neonatal hyperbilirubinemia management

MANAGEMENT OF HYPERBILIRUBINEMIA IN NEWBORNS

Dr. ANIL KUMAR K MM.D. TRAINEE

DEPT. OF PEDIATRICSGOA MEDICAL COLLEGE

BilirubinBilirubin metabolism metabolism

PATHOPHYSIOLOGICAL IMPORTANCE OF BILIRUBIN

METABOLISM It is the end product of heme degradation.Serum bilirubin level is an important clinical

marker of hepatobiliary excretory function.Bilirubin is an endogenous model for plasma

carriage and hepatic throughput of organic anions.

Hepatic uptake, storage, conjugation and excretion of bilirubin are finely balanced. Therefore, enhancement of bilirubin throughput requires coordinated induction of multiple genes, which may be mediated by nuclear receptors.

Erythroid Non-erythroid

Normal:Normal: Senescent erythrocytesSenescent erythrocytes Free heme Free hemeAbnormal:Abnormal:• Hemolysis:Hemolysis: ExtravascularExtravascular Intravascular Intravascular• Ineffective erythropoiesiIneffective erythropoiesis

(80%) (20%)(80%) (20%)• Cytochromes• Catalase• Peroxidase• Tryptophane pyrrolase

• Myoglobin

Sources of bilirubinSources of bilirubin

Early bilirubin(15-20%)

0- 3 days

Late bilirubin(65%)

40- 80 days

Non-Hbsources (liver)

Increased erythropoiesis

Erythrocytesources

Early and late labeled peaks of radioisotope incorporation into bilirubinAfter injection of labeled porphyrin precursor (14C-glycine)

Opening of the heme ring and Enzyme-catalyzed formation of bilirubin

Bilirubin throughput: schema of a hepatocyteBilirubin throughput: schema of a hepatocyte

Sinusoidalsurface

Canalicularsurface

Tight junction

Liversinusoid

Fenestratedendothelium

Bilirubin circulates bound to serum albumin.

BBalb

Albumin- binding: Keeps bilirubin soluble Prevents tissue deposi- tion. Prevents renal excretion Drugs that displace bilirubin from albumin may precipitate kernicterus: Sulfonamides Coumadin, etc.


At the sinusoidal surface of hepatocytes, it dissociates from albumin.

BBalb


At the sinusoidal surface of hepatocytes, it dissociates from albumin.

BB

alb

Bilirubin enters through the sinusoidal surface, probably by facilitated diffusion.

Uptake is energy independent and bidirectional.

BB

Bilirubin uptakeis reduced: In neonates In cirrhosis From drug effect: novobiocin In some cases of Gilbert syndrome

B

Inside the hepatocyte, bilirubin binds to cytosolic proteins termed ligandins, which are the same as glutathione-S- transferases (GSTs).

GSTs

B

GST bindinginhibits theefflux of bilirubin,thereby increasingits net uptake

B

GSTs

B

B

Conjugation of bilirubin with glucuronic acid is catalyzed by UGT1A1, which transfers glucuronic acid from UDP-glucuronic acid to bilirubin

GSTsUDPUDPGAGA UDPUDP

BB GAGAUGT1A1

B

Conjugation with glucuronic acid makes bilirubin water-soluble and non-toxic. Glucuronidation is essential for biliary excretion of bilirubin.

UDP-UDP-glucuronosyltransferases glucuronosyltransferases (UGTs)(UGTs)

• UGTs are ER proteins that convert many internal and UGTs are ER proteins that convert many internal and exogenous toxins to non-toxic metabolites.exogenous toxins to non-toxic metabolites.

• UGT’s are a family of enzymes concentrated in the liver.UGT’s are a family of enzymes concentrated in the liver.• One UGT isoform, UGT1A1, conjugates bilirubin and is One UGT isoform, UGT1A1, conjugates bilirubin and is

essential for its excretion. essential for its excretion. • Inherited UGT1A1 deficiency causes jaundice.Inherited UGT1A1 deficiency causes jaundice.

Substrate

UDPGAUDPGA

•UGTUGT GlucuronideGlucuronide

UDPUDP

Inherited disorders of bilirubin metabolism causing Inherited disorders of bilirubin metabolism causing

Unconjugated HyperbilirubinemiaUnconjugated Hyperbilirubinemia

• Crigler-Najjar syndrome Crigler-Najjar syndrome type 1:type 1:

• Crigler-Najjar syndrome Crigler-Najjar syndrome type 2:type 2:

• Gilbert syndrome:Gilbert syndrome:

Virtually no UGT1A1 activityVirtually no UGT1A1 activity

UGT1A1 activity below 10% UGT1A1 activity below 10%

UGT1A1 activity ~30% UGT1A1 activity ~30%

NEONATAL HYPERBILIRUBINEMIA• Clinical jaundice appears in newborns when the bilirubin levels is more

than 7 mg/dl

• 85% of term newborns and most of the premature infants develop clinical jaundice

• 6% have bilirubin more than 12.9mg/dl and 35 have bilirubin more than 15 mg/dl.

PHYSIOLOGICAL HYPERBILIRUBINEMIA

• Serum UCB rises to >2mg/dl in first week of life• Peaks to 6- 8 mg/dl by 3 to 5 days of age• This normal jaundice is attributed too following conditions:

Increased rbc volume per kgIncreased ineffective erythropoiesis and increased turnover of non heme

proteinsIncreased enterohepatic circulationDecreased uptake of bilirubin from plasma caused by decreased ligandinDefective conjugation due to decreased UGT activityDecreased hepatic excretion of bilirubin

NON PHYSIOLOGICAL HYPERBILIRUBINEMIA

• Onset of jaundice is before 24 hours• Elevation of serum bilirubin that requires phototherapy• A rise in serum bilirubin levels of >0.2 mg/dl/hour• Signs of underlying diseases in an infant(vomiting, lethargy, poor feeding,

excessive weight loss• Jaundice persisting after 8 days in a term infant or after 14 days in a

premature infant.

POINTS TO BE NOTED IN HISTORY..

1. A family history of jaundice , anemia, splenectomy or early gallbladder disease suggests hereditary hemolytic anemia (spherocytosis, G6PD deficiency)

2. A family history of liver disease may suggest galactosemia, alpha-1 anti trypsin deficiency, tyrosinosis, hypermethionemia, gilberts syndrome, criggler najjar syndrome type1 and 2 and cystic fibrosis

3. Sibling with jaundice or anemia may suggest blood group incompatibility

4. Maternal illness during pregnancy may indicate congenital viral infection / toxoplasmosis

• Maternal drugs may interfere with bilirubin metabolism like sulfonamides or may cause hemolysis in g6pd deficient infants.

• Labour and delivery history may show trauma associated with extravascular bleeding and hemolysis. Oxytocin use in labour may be associated with neonatal hyperbilirubinemia

• Infants with HIE , delayed cord clamping.• Delayed / infrequent stooling

BREAST FEEDING JAUNDICE BREAST MILK JAUNDICEHigher bilirubin levels in infants who are exclusively breast fed after day 3 of life

Peak level of bilirubin is >12 mg/dl in breast fed infants

Main factor responsible for breast feeding jaundice is decreased in take of milk that leads to slower eliminationof bilirubin and increased entero hepatic circulation

Late onset of more than 4 days after life

Bilirubin continues to rise and may reach upto 20 to 30 mg/dl by 14 days.

Mechanism thought to be due to unidentified factors in the milk interfering with the bilirubin metabolismand due to increased beta glucorinidase in breast milk causing increased enterohepatic circulation.

POINTS TO BE NOTED IN THE PHYSICAL EXAMINATION• Prematurity

• SGA ----------- polycythemia and in-utero infection• Microcephaly ---------- in-utero infection• Extra vascular blood bruising , cephalhematoma• Pallor ---------------- hemolytic anemia or extra vascular blood loss• Petechiae associated withcongenital infection, sepsis or

erythroblastosis• HSM --------- hemolytic anemia, congenital infection/ liver disease• Omphalitis • Chorioretinitis ------------- congenital infection• Evidence of hypothyroidism

METHODS OF BILIRUBIN ESTIMATION

• Visual inspection is not a reliable method of bilirubin estimation

• Screening of total serum bilirubin (TSB) collected predischarge from the baby and plotted on an hour specific normogram helps to identify the infants at risk.

• Trans cutaneous bilirubin measurement using multiple wavelength analysis can reliably estimate serum bilirubin levels

TRANSCUTANEOUS BILIRUBIN ESTIMATIONADVANTAGES DISADVANTAGES• Reliably estimates irrespective of skin

pigmentation post natal age and weight of infant

• Reduce the number of invasive blood tests performed

• Reduce the health care costs

• It’s a screening tool and needs to confirm the value with total serum bilirubin levels when

1. TcB is > 70 th percentile for the phototherapy value

2. When TcB exceeds more than 75th percentile in bhutani’s normogram

3. At follow up if TcB is more than 13 mg/dl.

• TcB monitoring is unreliable after phototherapy has begun due to bleaching of skin.

• End tidal corbon monoxide (ETCOc)

o Offers insight into the underlying pathological process contributing to hyperbilirubinemia

o Only parameter that provide direct information on the rate of bilirubin production

o Can differentiate between infants with increased production, decreased elimination or decreased conjugation if the test is used in combination with total serum bilirubin levels

OTHER CLINICAL TESTS TO BE DONE..

1. Blood type , Rh and antibody screen of the mother2. Blood test, Rh and antibody screen if the infant

• Routinely recommended if the mother is Rh negative

• Peripheral smear for RBC morphology and reticulocyte count• Hematocrit • Identification of antibody on infants RBC if result of direct Coomb’s test

is positive• Direct bilirubin• A G6PD screen in male infants

• In cases of prolonged jaundiceMeasure the direct componentTest for liver diseaseCongenital infectionSepsis, metabolic defectsHypothyroidismTPN is an important cause for prolonged hyperbilirubinemia

BILIRUBIN TOXICITY• Bilirubin enters the brain as free unbound bilirubin or bilirubin bind to

albumin in case of disrupted blood-brain barrier.• FFAs and some drugs interfere with the binding of bilirubin to albumin • The blood brain barrier is disrupted in cases of hyperosmolarity, asphyxia

and hypercarbia.• More permeable in premature infants.

KERNICTERUS• Pathological diagnosis• Yellow staining of brain with bilirubin and evidence of neuronal injury• Most commonly in basal ganglia, various cranial nuclei, brainstem nuclei,

cerebellar nuclei, hippocampus, anterior horn cells of spinal cord.• Microscopically there is necrosis, neuronal loss and gliois.• Clinically characterized by athetosis, auditory neuropathy, upward gaze

limitation, dental dysplasia and intellectual defects.

ACUTE BILIRUBIN ENCEPHALOPATHY

3 phases :1.Early phase : hypotonia, lethargy, high-pithced cry and poor suck2.Intermediate phase : hypertonia of extensor muscles, irritability, fever and seizures. Mostly fatal. If infants survive this phase then chronic bilirubin encephalopathy (clinical diagnosis of kernicterus is made).3.Advanced phase : pronounced ophisthotonus, shrill cry, apnoea, seozures, coma and death.

MANAGEMENT OF UNCONJUGATED HYPERBILIRUBINEMIA

• GENERAL PRINCIPLES

• PREVENTIVE MEASURES AND EARLY IDENTIFICATION OF CAUSE IMPORTANT• ANY MEDICATION THAT INTERFERE WITH BILIRUBIN METABOLISM/ INTEGRITY

OF BLOOD-BRAIN BARRIER SHOULD BE DISCONTINUED• CORRECT INADEQUATE FEEDING OF INFANTS AND EVACUATION OF

MECONIUM• ASPIRATION OF CEPHALHEMATOMA• TREATMENT OF SEPSIS AND HEPATITIS• CORREECT HYPOTHYROIDISM IF PRESENT

• ROLE OF PHENOBARBITONE:• Barbiturates shown to improve the maturation of microsomal enzymes,

ligandin and gludoronyl transferace thus improving the uptake conjugation and maturation of bilirubin

• Lag period of 48 to 72 hours exists before enzyme activity is induced by phenobarbitone so is administered within 72 hours of life even administered prenatally

• Indicated in infants with i. Cord bili >2.5 mg/dlii. Early onset jaundice due to any causeiii. Difficult or instrumental / oxytocin induced deliveryiv. G6PD deficiency and type ii crigler najjar syndrome

• Added benefit of phenobarbitone is that it protects fetal brain against hypoxic damage and may reduce the incidence of intraventricular hemorrhage.

• Clofibrate is another drug which is a potent enhancer of glucoronyl transferace than phenobarbital .

• 100% increase in hepatic metabiolism in one study in one week • But it is slow in action and takes several days for its action .

MEASURES TO REDUCE SERUM BILIRUBIN

• PHOTOTHERAPY

• IVIg

• EXCHANGE TRANSFUSION

• METALLOPORPHYRINS

PHOTOTHERAPY• Relatively safe and effective method for treatment of neonatal

hyperbilirubinemia

• Bilirubin absorbs light maximally at 425- 475nm • 3 photochemical reactions occur when bilirubin is exposed to light:

A. Structural isomerizationB. Photoisomerization C. Photo- oxidation

• STRUCTURAL ISOMERIZATION• Intramolecular cyclization of bilirubin to lumirubin.• Lumirubin is rapidly excreted in bile and urine without conjugation• The conversion is irreversible• Most important pathway in the lowering of serum bilirubin• Strongly related to the dose of phototherapy used in the range of 6 to 12

micro watts/cm^2/ nm

NH

MV

ONH

M CH2OH

CH2

NH

NH

CH2

CH2

C

OOH M MV

O

CH2 C

O

Internal hydrogen bonds are disrupted transiently upon exposure of bilirubin to light.

C

C

The dipyrrole carbon bridges switch direction.

NH

MV

ONH

M CH2OH

CH2

NH

NH

CH2

CH2

C

OOH M MV

O

CH2 C

O

Thus a carbon atom comes in the way of the hydrogen bonds.


NH

MV

ONH

M CH2OH

CH2

NH

NH

CH2

CH2

C

OOH M MV

O

CH2 C

O

Thus a carbon atom comes in the way of the hydrogen bonds.


C

C

NH

MV

ONH

M CH2OH

CH2

NH

NH

CH2

CH2

C

OOH M MV

O

CH2 C

O

C

C

The bulky carbon atom disrupts the hydrogen bonds by steric hindrence.

Phototherapy changes the configuration of bilirubin makingit transiently water soluble

• Photo isomerization • Occurs in extravascular spaces of skin• The natural isomer of UCB is converted to less toxic polar isomer and it

diffuses into blood and is excreted in to bile without conjugation• But it’s a reversible reaction and the UCB thus formed again will be

reabsorbed from the gut • Not the major pathway of bilirubin is excretion after starting phototherapy

• Photo – oxidation • Converts bilirubin to small polar compounds that are excreted in urine

• Least important reaction for lowering of bilirubin

INDICATIONS OF PHOTOTHERAPY • Levels of bilirubin are hazardous to the infant although it has not reached

the levels requiring exchange transfusion

• Prophylactic phototherapy is indicated in • ELBW infant and Severely bruised infants where bilirubin is anticipated to

increase rapidly• In hemolytic disease of newborn when rise in serum bilirubin is plotted

• phototherapy is contraindicated in • Infants with direct hyperbilirubinemia caused by liver disease or obstructive

jaundice, and phototherapy may lead to bronze baby syndrome

TECHNIQUE OF PHOTOTHERAPY• Effective phototherapy depends on :

• Light spectrum• Irradiance • Distance from the infant• Extent of skin exposure

• Conventional phototherapy delivers spectral irradiance at infants level of 8 to 10 micro watts/cm^2/nm, 430 to 490 nm when positioned at 20cm above the infant

• Intensive phototherapy delivers atleast 30micro watt/cm^2/nm

• Methods to increase the efficacy of phototherapy:• Reducing the efficacy of phototherapy unit and infant to 15 to 20 cm• Using compact fluorescent tubes• Providing double surface phototherapy • Using slings/ cloth of white colout to reflect light on to the baby• Using high intensity gallium nitride light emitting diodes

PRECAUTIONS TO BE TAKEN IN PHOTOTHERAPY

• Eye patches and genital shield to be ensured• Infants are turned every 2 hours• Eye patches should not occlude the nares as asphyxia and apnoea can

result• Infant temperature should be properly maintained and servo controlled• Infants should be weighed daily• Skin colour is NOT a guide to bilirubin level so bilirubin has to repeated

every 10 to 12 hours

SIDE EFFECTS OF PHOTOTHERAPY

1. Insensible water loss – especially those under radiant warmers. Term infants 40% and pre term infants 80% - 190%, servo controlled warmers decrease this water loss

2. Redistributuin of blood flow -• in term infants the cerebral and pulmonary velocity increases and the left

ventricular and renal velocity decreases. Returns to normal after discontinuation of phototherapy

• In preterm infants the cerebral blood flow velocity increases and the renal bood flow decreases. Also the usual post prandial increase in superior mesenteric artery blood flow is blunted

4. Watery diarrhea and increased fecal loss. The diarrhea is due to increased bile salts and UCB in the bowel.

5. Low calcium levels seen in preterm infants receiving phototherapy6. Retinal damage7. Tanning of skin8. Bronze baby syndrome9. Mutations, sister chromatid exchange and DNA strand breakage10. Tryptophans are reduced. Also methionine and histidine.

EXCHANGE TRANSFUSION• Removes the partially hemolysed and antibody coated RBCs as well as

unattached antibodies and replaces it with donor RBCs lacking the sensitizing antigen

• Within in half an hour of exchange bilirubin levels decrease to 60% of its value

• Furthur increase in post exchange bilirubin is due to the antibody coated RBCs sequestrated in bone marrow and spleen.

INDICATIONS OF EXCHANGE TRANSFUSION

• When phototherapy fails to prevent a rise in bilirubin to toxic levels• To correct anemia and heart failure in hydropic infants with hemolytic

disease• To stop hemolysis and bilirubin production by removing antibody and

sensitized RBCs• In hemolytic disease immediate exchange is usually indicated if:

• Cord bilirubin level is more than 4.5 mg/dl and cord Hb level is under 11 mg/dl.

• Bilirubin level is rising more than 1mg/dl/hour despite phototherapy or more than 0.5 mg/dl/hour if Hb is between 11 and 13 mg/dl

• Progression of anemia despite adequate control of bilirubin levels

BLOOD FOR EXCHANGE TRANSFUSION

• We use fresh (< 7 days old), irradiated and reconstituted whole blood(PCV 45%-50%) made from PRBCs and FFP collected in CPD.

• In Rh hemolytic disease blood should be type Rh negative cross mathched against the mother

• In ABO incompatibility blood should be type O Rh negative or Rh compatible with the mother and infant, be cross mathched against the mother and the infant and have low titre of naturally occurring anti –a or anti- b antibodies. Usually type O cells with AB plasma used

• In other isoimmune hemolytic diseases, blood should not contain sensitizing antigen cross matched against the mother.

• Double the volume of infants blood is used for exchange transfusion(160ml/kg)

TECHNIQUE OF EXCHANGE TRANSFUSION

Infant under servo controlled radiant warmer and cardiac, blood pressure, and oxygen saturation monitor in place

An assistant should be assigned to the infant to record volume of blood, observe the infant and check vital signs

Measurement of potassium and pH of the blood may be indicated if the blood is > 7 days old or if metabolic abnormalities are noted following exchange transfusion

• Blood should be warmed to 37⁰c

• Sterile technique to be used. Old,dried umbilical cord can be softened with saline soaked gauze to facilitate loading the vein and inserting the catheter.

• Exchange is done by push-pull technique through the umbilical vein inserted only as far as to permit free flow of bood. Catheter in heart can lead to arrhythmia.

• Isovolumetric exchange transfusion involves simultaneously pulling blood out of umbilical artery and pushing new blood into the umbilical vein. Better tolerated in small sick or hydropic infants

• If not possible to insert catheter in umbilical vein, exchange transfusion can accomplished through a central venous catheter placed in the anterior cubital fossa or into the femoral vein through the saphenous vein

• In push pull technique blood is removed in aliquots that are tolerated by infants:

• 5ml for <1500 g• 10 ml for 1500-2500g• 15 ml for 2500-3500g• 20 ml for >3500g

• Blood in the pint should be gently mixed after every deci litre of clood transfused to prevent settling of RBCs.

• After exchange transfusion bilirubin levels are measured every 4 hourly**

COMPLICATIONS OF EXCHANGE TRANSFISION1. Hypocalcemia and hypomagnesemia

• Due to citrate in the blood

2. Hypoglycemia • Glucose conc of CPD is about 300mg/dl and may stimulate insulin secretion and

hypoglycemia

3. Acid – base balance disturbance• Citrate is metabolized to alkali and if not metabolized as the baby is ill will cause

acidosis4. Hyperkalemia

• Potassium levels are greatly elevated in stored PRBCS, but washing before before reconstitution removes the excess potassium

5. Cardiovascular complications• Perforation of vessels, embolization, vasospasm, thrombosis, infarction

5. Bleeding • Due to thrombocytopenia and deficient factors

6. Infections • Bacteremia, hepatitis, cytomegalovirus, HIV etc

7. Hemolysis • Hemoglobinemia, hemoglobinuria and hyperkalemia caused by

overheating of the blood8. Graft- versus host diseases

• Transient maculopapular rash, eosinophilia, lymphopenia and thrombocytopenia

• Can be prevented by using irradiated blood. 9. Miscellaneous ( hypothermia, hyperthermia)

IV IMMUNOGLOBULINS• Adjunctive treatment for hyperbilirubinemia due to hemolytic disease

• Recommended when serum bilirubin is approaching exchange levels despite maximal interventions including phototherapy

• IVIg (0.5-1 g/kg/dose; repeated in 12 hours) has been shown to reduce the need for exchange transfusion in both ABO and Rh incompatibility

• Presumably by reducing hemolysis

METALLOPORPHYRINS• Proposed mechanism is competitive enzymatic inhibition of rate-limiting

conversion of heme-protein to biliverdin by heme- oxygenase• A single intramuscular dose of metalloporphyrins reduce the need for

subsequent phototherapy.• Particularly useful when jaundice is anticipated like ABO incompatibility/

G6PD deficiency• Complications include transient erythema if the infant is receiving

phototherapy• Data on efficacy, toxicity and long term benefits are being evaluated.

CONJUGATED HYPERBILIRUBINEMIA

• Failure to excrete conjugated bilirubin from the hepatocyte in the duodenum

• Manifested by a CB level of >2mg/dl or CB level >15% of total bilirubin

• a/w hepatomegaly, splenomegaly and pale stools

DIFFERENTIAL DIAGNOSIS1. Liver cell injury(normal bile ducts)

a) Prologed use of parentral nutrition . Sepsis and ischemic necrosis also cause cholestasis

b) Infection : viral , bacterial, parasiticc) Metabolic : alpha 1 antitrypsin deficiency, cyctic fibrosis, galactosemia,

tyrosinemia, hypermethionemia,storage disorders, etc.2. Excessive bilirubin load(insipissated bile duct syndrome) :

• seen in any hemolytic condition especially in infants with erythroblastosis fetalis

• Also in infants supported on ECMO

3. Bile flow obstruction• Extra hepatic : isolated, a/w choledochal cyst, trisomy 13 or 18 or polysplenia• Intrahepatic : allagille syndrome , choledochal cyst, bile duct stenosis, rupture

of bile duct, lymph node enlargement

• In the NICU the most common cause of unconjugated hyperbilirubinemia in decreasing order are : • Parentral nutrition• Idiopathic hepatitis• Biliary atresia• Alpha 1 anti trypsin deficiency• Intra uterine infection > choledochal cyst > galactosemia > hemolytic

disorders

DIAGNOSTIC TESTS AND MANAGEMENT

• Evaluate for hepatomegaly, splenomegaly, petechiae, chorioretiitis and microcephaly

• Evaluate liver damage by assessing liver function by SGOT, SGPT, PT, APTT, and serum albumin levels

• Establish enteral feeds so that PN can be stopped• Test for bacterial, viral and intra uterine infections• Serum analysis of alpha 1 antitrypsin deficiency• Serum and urine amino acid determination• Urinalysis for glucose and reducing substances

• If known causes are ruled out we have to differentiate idiopathic neonatal hepatitis from bile duct abnormalities

• Investigations done for the same are:o abdominal usg for choledochal cyst or masso Hepatobiliary scan with Tco Nasoduodenal tube to be passed for duodenal fluid collection

• Most cholestasis in NICU is due to prolonged parenteral nutrition. After ruling out other causes(sepsis, metabolic disorders, choledochal cyst and presence of gallbladder) the following management is done :

Enteral feedings even @volumes of 10ml/kg/day is initiated safely

Once enteral feedings are restarted , infants should receive fat soluble vitamin supplements of A,D,E and K

patients on parenteral nutrition should have there LFTs regularly checked. decrease the mineral content ( like copper and manganese)

Phenobarbital should not be used to treat cholestasis in this population

neonatal hyperbilirubinemia management

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