Jaundice in Pregnancy

Dr Anusha Rao P

Summary of physiological changes in the liver during pregnancy

• 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 (AST, ALT, GGT)• Bilirubin level• Prothrombin time

CAUSES OF JAUNDICE IN PREGNANCY

UNRELATED TO PREGNANCY PREGNANCY SPECIFIC

HEPATIC CAUSES• Acute viral hepatitis• Drug induced hepatitis• Chronic hepatitis

-viral (HBV, HCV)-Autoimmune hepatitis

• Wilson’s disease• Cirrhosis of liver• Budd- chiari syndrome

PRE-HEPATIC CAUSES• Hemolytic anemia

POST-HEPATIC CAUSES• Common bileduct stone/ strictures• Biliary parasitosis

• Hyperemesis gravidarum

• Intrahepatic cholestasis of pregnancy

• Pre-eclampsia/ eclampsia

• HELLP Syndrome

• Acute fatty liver of pregnancy

Test Non pregnantadult

II trimester III trimester Cholestasis of pregnancy

ALP (U/L) 33-96 25-126 38-229 Higher than in normal

pregnancy

AST (U/L) 12-38 3-33 4-32 2-10 fold increase above

normal

Total Bilirubin (mg/dL)

0.3-1.3 0.1-0.8 0.1-1.1 2-5

features

Acute hepatits ICP HELLP AFLP

Trimester Any III III III

Presentation Fever, jaundice Pruritis HTN, N/V, pain N/V, pain

S. ALT & AST >>> > >> >>

S. ALP > > = =

Platelets = = < =

Fetal complications

Transmission of infection in

HBV and HCV

Prematurity Fetal distress

IUGR

IUGRPrematurity

Premature del.

Intrahepatic Cholestasis of Pregnancy

• Also called as recurrent jaundice of pregnancy, cholestatic jaundice of pregnancy, jaundice of late pregnancy, and hepatosis of pregnancy.

• It is a form of intrahepatic cholestasis associated with pruritus, elevated serum bile acid levels, and the findings of bland cholestasis on liver biopsy .

• 1.5 – 2% of pregnancies.

S. bile acid levels

• Mild : 10-39 umol/L

• Severe : > 40 umol/L

• Conjugated hyperbilirubinemia,

slight inc. in ALP/ GGT

• Synthetic function and architecture of liver-unaltered.

Pathogenesis

Unknown • Genetically susceptible women.• Low plasma selenium levels .• An enhanced sensitivity to estrogen .• A variation in the metabolism of

progesterone(diminished secretion of sulfatedprogesterone metabolites) .

• Molecular mechanism show many gene mutations that control hepatocellular transport systems– Multidrug resistance 3 (MDR3) gene found with progressive

familial intrahepatic cholestasis.– Decrease canalicular transport of bile acids .

Clinical Presentation :

Pruritus

dominant and initial symptom third trimester (> 70% of cases)usually involves the trunk and the extremities, including the palms and the soles of the feet.

Disappears 24-48 hours postpartum (but biochemical and histological abnormalities take longer to resolve)

• 10% to 25% patients develop obvious jaundice, and this is usually mild.

• Abdominal pain, biliary colic, fever, anorexia, nausea, vomiting, and arthralgias are absent.

Effects on the Mother

• Improvement of symptoms and laboratory test results begins with delivery of the infant .

• Is usually prompt and complete .

• No residual hepatic defect after resolution of the disorder .

• Increased risk for development of gallstones, cholecystitis, and pancreatitis.

• 60% to 70% of patients develop cholestasis during subsequent pregnancies

Effects on the Fetus

• Serious implications

• Increased incidence of prematurity and fetal death.

(intrapartum fetal distress, meconium aspiration, and neonatal respiratory distress)

• These complications correlate with maternal bile acid levels >

40 μmol/L.

• More likely if the disorder begins earlier in pregnancy.

Management Palliative

• Antihistamines and topical emollients.

• Ursodeoxycholic acid, 10-15 mg/kg/day

• Cholestyramine– Bile acid binders

– worsens steatorrhea and resultant fat-soluble and vitamin K deficiencies, fetal coagulopathy, intracranial hemorrhage and stillbirth

• S'-adenosyl-1.-methionine – lead to a significant improvement in pruritus and in serum transaminase

and bilirubin levels, perhaps by reducing the negative effects of estrogens on bile secretion.

Differential diagnosis:

• Primary biliary cirrhosis

• Primary sclerosing cholangitis

• Benign recurrent intrahepatic cholestasis

• Viral hepatitis

• Biliary obstruction

LIVER DISEASE OF PREECLAMPSIA

• Preeclampsia is a form of pregnancy-related

hypertension that is associated with damage and

dysfunction of one or more maternal organs, possibly

including the liver,that may produce severe, life-

threatening complications and affect pregnancy

outcome .

“HELLP” SYNDROME

• Hemolysis, Elevated Liver enzymes,and Low Platelet count (HELLP) syndrome .

• Multi-system disease variant of severe preeclampsia that is characterized by

– Microangiopathic hemolytic anemia (MAH),

– Hepatic dysfunction (hepatic necrosis),

– Thrombocytopenia (platelet count, <100,000/ mm3), and,

– In the syndrome’s most severe form, DIC.

– 12% of women with severe preeclampsia .

• CT and MRI, may be useful

– detects intrahepatic hemorrhage and infarction.

• Liver biopsy

– Periportal hemorrhage, intrasinusoidal fibrin deposition and irregular areas of liver cell necrosis with mild reactive hepatitis .

– There is little correlation between the severity of liver biopsy lesions and laboratory test abnormalities .

D/D of HELLP MiscellaneousIncreased Liver

enzymesThrombocytopenia

Systemic lupus

Drug-induced hemolytic anemia

Sepsis

Abruptio placenta

Amniotic fluid embolismcholecystitisAppendicitis

Acute viral hepatitis

Acute fatty liver of pregnancy

Hemolytic uremic syndrome

Immune thrombocytopenic purpura,

Thrombotic thrombocytopenic purpura,

Anti-phospholipid antibody syndrome

DIC

ACUTE FATTY LIVER OF PREGNANCY

• AFLP is a form of microvesicular fatty liver disease unique to human gestation that presents late in pregnancy, often as fulminant hepatic failure with sudden onset of coagulopathy and encephalopathy in a woman without a prior history of liver disease .

• Acute Yellow atrophy/ Acute Fatty metamorphosis

• AFLP is diagnosed in approximately 1 of 10,000 pregnancies / third trimester.

• Maternal mortality 10-15%

• Perinatal mortality 15-20%

Pathogenesis

Unknown

• Associated with inherited mitochondrial abnormalities of beta oxidation of fatty acid .

• Genetic mutations .

• The most common are the G1528C and E474Q mutations of the gene on chromosome 2 that code for long chain-3-hydroxyacyl-CoA-dehydrogenase (LCHAD).

• Autosomal recessive carnitine palmitoyltransferase1 (CPT1) deficiency has also been reported.

Clinical Characteristics

• AFLP presents late in pregnancy ;between 34 and 37

weeks of gestation .

• Rarely may present after delivery.

• Occur more commonly in first pregnancy and with

male fetus/ twins.

• Have signs of coexistant preeclampsia (50%)

• In severe cases progression over hours or days to

fulminant hepatic failure and death.

Clinical features

• Nonspecific symptoms like– Nausea and vomiting,

– Malaise and fatigue,

– Jaundice,

– Thirst, headache, and

– Altered mental status.

– Pruritus (overlap with ICP )

• There can be signs and symptoms of acute hepaticfailure.

• The histologic hallmark is microvesicular fatty infiltration of the liver that is most prominent in hepatocytes surrounding central veins (zone three) and spares those surrounding portal areas .

• Do not have the periportal hemorrhage and fibrin deposition seen in

preeclampsia and HELLP syndrome.

• Confusion

– lobular disarray suggestive of viral hepatitis and

– biliary ductular proliferation and inflammation suggestive of cholangitis

Complications

Cerebral edema,

Renal failure (60%),

Hypoglycemia (53%), Infections and sepsis (45%)Gastrointestinal hemorrhage (33%), Coagulopathy (30%),

Fetal death Severe postpartum hemorrhage

Course

• Patients with undiagnosed AFLP – Have unpredictable course and often within short time course,

to fulminant hepatic failure and death for both mother and fetus.

• Survival of patients with AFLP has been reported to be about 100% with prompt diagnosis, delivery of the infant, and intensive care.

• Recurrence of AFLP has been documented more likely if the woman has a homozygous enzyme- deficient fetus.

Management Early diagnosis, prompt delivery and supportive

care are the cornerstones in the management

Spontaneous resolution . Treated in intensive care units.

Transfusions with whole blood or packed red cells, along with FFP, cryoprecipitate, and platelets .

Mechanical ventilation , hemodialyisis and antibiotics

Hepatic encephalopathy is treated by measures intended to evacuate feces and bacteria from the colon.

Infusion of concentrated glucose solution may be required to treat or prevent hypoglycemia .

Prompt delivery The route should be guided by obstetric indications. Cesarean

section is not always necessary; vaginal delivery can be accomplished .

• Two associated conditions .– Transient diabetes insipidus. This presumably is due to

elevated vasopressinase concentrations caused by diminished hepatic production of its inactivating enzyme.

Trt – Vasopressin .

– Acute pancreatitis, which develops in up to half of women.

Liver transplantation has rarely been performed for AFLP .

USUAL HEPATIC DISORDERSAND PREGNANCY

• 1.VIRAL HEPATITIS

• 2. CHRONIC LIVER DISEASE AND PORTAL

HYPERTENSION

• 3. AUTOIMMUNE LIVER DISEASES

• 4. BUDD-CHIARI SYNDROME

• 5. HEPATIC NEOPLASIA AND MASS LESIONS

Viral hepatitis

Hepatitis A

• It does not appear to alter the normal course of pregnancy, nor does pregnancy appear to influence the natural history of hepatitis A.

Hepatitis E (non enveloped ss RNA)

• an epidemic disease during the monsoon season in central and south Asia and India.

• during the third trimester of pregnancy is a cause of fulminant hepatic failure and has a mortality rate of up to 20% .

• Associated with intrauterine fetal death .

• Maternal fetal transmission of hepatitis E resulting in symptomatic neonatal hepatitis .

• No known therapy prevents vertical transmission of this virus

Hepatitis B

• As a rule, maternal hepatitis B virus infection does not influence the course of pregnancy, nor does pregnancy alter the natural history of maternal hepatitis B infection.

• Most women of childbearing age with chronic hepatitis B are healthy virus carriers with a very low risk of developing complications of their disease.

• Vertical transmission is 10%(second tri.) and 90%(third tri. Infections)

HBsAg Anti HBc IgM- Anti HBc Anti-HBs Interpretation

- - - - Never infected

- + - + Immune due to natural infection

- - - + Immune due to vaccination

+ + + - Acute infection

+ + - - Chronic infection

- + - - • Past infection • Low level chr.

Infection• Passive

transfer to the infant

• False positive anti HBc

• Without treatment, vertical transmission is 90% in the infants born to both HBsAg and HBeAg positive and 10% in the infants born to HbsAg postive mothers .

• Antivirals to given to those mothers who are HBeAg positive and whose HBV DNA is > 109 copies

• The infants of mothers with a reactive serum test for hepatitis B surface antigen should

– receive HBIG and first dose of Hep B vaccine (0, 1, 6 mnths) within 12 hrs at birth .

Antiviral therapy

• Based on the severity of disease (hepatic activity and fibrosis)

• Interferon therapy C/I during pregnancy .

• Oral agents – Telbivudine and tenofovir are pregnancy category B

drugs and are preferred.

– Lamivudine is a pregnancy category C drug, but is thought to be associated with a low risk of complications .

– Other drugs insufficient data .

D/D in the III trimester

Disorder AST Bilirubin

Cholestasis of pregnancy <200 1-5

Acute fatty liver of pregnancy

200-800 4-10

Hepatitis >2000 5-20

Budd Chiari Syndrome

• Pregnancy is a predisposing factor for the development of venous thrombosis.

• Hepatic vein thrombosis may occur in association with HELLP syndrome and with preeclampsia in women who have antiphospholipid antibody.

• Should be evaluated for the presence of antiphospholipid antibody and and other circulating procoagulants( factor V Leiden )

Autoimmune hepatitis

• Women with autoimmune hepatitis can becomepregnant and can still carry a successfulpregnancy.

• The course of the disease is unpredictable.

• Although spontaneous remission may occur,maternal death and exacerbation duringpregnancy and after delivery have been reported.

• Corticosteroids are the treatment of choice inautoimmune hepatitis and appear to be safe inpregnancy.

• They seem to induce rapid remission of autoimmunehepatitis, whether during the initial onset or during aflare.

• Azathioprine

– FDA category D (positive evidence of risk),

– However data from patients with IBD suggest it is likelyto be safe in pregnancy at dosages less than 100mg/day.

CHRONIC LIVER DISEASE AND PORTAL

HYPERTENSION

• Pregnancy is uncommon in women with established liver cirrhosis,including primary biliary cirrhosis,– because they tend to be past childbearing age or– infertile due to the condition

• Portal hypertension, ascites, and compensatory dilation of submucosal esophageal veins connecting the portal circulation and the azygosvein can occur in pregnant women with noncirrhotic portal hypertension aggravated by increased circulating blood volume .

• Even in the absence of pathologic causes of portal

hypertension, these esophageal venous collaterals may become

engorged during gestation due to increased blood flow and

compression of the inferior vena cava by the enlarging uterus .

• Treating bleeding esophageal varices with nonselective beta-

blockers, band ligation, sclerotherapy and octreotide is safe

and effective during pregnancy.

Pregnancy and liver transplantation

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

• The first report of successful pregnancy after liver transplantation was published in 1978.

• 37 cases of pregnancies after liver transplantation have been reported worldwide.

• Pregnancy planned at least 2 years after liver transplantation with stable allograft function can have excellent maternal and neonatal outcome.

• Transplant patients should continue immunosuppressive therapy during gestation .

• Treatment regimens (esp Tacrolimus ) used to prevent graft rejection have not been associated with teratogenicity.

• Adverse effects of these medications,however, including hypertension and hyperglycemia, may increase the incidence of fetal distress and preeclampsia .

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