain fatty acids. Parents and physicians should be educated in the risk of metabolic crises and sudden death and instructed in the need for early intervention with intravenous glucose during episodes of vomiting, lethargy, and even minor illnesses. Recent results do not justify routine screening of newborns in pregnancies complicated by HELLP syndrome. Molecular diagnostic testing should, however, be considered in women with recurrent HELLP syndrome in multiple pregnancies. CARE OF PATIENTS WITH PREEXISTING LIVER DISEASE BEFORE
• • • • •
AND
DURING PREGNANCY
Contraception Management of underlying liver disease Management of portal hypertension Management in the setting of transplantation Prevention of vertical transmission
CONTRACEPTION 35. What methods of contraception are available for patients with liver disease? Patients with advanced or untreated liver disease commonly experience amenorrhea and infertility. If clinical improvement leads to restoration of fertility, multiple methods of contraception are available, including barrier methods and intrauterine devices. Tubal ligation may be used in women who have completed their families. Estrogen-based contraceptive agents are generally contraindicated, especially for patients with acute liver disease, but progestin contraceptives are safe alternatives. Combination contraceptives are absolutely contraindicated in patients with cholestatic jaundice of pregnancy or jaundice with prior use, and World Health Organization is listing them as category 4 type of drugs for patients with decompensated cirrhosis of any etiology. Numerous formulations and delivery systems are available.
Chapter 22 Pregnancy and Liver Disease
MANAGEMENT OF UNDERLYING LIVER DISEASE 36. How should patients with preexisting liver disease be managed if pregnancy occurs? Patients are best managed by a multidisciplinary team that includes a maternal-fetal medicine specialist, perinatologist, and hepatologist. They have an increased risk for maternal complications along with a higher incidence of fetal wastage and prematurity. In general, patients should be maintained on the previous therapy that was successful in controlling liver disease and restoring fertility. Women with autoimmune hepatitis should be continued on corticosteroids alone or in combination with azathioprine, which is not teratogenic at the usual dose. Patients with Wilson disease should be continued on the anticopper agent. Patients with portal hypertension should have a baseline endoscopy. If they have never bled and medium or large varices are present, they are at increased risk for variceal hemorrhage during pregnancy. Primary prophylaxis with a nonselective beta blocker or isosorbide mononitrate should be instituted. The fetus should be monitored for bradycardia or growth retardation if the mother is maintained on beta blockers. Variceal bleeding is safely managed with variceal band ligation or sclerotherapy. Octreotide in customary doses is safe in pregnancy. Performing surgical portacaval shunts for patients with well-preserved liver function is possible. Placement of a transjugular intrahepatic portosystemic shunt and splenectomy (in patients with massive splenomegaly, varices, and thrombocytopenia) also have been reported. MANAGEMENT OF PORTAL HYPERTENSION 37. What are the effects of pregnancy on the mother with portal hypertension? The morbidity rate is 30% to 50% because of possible onset of hepatic encephalopathy, spontaneous bacterial peritonitis, and progressive liver failure. The incidence of variceal hemorrhage is 19% to 45%, especially in the second trimester and during labor. Postpartum hemorrhage is seen in 7% to 10% of women, most frequently in those with cirrhotic portal hypertension; thrombocytopenia plays a major role. The mortality rate of these complications is 4% to 7% in noncirrhotic and 10% to 18% in cirrhotic patients with portal hypertension. Data regarding this topic originate mostly from case series and prospectively acquired data are few. 38. What is the effect of maternal portal hypertension on pregnancy? Spontaneous abortion rates for patients with cirrhosis range from 15% to 20%. Most cases occur in the first trimester. Of interest, patients with extrahepatic portal hypertension and patients with well-compensated cirrhosis who underwent surgical shunting before conception have abortion rates similar to the general population. The incidence of premature termination of pregnancy in the second and third trimesters is similar in all of the above groups. Fetal mortality rates are around 50% if the mother requires emergent surgical intervention for variceal hemorrhage. Perinatal mortality rates in cirrhotic mothers are as high as 11% to 18% because of premature delivery, stillbirth, and neonatal death, but they are similar to those for the general population in noncirrhotic patients with portal hypertension and patients who underwent previous portal surgical decompressive procedures. MANAGEMENT IN THE SETTING OF ORTHOTOPIC LIVER TRANSPLANTATION 39. When can a liver transplant recipient actively seek conception? At least a 1-year waiting period is advisable. Case reports suggest that conception close to the transplant date may result in increased maternal and fetal morbidity and mortality. Contraception should be instituted before resuming sexual relations, preferably with barrier methods. 40. Is pregnancy possible after liver transplantation? Pregnancy will become possible once normal menstrual cycles resume. In women with chronic liver disease, most pretransplant amenorrhea resolves in approximately 3 to 10 months following liver transplantation. 41. What are the possible complications of pregnancies occurring after liver transplantation? Hypertensive complications, preterm delivery, infection and fetal growth restriction. Immunosuppressive agents used such as cyclosporine and tacrolimus cause hypertension and renal insufficiency, as well as impairment of placental amino acid transport systems, leading to fetal growth restriction. Cytomegalovirus (CMV) infection can cause congenital anomalies and liver disease if the mother was infected early in the pregnancy. Risk for CMV infection is greatest immediately after transplant or in case of increased immunosuppression due to rejection episodes. Rejection is a rare complication; only about 10% of the reported pregnancies have been complicated by biopsy-proved rejection.
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42. What is recommended in the management of a pregnancy occurring post liver transplantation? Management as high-risk pregnancy by a specialist in maternal-fetal medicine is preferred. Immunosuppression should be continued with close monitoring of blood levels. Abnormal liver function tests should be evaluated aggressively. Percutaneous liver biopsy is not contraindicated but should be performed under ultrasound guidance. Monitoring for maternal and fetal CMV infection is indicated. Quantitative CMV immunoglobulins or detection of CMV viremia and viruria in the mother are adequate tests, and even amniotic fluid analysis could be used if there is suspicion of fetal infection. Deliveries should be via cesarean section if there are active herpes simplex lesions present. Prophylactic antibiotics should be used for deliveries in general. 43. What are pregnancy safety data regarding maintenance immunosuppressive agents used in orthotopic liver transplantation (OLT)? • Category B (no evidence of risk in humans): prednisone • Category C (risks cannot be ruled out): cyclosporine, tacrolimus (FK506), rapamycin (Sirolimus), OKT3, antithymocyte globulin, antilymphocyte globulin • Category D (evidence of risk): azathioprine • Category D with black box warning (high risk: mutagenic/teratogenic): mycophenolate mofetil (CellCept, Myfortic). It is advised that anyone pregnant or wishing to become pregnant be changed to azathioprine. 44. Is breastfeeding permitted after delivery in a liver transplant recipient? At this time, it is believed that breastfeeding should be discouraged. A woman administered immunosuppressive drugs should not breast feed. Calcineurin inhibitors could cause immunosuppression and nephrotoxicity, and no recommendation can be made at this time regarding azathioprine-based regimens because there is extremely limited experience. Manufacturer recommends against breastfeeding in mothers administered interferon therapy, ribavirin, ganciclovir, or lamivudine. No specific recommendation can be made regarding foscarnet. No data are available regarding ursodeoxycholic acid excretion in breast milk. 45. Are immunosuppressive agents safe during pregnancy? Corticosteroids, azathioprine, cyclosporine, tacrolimus, and OKT3 have no apparent teratogenic potential. All may contribute to low birth weights and fetal prematurity. Tacrolimus crosses the placenta and may contribute to transient perinatal hyperkalemia and mild, reversible renal impairment. There are no reports of allograft loss as a result of pregnancy in the tacrolimus-treated group of 35 patients at the University of Pittsburgh. The Philadelphia-based cyclosporine registry reports an allograft rejection rate of 17% and a graft loss rate of 5.7% in 35 patients taking cyclosporine during gestation and post partem period. PREVENTION OF VERTICAL TRANSMISSION 46. How may vertical transmission of viral hepatitis A be prevented? Maternal infection with the hepatitis A virus (HAV) is not associated with fetal wastage or teratogenic effects. Vertical transmission of HAV is rare. There are no restrictions concerning breastfeeding. Passive immunization with immunoglobulin for urgent postexposure prophylaxis, and HAV vaccine is safe and recommended in pregnant women at risk for acquiring the disease, such as women traveling to endemic areas. 47. How may vertical transmission of viral hepatitis B be prevented? The hepatitis B virus (HBV) may be transmitted vertically. If the mother acquires HBV in the first trimester of pregnancy, there is a 10% risk that the infant will test positive for hepatitis B surface antigen (HBsAg) at birth. The percentage dramatically increases to 80% to 90% if the acute maternal infection develops during the third trimester. In mothers who have chronic hepatitis B and test positive for the hepatitis Be antigen (HBeAg), 90% of neonates develop chronic hepatitis B without prophylaxis. If the mother has HBeAg- and HBeAb-negative chronic hepatitis B, 40% of neonates develop chronic hepatitis B infection without prophylaxis. The rate decreases to less than 5% if the mother is HBeAg negative and HBeAb positive. Antepartum serum HBsAg testing is mandatory. Neonates of HBsAg-positive mothers or HBsAg status–unknown mothers are treated with HBV human hyperimmune globulin (HBIG), 0.5 mL intramuscularly, at delivery. At the same time, they are given the first dose of HBV vaccine. The second dose is administered at 1 month of age, and the third dose at 6 months of age. If the mother is HBsAg negative, the child should be vaccinated only with the three-dose regimen, with the first inoculation at birth. The regimen is about 85% effective in preventing chronic hepatitis B in neonates and is ineffective in cases of hematogenous transplacental transmission, which are seen in about 15% of pregnancies as a result of small placental tears. Active and passive immunization at birth reduces also possibility of viral transmission by breastfeeding. Hepatitis B vaccination is safe in pregnant women. Lamivudine administered in the last month of pregnancy was recently shown to be safe and efficacious in decreasing risk of vertical transmission. Telbivudine has similar safety profile during pregnancy in animal studies.
Chapter 22 Pregnancy and Liver Disease
48. What about vertical transmission of viral hepatitis C? The risk of perinatal transmission is approximately 2% for infants of anti-HCV seropositive women. When a pregnant woman is HCV RNA positive at delivery, this risk increases to 4% to 7%. Higher HCV RNA levels appear to be associated with a greater risk. Levels of RNA of 1 million copies/mL are reportedly associated with vertical transmission rates as high as 50%. HCV transmission increases up to 20% in women coinfected with HCV and HIV. There are currently no data to determine whether antiviral therapy reduces perinatal transmission. Immunoglobulin therapy is ineffective. Rate of infection is similar among first- and second-born children. 49. Is it possible to prevent vertical transmission of viral hepatitis D and G? Perinatal transmission of the hepatitis D virus (HDV) is rare. There are no documented cases of vertical transmission of HDV in the United States. No clinical data about hepatitis G infection during pregnancy are available, and no studies of vertical transmission have been done. Due to the lack of data on HDV, recommendations regarding breastfeeding are unknown. 50. Are HCV-infected women allowed to breastfeed? HCV-infected women should be told that hepatitis C transmission via breastfeeding has not been documented. Current available studies show that the average rate of infection is 4%, similarly for breastfed and bottle-fed infants. According to the Centers for Disease Control and Prevention (CDC) and to a 1997 consensus statement from the National Institutes of Health (NIH), “Breastfeeding is not contraindicated for HCV-positive mothers,” and “the maternal to baby transmission of HCV infection through breast milk has not been documented.” Risk of transmission by breastfeeding was not found to be significant unless coinfection with HIV was present. 51. Does the mode of delivery influence hepatitis C transmission? Current data are limited but indicate that infection rates are similar in infants delivered vaginally and cesarean-delivered infants. There are no prospective studies evaluating the use of elective cesarean section for the prevention of mother-toinfant transmission of HCV. However, avoiding fetal scalp monitoring and prolonged labor after rupture of membranes may reduce the risk of transmission to the infant. 52. How can perinatal HCV infection be diagnosed? Infants passively acquire maternal antibodies that can persist for months. Anti-HCV antibodies after 15 months of age or positive HCV-RNA, which can be detected as early as 1 or 2 months, are diagnostic of perinatal transmission of HCV. A recent NIH consensus conference recommends that infants born to HCV-positive mothers be tested for HCV infection by HCV-RNA tests on two occasions between the ages of 2 and 6 months and/or have tests for anti-HCV after 15 months of age. Positive anti-HCV in infants prior to 15 months of age may be due to transplacental transfer of maternal anti-HCV antibody.
WE BSI TE S http://www.aasld.org http://www.liverfoundation.org
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