General objectiveAt the end of this teaching learning session, students will be able to explain jaundice during pregnancy and its management.

Specific objectives• Explain normal physiology of liver during pregnancy .• Define jaundice during pregnancy.• State the causes of jaundice during pregnancy Explain the physiology

of bilirubin production.• Define obstetric cholestasis.• State the diagnosis measure of OC.• State the maternal and fetal effect of OC.

Cont…• State the complication of OC.• Enumerate the preventive measure of jaundice. • Explain the management of OC.

NORMAL LIVER PHYSIOLOGY IN PREGNANCY• Outside pregnancy , liver receives upto 25-35 % of cardiac output

which does not change significantly during pregnancy• Size of the liver does not increase• Postero-superior displacement by the enlarging uterus.• Palpably enlarged liver is abnormal in pregnancy.• Metabolic ,synthetic & excretory functions of liver affected by

increased levels of estrogen & progesterone in pregnancy.

Cont…• The biochemical tests in the last trimester show the moderate increase in

alkaline phosphate, cholesterol and serum globulin.

• Hemoglobin , Serum albumin ,urea and uric acid concentration are reduced.

• About 10% to 15 % of normal women may be bilirubin level of over 1.0mg% due to delayed excretion of bilirubin which may cause pruritis during pregnancy.

• Decreased Gallbladder contractility.

INCIDENCE

• Worldwide jaundice occur in about 1 out of every 1500 gestation.(Haemmerlie 1966)• Overall incidence in india is 1-4/1000 deliveries (Datta D.C.)

INTRODUCTION OF JUNDICE

• Jaundice is the clinical manifestation of raised bilirubin levels in blood .Detected clinically at bilirubin concentration of 2 mg % or more ( normal being 0.2 – 0.8 mg % )

• Jaundice may be coincidental to the pregnancy or due to a condition that is specific to the pregnancy.

PSYSIOLOGY OF BILIRUBIN

• Following the destruction of red blood cell ,the released hemoglobin is broken down into globin and heme.

• The heme is broken down to biliverdin,which is reduced to form bilirubin usually amounting to 250 to 300mg daily .(this is not change by pregnancy)

• This bilirubin is unconjugated and water -insoluble and usually carried to the liver bond to albumin.

Cont….

• At the hepatocyte membrane, unconjugated bilirubin is actively taken up and conjugated to two molecule of glucuronide, by the action of uridine diphosphoglucurosyl (UDP) transferese.

• This conjugated bilirubin is water soluble and usually remain in liver.

• Hepatocyte damage allows it to enter the blood , and the part that remains unbound passes into urine and cause the dark urine of cholestatic jaundice

Cont …

• The protein-bound conjugated bilirubin contributes to the yellow discoloration of skin and mucus membrane.

• From the hepatocyte, bilirubin is actively taken up by the bile canaliculus.

• From the canaliculus conjugated bilirubin drains into the extra hepatic bile ducts, common bile duct and finally the small intestine.

Cont…

• The conjugated bilirubin is too large to be absorbed from the location so it passes to the terminal ileum where bacterial action hydrolyzes it free bilirubin which is then reduced to urobilinogen.

• Some of these undergoes further bacterial action in the stool, changing it to stercobilinogen, which contribute to dark color of feces- reduced entry of bilirubin into the gut accounts for the pale stool of cholestatic jaundice.

• The rest of urobilinogen is absorbed and returned to the liver via the enterohepatic circulation, from there it is re-excreted into the bile.

Cont…..

• These urobilinogen is water soluble, in normal circumstances, a small amount passes into the urine.

• Urinary urobilinogen is increased either there is an increased load of bilirubin, in which case the hepatic capacity to re-excrate the urobilinogen maybe over-whelmed, or if hepatic damage empairs re-exceration

Causes of jaundice during pregnancy

Jaundice specific to pregnancy• Hyperemesis gravidarum• Intrahepatic cholestasis of pregnancy• Pre-eclampsia/ eclampsia• HELLP Syndrome• Acute fatty liver of pregnancy

Jaundice unrelated to pregnant stateHEPATIC CAUSES• Acute viral hepatitis• Drug induced hepatitis• Chronic hepatitis -viral (HBV, HCV) -Autoimmune hepatitis• Wilson’s disease• Cirrhosis of liver

PRE-HEPATIC CAUSES• Hemolytic anemiaPOST-HEPATIC CAUSES• Common bile duct stone/

strictures

OBSTETRIC CHOLESTASIS

• 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 .• It is more common in certain parts of the world. For example, in some

countries in South America, especially Chile and Bolivia, up to 1 in 20 or more pregnant women develop this condition

Cont….• OC affects 0.7% of pregnancies in whites in the United Kingdom and

approximately double this proportion of women of South Asian origon.

• incidence being 1.24 % of all pregnancies in Indian population.

• Obstetric cholestasis occurs in less than 1 in 100 pregnancies in the UK. It is more common in women carrying twins, triplets, or more

Cont…• Cholestasis is a complication of pregnancy where pregnancy

hormones (particularly oestrogen) affect the liver by preventing the flow of bile into the intestines. Bile usually aids with the breakdown and absorption of food after digestion, but when a women has obstetric cholestasis, bile and other toxins accumulate in the bloodstream.

PATHOPHYSIOLOGY• Affected individuals have a defect involving the excretion of bile

salts, which leads to increased serum bile acids. These are deposited within the skin, causing intense pruritus.

• Up to 15% of OC cases are associated with the adenosine triphosphate binding cassette, subfamily B, member 4 (ABCB4/abcb4) gene. This gene, also known as multidrug resistant protein 3 (MDR3), encodes the transporter for phospholipids across the canaliculi membrane of hepatocytes.

Cont….• Up to 10 different MDR3 mutations have been identified and

any one of these mutations may result in loss of function and, therefore, raise bile acid levels. MDR3 is also associated with progressive familial intrahepatic cholestasis.

• Therefore, a careful and focused family history of a patient diagnosed with ICP, looking for a personal or family history of ICP or gallstones and cholestasis with oral contraceptive pill (OCP) use is important.

Cont ….• Changes induced by these genetic mutations lead to an increased

sensitivity to estrogen. Estrogen has a known role in causing cholestasis, and thus, cholestasis can arise from estrogen-containing OCPs.

• The hepatic transport mechanisms for biliary excretion can be altered by estrogen and progesterone .

• Which all contribute for obstetric cholestasis.

CAUSES

• Unknown • Previous history of OC and taking OCP. • Genetically susceptible women.• Women with hepatitis C more commonly develop OC than those who

do not have the virus.• An enhanced sensitivity to estrogen .(Mostly during third trimester)

• 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 .

SIGN AND SYMPTOMS

• Pruritus associated with abnormal liver transaminase or raised bile acid . More than 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)

• Malaise & insomnia• Dark urine, anorexia, steatorrhoea .• 10% to 25% patients develop obvious jaundice, and this is usually

mild.• Abdominal pain, biliary colic, fever, anorexia, nausea, vomiting, are

absent.

DIAGNOSIS • Ask about medical and family history to aid diagnosis. If close female

family members have been affected by OC/ICP then there may be at increased risk.• It is also important to exclude all other possible causes of itching, such

as allergies or eczema (but it is possible to have a skin condition and OC/ICP). Other signs such as pale stools or dark urine may indicate a problem with liver, including OC/ICP.• OC can be diagnosed from blood tests called liver function

tests (LFTs) and a serum bile salt test. Liver function tests are performed to gain an idea of how liver is functioning.

Cont…

• levels of the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) should be checked.• The most specific test involves measuring serum bile salts. Raised

levels would be a measurement of greater than 14µmol/L• Raised bilirubin may occur but this is not only marker of OC.• Ultrasound scan of liver and biliary can exclude other problem.• PT should be checked once a week. • If symptoms or biochemical abnormalities persist more than 3 month

postpartum , women should refer to hepatologist.

MATRENAL EFFECT• vitamin K deficiency• increased risk of PPH

FETAL EFFECT

• Intrauterine fetal death• Spontaneous preterm delivery• Intra partum fetal distress• Meconium stained liquor• The risk of still birth greatest after 37 weeks

COMPLICATION

• Maternal morbidity is low. • The importance of this disorder is the effects on the fetus.• It can lead to chronic placental insufficiency which may result in

anoxia, prematurity, perinatal death, fetal distress and stillbirth.

PREVENTION

1. A Healthy Diet:Eating healthy and hygienic food throughout pregnancy will help you keep jaundice and other health issues at bay. 2. Healthy Weight:Maintain a healthy weight and regulate the cholesterol levels in the blood by keeping fat intake under check. Follow diet chart strictly.3. Active Lifestyle:Consult doctor on safe exercises during pregnancy . It will help you ensure a proper supply of blood and oxygen to different parts of the body, including the liver.

Cont…4. Vaccinate Regularly:Avoid hepatitis infections. Follow gynecologist’s advice and accordingly get yourself vaccinated against the disease.5. Limit Your Drug Intake:Avoid the intake of medications or compounds that may be toxic to the liver. Avoid the overuse of OTC drugs. Consult your doctor before taking any medication during pregnancy.

Cont.. 5.Be On Guard While Traveling:• Avoid traveling to regions that have breakout of diseases like malaria.

If must visit , always use preventive measures.• Do not worry about having jaundice during pregnancy. Early

detection guarantees that mother and baby will be safe. Seek medical opinion as soon as the symptoms of jaundice appear to avail early treatment and ensure a speedy recovery.

MANAGEMENT

PRE PREGNANCY• If previous history of OC ,advice about recurrent risk(90%).• obtain biliary tract ultrasonography to exclude other pathology.PRENATAL• Regular antenatal check up should be done.• Conform the diagnosis with serum bile acid,ALT and AST

measurement.• Monitor serum bile acid in women with a proven diagnosis of OC.

• Exclude viral infection , including hepatitis C , autoimmune hepatitis and other cause of bilary obstruction.• Treat meternal symptoms with simple topical measures e.g. aqueous

cream with menthol.

• Consider ursodoxycholic acid 500 mg BID women with sever symptoms.

• Consider oral vitamin K to reduce the risk of PPH.

• Dexamethamethasone 12mg daily for 7 days with gradual reduction of dose over subsequent 3 days.to improvement in clinical symptoms

• Monitor fetal well being.

POSTNATAL• Blood test should be done before discharged from hospital to check

LFTs and bile salts are reducing, however, LFTs can be raised for the first 10 days after birth in normal pregnancy.

• Vitamin k supplement for baby.

• Use oral contraceptives only with close clinical and biochemical monitoring.• Consider referral to hepatologist if symptoms persist.

LOOKING AFTER YOURSELF/PATIENT TEACHING• There are no special foods to eat or to avoid. As with all pregnant

women, eat a well-balanced diet which includes lots of vegetables, fruit and whole wheat cereals, including bread.• As the flow of bile into the gut is reduced, patient cannot tolerate the

same amount of fat as normal , therefore mother should lower fat intake.

• To help with itching you may give the following suggestions .Have frequent tepid baths.Try not to get too hot.Use lotions such as calamine and aqueous cream with mentholWear loose cotton clothing.

• Few women report what is known as ‘cyclical itching’ during the menstrual cycle. This can happen just before ovulation or just prior to a period but the itching is usually only mild and stops either when ovulation has taken place or period has started.• OC do not influence mother’s ability to breastfeed.

THANK YOU

General objectives•At the end of this classroom session students will be

able to explain jaundice related to pregnancy.

Specific objectives•Define acute fatty liver of pregnancy.• State the etiology of acute fatty liver of pregnancy.• List sign and symptoms of AFLP.• State diagnosis measure of AFLP.• List the Complication of AFLP.• Explain the management of AFLP.•Describe eclampsia , hyperemesis graviderum and

HELLP in relation with jaundice.

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 .

• it is also known as Acute Yellow atrophy/ Acute Fatty metamorphosis .

Cont…

•Acute fatty liver of pregnancy (AFLP) is a serious complication unique to pregnancy first described by Sheehan in 1940. It is characterized by microvesicular steatosis in the liver.

Cont…

• It is a rare condition with an incidence of 5 in 100,000 pregnancies.Acute fatty liver of pregnancy (AFLP) tends to occur in late pregnancy.

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

•Maternal mortality 10-15%•Perinatal mortality 15-20%

Pathophysiology • The exact pathophysiology of AFLP is unknown. AFLP is unique

to pregnancy.

• It appears to occur more commonly in primiparous women than multiparous women.

•Women who develop AFLP are more likely to have a long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) deficiency.

Cont…

• LCHAD is found on the mitochondrial membrane and is involved in the beta oxidation of long-chain fatty acids. • This gene mutation is recessive; therefore, outside

of pregnancy under normal physiological conditions, women have normal fatty acid oxidation.

•However, if the fetus is homozygous for this mutation, it will be unable to oxidize fatty acids.

Cont…• These acids are passed to the mother, who,

because of diminished enzyme function, cannot metabolize the additional fatty acids.

• This results in hepatic strain leading to the development of AFLP, which can be relieved by delivery of the infant.

ETIOLOGY•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).

CLINICAL PRESENTATION•Rarely may present after delivery.

• Severe nausea , repeated vomiting and upper abdominal pain

•progressive jaundice.

• Leukocytosis and thrombocytopenia are common.

Cont….• Fragmented RBC are seen in those with disseminated

intravascular coagulation.

•Have signs of co existent preeclampsia (50%)

• In severe cases progression over hours or days to fulminant hepatic failure and death.

DIAGNOSIS• The condition is diagnosed by the clinical picture.

• The women’s liver is tender but no enlarged and USG and CT demonstrate the fatty infiltration.

• The liver enzyme is moderately high and women will quickly show the sign of renal failure and become hypoglycemic.

Cont…• Liver function test.

•Raised serum bilirubin.

•Abnormal clotting with coagulopathy (prolongation of prothrombin and partial thromboplastin times with depression of fibrinogen levels).

• Liver biopsy is strongly contraindicated.

Maternal effect• Fulminant hepatic failure • Hepatic encephalopathy •Coagulopathy •Death

Fetal risk• Intrauterine fetal death with a perinatal

mortality rate of 15-65%

•Neonatal risks include transient derangement in LFT ‘s and hypoglycemia

ComplicationsAFLP is a life-threatening condition with a reported 1.8% maternal and 23% fetal mortality rate. Serious complications include:•Disseminated intravascular coagulation (DIC ) and

gastrointestinal bleeding.•Hepatic coma.•Acute kidney injury.•Pancreatitis.•Hypoglycaemia.

MANAGEMENTPRE PREGNANCY• If previous AFLP , check baseline LFT.advice to report

any new symptoms.• Start home testing for urinary protein from 24 week

of gestation.•Monitor BP every two weeks.•Proper stablish diagnosis.

Cont…•Provide intensive care with high dependency setting.•Plan delivery and end pregnancy.

LABOUR AND DELIVERY•Maternal resuscitation by correction of hypoglycemia,

fluid balance and coagulopathy.•Use multidisciplinary approach ideally in liaison with liver

unit to manage liver failure.•Use intensive fetal monitoring.•Perform urgent delivery when maternal condition is

stabilized, vaginal delivery preferable for mother.•Maintain meticulous hemostasis.

POSTNATAL•Continue intensive care management.•Watch for postpartum wound hematoma formation

and sepsis.•Alert for possible PPH.•Recurrence risk is difficult to estimate, perhaps as high

as 10% to 20%.

Cont..• Support contraceptive measure.• Full hepatic recovery expected without further

sequel .occasionally emergency liver transplant needed.•Pediatricians to consider screening baby for LCHAD

deficiency.•Prenatal diagnosis of LCHAD possible by amniocentesis if

previous baby affected.

HYPEREMESIS GRAVIDARUMHyperemesis gravidarum (HG) is defined as intractable nausea and vomiting during pregnancy that often leads to fluid and electrolyte imbalance, weight loss of 5% or greater, and nutritional deficiency requiring hospital admission .

Cont… • Liver involvement is seen in about 50%-60% of patients with HG

.

•Most commonly seen are mild serum aminotransferases elevations, but there are reported cases of severe transaminase elevations (alanine aminotransferase (ALT) levels 400 to over 1000 U/L).

•Mild hyperbilirubinemia with mild jaundice can be seen as well.

PREECLAMPSIAPreeclampsia defined by the triad of hypertension, edema, and proteinuria. It affects about 5%-10% of all pregnant women and usually occurs late in the second trimester or in the third trimester.

Cont….Abnormal laboratory values include a 10- to 20-fold elevation in aminotransferases, elevations in alkaline phosphatase levels that exceed those normally observed in pregnancy, and bilirubin elevations of less than 5 mg/dL

Cont….Liver histology generally shows hepatic sinusoidal deposition of fibrin along with periportal hemorrhage, liver cell necrosis, and in severe cases, infarction; these changes are likely due to vasoconstriction of hepatic vasculature

HEMOLYSIS, ELEVATED LIVER TESTS AND LOW PLATELETS (HELLP)

HELLP syndrome is a multisystemic disorder of pregnancy involving hemolysis, elevated liver tests, and low platelets. About 70% of cases occur antenatally, during the last trimester of pregnancy

Cont…A dehydrogenase (LCHAD) has also been described, suggesting a possible overlap of HELLP syndrome and acute fatty liver of pregnancy. Laboratory findings include hemolysis with increased bilirubin levels (usually less than 5 mg/ dL)

• http://patient.info/health/obstetric-cholestasis-leaflet• James , Steer , weiner and Gonik; High Risk Pregnancy : Management

Option,4th edition ; Elsevier Publication.• Datta D.C.;Text Book Of Obstetric;6th edition ; New Central Book

Agency(P) LTD.• Patient.info/doctor/jaundice-in pregnancy