Download - Liver Diseases with Pregnancy

LIVER DISEASES LIVER DISEASES WITH PREGNANCYWITH PREGNANCY

Professor Mahmoud Farouk MidanProfessor Mahmoud Farouk Midan

Prof. & Head of Obstetrics & Gynecology DeptProf. & Head of Obstetrics & Gynecology Dept . . Faculty of MedicineFaculty of Medicine

Al-Azhar UniversityAl-Azhar University

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

(Bacq & Riely , 2004)(Bacq & Riely , 2004)

• Some of the normal physiologic changes Some of the normal physiologic changes of pregnancy can mimic abnormalities of pregnancy can mimic abnormalities associated with liver diseaseassociated with liver disease..

• Telangiectasia, particularly on the Telangiectasia, particularly on the chest, back, and face, and palmer chest, back, and face, and palmer erythema occur in up to 60 percent of erythema occur in up to 60 percent of normal pregnant women but disappear normal pregnant women but disappear after deliveryafter delivery..

(Riely, 2001)

Extreme vigilance is needed to detect early Extreme vigilance is needed to detect early signs and symptoms of liver dysfunction signs and symptoms of liver dysfunction and to distinguish these from the and to distinguish these from the anticipated benign hepatic changes of anticipated benign hepatic changes of pregnancy. Prompt management can save pregnancy. Prompt management can save the life of the mother and the baby. the life of the mother and the baby. Management of liver disease in pregnancy Management of liver disease in pregnancy requires a concerted effort between the requires a concerted effort between the primary care physician, liver specialist, primary care physician, liver specialist, obstetrician, and, on rare occasions, a liver obstetrician, and, on rare occasions, a liver transplant teamtransplant team..

(Moskovitz et al., 2004)(Moskovitz et al., 2004)

Anatomical, Physiological, Anatomical, Physiological, and Biochemical changes and Biochemical changes

during pregnancyduring pregnancy..

Anatomic ChangesAnatomic Changes::

• Liver weight increases during pregnancy has Liver weight increases during pregnancy has not been documented. Liver size is difficult not been documented. Liver size is difficult to estimate in pregnancy, but records fail to to estimate in pregnancy, but records fail to show any substantial increase in liver weight show any substantial increase in liver weight in comparison with nonpregnant controls.in comparison with nonpregnant controls.

• Therefore, detection of hepatomegaly is Therefore, detection of hepatomegaly is

strong evidence for the presence of liver strong evidence for the presence of liver disease.disease.

(Fagan, 1986)(Fagan, 1986)

PhysiologyPhysiology

• Hepatic blood flow is maintained at a Hepatic blood flow is maintained at a constant rate in pregnancy despite marked constant rate in pregnancy despite marked changes in the cardiovascular systemchanges in the cardiovascular system..

• Blood flow increases to the kidneys and Blood flow increases to the kidneys and other organs, but hepatic blood flow is other organs, but hepatic blood flow is unaltered, which results in a decline of unaltered, which results in a decline of approximately 35% in the proportion of approximately 35% in the proportion of cardiac output delivered to the liver.cardiac output delivered to the liver.

(Fagan, 1986)(Fagan, 1986)

Biochemical changes during Biochemical changes during pregnancypregnancy

• The total serum protein concentration The total serum protein concentration declines approximately 20% in declines approximately 20% in midpregnancy, primarily a result of the midpregnancy, primarily a result of the substantial decline in serum albumin which substantial decline in serum albumin which may be attributed to simple dilution caused may be attributed to simple dilution caused by the increase in total blood volume, by the increase in total blood volume, although most other serum proteins either although most other serum proteins either remain unchanged or increase in remain unchanged or increase in concentration.concentration.

(Maher et al., 1993)(Maher et al., 1993)

• A significant rise in serum fibrinogen A significant rise in serum fibrinogen regularly accompanies pregnancy. As a regularly accompanies pregnancy. As a consequence of increase fibrinogen consequence of increase fibrinogen synthesis.synthesis.

• Other coagulation proteins, including Other coagulation proteins, including factors VII, VIII, IX, and X, may be factors VII, VIII, IX, and X, may be increased during pregnancy or after increased during pregnancy or after estrogen treatmentestrogen treatment..

(Steingrub, 2005)(Steingrub, 2005)

• Most studies have failed to document Most studies have failed to document significant bilirubin Elevation in the significant bilirubin Elevation in the absence of specific cause during normal absence of specific cause during normal pregnancypregnancy.. Therefore, an increased Therefore, an increased serum bilirubin level in pregnancy should serum bilirubin level in pregnancy should be considered presumptive evidence for be considered presumptive evidence for the presence of liver or hematologic the presence of liver or hematologic disease. disease.

(Steingrub, 2004) (Steingrub, 2004)

• Alkaline phosphatase activity is Alkaline phosphatase activity is increased during the third trimester increased during the third trimester both because of leakage of placental both because of leakage of placental alkaline phosphatase into the alkaline phosphatase into the maternal circulation and because of maternal circulation and because of increased maternal bone turnoverincreased maternal bone turnover..

(Riely, 1999)(Riely, 1999)

Serum bile acid level is quite helpful in any Serum bile acid level is quite helpful in any form of cholestasis. The serum level is form of cholestasis. The serum level is normal in normal pregnancynormal in normal pregnancy..

Levels of serum aminotransferase-aspartate Levels of serum aminotransferase-aspartate aminotransferase (AST) and alanine aminotransferase (AST) and alanine aminotransferase (ALT) are normal in aminotransferase (ALT) are normal in normal pregnancy. Therefore, these two normal pregnancy. Therefore, these two serum enzyme determinations remain serum enzyme determinations remain sensitive indicators of liver damage during sensitive indicators of liver damage during pregnancy. The ALT is especially useful, pregnancy. The ALT is especially useful, because significant elevation of this because significant elevation of this enzyme does not occur with injury to enzyme does not occur with injury to tissues other than liver.tissues other than liver.

(Bacq et al., 2004)(Bacq et al., 2004)

Summary of physiological changes in the liver during Summary of physiological changes in the liver during pregnancypregnancy

• Increased:• Blood volume and cardiac ouput rise by 35%–50%• Alkaline phosphatase levels rise threefold or fourfold due to• placental production• Clotting factor changes create a hypercoagulable state• Decreased:• Gallbladder contractility• Hemoglobin• Uric acid levels• Albumin, total protein, and antithrombin III concentrations• No change:• Liver aminotransferase levels (aspartate aminotransferase,• alanine aminotransferase, gamma-glutamyl transferase)• Bilirubin level• Prothrombin time

Spectrum of liver diseases Spectrum of liver diseases in pregnancyin pregnancy

(Fleming & Zein, 2005)(Fleming & Zein, 2005)

• Preexistent liver diseasesPreexistent liver diseases– Portal hypertension, cirrhosis, primary Portal hypertension, cirrhosis, primary

biliary cirrhosisbiliary cirrhosis– Autoimmune hepatitisAutoimmune hepatitis– Wilson diseaseWilson disease– Chronic infection with hepatitis B or Chronic infection with hepatitis B or

hepatitis C virushepatitis C virus– Alcoholic liver diseaseAlcoholic liver disease

• Liver diseases coincidental with Liver diseases coincidental with but not induced by pregnancybut not induced by pregnancy– Acute viral hepatitis and other viral Acute viral hepatitis and other viral

infectionsinfections– Alcohol-related diseasesAlcohol-related diseases– Gallstone diseaseGallstone disease– Budd-Chiari syndromeBudd-Chiari syndrome

• Liver diseases induced by Liver diseases induced by pregnancypregnancy– First trimesterFirst trimester

•Hyperemesis gravidarumHyperemesis gravidarum

– Second and third trimestersSecond and third trimesters• Intrahepatic cholestasis of pregnancyIntrahepatic cholestasis of pregnancy

•Preeclampsia, eclampsia, and the HELLP Preeclampsia, eclampsia, and the HELLP syndromesyndrome

•(hemolysis, elevated liver enzymes, low platelet (hemolysis, elevated liver enzymes, low platelet counts) counts)

•Acute fatty liver of pregnancyAcute fatty liver of pregnancy

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

(Helmy &Hayes, 2001)(Helmy &Hayes, 2001)

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

(Sternlieb, 2005)(Sternlieb, 2005)

• The presence of severe portal The presence of severe portal hypertension with esophageal varices is hypertension with esophageal varices is associated with an increased risk of associated with an increased risk of hemorrhage during pregnancyhemorrhage during pregnancy..

The use of sclerotherapy for bleeding varices The use of sclerotherapy for bleeding varices during pregnancy may provide a safe during pregnancy may provide a safe alternative to portacaval anastomosis and alternative to portacaval anastomosis and has been reported to be effective.has been reported to be effective.

(Pauzner et al., 1991)(Pauzner et al., 1991)

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

(Heneghan et al., 2001)(Heneghan et al., 2001)

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

(Moskovitiz et al., 2004)(Moskovitiz et al., 2004)

Wilson disease is a rare disorder Wilson disease is a rare disorder characterized by cirrhosis, neurological characterized by cirrhosis, neurological abnormalities, and less commonly abnormalities, and less commonly hematological and renal dysfunctionhematological and renal dysfunction..

D-Penicillamine and trientine have been D-Penicillamine and trientine have been used during pregnancy. However, the used during pregnancy. However, the dosage should be reduced to the dosage should be reduced to the minimum necessary dose, which is minimum necessary dose, which is about 25% to 50% of the dose the about 25% to 50% of the dose the patient had been taking before the patient had been taking before the pregnancy.pregnancy.

(Roberts & Schilsky, 2003)(Roberts & Schilsky, 2003)

• Zinc is the agent of choice for Wilson Zinc is the agent of choice for Wilson disease during pregnancy because of disease during pregnancy because of its safety for the fetus. It should be its safety for the fetus. It should be maintained throughout the maintained throughout the pregnancy at 50 mg three times a pregnancy at 50 mg three times a day.day.

(Brewer et al., 2000)(Brewer et al., 2000)

Liver diseases Liver diseases coincidental with but coincidental with but

not induced by not induced by pregnancypregnancy

Liver diseases coincidental with Liver diseases coincidental with but not induced by pregnancybut not induced by pregnancy– Acute viral hepatitis and other viral Acute viral hepatitis and other viral


Hepatitis AHepatitis ACharacteristicsHepatitis A

Older nameInfectious hepatitis

Virus typeRNA

Virus size27 nm

Incubation period15 – 50 days

TransmissionFecal – oral

Vertical transmission to fetusNot observed

Serologic diagnosisHepatitis A antibody IgM and IgG types

Maximum infectivityProdrome

Carrier stateNone

Acute clinical formsAsymptomatic to fulminant

Chronic clinical formsNone

• The clinical syndrome of acute HAV The clinical syndrome of acute HAV infection consists of vague flu-like infection consists of vague flu-like symptoms with fatigue, weakness, nausymptoms with fatigue, weakness, nau sea, sea, and loss of appetite. The onset is usually and loss of appetite. The onset is usually abrupt. A variety of extrahepatic abrupt. A variety of extrahepatic manifestations including myalgia, manifestations including myalgia, arthralgias, arthritis, and urticaria, may arthralgias, arthritis, and urticaria, may occur. occur.

• Other forms of HAV infection include Other forms of HAV infection include cholestatic hepatitis, with a prolonged cholestatic hepatitis, with a prolonged course marked by itching and jaundice. course marked by itching and jaundice.

(Willner, et al., 1998)(Willner, et al., 1998)

• The characteristic changes in liver The characteristic changes in liver function test findfunction test find ings include marked ings include marked elevations in AST and ALT. Most often, elevations in AST and ALT. Most often, these reach levels of 1000 to 2000 U these reach levels of 1000 to 2000 U during the early part of the infection. during the early part of the infection. Elevations in bilirubin and alkaline Elevations in bilirubin and alkaline phosphatase also occur but are more phosphatase also occur but are more unpreunpre dictabledictable..

(Fiore, et al., 2003)(Fiore, et al., 2003)

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

(Atkinson, et al., 2002)(Atkinson, et al., 2002)

• Clinical management of pregnant patients Clinical management of pregnant patients with HAV infection does not differ from that of with HAV infection does not differ from that of those who are not pregnant. However, those who are not pregnant. However, hospitalization may be indicated, specially hospitalization may be indicated, specially during the last trimester and in the presence during the last trimester and in the presence of severe anorexia, nausea, and vomitingof severe anorexia, nausea, and vomiting..

• In rare circumstances in which the mother In rare circumstances in which the mother has acute HAV infection at the time of has acute HAV infection at the time of delivery, immune serum globulin may be delivery, immune serum globulin may be administered to the infant. Even under these administered to the infant. Even under these conditions, the risk of transmission to the conditions, the risk of transmission to the infant seems very small. infant seems very small.

(Fiore, et al., 2003) (Fiore, et al., 2003)

Hepatitis BHepatitis BCharacteristicsHepatitis B

Older nameSerum hepatitis

Virus typeDNA

Virus size42 nm


TransmissionParentral or body fluid

Vertical transmission to fetusCommon

Serologic diagnosisHBs Ag, HBs Ab, IgM, and IgG typesHBe Ag, Ab, Hepatitis B virus DNA

Maximum infectivityProdrome or HBe Ag Positive

Carrier state5 – 10%

Acute clinical formsAsymptomatic to fulminant

Chronic clinical formsChronic persistent hepatitisChronic active hepatitisCirrhosis

The incidence of the HBV carrier state The incidence of the HBV carrier state among pregamong preg nant women is variable and nant women is variable and depends on the patient group studied. depends on the patient group studied. The incidence of HBV carriers is The incidence of HBV carriers is considerably higher in populations in considerably higher in populations in which drug abuse is commonwhich drug abuse is common place or place or with n high incidence of sexual with n high incidence of sexual promiscuitypromiscuity..

(Van Zonneveld, et al., 2003)(Van Zonneveld, et al., 2003)

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

• The risk of transmission is highest in mothers The risk of transmission is highest in mothers who are HBeAg - positive at the time of who are HBeAg - positive at the time of delivery. delivery.

(Su, et al., 2004)(Su, et al., 2004)

• In women with chronic hepatitis B In women with chronic hepatitis B infection, taking lamivudine before infection, taking lamivudine before becoming pregnant and continuing to becoming pregnant and continuing to take it throughout the pregnancy has take it throughout the pregnancy has been reported to lower rates of been reported to lower rates of transmission of the virus from mother transmission of the virus from mother to newborn. Lower transmission rates to newborn. Lower transmission rates have also been seen in pregnant have also been seen in pregnant women with a high viral DNA load.women with a high viral DNA load.

(Su, et al., 2004)(Su, et al., 2004)

• The administration of hyperimmune The administration of hyperimmune globulin and HBV vaccine protects 90% globulin and HBV vaccine protects 90% to 95% of infants from HBV infectionto 95% of infants from HBV infection..

It is recommended that 0.5 ml, of HBIG It is recommended that 0.5 ml, of HBIG be given at birth and that three doses be given at birth and that three doses of HBV vaccine be given beginning at of HBV vaccine be given beginning at birth.birth.

(Sehgal, et al., 1992)(Sehgal, et al., 1992)

• Universal vaccination of all infants at Universal vaccination of all infants at birth for HBV is now the standard of birth for HBV is now the standard of care. Vaccinations for all children care. Vaccinations for all children previously not immunized is recompreviously not immunized is recom mended as they enter puberty, in mended as they enter puberty, in future generations, the specter of viral future generations, the specter of viral hepatitis B and its complications could hepatitis B and its complications could be eliminated. Vaccine for pregnant be eliminated. Vaccine for pregnant women exposed to hepatitis B is safe.women exposed to hepatitis B is safe.

(Watson, 2002)(Watson, 2002)

Hepatitis CHepatitis CCharacteristicsHepatitis C

Older nameNon A non B hepatitis

Virus typeRNA

Virus size30-60 nm


TransmissionParentral sporadic

Vertical transmission to fetusUncommon

Serologic diagnosisHepatitis C antibodyRNA by PCR

Maximum infectivityHIV co- infected

Carrier state50 – 85%

Acute clinical formsAsymptomatic to sever relapsing

Chronic clinical formsChronic persistent hepatitisChronic active hepatitisCirrhosis

• The rate of vertical transmission of The rate of vertical transmission of hepatitis C is less than 5%. The risk is hepatitis C is less than 5%. The risk is higher if the mother is co-infected with higher if the mother is co-infected with human immunodeficiency virus (HIV), if human immunodeficiency virus (HIV), if she is viremic at the time of delivery, if she is viremic at the time of delivery, if her viral DNA load is greater than 1 her viral DNA load is greater than 1 million copies/ml, and if the time from million copies/ml, and if the time from the rupture of membranes to delivery the rupture of membranes to delivery is more than 6 hours. is more than 6 hours.

• The mode of delivery does not seem to The mode of delivery does not seem to influence the rate of transmission from influence the rate of transmission from mother to child.mother to child.

(Ceci et al., 2001)(Ceci et al., 2001)

• Breastfeeding is not considered a risk Breastfeeding is not considered a risk factor for transmission, even though factor for transmission, even though viral RNA has been detected in breast viral RNA has been detected in breast milk. Spontaneous resolution of milk. Spontaneous resolution of infection in the mother and in the infection in the mother and in the newborn may occur.newborn may occur.

(Steininger et al., 2003)(Steininger et al., 2003)

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

(Ferrero et al., 2003)(Ferrero et al., 2003)

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

(Resti et al., 2003)

Hepatitis EHepatitis E Hepatitis E (HEV) is a nonenveloped, Hepatitis E (HEV) is a nonenveloped,

single-stranded RNA virus. It is single-stranded RNA virus. It is endemic in developing countries and endemic in developing countries and shares the route of transmission, risk shares the route of transmission, risk factors, and chronicity rate with HAV. factors, and chronicity rate with HAV. During pregnancy, HEV can cause During pregnancy, HEV can cause fulminant hepatitis indistinguishable fulminant hepatitis indistinguishable from AFLP. There is a significant from AFLP. There is a significant mortality rate of 16% in pregnant mortality rate of 16% in pregnant women with acute HEV infection. women with acute HEV infection.

(Aggarwal & Krawczynski, 2000)(Aggarwal & Krawczynski, 2000)

• Transmission occurs intrapartum and Transmission occurs intrapartum and peripartum through close contact of peripartum through close contact of mother and neonate. Evidence suggests mother and neonate. Evidence suggests significant vertical transmission among significant vertical transmission among HEV-RNA positive mothers of up to 50%. HEV-RNA positive mothers of up to 50%. Among women with symptomatic Among women with symptomatic infection the rate of transmission is up to infection the rate of transmission is up to 100%, with significant perinatal 100%, with significant perinatal morbidity and mortality. morbidity and mortality.

(Singh et al., 2003)

Management of Acute Viral Management of Acute Viral Hepatitis inHepatitis in PregnancyPregnancy

Establish type by serologic test

Institute appropriate isolation and precautions

Determine need for contact prophylaxis with scrum globulin

preparation and/or vaccine

Activity: determined by tolerance

Diet: patient preference, parentral if necessary Antiemetics: phenothiazines may be used

Corticostcroids: not indicated

Immunoprophylaxis of infant: if hepatitis B is present

Herpes simplex virusHerpes simplex virus

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

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

(Nigro , et al., 2003)(Nigro , et al., 2003)

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CytomegalovirusCytomegalovirus

• InfectionInfection may remain asymptomatic in may remain asymptomatic in pregnant women, and the prognosis is pregnant women, and the prognosis is favorable. The risk of transmission to the favorable. The risk of transmission to the fetus and of congenital abnormalities is fetus and of congenital abnormalities is highest when acute infection occurs in highest when acute infection occurs in the first 22 weeks of pregnancy. the first 22 weeks of pregnancy. Termination of the pregnancy may be an Termination of the pregnancy may be an option after appropriate counseling option after appropriate counseling regarding the potential serious risks to regarding the potential serious risks to the infected fetus.the infected fetus.

(Benachi A, et al., 2003)(Benachi A, et al., 2003)

Alcohol useAlcohol use

• Women are two to four times more Women are two to four times more likely than men to develop alcoholic likely than men to develop alcoholic liver disease for the same amount of liver disease for the same amount of alcohol ingested, and they exhibit a alcohol ingested, and they exhibit a tendency to disease progression tendency to disease progression even with abstinence.even with abstinence.

(Pares et al., 1986) (Pares et al., 1986)

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

(Lemoine et al., 2003)(Lemoine et al., 2003)

Gallstone diseaseGallstone disease

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

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

(Halpern , 1998)(Halpern , 1998)

Budd-Chiari syndromeBudd-Chiari syndrome

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

(Singh et al., 2000)(Singh et al., 2000)

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

(Deltenre et al., 2001)(Deltenre et al., 2001)

Hyperemesis GravidarumHyperemesis Gravidarum

• Hyperemesis gravidarum can be defined Hyperemesis gravidarum can be defined as excessive nausea and vomiting in as excessive nausea and vomiting in pregnancy that result in dehypregnancy that result in dehy dration and dration and ketosis, severe enough to necessitate ketosis, severe enough to necessitate hospitalization. Although this is not hospitalization. Although this is not primarily a liver disorder, it affects the primarily a liver disorder, it affects the liver in up to 50% of patients.liver in up to 50% of patients.

(Jeffrey et al., 2003)(Jeffrey et al., 2003)

• The origin of the liver disease associated The origin of the liver disease associated with hyperemesis gravidarum is unclear. with hyperemesis gravidarum is unclear. Not all affected patients have liver Not all affected patients have liver disease; therefore, the vomiting does disease; therefore, the vomiting does not appear to be secondary to the liver not appear to be secondary to the liver involvement. Starvation alone does not involvement. Starvation alone does not seem to be an adequate explanation for seem to be an adequate explanation for the liver dysfunction, particularly in as the liver dysfunction, particularly in as much as biopsy in affected patients fails much as biopsy in affected patients fails to show the fatty infiltration typical of to show the fatty infiltration typical of starvationstarvation..

(Mazzotta & Magee, 2000)(Mazzotta & Magee, 2000)

• Factors thought to favor an increased Factors thought to favor an increased risk for hyperemesis gravidarum risk for hyperemesis gravidarum include obesity, nulliparity, and twin include obesity, nulliparity, and twin gestation.gestation.

(Goodwin, 1998)(Goodwin, 1998)

• Affected patients present in the first Affected patients present in the first trimester, usually by weeks 10 to 12. trimester, usually by weeks 10 to 12. They have persistent nausea and They have persistent nausea and vomiting and experience weight loss, vomiting and experience weight loss, often of significant amounts. They often of significant amounts. They also have ptyalism (excessive also have ptyalism (excessive spitting). spitting).

(Lammert et al., 2000)(Lammert et al., 2000)

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

• Severely affected patients also have Severely affected patients also have elevations in bilirubin. elevations in bilirubin.

(Jeffrey et al., 2003)(Jeffrey et al., 2003)

Improvement in the nausea and Improvement in the nausea and vomiting and resolution of the liver test vomiting and resolution of the liver test abnormalities occur when most affected abnormalities occur when most affected patients are given intravenous fluids patients are given intravenous fluids and put to gut rest. Antiemetic therapy and put to gut rest. Antiemetic therapy is helpful. Corticosteroid therapy has is helpful. Corticosteroid therapy has been reported with success. Patients been reported with success. Patients affected with hyperemesis gravidarum affected with hyperemesis gravidarum have no increased rate of prematurity, have no increased rate of prematurity, infants with low birth weight, or infants infants with low birth weight, or infants with birth defects. with birth defects. (Tsang et al., 1996)(Tsang et al., 1996)

Intrahepatic Cholestasis of Intrahepatic Cholestasis of PregnancyPregnancy

• The syndrome has been variously called The syndrome has been variously called recurrent jaundice of pregnancy, recurrent jaundice of pregnancy, cholestatic jaundice of pregnancy, cholestatic jaundice of pregnancy, jaundice of late pregnancy, and hepatosis jaundice of late pregnancy, and hepatosis of pregnancy. ICP, however, is the of pregnancy. ICP, however, is the preferred term, because jaundice is preferred term, because jaundice is inconstant in any type of cholestatic inconstant in any type of cholestatic disorder. disorder.

(Gonzalez-Peralva et al., 1996)(Gonzalez-Peralva et al., 1996)

• The frequency of ICP is clearly higher The frequency of ICP is clearly higher among certain ethnic groups, including among certain ethnic groups, including Scandinavians and Chileans. In the Scandinavians and Chileans. In the latter group, ICP may appear in 2.4% or latter group, ICP may appear in 2.4% or more of pregnanmore of pregnan cies, the highest cies, the highest reported incidence in the world. The reported incidence in the world. The incidence is quite high (20.9%) in twin incidence is quite high (20.9%) in twin pregnancies.pregnancies.

• Several studies have demonstrated a Several studies have demonstrated a familial and genetic predisposition to familial and genetic predisposition to the syndrome in Sweden, Chile, and the the syndrome in Sweden, Chile, and the United States.United States.

(Lammert, et al., 2000)(Lammert, et al., 2000)

Clinical DescriptionClinical Description Pruritus is the dominant and initial Pruritus is the dominant and initial

symptom and appears in the third symptom and appears in the third trimester in more than 70% of cases. trimester in more than 70% of cases. Most of the remaining patients date Most of the remaining patients date their onset of symptoms to the their onset of symptoms to the second trimester.second trimester.

The symptom may become very severe The symptom may become very severe and usually involves the trunk and and usually involves the trunk and the extremities, including the palms the extremities, including the palms and the soles of the feet. As a result and the soles of the feet. As a result of the pruof the pru ritus, insomnia, fatigue, ritus, insomnia, fatigue, and even mental disturbances have and even mental disturbances have been reported been reported

(Milkiewicz et al., 2002)

Many patients report the Many patients report the appearance of dark urine without appearance of dark urine without frank jaundice shortly after the frank jaundice shortly after the onset of pruritus. Only a minority onset of pruritus. Only a minority of patients develop obvious of patients develop obvious jaundice, and this is usually mild.jaundice, and this is usually mild.

It is notable that abdominal pain, It is notable that abdominal pain, biliary colic, fever, anorexia, biliary colic, fever, anorexia, nausea, vomiting, and arthralgias nausea, vomiting, and arthralgias are absent.are absent.

(Milkiewicz et al., 2002)

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

• Subsequent pregnancies are Subsequent pregnancies are frequently accompanied by frequently accompanied by recurrences of the syndromerecurrences of the syndrome..

(Mazella et al., 2001)(Mazella et al., 2001)

Biochemical ChangesBiochemical Changes CLINICAL FEATURESBIOCHEMICAL CHANGES

PruritusJaundice*

No Anorexia or malasie 2nd or 3rd trimester onset*

Recurrent*Familial*

Serum bile acidAlkaline Phosphatase

5' NucleotidaseGGTP

Bilirubin (total)AST/ALT

Prothrombin timeCholesterol

Triglyceride

10-to 100 fold7- to 10 fold Two FoldsNormal to slight Normal to 5 mg/dLNormal to twofoldsTwo to Fourfolds Normal to twofolds

*These clinical features are not invariably present. ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGTP, -glutamyl-transpeptidase. ↑, increase.

Effects on the MotherEffects on the Mother

• Although earlier reports suggested that the Although earlier reports suggested that the only effect of ICP on the mother was related only effect of ICP on the mother was related to the discomfort of pruritus, more recent to the discomfort of pruritus, more recent studies have suggested more serious complistudies have suggested more serious compli cations. These include an increased risk of cations. These include an increased risk of postpartum hemorrhage, especially in those postpartum hemorrhage, especially in those given cholestyramine, and an increased risk given cholestyramine, and an increased risk for the development of gallstones after for the development of gallstones after pregnancy.pregnancy.

(Glantz, et al., 2005)(Glantz, et al., 2005)

Effects on the FetusEffects on the Fetus• The implications of ICP for the fetus are The implications of ICP for the fetus are

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

(Glantz, et al., 2004)(Glantz, et al., 2004)

TreatmentTreatment• Therapy is directed at alleviating pruritus in Therapy is directed at alleviating pruritus in

the mother. Ursodeoxycholic acid has been the mother. Ursodeoxycholic acid has been used successfully in the treatment of used successfully in the treatment of cholestasis in other settings, most cholestasis in other settings, most prominently primary biliary cirrhosis. prominently primary biliary cirrhosis. Improvement in both liver function test Improvement in both liver function test results and the symptom of pruritus has results and the symptom of pruritus has been documented in women with ICP treated been documented in women with ICP treated with a standard 15-mg/kg/day dosage. A with a standard 15-mg/kg/day dosage. A larger dosage, 20 to 25 mg/kg/day has been larger dosage, 20 to 25 mg/kg/day has been shown to be effective with no adverse affects shown to be effective with no adverse affects on either mother or baby.on either mother or baby.

(Mazella et al., 2001)

• Phenobarbital in a dosage of 100 mg/day has Phenobarbital in a dosage of 100 mg/day has been reported to be effective in been reported to be effective in approximately 50% of patients.approximately 50% of patients. Cholestyramine may be somewhat effective Cholestyramine may be somewhat effective and is usually given in a dosage of 4 g four or and is usually given in a dosage of 4 g four or five times per day. five times per day.

• Cholestyramine may worsen the Cholestyramine may worsen the malabsorption of fats and fat-soluble malabsorption of fats and fat-soluble vitamins. Therefore, the prothrombin time vitamins. Therefore, the prothrombin time must be monitored in patients treated with must be monitored in patients treated with this regimen, and parenteral vitamin K should this regimen, and parenteral vitamin K should be given before delivery.be given before delivery.

(Eloranta et al., 2002)(Eloranta et al., 2002)

• Intravenous or oral S'-adenosyl-1.-Intravenous or oral S'-adenosyl-1.-methionine has been reported to methionine has been reported to lead to a significant improvement in lead to a significant improvement in pruritus and in serum transaminase pruritus and in serum transaminase and bilirubin levels, perhaps by and bilirubin levels, perhaps by reducing the negative effects of reducing the negative effects of estrogens on bile secretion.estrogens on bile secretion.

(Frezza et al., 1999)(Frezza et al., 1999)

• Some investigators recommend Some investigators recommend elective induction at 38 weeks or as elective induction at 38 weeks or as early as 36 weeks in the presence of early as 36 weeks in the presence of jaundice or if the fetus's lungs have jaundice or if the fetus's lungs have matured.matured.

(Rioseco et al., 1994)




•Preeclampsia, eclampsiaPreeclampsia, eclampsia, and the HELLP , and the HELLP syndromesyndrome



Preeclampsia and Preeclampsia and eclampsiaeclampsia

• Preeclampsia affects up to 5% to 10% of Preeclampsia affects up to 5% to 10% of pregnancies, usually occurring in the late pregnancies, usually occurring in the late second and third trimesters and less second and third trimesters and less frequently occurring before 20 weeksfrequently occurring before 20 weeks’’ gestation. Preeclampsia commonly occurs in gestation. Preeclampsia commonly occurs in nulliparous women or multiparous women nulliparous women or multiparous women who are nonwhite; are older than 34; or who are nonwhite; are older than 34; or have new partners, past or current history have new partners, past or current history of hypertension, or previous postpartum of hypertension, or previous postpartum hemorrhage.hemorrhage.

(Benedetto et al., 2002)

• The disease is characterized by a triad of The disease is characterized by a triad of hypertension, proteinuria, and peripheral hypertension, proteinuria, and peripheral edema, and hypertension and proteinuria edema, and hypertension and proteinuria characteristically regress after delivery. characteristically regress after delivery. Eclampsia is characterized by seizures, Eclampsia is characterized by seizures, coma, and other signs of preeclampsia, coma, and other signs of preeclampsia, including hypereflexia, funduscopic including hypereflexia, funduscopic changes in severe cases, cerebral edema, changes in severe cases, cerebral edema, hepatic infarction, acute renal failure, hepatic infarction, acute renal failure, congestive heart failure, and acute congestive heart failure, and acute respiratory distress syndrome.respiratory distress syndrome.

(von Dadelszen et al., 2000)

PathophysiologyPathophysiology • A uteroplacental mismatch, whereby the A uteroplacental mismatch, whereby the

demands of the fetal placenta exceeds demands of the fetal placenta exceeds the maternal circulatory supply leads to the maternal circulatory supply leads to placenta hypoperfusion, local hypoxia, placenta hypoperfusion, local hypoxia, endothelial cell dysfunction, abnormal endothelial cell dysfunction, abnormal expression of inflammatory mediators, expression of inflammatory mediators, alteration of vasomotor tone, and alteration of vasomotor tone, and activation of the coagulation cascade.activation of the coagulation cascade.

(Sawhney et al., 2000)

Clinical manifestationsClinical manifestations

• The clinical course of preeclampsia The clinical course of preeclampsia includes nausea, vomiting, and epigastric includes nausea, vomiting, and epigastric pain and is associated with elevated pain and is associated with elevated levels of LDH, alkaline phosphatase, AST, levels of LDH, alkaline phosphatase, AST, ALT, and uric acid. The level of uric acid ALT, and uric acid. The level of uric acid is an excellent marker for assessing is an excellent marker for assessing disease severity and progression. Liver disease severity and progression. Liver function tests are abnormal in 20% to function tests are abnormal in 20% to 30% of patients with preeclampsia and 30% of patients with preeclampsia and may be attributed to vasoconstriction of may be attributed to vasoconstriction of the hepatic vascular bed.the hepatic vascular bed.

(Maki et al., 2000)(Maki et al., 2000)

Therapy and outcomeTherapy and outcome

• Women who develop preeclampsia Women who develop preeclampsia before 32 weeks of gestation are 22 before 32 weeks of gestation are 22 fold more likely to die than women fold more likely to die than women who develop the condition at term. who develop the condition at term.

(MacKay et al., 2001)

• The maternal mortality rate is less The maternal mortality rate is less than 1% at institutions with special than 1% at institutions with special skills in treating preeclampsia. skills in treating preeclampsia. Approximately 80% of maternal Approximately 80% of maternal deaths are attributed to central deaths are attributed to central nervous system complications, nervous system complications, usually cerebral edema. Hepatic usually cerebral edema. Hepatic complications, including sub-capsular complications, including sub-capsular hematoma and rupture, infarction, hematoma and rupture, infarction, and hepatic failure, account for the and hepatic failure, account for the remaining causes of mortality.remaining causes of mortality.

(Rolfes & Ishak, 1986)

• Fetal complications include Fetal complications include abruptioplacenta, prematurity, and abruptioplacenta, prematurity, and IUGR. Severe disseminated IUGR. Severe disseminated intravascular coagulation (DIC) is a intravascular coagulation (DIC) is a rare complication in the absence of rare complication in the absence of placenta abruption. placenta abruption.

• The only effective treatment for The only effective treatment for preeclampsia is delivery of the fetus and preeclampsia is delivery of the fetus and placenta, particularly if the condition is placenta, particularly if the condition is severe or develops after 36 weeks of severe or develops after 36 weeks of gestation or if the fetal lungs are mature. gestation or if the fetal lungs are mature. Most authorities suggest that the presence Most authorities suggest that the presence of Multi Organ system Dysfunction (MOSD), of Multi Organ system Dysfunction (MOSD), fetal distress, or gestational age greater fetal distress, or gestational age greater than 34 weeks warrants immediate delivery than 34 weeks warrants immediate delivery

(Sibai et al., 1994)

• If mild preeclampsia is evident in the If mild preeclampsia is evident in the third trimester, expectant third trimester, expectant management with intensive management with intensive monitoring may enhance fetal lung monitoring may enhance fetal lung maturity; however, any sign of maturity; however, any sign of maternal or fetal deterioration maternal or fetal deterioration requires emergent delivery. If requires emergent delivery. If eclampsia develops, magnesium eclampsia develops, magnesium sulfate is a treatment of choice for sulfate is a treatment of choice for seizure prophylaxis.seizure prophylaxis.

(Bernard et al., 2001)




•Preeclampsia, eclampsia, and the Preeclampsia, eclampsia, and the HELLP HELLP syndromesyndrome

(hemolysis, elevated liver enzymes, low platelet (hemolysis, elevated liver enzymes, low platelet counts)counts)


HELLP SyndromeHELLP Syndrome

• The HELLP syndrome is a multi-The HELLP syndrome is a multi-system disease variant of severe system disease variant of severe preeclampsia that is characterized by preeclampsia that is characterized by microangiopathic hemolytic anemia microangiopathic hemolytic anemia (MAH), hepatic dysfunction (hepatic (MAH), hepatic dysfunction (hepatic necrosis), thrombocytopenia (platelet necrosis), thrombocytopenia (platelet count, <100,000/ mm3), and, in the count, <100,000/ mm3), and, in the syndromesyndrome’’s most severe form, DIC. s most severe form, DIC.

• HELLP syndrome is more common among HELLP syndrome is more common among older multiparous women.older multiparous women.

• HELLP syndrome affects up to 20% of HELLP syndrome affects up to 20% of pregnancies involving severe preeclampsia. pregnancies involving severe preeclampsia.

• Although up to 11% of the cases occur Although up to 11% of the cases occur before 27 weeks of gestation, most cases before 27 weeks of gestation, most cases (70%) occur between 27 and 36 weeks of (70%) occur between 27 and 36 weeks of gestation and about a third occur after gestation and about a third occur after delivery. Exacerbations may occur after delivery. Exacerbations may occur after delivery, followed by recovery within 72 delivery, followed by recovery within 72 hours.hours.

(Martin et al., 1999)

Clinical manifestationsClinical manifestations• Several conditions mirror HELLP Several conditions mirror HELLP

syndrome, and timing of illness and syndrome, and timing of illness and findings may assist in differentiating findings may assist in differentiating HELLP syndrome from other HELLP syndrome from other diseases.diseases.

(Winbery & Blaho., 2001)

differential diagnosis of differential diagnosis of HELLP syndromeHELLP syndrome

Thrombotic coagulopathiesConsumptive disorders

Miscellaneous

Hemolytic uremic syndromeThrombotic

thrombocytopenia purpuraDrug-induced hemolytic

anemiaSepsis

DIC

AFLPSepsis

DICAbruptio placentae

Amniotic fluid embolism

Systemic lupusAntiphospholipid

syndromeCholecystitisAppendicitis

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

(Sibai et al., 1993)

Maternal morbidity in HELLP syndrome Maternal morbidity in HELLP syndrome can be classified into the following can be classified into the following four categories (in decreasing order four categories (in decreasing order of frequency)of frequency)

• Coagulation disorders associated with Coagulation disorders associated with hemorrhagic complications,hemorrhagic complications,

• Cardiopulmonary dysfunction,Cardiopulmonary dysfunction,• Central nervous system disorder andCentral nervous system disorder and• Hepatic or gastrointestinal Hepatic or gastrointestinal

dysfunction.dysfunction.(Isler et al., 1999)

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

(Sibai et al., 1995)(Sibai et al., 1995)

Laboratory investigationLaboratory investigation

Risk factors for HELLP syndrome include the Risk factors for HELLP syndrome include the following:following:

• LDH level, > 1400 IU/LLDH level, > 1400 IU/L• AST level, > 150 IU/LAST level, > 150 IU/L• ALT level, > 100 IU/LALT level, > 100 IU/L• Platelet count, < 50,000/mm3Platelet count, < 50,000/mm3• Uric acid level, > 7.8 mg/dLUric acid level, > 7.8 mg/dL• Creatinine level, > 1.0Creatinine level, > 1.0• Creatine phosphokinase level, > 200 IU/LCreatine phosphokinase level, > 200 IU/L

Liver functionLiver function• Patients usually are not jaundiced. Total Patients usually are not jaundiced. Total

bilirubin concentration rarely exceeds 1 to 2 bilirubin concentration rarely exceeds 1 to 2 mgmg..

• HELLP syndrome rarely leads to subcapsular HELLP syndrome rarely leads to subcapsular hemorrhage; hepatic rupture often leads to hemorrhage; hepatic rupture often leads to death of the mother and fetus. Typically, death of the mother and fetus. Typically, these patients present with shock and these patients present with shock and hemoperitoneum. The condition also may hemoperitoneum. The condition also may manifest hepatic infarcts with associated manifest hepatic infarcts with associated fevers, high levels of aminotranferase (N5000 fevers, high levels of aminotranferase (N5000 IU/L), and anemia. IU/L), and anemia.

(Krueger et al., 1995)

Therapy and outcomeTherapy and outcome

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

(Martin et al., 1999)

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

(Barton & Sibai, 1992)(Barton & Sibai, 1992)

• Termination of pregnancy and the Termination of pregnancy and the removal of the chorionic villi is the only removal of the chorionic villi is the only therapy that minimizes maternal and therapy that minimizes maternal and fetal compromise. Timing of delivery fetal compromise. Timing of delivery depends on the severity of the maternal depends on the severity of the maternal condition (DIC, MOSD, abruption), fetal condition (DIC, MOSD, abruption), fetal condition, placenta reserve, and condition, placenta reserve, and gestational age. With few exceptions, gestational age. With few exceptions, patients with pregnancies of at least 34 patients with pregnancies of at least 34 weeksweeks’’ gestation and class I pregnant gestation and class I pregnant patients with HELLP syndrome require patients with HELLP syndrome require prompt delivery. prompt delivery.

• HELLP syndrome - antepartum HELLP syndrome - antepartum managementmanagement

•assess and stabilize the maternal conditionassess and stabilize the maternal condition

•correct coagulopathy if DIC is presentcorrect coagulopathy if DIC is present

•give intravenous magnesium sulfate to prevent give intravenous magnesium sulfate to prevent seizuresseizures

•provide treatment for severe hypertension to provide treatment for severe hypertension to prevent strokeprevent stroke

•transfer to tertiary center if appropriatetransfer to tertiary center if appropriate

• if subcapsular hematoma of liver, computed if subcapsular hematoma of liver, computed tomography or ultrasound of the abdomentomography or ultrasound of the abdomen

• HELLP syndrome - antepartum HELLP syndrome - antepartum managementmanagement– evaluate fetal well-beingevaluate fetal well-being

•non stress testnon stress test

•biophysical profilebiophysical profile

– timing of deliverytiming of delivery• if > 34 weeks gestation, deliverif > 34 weeks gestation, deliver

• if < 34 weeks gestation, administer if < 34 weeks gestation, administer corticosteroids, then deliver in 48 hourscorticosteroids, then deliver in 48 hours

• HELLP syndrome - management HELLP syndrome - management for cesarean birthfor cesarean birth– use general anesthesia if platelet count use general anesthesia if platelet count

is < 75,000 / mmis < 75,000 / mm33

– transfuse 5 to 10 units of platelets transfuse 5 to 10 units of platelets before surgery if platelet count is < before surgery if platelet count is < 50,000 / mm50,000 / mm33

– leave vesicouterine peritoneum openleave vesicouterine peritoneum open– install subfascial draininstall subfascial drain

• HELLP syndrome - management HELLP syndrome - management for cesarean birthfor cesarean birth– schedule secondary closure of skin schedule secondary closure of skin

incision or subcutaneous drain incision or subcutaneous drain – administer postoperative transfusions administer postoperative transfusions

as neededas needed– perform intensive monitoring for at perform intensive monitoring for at

least 48 hours postpartumleast 48 hours postpartum– consider dexamethasone (10 mg IV consider dexamethasone (10 mg IV

every 12 hours) until postpartum every 12 hours) until postpartum resolution of disease occursresolution of disease occurs

• HELLP syndrome - management of HELLP syndrome - management of women with a subcapsular liver women with a subcapsular liver hematomahematoma– general considerations - blood bank aware general considerations - blood bank aware

for potential need of many units of bloodfor potential need of many units of blood– general or vascular surgeon consultationgeneral or vascular surgeon consultation– avoid direct and indirect manipulation of avoid direct and indirect manipulation of

liverliver– closely monitor hemodynamic statusclosely monitor hemodynamic status– management of hematoma depends on management of hematoma depends on

whether it is ruptured or notwhether it is ruptured or not





(hemolysis, elevated liver enzymes, low platelet (hemolysis, elevated liver enzymes, low platelet counts) counts)


Acute Fatty Liver of Acute Fatty Liver of PregnancyPregnancy

•Sheehan, first recognized this disorder as a distinct syndrome in 1940..

• He named it Acute yellow atrophy He named it Acute yellow atrophy but it is now more commonly known but it is now more commonly known as acute fatly liver of pregnancy. as acute fatly liver of pregnancy.

(Sheehan, 1940)(Sheehan, 1940)

• (AFLP) is rare, encountered in a (AFLP) is rare, encountered in a tertiary maternity hospital approxtertiary maternity hospital approx imately once a year, with a reported imately once a year, with a reported incidence of 1 in 13,000 to 1 in incidence of 1 in 13,000 to 1 in 16,000 deliveries.16,000 deliveries.

• Preeclampsia is present in 50% or Preeclampsia is present in 50% or more of cases of AFLP and may play more of cases of AFLP and may play a role in its origin. a role in its origin.

(Vigil-De, 2001)(Vigil-De, 2001)

• Reports of occasional recurrent cases Reports of occasional recurrent cases and an assoand an asso ciation with a deficiency ciation with a deficiency of long-chain 3-hydroxyacyl-of long-chain 3-hydroxyacyl-cocnzyme A (Co A) dehydrogenase, cocnzyme A (Co A) dehydrogenase, raise the interesting notion that, at raise the interesting notion that, at least in some instances, this disease least in some instances, this disease results from an inborn error of results from an inborn error of metabolism.metabolism.

(Ibdah et al., 1999)(Ibdah et al., 1999)

Clinical CharacteristicsClinical Characteristics

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

(Castro et al., 1999)(Castro et al., 1999)

• Affected women have nonspecific Affected women have nonspecific symptoms, including, promisymptoms, including, promi nently, nently, nausea and vomiting, malaise and nausea and vomiting, malaise and fatigue, jaunfatigue, jaun dice, thirst, headache, dice, thirst, headache, and altered mental status. These can and altered mental status. These can be signs and symptoms of acute be signs and symptoms of acute hepatic failure. hepatic failure.

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

• Most affected women have signs of Most affected women have signs of coexistent preeclampsia, including coexistent preeclampsia, including modest elevations in blood pressure, modest elevations in blood pressure, hyperuricemia, and proteinuria. hyperuricemia, and proteinuria.

With or without polyuria, frequently is an early With or without polyuria, frequently is an early symptom in AFLP.symptom in AFLP.

The patient may drink 2 or 3 liters of liquids The patient may drink 2 or 3 liters of liquids overnight. it often exceeds the magnitude of overnight. it often exceeds the magnitude of vomiting. It has been interpreted as a vomiting. It has been interpreted as a transient diabetes insipidus. transient diabetes insipidus.

(Cammu et al., 1987)(Cammu et al., 1987)

Polydipsia

Laboratory testsLaboratory tests

Clinical featuresBiochemical changes

Nausea, Vomiting Malaise, FatigueJaundice Abd. PainPreeclampsiaComaBleedingOnset in second half of gestation;

postpartum onset possible

Bilirubin (total)AST/ALT

GGTPProthrombin time

Fibrinogen Uric acid

AmmoniaGlucose

Leukocytesplatelets

Slight , normalnormal to 1000 U

Slight

,

• Imaging may be useful; fat in the liver Imaging may be useful; fat in the liver has been demonstrated in AFLP with has been demonstrated in AFLP with ultrasonography and CT scanning.ultrasonography and CT scanning.

• Liver biopsy is not indicated for Liver biopsy is not indicated for diagnosisdiagnosis

(Barton et al., 1998)(Barton et al., 1998)

Characteristics of HEELP syndrome and Characteristics of HEELP syndrome and

AFLPAFLP

HELLPAFLP

Early Platelet count, 50,000-150,000/mm3

LDH level, 600-1400 IU/LBilirubin/PT levels, Normal

Early Platelet count, >100,000/mm3

Uric acid – abnormalLDH level, normal

PT- AbnormalBilirubin/PT levels, abnormal

Late Platelet count, <50,000/mm3

LDH level, >1400 IU/LBilirubin/PT levels, abnormal

late Platelet count, <100,000/mm3

LDH level, < 600 IU/LHypoglycemiaPT- Abnormal

ComplicationsComplications

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

Course and ManagementCourse and Management• Patients with undiagnosed AFLP are at risk for Patients with undiagnosed AFLP are at risk for

progresprogres sion, with an unpredictable but often sion, with an unpredictable but often short time course, to fulminant hepatic failure short time course, to fulminant hepatic failure and death for both mother and fetus. and death for both mother and fetus.

• Now it is rare for a patient to die, with Now it is rare for a patient to die, with appropriate diagnosis and aggressive appropriate diagnosis and aggressive management.management.

• Similarly, the outlook for the fetus of the Similarly, the outlook for the fetus of the affected pregnancy has also improved, affected pregnancy has also improved, although it remains worse than that of the although it remains worse than that of the mother. mother.

(Usta et al., 1994)(Usta et al., 1994)

All patients should be All patients should be hospitalizedhospitalized as as soon as the diagnosis of AFLP is soon as the diagnosis of AFLP is suspected suspected

Moderate or severely affected patients Moderate or severely affected patients (encephalopathic, deeply jaundiced, (encephalopathic, deeply jaundiced, with a prothrombin time less than 40% with a prothrombin time less than 40% of the control), or with any extrahepatic of the control), or with any extrahepatic complications, should be attended in complications, should be attended in intensive care units. intensive care units.

it seems convenient to it seems convenient to maintain maintain glucose infusionsglucose infusions . Because of the . Because of the risk of a sudden hypoglycemia until a risk of a sudden hypoglycemia until a full metabolic recovery is obtained.full metabolic recovery is obtained.

•Treatment of AFLP begins with Treatment of AFLP begins with delivery. The route should be delivery. The route should be guided by obstetric indications. guided by obstetric indications. Cesarean section is not always Cesarean section is not always necessary; vaginal delivery can be necessary; vaginal delivery can be accomplishedaccomplished..

• With delivery, repair of the liver With delivery, repair of the liver disease begins, the initial sign of disease begins, the initial sign of improvement being a fall in improvement being a fall in prothrombin time elevation.prothrombin time elevation.

• The management should include The management should include maximal support in an intensive care maximal support in an intensive care unit by a team that includes both unit by a team that includes both obstetriobstetri cians and hepatologists. Liver cians and hepatologists. Liver transplantation for AFLP has been transplantation for AFLP has been reported.reported.

(Paternoster et al., 2004)

• There are no residua after AFLP, and There are no residua after AFLP, and complete recovery of the affected complete recovery of the affected patient should be expected. Cases of patient should be expected. Cases of recurrecur rent AFLP, as well as cases ofrent AFLP, as well as cases of nonketotic hypoglycemia in the nonketotic hypoglycemia in the offspring, have been reported. offspring, have been reported.

Pregnancy Following Pregnancy Following Liver TransplantationLiver Transplantation

• With advances in transplantation, and With advances in transplantation, and particularly in immunosuppression, it is particularly in immunosuppression, it is unnecessary to discourage pregnancy unnecessary to discourage pregnancy of most female liver transplant of most female liver transplant recipients at reproductive age.recipients at reproductive age.

(Parolin et al., 2004)(Parolin et al., 2004)The first report of successful pregnancy

after liver transplantation was published in 1978.

(Miniero et al., 2005)(Miniero et al., 2005)

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

((Nagy et al., 2003Nagy et al., 2003))

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

(Nagy et al., 2003)(Nagy et al., 2003)

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

(Armenti et al., 2000)(Armenti et al., 2000)

• immunosuppression during pregnancy immunosuppression during pregnancy is not teratogenic and does not lead to is not teratogenic and does not lead to congenital anomalies.congenital anomalies.

• Nearly 70% of pregnancies after Nearly 70% of pregnancies after systemic administration of tacrolimus systemic administration of tacrolimus resulted in a favourable outcome resulted in a favourable outcome without any significant effect on without any significant effect on intrauterine growth.intrauterine growth.

(Jabiry et al., 2005)

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

• To the present, 37 cases of To the present, 37 cases of pregnancies after liver transplantation pregnancies after liver transplantation have been reported worldwide. have been reported worldwide.

• In conclusion:In conclusion:

Under careful monitoring a childbearing Under careful monitoring a childbearing age woman with stable and adequate age woman with stable and adequate liver function may have a successful liver function may have a successful pregnancy and a delivery after liver pregnancy and a delivery after liver transplantation.transplantation.

(Pan et al., 2007) (Pan et al., 2007)