Neonatal hpyerbilirubinemia dr.sameer

NEONATAL HYPERBILIRUBINEMIA

Prepared by

Dr. Sameer Bajubair

BACKGROUND

• The normal TSB level is < 1 mg/dl

• Neonatal clinical jaundice is Dx. If the TSB is

> 5 mg/dL in FT NB.

> 7 mg/dL in preterm NB .

Neonatal HyperbilirubinemiaDefinition : Is an elevation of TSB level is > 2mg /dl , it is a common condition among NB babies ,and most of

the cases are benign problem

However, untreated sever unconjugated hyperbilirubinemia is potentially neurotoxic,

whereas conjugated hyperbilirubinemia is often signifies a serious underling illnesses

Definition of Jaundice :Yellowish discoloration of skin , mucous membranes , and

sclera

Neonatal Hyperbilirubinemia

IncidenceUp to to 60% of all full-term NB & 80% preterm NB

Source of Bilirubin 75% comes from breakdown of Hb 25% comes from breakdown of free heme , non-

Hb proteins and ineffective erythropoisis

• 1gm of Hb produce about 34-35mg of bilirubin• 1gm of albumin bind 8.5 mg of bilirubin

Bilirubin Production & Metabolism

Metabolism

1. Bilirubin Transport

2. Bilirubin Hepatic uptake

3. Bilirubin Conjugation

4. Bilirubin Excretion


RBC catabolism •Heme-proteins •Infective erythropoisis

Biliverdin

Accepter protein (Y or Z) Glucronyl

transferase

Smooth RES

Bilirubin glucuronide B-glucuronidase Fecal bilirubin

Bilirubin +

Albuimn

25%Heme 75%Heme

Hemeoxidase

RES Biliverdin

reductase

Enterohepatic Recirculation

Of bilirubin Intestinal Bacteria

urobilinoids


Forms Of Hyperbilirubinemia

• unconjugated hyperbilirubinemiaElevation of serum UCB 2 mg/dl or more

• conjugated hyperbilirubinemiaIs increase level of CB > 20% of the total serum

bilirubin It is a sign of hepatobiliry dysfunction

UNCONJUGATED B( indirect B)

CONJUGATED B(direct B)

Lipid-soluble Can not be excreted by the kidney Can enter the CNS particularly in NB (neurotoxic) Skin color lemon yellow or orange yellow Physiological & pathological

Water solubleCan be excreted by the kidney Can not enter the CNS ( non neurotoxic)Skin color greenish or muddy yellow Always pathological

Neonatal Hyperbilirubinemia

1. Increased bilirubin production Physiological jaundice Pathological jaundice Hemolytic diseases

immune ( RH, ABO incompatibility ) or subgroup

non-immune ( G6PD deficinciecy H. spherocytosis)

Extravasated blood (cephalhematoma, extensive bruises )

polycythemia sepsis 2. Defective transport of bilirubin in the circulation Hypoalbuminemia ( prematurity , postnatal malnutrition ) Drugs e.g. synthetic vit. K, sulfonamide , salicylate , gentamicin , aminophyline furosemide , and digoxin .)

by displacement of bilirubin from its albumin binding sites

3. Defective bilirubin uptake by the liver Physiological jaundice Pathological jaundice prematurity deficiency of lgandin ( Y and Z proteins ) sepsis breast milk jaundice

4. Defective conjugation of bilirubin Physiological jaundice Pathological jaundice Hypothyroidism sepsis Crigler-Najjar syndrome (Type I and II) Lucey – Driscoll syndrome

5. Increased enterohepatic circulation Bowel obstruction ( meconum ileus) Delayed passage of meconum ( meconum plug , delayed feeding ( breast feeding jaundice ) and hypothyroidism

Etiology of Unconjugated Hyperbilirubinemia

Etiology of neonatal Hyperbilirubinemia

Physiological jaundice

criteria• Onset after 36 hr of age ( 2nd – 3rd day ) • Rate of bilirubin rise < 5mg/dl /day • Peak of bilirubin con. Up to 12mg/dl in FT & Up to 14mg/dl in preterm • Duration 8 days in FT NB. & 14 days in preterm• Serum CB level < 2mg/dl at any time • The NB. Looks normal not anemic not sick active

with normal color of urine and stool • It dose not require any treatment

Mechanism of Physiologic Jaundice

Increased RBC volume

Shortened RBC lifespan

Immature hepatic uptake & conjugation

Increased enterohepaticCirculation

Physiological VS Pathological JaundicePATHOLOGICAL JAUNDICE PHYSIOLOGICAL JAUNDICE

At any time, even 1st hr After 36hr ( 2nd – 3rd day ) ONSET

>5 mg/dl per 24hr or >0.5mg/dl/hr

<5 mg/dl per 24hr RATE OF BILIRUBIN RISE

>12 mg/dl in FT NB >14 mg/dl in preterm NB

Up to 12mg/dl in FT NBUp to 14mg/dl in preterm NB

PEAK BILIRUBIN CONC.

> 1 wk in FT NB > 14 days in preterm NB

8 days in FT NB 14 days in preterm NB

DURATION OF PERSISTENCE

>2 mg/dl at any time <2 mg/dl at any time SERUM CB LEVEL

Looks abnormal , anemic sick & abnormal color of urine & stool

Looks normal not anemic not sick normal urine & stool color

CINICALLY NB.

Jaundice Associated With Breast-Milk Feeding

Two types of jaundice may occur in newborns who are breast fed. Both types are usually harmless. Breastfeeding jaundice• Occurs in babies who do not nurse well or if the mother's

milk is slow to come in.• Poor weight gain , Delayed stooling

Breast milk jaundice• appear in some healthy Infant show good weight gain ,

normal LFT no evidence of hemolysis or illness

Jaundice Associated With Breast-Milk Feeding Breast milk jaundice Breast feeding jaundice

2% of breast-fed term infant develop UCHB after 1st wk. (10-30mg/dl) during 2nd – 3rd wk. & if BF. Continued slow UCB (3-10 wk)

30% of breast-fed infant Have higher UCB level (>12mg/dl) during the first week of life

After 7 days ( late onset ) (early onset )during the first weekBreast milk has increased B-glucuronidase enzyme activity ,has pregnanediol or unknown substance or FFA that interfere or inhibit H uptake or conjugation

Milk intake , dehydration , Occurs due to delayed stooling or reduced caloric intake

ttt. stop breast feeding for 1-2 days & give other milk formula

then resume breast feeding Rapid UCB in 48 hr

ttt. Frequent breast feeding ( >10 feeding/day)Do not supplement with glucose water

Risk factors for developing severe hyperbilirubinaemia

• Major risk factors– jaundice in first 24 hours (always

pathologic)– ABO or Rh incompatibility and

positive coombs test– G6PD deficiency – Delivery at 35 to 36 weeks gestation– Significant Birth trauma

• Cephalhematoma • Large hematomas

– Infant Breast feeds only (especially before milk let-down occurs)

– F.H/O sibling who required phototherapy for Neonatal jaundice

– Serum bilirubin in high risk range for age in hours

• Minor risk factors– Male gender– Maternal age over 25 years old– Macrosomic IDM– Delivery at 37 to 38 weeks

gestation– Serum bilirubin in intermediate

range for age in hours• Other risk factors

– Polycythemia– Medication exposure

• Mother: Diazepam, Oxytcin• Infant: Pediazole,

Chloramphenicol

Time appearance of jaundice may suggest the cause

Within 1st 24hr of life • Erythroblastsis fetalis • TORCH infection • Extravascular hematoma • Sepsis • polycythemia On the 2nd -3rd day • Physiological• Crigler-Najjar syndrome• Early onset Breast feeding

jaundice After 3rd day and Within the 1st wk • Bacterial sepsis • TORCH + Enterovirus • Hematoma

After 1st wk of life • Breast milk jaundice • Extrahepatic Biliary atresia • HypothyroidismPersistent jaundice during the 1st mo of

life • Inpsissated bile syndrome (post-

hemolytic cholestasis )• Hyperalimenation-associated

cholestasis• Hypothyroidism• pyloric stenosis • Hepatitis (TORCH infection)• Extrahepatic Biliary atresia• Galactsemia • Breast milk jaundice • Crigler-Najjar syndrome

Time appearance of jaundice may suggest the cause

NOTE: • Jaundice due to hemolytic anemia , in utero

infection (TORCH) and sepsis may present at any time after birth

Approach to any pt whit jaundice in neonatal period

History 1. Family H/O jaundice , anemia , splenectomy (chronic

hemolytic anemia), liver disease 2. Previous sibling with jaundice (blood group incompatibility)

or Breast milk jaundice 3. Maternal illness during pregnancy : TORCH infection or DM

febrile illness

4. Maternal drugs : sulphonamides , antimalaria or

salicylate (may cause hemolysis in G6PD-def. infant )5. Maternal blood group and RH , 6. Hx. Of abortion or SB & use of Anti-D if she was Rh – ve 7. Labor history : use of forceps vacuum asphyxia ,delayed

cord clamping 8. Postnatal H/O day of Onset, general condition, vomiting,

infrequent stooling , light colored stool, delayed Breast feeding, whether the infant is breast-fed or formula-fed



Physical Examination• Color of Jaundice (lemon yellow or orange yellow UCB type ,

greenish or muddy yellow CB type)• (face =5mg/dl, mid abdomen =15mg/dl, sole = 20mg/dl )• Pallor , plethora , petechiae • Signs of Prematurity • SGA (polycythemia ,TORCH infection ) • Microcephaly (TORCH infection)• Cephalhematoma , bruises • Hepatospleomegaly ( hemolytic anemia , infection )• Signs of Hypothyroidism • Signs of neonatal sepsis • Omphalitis ( septicemia )• Signs of Kernicterus


Laboratory investigation & other paraclinical • Serum bilirubin total & direct• blood group and RH of the infant & mother • Coombs test • CBC (Hb, Hct ,WBC )& Red cell morphology, S. electrolyte, RBS • Reticulocyte count , G6PD enzyme assay ,osmotic fragility test • Screening for TORCH infection • Screening for sepsis (CRP, Blood cultures & other sites cultures , ESR )• LFT ( serum albumin )• Stool & urine analysis • CXR • Abdominal U/S • ERCP

• Thyroid Stimulating Hormone• Galactosemia Screen

Kernicterus

Definition ( Bilirubin Encephalopathy )Neurological syndrome resulting from the

deposition of UCB in the • Basal ganglia • Brainstem nuclei• Various cranial nerve nuclei • Cerebellar nuclei

Kernicterus

Incidence 30% in of infant of all gestational age with

untreated hemolytic disease

Total Bilirubin > 25 to 30 mg/dl

Kernicterus

Risk factors • UCB level > 30mg/dl but the range is wide (21-

50mg/dl)• Duration of exposure to hyperbilirubinaemia• Hypoproteinemia , Drugs , free FA • Prematurity , Asphyxia , hyperosmlarity ,Seizures ,

hypertension , infection ( increase permeability of BBB to bilirubin )

Kernicterus

Kernicterus

Clinical manifestations• onset 2nd – 5th day of life , or as late 2nd - 3rd wk. • Acute form• Chronic form

Phase 3 ( after the 1st wk ) Phase 2 ( middle of 1st wk ) Phase 1 ( 1st 12 days )

Hypotonia Hypertonia Hypotonia apnea Irritability Lethargy

opisthotonus RD Poor feeding

Seizures Fever Vomiting

If pt. recover show few abnormality (hypertonia)

Bulging Fontanel High – pitched cry

Seizures loss of Moro reflex opisthotonus Seizures

Death Death Death

Acute form

Kernicterus

Kernicterus

Chronic form• Kernicterus (Residual deficits)

– Spasticity– Severe athetoid Cerebral Palsy– High frequency Hearing Loss or Deafness– Mild Mental Retardation – Upward gaze paralysis

• Dental dysplasia

Prevention of Kernicterus American academy of pediatrics has identified potentially preventable

causes of Kernicterus :• Early discharge (<48hr ) with no early follow-up within 48hr • Failure to check the bilirubin level in infant noted to be jaundiced in

the 1st 24hr • Failure to recognize the presence of risk factors for hyperbilirubinaemia • Underestimation of the severity of jaundice by clinical ( visual )

assessment • Lack of concern regarding the presence of jaundice • Delay in measuring S.Bilirubin level despite marked jaundice or delay

in initiating phototherapy in presence of elevated Bilirubin level • Failure to respond to parental concern regarding jaundice , poor

feeding or lethargy

Recommendation

• Any infant who is jaundiced before 24hr requires measurement of TSB

level & if it is elevated then should evaluated for possible hemolytic

disease

• Follow-up within 2-3 days of discharge to all NB discharged earlier

than 48hr after birth esp. < 38 wk gestation

• Avoid routine supplementation with water or glucose water

• Provide parents with written &verbal information about NB jaundice

Prevention of Kernicterus

• The goal of therapy is to prevent kernicterus

• Interpret all bilirubin levels according to the infants age in hours

• Treat newborn ,when indicated with phototherapy or exchange

Management of unconjugated hyperbilirubinaemia

Management of UC hyperbilirubinaemia

1. Phototherapy 2. Exchange Transfusion 3. Treatment of the Etiological factor : Hypothyroidism Stop drugs Correction any factor that increase the

permeability of UCB eg. Acidosis Increase frequency & volume of milk feeding

A . Conventional Phototherapy

A blue light and day light with wave 425-475nm and 550-600 consequently is best

B . Intensive phototherapy

Fluorescent blue , fiberoptic blanket phototherapy

NOTE : Phototherapy decrease the need for exchange transfusion & decrease No. of exchange transfusion, but it is not substitute for exchange transfusion

Phototherapy

The effectiveness of phototherapy in reducing UCB depends on :

A. The light emitted in the effective range of wavelengths (240- 470nm)

B. The distance between light source and infant (most effective if 45cm)

C. The surface area of skin exposed D. The rate of hemolysis and excretion

Phototherapy

In premature NB without of significant of hemolysis, UCB level usually declines 1-3 mg/dl after 12- 24hr of exposure

Phototherapy

Complicated Course Uncomplicated Course Birth weight ( g )

10- 12 mg/dl 12-13mg/dl <1,000

10- 12 mg/dl 12 - 14 mg/dl 1,000 – 1,25012 -14 mg/dl 14 - 16 mg/dl 1,251 – 1,499

15 – 17 mg/dl 16 - 20 mg/dl 1,500 – 1,999 18 – 20 mg/dl 20 – 22 mg/dl 2,000 – 2,500

Suggested Maximal UCB concentration in preterm infant

Complications as: p.asphyxia,acidosis,hypoxia,hypothermia,hypoalbuminemia,me

ningitis,IVH,hemolysis,hypoglycemia,signs of kernicterus.


• Phototherapy is usually started at 50 – 70 % of

the maximal indirect level

• If the values exceed this level ,if Phototherapy

is unsuccessful in reducing the maximal

indirect level ,or if signs of kernicterus are

evident EXCHANGE TRANSFUION is indicated


Phototherapy

Indication of Phototherapy1. Abnormal rise of UCB level 2. While waiting for & in between exchange

transfusion 3. Prophylactic in some cases : a. VLBW infant

b. Hemolytic disease of NB c. Severely bruised premature infant

Phototherapy

Procedure • It is applied continuously except during feeding • Infant kept naked except for eyes bandage and a diaper • The infants are turned every 2 hr • Monitoring of Temp. /2hr , UCB level & Hct. /4-8hr in

case of hemolysis and 12-24hr for other cases , and body Wt. daily

• The Lamps should be changed after 2,000 hr of use

Phototherapy

When discontinue phototherapy ?When the level of UCB is low to eliminate

concern about toxic effects of UCB

• TSB level should be followed for at least 24hr after discontinue phototherapy

• Risk factors for toxic level of UCB are absent • The baby is old enough to handle the bilirubin load • Usually at the level < 13-14 mg/dl in term NB

Phototherapy

Guidelines for phototherapy in hospitalized infants of 35 or more weeks’ gestation. Note: These guidelines are based on limited evidence and the levels shown are approximations .

Contraindication of phototherapy • Conjugated hyperbilirubinaemia Risk of bronze baby syndrome

Phototherapy

Side effects of phtoyherapy 1. Dehydration 2. GIT ( loose or watery Diarrhea ) 3. Damage of Corneal4. Dermatitis (erythemtous macular rash & purpuric rash

)5. DNA damage 6. Decrease maternal-infant interaction 7. Dark grayish-brown discoloration of skin (bronze baby

syndrome)

Phototherapy

2- Exchange transfusionThe goals of exchange transfusion in immune

Hemolytic disease :o To correct anemia o To remove the sensitized RBCs o To remove the antibodies o To reduce the UCB level

Management of UC hyperbilirubinaemia

Exchange Transfusion

Indications A. Severe hyperbilirubinaemia refractory to phototherapyB. Hemolytic disease of NBC. Others :

Septicemia DIC Polycythemia IEM Hypomagnesaemia Respiratory depression

Procedure Start phototherapy until Exchange transfusion• Estimate the BWt , GA, vital signs and CVP• Pre-exchange blood sample labs Serum bilirubin total & direct blood group and RH of the infant Coombs test CBC (Hb, Hct ,WBC )& Red cell morphology Reticulocyte count S,Ca ,RBS LFT ABG


• Aspirate 20 cc of infant's blood• Infuse 20 cc of donors blood

• Exchange transfusion should carried out over (45-60 min )• Monitoring during Exchange transfusion: Body temp., CVP , Bp , PaO2 , pH,BS, S.Ca , • Blood Volume is double the blood volume of the infant = 2 × 85 ml /kg = 170 ml /kg

• Umbilical Venous Catheter placed at 7 cm or less• Alternate aspiration and infusion


Blood used in exchange transfusion :• Fresh , warm , washed and irradiated • Grouping : in Rh incompatibility use infant’s ABO group, Rh – ve in ABO incompatibility use group O, infant’s Rh type For others infant’s ABO, Rh group.




Guidelines for exchange transfusion in infants 35 or more weeks’ gestation. Note that these suggested levels represent a consensus of most of the committee but are based on limited

evidence, and the levels shown are approximations .

Complications1. Vascular :Embolization (air , clot), vasospasm and

thrombosis (portal vein)2. Cardiac : Arrhythmia, arrest, CCF 3. Electrolyte disturbance : Hyperkalemia,

hypoglycemia, hypernatremia, hypocalcaemia and metabolic acidosis

4. Bleeding : Thrombocytopenia, deficient clotting factors

5. Infections : Bacteremia, HBV, HCV, AIDS, CMV, malaria 6. Miscellaneous : Hypothermia, NEC 7. Death : 0.3/100


Sick infant (Total serum bilirubin (TSB)mg/dl)

Healthy infant (Total serum bilirubin (TSB)mg/dl)

Weight (g)

Exchange transfusion phototherapy Exchange transfusion phototherapy

Variable 4 – 6 Variable 5 – 7 UP TO 1,000

Variable 6 – 8 Variable 7 – 10 1,001-1,500

Variable 8 – 10 Variable 10 – 12 1,501-2,000

Variable 10 – 12 12 – 15 Variable

2,001-2,500

18 - 20 12 – 10 15 – 18 20 – 25 > 2,500

Management of UC hyperbilirubinaemia based on

birth Wt. & relative health of the NB

Other therapies

• Phenobarbital: as adjunct management It is recommended only in Crigler-Najjar

type II

• Metalloporphyrins : by inhibits conversion of heme to biliverdin, so reduce UCB level in (ABO incompatibility or G6PD deficiency)

• Intravenous immunoglobulin 0.5 – 1 g/kg/dose over 4 hr repeated in 12 hr it is

recommended in persist isoimmune hemolytic disease (both ABO & Rh ).

Familial UC Hyperbilirubinaemia

Crigler-Najjar Disease :• Congenital deficiency or absence of glucuronyl

transferase enzyme • Autosomal recessive Type I : Congenital absence of the enzyme kernicterus develops early leading to death Type II : partial deficiency of the enzyme

the condition improves on administration of phenobarbitone & kernicterus is unusual

Gilbert’s syndrome• Benign disorder • Can result from mutations to genes coding for

UDP-glucuronyl transferase

Familial UC Hyperbilirubinaemia

Definition An increased level of direct bilirubin >20% of the

total serum bilirubin It is a sing of hepatobiliry dysfunction

Conjugated Hyperbilirubinaemia


Hepatic Idiopathic neonatal hepatitis intrahepatic cholestasis with paucity

of bile duct (Alagille syndrome ) Infections

Sepsis Viral Hepatitis TORCH infections

Metabolic GalactosemiaAlpha-1-antitrypsin deficiencyCystic fibrosis

Drugs Total parenteral nutritionPost-hepatic Biliary atresia Bile duct obstruction Choledochal cyst

causes

Others Dubin-Johnson syndrome

Rotor s syndrome

http://en.wikipedia.org/wiki/Alpha-1-antitrypsin_deficiency

Clinical manifestations • Greenish jaundice due to CB • The stool are clay in color while urine is dark • Hepatospleomegaly • Other clinical manifestations of the etiology may

be present e.g. refuse feeding purpura ... etc.


Investigations • Sepsis work up • TORCH screen • LFT • Abdominal U/S• ERCP


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Neonatal hpyerbilirubinemia dr.sameer