LIVER DISEASES WITH PREGNANCY

Dr Walid Abdalla Mohamed Obstetrics & Gynecology Dept . Faculty of Medicine Zagazig University

Introduction
Liver disease is a rare complication of pregnancy, but when it occurs it may do so in a dramatic and tragic fashion for both mother and infant. Diseases such as acute fatty liver of pregnancy (AFLP) may begin gradually with mild symptoms and liver enzyme abnormalities but, if left untreated, can progress to jaundice, liver failure, and death. ( Bacq & Riely , )2004

 Some of the normal physiologic changes of pregnancy can mimic abnormalities associated with liver disease. Telangiectasia, particularly on the chest, back, and face, and palmer erythema occur in up to 60 percent of normal pregnant women but disappear after delivery. (Riely, 2001)

Anatomical, Physiological, and Biochemical changes during pregnancy.

Anatomic Changes:
Liver weight increases during pregnancy has not been documented. Liver size is difficult to estimate in pregnancy, but records fail to show any substantial increase in liver weight in comparison with nonpregnant controls.
Therefore, detection of hepatomegaly is strong evidence for the presence of liver disease. (Fagan, 1986)

Summary of physiological and biochemical changes in the liver during pregnancy

Increased: Alkaline phosphatase levels rise threefold or fourfold due to placental production Clotting factor changes create a hypercoagulable state Decreased: Gallbladder contractility Uric acid levels Albumin, total protein, and antithrombin III concentrations

 No change: Liver aminotransferase levels (aspartate aminotransferase, alanine aminotransferase(more specific as it rises only in liver injury) ,gamma-glutamyl transferase) Bilirubin level Prothrombin time

Spectrum of liver diseases in pregnancy (Fleming & Zein, 2005)

 Liver diseases induced by pregnancy

First trimester
Hyperemesis gravidarum

Second and third trimesters

Intrahepatic cholestasis of pregnancy HELLP syndrome (hemolysis, elevated liver enzymes, low platelet counts ) Acute fatty liver of pregnancy

 Liver diseases coincidental with but not induced by pregnancy

Acute viral hepatitis and other viral infections Alcohol-related diseases Gallstone disease Budd-Chiari syndrome

 Preexistent liver diseases

Portal hypertension, cirrhosis, primary biliary cirrhosis Autoimmune hepatitis Wilson disease Chronic infection with hepatitis B or hepatitis C virus Alcoholic liver disease

 Liver diseases induced by pregnancy

First trimester
Hyperemesis gravidarum

Second and third trimesters

Intrahepatic cholestasis of pregnancy HELLP syndrome (hemolysis, elevated liver enzymes, low platelet counts ) Acute fatty liver of pregnancy

Hyperemesis gravidarum
Def:* severe nausea and vomiting and unresponsive to simple dietary modification and anti-emetics. * vomiting suffiecently severe to produce weight loss, dehydration ,alkalosis from loss of hydrochloric acid and hypokalemia incidences : vary and appear to be ethnic and familial prediction and the risk increase among-obesity , nulliparity, and twin gestation. hospitalization rate is about 0.5-0.8 % and with those have previous history up to 20% require hospitalization.

Pregnancy-Unique Quantification of Emesis/Nausea (PUQE) index:

Total score is sum of replies to each of the three questions. Nausea Score: Mild NVP = 6; Moderate NVP = 712; Severe NVP = 13

Etiology: - High or rapid rise in serum level of pregnancy related hormones (HSG,E2, progesterone,placental growth hormone, prolactin,thyroxine and adreno-cortical hormone) -There is some studies implicated psychological component - for unknown reason a female fetus increase the risk by 1.5 folds.

 There is small evidence for the association between hyperemesis and H.pylori infection. Complications: - Acute renal failure from dehydration , and may require 5 day dialysis when S. creatinine reach 10.7 mg/l -Life-threating complication of retching include Mallory-weiss tears, rupture esophagus, pneumothorax and pneumomediastinum

Mallory Weiss tear syndrome

 Thiamine deficiency will lead to Wernicke encephalopathy half of patient have the triad of : ( confusion,ocular findings and Ataxia) and MR imaging findings , late sequelae are common and include blindness,convulsions and coma Vitamin K deficiency may lead to maternal coagulopathy and fetal intracranial hemorrhage.

 Laboratory testing demonstrates abnormal liver values in up to 50% of affected patients; the most sensitive test is the ALT, which may rise as high as 1000 U. Severely affected patients also have elevations in bilirubin.

Antiemetic therapy is helpful rectal or oral as first line Improvement in the nausea and vomiting and resolution of the liver test abnormalities occur when most affected patients are given intravenous fluids and put to gut rest, correct dehydration , ketonemia and acid base imbalances. . Corticosteroid therapy has been reported with little success.however pt treated by corticosteroids have fewer readmission

 Thiamine is given 100 mg to prevent Wernicke encephalopathy

if severe unresponsive vomiting appropriate steps should be taken to exclude underlying

disease( gastroenteritis,cholecystitis, pancreatitis,hepatitis peptic ulcer , preeclampsia and AFLP it was found that high level of thyroxine is implicated in hyperemesis more than HCG level

 If associated psychiatric and social factors improvement while hospitalization occur but may relapse after discharge in these situation assistance with psychosocial problem is beneficial Its important to know that
Patients affected with hyperemesis gravidarum have no increased rate of prematurity, infants with low birth weight, or infants with birth defects .

 Liver diseases induced by pregnancy

First trimester
Hyperemesis gravidarum

Second and third trimesters

Intrahepatic cholestasis of pregnancy Preeclampsia, eclampsia, and the HELLP syndrome (hemolysis, elevated liver enzymes, low platelet counts) Acute fatty liver of pregnancy

Intrahepatic Cholestasis of Pregnancy

The syndrome has been variously called recurrent jaundice of pregnancy, cholestatic jaundice of pregnancy,ictrus gravidarum, jaundice of late pregnancy, and hepatosis of pregnancy. ICP, however, is the preferred term, because jaundice is inconstant in any type of cholestatic disorder . (Gonzalez-Peralva et al., )1996

 The frequency of ICP is clearly higher among certain ethnic groups, including Scandinavians and Chileans. In the latter group, ICP may appear in 2.4% or more of pregnancies, the highest reported incidence in the world. The incidence is quite high (20.9%) in twin pregnancies. Several studies have demonstrated a familial and genetic predisposition to the syndrome in Sweden, Chile, and the United States. (Lammert, et al., 2000)

Clinical presentation Pruritus is the dominant and initial symptom and appears in the third trimester in more than 70% of cases. Most of the remaining patients date their onset of symptoms to the second trimester.some cases reported in the first trimester with hyperplacentosis and a triploid fetus. The symptom may become very severe and usually involves the trunk and the extremities, including the palms and the soles of the feet. As a result of the pruritus, insomnia, fatigue, and even mental disturbances have been reported

Many patients report the appearance of dark urine without frank jaundice shortly after the onset of pruritus. Only a minority of patients develop obvious jaundice, and this is usually mild. It is notable that abdominal pain, biliary colic, fever, anorexia, nausea, vomiting, and arthralgias are absent.

 The improvement in both pruritus and jaundice begins to occur quite promptly after delivery, most often within 24 hours. However, jaundice may continue for several days after delivery, and some of the abnormal chemistry profiles persist for as long as several months. Subsequent pregnancies are frequently accompanied by recurrences of the syndrome.

Biochemical Changes
CLINICAL FEATURES Pruritus Jaundice* No Anorexia or malasie 2nd or 3rd trimester onset* Recurrent* Familial* BIOCHEMICAL CHANGES Serum bile acid Alkaline Phosphatase 5' Nucleotidase GGTP Bilirubin (total) AST/ALT Prothrombin time Cholesterol Triglyceride -10to 100 fold -7to 10 fold Two Folds Normal to slight Normal to 5 mg/dL not exceed 250 U/L Normal to twofolds Two to Fourfolds Normal to twofolds

Effects on the Mother

Although earlier reports suggested that the only effect of ICP on the mother was related to the discomfort of pruritus, more recent studies have suggested more serious complications. These include an increased risk of postpartum hemorrhage, especially in those given cholestyramine, and an increased risk for the development of gallstones after pregnancy. (Glantz, et al., 2005)

Effects on the Fetus

The implications of ICP for the fetus are considerably more ominous. An increased incidence of prematurity and fetal death has been reported in several studies. Fetal distress is reported in one third of patients, leading to cesarean section in 30% to 60% of cases and prematurity in over 50% in some series. Stillbirths are recorded in more than 9%. These outcomes are more likely if the disorder begins earlier in pregnancy. Thus, ICP very clearly increases the risks to the fetus . ( Glantz, et al., )2004

Treatment
Therapy is directed at alleviating pruritus in the mother. Ursodeoxycholic acid has been used successfully in the treatment of cholestasis. Improvement in both liver function test results and the symptom of pruritus has been documented in women with ICP treated with a standard 15mg/kg/day dosage. A larger dosage, 20 to 25 mg/kg/day has been shown to be effective with no adverse affects on either mother or baby. (Mazella et al., 2001)

 Phenobarbital in a dosage of 100 mg/day has been reported to be effective in approximately 50% of patients. Cholestyramine may be somewhat effective and is usually given in a dosage of 4 g four or five times per day. Cholestyramine may worsen the malabsorption of fats and fat-soluble vitamins. Therefore, the prothrombin time must be monitored in patients treated with this regimen, and parenteral vitamin K should be given before delivery. (Eloranta et al., 2002)

 Antihistamininc and topical emollients may give some relif. Some investigators recommend elective induction at 38 weeks or as early as 36 weeks in the presence of jaundice or if the fetus's lungs have matured.

 Liver diseases induced by pregnancy

First trimester
Hyperemesis gravidarum

Second and third trimesters

Intrahepatic cholestasis of pregnancy HELLP syndrome (hemolysis, elevated liver enzymes, low platelet counts ) Acute fatty liver of pregnancy

HELLP Syndrome
The HELLP syndrome is a multi-system disease variant of severe preeclampsia that is characterized by microangiopathic hemolytic anemia (MAH) abnormal peripheral smear, increased bilirubin <1.2 mg/dL, and increased lactic dehydrogenase > 600 IU/L ,; Elevated liver enzymes aspartate aminotransferase )AST( 72 IU/L, lactate dehydrogenase (LDH) > 600 IU/ , Thrombocytopenia (platelet count, <100,000/ mm3(, and, in the syndromes most severe form, DIC .

 HELLP syndrome is more common among older multiparous women. HELLP syndrome affects up to 20% of pregnancies involving severe preeclampsia. Although up to 11% of the cases occur before 27 weeks of gestation, most cases (70%) occur between 27 and 36 weeks of gestation and about a third occur after delivery. Exacerbations may occur after delivery, followed by recovery within 72 hours. (Martin et al., 1999)

 Clinical presentation: Frequent presenting symptoms include nausea, malaise, epigastric or right upper quadrant abdominal pain (65%90% of cases), and edema. In a large series, HELLP syndrome was observed with DIC (21% of patients), abruption placenta (16%), acute renal failure (8%), and pulmonary edema (6%). The maternal mortality rate is approximately 1% to 4%, and the perinatal mortality rate ranges from 10% to 20%, depending on gestational age and severity of the condition at the time of delivery . (Sibai et al., )1993

Maternal morbidity in HELLP syndrome can be classified into the following four categories (in decreasing order of frequency) Coagulation disorders associated with hemorrhagic complications, Cardiopulmonary dysfunction, Central nervous system disorder and Hepatic or gastrointestinal dysfunction. (Isler et al., 1999)

 Women with HELLP syndrome should be considered to be at increased risk for obstetrical complications in subsequent pregnancies (preterm deliveries, IUGR, abruption-placenta), and the risk for recurrence ranges from 4% to 25% . Infants born to mothers with HELLP syndrome are at risk for thrombocytopenia. (Sibai et al., 1995)

differential diagnosis of HELLP syndrome

Thrombotic coagulopathies Hemolytic uremic syndrome Thrombotic thrombocytopenia purpura Drug-induced hemolytic anemia Sepsis DIC Consumptive disorders AFLP Sepsis DIC Abruptio placentae Amniotic fluid embolism Miscellaneous Systemic lupus Antiphospholipid syndrome Cholecystitis Appendicitis

Laboratory investigation
Risk factors for HELLP syndrome include the following: LDH level, > 1400 IU/L AST level, > 150 IU/L ALT level, > 100 IU/L Platelet count, < 50,000/mm3 Uric acid level, > 7.8 mg/dL Creatinine level, > 1.0 Creatine phosphokinase level, > 200 IU/L

Liver function
Patients usually are not jaundiced. Total bilirubin concentration rarely exceeds 1 to 2 mg. HELLP syndrome rarely leads to subcapsular hemorrhage; hepatic rupture often leads to death of the mother and fetus. Typically, these patients present with shock and hemoperitoneum. The condition also may manifest hepatic infarcts with associated fevers, high levels of aminotranferase (N5000 IU/L), and anemia. (Krueger et al., 1995)

Therapy and outcome

The maternal morbidity rate has been reported to be as high as 24%, but it ranges between 1% to 4% in optimal medical environments. In patients who died, the mean gestational age was 31 weeks, and death was attributed to sepsis, hemorrhagic shock, intracerebral insults, and cardiac pulmonary failure. Investigators found 16% maternal death rate attributed to hepatic complications. (Martin et al., 1999)

 The neonatal mortality rate associated with HELLP syndrome (10%20%) has been attributed to placenta ischemia leading to abruption, extreme prematurity, and intrauterine asphyxia. Factors associated with perinatal survival in preterm pregnancies with HELLP syndrome include achievement of a birth weight of at least 600g, elapsed time of 48 hours after medical therapy with steroids for perinatal lung maturity, and caesarian delivery. (Barton & Sibai, 1992)

 Termination of pregnancy and the removal of the chorionic villi is the only therapy that minimizes maternal and fetal compromise. Timing of delivery depends on the severity of the maternal condition , fetal condition, placenta reserve, and gestational age.

 HELLP syndrome - antepartum management

assess and stabilize the maternal condition correct coagulopathy if DIC is present give intravenous magnesium sulfate to prevent seizures provide treatment for severe hypertension to prevent stroke transfer to tertiary center if appropriate if subcapsular hematoma of liver, computed tomography or ultrasound of the abdomen

 HELLP syndrome - antepartum management

evaluate fetal well-being
non stress test biophysical profile

timing of delivery
if > 34 weeks gestation, deliver if < 34 weeks gestation, administer corticosteroids, then deliver in 48 hours

 HELLP syndrome - management for cesarean birth

use general anesthesia if platelet count is < 75,000 / mm3 transfuse 5 to 10 units of platelets before surgery if platelet count is < 50,000 / mm3 leave vesicouterine peritoneum open install subfascial drain

 HELLP syndrome - management for cesarean birth

schedule secondary closure of skin incision or subcutaneous drain administer postoperative transfusions as needed perform intensive monitoring for at least 48 hours postpartum consider dexamethasone (10 mg IV every 12 hours) until postpartum resolution of disease occurs

 Liver diseases induced by pregnancy

First trimester
Hyperemesis gravidarum

Second and third trimesters

Intrahepatic cholestasis of pregnancy Preeclampsia, eclampsia, and the HELLP syndrome (hemolysis, elevated liver enzymes, low platelet counts) Acute fatty liver of pregnancy

Acute Fatty Liver of Pregnancy

Sheehan, first recognized this disorder as a distinct syndrome in 1940. He named it Acute yellow atrophy but it is now more commonly known as acute fatly liver of pregnancy. (Sheehan, 1940)

 (AFLP) is rare,, with a reported incidence of 1 in 13,000 to 1 in 16,000 deliveries. Preeclampsia is present in 50% or more of cases of AFLP and may play a role in its origin. (Vigil-De, 2001)

 Reports of occasional recurrent cases and an association with a deficiency of longchain 3-hydroxyacyl-cocnzyme A (LCHAD) dehydrogenase, raise the interesting notion that, at least in some instances, this disease results from an inborn error of metabolism.

Clinical Characteristics
AFLP occurs in the latter half of pregnancy, usually close to term. As with HELLP syndrome, affected patients may present after delivery. It is reported to occur more commonly in a first pregnancy and in the presence of multiple pregnancy, also prevalent in preeclampsia. There are reports of an association between AFLP and gestation of a male fetus. (Castro et al., 1999)

 Affected women have nonspecific symptoms, including, prominently, nausea and vomiting, malaise and fatigue, jaundice, thirst, headache, and altered mental status. These can be signs and symptoms of acute hepatic failure.

 In severe cases that go untreated, there is progression over hours or days to fulminant hepatic failure, with hepatic coma, hypo-glycemia, severe coagulopathy with hemorrhage from the gastrointestinal tract or the uterus and death.

 Most affected women have signs of coexistent preeclampsia, including modest elevations in blood pressure,odema and protienuria .

Polydipsia
With or without polyuria, frequently is an early symptom in AFLP. The patient may drink 2 or 3 liters of liquids overnight. it often exceeds the magnitude of vomiting. It has been interpreted as a transient diabetes insipidus. (Cammu et al., 1987)

Laboratory tests
Clinical features Nausea, Vomiting Malaise, Fatigue Jaundice Abd. Pain Preeclampsia Coma polydipsia Bleeding Onset in second half of gestation; postpartum onset possible Biochemical changes Bilirubin (total) AST/ALT GGTP Prothrombin time Fibrinogen Uric acid Ammonia Glucose Leukocytes platelets Slight , normal normal to 1000 U Slight ,

 Imaging may be useful; fat in the liver has been demonstrated in AFLP with ultrasonography and CT scanning however none are particulary reliable with poor sensitivity. Liver biopsy is not indicated for diagnosis
(Barton et al., )1998

Characteristics of HEELP syndrome and AFLP

HELLP Early Platelet count, 50,000-150,000/mm3 LDH level, 600-1400 IU/L Bilirubin/PT levels, Normal AFLP Early Platelet count, >100,000/mm3 Uric acid abnormal LDH level, normal PT- Abnormal Bilirubin/ levels, abnormal late Platelet count, <100,000/mm3 LDH level, < 600 IU/L Hypoglycemia PT Abnormal

Late Platelet count, <50,000/mm3 LDH level, >1400 IU/L Bilirubin/PT levels, abnormal

Complications
cerebral edema, renal failure (60%), hypoglycemia (53%), infections (45%) gastrointestinal hemorrhage (33%), coagulopathy (30%), fetal death severe postpartum hemorrhage

MANAGMENT All patients should be hospitalized as soon as the diagnosis of AFLP is suspected Moderate or severely affected patients (encephalopathic, deeply jaundiced, with a prothrombin time less than 40% of the control), or with any extrahepatic complications, should be attended in intensive care units .

it seems convenient to maintain glucose infusions . Because of the risk of a sudden hypoglycemia until a full metabolic recovery is obtained. Treatment of AFLP begins with delivery. The route should be guided by obstetric indications. Cesarean section is not always necessary; vaginal delivery can be accomplished.

 With delivery ,resolve of hepatic dysfunctions begins, the initial sign of improvement being a fall in prothrombin time elevation. The management should include maximal support in an intensive care unit by a team that includes both obstetricians and hepatologists. Liver transplantation for AFLP has been reported. (Paternoster et al., )2004

 There are no residua after AFLP, and complete recovery of the affected patient should be expected. Cases of recurrent AFLP, as well as cases of nonketotic hypoglycemia in the offspring, have been reported There are two problems develop around these time one is DI due to elevated vasopressinase cause by diminsihed production of inactivating enzyme another is acute pancreatitis.

PRE-EXISTENT LIVER DISEASE

 Preexistent liver diseases

Portal hypertension, cirrhosis, primary biliary cirrhosis Autoimmune hepatitis Wilson disease Chronic infection with hepatitis B or hepatitis C virus Alcoholic liver disease

 Pregnancy is uncommon in women with established liver cirrhosis, including primary biliary cirrhosis, because they tend to be past childbearing age or infertile due to the condition. A life-threatening complication of liver cirrhosis is variceal bleeding associated with portal hypertension. Treating bleeding esophageal varices with nonselective beta-blockers, band ligation, and octreotide is safe and effective during pregnancy. (Helmy &Hayes, 2001)

 Ursodeoxycholic acid (FDA category B) at doses of 10 to 13 mg/kg is treatment of choice for primary biliary cirrhosis and may be continued during pregnancy and breastfeeding. (Sternlieb, 2005)

 The presence of severe portal hypertension with esophageal varices is associated with an increased risk of hemorrhage during pregnancy. The use of sclerotherapy for bleeding varices during pregnancy may provide a safe alternative to portacaval anastomosis and has been reported to be effective. (Pauzner et al., 1991)

 Preexistent liver diseases

Portal hypertension, cirrhosis, primary biliary cirrhosis Autoimmune hepatitis Wilson disease Chronic infection with hepatitis B or hepatitis C virus Alcoholic liver disease

 Women with autoimmune hepatitis can become pregnant and can still carry a successful pregnancy. The course of the disease is unpredictable. Although spontaneous remission may occur, maternal death and exacerbation during pregnancy and after delivery have been reported. (Heneghan et al., 2001)

Corticosteroids are the treatment of choice in autoimmune hepatitis and appear to be safe in pregnancy. They seem to induce rapid remission of autoimmune hepatitis, whether during the initial onset or during a flare. Although azathioprine is in FDA category D (positive evidence of risk), we have little evidence that it is toxic in pregnancy. Data from patients with inflammatory bowel disease suggest it is likely to be safe in pregnancy at dosages less than 100mg/day. (Moskovitiz et al., 2004)

 Preexistent liver diseases

Portal hypertension, cirrhosis, primary biliary cirrhosis Autoimmune hepatitis Wilson disease Chronic infection with hepatitis B or hepatitis C virus Alcoholic liver disease

Wilson disease is a rare disorder characterized by cirrhosis, neurological abnormalities, and less commonly hematological and renal dysfunction . D-Penicillamine and trientine have been used during pregnancy. However, the dosage should be reduced to the minimum necessary dose, which is about 25% to 50% of the dose the patient had been taking before the pregnancy. (Roberts & Schilsky, 2003)

 Zinc is the agent of choice for Wilson disease during pregnancy because of its safety for the fetus. It should be maintained throughout the pregnancy at 50 mg three times a day. (Brewer et al., 2000)

Liver diseases coincidental with but not induced by pregnancy

Liver diseases coincidental with but not induced by pregnancy

Acute viral hepatitis and other viral infections Alcohol-related diseases Gallstone disease Budd-Chiari syndrome

Hepatitis A
Characteristics Older name Virus type Virus size Incubation period Transmission Vertical transmission to fetus Serologic diagnosis Maximum infectivity Hepatitis A Infectious hepatitis RNA 27 nm 15 50 days Fecal oral Not observed Hepatitis A antibody IgM and IgG types Prodrome

Carrier state
Acute clinical forms

None
Asymptomatic to fulminant

Chronic clinical forms

None

 The clinical syndrome of acute HAV infection consists of vague flu-like symptoms with fatigue, weakness, nausea, and loss of appetite. The onset is usually abrupt. A variety of extrahepatic manifestations including myalgia, arthralgias, arthritis, and urticaria, may occur. Other forms of HAV infection include cholestatic hepatitis, with a prolonged course marked by itching and jaundice. (Willner, et al., 1998)

 The characteristic changes in liver function test findings include marked elevations in AST and ALT. Most often, these reach levels of 1000 to 2000 U during the early part of the infection. Elevations in bilirubin and alkaline phosphatase also occur but are more unpredictable. (Fiore, et al., 2003)

 There is substantial evidence that pregnancy does not alter the course of HAV infection. However, a higher incidence of fulminant disease during pregnancy has been reported in developing nations. Concurrent malnutrition has been a suspected cause. If the course of HAV infection is severe, it may precipitate premature labor in women in the third trimester of pregnancy. There is no evidence that HAV causes birth defects, and there is no evidence of maternal-fetal transmission. (Atkinson, et al., 2002)

 Clinical management of pregnant patients with HAV infection does not differ from that of those who are not pregnant. However, hospitalization may be indicated, specially during the last trimester and in the presence of severe anorexia, nausea, and vomiting. In rare circumstances in which the mother has acute HAV infection at the time of delivery, immune serum globulin may be administered to the infant. Even under these conditions, the risk of transmission to the infant seems very small. (Fiore, et al., 2003)

Hepatitis B
Characteristics
Older name Virus type Virus size Incubation period Transmission Vertical transmission to fetus Serologic diagnosis DNA 42 nm 30 180 days Parentral or body fluid Common HBs Ag, HBs Ab, IgM, and IgG types HBe Ag, Ab, Hepatitis B virus DNA Prodrome or HBe Ag Positive 5 10% Asymptomatic to fulminant Chronic persistent hepatitis Chronic active hepatitis Cirrhosis

Hepatitis B
Serum hepatitis

Maximum infectivity Carrier state Acute clinical forms Chronic clinical forms

The incidence of the HBV carrier state among pregnant women is variable and depends on the patient group studied. The incidence of HBV carriers is considerably higher in populations in which drug abuse or with high incidence of sexual promiscuity. (Van Zonneveld, et al., 2003)

 Evidence suggests that transmission of HBV to infants is common when mothers have acute infection in the third trimester or when they are chronic carriers of HBV infection and have positive results of serum tests for HBeAg or HBV DNA. (Su, et al., 2004)

 In women with chronic hepatitis B infection, taking lamivudine ( nucleotide analogue used against HIV and HBV alone or with combination with other anti-viral) before becoming pregnant and continuing to take it throughout the pregnancy has been reported to lower rates of transmission of the virus from mother to newborn. (Su, et al., 2004)

 The administration of hyperimmune globulin and HBV vaccine protects 90% to 95% of infants from HBV infection. It is recommended that 0.5 ml, of HBIG be given at birth and that three doses of HBV vaccine be given beginning at birth. (Sehgal, et al., 1992)

Hepatitis C
Characteristics Older name Virus type Virus size Incubation period Transmission Vertical transmission to fetus Serologic diagnosis Maximum infectivity Carrier state Acute clinical forms Chronic clinical forms RNA 30-60 nm 30 160 days Parentral sporadic Uncommon Hepatitis C antibody RNA by PCR HIV co- infected 50 85% Asymptomatic to sever relapsing Chronic persistent hepatitis Chronic active hepatitis Cirrhosis Hepatitis C Non A non B hepatitis

 The rate of vertical transmission of hepatitis C is less than 5%. The risk is higher if the mother is co-infected with human immunodeficiency virus (HIV), if she is viremic at the time of delivery, if her viral DNA load is greater than 1 million copies/ml, and if the time from the rupture of membranes to delivery is more than 6 hours. The mode of delivery does not seem to influence the rate of transmission from mother to child. (Ceci et al., 2001)

 Breastfeeding is not considered a risk factor for transmission, even though viral RNA has been detected in breast milk. . (Steininger et al., 2003)

 Newborns of infected mothers should be tested at 12 to 18 months of age, when IgG antibodies to hepatitis C virus that may have passively transferred from the placenta to the fetus would have been lost, and the persistence of hepatitis C viral RNA would indicate infection with hepatitis C. (Ferrero et al., 2003)

 Interferon is in FDA category C, and ribavirin is in category X. Both drugs are contraindicated in pregnancy. If a woman gets pregnant while on combination therapy, then both drugs should be stopped, and she should be advised that she has already put the fetus at risk of teratogenicity. (Resti et al., 2003)

Herpes simplex virus

It can cause fulminant liver failure and death if infection occurs during pregnancy, and the rate of transmission to the fetus can reach 30% to 50% if the primary episode occurs at delivery.

 About 90% of pregnant women with this infection have abnormal liver enzyme tests and an abnormal prothrombin time. Acyclovir (FDA pregnancy category B) is very effective if promptly given at doses of 400 mg three times daily for 5 to 7 days, and early delivery is not required. (Nigro , et al., 2003)

Cytomegalovirus
Infection may remain asymptomatic in pregnant women, and the prognosis is favorable. The risk of transmission to the fetus and of congenital abnormalities is highest when acute infection occurs in the first 22 weeks of pregnancy. Termination of the pregnancy may be an option after appropriate counseling regarding the potential serious risks to the infected fetus. (Benachi A, et al., 2003)

Liver diseases coincidental with but not induced by pregnancy

Acute viral hepatitis and other viral infections Alcohol-related diseases Gallstone disease Budd-Chiari syndrome

Alcohol use
Women are two to four times more likely than men to develop alcoholic liver disease for the same amount of alcohol ingested, and they exhibit a tendency to disease progression even with abstinence. (Pares et al., 1986)

 Continued drinking during pregnancy may lead to miscarriage, stillbirth, prematurity, growth retardation, and the fetal alcohol syndrome (growth retardation, behavioral disturbances ,cardiac defects, spinal defects, and craniofacial anomalies). Alcohol abstinence throughout pregnancy should be emphasized. (Lemoine et al., )2003

Liver diseases coincidental with but not induced by pregnancy

Acute viral hepatitis and other viral infections Alcohol-related diseases Gallstone disease Budd-Chiari syndrome

Gallstone disease
Pregnancy is a risk factor for sludge and gallstone formation. By the end of the third trimester, 10% to 12% of pregnant women have gallstones. Most gallstones disappear spontaneously without causing symptoms. If symptoms develop, the treatment may be conservative or surgical, depending on the severity of the symptoms.

 Laparoscopic surgery seems to be safe and should be considered. The optimal time for it appears to be during the second trimester, when fetal organogenesis is completed and the size of the uterus does not interfere with the surgery. (Halpern , 1998)

Liver diseases coincidental with but not induced by pregnancy

Acute viral hepatitis and other viral infections Alcohol-related diseases Gallstone disease Budd-Chiari syndrome

Budd-Chiari syndrome
Budd-Chiari syndrome is very rare and often insidious, manifesting after delivery. It is characterized by thrombosis of the hepatic veins and portal hypertension. Its clinical manifestations include ascites, hepatomegaly, and abdominal pain. (Singh et al., 2000)

 Proper diagnosis and management require imaging studies such as Doppler ultrasonography and CT and liver biopsy. Treatment with anticoagulants, thrombolytics (warfarin is contraindicated in pregnancy), diuretics, and portocaval shunting may be required. Liver transplantation is indicated when hepatic decompensation develops. (Deltenre et al., 2001)

Pregnancy Following Liver Transplantation

 Pregnancy after liver transplantation is often successful, but it must be regarded as a high risk, associated with hypertension, preeclampsia, intrauterine growth retardation, and prematurity. It is best delayed until 1 to 2 years after grafting. Pregnancy planned at least 2 years after liver transplantation with stable allograft function can have excellent maternal and neonatal outcome. (Nagy et al., 2003)

 In most female recipients studied, pregnancy does not appear to cause excessive or irreversible problems in graft function if the function of transplanted organ is stable prior to pregnancy, including twins if the woman has stable hepatic function before pregnancy. (Nagy et al., 2003)

 In female recipients in contrast to the general population, a high incidence of low birth-weight and prematurity has been a consistent outcome. Immunosuppressive agents may cause hypertension, preeclampsia and renal dysfunction in these recipients. However, there has been no specific pattern of malformation in their newborns or any apparent increase in the incidence of small-for-gestational-age newborns. (Armenti et al., 2000)

 immunosuppression during pregnancy is not teratogenic and does not lead to congenital anomalies. Nearly 70% of pregnancies after systemic administration of tacrolimus resulted in a favourable outcome without any significant effect on intrauterine growth. (Jabiry et al., 2005)

 Also, it was found that tacrolimus may decrease the incidence of onset of hypertension and toxemia of pregnancy. Thus, during pregnancy, the female recipient may continue the immunosuppressive regimen to stabilize the transplanted liver function but prevent the effect on the intrauterine growth.

 To the present, 37 cases of pregnancies after liver transplantation have been reported worldwide. In conclusion: Under careful monitoring a childbearing age woman with stable and adequate liver function may have a successful pregnancy and a delivery after liver transplantation. (Pan et al., 2007)