Module 3. Neonatology. Lesson 7. nTopics:

Hemolytic nand hemorrhagic disease of the newborn. Etiology. Pathogenesis. Classification. Clinic. Diagnostics. nDifferential diagnosis. Treatment. Prevention. Outlook.

 

1. Hemolytic ndisease of newborns.

Background: Jaundice is the nmost common condition requiring medical attention iewborns. Approximately n60% of term and 80% of preterm babies develop jaundice in the first week of nlife, and about 10% of breastfed babies are still jaundiced at 1 month of age. nIn most babies with jaundice thevre is no underlying ndisease, and this early jaundice (termed ‘physiological jaundice’) is generally nharmless. However, there are pathological causes of jaundice in the newborn, nwhich, although rare, need to be detected. Such pathological jaundice may nco-exist with physiological jaundice.

Neonatal jaundice refers to yellow colouration of the nskin and the sclera (whites of the eyes) of newborn babies that results from naccumulation of bilirubin in the skin and mucous nmembranes. This is associated with a raised level of bilirubin nin the circulation, a condition known as hyperbilirubinaemia.

The yellow ncoloration of the skin and sclera iewborns with jaundice is the result of naccumulation of unconjugated bilirubin. nIn most infants, unconjugated hyperbilirubinemia nreflects a normal transitional phenomenon. However, in some infants, serum bilirubin levels may rise excessively, which can be cause nfor concern because unconjugated bilirubin nis neurotoxic and can cause death iewborns and lifelong nneurologic sequelae in infants who survive (kernicterus). For these reasons, the presence of neonatal njaundice frequently results in diagnostic evaluation.

Physicians nrecognized neonatal jaundice as early as the 18th century. Supposedly, Morgagni described 15 infants with jaundice (all of them nhis). Descriptions of the clinical course and epidemiology of neonatal jaundice nare found in a number of 19th-century theses and other publications.

Bilirubin

 

Bilirubin is a breakdown product of the red cells in the blood. Red cell nbreakdown produces unconjugated (or ‘indirect’) bilirubin, which is mostly nbound to albumin. Unconjugated bilirubin is metabolised in the liver to produce nconjugated (or ‘direct’) bilirubin, which then passes through the gut and is nexcreted in the stool. Bilirubin can be reabsorbed again from stools remaining nin the gut.

Newborn babies’ red blood cells have a shorter lifespan than those of nadults. The concentration of red blood cells in the circulation is also higher niewborns than it is in adults, so bilirubin levels are higher than they are nlater in life. The metabolism, circulation and excretion of bilirubin is also nslower than in adults. Thus a degree of hyperbilirubinaemia occurring as a nresult of this normal physiological mechanism is common iewborn babies and nusually harmless. It is difficult to tell which babies are at risk of ndeveloping high levels of bilirubin that could become dangerous, or who have a nserious problem as the explanation for their jaundice, which is why this nguideline has been developed.

 

PHYSIOLOGY OF BILIRUBIN IN THE FETUS AND NEWBORN INFANT
nRed blood cells continuously haemolyse in the body nreleasing haemoglobin (Hb) nwhich is converted to unconjugated bilirubin in the reticulo-endothelial nsystem (especially spleen).  One gram Hb yields n600 µmol bilirubin.  In the plasma, unconjugated bilirubin is bound nto albumin. This prevents this fat-soluble pigment from penetrating braitissue to cause damage.

 

 

In the fetus most unconjugated bilirubin is removed by the placenta. However, about 10% is nstill conjugated in the fetal liver and excreted into the gut where it is deconjugated by the enzyme beta glucuronidase nand then reabsorbed via the enterohepatic circulation. nThe fetus therefore ensures that all the bilirubin is nunconjugated to fascilitate nexcretion.

In the newborn infant progressively more bilirubin is taken up by the liver and conjugated with glucuronic acid in the presence of the enzyme glucuronyl transferase. nConjugated bilirubin is water-soluble and is not ntoxic to brain tissue.  It is excreted through the bile duct system into nthe duodenum.  While most is excreted in the stool, but some is changed nback to unconjugated bilirubin nand reabsorbed as the enterohepatic circulation of bilirubin remains for a few weeks after delivery. The nintestinal enzyme beta glucuronidase, which is nresponsible for the enterohepatic circulation of bilirubin, is also present in breast milk. Neonatal jaundice is therefore ncommoner in breast fed than bottle fed infants.

If there is obstruction to the biliary tree, nconjugated bilirubin enters the plasma and may be nexcreted in the urine.

Pathophysiology: Neonatal nphysiologic jaundice results from simultaneous occurrence of the following 2 nphenomena:                                                                                                                     Bilirubin is produced in the reticuloendothelial nsystem as the end product of heme catabolism and is nformed through oxidation-reduction reactions. Approximately 75% of bilirubin is derived from hemoglobin, but degradation of myoglobin, cytochromes, and catalase also contributes. In the first oxidation step, biliverdin is formed from heme nthrough the action of heme oxygenase, nthe rate-limiting step in the process, releasing iron and carbon monoxide. The niron is conserved for reuse, while carbon monoxide is excreted through the nlungs and can be measured in the patient’s breath to quantify bilirubin production.

Next, nwater-soluble biliverdin is reduced to bilirubin, which, because of the intramolecular nhydrogen bonds, is almost insoluble in water in its most common isomeric form (bilirubin IX Z,Z). Due to its hydrophobic nature, unconjugated bilirubin is ntransported in the plasma tightly bound to albumin. Binding to other proteins nand erythrocytes also occurs, but the physiologic role is probably limited. nBinding of bilirubin to albumin increases postnatally with age and is reduced in infants who are ill. nThe presence of endogenous and exogenous binding competitors, such as certaidrugs, also decreases the binding affinity of albumin for bilirubin. nA minute fraction of unconjugated bilirubin nin serum is not bound to albumin. This free bilirubin nis able to cross lipid-containing membranes, including the blood-brain barrier, nleading to neurotoxicity.

When the bilirubin-albumin complex reaches the hepatocyte, nbilirubin is transported into the cell, where it npartially binds to ligandin. Uptake of bilirubin into hepatocytes nincreases with increasing ligandin concentrations. Ligandin concentrations are low at birth, but they increase nrapidly over the first few weeks of life. Ligandin nconcentrations may be increased by the administration of pharmacologic agents nsuch as phenobarbital.

Bilirubin is nbound to glucuronic acid (conjugated) in the hepatocyte endoplasmic reticulum in a reaction catalyzed by nuridine diphosphoglucuronyltransferase n(UDPGT). Monoconjugates are formed first and npredominate in the newborn. Diconjugates appear to be nformed at the cell membrane and may require the presence of the UDPGT tetramer. n

Bilirubin nconjugation is biologically critical because it transforms a water-insoluble bilirubin molecule into a water-soluble molecule. nWater-solubility allows bilirubin to be excreted into nbile. The activity of UDPGT is low at birth, but increases to adult values by nage 4-8 weeks. In addition, certain drugs (phenobarbital, ndexamethasone, clofibrate) ncan be administered to increase UDPGT activity.

Once excreted into nbile and transferred to the intestines, bilirubin neventually is reduced to colorless tetrapyrroles by nmicrobes in the colon. However, some deconjugation noccurs in the proximal small intestine through the –glucuronidases nlocated in the brush border. Thisbaction of  unconjugated bilirubin can be nreabsorbed into the circulation, increasing the total plasma bilirubin pool. This cycle of uptake, conjugation, nexcretion, deconjugation, and reabsorption nis termed the enterohepatic circulation. The process nmay be extensive in the neonate, partly because nutrient intake is limited ithe first days of life, prolonging the intestinal transit time. Certain factors npresent in the breast milk of some mothers also may contribute to increased enterohepatic circulation of bilirubin n(breast milk jaundice), but the mechanism behind this phenomenon remains unelucidated.

Neonatal jaundice, nwhile a normal transitional phenomenon in most infants, can occasionally become nmore pronounced. Blood group incompatibilities (Rh, nABO, and others) may increase bilirubin productiothrough increased hemolysis. Historically, Rh isoimmunization was aimportant cause of severe jaundice, often resulting in the development of kernicterus. While this condition has become relatively nrare in industrialized countries following the use of Rh nprophylaxis in Rh-negative women, Rh isoimmunization remains common in developing countries. Nonimmune hemolytic disorders (spherocytosis, nG-6-PD deficiency) also may cause increased jaundice through increased hemolysis.

A number of other nonhemolytic nprocesses can increase serum bilirubin levels. nAccumulation of blood in extravascular compartments (cephalhematomas, bruising, occult bleeding) may increase bilirubin production as the blood is absorbed and degraded. nIncreased bilirubin production also is seen ipatients with polycythemia and in infants of mothers nwith diabetes. Increased enterohepatic circulatioleading to elevated bilirubin levels is seen ipatients with bowel obstruction or ileus and wheinfants are not fed for other reasons.

Decreased clearance of bilirubin nis seen in certain inborn errors of metabolism, such as Crigler-Najjar nsyndrome, Gilbert syndrome, galactosemia, tyrosinemia, and hypermethioninemia. nIn the latter 3 conditions, elevations of conjugated serum bilirubin noccur frequently. Hormone deficiencies, such as hypothyroidism and hypopituitarism, also can decrease bilirubin nclearance. Finally, decreased clearance may play a role in breast milk njaundice.

Compared to unconjugated hyperbilirubinemia, nconjugated (direct) hyperbilirubinemia is rare ineonates. Conjugated hyperbilirubinemia can be nbroadly classified into the following 2 groups:

·                     nObstructed bile flow with or without hepatocellular ninjury

·                     nHepatocyte injury with nnormal bile ducts

Obstructed bile flow with or without hepatocellular injury may result from biliary natresia or choledochal ncyst. Hepatocyte injury with normal bile ducts may be ndue to iatrogenic, infectious, or metabolic causes. Iatrogenic causes include nintravenous hyperalimentation. Infectious causes may nbe viral (cytomegalovirus, hepatitis B, other viruses), bacterial (septicemia), nor parasitic (toxoplasmosis). Metabolic disorders include enzyme deficiencies n1-antitrypsin deficiency, galactosemia, cystic nfibrosis, tyrosinemia,a( fructosemia, hypermethioninemia), nstorage diseases, Rotor syndrome, Dubin-Johnsosyndrome, Byler disease, Zellweger syndrome, and Aagenaes syndrome.

Neonatal hyperbilirubinemia is nextremely common because almost every newborn develops an unconjugated nserum bilirubin level greater than 30 mol/L (1.8 mg/dL) during the first week of life.m

 

 

PHYSIOLOGICAL nJAUNDICE Jaundice is the yellow discolouration nof the skin and sclera due to the deposition of bilirubin.  nAll normal newborn infants have increased amounts of unconjugated nbilirubin in their blood while up to 50% develop njaundice on the third or fourth day of life.  In full-term infants, njaundice reaches maximum intensity by day 4 or 5 and is usually no longer nevident after day 7. The total serum bilirubin (TSB) nusually does not usually exceed 200 µmol/l (12 mg%) although in some well nbreast fed infants it might reach as high as 270 µmol/l (15mg%).

 Breastfed babies are more likely nthan bottle-fed babies to develop physiological jaundice within the first week nof life but the appearance of jaundice is not a reason to stop breastfeeding. nPhysiological jaundice refers to the common, generally harmless, jaundice seein many newborn babies in the first weeks of life and for which there is no nunderlying cause. The reasons for the association between breastfeeding and nneonatal jaundice have not yet been fully elucidated but may include inadequate nbreastfeeding support leading to a reduced intake, sluggish gut action leading nto an increase in the entero-hepatic circulation of bilirubin, or unidentified nfactors in breast milk. Finally, it may be that there is a relative reductioof bilirubin levels in formula-fed babies due to increased clearance of nbilirubin from the gut. Current NHS

practice of early postnatal discharge, oftewithin 24 hours, reduces the opportunity to assess whether successful lactatiohas been established and to provide adequate breastfeeding support and advice.

 

Physiological jaundice is the “normal” jaundice seen in many nhealthy newborn infants. Physiological jaundice never appears within the first n24 hours of life and seldom lasts beyond 14 days. These infants show no sign of nillness – they remain afebrile, drink well, gaiweight and have normal stools.

·                     nPhysiological njaundice is due to:

o                     nthe nhigh Hb level which results in a high bilirubin production

o                     nslow nhepatic conjugation

o                     nthe enterohepatic circulation of bilirubin n

The term “idiopathic hyperbilirubinaemia” is used when the bilirubin level exceeds the values accepted as n”physiological” but no pathological cause is found.  Idiopathic hyperbilirubinaemia is more common in preterm and breast nfed infants.

Note that jaundice nis a clinical sign while hyperbilirubinaemia is idetected by measuring the TSB in a laboratory.

 

Prolonged jaundice

Prolonged njaundice, that is jaundice persisting beyond the first 14 days, is also seemore commonly in term breastfed babies. The mechanism for this ‘breast milk njaundice’ is still not completely understood and the condition appears to be ngenerally harmless. However, prolonged jaundice can be a clue to serious nunderlying liver disease and should be assessed carefully.

 

Causes:

·                   nPhysiologic jaundice is caused by a combination of increased bilirubin production secondary to accelerated destructioof erythrocytes, decreased excretory capacity secondary to low levels of ligandin in hepatocytes, and low nactivity of the bilirubin-conjugating enzyme UDPGT.

·                   nPathologic neonatal jaundice occurs when additional factors are nsuperimposed on the basic mechanisms described above. Such is the case iimmune or nonimmune hemolytic anemia and in polycythemia.

·                   nDecreased clearance of bilirubin may play a nrole in breast milk jaundice and in several metabolic and endocrine disorders.

·                   nRisk factors

o       nRace: Incidence is higher in East Asians and American Indians and is nlower in African Americans.

o       nGeography: Incidence is higher in populations living at high altitudes. nGreeks living in Greece have na higher incidence than those living outside of Greece.

o       nGenetics and familial risk: Incidence is higher in infants with siblings nwho had significant neonatal jaundice. Incidence also is higher in infants with nmutations in the gene coding for UDPGT (Gilbert syndrome) and/or in infants nwith homozygous or heterozygous G-6-PD deficiency.

o       nNutrition: Incidence is higher in infants who are breastfed.

o       nMaternal factors: Infants of mothers with diabetes have higher nincidence. Use of some drugs may increase incidence, while others decrease nincidence.

o       nBirthweight and gestational nage: Incidence is higher in premature infants and/or in infants with low birthweight.

COMMON CAUSES OF nJAUNDICE:

·                     nEarly nonset

o                     n Haemolytic disease especially Rh ndisease

·                     nOnset nafter 24 hours: Physiological/Idiopathic jaundice

o                     n   nInfection

o                     n   nABO haemolytic disease

CLASSIFICATION

·                     nUnconjugated Hyperbilirubinaemia

o                     n Excessive nhaemolysis:
n – Haemolytic jaundice – ABO and Rh blood group incompatibilities
n – Hereditary spherocytosis
n – G-6-PD deficiency
n – Haematomas e.g. cephalohaematoma nor bruising
n – Polycythemia
n – Infection

o                     n Defective nconjugation: n
n – Physiological njaundice – iormal full–term and preterm infants
n – Idiopathic hyperbilirubinaemia
n – Drugs e.g. oxytocin
n – Hypoxia
n – Hypothyroidism
n – Infection

·                     n Conjugated Hyperbilirubinaemia

o                     n   nHepatocellular disease:
n – Infections:  bacterial e.g. septicaemia

§                                              n   nviral e.g. virus hepatitis, herpes, CMV, rubella
n   nspirochaetal – congenital syphilis
n   nprotozoal e.g. toxoplasmosis

 – Galactosaemia (very nrare)

o                     nObstructive: n
n – Atresia of bile ducts (usually older than 4 nweeks)
n – Inspissated bile syndrome
n – Choledochal cyst

 

 

INVESTIGATION:

Lab Studies:

Bilirubin

·                   nTranscutaneous bilirubinometry can be performed using handheld devices nthat incorporate sophisticated optical algorithms to filter out most of the unreflected light from the bilirubin nmolecules.

·                   nIn infants with mild jaundice, transcutaneous bilirubinometry may be all that is needed to assure that ntotal bilirubin levels are safely below those requiring nintervention.

·                   nIn infants with moderate jaundice, transcutaneous nbilirubinometry may be useful in selecting patients nwho require phlebotomy for serum bilirubin nmeasurement.

·                   nUsually, a total serum bilirubin level is the nonly testing required in a moderately jaundiced infant who presents on the ntypical second or third day of life without a history and physical findings nsuggestive of a pathologic process.

Additional studies may be nindicated in the following situations:

·                   nInfants who present with jaundice on the first or after the third day of nlife

·                   nInfants who are anemic at birth

·                   nInfants who otherwise appear ill

·                   nInfants in whom serum bilirubin levels are nvery elevated

·                   nInfants in whom significant jaundice persists beyond the first 2 weeks nof life

·                   nInfants in whom family, maternal, pregnancy, or case histories suggest the npossibility of a pathologic process

·                   nInfants in whom physical examination reveals findings not explained by nsimple physiologic hyperbilirubinemia

In addition to ntotal serum bilirubin levels, other suggested nstudies may include the following:

·                   nBlood type and Rh determination in mother and ninfant

·                   nDirect Coombs testing in the infant

·                   nHemoglobin and hematocrit values

·                   nSerum albumin levels: This may be a useful adjunct in evaluating risk of ntoxicity levels, since albumin binds bilirubin in a nratio of 1:1 at the primary high-affinity binding site.

·                   nNomogram for hour-specific nbilirubin values: This may be a useful tool for npredicting, either before or at the time of hospital discharge, which infants nare likely to develop high serum bilirubin values. nThese infants require close follow-up monitoring and repeated bilirubin measurements. The predictive ability has beeshown both for bilirubin values measured in serum and nfor values measured transcutaneously.

·                   nMeasurement of end-tidal carbon monoxide in breath (ETCO): ETCO may be nused as an index of bilirubin production. Measurement nof ETCO may assist in identifying individuals with increased bilirubin production and, thus, at increased risk of ndeveloping high bilirubin levels. An apparatus has nbeen developed that makes measuring ETCO simple (CO-Stat End Tidal Breath nAnalyzer, Natus Medical Inc).

·                   nPeripheral blood film for erythrocyte morphology

·                   nReticulocyte count

·                   nConjugated bilirubin: Note that direct bilirubin measurements are often inaccurate, are subject to nsignificant interlaboratory and intralaboratory nvariation, and generally are not a sensitive tool for diagnosing cholestasis.

·                   nLiver function tests: Aspartate aminotransferase (ASAT or SGOT) and alanine naminotransferase (ALAT or SGPT) levels are elevated nin hepatocellular disease. Alkaline phosphatase and –glutamyltransferase n(GGT) levels often are elevated in cholestaticg ndisease. A GGT/ALAT ratio greater than 1 is strongly suggestive of biliary obstruction.

·                   nTests for viral and/or parasitic infection may be indicated in infants nwith hepatosplenomegaly or evidence of hepatocellular disease.

·                   nReducing substance in urine is a useful screening test for galactosemia, provided the infant has received sufficient nquantities of milk.

·                   nBlood gas measurements: The risk of bilirubin nCNS toxicity is increased in acidosis, particularly respiratory acidosis.

·                   nBilirubin-binding tests: nAlthough they are interesting research tools, these tests have not found nwidespread use in clinical practice. Although elevated levels of unbound bilirubin are associated with an increased risk of bilirubin encephalopathy, unbound bilirubin nis but one of several factors that mediate/modulate bilirubin ntoxicity.

·                   nThyroid function tests

Imaging Studies:

·                   nUltrasound: Ultrasound examination of the liver and bile ducts is nwarranted in infants with laboratory and/or clinical signs of cholestatic disease.

·                   nRadionuclide scanning: A radionuclide liver scan for uptake of hepatoiminodiacetic acid (HIDA) is indicated if extrahepatic biliary atresia is suspected. At the author’s institution, patients nare pretreated with phenobarbital 5 mg/kg/d for 3-4 ndays before performing the scan.

Other Tests:

·                   nAuditory and visual evoked potentials are affected during ongoing nsignificant jaundice; however, no criteria have been established that allow nextrapolation from evoked potential findings to risk of bilirubin nencephalopathy. Brainstem auditory evoked potentials should be obtained in the naftermath of severe neonatal jaundice to exclude sensorineural nhearing loss.

 

Tests nto detect underlying disease in all babies with significant hyperbilirubinaemia

In addition to a full clinical nexamination by a suitably trained healthcare professional, carry out all of the nfollowing tests in babies with significant hyperbilirubinaemia as part of aassessment for underlying disease and treatment threshold graphs

 

• serum bilirubin (for baseline nlevel to assess response to treatment)

 

• blood packed cell volume

 

• blood group (mother and baby)

 

• DAT (Coombs’ test). Interpret the nresult taking account of the strength of reaction, and whether mother received nprophylactic anti-D immunoglobulin during pregnancy.

When assessing the baby for nunderlying disease consider whether the following tests are clinically nindicated:

 

• full blood count and nexamination of blood film

 

• blood glucose-6-phosphate ndehydrogenase levels, taking account of ethnic origin

 

• microbiological cultures of nblood, urine and/or cerebrospinal fluid (if infection is

suspected).

Do not use the albumin/bilirubin ratio nwhen making decisions about the management of hyperbilirubinaemia

Do not subtract conjugated nbilirubin from total serum bilirubin when making decisions about the management nof hyperbilirubinaemia  and treatment nthreshold graphs

 

Tests that ndo not predict hyperbilirubinaemia

Umbilical ncord blood bilirubin

Description of included studies

Four studies of EL II conducted nin various countries (Germany, India, Denmark and Spain) have been included. nThe study population was made up of healthy term babies in three studies, while nin the German study the population included healthy term babies who were nappropriate for gestational age, healthy term babies who were small for ngestational age and healthy preterm babies (gestational age > 34 weeks). Data nfrom this study  were extracted and nanalysed separated for both appropriate for gestational age and small for ngestational age. In three studies cord blood bilirubin was measured within 2 nhours of birth and the standard reference test (laboratory serum bilirubimeasurement) was carried out within 3–4 days, while in the German study blood ntesting was done only in those babies who had a Minolta JM-102

transcutaneous bilirubin reading n> 16 reflectance units. A meta-analysis was conducted with data from three nstudies26;30;31 that had defined hyperbilirubinaemia as serum bilirubin levels ≥ n290 micromol/litre. The threshold values of cord blood bilirubin in these nstudies were ≥ 30, > 34 and ≥ 37 micromol/litre, respectively. nIn the Danish study,29 the ability of cord blood bilirubin at levels ≥ 35 nmicromol/litre (best cut-off value derived from the ROC curve) to predict serum nbilirubin levels ≥ 200 microm

 

Tests nthat do not predict significant hyperbilirubinaemia

Do not use any of the following nto predict significant hyperbilirubinaemia

• umbilical ncord blood bilirubin level

• end-tidal ncarbon monoxide (ETCOc) measurement

• umbilical ncord blood direct antiglobulin test (DAT) (Coombs’ test).

 

·                   nCrying characteristics are changed in significant neonatal jaundice; nhowever, computerized crying analyses are not used in clinical practice.

HAEMOLYTIC DISEASE OF THE NEWBORN In simplified nterms, there are two main types of blood group incompatibilities between fetus nand mother, i.e. Rhesus and ABO haemolytic ndisease..  In the former, the Rh-negative mother, forms anti-D antibody iresponse to a transfer of red cells from a Rh-positive fetus.  These fetal nred cells usually cross the placenta at delivery.  Rarely anti-D nantibodies may form in response to a previous incompatible transfusion of nRh-positive blood.  In a subsequent pregnancy, this maternal antibody npasses back across the placenta and, if the fetus is Rh-positive, causes haemolytic disease by damaging the fetal red cells. In ABO haemolytic disease, anti-A or anti-B antibodies which are npresent in the blood of all group O mothers, are transferred across the nplacenta to the fetus. They cause haemolysis if the nfetal blood group is A, B or AB.  Unlike Rhesus incompatibility, ABO nincompatibility commonly affects first born infants.  ABO incompatibility nis rarely severe enough to cause fetal hydrops.

There are also incompatibilities involving much rarer blood groups which noccasionally cause similar problems.

HAEMOLYTIC DISEASE DUE TO Rh nINCOMPATIBILITY There is a wide spectrum of clinical presentation.  The disease nmay take one of three main forms:

1.                 nHydrops fetalis in which the infant nis usually stillborn with gross oedema, ascites and anaemia.

2.                 nJaundice narising during the first few hours after birth associated with a variable ndegree of progressive haemolytic anaemia.  nThe jaundice is not obviously present at birth because until then the excess bilirubin has been excreted via the placenta.

3.                 nGradual nonset during the course of the first few weeks without of anaemia nmore than slight jaundice.

The main threats to nthe life of the baby, if live born, are a rapidly progressive anaemia, cardiac failure or bilirubin nencephalopathy.

 

Visual/clinical examination

In all babies:

• check whether there are factors associated with an increased likelihood nof developing significant hyperbilirubinaemia soon after birth

• examine the baby for jaundice at every opportunity especially in the nfirst 72 hours.

Parents, carers and healthcare professionals should all look for jaundice n(visual inspection).

When looking for jaundice (visual inspection):

• check the naked baby in bright and preferably natural light

• examination of the sclerae, gums and blanched skin is useful across all nskin tones.

Ensure babies with factors associated with an increased likelihood of ndeveloping significant hyperbilirubinaemia receive an additional visual ninspection by a healthcare professional during the first 48 hours of life.

Do not rely on visual inspection alone to estimate the bilirubin level in a nbaby with jaundice.

Measure and record the bilirubin level urgently (within 6 hours) in all babies nmore than 24 hours old with suspected or obvious jaundice.

 

Prevention: The use of anti-D immunoglobulin is almost completely neffective in preventing Rh disease except in those ncases where maternal Rh antibodies are already npresent.  By giving the mother anti-D globulin by injection as soon as npossible after delivery (within 72 hours) the “transfused” fetal nRh-positive red cells are destroyed before they can sensitize the mother.

If the mother has already been sensitized, plasmapheresis nhas on occasion been used to reduce the amount of Rh nantibody.

Antenatal ncare:

o                     ndetect nall Rh-negative women

o                     nhistory nof previous pregnancies and complications, blood transfusions

o                     ntest nfor presence of anti-D antibody at first antenatal visit:

§                                              n if nantibodies absent:  test for antibodies every 4 weeks
n if antibodies present:  measure level every 2-4 weeks

o                     namniocentesis nif antibody titre 1/16 or more, or if a rapid rise ititre is shown

o                     namniotic nfluid used to assess:

o                     nseverity nof Rh disease (optical density, bilirubin nlevel)

o                     nfetal nlung maturity (bubbles, phospholipid content)

The above factors are considered when the decision is nmade whether to induce early labour in order to nprevent a stillbirth or to prolong life of the fetus by giving an intrauterine ntransfusion.

Postnatal management:

·                     nConfirm ndiagnosis

o         nclinical nfeatures: pale large placenta

§        anaemia
n                 jaundice of rapid onset
n                enlarged liver and nspleen
n                 oedema and ascites

o         n laboratory ntests: blood group

§        direct Coombs test n
n                 serum bilirubin
n                haemoglobin and PCV

·                     nResuscitatio

o         nanticipate nproblems if the fetus is severely affected or preterm

o         ntreat perinatal asphyxia, respiratory distress, etc.

o         ncorrect nhypoxia, acidosis, hypoglycaemia, hypothermia

·                     nPhototherapy n

o         nstart nimmediately if Coombs positive or there is evidence of jaundice or anaemia

o         ncheck nTSB every 2-4 hours

             

HAEMOLYTIC DISEASE nDUE TO ABO INCOMPATIBILITY This is now the most common cause of haemolytic disease in the newborn.  The mother is ngroup O and the baby group A, B or AB.  Unlike Rh ndisease the disease process is milder and does not cause hydrops nfetalis.  It usually presents with the onset of nearly jaundice in the first 48 hours, although late onset of jaundice may noccasionally occur.

The cord haemoglobin is normal and the direct nCoombs test is positive.  Typically the infant has a high reticulocyte count and spherocytes nare seen on a peripheral blood smear.  The TSB at 6 hours is usually above n80 µmol/l.

Although exchange transfusion may be necessary, in most cases nphototherapy prevents the bilirubin rising to a ndangerous level.  As with Rh disease, late anaemia may occur.

As the blood group of infants is usually not routinely measured, all ninfants born to group O mothers should have their TSB measured at 6 hours after ndelivery.  If the TSB is above 80 µmol/l then phototherapy should be nstarted and the infant’s blood group and Coombs test done.

Table 1. nComparison of Rh and ABO Incompatibility

n

Characteristics		Rh	ABO
Clinical aspects	First born	5%	50%
	Later pregnancies	More severe	No increased severity
	Stillborn/hydrops	Frequent	Rare
	Severe anemia	Frequent	Rare
	Jaundice	Moderate to severe, frequent	Mild
	Late anemia	Frequent	Rare
Laboratory findings	DAT	Positive	Weakly positive
	Indirect Coombs test	Positive	Usually positive
	Spherocytosis	Rare	Frequent

Complications: The 2 nmajor complications of HDN are bilirubin nencephalopathy (kernicterus) and late anemia of ninfancy.

Bilirubin nencephalopathy

 

·                     nBefore the advent of exchange transfusion, kernicterus naffected 15% of infants born with erythroblastosis. nApproximately 75% of these neonates died within 1 week of life, and a small nremainder died during the first year of life. Survivors had permanent nneurologic sequelae and were thought to have naccounted for 10% of all patients with cerebral palsy (CP).

·                     nThe mechanism by which unconjugated bilirubin enters the brain and damages it is unclear. Bilirubin enters the brain as lipophilic nfree bilirubin unbound to albumin, as supersaturated bilirubin acid that precipitates on lipid membrane in low npH, or as a bilirubin-albumin complex that transfers bilirubin to tissue by direct contact with cellular nsurface. A damaged blood-brain barrier enhances the entry of all forms of bilirubin into the brain, which is especially important ipreterm neonates with respiratory acidosis and vascular injury.

·                     nBilirubin has beepostulated to cause neurotoxicity via 4 distinct mechanisms: (1) interruptioof normal neurotransmission (inhibits phosphorylation nof enzymes critical in release of neurotransmitters), (2) mitochondrial ndysfunction, (3) cellular and intracellular membrane impairment (bilirubin acid affects membrane ion channels and nprecipitates on phospholipid membranes of nmitochondria), and (4) interference with enzyme activity (binds to specific bilirubin receptor sites on enzymes).

·                     nThe pathologic findings include characteristic staining and neuronal nnecrosis in basal ganglia, hippocampal cortex, subthalamic nuclei, and cerebellum. The cerebral cortex is ns generally pared. About half of these neonates also have extraneuronal nlesions, such as necrosis of renal tubular, intestinal mucosal, and pancreatic ncells.

·                     nClinical signs of bilirubin encephalopathy ntypically evolve in 3 phases. Phase 1 is marked by poor suck, hypotonia, and depressed sensorium. nFever and hypertonia are observed in phase 2, and at ntimes, the condition progresses to opisthotonus. nPhase 3 is characterized by high-pitched cry, hearing and visual abnormalities, npoor feeding, and athetosis. The long-term sequelae include choreoathetoid nCP, upward gaze palsy, sensorineural hearing loss, nand, less often, mental retardation.

 

 Kernicterus

Identified nstudies included babies who met recognised criteria for kernicterus nincluding the

following nclinical features:

● poor feeding

● lethargy

● high-pitched cry

● increased tone

● opisthotonos

● seizures

● sensorineural hearing nloss,

● motor delay, extrapyramidal disturbance

● gaze palsy

● dental dysplasia.

 

Risk nfactors for kernicterus/or adverse sequelae

Identify nbabies with hyperbilirubinaemia as being at increased nrisk of developing kernicterus if they have any of the nfollowing:

 

• a serum nbilirubin level greater than 340 micromol/litre nin babies with a gestational age of

37 nweeks or more

 

• a nrapidly rising bilirubin level of greater than 8.5 micromol/litre per hour

 

• clinical features of acute bilirubin encephalopathy

 

·                     nCurrently, the mortality rate stands at 50% in term newborns, but nmortality is nearly universal in the preterm population who may simply appear nill without signs specific for kernicterus. Lately, nresearch has indicated that bilirubin productiorates may be the critical piece of information identifying jaundiced infants at nrisk of neurotoxicity. A high bilirubin productiorate is thought to result in rapid transfer of bilirubin nto tissue, causing high tissue load, in which case any small further increase nhas great potential to enter the brain. Because the total serum bilirubin represents not only bilirubin nproduction but also distribution and elimination, it is not an absolute indicator nof risk of kernicterus. Techniques have beedeveloped to measure the bilirubin production rates naccurately and noninvasively using end-tidal carbon monoxide measurement and percutaneous measurement of carboxyhemoglobin. n

 

Bilirubin encephalopathy and kernicterus

In young babies, unconjugated nbilirubin can penetrate the membrane that lies nbetween the brain and the blood (the blood–brain barrier). Unconjugated nbilirubin is potentially toxic to neural tissue n(brain and spinal cord). Entry of unconjugated bilirubin into the brain can cause both short-term and nlong-term neurological dysfunction. Acute features include lethargy, nirritability, abnormal muscle tone and posture, temporary cessation of nbreathing (apnoea) and convulsions. This presentation is known as acute bilirubin encephalopathy. Bilirubin nis deposited particularly in a part of the brain known as the globus pallidus, part of the n‘deep grey

matter’ of the brain. On pathological nexamination of the brain, this produces yellow staining; this staining is nreferred to as kernicterus. The term kernicterus is also used to denote the clinical features of nacute or chronic bilirubin encephalopathy. Features nof the latter include athetoid cerebral palsy, nhearing loss, and visual and dental problems. The exact level of bilirubin that is likely to cause neurotoxicity in any nindividual baby varies, and depends on the interplay of multiple factors which ninclude acidosis, gestational and postnatal age, rate of rise of serum bilirubin, serum albumin concentration, and concurrent nillness (including infection).

Although neonatal jaundice is very ncommon, kernicterus is very rare. There is a poor ncorrelation between levels of circulating bilirubin nand the occurrence of bilirubin encephalopathy. There nseems to be tremendous variability in susceptibility towards bilirubin encephalopathy among newborns for a variety of nunexplained reasons. However, there are certain factors that probably influence nthe passage of bilirubin into the brain and hence nincrease the risk of acute bilirubin

encephalopathy. These include preterm nbirth, sepsis, hypoxia, seizures, acidosis and

hypoalbuminaemia. The rate of rise of the level of bilirubin nis probably important, hence the increased risk of kernicterus nin babies with haemolytic disease such as G6PD deficiency, ABO or Rhesus nhaemolytic disease.

Kernicterus in healthy term babies with none of the above factors is virtually nunknown below a serum bilirubin concentration of 450 nmicromoles of bilirubin per litre (micromol/litre), but the incidence increases above this nthreshold level and the risk of kernicterus is ngreatly increased in term babies with bilirubin nlevels above 515 micromol/litre. Kernicterus nis also known to occur at lower levels nof bilirubin in preterm and in term babies who have nany of the factors described above

 

Potential ncomplications of exchange transfusion include the nfollowing:

·                   nCardiac – Arrhythmia, volume overload, congestive failure, and arrest

·                   nHematologic – Overheparinization, neutropenia, thrombocytopenia, and graft versus host ndisease

·                   nInfectious – Bacterial, viral (CMV, HIV, hepatitis), and malarial

·                   nMetabolic – Acidosis, hypocalcemia, nhypoglycemia, hyperkalemia, and hypernatremia

·                   nVascular – Embolization, thrombosis, nnecrotizing enterocolitis, and perforation of numbilical vessel

·                   nSystemic – Hypothermia

 

 

Treatment nof jaundice

Levels of nbilirubin can be controlled by placing the baby under na lamp emitting light in the blue spectrum, which is known as phototherapy. nLight energy of the appropriate wavelength converts the bilirubin nin the skin to a harmless form that can be excreted in the urine. Phototherapy nhas proved to be a safe and effective treatment for jaundice iewborn babies, nreducing the need to perform an exchange transfusion of blood (the only other nmeans of removing bilirubin from the body).

Clinical nrecognition and assessment of jaundice can be difficult. This is particularly nso in babies

with ndarker skin. Once jaundice is recognised, there is uncertainty about when to ntreat. Currently, there is widespread variation in the use of phototherapy, nexchange transfusion and other treatments when using charts, but there is nalready a degree of consistency in the NHS about treatment thresholds whehealthcare professionals base their decisions on a formula that uses ngestational age.1 There is a need for more uniform, evidence-based practice, nand for consensusbased practice where such evidence nis lacking, hence the importance of this guideline.

 

 

Care for all babies

Identify babies as nbeing more likely to develop significant hyperbilirubinaemia nif they have any

of the following nfactors:

 

• gestational nage under 38 weeks

 

• a nprevious sibling with neonatal jaundice requiring phototherapy

 

• mother’s nintention to breastfeed exclusively

 

• visible njaundice in the first 24 hours of life.

 

In all babies:

• check nwhether there are factors associated with an increased likelihood of developing nsignificant hyperbilirubinaemia soon after birth

 

• examine nthe baby for jaundice at every opportunity especially in the first 72 hours.

 

When looking for njaundice (visual inspection):

 

• check nthe naked baby in bright and preferably natural light

 

• examinatioof the sclerae, gums and blanched skin is useful nacross all skin tones.

 

 

Additional care

Ensure nbabies with factors associated with an increased likelihood of developing significant nhyperbilirubinaemia receive an additional visual ninspection by a healthcare professional during the first 48 hours of life.

 

Measuring bilirubin in all babies with jaundice

Do not nrely on visual inspection alone to estimate the bilirubin nlevel in a baby with jaundice.

 

How to measure the bilirubin level

Whemeasuring the bilirubin level:

 

• use a transcutaneous bilirubinometer ibabies with a gestational age of 35 weeks or more and postnatal age of more nthan 24 hours

 

• if a transcutaneous bilirubinometer is nnot available, measure the serum bilirubin

 

• if a transcutaneous bilirubinometer nmeasurement indicates a bilirubin level greater tha250 micromol/litre check the result by measuring the nserum bilirubin

 

• always nuse serum bilirubin measurement to determine the bilirubin level in babies with jaundice in the first 24 nhours of life

 

• always nuse serum bilirubin measurement to determine the bilirubin level in babies less than 35 weeks gestational nage

 

• always nuse serum bilirubin measurement for babies at or nabove the relevant treatment threshold for their postnatal age, and for all nsubsequent measurements

 

• do not nuse an icterometer.

 

 

How to manage hyperbilirubinaemia

Use the nbilirubin level to determine the management of hyperbilirubinaemia in all babies (see

threshold ntable (Section 1.3) and treatment threshold graphs (Section 1.6)).

 

          Threshold table (Section 1.3)

n

Age (hours)	Bilirubin measurement (micromol/litre)
0			> 100	> 100
6	> 100	> 112	> 125	> 150
12	> 100	> 125	> 150	> 200
18	> 100	> 137	> 175	> 250
24	> 100	> 150	> 200	> 300
30	> 112	> 162	> 212	> 350
36	> 125	> 175	> 225	> 400
42	> 137	> 187	> 237	> 450
48	> 150	> 200	> 250	> 450
54	> 162	> 212	> 262	> 450
60	> 175	> 225	> 275	> 450
66	> 187	> 237	> 287	> 450
72	> 200	> 250	> 300	> 450
78		> 262	> 312	> 450
84		> 275	> 325	> 450
90		> 287	> 337	> 450
96+		> 300	> 350	> 450
Action	Repeat bilirubin   in 6-12 hours	Consider phototherapy and repeat measurement in 6 hours	Start phototherapy	Perform an exchange transfusion unless bilirubin level falls below threshold while the treatment is prepared

 

 

n

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

n

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Urgent additional ncare for babies with visible jaundice in the first 24 hours nMeasure and record the serum bilirubin level urgently n(within 2 hours) in

all nbabies with suspected or obvious jaundice in the first 24 hours of life.

Continue nto measure the serum bilirubin level every 6 hours nfor all babies

with nsuspected or obvious jaundice in the first 24 hours of life until the

level nis both:

• below nthe treatment threshold

• stable nand/or falling.

Arrange na referral to ensure that an urgent medical review is conducted (as

soon as npossible and within 6 hours) for babies with suspected or obvious jaundice ithe first 24 hours of life to exclude pathological causes of jaundice.

Interpret nbilirubin levels according to the baby’s postnatal nage in hours and manage hyperbilirubinaemia according nto the threshold table (Section 1.3) and treatment threshold graphs (Sectio1.6).

 

 

Care for babies nmore than 24 hours old

Measure nand record the bilirubin level urgently (within 6 nhours) in all babies more than 24 hours old with suspected or obvious jaundice.

 

Do not nuse the albumin/bilirubin ratio when making decisions nabout the management of hyperbilirubinaemia.

 

Do not nsubtract conjugated bilirubin from total serum bilirubin when making decisions about the management of hyperbilirubinaemia (see management thresholds in the nthreshold table (Section 1.3) and treatment threshold graphs (Section 1.6)).

 

 

 

Measuring and nmonitoring bilirubin thresholds during phototherapy

Starting nphototherapy

Use nserum bilirubin measurement and the treatment nthresholds in the threshold table (Section 1.3) and treatment threshold graphs n(Section 1.6) when considering the use of phototherapy.

Ibabies with a gestational age of 38 weeks or more whose bilirubin nis in the ‘repeat bilirubin measurement’ category ithe threshold table (Section 1.3) repeat the bilirubin nmeasurement in 6–12 hours.

Ibabies with a gestational age of 38 weeks or more whose bilirubin nis in

the n‘consider phototherapy’ category in the threshold table (Section 1.3)

repeat nthe bilirubin measurement in 6 hours regardless of nwhether or not phototherapy has subsequently been started.

 

Do not nuse phototherapy in babies whose bilirubin does not nexceed the

phototherapy nthreshold levels in the threshold table (Section 1.3) and

treatment nthreshold graphs (Section 1.6).

 

During phototherapy

During nphototherapy:

• repeat nserum bilirubin measurement 4–6 hours after ninitiating phototherapy

• repeat nserum bilirubin measurement every 6–12 hours when the nserum bilirubin level is stable or falling.

 

 

Stopping phototherapy

Stop nphototherapy once serum bilirubin has fallen to a nlevel at least 50 micromol/litre below the nphototherapy threshold (see threshold table (Section 1.3) and treatment nthreshold graphs (Section 1.6)).

Check nfor rebound of significant hyperbilirubinaemia with a nrepeat serum

bilirubin measurement 12–18 hours after stopping nphototherapy. Babies do not necessarily have to remain in hospital for this to nbe done.

Type of nphototherapy to use

Do not use sunlight nas treatment for hyperbilirubinaemia.

Single phototherapy ntreatment for term babies

Use conventional n‘blue light’ phototherapy as treatment for significant hyperbilirubinaemia nin babies with a gestational age of 37 weeks or more unless:

• the serum bilirubin level is rising rapidly (more than 8.5 micromol/litre

per hour)

 

• the serum bilirubin is at a level that is within 50 micromol/litre below the threshold for which exchange transfusiois indicated after 72 hours (see the threshold table (Section 1.3) and ntreatment threshold graphs (Section 1.6)).

 

Do not use fibreoptic phototherapy as first-line treatment for hyperbilirubinaemia for babies with a gestational age of 37 nweeks or more.

 

Single phototherapy ntreatment in preterm babies

Use either fibreoptic phototherapy or conventional ‘blue light’ nphototherapy as treatment for significant hyperbilirubinaemia nin babies less than 37 weeks unless:

 

• the serum bilirubin level is rising rapidly (more than 8.5 micromol/litre

per hour)

 

• the serum bilirubin is at a level that is within 50 micromol/litre below the threshold for which exchange ntransfusion is indicated after 72 hours (see treatment threshold table (Sectio1.3) and treatment threshold graphs (Section 1.6)).

 

Continuous multiple nphototherapy treatment for term and pre term babies

Initiate continuous nmultiple phototherapy to treat all babies if any of the

following apply:

 

• the serum bilirubin level is rising rapidly (more than 8.5 micromol/litre per hour)

 

• the serum bilirubin is at a level within 50 micromol/litre nbelow the threshold for which exchange transfusion is indicated after 72 hours n(see threshold table (Section 1.3) and treatment threshold graphs (Sectio1.6)).

 

• the bilirubin level fails to respond to single phototherapy n(that is, the level of serum bilirubin continues to nrise, or does not fall, within 6 hours of starting single phototherapy)

 

 

If the serum bilirubin level falls during continuous multiple nphototherapy to a level 50 micromol/litre below the nthreshold for which exchange transfusion is indicated step down to single nphototherapy

 

. nGeneral care of the baby during phototherapy

During nphototherapy:

• place nthe baby in a supine position unless other clinical conditions prevent this

• ensure ntreatment is applied to the maximum area of skin

• monitor nthe baby’s temperature and ensure the baby is kept in an environment that will nminimise energy expenditure (thermoneutral nenvironment)

• monitor nhydration by daily weighing of the baby and assessing wet nappies

• support nparents and carers and encourage them to interact with the

baby.

 Give the baby eye protection and routine eye ncare during phototherapy.

 Use tinted headboxes nas an alternative to eye protection in babies with a gestational age of 37 nweeks or more undergoing conventional ‘blue light’

phototherapy.

Monitoring nthe baby during phototherapy

During nconventional ‘blue light’ phototherapy:

• using nclinical judgement, encourage short breaks (of up to 30 minutes) for nbreastfeeding, nappy changing and cuddles

• continue nlactation/feeding support

• do not ngive additional fluids or feeds routinely.

Maternal nexpressed milk is the additional feed of choice if available, and wheadditional feeds are indicated.

During nmultiple phototherapy:

• do not ninterrupt phototherapy for feeding but continue administering intravenous/enteral feeds

• continue nlactation/feeding support so that breastfeeding can start again when treatment nstops.

Maternal nexpressed milk is the additional feed of choice if available, and wheadditional feeds are indicated.

Feeding nand hydration during phototherapy

During nconventional ‘blue light’ phototherapy:

• using nclinical judgement, encourage short breaks (of up to 30 minutes) for nbreastfeeding, nappy changing and cuddles

• continue nlactation/feeding support

• do not ngive additional fluids or feeds routinely.

Maternal nexpressed milk is the additional feed of choice if available, and wheadditional feeds are indicated

During nmultiple phototherapy:

• do not ninterrupt phototherapy for feeding but continue administering intravenous/enteral feeds

• continue nlactation/feeding support so that breastfeeding can start again when treatment nstops.

Maternal nexpressed milk is the additional feed of choice if available, and wheadditional feeds are indicated

 

              

Intravenous immunoglobulin

 

          Use intravenous nimmunoglobulin (IVIG) (500 mg/kg over 4 hours) as an                                

            adjunct to continuous nmultiple phototherapy in cases of Rhesus

            haemolytic ndisease or ABO haemolytic disease when the serum bilirubin

            continues to rise by nmore than 8.5 micromol/litre per hour.

 

          Offer parents or carers information on IVIG including:                                                 n

             •  why IVIG is being considered

             •  why IVIG may be needed to treat significant hyperbilirubinaemia

             •  the possible adverse effects of IVIG

             •  nwhen it will be possible for parents or carers nto see and hold the baby.

Exchange ntransfusion

Offer parents nor carers information on exchange transfusion including:

• the nfact that exchange transfusion requires that the baby be admitted to aintensive care bed

• why aexchange transfusion is being considered

• why aexchange transfusion may be needed to treat significant hyperbilirubinaemia

• the npossible adverse effects of exchange transfusions

• when it nwill be possible for parents or carers to see and hold the baby after the nexchange transfusion.

Use a ndouble-volume exchange transfusion to treat babies:

• whose nserum bilirubin level indicates its necessity (see nthreshold table (Section 1.3) and treatment threshold graphs (Section 1.6))

and/or

• with nclinical features and signs of acute bilirubin nencephalopathy.

During nexchange transfusion do not :

• stop ncontinuous multiple phototherapy

• perform na single-volume exchange

• use nalbumin priming

• routinely nadminister intravenous calcium.

Following nexchange transfusion:

• maintaicontinuous multiple phototherapy

• measure nserum bilirubin level within 2 hours and manage naccording to threshold table (Section 1.3) and treatment threshold graphs n(Section 1.6).

 

Other therapies

 

           Do not use any of the nfollowing to treat hyperbilirubinaemia:                                                n

 

             • agar

             • albumin

             • barbiturates

             • charcoal

             • cholestyramine n

             • clofibrate n

             •  nD-penicillamine

             • glycerin

             • manna

             • metalloporphyrins n

             • riboflavin

             • traditional Chinese medicine

             • acupuncture

             • homeopathy

 

 

Prognosis: Most nsurvivors of alloimmunized gestation are intact nneurologically. However, Janssens and colleagues have nreported neurologic abnormality to be closely associated with severity of nanemia and perinatal asphyxia.

INFECTION
nBacterial infection causes increased red cell destruction thereby releasing nmore bilirubin.  Infection also impairs the nability of the liver to excrete bilirubin by ninterfering with conjugation and by obstructing the flow of bile.  There nis thus usually an increase in both conjugated and unconjugated nbilirubin.  Unexplained jaundice, especially if nassociated with reluctance to feed, drowsiness or vomiting, should always raise nthe suspicion of infection somewhere e.g. urinary tract.

PROLONGED JAUNDICE  (more than 14 days)

·                     nBreast nmilk jaundice:

o                     nDue to nincreased enterohepatic circulation of bilirubin. The infant is usually thriving.  No ntreatment is necessary as it rarely gives high levels of bilirubin. n

·                     n Hypothyroidism: n

o                     n Though nrare, this should not be forgotten as a cause of abnormally prolonged njaundice.  Routine antenatal screening of TSH makes early diagnosis npossible.

·                     n Galactosaemia:

o                     n Rare.  nShould be suspected in the newborn who vomits, refuses feeds, fails to thrive nand develops prolonged jaundice.  Reducing substances in the urine are a nclue to the diagnosis.

·                     nHepatitis

 Obstructioof bile flow may also cause prolonged jaundice.

G6PD Deficiency

G6PD deficiency is nan inherited condition in which the body doesn’t have enough of the enzyme nglucose-6-phosphate dehydrogenase, or G6PD, which helps red blood cells (RBCs) nfunctioormally. This deficiency can cause hemolytic anemia, nusually after exposure to certain medications, foods, or even infections.

Most people with nG6PD deficiency don’t have any symptoms, while others develop symptoms of nanemia only after RBCs have been destroyed, a condition called hemolysis. nIn these cases, the symptoms disappear once the cause, or trigger, is removed. nIn rare cases, G6PD deficiency leads to chronic anemia.

With the right nprecautions, a child with G6PD deficiency can lead a healthy and active life.

About G6PD nDeficiency

G6PD is one of many enzymes that help the body nprocess carbohydrates and turn them into energy. G6PD also protects red blood ncells from potentially harmful byproducts that can accumulate when a persotakes certain medications or when the body is fighting an infection.

In people with nG6PD deficiency, either the RBCs do not make enough G6PD or what is produced ncannot properly function. Without enough G6PD to protect them, RBCs can be ndamaged or destroyed. Hemolytic anemia occurs when the bone marrow (the soft, nspongy part of the bone that produces new blood cells) cannot compensate for nthis destruction by increasing its production of RBCs.

Causes of G6PD nDeficiency

G6PD deficiency nis passed along in genes from one or both parents to a child. The gene nresponsible for this deficiency is on the X chromosome.

G6PD deficiency nis most common in African-American males. Many African-American females are ncarriers of G6PD deficiency, meaning they can pass the gene for the deficiency nto their children but do not have symptoms; only a few are actually affected by nG6PD deficiency.

People of nMediterranean heritage, including Italians, Greeks, Arabs, and Sephardic Jews, nalso are commonly affected. The severity of G6PD deficiency varies among these ngroups — it tends to be milder in African-Americans and more severe in people nof Mediterranean descent.

Why does G6PD ndeficiency occur more often in certain groups of people? It is known that nAfrica and the Mediterranean basin are high-risk areas for the infectious ndisease malaria. Researchers have found evidence nthat the parasite that causes this disease does not survive well iG6PD-deficient cells. So they believe that the deficiency may have developed as na protection against malaria.

G6PD Deficiency nSymptom Triggers

Kids with G6PD ndeficiency typically do not show any symptoms of the disorder until their red nblood cells are exposed to certain triggers, which can be:

• illness, such as bacterial and viral infections

• certain painkillers and fever-reducing drugs

• certain antibiotics (especially those that have “sulf” in their names)

• certain antimalarial drugs (especially those that have “quine” in their names)

n

Some kids with nG6PD deficiency can tolerate the medications in small amounts; others cannot ntake them at all. Check with your doctor for more specific instructions, as nwell as a complete list of medications that could pose a problem for a child nwith G6PD deficiency.

Other substances ncan be harmful to kids with this condition when consumed — or even touched — nsuch as fava beans and naphthalene (a chemical found in mothballs and moth ncrystals). Mothballs can be particularly harmful if a child accidentally nswallows one, so ANY contact should be avoided.

Symptoms of G6PD Deficiency

A child with G6PD ndeficiency who is exposed to a medication or infection that triggers the ndestruction of RBCs may have no symptoms at all. In more serious cases, a child nmay exhibit symptoms of hemolytic anemia (also known as a hemolytic crisis), nincluding:

paleness (idarker-skinned kids, paleness is sometimes best seen in the mouth, especially non the lips or tongue)

extreme tiredness

rapid heartbeat

rapid breathing or nshortness of breath

jaundice, or yellowing of nthe skin and eyes, particularly iewborns

an enlarged spleen

dark, tea-colored urine

Once the trigger is nremoved or resolved, the symptoms of G6PD deficiency usually disappear fairly nquickly, typically within a few weeks.

If symptoms are mild, no nmedical treatment is usually needed. As the body naturally makes new red blood ncells, the anemia will improve. If symptoms are more severe, a child may need nto be hospitalized for supportive medical care.

Diagnosis and Treatment

In most cases, cases of nG6PD deficiency go undiagnosed until a child develops symptoms. If doctors nsuspect G6PD deficiency, blood tests usually are done to confirm the diagnosis nand to rule out other possible causes of the anemia.

Treating the symptoms nassociated with G6PD deficiency is usually as simple as removing the trigger — nthat is, treating the illness or infection or stopping the use of a certaidrug. However, a child with severe anemia may require treatment in the hospital nto receive oxygen, fluids, and, if needed, a transfusion of healthy blood ncells. In rare cases, the deficiency can lead to other more serious health nproblems.

Polycythemia n

Polycythemia, defined as a central venous nhematocrit (Hct) level of greater than 65%, is a relatively common disorder. nThe primary concern with polycythemia is related to hyperviscosity and its nassociated complications. Blood viscosity increases exponentially as the Hct nlevel rises above 42%. This associated hyperviscosity is thought to contribute nto the symptom complex observed in approximately one half of infants with npolycythemia. However, only 47% of infants with polycythemia have nhyperviscosity, and only 24% of infants with hyperviscosity have a diagnosis of npolycythemia.

Pathophysiology

As the central nHct level increases, viscosity increases. The arterial oxygen content also nincreases. Changes in blood flow are observed in some organs; this is due to nchanges in viscosity or changes in arterial oxygen content. The change in blood nflow may influence oxygenation and may influence the delivery of substances to norgans that are dependent on plasma flow, such as glucose.

Many factors ndetermine blood viscosity. The primary factor in the newborn is the Hct. As nsuch, viscosity increases as Hct level rises. Other factors that uniquely ncontribute to blood viscosity in the neonate include increased RBC volume and ndecreased deformability of the fetal erythrocyte. Plasma proteins, platelets, nWBCs, and endothelial factors also contribute to viscosity; however, they are nnot clinically significant in the newborn.

Epidemiology

Frequency

United States

Polycythemia noccurs in 0.4-12% of neonates. It is more common in infants who are small for ntheir gestational age (SGA) and in infants who are large for their gestational nage (LGA). However, most infants with polycythemia are of appropriate size or nweight for their gestational age (AGA). Infants of mothers with diabetes have aincidence of more than 40%, and those born to mothers with gestational diabetes nhave an incidence of more than 30%. Polycythemia is also common in infants who nhave experienced delayed clamping of the umbilical cord. Hyperviscosity occurs nin 6.7% of infants.

Mortality/Morbidity

The central nnervous, cardiopulmonary, GI, and renal systems are at risk. Metabolic nderangements are common. Coagulation can also be affected.

Age

The central nvenous Hct level peaks 6-12 hours after birth and then declines until the ninfant is aged 24 hours, at which time it equals the Hct level in cord blood. nFewer than 40% of infants with a Hct level greater than 64% at 2 hours still nhave a high value at 12 hours or later.

Neonates with npolycythemia may have the following findings:

• Lethargy

• Irritability

• Jitteriness

• Tremors

• Seizures

• Cerebrovascular accidents

• Respiratory distress

• Cyanosis

• Apnea

• The central venous hematocrit (Hct) measurement is used as a surrogate for diagnosing hyperviscosity i newborns with polycythemia because it is readily available. Most clinical laboratories are not able to measure blood viscosity.

• Other laboratory tests include measurements of the following:

• Serum glucose and calcium levels: Measure these to determine if the patient has decreased levels that require treatment.

• Bilirubin level: Measure this level in the infant with jaundice and polycythemia because the increased RBC mass leads to an increased load of bilirubin precursors that can result in hyperbilirubinemia.

• Arterial blood gases (ABG): Consider measuring ABG values to assess oxygenation in the symptomatic infant with respiratory distress and cyanosis.

• Platelet count: This count may demonstrate thrombocytopenia if thrombosis or disseminated intravascular coagulation (DIC) are present.

n

Medical nCare                              

Therapy inewborns with polycythemia is based on both the measured central venous nhematocrit (Hct) level and the presence or absence of symptoms.

Treatment of polycythemia nwith partial exchange transfusion (PET) remains controversial. Regarding ntreatment with partial exchange, the Committee of the Fetus and Newborn of the nAmerican Academy of Pediatrics states, “The accepted treatment of npolycythemia is partial exchange transfusion (PET).” The group also nacknowledges that no evidence suggests that exchange transfusion affects the nlong-term outcome.

• Treatment for asymptomatic patients

• Hct level of 65-75%: Perform cardiorespiratory monitoring and monitoring of Hct and glucose levels every 6-12 hours and observe the patient for symptoms. Continue this monitoring for at least 24 hours or until the Hct level declines.

• Hct level of more than 75% on repeated measurements: Consider PET.

• Treatment for symptomatic patients

• Hct level of 60-65%: Consider alternative explanations for the symptoms. Although polycythemia and hyperviscosity may be the etiology of the symptoms, other causes for the symptoms must be excluded.

• Hct level more than 65% with symptoms attributable to polycythemia and hyperviscosity: Consider PET or observation with intravenous fluids for added hydration. Proceed to PET if symptoms worsen.

• PET

• Perform PET using an umbilical venous catheter to reduce the central Hct level to 50-55%.

• The total blood volume to be exchanged is determined as follows: [blood volume(patient’s Hct – desired Hct)]/(patient’s Hct), where blood volume = the patient’s weight in kilograms multiplied by 90 mL/kg.

• Normal saline is the replacement fluid of choice for exchange transfusions because it is effective and inexpensive. As alternatives, Plasmanate, 5% albumin, or fresh frozen plasma can be used. However, none of these is more effective thaormal saline. In addition, both 5% albumin and fresh frozen plasma are blood products, and certain religious beliefs prohibit their use. Lastly, these colloid products have been associated with complications such as necrotizing enterocolitis (NEC).

• Sterile technique is required.

• An exchange transfusion ca be performed in 3 ways, depending on the type of vascular access that is available. Regardless of the method used, aliquots should not exceed approximately 5 mL/kg delivered or removed over 2-3 minutes.

• If only a single umbilical venous catheter is in place, use a push-pull technique. With this technique, the withdrawal of blood is alternated with the administratio of replacement fluid through the single catheter. Do not remove more than 5 mL/kg in any single withdrawal.

• If both umbilical venous and arterial catheters are in place, withdraw blood from the arterial catheter while administering the replacement fluid through the venous catheter.

• If a venous or arterial umbilical catheter and a peripheral venous catheter are in place, the former can be used for blood withdrawal, whereas the latter is used to simultaneously and continuously infuse the replacement fluid.

n

Biliary atresia

Biliary atresia is a nlife-threatening condition in infants in which the bile ducts inside or outside nthe liver do not have normal openings.

Bile ducts in the liver, nalso called hepatic ducts, are tubes that carry bile from the liver to the ngallbladder for storage and to the small intestine for use in digestion. Bile nis a fluid made by the liver that serves two main functions: carrying toxins nand waste products out of the body and helping the body digest fats and absorb nthe fat-soluble vitamins A, D, E, and K.

nNormal liver and biliary system

With biliary natresia, bile becomes trapped, builds up, and damages the liver. The damage nleads to scarring, loss of liver tissue, and cirrhosis. Cirrhosis is a chronic, nor long lasting, liver condition caused by scar tissue and cell damage that nmakes it hard for the liver to remove toxins from the blood. These toxins build nup in the blood and the liver slowly deteriorates and malfunctions. Without ntreatment, the liver eventually fails and the infant needs a liver transplant nto stay alive.

The two types of nbiliary atresia are fetal and perinatal. Fetal biliary atresia appears while nthe baby is in the womb. Perinatal biliary atresia is much more common and does nnot become evident until 2 to 4 weeks after birth. Some infants, particularly nthose with the fetal form, also have birth defects in the heart, spleen, or nintestines.

Who is at risk nfor biliary atresia?

Biliary atresia nis rare and only affects about one out of every 18,000 infants.¹ nThe disease is more common in females, premature babies, and children of Asiaor African American heritage.

What are the symptoms of biliary atresia?

The first symptom of nbiliary atresia is jaundice––when the skin and whites of the eyes turn yellow. nJaundice occurs when the liver does not remove bilirubin, a reddish-yellow nsubstance formed when hemoglobin breaks down. Hemoglobin is an iron-rich proteithat gives blood its red color. Bilirubin is absorbed by the liver, processed, nand released into bile. Blockage of the bile ducts forces bilirubin to build up nin the blood.

Other common symptoms of nbiliary atresia include

dark urine, from the high nlevels of bilirubin in the blood spilling over into the urine

gray or white stools, nfrom a lack of bilirubin reaching the intestines

slow weight gain and ngrowth

What causes nbiliary atresia?

Biliary atresia likely has multiple causes, though none are nyet proven. Biliary atresia is not an inherited disease, meaning it does not npass from parent to child. Therefore, survivors of biliary atresia are not at nrisk for passing the disorder to their children.

Biliary atresia is most likely caused by an event in the nwomb or around the time of birth. Possible triggers of the event may include none or more of the following:

a viral or bacterial infection after birth, such as ncytomegalovirus, reovirus, or rotavirus

an immune system problem, such as when the immune system nattacks the liver or bile ducts for unknown reasons

a genetic mutation, which is a permanent change in a ngene’s structure

a problem during liver and bile duct development in the nwomb

exposure to toxic substances

How is biliary natresia diagnosed?

No single test ncan definitively diagnose biliary atresia, so a series of tests is needed. All ninfants who still have jaundice 2 to 3 weeks after birth, or who have gray or nwhite stools after 2 weeks of birth, should be checked for liver damage.²

Infants with nsuspected liver damage are usually referred to a

• pediatric gastroenterologist, a doctor who specializes in children’s digestive diseases

• pediatric hepatologist, a doctor who specializes in children’s liver diseases

• pediatric surgeon, a doctor who specializes in operating on children’s livers and bile ducts

n

The health care nprovider may order some or all of the following tests to diagnose biliary natresia and rule out other causes of liver problems. If biliary atresia is nstill suspected after testing, the next step is diagnostic surgery for nconfirmation.

Blood ntest. A blood test involves drawing blood at a health care provider’s office or commercial nfacility and sending the sample to a lab for analysis. High levels of bilirubiin the blood can indicate blocked bile ducts.

Abdominal nx rays. An x ray is a picture created by using radiation and recorded on film or non a computer. The amount of radiation used is small. An x ray is performed at na hospital or outpatient center by an x-ray technician, and the images are ninterpreted by a radiologist—a doctor who specializes in medical imaging. nAnesthesia is not needed, but sedation may be used to keep infants still. The ninfant will lie on a table during the x ray. The x-ray machine is positioned nover the abdominal area. Abdominal x rays are used to check for an enlarged nliver and spleen.

Ultrasound. Ultrasound uses a ndevice, called a transducer, that bounces safe, painless sound waves off organs nto create an image of their structure. The procedure is performed in a health ncare provider’s office, outpatient center, or hospital by a specially trained ntechnician, and the images are interpreted a radiologist. Anesthesia is not nneeded, but sedation may be used to keep the infant still. The images can show nwhether the liver or bile ducts are enlarged and whether tumors or cysts are nblocking the flow of bile. An ultrasound cannot be used to diagnose biliary atresia, nbut it does help rule out other common causes of jaundice.

Liver nscans. Liver scans are special x rays that use chemicals to create an image of nthe liver and bile ducts. Liver scans are performed at a hospital or outpatient nfacility, usually by a nuclear medicine technician. The infant will usually nreceive general anesthesia or be sedated before the procedure. Hepatobiliary niminodiacetic acid scanning, a type of liver scan, uses injected radioactive ndye to trace the path of bile in the body. The test can show if and where bile nflow is blocked. Blockage is likely to be caused by biliary atresia.

Liver nbiopsy. A biopsy is a procedure that involves taking a piece of liver tissue for nexamination with a microscope. The biopsy is performed by a health care nprovider in a hospital with light sedation and local anesthetic. The health ncare provider uses imaging techniques such as ultrasound or a computerized ntomography scan to guide the biopsy needle into the liver. The liver tissue is nexamined in a lab by a pathologist—a doctor who specializes in diagnosing ndiseases. A liver biopsy can show whether biliary atresia is likely. A biopsy ncan also help rule out other liver problems, such as hepatitis—an irritation of nthe liver that sometimes causes permanent damage.

Diagnostic nsurgery. During diagnostic surgery, a pediatric surgeon makes an incision, or cut, nin the abdomen to directly examine the liver and bile ducts. If the surgeoconfirms that biliary atresia is the problem, a Kasai procedure will usually be nperformed immediately. Diagnostic surgery and the Kasai procedure are performed nat a hospital or outpatient facility; the infant will be under general nanesthesia during surgery.

How is nbiliary atresia treated?

Biliary atresia is treated with surgery, called nthe Kasai procedure, or a liver transplant.

Kasai nProcedure

The Kasai nprocedure, named after the surgeon who invented the operation, is usually the nfirst treatment for biliary atresia. During a Kasai procedure, the pediatric nsurgeon removes the infant’s damaged bile ducts and brings up a loop of nintestine to replace them. As a result, bile flows straight to the small nintestine.

While this noperation doesn’t cure biliary atresia, it can restore bile flow and correct nmany problems caused by biliary atresia. Without surgery, infants with biliary natresia are unlikely to live past age 2. This procedure is most effective iinfants younger than 3 months old, because they usually haven’t yet developed npermanent liver damage. Some infants with biliary atresia who undergo a nsuccessful Kasai procedure regain good health and no longer have jaundice or nmajor liver problems.

nThe Kasai procedure

If the Kasai nprocedure is not successful, infants usually need a liver transplant within 1 nto 2 years. Even after a successful surgery, most infants with biliary atresia nslowly develop cirrhosis over the years and require a liver transplant by nadulthood.

Liver Transplant

Liver ntransplantation is the definitive treatment for biliary atresia, and the nsurvival rate after surgery has increased dramatically in recent years. As a nresult, most infants with biliary atresia now survive. Progress in transplant nsurgery has also increased the availability and efficient use of livers for ntransplantation in children, so almost all infants requiring a transplant careceive one.

In years past, nthe size of the transplanted liver had to match the size of the infant’s liver. nThus, only livers from recently deceased small children could be transplanted ninto infants with biliary atresia. New methods now make it possible to ntransplant a portion of a deceased adult’s liver into an infant. This type of nsurgery is called a reduced-size or split-liver transplant.

Part of a living nadult donor’s liver can also be used for transplantation. Healthy liver tissue ngrows quickly; therefore, if an infant receives part of a liver from a living ndonor, both the donor and the infant can grow complete livers over time.

Infants with nfetal biliary atresia are more likely to need a liver transplant—and usually nsooner—than infants with the more common perinatal form. The extent of damage ncan also influence how soon an infant will need a liver transplant.

What are npossible complications after the Kasai procedure?

After the Kasai nprocedure, some infants continue to have liver problems and, even with the nreturn of bile flow, some infants develop cirrhosis. Possible complications nafter the Kasai procedure include ascites, bacterial cholangitis, portal nhypertension, and pruritus.

Ascites. Problems with liver nfunction can cause fluid to build up in the abdomen, called ascites. Ascites ncan lead to spontaneous bacterial peritonitis, a serious infection that nrequires immediate medical attention. Ascites usually only lasts a few weeks. nIf ascites lasts more than 6 weeks, cirrhosis is likely present and the infant nwill probably need a liver transplant.

Bacterial ncholangitis. Bacterial cholangitis is an infection of the bile ducts that is treated nwith bacteria-fighting medications called antibiotics.

Portal nhypertension. The portal vein carries blood from the stomach, intestines, spleen, ngallbladder, and pancreas to the liver. In cirrhosis, scar tissue partially nblocks and slows the normal flow of blood, which increases the pressure in the nportal vein. This condition is called portal hypertension. Portal hypertensiocan cause gastrointestinal bleeding that may require surgery and an eventual nliver transplant.

Pruritus. Pruritus is caused by nbile buildup in the blood and irritation of nerve endings in the skin. nPrescription medication may be recommended for pruritus, including resins that nbind bile in the intestines and antihistamines that decrease the skin’s nsensation of itching.

What medical care is needed after a liver ntransplant?

After a liver ntransplant, a regimen of medications is used to prevent the immune system from nrejecting the new liver. Health care providers may also prescribe blood npressure medications and antibiotics, along with special diets and vitamisupplements.

Eating, Diet, and Nutrition

Infants with nbiliary atresia often have nutritional deficiencies and require special diets nas they grow up. They may need a higher calorie diet, because biliary atresia nleads to a faster metabolism. The disease also prevents them from digesting nfats and can lead to protein and vitamin deficiencies. Vitamin supplements may nbe recommended, along with adding medium-chain triglyceride oil to foods, nliquids, and infant formula. The oil adds calories and is easier to digest nwithout bile than other types of fats. If an infant or child is too sick to neat, a feeding tube may be recommended to provide high-calorie liquid meals.

After a liver ntransplant, most infants and children can go back to their usual diet. Vitamisupplements may still be needed because the medications used to keep the body nfrom rejecting the new liver can affect calcium and magnesium levels.

 

Idiopathic Neonatal Hepatitis
n
nIdiopathic neonatal hepatitis (INH) is a general term for inflammation of the nliver that occurs shortly after birth iewborns (less than 3 months of age) nfor which a specific cause cannot be identified.  Neonatal hepatitis cahave one of a number of causes including metabolic, infectious, and genetic ncauses.  Metabolic diseases include αa1-antitrypsin deficiency, ncystic fibrosis, neonatal iron storage disease, respiratory chain defects, and nfatty acid oxidation defects. Infectious causes include congenital syphilis, nechovirus, and some herpes viruses.  The classic hepatitis viruses (A, B, nand C) are less common causes. There are also a number of less common genetic ndefects, such as Alagille syndrome and progressive familial intrahepatic ncholestasis.  In Idiopathic Neonatal Hepatitis, however, the cause of ninflammation remains unknown.

What are nthe symptoms?
n
nThe symptoms of idiopathic neonatal hepatitis can vary greatly from one nindividual to another.  Infants with INH may have jaundice as their only symptom; nusually in the first two weeks of life developing up to the third month of nlife.  There may also be the presence of dark urine, pale stools and nenlargement of the liver, Other symptoms may also include poor growth, nirritability, and severe itching.

nHow is it diagnosed?
n
nMorphologic picture of nneonatal hepatitis

The greatest challenge in diagnosing idiopathic neonatal hepatitis is idifferentiating it from other neonatal liver diseases with known causes.  nINH is diagnosed when tests for  metabolic, infectious, and genetic causes nare negative.  This is done through blood tests, hepatobiliary scans, nmetabolic or genetic testing, and a liver biopsy.  On biopsy, the nhepatocytes are enlarged, often filled with bile, and sometimes dying. There nmay be early scarring in some instances. Electron micrscopic examination is nsometimes useful in detecting otherwise subtle changes and directing further ntesting.

nHow is it treated?
n
nSince there is no known cause in idiopathic neonatal hepatitis, treatment is nfocused on symptom management and good nutritional support. This includes nmedications to stimulate bile flow, predigested formulas, and extra vitamins A, nD, E, and K, which are important because the lack of bile in the intestine nimpairs absorption of those vitamins.

What is nthe outlook for infants diagnosed with INH?
n
nApproximately 80% of infants diagnosed with idiopathic neonatal hepatitis nrecover fully from the condition. Over the years, as more specific causes of nneonatal jaundice are diagnosed, the number of cholestatic infants without a nspecific diagnosis has decreased. It is expected that this number will continue nto decrease as more specific causes are described.

 

Clinical management

a) Identificatioof factors that increase the risk of kernicterus in a nbaby with jaundice

b) nRecognition and management in primary care (includes community care).

• Role nand timing of assessment in primary care.

• Estimatioof hyperbilirubinaemia and its management.

• Management nat home, in the community and after discharge.

• Indications nfor referral to secondary care

c) nRecognition and management in secondary care.

• Assessment nin secondary care.

• Investigations nincluding:

– bilirubin – components and methods of estimation

– other nrelevant haematological and biochemical tests

– urine ntests

– nscreening for metabolic disorders

– end ntidal carbon monoxide concentration

• Timing nof lab investigations including point of care testing. Indications for referral nto

tertiary ncare.

d) nTreatment of hyperbilirubinaemia.

• Interpretatioof bilirubin levels and use of nomograms.

• Phototherapy n(various modalities).

• Blood nexchange transfusion.

• Other ntreatment modalities.

• Role of nnutritional support and rehydration.

e) nOutcomes that will be considered:

• major noutcomes:

– nmortality

– nmorbidity, seizures

– nneurological complications (immediate, short-term and long-term)

– nimpact on resource use and costs

• other noutcomes:

– nauditory, visual and other non-neurological complications

– nhospital admission (duration, frequency, acquired infections)

– neffect on maternal infant bonding, breastfeeding and family bonding

f) nInformation and support that should be given to parents and carers:

• at the ntime of initial presentation

• after ndiagnosis and during management

• about nlong-term effects, including significant morbidities and functional outcome.

 

2. Haemorrhagic Disease of the Newborn (HDN)

Epidemiology The incidence of late HDN in the developed nworld is about 4-25 per 100,000 births. In the UK the incidence is reported as n8.6 per 100,000 of which 44% were classic HDN and 56% late HDN.

Males are at a greater risk of developing HDN than females with a M:F nratio of approximately 2:1. Children who are entirely breastfed have a 20 times ngreater risk of developing HDN than those who receive formula milk due to the nlow level of vitamin K in breast milk and also the low levels of bacteria which nhelp to synthesize vitamin K in the guts of breastfed babies. Several drugs nsuch as isoniazid, rifampicin, nanticoagulants and anticonvulsant agents, which have been taken by the mother, nmake the infant at risk of developing early HDN. Warm environmental ntemperatures also predispose babies to developing late HDN.

Haemorrhagic disease of the newborn was first described over a hundred nyears ago but its relationship to vitamin K was not realised until 40 years nlater. Vitamin K is required for the production of clotting factors II, VII, IX n& X an essential factor involved in the normal clotting of blood, it is npresent in some plants and is also synthesized by some E. coli in the gut. All nnewborn infants have low levels of vitamin K and are at risk of developing nhaemorrhagic disease of the newborn (HDN). HDN may occur within 24 hours of nbirth (early HDN), between day 1 and day 7 of life (classic HDN) or betweeweeks 2 and 12 of life (late HDN). Late HDN can result in significant morbidity nand mortality (25%) due to intracranial bleeds, and has resulted in most developed ncountries having in place a protocol for the giving of supplemental vitamin K nto all new born babies.

Presentation
nEarly HDN, is limited to babies whose mothers received various drugs nduring pregnancy, and due to routine ant-natal care is now extremely rare. nEarly HDN presents with bleeding at sites related to the trauma of birth e.g.

·                     nBleeding from scalp monitor site

·                     nCephalohaematoma

·                     nIntracranial bleeding, irritability, convulsions

·                     nIntrathoracic bleeding, blood stained sputum,+/- nrespiratory distress

·                     nIntra-abdominal bleeding, melena

·                     nTachycardia

Classic HDN occurs both in babies whose mothers were nreceiving various forms of medication during pregnancy, and also babies who are nexclusively breast fed. The bleeding in classic HDN most often affects nnon-vital organs such as:

·                     nGastrointestinal bleeding

·                     nBleeding from the skin and mucous membranes e.g. nose and gums

·                     nProlonged bleeding following circumcision

·                     nBleeding from the umbilical stump

Late HDN occurs in predominantly in exclusively breastfed ninfants, but may also occur in babies with malabsorption nsyndromes who are unable to absorb the fat soluble vitamin K e.g. cystic fibrosis, npersistent diarrhoea, cholestatic jaundice etc. nChildren on long term antibiotics may also develop altered gut flora with ndecreased synthesis of vitamin K by E.coli. Late HDN nproduces the greatest morbidity and mortality amongst the infants due to suddebleeding into the CNS resulting in:-
nSubarachnoid haemorrhage (90%)
n  +/- subdural haemorrhage
n  +/- parenchymal haemorrhage
n  +/- intraventricular haemorrhage
nIrritability
nConvulsions
nWeakness of arms and/or legs
n  +/- blindness
n  +/- coma

Differential Diagnosis The differential diagnosis must include nother causes of bleeding in young babies such as:

·                     nHaemophilia (boys)

·                     nTrauma

·                     nAccidental or non-accidental injury

·                     nDisseminated intravascular coagulopathy

·                     nThrombocytopenia

·                     nNecrotising enterocolitis

·                     nIntussusecption

·                     nLeukaemia

Investigations

§                     nPregnancy history especially drugs, gestation at delivery, type and length of ndelivery.

§                     nFull history of child including feeding history e.g. breast fed or bottle fed

§                     nFBC

§                     nClotting screen including prothrombin time, ncoagulation time and partial thromboplastin time.

§                     nCXR or Ultrasound scan may confirm intrathoracic nbleed.

§                     nCT or MRI scan if intracranial nhaemorrhage or other major haemorrhage suspected, to ascertain the extent of nthe bleed.

Management
nImmediate management When HDN is suspected, vitamin K should be ngiven as a supplement as soon as possible which will result in a reduction ithe bleeding time within a few hours.

Babies with severe bleeding or intracranial bleeding may require fresh nfrozen plasma to be given in addition to vitamin K in order to arrest the nbleeding as soon as possible.

Babies who have lost a large percentage of their circulating volume into na bleed may require transfusions with whole blood.

Long term management Babies nwith late HDN who have suffered intracranial bleeds will require assessment nfrom a specialist team to help minimise the long term sequelae nof the bleed. They will require early and continuing physiotherapy to minimise nspasticity and retain function, they may require nutritional assistance if nunable to swallow or suck, they may require surgery or intracranial shunts to nreduce intracranial pressure.

Complications The complications nof HDN mainly relate to bleeds involving the central nervous system, and 40% of nchildren who survive HDN will have some form of long term neurological handicap

Prognosis In a review of all nreported cases of HDN up to 1993, 14% of all cases died and 40% had long term nneurological deficit.

Prevention The incidence of nall forms of HDN has been considerably reduced over the last decade or so. This nhas been brought about by the greater understanding of the role that Vitamin K nplays in the disease, and also the factors such as drugs taken by both mother nand child which may affect the levels of vitamin K. Routine antenatal screening nof all mothers has allowed for the early identification of babies who may be at nrisk of early HDN, and where possible therapeutic regimes are altered.

The largest reduction has been brought nabout by the routine supplementation of vitamin K in all new born babies, nusually at birth. This is given either in the form of an intramuscular ninjection or a series of oral supplements and, as a consequence, HDN is now nrarely seen in the UK and other countries where this policy has been adopted.

 

References:

1.     Avery‘s neonatology: pathophysiology and management of the newborn / G. B. Avery, M. G. MacDonald, M. M. K. Seshia [et al.]. – 6th ed. – Philadelphia : Lippincott Williams and Wilkins, 2005. – 354 p.

2.     Nelson Textbook of Pediatrics, 19th Edition. – Expert nConsult Premium Edition – Enhanced Online Features and Print / by Robert M. nKliegman, MD, Bonita M.D. Stanton, MD, Joseph St. Geme, Nina Schor, MD, PhD and nRichard E. Behrman, MD. – 2011. – 2680 p.

3.     Pediatrics / Edited by O.V. Tiazhka, T.V. Pochinok, nA.M. Antoshkina/ – Vinnytsa: Nova Knyha Publishers, 2011. – 584 p.

 

WEB–adresses

http://www.emedicine.com

htttp;//www.babynet.at

www.medscape.com

http://www.neonatology.org/neo.clinical.html n