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Jaundice is the yellow colour of the skin and sclerae caused by deposits of bilirubin. In newborn infants the sclerae (white of the eye) are difficult to see and, therefore, the skin colour is used to detect jaundice. Jaundice is a clinical sign and not a laboratory measurement.
Neonatal jaundice is a yellow colour of the skin caused by bilirubin.
Red blood cells contain a red pigment called haemoglobin which carries oxygen. Red cells in the fetus and newborn infant live for 3 months only. Therefore, the body is continually forming new red cells in the bone marrow to replace the old red cells which are broken down in the liver and spleen.
When red cells die, their haemoglobin is changed into a yellow pigment called bilirubin. This unconjugated bilirubin is carried by albumin in the blood stream to the liver where it is first conjugated (joined to another substance) and then excreted in the bile. If the concentration of bilirubin in the serum (blood) rises, it becomes visible in the skin causing jaundice. Newborn infants normally have a high haemoglobin concentration and, therefore, produce a lot of bilirubin.
Normal newborn infants produce a lot of bilirubin.
Hyperbilirubinaemia is defined as concentration (level) of total serum bilirubin (TSB) that is higher than the normal range. Normally the bilirubin concentration in the serum is low at birth, less than 35 µmol/l. It then climbs steadily for the first few days before returning again to an adult level of less than 35 µmol/l by 2 weeks. The total serum bilirubin concentration in term infants usually does not rise above 200 µmol/l (12 mg/dl).
The upper limit of the total serum bilirubin concentration (TSB) in most healthy term infants is approximately:
|Days after birth||0||0.5||1||2||3||4||5|
It is both difficult and inaccurate to assess the concentration of bilirubin in the serum by clinical examination of the degree of jaundice, especially in an infant with a dark skin. Therefore, it is important to measure the bilirubin concentration of the serum if an infant is jaundiced. Usually a sample of blood is collected into a capillary tube and spun down to separate the serum from the red cells. The total serum bilirubin (TSB) is then measured with a bilirubinometer and expressed in µmol/l. The TSB includes both unconjugated and conjugated bilirubin. However, in the newborn infant the TSB usually consists mainly of unconjugated bilirubin.
The total serum bilirubin (TSB) cannot be estimated accurately by clinically assessing the degree of jaundice in the skin.
Unconjugated bilirubin, formed by the breakdown of red cells, is carried by albumin in the blood stream to the liver. In the liver cells enzymes combine the unconjugated bilirubin with glucuronic acid to form conjugated bilirubin. This chemical process, called conjugation, makes the bilirubin water soluble. Only when the bilirubin is water soluble can the liver cells excrete it into the small bile ducts. From here the conjugated bilirubin is carried in the bile to the intestine where it is further converted by bacteria into the brown pigment, stercobilin. In the adult, bilirubin is not reabsorbed from the intestine. Therefore the final breakdown products of bilirubin are passed in the stool.
Conjugation of bilirubin in the liver is essential before it can be excreted into the bile.
The fetus is unable to excrete conjugated bilirubin via the stool as it usually does not pass meconium and also lacks bacteria in the intestines to convert bilirubin into stercobilin. Instead, fetal bilirubin, is excreted by the placenta into the mother’s blood. However, the placenta can only remove fat soluble, unconjugated bilirubin and not water soluble, conjugated bilirubin. To ensure that most of the fetal bilirubin remains unconjugated, the enzyme system that controls bilirubin conjugation in the liver functions very slowly. The small amount of conjugated bilirubin that is excreted into the bile is carried to the fetal intestine. Here a special fetal enzyme deconjugates the bilirubin, which is then reabsorbed back into the fetal blood stream as unconjugated bilirubin. In this way the fetus ensures that all the bilirubin can be excreted by the placenta.
Bilirubin in the fetus is excreted by the placenta rather than the liver.
During the first week of life the enzyme system that conjugates bilirubin with glucuronic acid in the liver functions slowly, as in the fetus. Therefore, unconjugated bilirubin accumulates in the serum as the placenta is no longer present to remove it. As a result, newborn infants commonly become jaundiced due to an increased concentration of unconjugated bilirubin in the serum. After a few days the rate of liver conjugation increases and the bilirubin concentration in the serum slowly returns to the normal adult range of less than 35 µmol/l. Jaundice at birth or in the first 24 hours is unusual, however, as the bilirubin is adequately excreted by the placenta up until the time of delivery.
Some of the bilirubin that is conjugated and excreted by the liver in the first week of life is broken down by the fetal enzyme in the intestine which continues to function for a few weeks after birth. This unconjugated bilirubin is reabsorbed by the intestine, adding to the increase of the TSB.
Jaundice during the first 24 hours is always abnormal.
The main causes of jaundice in the newborn infant are:
There are many causes of an increased bilirubin production:
In all these conditions, with an increased production or slow conjugation of bilirubin, the serum bilirubin is unconjugated.
Prolonged jaundice may be due to hypothyroidism.
Diseases of the liver (hepatitis and biliary atresia) prevent the excretion of conjugated bilirubin into the bile. Conjugated bilirubin is, therefore, reabsorbed into the blood stream, resulting in jaundice. This is called obstructive jaundice, and can be diagnosed by finding a high concentration of conjugated bilirubin in the serum. If bilirubin cannot be excreted in the bile, the stools become pale. Some of the excess conjugated bilirubin is excreted by the kidneys, giving dark urine. Jaundice due to decreased excretion of bilirubin is far less common in newborn infants than jaundice due to the excessive production or decreased conjugation of bilirubin.
Pale stools and dark urine suggest that the jaundice is due to liver disease.
All healthy newborn infants have a total serum bilirubin concentration (TSB) higher than in adults. This is due to the normal increase in production, slow conjugation and decreased excretion of bilirubin. As a result, 50% of normal, term infants have mild jaundice during the first 2 weeks of life. However, they are clinically well, their jaundice disappears within 14 days and their TSB does not rise above 200 µmol/l (12 mg/dl). This is known as physiological jaundice. Mild jaundice is, therefore, very common in normal infants.
Mild jaundice in healthy infants is very common in the first two weeks of life.
Haemolytic disease of the newborn is the condition where antibodies (immunoglobulins) from the mother cross the placenta into the fetal blood stream. Here these antibodies destroy the fetal red cells (haemolysis) causing anaemia and an increased production of bilirubin in the fetus and newborn infant.
The 2 most important causes of haemolytic disease of the newborn are:
There are also other uncommon forms of haemolytic disease in newborn infants.
Red cells have proteins on their surface called antigens, which determine a person’s blood group. The red cell antigens of a fetus are inherited from both parents and, therefore, may differ from that of the mother. The most important red cell antigens are the ABO antigens and the D (Rhesus) antigen. If the A antigen is present on a person’s red cells the blood group will be A. Similarly, the presence of the B antigen makes the blood group B. If both antigens are present the blood group will be AB while if both antigens are absent the blood group will be O. Most people are blood group O.
The D antigen is inherited separately from the ABO antigens. The presence of the D antigen on the red cells makes a person Rhesus positive. If the D antigen is missing, then the person is Rhesus negative.
Therefore, a person with both A and D antigens will have the A positive blood group while another with neither A, B nor D antigens will be blood group O negative.
ABO haemolytic disease occurs when the mother is blood group O and her fetus is blood group A or B, the fetus having inherited these blood groups from the father. For reasons unknown, some group O mothers start producing anti-A or anti-B antibodies which cross the placenta and cause fetal haemolysis by attacking the fetal red cells. The haemolysis is not severe enough to damage the fetus but may cause severe jaundice in the newborn infant. ABO haemolytic disease may occur in a first pregnancy or any later pregnancy.
The maternal antibodies, which stick to the fetal red cells, give a positive Coomb’s test in the newborn infant, while the haemolysis results in a low packed cell volume and haemoglobin, and a raised TSB. An infant with ABO haemolytic disease usually appears normal at delivery, as the placenta has been able to remove the excess bilirubin produced during pregnancy. However, the infant becomes jaundiced within the first 24 hours after birth. The TSB may increase rapidly and reach dangerous levels. Due to the haemolysis, the infant becomes anaemic. Unfortunately ABO haemolytic disease is not preventable nor can it be diagnosed accurately before delivery. ABO haemolytic disease is the commonest cause of severe jaundice in term infants.
ABO haemolytic disease is the commonest cause of severe jaundice in term infants.
Jaundice on day 1 suggests haemolytic disease.
Rhesus haemolytic disease is haemolytic disease of the newborn caused by maternal antibodies to the D antigen. With Rhesus haemolytic disease, the mother is always Rhesus negative (Rh negative or Rh –ve) while the fetus and infant (and father) are always Rhesus positive (Rh positive or Rh +ve).
Normally the fetal red blood cells do not enter the maternal circulation during pregnancy or delivery. However, if the fetal capillaries in the placenta are damaged, fetal red blood cells may cross into the maternal blood. If the fetal red cells have the D antigen (Rh positive) but the mother’s do not (Rh negative), then the fetal cells may be recognised by the mother’s immune system as foreign. As a result the Rh-negative mother will respond by producing antibodies (anti-D) against these foreign red cells. This process is known as sensitisation. Rarely an Rh-negative woman may also be sensitised against the D antigen if she receives an incompatible blood transfusion with Rh positive red cells.
Rhesus haemolytic disease is more severe than ABO haemolytic disease. Rhesus haemolytic disease is rare in first pregnancies as it only occurs if fetal blood crosses the placenta (a fetomaternal bleed) to reach the mother’s blood and, thereby, sensitises her into producing anti-D antibodies. Rhesus haemolytic disease becomes progressively worse with each further pregnancy. Unlike ABO haemolytic disease, with Rhesus haemolytic disease the degree of fetal haemolysis is severe and the fetus may go into heart failure with resulting generalised oedema (called hydrops) due to anaemia and die. Fortunately Rhesus haemolytic disease is not common, because most people are Rh positive. Rhesus haemolytic disease can be prevented.
Fetal red cells may cross the placenta into the mother’s blood:
The fetus can die of Rhesus haemolytic disease.
The Rh positive fetal red cells that cross the placenta can be destroyed, before they sensitise the mother, by giving her 100 µg (4 ml) anti-D immunoglobulin by intramuscular injection within 72 hours. This is usually given after delivery of an Rh-negative mother. However, anti-D immunoglobulin must also be given after any of the above complications of pregnancy. Unfortunately it is useless giving the mother anti-D immunoglobulin if she has already been sensitised and has developed her own anti-D antibodies.
Give all Rhesus-negative mothers anti-D immunoglobulin after delivery.
The blood group of all pregnant women should be determined at the start of antenatal care. If you suspect that the pregnancy is complicated by Rhesus haemolytic disease (i.e. a Rh-negative patient with anti-D antibodies), the mother must be referred urgently to a hospital where specialist care is available.
All women must have their blood groups identified during pregnancy.
Rhesus haemolytic disease should be considered if the infant is jaundiced, pale and oedematous in the first 24 hours of life. Severe Rhesus haemolytic disease affecting the fetus can be diagnosed during pregnancy if antenatal ultrasound examination shows signs of fetal oedema and heart failure (hydrops fetalis).
Rhesus haemolytic disease should be diagnosed during pregnancy.
Jaundice can become dangerous when the concentration of unconjugated bilirubin in the blood becomes very high. Unconjugated bilirubin may then enter the brain of the newborn infant and cause bilirubin encephalopathy (kernicterus). Conjugated bilirubin is not toxic to the brain. In clinical practice the TSB is used to assess whether the bilirubin is reaching dangerous concentrations as the TSB in newborn infants usually consists almost entirely of unconjugated bilirubin.
The risk of bilirubin encephalopathy depends on:
In well, term infants the TSB becomes dangerous above 350 µmol/l (20 mg/dl) while in preterm infants the TSB becomes dangerous above 250 µmol/l (15 mg/dl). The dangerous level is lower if factors that make the blood brain barrier more permeable to bilirubin are also present.
A high serum concentration of unconjugated bilirubin can damage the brain.
Many infants with bilirubin encephalopathy die while the survivors survivorsare at high risk for deafness and cerebral palsy. Therefore, every effort must be made to prevent bilirubin encephalopathy.
By not allowing the TSB to reach dangerous levels. A number of methods can be used to reduce the TSB:
Early milk feeds help to lower the total serum bilirubin concentration.
Phototherapy uses white or blue light (i.e. visible light) to change unconjugated bilirubin in the skin into a water-soluble form of bilirubin. The water-soluble bilirubin is then carried by albumin in the blood to the liver, from where it can easily be excreted without first having to be conjugated. Phototherapy is, therefore, able to rapidly lower the TSB. Bright light is able to change the shape but not the chemical composition of the bilirubin molecule. Ultraviolet light, which causes sunburn and severe tissue damage, could kill an infant and is not used for phototherapy.
Phototherapy is usually given with a phototherapy unit which consists of a row of fluorescent tubes. Daylight tubes (SABS No. 5) or white tubes (SABS No. 2) are used. They should be changed after 1000 hours use as, despite still appearing bright, their effectiveness decreases with time and they produce ultraviolet light which is dangerous. A perspex (clear plastic) sheet must be placed below the tubes to reduce heat. A perspex sheet also protects the infant if a fluorescent tube breaks or comes loose. Sometimes a special white halogen spot light or blue LED (light emitting diode) spotlight is also used to provide phototherapy.
Although exposure to sunlight also lowers the TSB, an infant placed in the sun may rapidly become hyperthermic. Therefore, this form of phototherapy must be used with great caution, if at all.
Phototherapy can be used either therapeutically or prophylactically.
Therapeutic phototherapy should be given whenever the TSB is above the normal range and approaches dangerous levels. In practice a simple chart is used to decide when to give therapeutic phototherapy. If the TSB for the infant’s age reaches the phototherapy line, treatment should be started. Phototherapy is usually started earlier in preterm or sick infants. Phototherapy should not be given to healthy, term infants who are jaundiced with a TSB below the phototherapy line.
All infants born to women who are blood group O should have their TSB measured at 6 hours after birth. If the TSB is above 80 µg/dl phototherapy should be started.
With phototherapy it is possible to avoid almost all exchange transfusions.
Prophylactic phototherapy is given when the TSB is still below the phototherapy line but either the TSB is expected to increase rapidly or the infant is at an increased risk of bilirubin encephalopathy. Therefore, prophylactic phototherapy is started immediately after birth if haemolytic disease of the newborn is suspected or diagnosed. Prophylactic phototherapy in preterm infants is usually started when the TSB reaches 125 µmol/l in infants weighing less than 1250 g, at 150 µmol/l in infants less than 1500 g, and at 200 µmol/l in infants weighing less than 2000 g.
Figure 9-1: Simple phototherapy guide for term infants showing the phototherapy line.
Figure 9-2: Detailed phototherapy chart for infants in different birth weight and gestational age categories (e.g. 34 to 34 weeks and 6 days or 34 to less than 35 weeks). (From: A R Horn: Neonatal Medicine, University of Cape Town.) Start intensive phototherapy when the TSB is above the line according to gestation or weight.
Continue phototherapy until the TSB has been under the phototherapy line for 24 hours. Sometimes the TSB rises above the line again after the phototherapy has been stopped and treatment has to be restarted. However, once the TSB drops it usually stays down. Most phototherapy can be stopped after 3 days.
The total serum bilirubin should be measured in all infants receiving phototherapy.
There is little evidence that giving oral or intramuscular phenobarbitone adds to the effectiveness of phototherapy. It may also cause lethargy and poor feeding. Phenobarbitone is, therefore, not recommended to treat neonatal jaundice. It should not be used instead of phototherapy.
Routine use of phenobarbitone to reduce jaundice is not advised.
Except for infants with severe Rhesus haemolytic disease, an exchange transfusion is rarely needed today if phototherapy is used correctly when indicated. However, an exchange transfusion may still be needed if there is a delay in starting phototherapy and the progressive increase in TSB cannot be controlled.
The indications for an exchange transfusion are:
|Below 1500 g||1500–1999 g||2000–2499 g||2500 g|
|Well infant||250 µmol/l||300 µmol/l||350 µmol/l||400 µmol/l|
|Sick infant or infant with haemolysis||200 µmol/l||250 µmol/l||300 µmol/l||350 µmol/l|
All infants who may need an exchange transfusion must be transferred urgently to a hospital with the staff and equipment needed. Send parental consent and a tube of clotted maternal blood with the infant for cross-matching. Give phototherapy in the meantime. Remember that an exchange transfusion has its dangers and side-effects.
To determine whether an infant has anaemia, either of the following can be measured:
Anaemia is defined as a PCV or Hb that falls below the normal range for the postnatal age of the infant.
The normal PCV at birth is 45–65% and the Hb 15–25 g/dl. After delivery the PCV and Hb in term infants falls steadily until about 8 weeks of age and then slowly increases. The PCV should not fall below 35% and the Hb below 12 g/dl in a term infant. The life span of the red cell in the infant is only 90 days (3 months) compared to 120 days in the adult.
It is important that the PCV or Hb is measured on a sample of venous or arterial blood, or blood collected from a warm heel. Capillary blood sampled from a cold heel will give a falsely high reading.
Iron deficiency is a very rare cause of anaemia in the newborn period. However, iron deficiency anaemia is common after 3 months of age especially in preterm infants who have their umbilical cord clamped immediately after delivery and do not receive regular iron supplements.
The PCV and Hb of the preterm infant are normal at birth but fall faster and to a lower level than those in the term infant. The more preterm the infant the faster and lower will be the fall in PCV and Hb. In most preterm infants the PCV falls to 30% and the Hb to 10 g/dl. A Hb or PCV below these levels is common, especially in very preterm infants, and is called ‘anaemia of prematurity’. Anaemia of prematurity is often made worse by repeated blood sampling. Oral iron supplements do not prevent or correct anaemia of prematurity.
An infant should be transfused with packed cells if the PCV is below 45% or the Hb below 15 g/dl at birth or during the first 24 hours. Thereafter, term infants are usually considered for transfusion at a PCV below 30% or a Hb below 10 g/dl.
Packed cells should be given to an infant with anaemia of prematurity if the PCV falls below 25% or the Hb below 8.5 g/dl. An earlier transfusion is indicated if the PCV is below 30% or the Hb below 10 g/dl and the infant develops respiratory distress, signs of heart failure or patent ductus arteriosus, fails to grow or has severe infection.
The packed cells must be fully cross-matched with the infant. Usually 10 ml/kg are given over 4 hours. Very small infants may need a number of transfusions during the first few months of life before their PCV and Hb returns to normal spontaneously. The PCV should be checked a week after the transfusion.
Polycythaemia (too many red blood cells) is defined as a packed cell volume above 65% or a haemoglobin concentration above 25 g/dl. It is important that the blood is venous, arterial, or capillary blood from a warm foot.
Polycythaemic infants appear very red (plethoric). Usually polycythaemia causes no major problems although the infant may become jaundiced. However, if the PCV and Hb are very high, the blood becomes thick and sticky causing neurological signs, respiratory distress, hypoglycaemia and heart failure.
If the polycythaemia causes no clinical problem it does not need to be treated. During the first few weeks the PCV and Hb gradually return to normal. However, if the infant has neurological signs (very jittery, convulsions or feeds poorly), respiratory distress, hypoglycaemia or heart failure due to the polycythaemia, then it must be treated by partial plasma exchange transfusion. The method is the same as an exchange transfusion for jaundice except that the infant is given normal saline, fresh frozen plasma or stabilised human serum. The exchange is limited to 20 ml/kg.
A well, breastfed, term infant develops jaundice on day 3 and the TSB (total serum bilirubin) is 120 µmol/l. Both the mother and infant are blood group 0+ve. The infant’s packed cell volume is 60% (haemoglobin 20 g/dl) and the Coomb’s test is negative.
This infant probably has physiological jaundice caused by the normally high bilirubin production, slow bilirubin conjugation by the liver, and increased bilirubin reabsorption by the intestines.
Because both the mother and infant have the same ABO blood groups and are both Rhesus positive, the infant’s Coomb’s test is negative, and the PCV (Hb) is normal. With haemolytic disease, the TSB would probably be much higher and the PCV low.
No, this infant does not have hyperbilirubinaemia because the TSB falls within the normal range for a 3 day old infant.
The infant should be managed as for a healthy, normal infant except that the TSB should be repeated daily until it starts to fall.
No. There is no reason for phototherapy.
No. she should continue to breastfeed. Although breastfeeding may result in a slightly higher TSB, it is not necessary to stop breastfeeding.
An infant scores at 32 weeks and weighs 1600 g at birth. The infant has bilateral cephalhaematomas and becomes jaundiced on day 2 with a TSB of 190 µmol/l. No treatment is given. On day 5 the infant becomes lethargic and hypotonic with a weak cry. The TSB is now 370 µmol/l.
Because the infant was born preterm and has an immature liver with slow conjugation of bilirubin. In addition there is an increased production of bilirubin by the breakdown of haemoglobin in the cephalhaematomas.
Phototherapy should have been started as soon as the TSB was above the phototherapy line.
Because these are early signs of bilirubin encephalopathy. Remember that they may also be early signs of other problems such as septicaemia.
The TSB is so high that the infant must be given an exchange transfusion as soon as possible. In the meantime, phototherapy must be started. Do not drain the cephalhaematomas.
A term infant becomes jaundiced at 12 hours. The mother is blood group O+ve and the infant is blood group B+. Phototherapy is started and after 24 hours the infant no longer appears jaundiced.
Haemolytic disease as the jaundice was noticed within the first 24 hours. The blood groups suggest ABO haemolytic disease (i.e. mother group O and infant blood group B). A positive Coomb’s test would confirm the diagnosis of haemolytic disease.
The infant’s TSB must be measured.
No. Phototherapy may clear the jaundice although the TSB remains high.
When the TSB has been below the phototherapy line for 24 hours. Thereafter, the TSB should still be monitored for a few days as the TSB may increase again due to continuing haemolysis.
A preterm infant who weighed 1200 g at birth is now a month old. For the past week the infant has not gained weight but otherwise appears to be well. The PCV is 22%. The infant is being treated with iron supplements. As the infant now weights 1800 g, the mother wants to take him home.
Yes, because the PCV is below 30%.
Anaemia of prematurity. Many preterm infants fail to produce red cells for a few weeks after birth.
The infant needs a transfusion with packed cells. Normally, 10 ml/kg of blood is given over 4 hours.
Because the PCV (and Hb) may still continue to fall. Once the infant has been transfused he can be discharged. He should be brought back to the clinic or hospital to have his PCV checked after a week.
Yes. Iron supplements will help to prevent iron deficiency in a few months time. However, iron supplements will not prevent or correct the anaemia of prematurity.
A term infants is born at home and then taken to the nearest hospital. On examination the infant appears well but is noted to be very plethoric. A capillary sample of blood is taken. The PCV is 70%.
The infant has polycythaemia. This is suggested clinically by the red colour and confirmed by the high PVC.
At birth the normal PCV is 45 to 65%. During the first few weeks the PCV gradually drops.
The heel must be warm and should not be squeezed. Otherwise the PCV result will be falsely high.
As the infant appears well there is no special treatment needed. However, the infant should be observed for jaundice.
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