This chapter should be cited as follows: This chapter was last updated:
Larraín, S, Rinella, M, Glob. libr. women's med.,
(ISSN: 1756-2228) 2011; DOI 10.3843/GLOWM.10171
October 2011

Medical complications

Liver Diseases in Pregnancy

Soledad M. Larraín, MD
Visiting Physician Investigator, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
Mary E. Rinella, MD
Associate Professor of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA

INTRODUCTION

Liver diseases in pregnancy encompass a diverse range of problems. Some of these disorders are unique to the gestational state, whereas others may reflect a preexisting condition that has been unmasked or exacerbated by pregnancy. Knowledge of the spectrum of liver disease in pregnancy is important because some of these entities require specific or urgent management. Because not all changes to the liver during pregnancy are pathologic, familiarity with interpretation of liver function tests is necessary to direct a proper workup of abnormalities, especially those found incidentally on routine biochemical screening. The goals of this chapter thus encompass discussion of physiologic hepatic changes associated with the pregnant state, the effect of pregnancy on preexistent liver disease, liver diseases specific to pregnancy, and a problem-oriented approach to diagnosis and treatment.

THE LIVER DURING NORMAL PREGNANCY

Physiological changes that occur throughout pregnancy affect portal blood flow, however, normal pregnancy is not accompanied by changes in hepatic function. On physical examination spider angiomata and palmar erythema can often be appreciated. While these can also represent classic cutaneous signs of liver disease, they can be features of an uncomplicated pregnancy and usually disappear after delivery. The liver on physical examination does not change, other than a mild upward shift due to the enlarging uterus, making it more difficult to appreciate. If the liver is palpable below the rib cage in later stages of pregnancy, this should raise the possibility of underlying liver disease.

On liver ultrasonography the biliary tract is usually normal though gallbladder volume may be increased. A mildly cholestatic profile may be present in later stages of pregnancy, possibly due to hormonal changes. Effects of sex hormones likely mediate smooth muscle relaxation in the biliary tree, leading to increased gallbladder volume and decreased contractility.1 Furthermore, estrogens change the permeability of the biliary canalicular membrane, reducing both bile salt-dependent and bile salt-independent fractions of bile flow as well as diminishing hepatic transporter expression.2, 3 Bile lithogenicity also may be increased because of the effects of sex hormones on the relative concentrations of cholesterol, phospholipids, and bile acids with an increase in cholesterol synthesis and excretion into bile.4, 5 Despite these physiologic abnormalities, symptomatic cholestasis is not a typical feature of normal pregnancy.

On hepatic Doppler ultrasound there are some changes in the hepatic venous flow pattern and portal flow velocity,6 due to hemodynamic changes during pregnancy. Throughout pregnancy there is a 40% increase in blood volume, which is maximal in the third trimester. Cardiac output increases until the second trimester and then may decrease or plateau during the third trimester. Despite these systemic hemodynamic changes in pregnancy, absolute hepatic blood flow is unchanged. This relative decrease in hepatic blood flow is an intriguing observation in view of the generalized hyperdynamic state of pregnancy.7 This relative reduction may impair the clearance of substances requiring adequate hepatic perfusion.

Regarding laboratory tests, there are also some changes related to pregnancy. It is important to remark that most liver “function” tests detected on automated panels do not truly evaluate a specific hepatic function. Even those that qualify as such do so partially, since other factors may influence their serum concentrations. Bilirubin levels may reflect liver uptake, metabolic transformation or canalicular excretion. Serum albumin may reflect its synthetic function but also may be related to nutrition. Serum aminotransferases, alkaline phosphatase (AP), and γ-glutamyl transferase (GGT) are markers of hepatic injury. However, AP is not specific to liver disease as it is also produced in other organs such as the kidney, intestine, bone, and placenta. Similarly, elevations in aminotransferases or lactate dehydrogenase (LDH) may be due to muscle injury.

A series comparing liver test results of 103 pregnant patients with 103 control subjects showed differences in liver chemistries during pregnancy.8 SpecificallyAP was significantly higher, particularly in the third trimester, however, this represents AP of placental, not canalicular, origin. Similarly, alanine aminotransferase (ALT) and 5'-nucleotidase were mildly elevated but still within the normal range and aspartate aminotransferase (AST) and total bile acids were not significantly different compared with those of control subjects. Conversely, serum albumin levels were significantly lower during all trimesters because of hemodilution. Furthermore, total and indirect bilirubin were lower in all trimesters, and direct bilirubin and GGT were lower in the second and third trimesters (Table 1). In another study 430 women were compared with 85 women with gestational hypertension (GH) and women without GH had aminotransferases below the standard reference range. Interestingly, using a lower reference range (now advocated by some),9, 10 more subtle abnormalities in liver tests could be appreciated in patients with either preeclampsia or pregnancy induced hypertension.11 Such abnormalities were clinically important as they significantly correlated with more maternal complications.11 Aminotransferases may transiently increase in the puerperium and can be affected by mode of delivery.12 Finally, in another study, coagulation tests were obtained from 186 women with uncomplicated pregnancy, and levels of prothrombin time remained unchanged compared to non-pregnant reference intervals.13 While we can appreciate also some alterations of specialized tests that reflect mild cholestasis during pregnancy, these are not performed routinely and are not typically clinically significant.14, 15

A marked increase in serum triglycerides and, to a lesser extent, cholesterol also may be seen. This effect is due in part to increased hepatic secretion of very low-density liproprotein in pregnancy.

Finally, on liver histopathology, no alterations are appreciated during normal pregnancy.16

Table 1. Hepatic chemistries in normal pregnancy

 TestComment
BilirubinNormal; urine bilirubin may be positive in the absence of jaundice
AlbuminDecreased because of hemodilution
Prothrombin timeNormal
Serum bile acidsRemain within normal limits
AminotransferasesUnchanged or lower 
Alkaline phosphataseElevated in third trimester; placental origin
Leucine aminopeptidaseElevated in third trimester; placental origin
5'-nucleotidaseNormal
 γ-Glutamyl transferaseMay not rise with hepatic injury

MANAGEMENT OF LIVER DISEASE OCCURRING DURING PREGNANCY

Abnormal aminotransferases in an otherwise healthy pregnant women

Healthy pregnant women typically do not have elevated aminotransferases and, in fact, levels may decrease in pregnancy.11 However, in normal pregnancy aminotransferases can rise in the puerperium.12 Non-alcoholic fatty liver disease (NAFLD) is the most common cause of abnormal aminotransferases in the general population and thus also seen in pregnancy. This is distinct from fatty liver of pregnancy which is discussed later. In patients with a history of intravenous drug use or a remote history of blood transfusion, hepatitis B or C must be considered. Patients should be questioned about alcohol intake and use of medications as they both commonly cause liver enzyme abnormalities. In the case of alcohol, the enzyme profile can be characteristic. An elevated ratio of AST:ALT >2 can suggest alcoholic hepatitis as can an elevated GGT, however, neither of these is specific. AST is present in other tissues, including red blood cells and muscle, thus such sources need to be considered as well. Physical examination should be complete and include evaluation for stigmata of liver disease such as the presence of multiple spider angiomata (a few angiomata may present in normal pregnancy), palmar erythema, Terry’s or Lindsay’s nails, muscle wasting and ascites. The presence of tattoos should prompt an evaluation for hepatitis C. If the physical exam is noncontributory, and the liver enzyme abnormalities confirmed, a basic evaluation should be undertaken in two tiers, beginning with the most common causes. Initial testing should check for hepatitis A, B, and C as well as antinuclear antibody (ANA), anti-smooth muscle antibody (ASMA), quantitative IgG, and anti-liver-kidney-microsomal antibody if necessary to evaluate for autoimmune hepatitis. Wilson’s disease should also be considered and evaluated with serum ceruloplasmin, free copper level and a 24 hour urine copper. A hepatic ultrasound examination with Doppler flow should be performed to identify evidence of portal hypertension, mass lesion or vascular obstruction such as portal vein or hepatic vein (Budd-Chiari) thrombosis. If abnormalities persist and the cause is not forthcoming on this evaluation, then referral to a hepatologist should be considered.

Liver diseases in pregnancy are more conspicuous in the second and third trimesters. Even if clinically stable, a complete liver panel should be repeated periodically in a patient with abnormal serum liver chemistries. It is important to be aware of clinical changes suggestive of a more serious picture such as acute fatty liver of pregnancy (AFLP), overt preeclampsia or the hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome, since prompt intervention is imperative in either of these conditions. Liver tests should be followed after delivery with a wide differential diagnosis if abnormalities persist.

Acute right upper quadrant pain

Sudden onset of right upper quadrant abdominal pain should alert the clinician to several important diagnoses, the most common of which is cholelithiasis. The pregnant state results in the production of lithogenic bile, and it is not uncommon for the patient, especially the multipara, to develop her first symptoms during pregnancy. Cholelithiasis can result in cholecystitis, choledocholithiasis or acute pancreatitis. However, only the latter two should increase liver enzymes or result in jaundice. Pain associated with biliary colic typically is intermittent and builds to a crescendo. Choledocholithiasis can be complicated by severe cholangitis with sepsis or acute pancreatitis. An abdominal MRI with magnetic resonance cholangiopancreatography (MRCP) may be a good adjunct to ultrasound for more detailed evaluation of the bile and pancreatic ducts, though gadolinium is generally avoided in pregnancy. Severe unremitting pain should raise the possibility of a subcapsular hematoma or a ruptured liver, either spontaneous (as seen in HELLP) or complicating a hepatic adenoma. If blood is found on peritoneal aspiration or there is any evidence of shock, a ruptured splenic artery aneurysm should also be considered, since this occurs with increased frequency in pregnancy and requires emergency laparotomy.

Parenchymal liver disease also may present as right upper quadrant or epigastric pain, generally because of stretching of the hepatic capsule. The pain is dull, and the liver edge may be tender on examination. Patients with viral hepatitis, Budd-Chiari syndrome, AFLP, or preeclampsia may present with such symptoms.


Jaundice during pregnancy: a differential diagnosis

Viral hepatitis is the most common cause of jaundice during pregnancy in most populations. The next most frequent cause is intrahepatic cholestasis of pregnancy (ICP), but this may vary with geographic location. An approach to the differential diagnosis of jaundice during pregnancy is offered in Table 2.

Table 2. Jaundice in pregnancy differential diagnosis

DiseaseAssociated symptomsLaboratory abnormalities

Outcome

Viral hepatitisMalaise, abdominal painAminotransferases + + + + 

A

HAV IgM

Generally good

B

HBV serologies

Transmission likely without prophylaxis

C

HCV Ab, HCV RNA

Low vertical transmission

D

HDV RNA

Low vertical transmission

E

HEV Ab, serum RT-PCR, stool sample less reliable

High fetal wastage, high maternal mortality

Cholecystitis

Epigastric pain, fever, nausea

Ultrasound

Surgery if needed ideally in 2nd trimester

Choledocholithiasis/cholangitis

Epigastric pain, nausea +/− fever

Ultrasound, magnetic resonance cholangiopancreatography

Endoscopic ultrasound, endoscopic retrograde cholangiopancreatography if needed – radiation exposure

Pancreatitis

Epigastric pain

Ultrasound

Endoscopic ultrasound, endoscopic retrograde cholangiopancreatography

Acute fatty liver of pregnancyHeadache, nausea/vomiting, abdominal pain
Variable bilirubin, variable transaminases, increased uric acid, decreased plateletsFetal/maternal death possible without early delivery

Intrahepatic cholestasis of pregnancy

Pruritus in 3rd trimester, steatorrhea, nausea, vomiting

AP increased, increased serum bile acids

Increased fetal wastage, maternal morbidity low

PreeclampsiaEpigastric pain, malaise, fatigue, nausea, vomitingMild jaundice, variable transaminases, decreased plateletsPoor if hepatic rupture

HAV, hepatitis A virus; IgM, immunoglobulin M; HBV, hepatitis B virus; HCV, hepatitis C virus; AFLP, acute fatty liver of pregnancy; RT-PCR, reverse transcriptase polymerase chain reaction; AP, alkaline phosphatase.


Indirect hyperbilirubinemia may be seen in cases of hemolytic anemia, such as preeclampsia. In the absence of renal insufficiency, hemolysis rarely produces bilirubin levels greater than 5 mg/dL. Urinary dipstick test results should be negative in the case of indirect bilirubinemia, as only conjugated bilirubin is excreted into the urine.
 


Acute viral hepatitis

Viral hepatitis acquired during pregnancy is a common cause of altered liver biochemistry and jaundice in pregnancy. This section addresses the risk to the mother.

HEPATITIS A

Hepatitis A virus infection leads to an acute and self-limited hepatitis. Very rarely, fulminant hepatitis may develop secondary to hepatitis A and often is related to a poor nutritional state, advanced maternal age, or coexistent hepatitis B infection.17 A chronic carrier state of hepatitis A is not known to occur, however, a relapsing form of hepatitis A does occur. Management in pregnancy is supportive and not different from management of hepatitis A infection in the nonpregnant patient. However, Hepatitis A virus infection during the second and third trimester may be associated with gestational complications such as premature contractions, placental separation, premature rupture of membranes, fetal distress, vaginal bleeding, and preterm labor.18, 19 Serum hepatitis A virus immunoglobulin M should be checked in all patients suspected of having hepatitis A infection and may persist for up to 6 months after acute infection. Travelers to endemic areas should be immunized for hepatitis A. The vaccine appears to be safe in pregnancy.20

HEPATITIS B  

 

Hepatitis B virus (HBV) infection acquired in adulthood leads to chronic hepatitis in approximately 5% of those exposed.21 Pregnancy neither confers a higher risk of chronic infection nor a worse clinical course of hepatitis.22 Conversely, pregnancy course and outcome are not adversely affected by the presence of active HBV infection, except in cases of fulminant hepatitis.23 Cessation of viral replication has been observed after delivery.24 Hepatitis B testing may yield evidence of infection through “classic” antibody patterns and should be confirmed by checking for the presence of HBV DNA in serum. Management of acute hepatitis B during pregnancy is mainly supportive, except in the case of fulminant hepatitis, which occurs in fewer than 1% of patients, where lamivudine might be a reasonable option since some case reports have shown its safety and efficacy.25, 26, 27 Vaccination of patients is associated with a weak antibody response, especially in obese mothers with advanced age.28 Hepatitis D (delta hepatitis), an RNA virus that requires hepatitis B surface antigen (HBsAg) to replicate, may coinfect or superinfect persons with acute hepatitis B or hepatitis B carriers. This signals an unfavorable prognosis for the patient but is no worse in pregnancy than in the nongravid patient.

 

HEPATITIS C

 

Hepatitis C (HCV) is an RNA virus that causes chronic infection in 75–85% of those exposed. The clinical course is not affected by pregnancy nor is the course of pregnancy affected by the presence of the virus.29 However, viral replication appears to increase with a lowering of serum aminotransferases.30, 31 Postpartum values return to prepregnancy levels. Unlike hepatitis B, there have been few reports of HCV causing fulminant hepatitis. When suspected, anti-HCV antibody should be measured and confirmed with serum HCV-RNA if positive. Current regimens for the treatment of HCV include ribavirin, which is teratogenic and hence contraindicated during pregnancy. No vaccination currently is available for hepatitis C prophylaxis.

 

HEPATITIS E

 

Hepatitis E virus, unlike hepatitis A, B, or C, does convey an acute risk to both mother and fetus.32 Patients who acquire hepatitis E in the third trimester are at higher risk of acute liver failure and consequently have 20% mortality. Even in uncomplicated cases, there is a higher rate of abortion and intrauterine death reported.33 Furthermore, levels of HEV viral load are higher in the pregnant woman, and also related to the severity of the disease.34 The route of spread is fecal–oral, and epidemics have occurred in India, Pakistan, southeast Asia, Africa, Mexico, and China. Sporadic cases are rare in women who have not traveled to these areas. As in the case of hepatitis A, a chronic carrier state does not exist. Confirmation of infection may be obtained by stool or serum. Management of infection remains supportive. A hepatitis E vaccine was recently tested in an endemic area and found to be 95% effective, however, safety and efficacy in pregnancy has not been reported.35, 36

 

Risk of viral hepatitis in the newborn

HEPATITIS A

Hepatitis A infection is transmitted via the fecal–oral route and is only rarely passed vertically. However, there have been isolated reports of perinatal transmission.37 Horizontal transmission from an acutely infected mother who is caring for her newborn is possible. Therefore, an infant born to a woman who is acutely infected with hepatitis A virus and who presents symptoms in the period from 2 weeks before to 1 week after delivery, may benefit immune globulin.38, 39

HEPATITIS B

Hepatitis B virus carries a significant risk of vertical transmission, with most affected infants becoming chronic carriers. Transmission is not affected by route of delivery, and breastfeeding is thought to play a minimal role in transmission, since 95% of cases are acquired intrapartum.40 However, recent studies have shown that breastfeeding after standard immunoprophylaxis does not contribute to HBV transmission at all.41 The likelihood of transmission is related to the timing of onset of acute hepatitis or active viral replication in the mother.

Acute hepatitis B infection in the first two trimesters carries a low risk of transmission to the fetus versus acute infection in the third trimester, which carries a 70% risk of transmission.23 In chronic hepatitis, mothers who are hepatitis B e antigen-positive (HBeAg+) have 80–90% chance of vertical transmission, with 85% of these becoming chronic carriers.42, 43 The high rate of carriage may be because of tolerance induced by HBeAg, which, unlike HBsAg, can cross the placental barrier. The transmission rate in chronic hepatitis also is related to levels of HBV-DNA present in maternal serum.44, 45 In mothers who are HBeAg− and HBsAg+, the rate of transmission is 2–15% and only 10–15% of these infants become carriers.43, 46 There have been cases of infected newborns showing fulminant hepatitis from mothers who are HBeAg−, and these likely are caused by a mutant strain of HBV.47

All women should have screening for hepatitis B at the first antenatal care visit.48 If positive, further workup to assess the extent of liver disease should be undertaken. In addition, women testing positive for HBV should have serologies and, if appropriate, HBV-DNA levels repeated in the third trimester.

Because 95% of transmission is thought to occur at or near the time of birth, postexposure prophylaxis at birth is a reasonable strategy. Indications include acute infection in the third trimester or chronic infection with positive serology for HBeAg or HBV-DNA.48 Hepatitis B immune globulin (HBIg) should be given within 2 days of birth, preferably within 12 hours.49, 50, 51 Recombinant vaccine also should be given at birth, followed by repeat injections at 1 and 6 months after the initial dose, or an accelerated vaccine regimen.49, 50, 52 This strategy has been shown to be 85–95% effective in preventing neonatal transmission.49, 50 If the recombinant vaccine is not given, repeat doses of HBIg at 3 and 6 months have been shown to have further protective effects than a single dose.53, 54 In patients who are delivering without knowledge of hepatitis B status and in whom the results will not be known for more than 12 hours postpartum, consideration should be given to empiric coverage of the newborn with HBIg as efficacy falls rapidly after 12 hours.55 Some recent studies have reported that injection of multiple doses of HBIg in carrier mothers with a high degree of infectiousness in late pregnancy, plus standard immunoprophylaxis in the newborn, effectively and safely prevent intrauterine transmission.56, 57, 58 Furthermore, several studies have shown that addition of lamivudine in the highly viremic mother during late pregnancy, plus standard immunoprophylaxis in the newborn, significantly reduced mother-to-child transmission.59, 60, 61, 62 Moreover, two recent Chinese studies reported that the use of telbivudine during later pregnancy can safely reduce perinatal HBV transmission.63, 64


Delta superinfection rarely is transmitted vertically and is equally protected by postexposure prophylaxis as is HBV.

HEPATITIS C

Unlike HBV, vertical transmission plays a small role in the transmission of HCV. A large study investigating vertical transmission of HCV has shown a 5.1% rate of HCV-RNA viremia at 1 year in newborns whose mothers were known to have HCV viremia.65 High maternal viremia levels, maternal peripheral blood mononuclear infection by HCV, membrane rupture of longer than 6 hours and procedures exposing the infant to maternal blood infected are associated with an increased risk of perinatal transmission.66, 67 HIV coinfection also confers higher rates of transmission and may do so via immunosuppression of the mother with subsequent increased viremic titers.68, 69, 70 Further investigation is necessary to determine whether HCV genotype plays a role in transmission rate. Breastfeeding is not contraindicated, as only very low levels of HCV-RNA are detected in breast milk.71 The administration immune globulin to newborns has not been examined in controlled clinical trials. 

HEPATITIS E

A series of eight mothers with hepatitis E virus infection showed that six of their newborns had evidence for clinical hepatitis E infection, two of whom died within 24 hours after delivery.72 Another series of 19 HEV infected pregnant women showed that 15 babies had evidence of vertically transmitted HEV infection at birth, and mortality in the first week was nearly 50%.73 Current evidence suggests that, intrauterine transmission of hepatitis E virus from mother to child is accompanied by increased fetal and neonatal risks.33 Children born to women with known hepatitis E virus infection should be monitored closely after birth for signs of infection.71 There is at present no proof of the efficacy of immune globulin prophylaxis for the prevention of HEV.74

Table 3 summarizes the strategies currently used in neonatal prophylaxis.

Table 3. Neonatal prophylaxis

Disease

Prophylaxis

Hepatitis A

0.02 mL/kg immune globulin IM at birth

Hepatitis B

Hepatitis B recombinant vaccine (HBIg) (Recombivax 5 μg IM or Energix-B 10 μg IM) at birth and at 1 and 6 months

Hepatitis C

No proven therapy

Hepatitis E

Undergoing clinical trials

THE IMPACT OF PREGNANCY ON PREEXISTENT LIVER DISEASE

Cholestatic disorders

Cholestasis can be defined physiologically as a decrease in bile flow. The differential diagnosis of biliary stasis, schematically divided into intrahepatic and extrahepatic types, progresses from biliary structures within the liver (bile canaliculi, ductules, and ducts) to the extrahepatic tree. Both share symptoms, such as jaundice and generalized pruritus. Right upper quadrant pain is more suggestive of extrahepatic biliary obstruction. Elevations of AP, 5'-nucleotidase, or GGT are common in such cases. Bilirubin rises in accordance with the extent of impairment of bile flow. Ultrasonography is the test of choice for the initial evaluation of cholestasis in pregnancy, being mindful that common bile duct or intrahepatic ductal dilatation may be intermittent in the presence of an intraluminal stone.

In the second and third trimester, cholesterol secretion into bile increases relative to bile acids and phospholipid, promoting the formation of supersaturated lithogenic bile. The prevalence of gallstones increases 5–12% in pregnancy, though only 0.1–0.3% patients become symptomatic. A review of the literature suggests that surgical management of cholecystitis should be reserved only for complicated or unremitting cases, since 73–90% of cases of acute cholecystitis in pregnancy resolve with medical management.75, 76 Surgical intervention is necessary at times, however, indications for surgery in the pregnant woman are not yet clearly established. Recent studies have suggested earlier surgical intervention may be associated with less complications compared to conservative management.75, 77, 78 While studies have shown the safety of laparoscopic cholecystectomy in all trimesters, avoiding surgery in the first trimester lessens the risk to the fetus. Optimally surgery is recommended during the second (preferably) or third trimester, noting that as the gravid uterus expands, surgery may become more technically challenging.79, 80, 75, 77, 78 For patients with symptomatic choledocholithiasis, endoscopic retrograde cholangiopancreatography (ERCP) appears to be reasonably safe if the radiation dose is kept to a minimum.75, 81, 82

Pregnancy may worsen or unmask underlying intrahepatic cholestatic disorders, a reflection of the hormonal changes discussed previously. Women with primary biliary cirrhosis (PBC) do not have impaired fertility.83, 84 Overall, pregnancy is well tolerated in patients with PBC and does not adversely affect disease course or pregnancy outcome.85 Rarely, jaundice may worsen in pregnant PBC patients, but this does not necessarily reflect a worsening of the overall disease process. Ursodeoxycholic acid (UDCA) therapy during the last trimester of pregnancy appears to be safe and may be beneficial in mothers with cholestasis.86, 87, 88 The Dubin-Johnson syndrome, one of the familial conjugated hyperbilirubinemia disorders, may worsen during the second or third trimester.89 In one case of Alagille's syndrome, a familiar disorder of intrahepatic cholestasis, worsening of pruritus was noted in the third trimester.90 A common theme in all these disorders is their clinical expression in the latter part of pregnancy, when the hormonal change that affects biliary transport and function is at its peak.


Chronic hepatitis

Chronic hepatitis has various etiologies ranging from viral to autoimmune to metabolic. Adult-acquired hepatitis B and C progress to chronic hepatitis in 5–10% and 75–85% of cases, respectively.91, 92 The most common cause of abnormal liver chemistries is non-alcoholic fatty liver disease (NAFLD), attributed largely to the mounting epidemic of obesity. Its aggressive subtype, non-alcoholic steatohepatitis (NASH) is a common indication for liver transplantation. Other etiologies include Wilson's disease, continued use of some drugs such as amiodarone, nitrofurantoin or α-methyldopa, and α1-antitrypsin deficiency. Secondary amenorrhea is a common feature of advanced chronic liver disease, and thus such patients infrequently become pregnant.

The clinical course of chronic viral hepatitis usually remains stable in the pregnant state; however, changes in viral replication occur. In the case of hepatitis C, recent studies document a decrease in serum alanine transaminase and an increase in serum hepatitis C virus (HCV)-RNA during pregnancy,93, 30, 31 with a postpartum return to prepregnancy values. In the case of hepatitis B, changes in the immune status after delivery could account for the subsidence of viral replication.24 The risk of vertical transmission and treatment during pregnancy has been discussed previously.

Despite the fact that NAFLD is the most common cause of abnormal liver chemistries, it is rarely appreciated in pregnancy. However, it is known that 29% of women of reproductive age (20–39 years) in USA are obese.94 A recent study reported a cohort of women found to have rising liver chemistry tests during or shortly after pregnancy, attributed to NAFLD.95 In those patients, other causes of abnormal liver tests were excluded, and all patients had either fatty liver on ultrasound or steatosis in liver biopsy. The author proposed that the association between NAFLD and pregnancy may be due to in part to pregnancy-related insulin resistance.95 Further studies are needed to determine the incidence of NAFLD and its association with pregnancy.

Autoimmune hepatitis is a disease that is 3.6 times more prevalent in women than in men.96 It has a bimodal age distribution that frequently affects women of childbearing age. There is no consensus regarding the course of autoimmune hepatitis in pregnancy. Although some reports have described a worsening of liver disease, others have described no change or even improvement in histology and biochemistry.97 The presence of specific maternal antibodies such as antibodies to SLA and Ro/SSA seems to be associated with a more complicated course.98, 99  Pregnancy in women with autoimmune hepatitis has been associated with preterm delivery and an increased risk of fetal loss.98100, 101 Also, hepatitis flares are reported in the postpartum period.102 Steroid therapy may be continued safely. Azathioprine, used at the low doses required for autoimmune hepatitis, has a quite low risk of teratogenesis, therefore may be continued.103

Wilson's disease is a rare genetic disorder of copper accumulation and toxicity, caused by a defect in an enzyme that is part of the pathway of biliary copper excretion.104 In the absence of specific therapy, patients have a relentless, deteriorating course. Copper accumulation in specific tissues such as liver, brain, cornea, and kidney is the basis for its symptomatology. Ideally, the disease should be well controlled before pregnancy, however, the disease may first manifest during pregnancy.105 A positive diagnosis may be difficult during this stage, since serum ceruloplasmin levels (traditionally below normal in this disease) may rise as a nonspecific effect of pregnancy on plasma proteins.106 Every effort should be made to exclude such a treatable disease, preferably with serum-free copper, ceruloplasmin and 24 hour urine copper.104 Patients treated with D-penicillamine, trientene (copper chelators) or zinc salts have carried their pregnancy to term successfully, although some evidence of prematurity with penicillamine has been reported.105, 107 Although it generally is recommended that these drugs be discontinued when pregnancy is discovered in many other diseases, doing so in Wilson's disease may lead to fulminant hepatic failure and death.104, 108, 109 Therefore, patients with Wilson's disease discovered to be pregnant should continue therapy.

Although little is known about the course of α1-antitrypsin (AT) deficiency-related liver disease in pregnancy, there are several cases of healthy offspring being carried to term. Occasionally, it is the lung disease that is the limiting factor for healthy pregnancy.110, 111

Another rare cause of chronic hepatitis is erythropoietic protoporphyria, a disorder that may cause photosensitive cutaneous reactions and hepatic dysfunction. There have been reports of a lessening of the severity of cutaneous reactions to light, possibly secondary to the lower circulating erythrocyte protoporphyrin burden in pregnancy.112, 113 Little is known of the hepatic aspects of this disease in pregnancy.

 

Cirrhosis/portal hypertension

In the United States, alcohol abuse, hepatitis C, and NASH are the most common etiologies of cirrhosis. With respect to alcohol, women develop alcohol related liver disease at a younger age and at a substantially lower cumulative alcohol dose than men.17 Alcohol itself disrupts reproductive function, as seen in experimental animals, though women who abuse alcohol become pregnant and need to be warned of the risk of fetal alcohol syndrome.114 Since amenorrhea is common in women with advanced liver disease secondary to hypothalamic pituitary dysfunction and the spontaneous abortion rate is higher than that of the general population (reaching 30–40%), it is a minority of such women who become pregnant.115 That being said, a fair number of cirrhotic women are able to become pregnant and good prenatal care is paramount to a successful pregnancy. In pregnant patients with cirrhosis, the risk of prematurity is increased up to 25%.116 The frequency and severity of complications during pregnancy are related to the severity of liver function.117 In patients with cirrhosis and significant portal hypertension, 50% will develop maternal/fetal complications.118 Early termination of pregnancy should be considered if severe hepatic decompensation exists.119 However, in those with well-compensated cirrhosis, pregnancy generally is considered to be safe.117

If portal hypertension is suspected clinically, upper endoscopy should be part of the routine prenatal workup to document the presence of esophageal varices. The absence of varices does not preclude development later in pregnancy but makes their occurrence less likely. If no varices are seen early on, patients should be rescreened in the second trimester when increased pressure on the vena cava may exacerbate portal hypertension. Beta-blockers, commonly used to prevent variceal bleeding in nonpregnant patients, have been associated with fetal growth retardation, thus patients with high risk varices can undergo variceal obliteration through band ligation to avert future bleeding.

Variceal hemorrhage is a common complication in pregnant cirrhotic patients. From 20% to 24% of all pregnancies in patients with cirrhosis will be complicated by variceal bleeding,120, 121, 122 with a mortality rate of 18–50%.123, 124 The combination of increased blood volume and inferior vena cava compression makes bleeding more likely in the second and third trimesters. Maternal mortality is much higher from variceal bleeding in the cirrhotic patient than in the noncirrhotic patient.125 In addition to hemodynamic stabilization, management of acute variceal hemorrhage in a pregnant woman includes endoscopic intervention. The safety of octreotide, a common adjunct to endoscopic therapy, in pregnancy is not known. No large series have addressed the safety and efficacy of band ligation in pregnancy, though case reports do support the use of band ligation and even transjugular intrahepatic portosystemic shunt (TIPS) in cases of severe or recurrent bleeding during pregnancy.126, 127, 128, 129 Surgical shunting has been reported but should be reserved for refractory life-threatening bleeding after medical, endoscopic, and radiologic therapies have failed.130, 131 In a high volume, experienced centers using coated TIPS, surgical shunting is rarely needed. Although the Valsalva maneuver during delivery may acutely increase portal pressures, cesarean delivery is not routinely recommended because of the increased risk associated with surgical procedures in the cirrhotic patient.132 Ideally delivery is vaginal with an assisted short second stage, however, if very large high risk varices are present, a cesarean section can be considered to avoid acute worsening of portal pressures that could occur during vaginal delivery.

The medical regimen used for the complications of cirrhosis should be tailored to each patient individually. However, medications known to have teratogenic potential such as spironolactone, shown to be associated with fetal genital malformations, should be discontinued. Nonselective beta-adrenergic blockers are commonly used as primary prophylaxis for variceal bleeding, however, their use is not generally recommended in pregnancy as they have been associated with fetal growth retardation.133 They may be considered in cases of large or high risk appearing esophageal varices with red wales, findings that increase the likelihood of hemorrhage. An alternative approach to beta-blockers is esophageal band ligation, as previously discussed.

Up to 24% of pregnant patients with cirrhosis will experience hepatic decompensation.122134 A rare but life threatening complication is splenic artery aneurysm rupture which occurs in 2.6% of pregnant patients with cirrhosis, predominantly in the third trimester.135, 136 Left upper quadrant pain or syncope may precede hemorrhagic shock. Because fetal and maternal mortalities are 80% and 70%, respectively, a high index of suspicion and rapid intervention are essential. During the postpartum period, 7–10% of the patients may suffer from uterine hemorrhage, for which management is similar to that in patients without cirrhosis.116


Pregnancy and liver transplantation

The patient should be aware that in the absence of liver transplantation, a mother with advanced cirrhosis has a very poor chance of raising the child to adulthood.137 Orthotopic liver transplant is being performed at an increasing number of medical centers, many on women of childbearing age. If transplantation is to be undertaken, pregnancy should ideally be delayed until after transplant. Conception occurring during the first 6–12 months posttransplant carries a higher risk of allograft rejection and opportunistic infection.138 All women of childbearing age undergoing liver transplantation should be counseled on the need for contraception. During the first year after transplant, there is increased risk of prematurity, intrauterine growth retardation, and low birth weight.139 Most recommend that pregnancy should be postponed for at least 1 year after transplant when infection is less of a risk and immunosuppression is optimized.140, 141 Immunosuppression with prednisone, cyclosporine and tacrolimus are the best studied in pregnancy and are associated with an acceptable risk profile. Mycophenolate mofetil (Cellcept) is to be avoided given the risks of fetal malformation that have been reported.142, 143 Although pregnancy after transplant is considered safe, patients need to be followed closely by both a high risk obstetrician and a transplant hepatologist.

Pregnant women after transplantation are at higher risk of having preeclampsia, hypertension, premature rupture of membranes, preterm delivery, fetal mortality, and cesarean delivery than are normal obstetric patients.138 Offspring of such mothers have higher rates of fetal distress and growth restriction, but not congenital anomalies.144 Women who enter pregnancy with renal insufficiency appear to be at particular risk.138 Pregnancies have been described in women using various immunosuppressive regimens and generally are thought to carry an acceptable risk if the patient is under the care of experienced transplant physicians to minimize the necessary dose of immunosuppressives.145

 
Miscellaneous conditions

Hepatic adenomas are observed most often in women taking oral contraceptives.146 The tumors may grow during pregnancy with a risk of rupture of 59% in lesions larger than 6.5 cm, endangering the life of the mother and fetus with a mortality rate of 44% and 38%, respectively.147 The mechanism of growth is related to the effects of sex hormones.148 Similarly, focal nodular hyperplasia and hepatic hemangiomas may grow during pregnancy, a mechanism likely related to the increase in blood volume. In patients with a known history of these tumors, a baseline ultrasound examination early in pregnancy is prudent. It is advisable that adenomas be resected before pregnancy, particularly if they are large, have complicated previous pregnancies or are near the hepatic capsule.149 Pregnancy is considered a risk factor for severe cystic liver disease.150 Despite the latter, only two cases of pregnancy complicated by symptomatic adult polycystic liver disease have been reported.151, 152 Multiple transcutaneous cyst aspirations were performed to alleviate pain. Both mothers and fetuses did well, one with labor induced at 35 weeks' and the other at 39 weeks' gestation.

Acute hepatic vein thrombosis (Budd-Chiari syndrome) can be a life-threatening condition and has been reported both during pregnancy and postpartum.153, 154 There are many known causes, but the hypercoagulable state of pregnancy may be a contributing factor. The majority of patients with Budd-Chiari have an underlying hypercoagulable site, thus the evaluation of Budd-Chiari in pregnancy should include a thorough hypercoagulable workup that includes looking for the JAK2 mutation. Budd-Chiari syndrome has been reported with the HELLP syndrome.155 Right upper quadrant pain, hepatomegaly, and ascites are hallmarks of this disease caused by the acute reduction of hepatic outflow. Urgent consultation with a hepatologist is important to assess the degree of hepatic impairment and the role of urgent TIPS. Doppler ultrasonography is the test of choice for the initial evaluation, and once the diagnosis is confirmed, anticoagulation is the first step of treatment.156 In patients with known and treated Budd-Chiari syndrome with well controlled disease, pregnancy is not  contraindicated, since maternal and fetal outcome are good beyond week 20. However, higher rates of fetal loss before week 20 and preterm delivery have been reported in such patients.157, 158

Hepatocellular carcinoma occurs very rarely in pregnancy.159 Until now, only 47 cases have been reported worldwide.160 The morbidity and mortality of hepatocellular carcinoma during pregnancy has improved over time since diagnoses have tended to be made earlier and patients have tended to receive surgical and other treatments.160 Abdominal ultrasonography is a good initial diagnostic method if hepatocellular carcinoma is suspected. On the rare occasion in which a hepatocellular carcinoma is diagnosed during pregnancy, management is individualized and varies depending on gestational age and patient preference. There are reports both of termination of pregnancy, followed by appropriate surgical treatment, chemotherapy, or ablative therapy as well as surgical resection without chemotherapy during pregnancy with no untoward effects on pregnancy duration or outcome.161

LIVER DISEASE SPECIFIC TO PREGNANCY

Hyperemesis gravidarum

Hyperemesis gravidarum is a condition of severe nausea and vomiting associated with early pregnancy. It is characterized by persistent vomiting, weight loss of more than 5%, ketonuria, electrolyte abnormalities, and dehydration.162 It complicates 0.3–2% of pregnancies.163 Known risk factors for the development of hyperemesis gravidarum include twin or molar pregnancy, diabetes, hyperthyroidism, and psychiatric disease.164 Approximately 20% of cases will be associated with elevated aminotransferases. Although most commonly such elevations are mild, jaundice can be a feature (bilirubin <4 mg/dL) and ALT and AST can increase to levels upwards of 20 times the upper limit of normal.165, 166 In the latter situation, it would be appropriate to consider other conditions in the differential diagnosis including biliary tract disease, viral hepatitis and pregnancy-related diseases. Liver enzymes should return to normal when hyperemesis gravidarum is successfully treated.165 Rare maternal complications are peripheral neuropathies due to vitamin B6 and B12 deficiency and Wernicke´s encephalopathy due to vitamin B1 deficiency.162 Treatment of hyperemesis gravidarum is supportive with correction of dehydration and electrolyte disturbance, antiemetic therapy and prevention and treatment of complications.167


Intrahepatic cholestasis of pregnancy

Intrahepatic cholestasis of pregnancy (ICP) predominantly affects women in the third trimester, although symptoms also may become manifest as early as the first trimester. It is characterized by cholestasis (pruritus and elevated serum bile acids) late in pregnancy. In general, ICP is a rare disorder, affecting 1 in 1000–10,000 pregnancies worldwide.168 However, there is a much higher incidence in Scandinavia (1–2%) and Chile (14%); in the latter, native Araucanians (24%) are preferentially affected.168, 169 The condition recurs in 60–70% of subsequent pregnancies170 and is more common in multiple gestation pregnancies. Environmental factors also seem to play a role, with a decreased incidence in Scandinavia in winter months.171

The etiology of ICP is not well defined though current evidence illustrates several factors, including subclinical bile transporter defects, likely contribute to its pathogenesis. Its occurrence late in pregnancy and correlation with rising hormone levels in addition to a higher prevalence in twin gestations suggest that sex hormones may be an important influential factor. Estrogen and progesterone have known effects on bile transport such as inhibition of the bile salt export pump.172, 173 Estrogen can alter biliary excretion in normal subjects, and patients with a history of ICP show an exaggerated response.174 However, ICP only recurs in up to 70% of subsequent pregnancies suggesting that there are likely additional factors that play a role in the development of the disease. Studies of high-prevalence populations have suggested an autosomal-dominant pattern of inheritance.175 This finding, along with the observation that women with ICP are more likely to have a sister or mother with a history of the disorder, suggests a genetic predisposition for the disease.176 MDR3, a phospholipid transporter on the biliary canalicular membrane, has been associated with ICP and several mutations in this gene (ABCB4) have been uncovered in patients with ICP and such cases may account for up to 15% of cases of ICP.177, 178, 179 Furthermore, genes encoding other canalicular transport proteins or their regulator may also play a role in the pathogenesis of ICP.180, 181 In addition, seasonal variation and dietary factors such as selenium deficiency have been reported.182

The diagnosis of ICP is one of exclusion and cannot be made without first ruling out viral hepatitis, drug reaction, or, in severe cases, HELLP syndrome. Pruritus, a primary feature of ICP, is unlikely in these other conditions and can suggest the possibility of exacerbation of a preexisting biliary process such as primary biliary cirrhosis. Right upper quadrant ultrasound examination should be performed to exclude evidence of biliary tract dilation. Patients with ICP appear to be at increased risk for the development of cholelithiasis.183 If present, further investigation and potentially treatment is warranted. Urinary tract infections also are more likely in cases of ICP, with treatment of urinary tract infection in some patients improving pruritus and biochemical markers.184, 185

Clinical expression varies from pregnancy to pregnancy, but the main complaint is pruritus that often begins in the palms and soles extending to the legs and abdomen. Jaundice occurs in approximately 20% of patients and typically is mild.170 In concert with this, bilirubin elevation typically does not exceed 10 mg/dL.170 Aminotransferases can be mildly elevated or dramatically elevated with levels up to 20-fold the upper limit of normal. The AP levels also may be increased, but the difficulty in evaluating mildly elevated AP levels in pregnancy has already been discussed. Although some patients show significant elevations in GGT and 5'-nucleotidase, levels usually are normal to only mildly elevated.171 Elevation in serum bile acids (>10 μmol/L) is the most sensitive and specific marker for ICP, and levels can exceed 100 times the upper limit of normal.186 Abdominal pain is unusual, and most patients appear clinically well; however, nocturnal pruritus and insomnia may cause increasing distress to the expectant mother. Anorexia, nausea, vomiting, and diarrhea also may be reported by some patients. Pruritus should resolve within days of delivery and laboratory abnormalities within 2–4 weeks.170

Liver biopsy, only rarely needed for diagnosis, shows evidence of “bland” cholestasis, with canalicular bile plugs, intracellular bile pigment, and scant evidence of inflammatory reaction. Electron microscopy shows dilated canaliculi, loss of microvilli, and thickening of the pericanalicular filamentous network.187

Antihistamines have been used to control pruritus, but they are typically only minimally effective and have not been shown to improve the laboratory abnormalities. Cholestyramine, 8–16 g/day in divided doses, is a treatment option for the ICP-related pruritus and has been shown to improve symptoms.188 However, recent studies have shown that cholestyramine does not significantly decrease aminotransferases, gamma-glutamyl transpeptidase or bile acid levels, and that UDCA is more effective in pruritus relief.189, 190 Care must be taken when using cholestyramine, as malabsorption of other medications or fat-soluble vitamins is common. Both ICP (via cholestasis) itself and cholestyramine (binding) can lead to vitamin K malabsorption, deficiency and subsequent coagulopathy in both the mother and the fetus.191 Therefore, vitamin K administration along with cholestyramine therapy seems a reasonable option; though, there are no studies performed to support this practice.189 Cholestyramine also may worsen constipation, a common problem in pregnancy. However, because of the lack of proven efficacy of cholestyramine in this setting as well as common side-effects, its use in ICP remains somewhat controversial.

UDCA is the treatment of choice for ICP. UDCA is a hydrophilic bile acid that induces changes in the bile acid pool, making it more hydrophillic and hence less hepatotoxic. It is generally considered safe in typical doses of 12–15 mg/kg and has shown efficacy in controlling symptoms and reducing bile acid levels in women with ICP.192, 193, 194, 195 It should be noted that although no adverse fetal effects have been reported in humans receiving UDCA therapy, animal studies have suggested possible cytotoxic and embryotoxic effects.196, 197 Further investigation is necessary to determine the risk to the human fetus, since initiation of therapy often occurs after organogenesis has been completed. Randomized controlled trials have shown UDCA to be effective in the control of symptoms as well as improvement in fetal outcome.198, 199 Furthermore, UDCA is more effective to decrease pruritus and to improve liver test and serum bile acids, when compared to placebo, cholestyramine and dexamethasone.190, 200, 201 Dexamethasone has been shown to improve both pruritus scores and bile acid levels,202 though it is less effective than UDCA.200 However, there has been a report of dramatic worsening of a patient's condition after beginning therapy.203 More investigation into the safety of dexamethasone is necessary before its acceptance for widespread use.

Management of the patient with ICP not only involves symptomatic treatment but also close monitoring and early delivery of the fetus if necessary. The highest risk in this condition is not to the mother, but to the fetus. Contrary to earlier beliefs, ICP conveys higher rates of fetal distress, spontaneous preterm delivery, thick meconium, and perinatal morbidity and mortality.204, 205, 206 The exact mechanism is not known but likely relates to increased levels of maternal and fetal bile acid levels.207 Regarding to the respiratory fetal distress, it appears to be related to the entering of bile acids into the lung.208

Monitoring for chronic placental insufficiency is very important. Reliable predictors of fetal outcome are lacking in ICP and 60% of children are born preterm from mothers with ICP. Fetal deaths are not predicted by antepartum fetal nonstress testing, suggesting a more acute cause of fetal loss.206, 209, 210, 211 Some authors suggest that the cause of the fetal sudden death is a fetal cardiac event; in fact, one recent study found that ICP was associated with an increase in the fetal PR interval.212 A large Swedish study with 693 cases of ICP showed that fetal complications correlated with maternal bile acid levels, particularly when levels exceeded 40 μmol/L.213 UDCA has been shown to improve bile acid transport across the placenta and decrease endogenous bile acid levels in colostrum, while not adversely affecting bile acid concentrations in meconium.198, 214, 215, 216 Larger studies are necessary to determine whether the changes in bile acid concentrations translate into positive effects on fetal morbidity and mortality. Early delivery has been shown to decrease fetal morbidity and mortality, and is used frequently once fetal lung maturity has been ensured. However, so far there is no consensus whether delivery should be at 37 or 38 weeks of gestation, or earlier. One retrospective study reported that delivering at 37 weeks was associated with low risk of adverse outcomes.217 In general, maternal outcome is good. However, care must be given to minimize the morbidity associated with nocturnal pruritus, nausea, and vomiting in the expectant mother so that excessive malabsorption and subsequent malnutrition are avoided. In addition, the physician should be aware of possible vitamin K deficiency and coagulopathy, especially at the time of delivery. Interestingly, a study showed that intrahepatic cholestasis might be a predictor for the development of biliary and liver disease in the future, thus follow-up should be considered for these patients.218

Acute fatty liver of pregnancy

Nonalcoholic fatty liver disease, the most common cause of abnormal aminotransferases, is associated with macrovesicular hepatic steatosis. In contrast, AFLP results in microvesicular hepatic steatosis which presents in a more acute fashion. The differential diagnosis of acute hepatic failure in the third trimester of pregnancy includes AFLP, HELLP, and acute viral hepatitis, the latter of which can typically be excluded serologically. Given the potential severity of these diagnoses, a high index of suspicion and understanding of each of these entities is paramount to a successful outcome. AFLP was first described in 1934 as "yellow acute atrophy of the liver" and then recognized as a discrete clinical entity in 1940.219 AFLP is a fascinating and serious disease that likely involves an interplay between genetic defects in the fetus and mother. It typically manifests in the third trimester with liver failure and mental status changes, though its appearance in the late second trimester has been reported. Although it never develops after delivery, the diagnosis can be delayed in some patients who present with jaundice in the postpartum period. Approximately half of patients with AFLP have preeclampsia. Its presentation may range from mild biochemical abnormalities to fulminant hepatic failure. It is an important diagnosis to establish in view of urgent therapeutic decisions that must be made.

Although the exact mechanism of liver injury still is unknown, great advances have been made in understanding the pathophysiology of AFLP. Many cases of AFLP are linked to fetal defects in mitochondrial fatty acid oxidation. Defects in two key mitochondrial beta-oxidation enzymes; the mitochondrial trifunctional protein and its alpha subunit, long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) result in microvesicular hepatic steatosis.220 Several mutations of these enzymes have been associated with AFLP and HELLP syndrome, however, the G1548C LCHAD mutation, inherited in an autosomal-recessive fashion, has most commonly been implicated.221, 222 LCHAD deficiency has been observed in only 20% of babies born to mothers with AFLP. Conversely, in a study of children with LCHAD deficiency, 67% of their mothers developed either AFLP or HELLP during pregnancy.223 One explanation is that heterozygous mothers pregnant with homozygous fetuses manifest more a profound inability to properly metabolize long-chain fatty acids in the liver and placenta.223 This interaction, in conjunction with the increased metabolic stress of pregnancy, leads to excessive concentrations of toxic fetal metabolites crossing the placental barrier and causing maternal hepatic injury. Additionally, maternal mitochondrial oxidation of fatty acids is decreased during late pregnancy, likely secondary to ultrastructural changes in the mitochondria induced by elevated levels of sex hormones.220 Another less well known fetal deficiency, hepatic carnitine palmitoyltransferase I, may be seen in the setting of AFLP.224

The incidence of AFLP has been estimated to range from approximately 1 per 7000 deliveries to 1 per 16,000.225, 226 Two recent studies, one from the United Kingdom and the other from The Netherlands, reported an incidence of AFLP of 5 and 3.2 per 100,000 deliveries, respectively.227, 228 In contrast to HELLP, AFLP occurs in nulliparous women 40–50% of the time and has a higher incidence in twin gestations.229, 230, 227 Some have suggested that a low BMI may be related to the occurrence of the disease.227 Although once believed not to recur in subsequent pregnancies, there have been several reports of recurrence of the condition in some women.229, 231, 232, 233 Therefore, women with a history of AFLP should be monitored closely for recurrence in the third trimester of subsequent pregnancies.

Presenting symptoms include nausea or vomiting, epigastric pain, anorexia, or jaundice. Hepatic impairment is variable and ranges from mild to fulminant hepatic failure. Jaundice typically is mild and may be absent completely with early diagnosis. Headaches are common, and altered sensorium may be noted on presentation as well. Approximately half of the patients with AFLP show clinical signs of preeclampsia, namely hypertension, proteinuria, and peripheral edema.229 Pruritus usually is not a feature of AFLP and may suggest another cholestatic process such as ICP.226, 229

Laboratory test results show mild hyperbilirubinemia without gross evidence of hemolysis. Serum aminotransferases rarely are elevated above 300 IU/mL. A marked prolongation of the prothrombin time, unresponsive to vitamin K, signals hepatic insufficiency and poor outcome. Leukocytosis and thrombocytopenia may be present. Any patient in whom thrombocytopenia develops in the third trimester should be evaluated closely for AFLP and HELLP. A decrease in the serum fibrinogen and a rise in fibrin split products may signal the presence of disseminated intravascular coagulation. Hyperuricemia, rarely present, may be caused by tissue destruction and a decrease in renal function. Hyperammonemia and hypoglycemia may also be present and are markers of severe disease.

Radiographically, macrovesicular fatty infiltration of the liver is reflected by increased echogenicity on ultrasound, increased T-1 weighted signal on MRI or decreased attenuation on computed tomography (CT) when compared with the spleen, or prior studies, however, radiographic evidence of microvesicular steatosis as seen in AFLOP can be more elusive.234, 235 One recent study compared both methods for AFLP diagnosis, ultrasound and CT, showing no significant difference between them.236, 237

Although liver biopsy is considered the gold standard for the diagnosis, this is rarely necessary.238 Usually the AFLP diagnosis is made clinically, supported by compatible laboratory results and imaging tests. In 2002 Ch’ng et al. proposed the Swansea criteria for the AFLP diagnosis but, despite its good negative predictive value as a screening tool, it is not yet generally accepted.239, 240 Histologically, there is little evidence of widespread necrosis, although scattered areas of necrosis may be present.241 On hematoxylin-eosin stain, the hepatic cells are enlarged and contain clear vacuoles that do not displace the nucleus and give the cytoplasm a foamy appearance. Unlike other causes of microvesicular hepatic steatosis such as Reye's syndrome, carnitine deficiency, Jamaican vomiting sickness, and certain drug toxicities, AFLP resolves fairly rapidly with delivery.230, 242

AFLP is an obstetric emergency. It does not resolve spontaneously, and delayed delivery exposes the mother and fetus to an increased risk of death. Early delivery is therefore crucial in the management of AFLP. If no fetal or maternal distress exists, vaginal delivery may be attempted; however, cesarean delivery is warranted in the acute setting.243 Other treatment is mainly supportive, with the level of care being set by the degree of hepatic dysfunction. When any signs of liver failure are present (altered mental status, elevated INR) the patient needs to be monitored in an intensive care unit and evaluated expeditiously at a transplant center in addition to prompt delivery of the fetus. In patients with hepatic failure, special attention must be paid to respiratory status, the prevention of infection and gastrointestinal tract hemorrhage. Qiang Wei and colleagues report that in 353 cases of AFLP, multiple organ failure was the most common cause of death (70.1%).237 Furthermore, in the setting of advanced coma, cerebral herniation from elevation in intracranial pressure is the most common cause of death. Patients should be monitored and managed if intracranial hypertension develops, by an experienced center. At times the risk of surges in intracranial pressure continue into the postpartum period, thus patients should be monitored until clinically stable. In extreme cases, liver transplantation may be necessary.244, 245 For the surviving mother, complete hepatic recovery is expected. However, because of the risk of an associated fatty acid oxidation defect in the child, closer monitoring is warranted. Identification of fatty acid β oxidation defects in the child may be obtained from cultured skin fibroblasts.246 In those that manifest a defect in fatty acid oxidation, mortality remains high without appropriate dietary management.247

Advances in both adult and neonatal intensive care as well as earlier recognition have allowed a great reduction in the mortality once associated with AFLP. The maternal mortality rate, greater than 90% in 1970,229 has been decreased to less than 10% with prompt intervention and delivery. Similarly, fetal mortality has been reduced significantly from approximately 50% quoted before 1985.229, 248 In the UK study previously mentioned, Knight and colleagues reported one death among 57 pregnant women with AFLP (maternal mortality of 1.8%), and seven fetal deaths among 67 infants (perinatal mortality rate of 104 per 1000 births), demonstrating that maternal and fetal outcomes in AFLP have improved.227


Hemolysis, elevated liver enzymes, and low platelets syndrome

A range of hepatic abnormalities have been reported in preeclampsia/eclampsia and one of its more severe forms, the syndrome of hemolysis (H), elevated liver enzymes (EL), and low platelets (LP) or HELLP.249 Diagnosis requires the presence of all three features. HELLP develops in up to 20% of cases of severe preeclampsia, but can occur in the absence of preeclampsia and in 0.2–0.6% of pregnancies overall.250, 251 It is more common in multiparous, older women. There is a significant degree of overlap in the presentations of HELLP syndrome, hemolytic uremic syndrome, thrombotic thrombocytic purpura, and AFLP. It typically presents between 27 and 36 weeks' gestation though a quarter of patients will be diagnosed in the postpartum period.250

Ninety per cent of patients experience fatigue or malaise prior to seeking medical attention. One-half to two-thirds report epigastric or right upper quadrant pain. Fifty per cent report nausea, vomiting, or headache.252, 253, 254 The degree of elevation of aminotransferases reported has been variable.255, 256, 257 Jaundice usually is mild, and if more severe, should raise the suspicion of another process, though higher values of bilirubin may be observed.255 Other laboratory findings are high levels of LDH (due to hemolysis) and low platelet count.258 There are two recognized classification systems for HELLP: the Tennessee system and the Mississippi system, which include levels of AST, LDH and platelets in their criteria.258, 259

HELLP is characterized by a microangiopathic hemolytic anemia associated with vascular endothelial injury that promotes the deposition of fibrin in the vessel lumen. Liver biopsy confirms periportal fibrin deposits.260 Even in asymptomatic cases, perisinusoidal deposits of fibrinogen may be observed. Fatty infiltration occasionally may be seen in the periportal region.261 In more dramatic cases, the periportal fibrin deposits may extend and result in either subcapsular hematomas or overt hepatic rupture, which occurs in 1–2% of HELLP cases and carries a 50% maternal and 10–60% fetal mortality.262, 263 In the latter, abdominal pain and shock quickly ensue, and emergent laparotomy with packing of the affected area is mandatory. Serious maternal complications are common and include disseminated intravascular coagulation, placental abruption, pulmonary edema, retinal detachment, as well as acute liver and renal failure. The maternal mortality rate ranges from 0 to 30%.264 Common fetal complications include fetal growth restriction, oligohydramnios and death; the latter most commonly due to intrauterine asphyxia related to shock or placental rupture or prematurity. Perinatal mortality is approximately 11%.

The only effective management strategy is urgent delivery which results in resolution of symptoms within 5 days of delivery. If severe liver dysfunction occurs, patients should ideally be managed in a tertiary care center with a liver transplant program. Most patients, if not delivered, will deteriorate in 1–10 days and have a high rate of fetal demise or severe maternal complications. Treatment involves management of the hypertension, prevention of eclampsia (with magnesium sulfate) and correction of coagulation abnormalities, if needed. Many treatments have been attempted, but no rigorous clinical trials have supported their efficacy. The use of corticosteroids in the management of HELLP has not shown improvements on substantive clinical outcomes.265 In the exceptional cases of persistent bleeding from hematoma, hepatic rupture or fulminant hepatic failure, liver transplantation has been performed successfully with an 88% survival rate after 5 years.266 The use of corticosteroids (betamethasone or dexamethasone) to accelerate fetal lung maturity earlier than 34 weeks' gestation when delivery is needed has not been proven in good clinical studies, though expert opinion recommends it.

The risk of HELLP recurrence in subsequent pregnancies is not yet clearly established. In a group of 152 women with HELLP syndrome, the risk of obstetric complications in subsequent pregnancies was high, but recurrence of HELLP was low.267 However, in another recent study of 128 women with HELLP syndrome, the risk of HELLP and preeclampsia in subsequent pregnancies were both increased.268

 

SUMMARY

The most important distinction that must be made when initially evaluating a pregnant patient presenting with hepatic abnormalities is whether the clinical picture represents liver disease unrelated to pregnancy, one that occurs with more frequency or severity in pregnancy, or a disease entity specific to pregnancy. Pregnancy can be safe in patients with chronic liver disease and even after liver transplantation though a successful outcome for both mother and fetus depends on the careful attention of both a high risk obstetrician and a hepatologist. Chronic conditions such as portal hypertension can worsen during pregnancy thus necessitating closer follow-up to prevent complications such as a variceal bleeding. Careful monitoring of patients with viral hepatitis helps determine the risk of transmission to the newborn as well as the need for intervention. Liver diseases unique to pregnancy are typically severe, threatening the survival of both mother and fetus if not recognized and managed urgently. Fortunately, most occur later in pregnancy allowing for prompt delivery of the fetus which is often the only effective treatment. 

REFERENCES

1

Braverman DZ, Johnson MC, Kern F Jr: Effects of pregnancy and contraceptive steroids on gallbladder function. N Engl J Med 302: 362, 1980

 

2

Vore M, Liu Y, Huang L: Cholestatic properties and hepatic transport of steroid glucuronides. Drug Metab Rev 29: 183, 1997

 

3

Kullak-Ublick GA, Beuers U, Paumgartner G: Hepatobiliary transport. J Hepatol 32: 3, 2000

 

4

Kern F Jr, Everson GT, Klein PD et al: Biliary lipids, bile acids, and gallbladder function in the human female. Effects of pregnancy and the ovulatory cycle. J Clin Invest 68: 1229, 1981

 

5

Valdivieso V, Corrubias C, Siegal F et al: Pregnancy and cholelithiasis: Pathogenesis and natural course of gallstones diagnosed early in puerperium. Hepatology 17: 1, 1993

 

6

Bozgeyik Z, Ozdemir H, Kocakoc E et al: Hepatic and portal venous Doppler waveforms and flow velocities in normal pregnancy. Med Sci Monit, 2009; 15(12): CR624-627.

 

7

Robson SC, Mutch E, Woodhouse KW et al: Apparent liver blood flow during pregnancy: A serial study using indocyanine green clearance. Br J Obstet Gynaecol 97: 720, 1990

 

8

Bacq Y, Zarca O, Weill J et al: Liver function tests in normal pregnancy: A prospective study of 103 pregnant women and 103 matched controls. Hepatology 23: 1030, 1996

 

9

Rahman TM, Wendon J: Severe hepatic dysfunction in pregnancy. QJM. 2002 Jun;95(6):343-57

 

10

Jamjute P, Ahmad A, Ghosh T: Liver function test and pregnancy. J Matern Fetal Neonatal Med. 2009 Mar;22(3):274-83.

 

11

Girling JC, Dow E, Smith JH: Liver function tests in pre-eclampsia: importance of comparison with a referencerange derived for normal pregnancy. Br J Obstet Gynaecol. 1997 Feb;104(2):246-50.

 PubMed

12

David AL, Kotecha M, Girling JC: Factors influencing postnatal liver function tests. BJOG. 2000 Nov;107(11):1421-6.

 PubMed

13

Szecsi PB, Jørgensen M, Klajnbard A et al: Haemostatic reference intervals in pregnancy. Thromb Haemost. 2010 Apr;103(4):718-27

 

14

Combes B, Shibata H, Adams R et al: Alterations in bromosulphonphthalein sodium-removal mechanisms from blood during pregnancy. J Clin Invest 42: 1431, 1963

 

15

Lunzer M, Barnes P, Byth K et al: Serum bile acid concentrations during pregnancy and their relationship to obstetric cholestasis. Gastroenterology 91: 825, 1986

 

16

Ingerslev M, Teilum G: Biopsy studies on the liver in pregnancy. II. Liver biopsy in normal pregnant women. Acta Obstet Gynecol Scand 25: 352, 1945

 

17

Lieber CS: Alcoholic liver disease: New insights in pathogenesis lead to new treatments. J Hepatol 32: 113, 2000

 

18

Elinav E, Ben-Dov IZ, Shapira Y, et al: Acute hepatitis A infection in pregnancy is associated with high rates of gestational complications and preterm labor. Gastroenterology 2006; 130(4): 1129-1134

 

19

Ryu HS, Park SY, Lim SR: Clinical characteristics and gestational complications associated with acute hepatitis a in pregnancy. Korean J Gastroenterol 2010 Nov; 56(5):307-13

 

20

Duff B, Duff P: Hepatitis A vaccine: Ready for prime time. Obstet Gynecol 91: 468, 1998

 

21

Hyams KC: Risk of chronicity following acute hepatitis B virus infection: A review. Clin Infect Dis 20: 992, 1995

 

22

Rustgi VK, Hoofnagle JH: Viral hepatitis during pregnancy. Semin Liver Dis 7: 40, 1987

 

23

Pastorek JG, Miller JM Jr, Summers PR: The effect of hepatitis B antigenemia on pregnancy outcome. Am J Obstet Gynecol 165: 152, 1988

 

24

Lin HH, Chen PJ, Lee TY et al: Postpartum subsidence of hepatitis B viral replication in HbeAg-positive carrier mothers. J Med Virol 29: 1, 1989

 

25

Degertekin B, Lok AS: Indications for therapy in hepatitis B.Hepatology. 2009;49(5 Suppl):S129

 

26

Potthoff A, Rifai K, Wedemeyer H et al: Successful treatment of fulminant hepatitis B during pregnancy. Z Gastroenterol. 2009;47(7):667

 

27

Yu M, Ji Y, Jiang H et al: Efficacy of peripartum antiviral treatment for hepatic failure due to hepatitis B virus. Int J Gynaecol Obstet. 2011 Jul;114(1):33-6

 

28

Ingardia CJ, Kelley L, Wax JR et al: Hepatitis B vaccination in pregnancy: Factors influencing efficacy. Obstet Gynecol 93: 983, 1999

 

29

Floreani A, Paternoster D, Zappala F et al: Hepatitis C virus infection in pregnancy. Br J Obstet Gynecol 103: 325, 1996

 

30

Gervais A, Bacq Y, Bernuau J et al: Decrease in serum ALT and increase in serum HCV RNA during pregnancy in women with chronic hepatitis C. J Hepatol. 2000 Feb;32(2):293-9

 

31

Wejstål R, Widell A, Norkrans G: HCV-RNA levels increase during pregnancy in women with chronic hepatitis C. Scand J Infect Dis. 1998;30(2):111-3

 

32

Dilwari JB, Singh K, Chawla YK et al: Hepatitis E virus: Epidemiological, clinical and serological studies of north Indian epidemic. Indian J Gastroenterol 13: 44, 1994

 

33

Khuroo MS, Teli MR, Khuroo M et al: Incidence and severity of viral hepatitis in pregnancy. Am J Med 70: 252, 1981

 

34

Kar P, Jilani N, Husain SA et al: Does hepatitis E viral load and genotypes influence the final outcome of acute liver failure during pregnancy? Am J Gastroenterol. 2008;103(10):2495-501

 

35

Shrestha MP, Scott RM, Joshi DM et al: Safety and efficacy of a recombinant hepatitis E vaccine. N Engl J Med. 2007 Mar 1;356(9):895-903.

 PubMed

36

Zhu FC, Zhang J, Zhang XF et al: Efficacy and safety of a recombinant hepatitis E vaccine in healthy adults: a large-scale, randomised, double-blind placebo-controlled, phase 3 trial. Lancet. 2010;376(9744):895

 

37

Duff P: Hepatitis in pregnancy. Semin Perinat 22: 277, 1998

 

38

American Academy of Pediatrics. Hepatitis A. In: Red Book: 2009 Report of the Committee on Infectious Diseases, 28th ed, Pickering, LK (Ed), American Academy of Pediatrics, Elk Grove Village, IL, 2009. p. 326

 

39

Committee on Infectious Diseases: Prevention of hepatitis A infections: guidelines for use of hepatitis A vaccine and immune globulin. American Academy of Pediatrics. Pediatrics. 1996 Dec;98(6 Pt 1):1207-15

 

40

Beasley RP, Stevens CE, Meng HC et al: Evidence against breast feeding as a mechanism for vertical transmission of hepatitis B. Lancet 2: 740, 1975

 

41

Shi Z, Yang Y, Wang H: Breastfeeding of Newborns by Mothers Carrying Hepatitis B Virus: A Meta-analysis and Systematic Review. Arch Pediatr Adolesc Med. 2011 May 2

 

42

Beasley RP, Trepo C, Szumuness W et al: The e antigen and vertical transmission of hepatitis B surface antigen. Am J Epidemiol 105: 94, 1977

 

43

Stevens CE, Neurath RA, Szumuness W et al: HbeAg and anti-Hbe detection by radioimmunoassay: Correlation with vertical transmission of hepatitis B virus in Taiwan. J Med Virol 3: 237, 1979

 

44

Burk RD, Hwang LY, Ho GY et al: Outcome of perinatal hepatitis B virus exposure is dependent on maternal virus load. J Infect Dis. 1994;170(6):1418

 

45

Wiseman E, Fraser MA, Holden S et al: Perinatal transmission of hepatitis B virus: an Australian experience. Med J Aust. 2009;190(9):489

 

46

Okada K, Kamiyama I, Mayumi M et al: e Antigen and anti-e in the serum of asymptomatic carrier mothers as indicators of positive and negative transmission of hepatitis B virus to their infants. N Engl J Med 294: 746, 1976

 

47

Terazawa S, Kojima M, Mayumi M et al: Hepatitis B virus mutants with pre-core region defects in two babies with fulminant hepatitis and their mothers positive for antibody to hepatitis Be antigen. Ped Res 29: 5, 1991

 

48

Centers for Disease Control: Hepatitis B: A comprehensive strategy for eliminating transmission in the United States through universal childhood vaccination: Recommendation of the Immunization Practices Advisory Committee (ACIP). MMWR 40:1, 1991

 

49

American College of Obstetricians and Gynecologists: Hepatitis in pregnancy. ACOG Tech Bull 174:1, 1992

 

50

Centers for Disease Control: Protection against viral hepatitis: Recommendations of the Immunization Practices Advisory Committee. MMWR 39:1, 1990

 

51

Hoofnagle JH: Chronic hepatitis B. N Engl J Med 323: 337, 1990

 

52

Lemon SM, Thomas DL: Vaccines to prevent viral hepatitis. N Engl J Med 336: 196, 1997

 

53

Beasley RP, Hwang LY, Chen CL et al: Prevention of perinatally transmitted hepatitis B virus infections with hepatitis B immune globulin and hepatitis B vaccine. Lancet 2: 1099, 1983

 

54

Beasley RP, Hwang LY, Sun TS et al: Efficacy of hepatitis B immune globulin for prevention of perinatal transmission of the hepatitis B virus carrier state: Final report of a randomized double-blind, placebo-controlled trial. Hepatology 3: 135, 1983

 

55

Beasley RP, Hwang LY, Szmuness W et al: Hepatitis B immune globulin (HBIG) efficacy in the interruption of perinatal transmission of hepatitis B carrier state. Lancet 2: 388, 1981

 

56

Shi Z, Li X, Ma L et al: Hepatitis B immunoglobulin injection in pregnancy to interrupt hepatitis B virus mother-to-child transmission-a meta-analysis. Int J Infect Dis. 2010;14(7):e622-34

 

57

Li XM, Shi MF, Yang YB et al: Effect of hepatitis B immunoglobulin on interruption of HBV intrauterine infection. World J Gastroenterol. 2004;10:3215-7

 

58

Xiao XM, Li AZ, Chen X et al: Prevention of vertical hepatitis B transmission by hepatitis B immunoglobulin in the third trimester of pregnancy. Int J Gynaecol Obstet. 2007;96:167-70

 

59

Xu WM, Cui YT, Wang L et al: Lamivudine in late pregnancy to prevent perinatal transmission of hepatitis B virus infection: a multicentre, randomized, double-blind, placebo-controlled study. J Viral Hepat. 2009;16(2):94-103

 

60

Shi Z, Yang Y, Ma L et al: Lamivudine in late pregnancy to interrupt in utero transmission of hepatitis B virus: a systematic review and meta-analysis. Obstet Gynecol. 2010 Jul;116(1):147-59

 

61

Tran TT: Management of hepatitis B in pregnancy: weighing the options. Cleve Clin J Med. 2009;76 Suppl 3:S25-9

 

62

Köse S, Türken M, Devrim I et al: Efficacy and safety of lamivudine treatment in late pregnancy with high HBV DNA: a perspective for mother and infants. J Infect Dev Ctries. 2011 Apr 26;5(4):303-6

 

63

Pan C, Han GR, Zhao W et al: A prospective open-label study to evaluate the efficacy, safety and tolerability of telbuvidine (Ltd) in HBeAg+Chronic Hepatitis B (CHB) pregnant women. Hepatology 2010;52(Suppl 1):500A

 

64

Han GR, Cao MK, Zhao W et al: A prospective and open-label study for the efficacy and safety of telbivudine in pregnancy for the prevention of perinatal transmission of hepatitis B virus infection. J Hepatol. 2011 Apr 15. [Epub ahead of print]

 

65

Conte D, Fraquelli M, Minola E et al: Prevalence and clinical course of chronic hepatitis C virus (HCV) infection and rate of HCV vertical transmission in a cohort of 15,250 pregnant women. Hepatology 31: 751, 2000

 

66

Indolfi G, Resti M: Perinatal transmission of hepatitis C virus infection. J Med Virol. 2009;81(5):836-43

 

67

Airoldi J, Berghella V: Hepatitis C and pregnancy. Obstet Gynecol Surv. 2006;61(10):666-72

 

68

Giovannini M, Tagger A, Ribero ML et al: Maternal-infant transmission of hepatitis C virus and HIV infection: A possible interaction. Lancet 335: 1166, 1990

 

69

Ohto H, Terazawa S, Sasaki N et al: Transmission of hepatitis C virus from mothers to infants. N Engl J Med 330: 744, 1994

 

70

Ngo-Giang-Huong N, Jourdain G, Sirirungsi W et al: Human immunodeficiency virus-hepatitis C virus co-infection in pregnant women and perinatal transmission to infants in Thailand. Int J Infect Dis. 2010;14(7):e602-7

 

71

Lin HK, Kao JH, Chen DS et al: Absence of infection in breast-fed infants born to hepatitis C virus-infected mothers. J Pediatr 126: 589, 1995

 

72

Khuroo MS, Kamili S, Jameel S: Vertical transmission of hepatitis E virus. Lancet 345: 1025, 1995

 

73

Khuroo MS, Kamili S, Khuroo MS, J Clinical course and duration of viremia in vertically transmitted hepatitis E virus (HEV) infection in babies born to HEV-infected mothers. Viral Hepat. 2009;16(7):519-23

 

74

Khuroo MS, Dar MY: Hepatitis E: evidence for person-to-person transmission and inability of low dose immune serum globulin from an Indian source to prevent it. Indian J Gastroenterol. 1992;11(3):113

 

75

Date RS, Kaushal M, Ramesh A: A review of the management of gallstone disease and its complications in pregnancy. Am J Surg. 2008 Oct;196(4):599-608

 

76

Ghumman E, Barry M, Grace PA: Management of gallstones in pregnancy. Br J Surg 84: 1646, 1997

 

77

Dhupar R, Smaldone GM, Hamad GG: Is there a benefit to delaying cholecystectomy for symptomatic gallbladder disease during pregnancy? Surg Endosc. 2010 Jan;24(1):108-12

 

78

Jelin EB, Smink DS, Vernon AH et al: Management of biliary tract disease during pregnancy: a decision analysis. Surg Endosc. 2008 Jan;22(1):54-60

 

79

Lee S, Bradley JP, Ludmir J et al: Cholelithiasis in pregnancy: Surgical versus medical management. Obstet Gynecol 95: S70, 2000

 

80

Barone JE, Bears S, Russel JC et al: Outcome study of cholecystectomy during pregnancy. Am J Surg 177: 232, 1999

 

81

Chong VH, Jalihal A: Endoscopic management of biliary disorders during pregnancy. Hepatobiliary Pancreat Dis Int. 2010 Apr;9(2):180-5

 

82

Tang SJ, Mayo MJ, Rodriguez-Frias E et al: Safety and utility of ERCP during pregnancy. Gastrointest Endosc. 2009 Mar;69(3 Pt 1):453-61

 

83

Parikh-Patel A, Gold E, Utts J et al: The association between gravidity and primary biliary cirrhosis. Ann Epidemiol. 2002 May;12(4):264-72.

 PubMed

84

Howel D, Fischbacher CM, Bhopal RS et al: An exploratory population-based case-control study of primary biliary cirrhosis. Hepatology. 2000 May;31(5):1055-60.

 PubMed

85

Poupon R, Chretien Y, Chazouilleres O et al: Pregnancy in women with ursodeoxycholic acid-treated primary biliary cirrhosis. J Hepatol. 2005 Mar;42(3):418-9.

 PubMed

86

Heathcote EJ: Management of primary biliary cirrhosis. The American Association for the Study of Liver Diseases practice guidelines. Hepatology. 2000;31(4):1005-13

 

87

Poupon R, Chretien Y, Chazouilleres O et al: Pregnancy in women with ursodeoxycholic acid-treated primary biliary cirrhosis. J Hepatol 2005; 42: 418-419

 

88

Lee NM, Brady CW: Liver disease in pregnancy. World J Gastroenterol. 2009;15(8):897-906

 

89

Cohen L, Lewis C, Arias IM: Pregnancy, oral contraceptives and chronic familial jaundice with predominantly conjugated hyperbilirubinemia (Dubin-Johnson syndrome). Gastroenterology 62: 1182, 1972

 

90

Romero R, Reue EA, Riely CA et al: Arteriohepatic dysplasia in pregnancy. Am J Obstet Gynecol 147: 108, 1983

 

91

Lok AS: Hepatitis B infection: Pathogenesis and management. J Hepatol 32: 89, 2000

 

92

Boyer N, Marcellin P: Pathogenesis, diagnosis and management of hepatitis C. J Hepatol 32: 98, 2000

 

93

Gervais A, Bacq Y, Marcellin P et al: Decrease in serum ALT and increase in serum HCV-RNA during pregnancy in women with chronic hepatitis C. J Hepatol 32: 293, 2000

 

94

Hedley AA, Ogden CL, Johnson CL et al: Prevalence of overweight and obesity among US children, adolescents, and adults, 1999–2002. JAMA 2004;291:2847–2850

 

95

Page L, Girling J: A novel cause for abnormal liver function tests in pregnancy and the puerperium: non-alcoholic fatty liver disease. BJOG. 2011 Aug 22. [Epub ahead of print]

 

96

Obermayer-Straub P, Strassburg CP, Manns MP: Autoimmune hepatitis. J Hepatol 32: 181, 2000

 

97

Colle I, Hautekeete M: Remission of autoimmune hepatitis during pregnancy: A report of two cases. Liver 19: 55, 1999

 

98

Schramm C, Herkel J, Beuers U et al: Pregnancy in autoimmune hepatitis: outcome and risk factors. Am J Gastroenterol 2006; 101: 556-560

 

99

Czaja AJ: Difficult treatment decisions in autoimmune hepatitis. World J Gastroenterol 2010 February 28; 16(8): 934-947

 

100

Steven MM, Buckley JD, Mackay IR: Pregnancy in chronic active hepatitis. Q J Med 48: 519, 1979

 

101

Czaja AJ: Special clinical challenges in autoimmune hepatitis: the elderly, males, pregnancy, mild disease, fulminant onset, and nonwhite patients. Semin Liver Dis. 2009;29(3):315-30

 

102

Candia L, Marquez J, Espinoza LR: Autoimmune hepatitis and pregnancy: a rheumatologist's dilemma. Semin Arthritis Rheum. 2005 Aug;35(1):49-56.

 PubMed

103

Lee NM, Brady CW: Liver disease in pregnancy. World J Gastroenterol. 2009;15(8):897-906

 

104

Brewer GJ: Recognition, diagnosis, and management of Wilson's disease. Proc Soc Exp Biol Med 223: 39, 2000

 

105

Scheinberg IH, Sternlieb I: Pregnancy in penicillamine-treated patients with Wilson's disease. N Engl J Med 293: 1300, 1975

 

106

Elliot JR, O'Kell RT: Normal clinical chemical values for pregnant women at term. Clin Chem 17: 156, 1971

 

107

Walshe JM: Pregnancy in Wilson's disease. Q J Med 46: 73, 1977

 

108

Shimono N, Ishibashi H, Ikematsu H et al: Fulminant hepatic failure during perinatal period in a pregnant woman with Wilson's disease. Gastroenterol Jpn 26: 69, 1991

 

109

Roberts EA, Schilsky ML: Diagnosis and treatment of Wilson disease: an update; American Association for Study of Liver Diseases (AASLD)Hepatology. 2008;47(6):2089-111

 

110

Dempsey OJ, Godden DJ, Danielian PJ et al: Severe alpha-1 antitrypsin deficiency and pregnancy. Eur Respir J 13: 1492, 1999

 

111

Kuller JA, Katz VL, Bristow CL et al: Alpha-1 antitrypsin deficiency and pregnancy. Am J Perinatol 12: 303, 1995

 

112

Bewley AP, Keefe M, White JE: Erythropoietic protoporphyria improving during pregnancy. Br J Dermatol 139: 145, 1998

 

113

Poh-Fitzpatrick MB: Human protoporphyria: Reduced cutaneous photosensitivity and lower erythrocyte porphyrin levels during pregnancy. J Am Acad Dermatol 36: 40, 1997

 

114

Mello NK, Bree MP, Sehgal P et al: Alcohol self-administration disrupts reproductive function in female macaque monkeys. Science 221: 677, 1983

 

115

Lee WM: Pregnancy in patients with chronic liver disease. Gastroenterol Clin North Am 1992;21:889-903

 

116

Tan J, Surti B, Saab S: Pregnancy and cirrhosis. Liver Transpl. 2008 Aug;14(8):1081-91

 

117

Lee W: Pregnancy in patients with chronic liver disease. Gastroenterol Clin North Am 21: 889, 1992

 

118

Hay JE: Liver disease in pregnancy. Hepatology. 2008 Mar;47(3):1067-76.

 PubMed

119

Yip D, Baker A: Liver diseases and pregnancy. Clin Perinatol 12: 683, 1985

 

120

Pajor A, Lehoczky D: Pregnancy in liver cirrhosis. Gynecol Obstet Invest 38: 45, 1994

 

121

Cheng Y: Pregnancy in liver cirrhosis and portal hypertension. Am J Obstet Gynecol 128: 812, 1977

 

122

Varma RR, Michelsohn NH, Borkowf HI et al: Pregnancy in cirrhotic and noncirrhotic portal hypertension. Obstet Gynecol. 1977 Aug;50(2):217-22

 

123

Britton RC: Pregnancy and esophageal varices. Am J Surg. 1982 Apr;143(4):421-5

 

124

Schreyer P, Caspi E, El-Hindi JM: Cirrhosis--pregnancy and delivery: a review. Obstet Gynecol Surv. 1982 May;37(5):304-12

 

125

Schreyer P, Caspi E, Mohamad J et al: Cirrhosis-pregnancy and delivery: A review. Obstet Gynecol 37: 304, 1982

 

126

Vannozzi G, Tozzi A, Chibbaro G et al: Hepatic and mesenteric sarcoidosis without thoracic involvement: a case of severenoncirrhotic portal hypertension and successful pregnancy. Eur J Gastroenterol Hepatol. 2008 Oct;20(10):1032-5.

 PubMed

127

Savage C, Patel J, Lepe MR et al: Transjugular intrahepatic portosystemic shunt creation for recurrentgastrointestinal bleeding during pregnancy. J Vasc Interv Radiol. 2007 Jul;18(7):902-4.

 PubMed

128

Dhiman RK, Biswas R, Chawla Y et al: Management of variceal bleeding in pregnancy with endoscopic variceal ligation and N-butyl-2-cyanoacrylate: Report of three cases. Gastrointest Endosc 51: 91, 2000

 

129

Lodato F, Cappelli A, Montagnani M et al: Transjugular intrahepatic portosystemic shunt: a case report of rescue management of unrestrainable variceal bleeding in a pregnant woman. Dig Liver Dis. 2008;40(5):387-90

 

130

Brown H: Splenorenal shunting during pregnancy. Am Surg 37: 441, 1971

 

131

Salam A, Warren D: Distal splenorenal shunt for the treatment of variceal bleeding during pregnancy. Arch Surg 105: 643, 1972

 

132

Heriot J, Steven C, Sattin R: Elective forceps delivery and extradural anesthesia in a primigravida with portal hypertension and oesophageal varices. Br J Anesth 76: 325, 1996

 

133

Reymond G: Propranolol and fetal growth retardation. Semin Perinatol 6: 142, 1982

 

134

Benjaminov FS, Heathcote J: Liver disease in pregnancy. Am J Gastroenterol 2004;99:2479-2488

 

135

O'Grady J, Day E, Toole A: Splenic artery aneurysm in pregnancy. Obstet Gynecol 50: 627, 1977

 

136

Brass B: Splenic artery rupture during pregnancy. Am J Obstet Gynecol 128: 228, 1977

 

137

Whelton M, Sherlock S: Pregnancy in patients with hepatic cirrhosis: Management and outcome. Lancet 2: 995, 1968

 

138

Casele HL, Laifer SA: Pregnancy after liver transplantation. Semin Perinatol 22: 149, 1998

 

139

Laifer SA, Abu-Elmagd K, Fung JJ: Hepatic transplantation during pregnancy and the puerperium. J Matern Fetal Med. 1997 Jan-Feb;6(1):40-4.

 PubMed

140

Christopher V, Al-Chalabi T, Richardson PD et al: Pregnancy outcome after liver transplantation: a single-center experience of 71pregnancies in 45 recipients. Liver Transpl. 2006 Jul;12(7):1138-43.

 PubMed

141

McKay DB, Josephson MA: Reproduction and transplantation: report on the AST consensus conference on reproductive issues and transplantation. Am J Transpl 2005; 5: 1592–9

 

142

Surti B, Tan J, Saab S: Pregnancy and liver transplantation. Liver Int. 2008 Nov;28(9):1200-6.

 PubMed

143

Sifontis NM, Coscia LA, Constantinescu S et al: Pregnancy outcomes in solid organ transplant recipients with exposure tomycophenolate mofetil or sirolimus. Transplantation. 2006 Dec 27;82(12):1698-702.

 PubMed

144

Coffin CS, Shaheen AA, Burak KW et al: Pregnancy outcomes among liver transplant recipients in the United States: a nationwide case-control analysis. Liver Transpl. 2010;16(1):56-63

 

145

Jain A, Venkataramanan R, Starzl TE et al: Pregnancy after liver transplantation under tacrolimus. Transplantation 64: 559, 1997

 

146

Nagorney DM: Benign hepatic tumors: Focal nodular hyperplasia and hepatocellular adenoma. World J Surg 19: 13, 1995

 

147

Cobey FC, Salem RR: A review of liver masses in pregnancy and a proposed algorithm for their diagnosis and management. Am J Surg. 2004;187(2):181-91

 

148

Kent DR, Nissen ED, Nissen SE et al: Effect of pregnancy on liver tumor associated with oral contraceptives. Obstet Gynecol 51: 148, 1978

 

149

Noels JE, van Aalten SM, van der Windt DJ et al: Management of hepatocellular adenoma during pregnancy. J Hepatol. 2011 Mar;54(3):553-8

 

150

Everson GT, Taylor MR: Management of polycystic liver disease. Curr Gastroenterol Rep. 2005 Feb;7(1):19-25

 

151

Kesby GJ: Pregnancy complicated by symptomatic adult polycystic liver disease. Am J Obstet Gynecol 179: 266, 1998

 

152

Trujillo Carrillo JL, Alvarez M, Padilla A et al: Symptomatic hepatic polycystic disease and pregnancy. BJOG. 2004 Oct;111(10):1146-7.

 PubMed

153

Oettinger M, Levy N, Lewy Z et al: Budd-Chiari syndrome in pregnancy. J Obstet Gynaecol Br Commonw 77:147, 170

 

154

Khuroo MS, Datta DV: Budd-Chiari syndrome following pregnancy: Report of 16 cases, with roengenologic, hemodynamic and histologic studies of the hepatic outflow tract. Am J Med 68: 113, 1980

 

155

Gordon S, Polson D, Shirkhoda A: Budd-Chiari syndrome complicating preeclampsia: Diagnosis by magnetic resonance imaging. J Clin Gastroenterol 13: 460, 1991

 

156

Perarnau JM, Bacq Y: Hepatic vascular involvement related to pregnancy, oral contraceptives, and estrogen replacement therapy. Semin Liver Dis. 2008;28(3):315-27

 

157

Rautou PE, Angermayr B, Raffa S, et al: Maternal and fetal outcome in 27 women with Budd-Chiari syndrome (BCS) and 41 pregnancies. Hepatology 2007;46:563

 

158

Rautou PE, Angermayr B, Garcia-Pagan JC et al: Pregnancy in women with known and treated Budd-Chiari syndrome: maternal and fetal outcomes. J Hepatol. 2009;51(1):47-54

 

159

Lau WY, Leung WT, Li AK et al: Hepatocellular carcinoma during pregnancy and its comparison with other pregnancy-associated malignancies. Cancer 75: 2669, 1995

 

160

Choi KK, Hong YJ, Choi SB et al: Hepatocellular carcinoma during pregnancy: is hepatocellular carcinoma more aggressive in pregnant patients? J Hepatobiliary Pancreat Sci. 2011;18(3):422-31

 

161

Gisi P, Floyd R: Hepatocellular carcinoma in pregnancy: A case report. J Reprod Med 44: 65, 1999

 

162

Niebyl JR: Clinical practice. Nausea and vomiting in pregnancy. N Engl J Med. 2010;363(16):1544-50

 

163

Goodwin TM: Hyperemesis Gravidarum. Obstet Gynecol Clin N Am. 2008;35:401-417

 

164

Fell DB, Dodds L, Joseph KS et al: Risk factors for hyperemesis gravidarum requiring hospital admission duringpregnancy. Obstet Gynecol. 2006 Feb;107(2 Pt 1):277-84.

 PubMed

165

Lee NM, Saha S: Nausea and vomiting of pregnancy. Gastroenterol Clin North Am. 2011;40(2):309-34

 

166

Kuscu NK, Koyuncu F: Hyperemesis gravidarum: current concepts and management. Postgrad Med J. 2002 Feb;78(916):76-9.

 PubMed

167

Sonkusare S: The clinical management of hyperemesis gravidarum. Arch Gynecol Obstet. 2011;283(6):1183-92

 

168

Reyes H: Intrahepatic cholestasis of pregnancy: An estrogen related disease. Semin Liver Dis 13: 289, 1993

 

169

Reyes H: The enigma of intrahepatic cholestasis of pregnancy: Lessons from Chile. Hepatology 2: 87, 1982

 

170

Reyes H: The spectrum of liver and gastrointestinal disease seen in cholestasis of pregnancy. Gastroenterol Clin North Am 21: 905, 1992

 

171

Berg B, Helm G, Tryding N et al: Cholestasis of pregnancy: Clinical and laboratory studies. Acta Obstet Scand 65: 107, 1986

 

172

Beuers U, Pusl T: Intrahepatic cholestasis of pregnancy—a heterogeneous group of pregnancy-related disorders? Hepatology 2006;43(4):647–9

 

173

Pan C, Perumalswami PV: Pregnancy-related liver diseases. Clin Liver Dis. 2011 Feb;15(1):199-208

 

174

Reyes H, Ribalta J, Gonzalez MC et al: Sulfobromophthalein clearance tests before and after ethinyl estradiol administration in men and women with familial histories of intrahepatic cholestasis of pregnancy. Gastroenterology 81: 226, 1981

 

175

Holzbach RT, Sivak DA, Braun WE: Familial recurrent intrahepatic cholestasis of pregnancy: A genetic study providing evidence of transmission of a sex-linked dominant trait. Gastroenterology 85: 175, 1983

 

176

Dalen E, Westerholm B: Occurrence of hepatic impairment in women jaundiced by oral contraceptives and in their mothers and sisters. Acta Med Scand 195: 459, 1994

 

177

Keitel V, Vogt C, Haussinger D et al: Combined mutations of canalicular transporter proteins cause severe intrahepaticcholestasis of pregnancy. Gastroenterology. 2006 Aug;131(2):624-9.

 PubMed

178

Floreani A, Carderi I, Paternoster D et al: Intrahepatic cholestasis of pregnancy: three novel MDR3 gene mutations. Aliment Pharmacol Ther. 2006 Jun 1;23(11):1649-53.

 PubMed

179

Schneider G, Paus TC, Kullak-Ublick GA et al: Linkage between a new splicing site mutation in the MDR3 alias ABCB4 gene andintrahepatic cholestasis of pregnancy. Hepatology. 2007 Jan;45(1):150-8.

 PubMed

180

Sookoian S, Castaño G, Burgueño et al: A Association of the multidrug-resistance-associated protein gene (ABCC2) variants with intrahepatic cholestasis of pregnancy. J Hepatol. 2008;48(1):125

 

181

Dixon PH, van Mil SW, Chambers J et al: Contribution of variant alleles of ABCB11 to susceptibility to intrahepatic cholestasis of pregnancy. Gut. 2009;58(4):537-44

 

182

Reyes H, Baez ME, Gonzalez MC et al: Selenium, zinc and copper plasma levels in intrahepatic cholestasis of pregnancy,in normal pregnancies and in healthy individuals, in Chile. J Hepatol. 2000 Apr;32(4):542-9.

 PubMed

183

Furhoff AK: Itching in pregnancy: A 15-year follow-up study. Acta Med Scand 196: 403, 1974

 

184

Furhoff AK, Hellstrom K: Jaundice in pregnancy: A follow-up study of the series of women originally reported by L. Thorling. I. The pregnancies. Acta Med Scand 193: 259, 1973

 

185

Glasinovic JC, Marinovic I, Vela P et al: Association between urinary infection and cholestasis of pregnancy. Rev Med Chile 110: 547, 1982

 

186

Heikkinen J, Maentausta O, Ylostalo P et al: Changes in serum bile acid concentrations during normal pregnancy, in patients with intrahepatic cholestasis of pregnancy, and in pregnant women with itching. Br J Obstet Gynaecol 88: 240, 1981

 

187

Eliakim M, Sadovsky E, Stein O et al: Recurrent cholestasis jaundice of pregnancy: A report of five cases and electron microscopic observations. Arch Intern Med 117: 696, 1966

 

188

Heikkinen J, Maentausta O, Ylostal OP et al: Serum bile acid levels in intrahepatic cholestasis of pregnancy during treatment with phenobarbital or cholestyramine. Eur J Obstet Gynecol Reprod Biol 14: 153, 1982

 

189

Pathak B, Sheibani L, Lee RH: Cholestasis of pregnancy. Obstet Gynecol Clin North Am. 2010 Jun;37(2):269-82

 

190

Kondrackiene J, Beuers U, Kupcinskas L. Efficacy and safety of ursodeoxycholic acid versus cholestyramine in intrahepatic cholestasis of pregnancy. Gastroenterology 2005;129(3):894–901

 

191

Acuna R, Gonzalez MC: Hypoprothrombinemia and bleeding associated to treatment with cholestyramine. Rev Med Chile 105: 27, 1977

 

192

Galle PR, Theilmann L, Raedsch R et al: Ursodeoxycholate reduces hepatotoxicity of bile salts in primary human hepatocytes. Hepatology 12: 486, 1990

 

193

Floreani A, Paternoster D, Grella V et al: Ursodeoxycholic acid in intrahepatic cholestasis of pregnancy. Br J Obstet Gynaecol 101: 64, 1994

 

194

Palma J, Reyes H, Ribalta J et al: Effects of ursodeoxycholic acid in patients with intrahepatic cholestasis of pregnancy. Hepatology 15: 1043, 1992

 

195

Mazella G, Rizzo N, Sulzetta A et al: Management of intrahepatic cholestasis in pregnancy. Lancet 338: 1594, 1991

 

196

Celle G, Cavanna M, Bocchini R et al: Chenodeoxycholic acid (CDCA) versus ursodeoxycholic acid: A comparison of their effects in pregnant rats. Arch Int Pharmacodyn Ther 246: 149, 1980

 

197

Ward A, Brogden RN, Heel RC et al: Ursodeoxycholic acid: A review of its pharmacologic properties and therapeutic efficacy. Drugs 27: 95, 1984

 

198

Palma J, Reyes H, Silva JJ et al: Ursodeoxycholic acid in the treatment of cholestasis of pregnancy: A randomized, double-blind study controlled with placebo. J Hepatol 27: 1022, 1997

 

199

Glantz A, Reilly SJ, Benthin L et al: Intrahepatic cholestasis of pregnancy: Amelioration of pruritus by UDCA is associated with decreased progesterone disulphates in urine. Hepatology. 2008 Feb;47(2):544-51.

 PubMed

200

Glantz A, Marschall HU, Lammert F et al: Intrahepatic cholestasis of pregnancy: a randomized controlled trial comparing dexamethasone and ursodeoxycholic acid. Hepatology. 2005 Dec;42(6):1399-405.

 PubMed

201

Diaferia A, Nicastri PL, Tartagni M, et al: Ursodeoxycholic acid therapy in pregnant women with cholestasis. Int J Gynaecol Obstet 1996;52(2):133–40

 

202

Hirvioja M-L, Tuimala R: The treatment of intrahepatic cholestasis of pregnancy by dexamethasone. Br J Obstet Gynecol 99: 109, 1992

 

203

Kretowicz E, McIntyre HD: Intrahepatic cholestasis of pregnancy, worsening after dexamethasone. Aust N Z J Obstet Gynecol 34: 211, 1994

 

204

Reid R, Ivey KJ, Rencoret RH et al: Fetal complications of obstetric cholestasis. Br Med J 1: 870, 1976

 

205

Shaw D, Frohlich J, Wittman BA et al: A prospective study of 18 patients with cholestasis of pregnancy. Am J Obstet Gynecol 142: 621, 1982

 

206

Fisk N, Bye KB, Storey GNB: Maternal features of obstetric cholestasis: 20 years experience at King George V hospital. Austr NZ J Obstet Gynecol 28: 172, 1988

 

207

Monte MJ, Morales AI, Arevalo M et al: Reversible impairment of neonatal hepatobiliary function by maternal cholestasis. Hepatology 23: 1208, 1996

 

208

Zecca E, De Luca D, Baroni S et al: Bile acid-induced lung injury in newborn infants: a bronchoalveolar lavage fluid study. Pediatrics. 2008;121(1):e146

 

209

Rioseco A, Ivankovic M, Manzur A et al: Intrahepatic cholestasis of pregnancy: A retrospective case-control study of perinatal outcome. Am J Obstet Gynecol 170: 890, 1994

 

210

Alsulyman OM, Ouzounian JG, Ames-Castro M et al: Intrahepatic cholestasis of pregnancy: Perinatal outcome associated with expectant management. Am J Obstet Gynecol 175: 957, 1996

 

211

Lee RH, Incerpi MH, Miller DA et al: Sudden fetal death in intrahepatic cholestasis of pregnancy. Obstet Gynecol. 2009;113(2 Pt 2):528

 

212

Strehlow SL, Pathak B, Goodwin TM et al: The mechanical PR interval in fetuses of women with intrahepatic cholestasis of pregnancy. Am J Obstet Gynecol. 2010;203(5):455.e1-5

 

213

Glantz A, Marschall HU, Mattsson LA: Intrahepatic cholestasis of pregnancy: Relationships between bile acid levels andfetal complication rates. Hepatology. 2004 Aug;40(2):467-74.

 PubMed

214

Brites D, Rodrigues CMP: Elevated levels of bile acids in colostrum of patients with cholestasis of pregnancy are decreased following ursodeoxycholic acid therapy. J Hepatol 29: 743, 1998

 

215

Serrano MA, Brites D, Marin JJ et al: Beneficial effect of ursodeoxycholic acid on alterations induced by cholestasis of pregnancy in bile acid transport across the human placenta. J Hepatol 28: 829, 1998

 

216

Brites D, Rodrigues CMP, Graca LM et al: Correction of maternal serum bile acid profile during ursodeoxycholic acid therapy in cholestasis of pregnancy. J Hepatol 28: 91, 1998

 

217

Lee RH, Kwok KM, Ingles S et al: Pregnancy outcomes during an era of aggressive management for intrahepatic cholestasis of pregnancy. Am J Perinatol. 2008;25(6):341-5

 

218

Ropponen A, Sund R, Riikonen S et al: Intrahepatic cholestasis of pregnancy as an indicator of liver and biliary diseases: a population-based study. Hepatology. 2006;43(4):723-8

 

219

Sheehan HL: The pathology of acute yellow atrophy and delayed chloroform poisoning. J Obstet Gyneacol Br Emp 47: 49-62, 1940

 

220

Grimbert S, Fisch C, Pessayre D et al: Effects of female sex hormones on mitochondria: Possible role in acute fatty liver of pregnancy. Am J Physiol 268: G107, 1995

 

221

Shames BD, Fernandez LA, Sollinger HW et al: Liver transplantation for HELLP syndrome. Liver Transpl. 2005 Feb;11(2):224-8.

 PubMed

222

Ibdah JA, Bennett MJ, Strauss AW et al: A fetal fatty-acid oxidation disorder as a cause of liver disease in pregnant women. N Engl J Med 340: 1723, 1999

 

223

Sibai BM: Imitators of severe preeclampsia. Obstet Gynecol. 2007 Apr;109(4):956-66.

 PubMed

224

Innes AM, Seargeant LE, Greenberg CR et al: Hepatic carnitine palmitoyltransferase I deficiency presenting as maternal illness in pregnancy. Pediatr Res 47: 43, 2000

 

225

Castro MA, Fassett MJ, Goodwin TM et al: Reversible peripartum liver failure: A new perspective on the diagnosis, treatment, and cause of acute fatty liver of pregnancy, based on 28 consecutive cases. Am J Obstet Gynecol 181: 389, 1999

 

226

Reyes H, Sandoval L, Wainstein A et al: Acute fatty liver of pregnancy: A clinical study of 12 episodes in 11 patients. Gut 35: 101, 1994

 

227

Knight M, Nelson-Piercy C, Kurinczuk JJ et al: A prospective national study of acute fatty liver of pregnancy in the UK. Gut. 2008;57(7):951-6

 

228

Dekker RR, Schutte JM, Stekelenburg J et al: Maternal mortality and severe maternal morbidity from acute fatty liver of pregnancy in the Netherlands. Eur J Obstet Gynecol Reprod Biol. 2011;157(1):27-31

 

229

Bacq Y, Constans T, Body G et al: La steatose hepatique aigue gravidique. J Gynecol Obstet Biol Reprod 15: 851, 1986

 

230

Riely CA: Acute fatty liver of pregnancy. Semin Liver Dis 7: 47, 1987

 

231

Barton JR, Sibai BM, Mabie WC et al: Recurrent acute fatty liver of pregnancy. Am J Obstet Gynecol 163: 534, 1990

 

232

Schoeman MN, Batey RG, Wilcken B: Recurrent acute fatty liver of pregnancy associated with a fatty-acid oxidation defect in the offspring. Gastroenterology 100: 544, 1991

 

233

Dekker RR, Schutte JM, Stekelenburg J et al: Maternal mortality and severe maternal morbidity from acute fatty liver of pregnancy in the Netherlands. Eur J Obstet Gynecol Reprod Biol. 2011;157(1):27-31

 

234

Campillo B, Bernuau J, Witz MO et al: Ultrasonography in acute fatty liver of pregnancy. Ann Intern Med 105: 383, 1986

 

235

Goodacre RL, Hunter DJ, Millward S et al: The diagnosis of acute fatty liver of pregnancy by computed tomography. J Clin Gastroenterol 10: 680, 1988

 

236

Castro MA, Ouzounian JG, Colletti PM et al: Radiologic studies in acute fatty liver of pregnancy: A review of the literature and 19 new cases. J Reprod Med 41: 839, 1996

 

237

Wei Q, Zhang L, Liu X: Clinical diagnosis and treatment of acute fatty liver of pregnancy: a literature review and 11 new cases. J Obstet Gynaecol Res. 2010;36(4):751-6

 

238

Rajasri AG, Srestha R, Mitchell J: Acute fatty liver of pregnancy (AFLP)--an overview. J Obstet Gynaecol. 2007;27(3):237

 

239

Ch’ng CL, Morgan M, Hainsworth I, Kingham JG. Prospective study of liver dysfunction in pregnancy in Southwest Wales. Gut 2002;51:876–80

 

240

Goel A, Ramakrishna B, Zachariah U et al: How accurate are the Swansea criteria to diagnose acute fatty liver of pregnancy in predicting hepatic microvesicular steatosis? Gut. 2011;60(1):138-9; author reply 139-40

 

241

Bacq Y: Acute fatty liver of pregnancy. Semin Perinatol 22: 134, 1999

 

242

Sherlock S: Acute fatty liver of pregnancy and the microvesicular fat diseases. Gut 24: 265, 1983

 

243

Mabie WC: Acute fatty liver of pregnancy. Gastroenterol Clin North Am 21: 951, 1992

 

244

Ockner SA, Brunt EM, Peters MG et al: Fulminant hepatic failure caused by acute fatty liver of pregnancy treated by orthotopic liver transplantation. Hepatology 11: 59, 1990

 

245

Franco J, Newcomer J, Saeian K et al: Auxiliary liver transplant in acute fatty liver of pregnancy. Obstet Gynecol 95: 1042, 2000

 

246

Treem WR, Rinaldo P, Hale DE et al: Acute fatty liver of pregnancy and long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency. Hepatology 19: 339, 1994

 

247

Rinaldo P, Raymond K, Bennett MJ et al: Clinical and biochemical features of fatty acid oxidation disorders. Curr Opin Pediatr 10: 615, 1998

 

248

Riely CA, Latham PS, Romero R et al: Acute fatty liver of pregnancy: A reassessment based on observations in nine patients. Ann Intern Med 106: 703, 1987

 

249

Saphier CJ, Repke JT: Hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome: A review of diagnosis and management. Semin Perinatol 22: 118, 1998

 

250

Sibai BM, Ramadan MK, Friedman SA et al: Maternal morbidity and mortality in 442 pregnancies with hemolysis, elevated liver enzymes, and low platelets. Am J Obstet Gynecol 169: 1000, 1993

 

251

Barton JR, Sibai BM: Diagnosis and management of hemolysis, elevated liver enzymes, and low platelets syndrome. Clin Perinatol. 2004 Dec;31(4):807-33, vii.

 PubMed

252

Schwartz ML, Brenner WE: Pregnancy-induced hypertension presenting with life-threatening thrombocytopenia. Am J Obstet Gynecol 146: 756, 1983

 

253

McKay DG: Hematologic evidence of disseminated intravascular coagulation in eclampsia. Obstet Gynecol Surv 27: 399, 1972

 

254

Martin Jr JN, Files JC, Blake PG et al: Postpartum plasma exchange for atypical preeclampsia-eclampsia as HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome. Am J Obstet Gynecol 164: 1500, 1991

 

255

Weinstein L: Syndrome of hemolysis, elevated liver enzymes, and low platelet count: A severe consequence of hypertension in pregnancy. Am J Obstet Gynecol 142: 159, 1982

 

256

Sibai BM, Taslimi MM, el-Nazer A et al: Maternal-perinatal outcome associated with the syndrome of hemolysis, elevated liver enzymes, and low platelets in severe preeclampsia-eclampsia. Am J Obstet Gynecol 155: 501, 1986

 

257

Martin Jr JN, Files JC, Blake PG et al: Plasma exchange for preeclampsia. I. Postpartum use for persistently severe preeclampsia with HELLP syndrome. Am J Obstet Gynecol 162: 126, 1990

 

258

Joshi D, James A, Quaglia A et al: Liver disease in pregnancy. Lancet. 2010;375(9714):594-605

 

259

Magann EF, Martin JN Jr: Twelve steps to optimal management of HELLP syndrome. Clin Obstet Gynecol. 1999 Sep;42(3):532-50

 

260

Arias F, Mancilla-Jimenez R: Hepatic fibrinogen deposits in preeclampsia: Immunofluorescent evidence. N Engl J Med 295: 578, 1976

 

261

Barton JR, Sibai BM: HELLP and the liver diseases of preeclampsia. Clin Liver Dis 3: 31, 1999

 

262

Sheikh RA, Yasmeen S, Riegler JL et al: Spontaneous intrahepatic hemorrhage and rupture in the HELLP syndrome: Four cases and a review. J Clin Gastroenterol 28: 323, 1999

 

263

Haram K, Svendsen E, Abildgaard U: The HELLP syndrome: clinical issues and management. A Review. BMC Pregnancy Childbirth. 2009;9:8

 

264

Yucesoy G, Cakiroglu Y, Bodur H et al: An analysis of HELLP syndrome cases: does platelet count predict adverse maternal and fetal outcomes in women with HELLP syndrome? Arch Gynecol Obstet. 2011;283(5):941-5

 

265

Woudstra DM, Chandra S, Hofmeyr GJ et al: Corticosteroids for HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome in pregnancy. Cochrane Database Syst Rev. 2010;(9):CD008148

 

266

Zarrinpar A, Farmer DG, Ghobrial RM et al: Liver transplantation for HELLP syndrome. Am Surg. 2007;73(10):1013-6

 

267

Sibai BM, Ramadan MK, Friedman SA et al: Pregnancies complicated by HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets): Subsequent pregnancy outcome and longterm prognosis. Am J Obstet Gynecol 172: 125, 1995

 

268

Habli M, Eftekhari N, Wiebracht E et al: Long-term maternal and subsequent pregnancy outcomes 5 years after hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome. Am J Obstet Gynecol. 2009;201(4):385.e1-5

 
Back to Top