Neonatology. Lesson 2. Topics:
1. Hemolytic disease of newborns.
2. Haemorrhagic disease of newborns.
1. Hemolytic disease of newborns.
Background: Jaundice is the most common condition requiring medical attention iewborns. The yellow coloration of the skin and sclera iewborns with jaundice is the result of accumulation of unconjugated bilirubin. In most infants, unconjugated hyperbilirubinemia reflects a normal transitional phenomenon. However, in some infants, serum bilirubin levels may rise excessively, which can be cause for concern because unconjugated bilirubin is neurotoxic and can cause death iewborns and lifelong neurologic sequelae in infants who survive (kernicterus). For these reasons, the presence of neonatal jaundice frequently results in diagnostic evaluation.
Physicians recognized neonatal jaundice as early as the 18th century. Supposedly, Morgagni described 15 infants with jaundice (all of them his). Descriptions of the clinical course and epidemiology of neonatal jaundice are found in a number of 19th-century theses and other publications.
PHYSIOLOGY OF BILIRUBIN IN THE FETUS AND NEWBORN INFANT
Red blood cells continuously haemolyse in the body releasing haemoglobin (Hb) which is converted to unconjugated bilirubin in the reticulo-endothelial system (especially spleen). One gram Hb yields 600 µmol bilirubin. In the plasma, unconjugated bilirubin is bound to albumin. This prevents this fat-soluble pigment from penetrating brain tissue to cause damage.
In the fetus most unconjugated bilirubin is removed by the placenta. However, about 10% is still conjugated in the fetal liver and excreted into the gut where it is deconjugated by the enzyme beta glucuronidase and then reabsorbed via the enterohepatic circulation. The fetus therefore ensures that all the bilirubin is unconjugated to fascilitate excretion.
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. Conjugated bilirubin is water-soluble and is not toxic to brain tissue. It is excreted through the bile duct system into the duodenum. While most is excreted in the stool, but some is changed back to unconjugated bilirubin and reabsorbed as the enterohepatic circulation of bilirubin remains for a few weeks after delivery. The intestinal enzyme beta glucuronidase, which is responsible for the enterohepatic circulation of bilirubin, is also present in breast milk. Neonatal jaundice is therefore commoner in breast fed than bottle fed infants.
If there is obstruction to the biliary tree, conjugated bilirubin enters the plasma and may be excreted in the urine.
Pathophysiology: Neonatal physiologic jaundice results from simultaneous occurrence of the following 2 phenomena:
Bilirubin is produced in the reticuloendothelial system as the end product of heme catabolism and is formed 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 through the action of heme oxygenase, the rate-limiting step in the process, releasing iron and carbon monoxide. The iron is conserved for reuse, while carbon monoxide is excreted through the lungs and can be measured in the patient’s breath to quantify bilirubin production.
Next, water-soluble biliverdin is reduced to bilirubin, which, because of the intramolecular hydrogen bonds, is almost insoluble in water in its most common isomeric form (bilirubin IX Z,Z). Due to its hydrophobic nature, unconjugated bilirubin is transported in the plasma tightly bound to albumin. Binding to other proteins and erythrocytes also occurs, but the physiologic role is probably limited. Binding of bilirubin to albumin increases postnatally with age and is reduced in infants who are ill. The presence of endogenous and exogenous binding competitors, such as certain drugs, also decreases the binding affinity of albumin for bilirubin. A minute fraction of unconjugated bilirubin in serum is not bound to albumin. This free bilirubin is able to cross lipid-containing membranes, including the blood-brain barrier, leading to neurotoxicity.
When the bilirubin-albumin complex reaches the hepatocyte, bilirubin is transported into the cell, where it partially binds to ligandin. Uptake of bilirubin into hepatocytes increases with increasing ligandin concentrations. Ligandin concentrations are low at birth, but they increase rapidly over the first few weeks of life. Ligandin concentrations may be increased by the administration of pharmacologic agents such as phenobarbital.
Bilirubin is bound to glucuronic acid (conjugated) in the hepatocyte endoplasmic reticulum in a reaction catalyzed by uridine diphosphoglucuronyltransferase (UDPGT). Monoconjugates are formed first and predominate in the newborn. Diconjugates appear to be formed at the cell membrane and may require the presence of the UDPGT tetramer.
Bilirubin conjugation is biologically critical because it transforms a water-insoluble bilirubin molecule into a water-soluble molecule. Water-solubility allows bilirubin to be excreted into bile. The activity of UDPGT is low at birth, but increases to adult values by age 4-8 weeks. In addition, certain drugs (phenobarbital, dexamethasone, clofibrate) can be administered to increase UDPGT activity.
Once excreted into bile and transferred to the intestines, bilirubin eventually is reduced to colorless tetrapyrroles by microbes in the colon. However, some deconjugation occurs in the proximal small intestine through the action of -glucuronidases located in the brush border. This unconjugated bilirubin can be reabsorbed into the circulation, increasing the total plasma bilirubin pool. This cycle of uptake, conjugation, excretion, deconjugation, and reabsorption is termed the enterohepatic circulation. The process may be extensive in the neonate, partly because nutrient intake is limited in the first days of life, prolonging the intestinal transit time. Certain factors present in the breast milk of some mothers also may contribute to increased enterohepatic circulation of bilirubin (breast milk jaundice), but the mechanism behind this phenomenon remains unelucidated.
Neonatal jaundice, while a normal transitional phenomenon in most infants, can occasionally become more pronounced. Blood group incompatibilities (Rh, ABO, and others) may increase bilirubin production through increased hemolysis. Historically, Rh isoimmunization was an important cause of severe jaundice, often resulting in the development of kernicterus. While this condition has become relatively rare in industrialized countries following the use of Rh prophylaxis in Rh-negative women, Rh isoimmunization remains common in developing countries. Nonimmune hemolytic disorders (spherocytosis, G-6-PD deficiency) also may cause increased jaundice through increased hemolysis.
A number of other nonhemolytic processes can increase serum bilirubin levels. Accumulation of blood in extravascular compartments (cephalhematomas, bruising, occult bleeding) may increase bilirubin production as the blood is absorbed and degraded. Increased bilirubin production also is seen in patients with polycythemia and in infants of mothers with diabetes. Increased enterohepatic circulation leading to elevated bilirubin levels is seen in patients with bowel obstruction or ileus and when infants are not fed for other reasons.
Decreased clearance of bilirubin is seen in certain inborn errors of metabolism, such as Crigler-Najjar syndrome, Gilbert syndrome, galactosemia, tyrosinemia, and hypermethioninemia. In the latter 3 conditions, elevations of conjugated serum bilirubin occur frequently. Hormone deficiencies, such as hypothyroidism and hypopituitarism, also can decrease bilirubin clearance. Finally, decreased clearance may play a role in breast milk jaundice.
Compared to unconjugated hyperbilirubinemia, conjugated (direct) hyperbilirubinemia is rare ieonates. Conjugated hyperbilirubinemia can be broadly classified into the following 2 groups:
· Obstructed bile flow with or without hepatocellular injury
· Hepatocyte injury with normal bile ducts
Obstructed bile flow with or without hepatocellular injury may result from biliary atresia or choledochal cyst. Hepatocyte injury with normal bile ducts may be due to iatrogenic, infectious, or metabolic causes. Iatrogenic causes include intravenous hyperalimentation. Infectious causes may be viral (cytomegalovirus, hepatitis B, other viruses), bacterial (septicemia), or parasitic (toxoplasmosis). Metabolic disorders include enzyme deficiencies (1-antitrypsin deficiency, galactosemia, cystic fibrosis, tyrosinemia, fructosemia, hypermethioninemia), storage diseases, Rotor syndrome, Dubin-Johnson syndrome, Byler disease, Zellweger syndrome, and Aagenaes syndrome.
Neonatal hyperbilirubinemia is extremely common because almost every newborn develops an unconjugated serum bilirubin level greater than 30 mol/L (1.8 mg/dL) during the first week of life.
PHYSIOLOGICAL JAUNDICE Jaundice is the yellow discolouration of the skin and sclera due to the deposition of bilirubin. All normal newborn infants have increased amounts of unconjugated bilirubin in their blood while up to 50% develop jaundice on the third or fourth day of life. In full-term infants, jaundice reaches maximum intensity by day 4 or 5 and is usually no longer evident after day 7. The total serum bilirubin (TSB) usually does not usually exceed 200 µmol/l (12 mg%) although in some well breast fed infants it might reach as high as 270 µmol/l (15mg%).
Physiological jaundice is the “normal” jaundice seen in many healthy newborn infants. Physiological jaundice never appears within the first 24 hours of life and seldom lasts beyond 14 days. These infants show no sign of illness – they remain afebrile, drink well, gain weight and have normal stools.
· Physiological jaundice is due to:
o the high Hb level which results in a high bilirubin production
o slow hepatic conjugation
o the enterohepatic circulation of bilirubin
The term “idiopathic hyperbilirubinaemia” is used when the bilirubin level exceeds the values accepted as “physiological” but no pathological cause is found. Idiopathic hyperbilirubinaemia is more common in preterm and breast fed infants.
Note that jaundice is a clinical sign while hyperbilirubinaemia is idetected by measuring the TSB in a laboratory.
Causes:
· Physiologic jaundice is caused by a combination of increased bilirubin production secondary to accelerated destruction of erythrocytes, decreased excretory capacity secondary to low levels of ligandin in hepatocytes, and low activity of the bilirubin-conjugating enzyme UDPGT.
· Pathologic neonatal jaundice occurs when additional factors are superimposed on the basic mechanisms described above. Such is the case in immune or nonimmune hemolytic anemia and in polycythemia.
· Decreased clearance of bilirubin may play a role in breast milk jaundice and in several metabolic and endocrine disorders.
· Risk factors
o Race: Incidence is higher in East Asians and American Indians and is lower in African Americans.
o Geography: Incidence is higher in populations living at high altitudes. Greeks living in
o Genetics and familial risk: Incidence is higher in infants with siblings who had significant neonatal jaundice. Incidence also is higher in infants with mutations in the gene coding for UDPGT (Gilbert syndrome) and/or in infants with homozygous or heterozygous G-6-PD deficiency.
o Nutrition: Incidence is higher in infants who are breastfed.
o Maternal factors: Infants of mothers with diabetes have higher incidence. Use of some drugs may increase incidence, while others decrease incidence.
o Birthweight and gestational age: Incidence is higher in premature infants and/or in infants with low birthweight.
· Early onset
o Haemolytic disease especially Rh disease
· Onset after 24 hours: Physiological/Idiopathic jaundice
o Infection
o ABO haemolytic disease
· Unconjugated Hyperbilirubinaemia
o Excessive haemolysis:
– Haemolytic jaundice – ABO and Rh blood group incompatibilities
– Hereditary spherocytosis
– G-6-PD deficiency
– Haematomas e.g. cephalohaematoma or bruising
– Polycythemia
– Infection
o Defective conjugation:
– Physiological jaundice – iormal full-term and preterm infants
– Idiopathic hyperbilirubinaemia
– Drugs e.g. oxytocin
– Hypoxia
– Hypothyroidism
– Infection
· Conjugated Hyperbilirubinaemia
o Hepatocellular disease:
– Infections: bacterial e.g. septicaemia
§ viral e.g. virus hepatitis, herpes, CMV, rubella
spirochaetal – congenital syphilis
protozoal e.g. toxoplasmosis
– Galactosaemia (very rare)
o Obstructive:
– Atresia of bile ducts (usually older than 4 weeks)
– Inspissated bile syndrome
– Choledochal cyst
Bilirubin
· Transcutaneous bilirubinometry can be performed using handheld devices that incorporate sophisticated optical algorithms to filter out most of the unreflected light from the bilirubin molecules.
· In infants with mild jaundice, transcutaneous bilirubinometry may be all that is needed to assure that total bilirubin levels are safely below those requiring intervention.
· In infants with moderate jaundice, transcutaneous bilirubinometry may be useful in selecting patients who require phlebotomy for serum bilirubin measurement.
· Usually, a total serum bilirubin level is the only testing required in a moderately jaundiced infant who presents on the typical second or third day of life without a history and physical findings suggestive of a pathologic process.
Additional studies may be indicated in the following situations:
· Infants who present with jaundice on the first or after the third day of life
· Infants who are anemic at birth
· Infants who otherwise appear ill
· Infants in whom serum bilirubin levels are very elevated
· Infants in whom significant jaundice persists beyond the first 2 weeks of life
· Infants in whom family, maternal, pregnancy, or case histories suggest the possibility of a pathologic process
· Infants in whom physical examination reveals findings not explained by simple physiologic hyperbilirubinemia
In addition to total serum bilirubin levels, other suggested studies may include the following:
· Blood type and Rh determination in mother and infant
· Direct Coombs testing in the infant
· Hemoglobin and hematocrit values
· Serum albumin levels: This may be a useful adjunct in evaluating risk of toxicity levels, since albumin binds bilirubin in a ratio of 1:1 at the primary high-affinity binding site.
· Nomogram for hour-specific bilirubin values: This may be a useful tool for predicting, either before or at the time of hospital discharge, which infants are likely to develop high serum bilirubin values. These infants require close follow-up monitoring and repeated bilirubin measurements. The predictive ability has been shown both for bilirubin values measured in serum and for values measured transcutaneously.
· Measurement of end-tidal carbon monoxide in breath (ETCO): ETCO may be used as an index of bilirubin production. Measurement of ETCO may assist in identifying individuals with increased bilirubin production and, thus, at increased risk of developing high bilirubin levels. An apparatus has been developed that makes measuring ETCO simple (CO-Stat End Tidal Breath Analyzer, Natus Medical Inc).
· Peripheral blood film for erythrocyte morphology
· Reticulocyte count
· Conjugated bilirubin: Note that direct bilirubin measurements are often inaccurate, are subject to significant interlaboratory and intralaboratory variation, and generally are not a sensitive tool for diagnosing cholestasis.
· Liver function tests: Aspartate aminotransferase (ASAT or SGOT) and alanine aminotransferase (ALAT or SGPT) levels are elevated in hepatocellular disease. Alkaline phosphatase and -glutamyltransferase (GGT) levels often are elevated in cholestatic disease. A GGT/ALAT ratio greater than 1 is strongly suggestive of biliary obstruction.
· Tests for viral and/or parasitic infection may be indicated in infants with hepatosplenomegaly or evidence of hepatocellular disease.
· Reducing substance in urine is a useful screening test for galactosemia, provided the infant has received sufficient quantities of milk.
· Blood gas measurements: The risk of bilirubin CNS toxicity is increased in acidosis, particularly respiratory acidosis.
· Bilirubin-binding tests: Although they are interesting research tools, these tests have not found widespread use in clinical practice. Although elevated levels of unbound bilirubin are associated with an increased risk of bilirubin encephalopathy, unbound bilirubin is but one of several factors that mediate/modulate bilirubin toxicity.
· Thyroid function tests
Imaging Studies:
· Ultrasound: Ultrasound examination of the liver and bile ducts is warranted in infants with laboratory and/or clinical signs of cholestatic disease.
· Radionuclide 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 are pretreated with phenobarbital 5 mg/kg/d for 3-4 days before performing the scan.
Other Tests:
· Auditory and visual evoked potentials are affected during ongoing significant jaundice; however, no criteria have been established that allow extrapolation from evoked potential findings to risk of bilirubin encephalopathy. Brainstem auditory evoked potentials should be obtained in the aftermath of severe neonatal jaundice to exclude sensorineural hearing loss.
· Crying characteristics are changed in significant neonatal jaundice; however, computerized crying analyses are not used in clinical practice.
HAEMOLYTIC DISEASE OF THE NEWBORN In simplified terms, there are two main types of blood group incompatibilities between fetus and mother, i.e. Rhesus and ABO haemolytic disease.. In the former, the Rh-negative mother, forms anti-D antibody in response to a transfer of red cells from a Rh-positive fetus. These fetal red cells usually cross the placenta at delivery. Rarely anti-D antibodies may form in response to a previous incompatible transfusion of Rh-positive blood. In a subsequent pregnancy, this maternal antibody passes 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 present in the blood of all group O mothers, are transferred across the placenta to the fetus. They cause haemolysis if the fetal blood group is A, B or AB. Unlike Rhesus incompatibility, ABO incompatibility commonly affects first born infants. ABO incompatibility is rarely severe enough to cause fetal hydrops.
There are also incompatibilities involving much rarer blood groups which occasionally cause similar problems.
HAEMOLYTIC DISEASE DUE TO Rh INCOMPATIBILITY There is a wide spectrum of clinical presentation. The disease may take one of three main forms:
1. Hydrops fetalis in which the infant is usually stillborn with gross oedema, ascites and anaemia.
2. Jaundice arising during the first few hours after birth associated with a variable degree of progressive haemolytic anaemia. The jaundice is not obviously present at birth because until then the excess bilirubin has been excreted via the placenta.
3. Gradual onset during the course of the first few weeks without of anaemia more than slight jaundice.
The main threats to the life of the baby, if live born, are a rapidly progressive anaemia, cardiac failure or bilirubin encephalopathy.
Prevention: The use of anti-D immunoglobulin is almost completely effective in preventing Rh disease except in those cases where maternal Rh antibodies are already present. By giving the mother anti-D globulin by injection as soon as possible after delivery (within 72 hours) the “transfused” fetal Rh-positive red cells are destroyed before they can sensitize the mother.
If the mother has already been sensitized, plasmapheresis has on occasion been used to reduce the amount of Rh antibody.
o detect all Rh-negative women
o history of previous pregnancies and complications, blood transfusions
o test for presence of anti-D antibody at first antenatal visit:
§ if antibodies absent: test for antibodies every 4 weeks
if antibodies present: measure level every 2-4 weeks
o amniocentesis if antibody titre 1/16 or more, or if a rapid rise in titre is shown
o amniotic fluid used to assess:
o severity of Rh disease (optical density, bilirubin level)
o fetal lung maturity (bubbles, phospholipid content)
The above factors are considered when the decision is made whether to induce early labour in order to prevent a stillbirth or to prolong life of the fetus by giving an intrauterine transfusion.
o clinical features: pale large placenta
§ anaemia
jaundice of rapid onset
enlarged liver and spleen
oedema and ascites
o laboratory tests: blood group
§ direct Coombs test
serum bilirubin
haemoglobin and PCV
o anticipate problems if the fetus is severely affected or preterm
o treat perinatal asphyxia, respiratory distress, etc.
o correct hypoxia, acidosis, hypoglycaemia, hypothermia
o start immediately if Coombs positive or there is evidence of jaundice or anaemia
To make decision about strategy of newborn’s management is recommended to use ready scemes (Fig. 1, Fig. 2).
HAEMOLYTIC DISEASE DUE TO ABO INCOMPATIBILITY This is now the most common cause of haemolytic disease in the newborn. The mother is group O and the baby group A, B or AB. Unlike Rh disease the disease process is milder and does not cause hydrops fetalis. It usually presents with the onset of early jaundice in the first 48 hours, although late onset of jaundice may occasionally occur.
The cord haemoglobin is normal and the direct Coombs test is positive. Typically the infant has a high reticulocyte count and spherocytes are seen on a peripheral blood smear. The TSB at 6 hours is usually above 80 µmol/l.
Although exchange transfusion may be necessary, in most cases phototherapy prevents the bilirubin rising to a dangerous level. As with Rh disease, late anaemia may occur.
As the blood group of infants is usually not routinely measured, all infants born to group O mothers should have their TSB measured at 6 hours after delivery. If the TSB is above 80 µmol/l then phototherapy should be started and the infant’s blood group and Coombs test done.
Table 1. Comparison of Rh and ABO Incompatibility
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 major complications of HDN are bilirubin encephalopathy (kernicterus) and late anemia of infancy.
Bilirubin encephalopathy
· Before the advent of exchange transfusion, kernicterus affected 15% of infants born with erythroblastosis. Approximately 75% of these neonates died within 1 week of life, and a small remainder died during the first year of life. Survivors had permanent neurologic sequelae and were thought to have accounted for 10% of all patients with cerebral palsy (CP).
· The mechanism by which unconjugated bilirubin enters the brain and damages it is unclear. Bilirubin enters the brain as lipophilic free bilirubin unbound to albumin, as supersaturated bilirubin acid that precipitates on lipid membrane in low pH, or as a bilirubin-albumin complex that transfers bilirubin to tissue by direct contact with cellular surface. A damaged blood-brain barrier enhances the entry of all forms of bilirubin into the brain, which is especially important in preterm neonates with respiratory acidosis and vascular injury.
· Bilirubin has been postulated to cause neurotoxicity via 4 distinct mechanisms: (1) interruption of normal neurotransmission (inhibits phosphorylation of enzymes critical in release of neurotransmitters), (2) mitochondrial dysfunction, (3) cellular and intracellular membrane impairment (bilirubin acid affects membrane ion channels and precipitates on phospholipid membranes of mitochondria), and (4) interference with enzyme activity (binds to specific bilirubin receptor sites on enzymes).
· The pathologic findings include characteristic staining and neuronal necrosis in basal ganglia, hippocampal cortex, subthalamic nuclei, and cerebellum. The cerebral cortex is s generally pared. About half of these neonates also have extraneuronal lesions, such as necrosis of renal tubular, intestinal mucosal, and pancreatic cells.
· Clinical signs of bilirubin encephalopathy typically evolve in 3 phases. Phase 1 is marked by poor suck, hypotonia, and depressed sensorium. Fever and hypertonia are observed in phase 2, and at times, the condition progresses to opisthotonus. Phase 3 is characterized by high-pitched cry, hearing and visual abnormalities, poor feeding, and athetosis. The long-term sequelae include choreoathetoid CP, upward gaze palsy, sensorineural hearing loss, and, less often, mental retardation.
· Currently, the mortality rate stands at 50% in term newborns, but mortality is nearly universal in the preterm population who may simply appear ill without signs specific for kernicterus. Lately, research has indicated that bilirubin production rates may be the critical piece of information identifying jaundiced infants at risk of neurotoxicity. A high bilirubin production rate is thought to result in rapid transfer of bilirubin to tissue, causing high tissue load, in which case any small further increase has great potential to enter the brain. Because the total serum bilirubin represents not only bilirubin production but also distribution and elimination, it is not an absolute indicator of risk of kernicterus. Techniques have been developed to measure the bilirubin production rates accurately and noninvasively using end-tidal carbon monoxide measurement and percutaneous measurement of carboxyhemoglobin.
Potential complications of exchange transfusion include the following:
· Cardiac – Arrhythmia, volume overload, congestive failure, and arrest
· Hematologic – Overheparinization, neutropenia, thrombocytopenia, and graft versus host disease
· Infectious – Bacterial, viral (CMV, HIV, hepatitis), and malarial
· Metabolic – Acidosis, hypocalcemia, hypoglycemia, hyperkalemia, and hypernatremia
· Vascular – Embolization, thrombosis, necrotizing enterocolitis, and perforation of umbilical vessel
· Systemic – Hypothermia
Prognosis: Most survivors of alloimmunized gestation are intact neurologically. However, Janssens and colleagues have reported neurologic abnormality to be closely associated with severity of anemia and perinatal asphyxia.
INFECTION
Bacterial infection causes increased red cell destruction thereby releasing more bilirubin. Infection also impairs the ability of the liver to excrete bilirubin by interfering with conjugation and by obstructing the flow of bile. There is thus usually an increase in both conjugated and unconjugated bilirubin. Unexplained jaundice, especially if associated with reluctance to feed, drowsiness or vomiting, should always raise the suspicion of infection somewhere e.g. urinary tract.
PROLONGED JAUNDICE (more than 14 days)
· Breast milk jaundice:
o Due to increased enterohepatic circulation of bilirubin. The infant is usually thriving. No treatment is necessary as it rarely gives high levels of bilirubin.
· Hypothyroidism:
o Though rare, this should not be forgotten as a cause of abnormally prolonged jaundice. Routine antenatal screening of TSH makes early diagnosis possible.
· Galactosaemia:
o Rare. Should be suspected in the newborn who vomits, refuses feeds, fails to thrive and develops prolonged jaundice. Reducing substances in the urine are a clue to the diagnosis.
· Hepatitis
Obstruction of bile flow may also cause prolonged jaundice.
Fig 1. Nomogram for designation of risk in 2840 well newborns at 36 or more weeks’ gestational age with birth weight of
Fig 2. Guidelines for phototherapy in hospitalized infants of 35 or more weeks’ gestation.
2. Haemorrhagic Disease of the Newborn (HDN)
Epidemiology The incidence of late HDN in the developed world is about 4-25 per 100,000 births. In the
Males are at a greater risk of developing HDN than females with a M:F ratio of approximately 2:1. Children who are entirely breastfed have a 20 times greater risk of developing HDN than those who receive formula milk due to the low level of vitamin K in breast milk and also the low levels of bacteria which help to synthesize vitamin K in the guts of breastfed babies. Several drugs such as isoniazid, rifampicin, anticoagulants and anticonvulsant agents, which have been taken by the mother, make the infant at risk of developing early HDN. Warm environmental temperatures also predispose babies to developing late HDN.
Haemorrhagic disease of the newborn was first described over a hundred years ago but its relationship to vitamin K was not realised until 40 years later. Vitamin K is required for the production of clotting factors II, VII, IX & X an essential factor involved in the normal clotting of blood, it is present in some plants and is also synthesized by some E. coli in the gut. All newborn infants have low levels of vitamin K and are at risk of developing haemorrhagic disease of the newborn (HDN). HDN may occur within 24 hours of birth (early HDN), between day 1 and day 7 of life (classic HDN) or between weeks 2 and 12 of life (late HDN). Late HDN can result in significant morbidity and mortality (25%) due to intracranial bleeds, and has resulted in most developed countries having in place a protocol for the giving of supplemental vitamin K to all new born babies.
Presentation
Early HDN, is limited to babies whose mothers received various drugs during pregnancy, and due to routine ant-natal care is now extremely rare. Early HDN presents with bleeding at sites related to the trauma of birth e.g.
· Bleeding from scalp monitor site
· Cephalohaematoma
· Intracranial bleeding, irritability, convulsions
· Intrathoracic bleeding, blood stained sputum,+/- respiratory distress
· Intra-abdominal bleeding, melena
· Tachycardia
Classic HDN occurs both in babies whose mothers were receiving various forms of medication during pregnancy, and also babies who are exclusively breast fed. The bleeding in classic HDN most often affects non-vital organs such as:
· Gastrointestinal bleeding
· Bleeding from the skin and mucous membranes e.g. nose and gums
· Prolonged bleeding following circumcision
· Bleeding from the umbilical stump
Late HDN occurs in predominantly in exclusively breastfed infants, but may also occur in babies with malabsorption syndromes who are unable to absorb the fat soluble vitamin K e.g. cystic fibrosis, persistent diarrhoea, cholestatic jaundice etc. Children on long term antibiotics may also develop altered gut flora with decreased synthesis of vitamin K by E.coli. Late HDN produces the greatest morbidity and mortality amongst the infants due to sudden bleeding into the CNS resulting in:-
Subarachnoid haemorrhage (90%)
+/- subdural haemorrhage
+/- parenchymal haemorrhage
+/- intraventricular haemorrhage
Irritability
Convulsions
Weakness of arms and/or legs
+/- blindness
+/- coma
Differential Diagnosis The differential diagnosis must include other causes of bleeding in young babies such as:
· Haemophilia (boys)
· Trauma
· Accidental or non-accidental injury
· Disseminated intravascular coagulopathy
· Thrombocytopenia
· Necrotising enterocolitis
· Intussusecption
· Leukaemia
Investigations
§ Pregnancy history especially drugs, gestation at delivery, type and length of delivery.
§ Full history of child including feeding history e.g. breast fed or bottle fed
§ FBC
§ Clotting screen including prothrombin time, coagulation time and partial thromboplastin time.
§ CXR or Ultrasound scan may confirm intrathoracic bleed.
§ CT or MRI scan if intracranial haemorrhage or other major haemorrhage suspected, to ascertain the extent of the bleed.
Management
Immediate management When HDN is suspected, vitamin K should be given as a supplement as soon as possible which will result in a reduction in the bleeding time within a few hours.
Babies with severe bleeding or intracranial bleeding may require fresh frozen plasma to be given in addition to vitamin K in order to arrest the bleeding as soon as possible.
Babies who have lost a large percentage of their circulating volume into a bleed may require transfusions with whole blood.
Long term management Babies with late HDN who have suffered intracranial bleeds will require assessment from a specialist team to help minimise the long term sequelae of the bleed. They will require early and continuing physiotherapy to minimise spasticity and retain function, they may require nutritional assistance if unable to swallow or suck, they may require surgery or intracranial shunts to reduce intracranial pressure.
Complications The complications of HDN mainly relate to bleeds involving the central nervous system, and 40% of children who survive HDN will have some form of long term neurological handicap
Prognosis In a review of all reported cases of HDN up to 1993, 14% of all cases died and 40% had long term neurological deficit.
Prevention The incidence of all forms of HDN has been considerably reduced over the last decade or so. This has been brought about by the greater understanding of the role that Vitamin K plays in the disease, and also the factors such as drugs taken by both mother and child which may affect the levels of vitamin K. Routine antenatal screening of all mothers has allowed for the early identification of babies who may be at risk of early HDN, and where possible therapeutic regimes are altered.
The largest reduction has been brought about by the routine supplementation of vitamin K in all new born babies, usually at birth. This is given either in the form of an intramuscular injection or a series of oral supplements and, as a consequence, HDN is now rarely seen in the
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