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Acknowledgment
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Table of Contents
3
Page
List of tables List of figures List of abbreviations Aim of work Introduction Part 1: Review of literature
Chapter 1: Neonatal hyperbillirubineamia Chapter 2: ABO blood group system Chapter 3: ABO hemolytic disease of newborn Chapter 4: Coombs' test
5 7 8 10 12 15 16 41 46 58 63 64 65 82 91 92 94 95 101
Part 2: Practical work Patients and method Results and analysis of data Part 3: Discussion Part 4: Summary and Conclusion Conclusion and recommendation Summary References Arabic summary
List of Tables
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Table No.
Page No.
Causes of Unconjugated Hyperbilirubinemia Causes of Conjugated Hyperbilirubinemia Differential diagnosis of hyperbilirubinemia Suggested maximum indirect serum bilirubin concentrations (mg per/dL) in preterm infants Interference according to total bilirubin levels Bilirubin / Albumin ratio as an additional factor in determining the need for exchange transfusion Antigens of the ABO blood group Antibodies produced against ABO blood group antigens Phenotype of ABO Blood Group System Inheritance of ABO Blood Group Tables of results
23 24 28 30 30 38 41 42 42 43
1 2 3 4 5
Distribution of cases of both groups (O-A and O-B groups) in our study Distribution of ABO jaundice according to gender in study group Comparison between O-A and O-B patients regarding maternal risk factors in study group Risk factors affecting ABO incompatibility neonatal jaundice in study group Risk factors affecting ABO incompatibility neonatal jaundice in study group
5
67 67 68 69 70
6 7 8
Comparison between O-A & O-B according to family history in study group Comparison between O-A & O-B according to neonatal history and Physical examination in study group Comparison between O-A & O-B according to level of serum bilirubin (total & direct) at admission at 6, 12, 24, 36 & 48 hours of admission Comparison between O-A & O-B according to mean number of hours for extensive phototherapy (double & triple) in study group Comparison between O-A & O-B according to mean number of time units of phototherapy (one unit of phototherapy = one hour of four lamps of valid potency, about 50 cm distance from patient) Comparison between O-A & O-B according to Duration of admission in study group Comparison between O-A & O-B according to number of exchange transfusion in study group Comparison between O-A & O-B according to results of Indirect coombs test in study group Comparison between O-A & O-B according to CRP in study group Comparison between O-A & O-B according to level of serum bilirubin (total & direct) at admission at 6, 12, 24, 36 &48 hours in response to treatment with phototherapy in study group Comparison between O-A and O-B regarding albumin level in study group Comparison between O-A & O-B according to blood picture in study group
71 72 74
9 10
75 75
11 12 13
76 76 77
14 15
77 78
16
79
17
80
List of figures
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FIGURE No. 1 2 3 4
Title The pathophysiology of neonatal hyperbilirubinemia Kramers rule Total serum bilirubin and age chart The management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation Baby under phototherapy Guidelines for exchange transfusion in infants 35 or more weeks gestation Bombay phenotype inheritance Direct Coombs' test Indirect Coombs' test
Page No. 20 28 29 31
5 6 7 8 9
36 37 44 58 59
List of abbreviations
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(AAP) (B/A) ratio (CB) (DsB) (HDN) (ISBT) (IVT) (LEDs) (NRN) (PDA) (TsB) (UCB) (vWF) CBC CO CRP CS DAT Ex. G6PD Hct. Hg
American Academy of Pediatrics Bilirubin / Albumin ratio Conjugated bilirubin Direct serum bilirubin level Haemolytic disease of the newborn International Society of Blood Transfusion intravascular transfusion light-emitting diodes Neonatal Research Network patent ductus arteriosus Total serum bilirubin level Unconjugated bilirubin von Willebrand factor Complete blood count Carbon Monoxide C-reactive protein Cessarian Section Direct anti-globulin test examination Glucose 6 phosphate dehydrogenase Hematocrit Hemoglobin
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Indirect anti-globulin test Intravenous Immunoglobulin Light Amplification by Stimulated Emission of Radiation Neonatal intensive care unit Normal Vaginal Delivery Red blood cells Sn-Mesoporphyrin Sn-Protoporphyrin White blood count
2- Compare between OA & O-B blood subgroups incompatibilities in incidence and severity
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Introduction
Introduction
Severe hyperbilirubinemia continues to be the most common cause of neonatal readmission to hospitals. Long-term results of severe hyperbilirubinemia, including bilirubin encephalopathy and kernicterus, were thought to be rare since the advent of exchange transfusion, maternal rhesus immunoglobulin prophylaxis and phototherapy. (Michael Sgro et al.; 2006) The risk factors of neonatal hyperbilirubinemia include race of the patient as Asians have the highest risk followed by Caucasian while the black infant have the lower risk. Other risk factors include breast feeding, pregnancy induced hypertension, diabetes mellitus, obstructed labor, oxytocin use, blood group incompatibility between mother and her baby, passive smoking and prolonged premature rupture of membranes. Family history of previously jaundiced baby as a child whose sibling needed phototherapy is 12 times more likely to also have significant jaundice. Neonatal risk factors include prematurity, sepsis, perinatal asphyxia, delayed passage of meconium and congenital infections, infant with bruising or cephalheamatoma. (Wennberg et al.; 2006) In a study conducted to Michael sgro, douglas Campbell and vibhuti shah 2006 showed that the percentage of ABO incompatibility as a cause of severe neonatal hyperbilirubinemia is about 51% followed by G6PD about 21.5% other antibody incompatibility about 13% and other causes about 14.5% ABO hemolytic disease of newborn occurring in about 15% of infants with A or B blood type born to blood type O mothers and, unlike non- hemolytic disease of newborn. ABO incompatibility is usually a problem of the neonate rather than of the fetus, A and B antigens are only weakly expressed on neonatal RBCs. ABO hemolytic disease of newborn therefore usually mild and characterized by negative or weakly positive Coombs' test. ABO hemolytic disease of newborn rarely requires whole blood exchange transfusion, in contrast to hemolytic disease of newborn due to anti-D or other antibodies.(Kathryn Drabik-Clary et al; 2006) In a study of demographic characteristic of newborn who did and who did not develop significant hyperbilirubinemia following serum bilirubin measurement and the use of the critical bilirubin levels of 4 mg/dl and 6mg/dl at the sixth hours of life will predict that the incidence of O-A blood group incompatibility is higher than that of O-B blood group incompatibility in newborns who will develop significant hyperbilirubineamia. (Olcay Oran et al.; 2002)
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Several studies have established that ABO hemolytic disease is more common in blacks and in children of mixed racial origin than among other races. For Caucasian populations about one fifth of all pregnancies have ABO incompatibility between the fetus and the mother. (Wang, M. et al.; 2005) In a study of hemolysis and hyperbilirubinemia in ABO blood group incompatibility in neonates it was documented that 62% of O-B incompatibility hemolytic disease develop hyperbilirubinemia in contrast to 46.8% of O-A blood group incompatibility hemolytic disease and it appear earlier in O-B incompatibility than O-A incompatibility despite that hyperbilirubinemia in the first 24 hour about 48.1% caused by O-B incompatibility while about 93.9% caused by O-A incompatibility. (Johnson l et al.; 2009)
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Review of literature
described yellow staining of the brain, in a pattern later referred to as kernicterus. (Thor W.R. Hansen, 2011)
Definition
Jaundice is a yellowish discoloration of skin and mucous membranes. It is caused by elevated serum concentration of bilirubin. Newborns appear jaundiced when it is >7mg/dl., (Martin and Cloerty, 2008) Neonatal jaundice usually happens during the first weeks of life. There are many types of jaundice, including: * Physiologic jaundice * Breast-feeding jaundice
* Breast milk jaundice (human milk jaundice syndrome) * Jaundice caused by hemolysis or increased bilirubin production * Jaundice caused by inadequate liver function (due to inborn errors of metabolism, prematurity, or enzyme deficiencies). The yellow coloring is caused by bilirubin, a waste product created by the body when it breaks down red blood cells in the normal course of metabolism. (J. Thomas Megerian, 2011)
Incidence
Hyperbilirubinemia is a common and, in most cases, benign problem in neonate. Jaundice is observed in 1st week of life in approximately 60% of term infant and 80% of preterm infant. (Piazza and Stoll, 2007) The incidence of Jaundice is higher in breast- fed babies than in the formula- fed ones. Asian male babies and Native American ones are reported to be most affected by Neonatal Jaundice. They are followed by Caucasian infants who in turn are followed by African Neonates. Babies who are either small or large for gestational age are at an increased risk of developing Neonatal Jaundice. (Sumana, 2011)
Pathophysiology of hyperbilirubinemia
Bilirubin
Bilirubin (formerly referred to as hematoidin) is the yellow breakdown product of normal heme catabolism. Heme is found in hemoglobin, a principal component of red blood cells. Bilirubin is excreted in bile and urine, and elevated levels may indicate certain diseases. It is
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responsible for the yellow color of bruises, the yellow color of urine (via its reduced breakdown product, urobilin), the brown color of feces (via its conversion to stercobilin), and the yellow discoloration in jaundice. (Pirone C. et al; 2009) During the neonatal period, metabolism of bilirubin is in transition from the fetal stage during which the placenta is the principal route of elimination of the lipid-soluble (unconjugated bilirubin) to the adult stage, during which the water-soluble (conjugated form) is excreted from hepatic cells into biliary system and gastrointestinal tract. (Piazza and Stoll, 2007)
Source of Bilirubin
Bilirubin is formed by breakdown of heme present in hemoglobin, myoglobin, cytochromes, catalase, peroxidase and tryptophan pyrrolase. Enhanced bilirubin formation is found in all conditions associated with increased red cell turnover such as intramedullary or intravascular hemolysis as (hemolytic, dyserythropoietic, and megaloblastic anemias). Heme consists of a ring of four pyrroles joined by carbon bridges and a central iron atom (ferroprotoporphyrin IX). Bilirubin is generated by sequential catalytic degradation of heme mediated by two groups of enzymes: Heme oxygenase & Biliverdin reductase. (Namita RoyChowdhury et al; 2012)
Metabolism of bilirubin
Bilirubin metabolism includes 5 steps: 1) Production 3) Uptake 2) Transport 4) Conjugation
5) Excretion
1-Production of Bilirubin
Heme oxygenases are the initial and rate-limiting enzymes in the breakdown of heme (iron protoporphyrin IX) that itself plays an essential role in the transport of oxygen and mitochondrial electron transport as a cofactor of hemoglobin, myoglobin, and cytochromes. Degradation of heme generates carbon monoxide, iron, and biliverdin, the latter of which is subsequently converted to bilirubin by biliverdin reductase. (Stuart T. Fraser et al; 2011)
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a) The Fe released is reincorporated into hemoglobin. b) The CO is excreted unchanged in the lung, where the amount serves as a measure of bilirubin synthesis. (Shapiro, 2003) Catabolism of 1 mol of hemoglobin produces 1 mol CO and bilirubin. Increased bilirubin production as measured by CO excretion rate accounts for the higher bilirubin level seen in Asian, Native American, and Greek infants. (Agarwal & Deorari, 2002)
2- Bilirubin Transport
Unconjugated bilirubin is extremely poorly soluble in water; it is present in plasma strongly bound to albumin. The dissociation constant for the first albumin-binding site. (Johan Fevery, 2008) If the albumin-binding sites are saturated, or if unconjugated bilirubin is displaced from the binding sites by medications (e.g. sulfisoxazole [Gantrisin], streptomycin, vitamin K), free bilirubin can cross the blood-brain barrier. (Mocrschel et al., 2008) Bilirubin Exists in 4 Different Forms in Serum: 1. Unconjugated bilirubin reversibly bound to albumin which makes up the major portion of unconjugated bilirubin in serum. 2. A tiny fraction of unconjugated bilirubin not bound to albumin "free" bilirubin. 3. Conjugated bilirubin, water soluble and easily excreted in both urine and bile. 4. Conjugated bilirubin covalently bound to albumin called delta bilirubin. This fraction is virtually absent in the first 2 weeks of life, but account for a significant portion of the total bilirubin in patients with cholestatic jaundice. (Chung et al., 2004)
3-Uptake of Bilirubin:
In the liver, bilirubin dissociates from albumin and enters the hepatocyte probably by carrier mediated diffusion. There is a significant amount of evidence indicating that bilirubin movement across the hepatocyte membranes is bi-directional; it has been estimated that up to 40% of the bilirubin taken up by the hepatocyte refluxes unchanged back into plasma.
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Efficient hepatic uptake of bilirubin is dependent on adequate hepatic blood flow. Conditions associated with a persistent ducts venous shunt, hyperviscosity or hypovolemia can lead to decreased hepatic perfusion, decreased hepatic bilirubin uptake and unconjugated hyperbilirubinaemia. (Doumas et al., 2004)
4-Conjugation of Bilirubin:
In the liver it is conjugated with by the enzyme glucuronyltransferase, making it soluble in water. Much of it goes into the bile and thus out into the small intestine. Some of the conjugated bilirubin remains in the large intestine and is metabolized by colonic bacteria to urobilinogen, which is further metabolized to stercobilinogen, and finally oxidized to stercobilin. This stercobilin gives feces its brown color. Some of the urobilinogen is reabsorbed and excreted in the urine along with an oxidized form, urobilin. Although the terms direct and indirect bilirubin are used equivalently with conjugated and unconjugated bilirubin, this is not quantitatively correct, because the direct fraction includes both conjugated bilirubin and delta bilirubin which appears in serum when hepatic excretion of conjugated bilirubin is impaired in patients with hepatobiliary disease. (Kliegman & Behrman, 2007)
Enterohepatic circulation Conjugated bilirubin is hydrolyzed in the intestine to UCB, which can be reabsorbed into the enterohepatic circulation. Hydrolysis of conjugated bilirubin to UCB can occur none enzymatically under the influence of mild alkaline conditions as in the duodenum or jejunum (Halamek and Stevenson, 2002), and enzymatically by beta-glucuronidase. (Martin and Cloerty, 2008)
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Conjugated bilirubin must be hydrolyzed to UCB before the tetrapyrrole ring be reduced to the colorless urobilinogens by the intestinal anaerobic bacteria (3 Clostridia species and Bacteroides fragilis). Intestinal bacteria can prevent enterohepatic circulation of bilirubin by converting CB to urobillinoids, which are not substrates for beta-glucuronidase. (Martin and Cloerty, 2008)
Bilirubin as Antioxidant
Bilirubin has the ability to function as an antioxidant in the brain, scavenging free radicals and protecting the brain against oxidative damage. (Jay Gordon, 2011)
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The proposed mechanisms by which heme oxygenase exerts cytoprotective effects include its abilities to degrade the pro oxidative heme to produce biliverdin and subsequently bilirubin and to generate carbon monoxide, which has anti proliferative and anti-inflammatory as well as vasodilator properties. (Morita, 2005)
(Maisels, 2005).
Premature babies born before 36 weeks of pregnancy. Babies who had a brother or sister treated for jaundice. Baby has a different blood type than mother, resulting in hemolysis. Babies of East Asian, Mediterranean, or Native American descent.
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Babies who are not feeding well, breast or bottle. Babies with large bruises or a condition called cephalhematoma (bleeding under the scalp related to labor and delivery). Since many red blood cells are broken down when large bruises heal, more bilirubin than usual is traveling in the blood. Babies with high bilirubin levels or signs of jaundice in the first 24 hours of life (before leaving the hospital) will be watched carefully by the doctor even after they have left the hospital. Certain liver enzyme deficiencies. Infection.
A) Physiological jaundice:
Most infants develop visible jaundice due to elevation of unconjugated bilirubin concentration during their first week. This common condition is called physiological jaundice. Essentials of diagnosis and typical features of physiologic jaundice:22
Visible jaundice appearing after 24 hours of age. Total bilirubin rises by < 5 mg/dl (86 mmol/L) per day. Peak bilirubin occurs at 3-5 days of age, with a total bilirubin of no more than 15 mg/dl (258 mmol/L). Visible jaundice resolves by 1 week in the full-term infant and by 2 weeks in the preterm infant. (Thilo and Rosenberg, 2009) This pattern of jaundice classified into two periods: In phase one the term infants' jaundice lasts for about 10 days with a rapid rise of serum bilirubin up to12 mg/dL, but preterm infants' jaundice lasts for about two weeks, with a rapid rise of serum bilirubin up to15 mg/dL. In phase two bilirubin levels decline to about 2 mg/dL for two weeks. Preterm infants can last more than one month. (McDonagh.; 2007)
B) Pathological jaundice
Any of the following features characterizes pathological jaundice: 1. Clinical jaundice appearing in the first 24 hours or greater than 48hrs of life. 2. Increases in the level of total bilirubin by more than 8.5 umol/l (0.5 mg/dL) per hour or (85 umol/l) 5 mg/dL per 24 hours. 3. Total bilirubin more than 331.5 umol/l (19.5 mg/dL) (hyperbilirubinemia). 4. Direct bilirubin more than 34 umol/l (2.0 mg/dL). (Miguel Helft, 2007)
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Table (1) Causes of Unconjugated Hyperbilirubinemia Hemolytic disease (hereditary or acquired) -lsoimmune hemolysis (neonatal; acute or delayed transfusion reaction; autoimmune) -Rh incompatibility, AB0 incompatibility and other blood group incompatibilities -Congenital spherocytosis -Hereditary elliptocytosis -Infantile pyknocytosis Erythrocyte enzyme defects -G6PD deficiency -Pyruvate kinase deficiency Hemoglobinopathy -Sickle cell anemia -Thalassemia Others -Sepsis -Hemolytic Uremic syndrome -Drugs as vitamin K and maternal oxytocin -infection -Polycythemia as in Diabetic mother, Fetal transfusion (recipient) and Delayed cord clamping Decreased delivery of UCB (in plasma) to hepatocytes: -Right-sided congestive heart failure -Portacaval shunt Decreased bilirubin uptake by hepatocytes membrane: -Breast milk jaundice -Lucey- Driscoll syndrome -Hypothyroidism -Hypoxia -Acidosis Decreased storage of UCB in cytosol: -Competitive inhibition -Fever Decreased conjugation: -Neonatal jaundice (physiologic) -inhibition (drugs) -Gilbert disease -Hereditary (Crigler-Najjar) Type I (complete enzyme deficiency) and Type Il (partial deficiency) INCREASED ENTEROHEPATIC CIRCULATION -Breast milk Jaundice -intestinal obstruction -Hirsch sprung disease -Cystic fibrosis -Pyloric stenosis -Antibiotic administration
(Balistreri, 2008)
** Conjugated hyperbilirubinemia:
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Conjugated hyperbilirubinemia is a sign of hepatobiliary dysfunction. It usually appears in the newborn infants after the first week of life, when the direct bilirubin level is > 2.0 mg per dL and > 20% of the TsB. It is always pathologic. (Barasotti, 2004)
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Listless, sick or difficult to wake High-pitched crying Poor sucking or feeding Backward arching of the neck and body Fever Vomiting (Lease M. et al; 2010)
** Kernicterus Causes It is a neurological syndrome resulting from the deposition of UCB in brain nuclei. In the past UCB was shown to impair mitochondrial tissues in the brain. Paper showed that UCB decrease cell membrane potential and disrupts transport of neurotransmitters. UCB also inhibits protein phosphorylation in brain membranes and glycolysis in brain as well as interferes with intracellular calcium homeostasis and glutamate efflux.(Shapiro 2005) Microglia cells and astrocytes damaged by UCB produce cytokines that may contribute to brain toxicity. (Fernandes et al., 2006) Kernicterus is the syndrome that occurs if acute bilirubin encephalopathy causes permanent damage to the brain( Lease M. et al; 2010) Symptoms The symptoms depend on the stage of kernicterus. Early stage: - Extreme jaundice - Poor feeding or sucking - Extreme sleepiness (lethargy) Mid stage: - High-pitched cry - Seizures - Arched back with neck hyperextended backwards Late stage (full neurological syndrome): - High-frequency hearing loss - Mental retardation - Muscle rigidity - Speech difficulties (Milton S. Hershey, 2011 )
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** Neonatal cholestasis Assessment: History - Scleral icterus may be apparent at conjugated bilirubin levels as low as 2 mg/dL. - Dark urine at higher levels of conjugated bilirubin. - Cutaneous jaundice - Severe pruritus secondary to elevated bile acids. (Poddar U. et al., 2009) Physical - Physical evidence of scratching or excoriation if they also have severe bile acid retention. - Xanthomas look like small white papules or plaques - Failure to thrive with altered anthropometrics, such as reduced height and reduced weight for height due to fat malabsorption. (Poddar U et al, 2009) Laboratory Studies - Serum bilirubin levels (total and direct bilirubin levels) - Total serum bile salt concentration levels - Qualitative serum and urine bile acids - The total serum cholesterol level - Serum lipoprotein-X levels - Serum alkaline phosphatase levels - Serum 5'-nucleotidase levels - Serum gamma-glutamyl transferase levels. (Suchy FJ. 2004) Imaging Studies - Ultrasonography of liver and bile ducts - Abdominal CT scanning - Biliary nuclear medicine study (i.e., hepatoiminodiacetic acid [HIDA] scanning) - Endoscopic retrograde cholangiography - Percutaneous trans-hepatic cholangiography (Suchy FJ, 2004) Procedure - Liver biopsy - Exploratory surgery - Operative cholangiography is simple, straightforward, time-efficient, and definitive. (Arnon R et al., 2012) Complications Poor growth of the infants due to malabsorption, poor nutrient utilisation, hormonal disturbances and secondary tissue injury. Malabsorption of fats and fat soluble vitamins result in rickets, neuropathy, hemolysis, blindness, hyperkeratotic skin, coagulopathy and bleeding. (B. R. Thapa., 2010)
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Diagnosis of Hyperbilirubinaemia
A-History:
Family history: A family history of anemia, splenectomy, or early gall bladder stones may be suggestive of hereditary haemolytic blood disorder. A history of previous siblings with jaundice and anemia may suggest blood group incompatibility, breast milk jaundice or G-6PD deficiency. A family history of liver diseases may suggest galactosemia, alph1-antitrypsin deficiency or cystic fibrosis. (Bhutani and Johnson, 2004) Maternal history: Maternal illnesses during pregnancy may point to maternal diabetes, congenital viral infection or toxoplasmosis, and maternal medications should be reviewed. History of instrumental delivery, oxytocin induced labor, delayed cord clamping, and Apgar score should be obtained. (Diane and Madlon-Kay, 2002) Neonatal history: History of delayed passage of meconium or infrequent stool may suggest increased enterohepatic circulation of bilirubin. History of vomiting may indicate sepsis, galactosemia, or pyloric stenosis. (Bhutani and Johnson, 2004)
B-Physical Examination:
The jaundiced neonate requires a full physical examination with emphasis on the following: General: Child look and difficulty feeding. Vitals: In hemolytic states, there can be an increase in heart rate and respiration rate as well as poor perfusion. Fever also detected. Growth Parameters: Obtain length, weight and head circumference and compare to measurements taken at birth. Surface: Is there pallor? Sclerae and mucous membranes should be closely inspected for jaundice. Look for cephalohematoma or bruising. Cardiovascular: Heart rate, pulse, blood pressure, apex site, perfusion. Severe haemolytic processes can result in heart failure. Respiratory: Respiration rate and rhythm and oxygen saturation. If the neonate is in heart failure, there may be respiratory signs.
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Abdomen: Is the abdomen distended? Are there any masses? Check for hepatomegaly and splenomegaly and or areas of tenderness? Neurologic: Level of consciousness. Cranial nerves, tone, gross motor movements, quality of the cry, and primitive reflexes (Moro, grasps, tonic-neck and step).
(Maisels, 2006)
Differential Diagnosis
The differential diagnoses of neonatal hyperbilirubinemia are summarized in (Table 3). Table (3): Differential diagnosis of hyperbilirubinemia. Jaundice appearing at birth or within 24 hours: sepsis, erythroblastosis fetalis, concealed hemorrhage, rubella, congenital toxoplasmosis. Jaundice appearing on the 2nd or 3rd day: physiologic jaundice of the newborn -severe type-, Crigler- Najjar syndrome. Jaundice appearing after the 3rd day, within the 1st week: septicemia, syphilis, and toxoplasmosis. Jaundice appearing after the 1st week: breast milk jaundice, septicemia, hepatitis, biliary atresia, galactosemia, hypothyroidism, spherocytosis (congenital hemolytic anemia) and G6PD Jaundice persisting during the 1st month: inspissated bile syndrome, hepatitis, syphilis, toxoplasmosis, familial non-hemolytic icterus, congenital atresia of bile ducts, galactosemia, rarely physiologic jaundice, pyloric stenosis, and hypothyroidism). (Stoll and Kliegman, 2004)
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D-Imaging Studies:
Ultrasonography: Ultrasonography of the liver and bile ducts is warranted in infants with laboratory or clinical signs of cholestatic disease. Radionuclide scanning: A radionuclide liver scan for uptake of hepatoiminodiacetic acid 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. (Ahlfors CE & Parker AE. 2008)
(AAP .; 2005)
1- Preterm Infants:
Table (4): Suggested maximum indirect serum bilirubin concentrations (mg per/dL) in premature infants
Complicated 10-12 10-12 12-14 15-17 18-20 (Stoll and Kliegman, 2000).
Action
The management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation is summarized in Figure (4).
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Current accepted modes of intervention: Hydration. Phototherapy. Exchange transfusion. Pharmacological agents. Drug that increase conjugation. Inhibiting reabsorption (binding in the gut). Inhibiting bilirubin production. (Valaes and Harvey-Wilkes, 1999) I- Hydration: It is important to maintain adequate hyration and urine output during phototherapy since urinary excretion of lumirubin is the principle mechanism by which phototherapy reduces TsB. Thus, during phototherapy, infants should continue oral feeding by breast or bottle. For TsB levels that approach the exchange transfusion level, phototherapy should be continuous until the TsB has declined to about 20 mg/dL (342 micromol/L). Thereafter phototherapy can be interrupted for feeding. Intravenous hydration may be necessary to correct hypovolemia in infants with significant volume depletion whose oral intake is inadequate; otherwise, intravenous fluid is not recommended. (Buhutani VK, 2004)
II-Phototherapy:
A) Background: Phototherapy is the primary treatment in neonates with unconjugated hyperbilirubinemia. This therapeutic principle was discovered rather serendipitously in England in the 1950s and is now arguably the most widespread therapy of any kind (excluding prophylactic treatments) used in newborns. )Kumar P. et al; 2011(
C) Indications of phototherapy:
1- Phototherapy should be used when the level of bilirubin may be harmful to the infant , and has not reached levels requiring exchange transfusion. 2- Prophylactic phototherapy may be indicated in special circumstances, such as extremely low - birth weight infants or severely bruised infants. In hemolytic disease of the newborn, phototherapy is stared immediately and while waiting for exchange transfusion. (McDonagh et al.; 2008) D) Mechanism of Action Phototherapy uses light energy to change the shape and structure of bilirubin, converting it to molecules that can be excreted even when normal conjugation is deficient. Absorption of light by dermal and subcutaneous bilirubin induces a fraction of the pigment to undergo several photochemical reactions that occur at very different rates. These reactions generate yellow stereoisomers of bilirubin and colorless derivatives of lower molecular weight. The products are less lipophilic than bilirubin, and unlike bilirubin, they can be excreted in bile or urine without the need for conjugation. Bilirubin elimination depends on the rates of formation as well as the rates of clearance of the photoproducts. Photoisomerization occurs rapidly during phototherapy, and isomers appear in the blood long before the level of plasma bilirubin begins to decline. Bilirubin absorbs light most strongly in the blue region of the spectrum near 460 nm, a region in which penetration of tissue by light increases markedly with increasing wavelength. Only wavelengths that penetrate tissue and are absorbed by bilirubin have a phototherapeutic effect. Taking these factors into account, lamps with output predominantly in the 460-to-490-nm blue region of the spectrum are probably the most effective for treating hyperbilirubinemia. A common misconception is that ultraviolet (UV) light (<400 nm) is used for phototherapy. Phototherapy lights in current use do not emit significant erythemal UV radiation. In addition, the plastic covers of the lamp and, in the case of preterm infants, the incubator, filter out UV light. (Maisels et al.; 2008) The dose and efficacy of phototherapy are also affected by the infant's distance from the light (the nearer the light source, the greater the irradiance) and the area of skin exposed, hence the need for a light source beneath the infant for intensive phototherapy. Although controlled trials have demonstrated that the more surface area exposed, the greater the reduction in the total demonstrated that the more surface area exposed, the greater the reduction in the total serum bilirubin level, it is usually unnecessary to remove the infant's diaper. If, however, the total serum bilirubin level continues to rise despite treatment, the diaper should be removed until there is a clinically significant decline. Aluminum foil or white cloth placed on either side of the infant to reflect light will also improve the efficacy of
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phototherapy. Because light can be toxic to the immature retina, the infant's eyes should always be protected with opaque eye patches. (Maisels et al.; 2008) E) Adverse effects: Insensible water loss may occur, but data suggest that this issue is not as important as previously believed. Rather than instituting blanket increases of fluid supplements to all infants receiving phototherapy, the author recommends fluid supplementation tailored to the infant's individual needs, as measured through evaluation of weight curves, urine output, urine specific gravity, and fecal water loss. In the NRN phototherapy trials in premature infants of less than 1000 gram birthweight, mortality was increased by 5 percentage points in the subgroup of 501-750 gram birth weight receiving aggressive phototherapy.[ Morris BH, Oh W, Tyson JE, 2008] Although not significant, it should be noted that the study was underpowered for this analysis, and a negative effect of aggressive phototherapy on the smallest and most immature infants cannot be ruled out with certainty. Phototherapy may be associated with loose stools. Increased fecal water loss may create a need for fluid supplementation. Retinal damage has been observed in some animal models during intense phototherapy. In an NICU environment, infants exposed to higher levels of ambient light were found to have an increased risk of retinopathy. Therefore, covering the eyes of infants undergoing phototherapy with eye patches is routine. Care must be taken lest the patches slip and leave the eyes uncovered or occlude one or both nares. The combination of hyperbilirubinemia and phototherapy can produce DNA-strand breakage and other effects on cellular genetic material. In vitro and animal data have not demonstrated any implication for treatment of human neonates. However, because most hospitals use (cut-down) diapers during phototherapy, the issue of gonad shielding may be moot. Skin blood flow is increased during phototherapy, but this effect is less pronounced in modern servo controlled incubators. However, redistribution of blood flow may occur in small premature infants. An increased incidence of patent ductus arteriosus has been reported in these circumstances. The appropriate treatment of PDA has been reviewed. Hypocalcaemia appears to be more common in premature infants under phototherapy lights. This has been suggested to be mediated by altered melatonin metabolism. Concentrations of certain amino acids in total parenteral nutrition solutions subjected to phototherapy may deteriorate. Shield total parenteral nutrition solutions from light as much as possible. Regular maintenance of the equipment is required because accidents have been reported, including burns resulting from a failure to replace UV filters. (Madan JC, Kendrick D., etc. 2009)
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F) Methods of administration:
i- Conventional phototherapy: With "Conventional phototherapy", the irradiance of the light is less, but actual numbers vary significantly between different manufacturers. In general, it is not necessary to routinely measure irradiance when administering phototherapy, but units should be checked periodically to ensure that the lamps are providing adequate irradiance, according to the manufacturer's guidelines. (Bernstein JA, 2012)
ii-Fiber optic phototherapy: Fiberoptic light is also used in phototherapy units. These units deliver high energy levels, but to a limited surface area. Efficiency may be comparable to that of conventional low-output overhead phototherapy units but not to that of overhead units used with maximal output. Advantages include the following : Low risk of overheating the infant No need for eye shields Ability to deliver phototherapy with the infant in a bassinet next to the mother's bed Simple deployment for home phototherapy The possibility of irradiating a large surface area when combined with conventional overhead phototherapy units (double/triple phototherapy)
(Kumar P. et al.; 2011)
iii-Double & Triple phototherapy: "Double" and "triple" phototherapy, which implies the concurrent use of 2 or 3 phototherapy units to treat the same patient, has often been used in the treatment of infants with very high levels of serum bilirubin. The studies that appeared to show a benefit with this approach were performed with old, relatively low-yield phototherapy units. Newer phototherapy units provide much higher levels of irradiance, which may in fact be close to the apparent saturation level of bilirubin photoisomerization. Whether double or triple phototherapy also confers a benefit with the newer units, has not been tested in systematic trials.
(Huizing K. et al.; 2008)
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v-Home phototherapy:
Home phototherapy for a term infant with neonatal jaundice is considered medically appropriate if ALL of the following criteria are met: Elevated bilirubin not due to any primary hepatic disorder Hospitalization is no longer required Diagnostic evaluation is performed prior to the therapy and should include ALL of the following: History and physical examination Hemoglobin concentration or hematocrit WBC count and differential count Blood smear for red cell morphology platelets Reticulocyte count Total and direct-reacting bilirubin concentration Maternal and infant blood typing and Coombs test Urinalysis including a test for reducing substances (Watchko J.; 2009)
vi-LASER phototherapy:
The word LASER is derived from English and means "Light Amplification by Stimulated Emission of Radiation". The LASER converts electrical energy into optical energy. This energy commonly referred to as the LASER beam is carried to the tissues through fiber optic as in the case of Argon LASER or a series of hollow tubes as in the case of Carbon dioxide LASER to be absorbed by the tissues or cellular components. All LASER machines have three elements, the LASER medium, power supply and .mirrors. The medium is stimulated by the power supply to emit light that is amplified as it reflects between mirrors, reaching a critical energy level and emerging through a partially transmitting mirror. The energy is released as an intense beam of monochromatic coherent light. The LASER emits a narrow beam of photons, all of which have the same energy, therefore a very pure light of single color and wavelength is produced, the Argon LASER emits a blue green light. (Palmieri, 1985).
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The following Bilirubin/Albumin ratios can be used together with but in not in lieu of the TSB level as an additional factor in determining the need for exchange transfusion. Table (6): Bilirubin / Albumin ratio as an additional factor in determining the need for exchange transfusion. Risk Category
Infants _38 0/7 wk Infants 35 0/736 6/7 wk and well or _38 0/7 wk if higher risk or isoimmune hemolytic disease or G6PD deficiency Infants 35 0/737 6/7 wk if higher risk or isoimmune hemolytic disease or G6PD deficiency B/A Ratio at Which Exchange Transfusion Should be Considered
TSB mg/dL/Alb, g/dL TSB _mol/L/Alb, _mol/L
8.0 7.2
0.94 0.84
6.8 0.80
If the TsB is at or approaching the exchange level, send blood for immediate type and cross match. Blood for exchange transfusion is modified whole blood (red cells and plasma) crossmatched against the mother and compatible with the infant. (Bhutan et al.; 2004)
* Intravenous Immunoglobulin IVIG : The American Academy of Pediatrics routinely uses 500 mg/kg infused intravenously over a period of 2 hours for Rh or ABO incompatibility when the total serum bilirubin levels approach or surpass the exchange transfusions limits. The author has, on occasion, repeated the dose 2-3 times. In most cases, when this is combined with intensive phototherapy, avoiding exchange transfusion is possible. In the authors' institution, with about 750 NICU admissions per year, the use of exchange transfusions has decreased to 0-2 per year following the implementation of IVIG therapy for Rh and ABO isoimmunization. (Huizing K. and Roislien J., 2008) *Albumin: Bilirubin in circulation is predominantly bound to albumin. Although the binding ratio is potentially 1:1 and avid, albumin levels are lower in premature and sick infants, and binding affinity is often diminished. Furthermore, some drugs can compete with bilirubin for binding to albumin, causing displacement of bilirubin, therefore, prior to exchange transfusion albumin can be administrated 1g per Kg to improve the efficacy of the exchange. (Stevenson et al., 2005) *Others: Oral bilirubin oxidase can reduce serum bilirubin levels, presumably by reducing enterohepatic circulation; however, its use has not gained wide popularity. The same may be said for agar or charcoal feeds, which act by binding bilirubin in the gut. Bilirubin oxidase is not available as a drug, and for this reason, its use outside an approved research protocol probably is proscribed in many countries. (Hansen, 2003)
V. Surgical Care:
Surgical care is not indicated in infants with physiologic neonatal jaundice. Surgical therapy is indicated in infants in whom jaundice is caused by bowel or external bile duct atresia. (Thor WR H., 2004)
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Frequency Blood group O is the most common phenotype in most populations. of ABO Caucasians: group O, 44%; A1, 33%; A2, 10%; B, 9%; A1B, 3%; A2B, phenotypes 1% Blacks: group O, 49%; A1, 19%; A2, 8%; B, 20%; A1B, 3%; A2B, 1% Asians: group O, 43%; A1, 27%; A2, rare; B, 25%; A1B, 5%; A2B, rare Note: Blood group A is divided into two main phenotypes, A1 and A2 Table (7): Antigens of the ABO blood group (Reid ME. et al.; 2004)
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** Antibodies produced against ABO blood group antigens Antibody type IgG and IgM Naturally occurring. Anti-A is found in the serum of people with blood groups O and B. Anti-B is found in the serum of people with blood groups O and A. Antibody reactivity Capable of haemolysis Anti-A and anti-B bind to RBCs and activate the complement cascade, which lyses the RBCs while they are still in the circulation (intravascular haemolysis).
Haemolytic No or mild disease disease of the HDN may occur if a group O mother has more than one pregnancy newborn with a child with blood group A, B, or AB. Most cases are mild and do not require treatment. Table (8) Antibodies produced against ABO blood group antigens (D.L. Bethesda., 2005)
Phenotypes
The table below shows the possible permutations of antigens and antibodies with the corresponding ABO type ("yes" indicates the presence of a component and "no" indicates its absence in the blood of an individual).
ABO Blood Type A B O AB
Genotype
The ABO locus encodes specific glycosyltransferases that synthesize A and B antigens on RBCs. For A/B antigen synthesis to occur, a precursor called the H antigen must be present. In RBCs, the enzyme that synthesizes the H antigen is encoded by the H locus. (Dean L. Bethesda., 2005)
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Non-antigen biology
The carbohydrate molecules on the surfaces of red blood cells have roles in cell membrane integrity, cell adhesion, membrane transportation of molecules, and acting as receptors for extracellular ligands, and enzymes. ABO antigens are found having similar roles on epithelial cells as well as red blood cells. (Mohandas et al.; 2005)
Inheritance
ABO blood types are inherited through genes on chromosome 9, and they do not change as a result of environmental influences during life. An individual's ABO type is determined by the inheritance of 1 of 3 alleles (A, B, or O) from each parent. The possible outcomes are shown below:
Parent Alleles A The possible ABO alleles for one parent are in the top row and the alleles of the other are in the left column. Offspring genotypes are shown in black. Phenotypes are red. O AO (A) BO (B) OO (O) B A AA (A) AB (AB) AB (AB) BB (B) AO (A) BO (B) B O
bleeding, (O'Donnell, 2001) as 30% of the total genetic variation observed in plasma vWF is explained by the effect of the ABO blood group, and individuals with group O blood normally have significantly lower plasma levels of vWF (and Factor VIII) than do non-O individuals. (Shima. M., 1995) In addition, vWF is degraded more rapidly due to the higher prevalence of blood group O with the Cys1584 variant of vWF (an amino acid polymorphism in VWF). (Bowen, DJ. & Collins PW., 2005).
Subgroups
A1 and A2 The A blood type contains about twenty subgroups, of which A1 and A2 are the most common (over 99%). A1 makes up about 80% of all A-type blood, with A2 making up the rest. These two subgroups are interchangeable as far as transfusion is concerned, but complications can sometimes arise in rare cases when typing the blood. (The Owen Foundation., 2008) Bombay phenotype
Figure (7): Bombay phenotype inheritance The H antigen is a precursor to the A and B antigens. For instance, the B allele must be present to produce the B enzyme that modifies the H antigen to become the B antigen. It is the same for the A allele. However, if only recessive alleles for the H antigen are inherited (hh), as in the case above, the H antigen will not produced. Subsequently, the A and B antigens also will not be produced. The result is an O phenotype by default since a lack of A and B antigens is the O type. This seemingly impossible phenotype result has been referred to as a Bombay phenotype because it was first described in that Indian city. The ABO blood system is further complicated by the fact that there are two subtypes of type A and two of AB. These are referred to as A1, A2, A1B, and A2B. (Dennis O'Neil., 2011)
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In a study conducted to Michael sgro, douglas Campbell and vibhuti shah 2006 showed that the percentage of ABO incompatibility as a cause of severe neonatal hyperbilirubinemia is about 51% followed by G6PD about 21.5% other antibody incompatibility about 13% and other causes about 14.5%. .ABO hemolytic disease of newborn occurring in about 15% of infants with A or B blood type born to blood type O mothers and unlike non- hemolytic disease of newborn,. ABO incompatibility is usually a problem of the neonate rather than of the fetus, A and B antigens are only weakly expressed on neonatal RBCs. ABO
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hemolytic disease of newborn therefore usually mild and characterized by negative or weakly positive Coombs' test. ABO hemolytic disease of newborn rarely requires whole blood exchange transfusion, in contrast to hemolytic disease of newborn due to anti-D or other antibodies. (Kathryn Drabik-Clary et al; 2006)
MECHANISM
Haemolysis associated with ABO incompatibility exclusively occurs in type-O mothers with foetuses who/ have type A or type B blood, although it has rarely been documented in type-A mothers with type-B infants with a high titre of anti-B IgG. In mothers with type A or type B, naturally occurring antibodies are of the IgM class and do not cross the placenta, whereas 1% of type-O mothers have a high titre of the antibodies of IgG class against both A and B. They cross the placenta and cause haemolyses in foetus. Haemolysis due to anti-A is more common than haemolyses due to anti-B, and affected neonates usually have positive direct Coombs test results. However, haemolyses due to anti-B IgG can be severe and can lead to exchange transfusion. (Luchtman-Jones L. & Schwartz AL. 2006) The reasons for the mildness of ABO erythroblastosis are that the foetal RBC membrane has fewer A and B antigenic sites; most anti-A and anti-B is IgM and does not cross into the foetal circulation; the small amount of anti-A or anti-B that is IgG and does cross into the foetal circulation has many antigenic sites in tissue and secretions other than on the RBCs to which it can bind. Because only a small amount of antibody is fixed to each RBC membrane, the direct antiglobulin test is only weakly positive when cord RBCs are tested and may be negative when capillary blood is tested at 1 or 2 days of age. (Bowman J., 2011)
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Moderating factors
In about a third of all ABO incompatible pregnancies maternal IgG anti-A or IgG anti-B antibodies pass through the placenta to the foetal circulation leading to a weakly positive direct Coombs test for the neonate's blood. However, ABO HDN is generally mild and short-lived and only occasionally severe because:
IgG anti-A (or IgG anti-B) antibodies that enter the fetal circulation from the mother find A (or B) antigens on many different fetal cell types, leaving fewer antibodies available for binding onto fetal red blood cells.
Fetal RBC surface A and B antigens are not fully developed during gestation and so there are a smaller number of antigenic sites on fetal RBCs. (Wang, M. et al.; 2005)
Diagnosis
ABO incompatibility occurs in 20-25% of pregnancies, but laboratory evidence of haemolytic disease occurs only in 1 of 10 such infants, ABO haemolytic disease occurs almost exclusively in infants of A or B type born of group O mothers. Normal anti-A and anti-B antibodies are IgM and therefore dont cross the placenta. For reasons not understood, however, some group O women have IgG anti-A and anti-B even without prior sensitization! In this situation, a firstborn child may be affected. Fortunately, even with transplacentally acquired antibodies, lysis of infant red cells is minimal. ABO incompatibility is diagnosed with same tests as Rh incompatibility (DAT, IAT, Kleihauer-Betke test). Theres no effective protection against ABO incompatibility reactions! Good thing theyre not very common. (Kristine Krafts., 2009)
Clinical picture
The typical diagnostic findings are jaundice, pallor, hepatosplenomegaly, and foetal hydrops in severe cases. The jaundice typically manifests at birth or in the
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first 24 hours after birth with rapidly rising unconjugated bilirubin level. Anaemia is most often due to destruction of antibody-coated RBCs by the reticuloendothelial system, and, in some infants, anaemia is due to intravascular destruction. The suppression of erythropoiesis by intravascular transfusion (IVT) of adult Hb to an anaemic foetus can also cause anaemia. Extra medullary haematopoiesis can lead to hepatosplenomegaly, portal hypertension, and ascites. (Moise KJ. ., 2008)
Postnatal problems also include: Asphyxia Pulmonary hypertension Pallor (due to anemia) Edema (hydrops, due to low serum albumin) Respiratory distress Coagulopathies ( platelets & clotting factors) Jaundice Kernicterus (from hyperbilirubinemia): explained previously. Hypoglycemia (due to hyperinsulinemnia from islet cell hyperplasia) (William H. Tooley., 2004)
Complications
Complications of hemolytic disease of the newborn during pregnancy:
Mild anemia: When the babys red blood cell count is deficient, his blood cannot carry enough oxygen from the lungs to all parts of his body, causing his organs and tissues to struggle.
Hyperbilirubinemia and jaundice: The breakdown of red blood cells produces bilirubin, a brownish yellow substance that is difficult for a baby to discharge and can build up in his blood (hyperbilirubinemia) and make his skin appear yellow.
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Severe anemia with enlargement of the liver and spleen: The babys body tries to compensate for the breakdown of red blood cells by making more of them very quickly in the liver and spleen, which causes the organs to get bigger. These new red blood cells are often immature and unable to function completely, leading to severe anemia. Hydrops fetalis: When the babys body cannot cope with the anemia, his heart begins to fail and large amounts of fluid build up in his tissues and organs. (Louis Diamond., 2010)
Severe hyperbilirubinemia and jaundice: Excessive build up of bilirubin in the babys blood causes his liver to become enlarged.
Kernicterus: Build-up of bilirubin in the blood is so high that it spills over into the brain, which can lead to permanent brain damage. (Louis Diamond., 2010)
LABORATORY FINDINGS
a) Complete blood count findings i. ii. Anaemia Increased nucleated RBCs, reticulocytosis, polychromasia, anisocytosis, iii. iv. Neutropenia Thrombocytopenia spherocytosis, and cell fragmentation
v.
Hypoglycaemia is common and is due to islet cell hyperplasia and hyperinsulinism. The abnormality is thought to be secondary to release of metabolic by-products such as glutathione from lysed RBCs. Hypokalaemia, hyperkalaemia, and hypocalcaemia are commonly observed during and after exchange transfusion
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(Vidnes., 1977)
In a recent study, positive direct antibody test findings have a positive predictive value of only 23% and a sensitivity of only 86% in predicting significant haemolysis and need for phototherapy, unless the findings are strongly positive (4+). (Murray NA., 2007)
This is because foetal RBCs have less surface expression of type-specific antigen compared with adult cells. Although the indirect Coombs test result (neonate's serum with adult A or B RBCs) is more commonly positive in neonates with ABO incompatibility, it also has poor predictive value for haemolysis. This is because of the differences in binding of IgG subtypes to the Fc receptor of phagocytic cells and, in turn, in their ability to cause haemolysis. (Bakkeheim E. & Bergerud U., 2009)
The spectral qualities of the delivered light (optimal wave length range 400 520 nm, with peak emissions of 460 nm) Irradiance (intensity of light) Body surface area receiving phototherapy Skin pigmentation Total serum bilirubin concentration at commencement of phototherapy Duration of exposure. (Hart G. et al.; 2005)
Modern phototherapy devices are designed to maximise the efficacy of phototherapy to the neonate and clinicians are more appreciative of the importance of ensuring such devices are employed correctly (i.e. ensuring correct distance between device and patient, proper maintenance and servicing of phototherapy units). Phototherapy units are now smaller, easier to use around the cot, more efficient - particularly high-intensity gallium nitride light-emitting diodes (LEDs), and more powerful- the total irradiance that can be applied to an individual neonate has vastly increased. In short phototherapy is now a viable alternative to the planned use of exchange transfusion in the therapy of even moderate to severe HDN, and as devices continue to develop and improve phototherapy is likely to play an even greater role in the therapy of HDN. For a fuller description of developments in
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neonatal phototherapy since its first use the reader is referred to recent reviews. (Irene A.G. Roberts., 2008)
In 2004 Miqdad et al., reported the use of IVIG in a study of 112 well term neonates with hyperbilirubinaemia resulting from DAT positive ABO HDN. In addition to phototherapy the intervention group (n=56) received 500 mg/kg IVIG over 4 h if the serum bilirubin was rising by 8.5 mmol/L per hour or greater. Exchange transfusion was carried out in all neonates if the serum bilirubin exceeded 340 mmol/L, or was rising by greater than 8.5 mmol/L per hour in the phototherapy only group. In the phototherapy only group 16 neonates were treated with exchange transfusion whereas only 4 neonates in the IVIG group required exchange transfusion. The duration of phototherapy was also reduced in the IVIG
Also Alpay et al. in 1999 studied 116 neonates with hyperbilirubinaemia resulting from DAT-positive ABO or Rh HDN of whom 58 received IVIG 1 g/kg over 4 h when the serum bilirubin exceeded 204 mmol/L. Exchange transfusion was performed if the serum bilirubin exceeded 290 mmol/L or was rising by more than 17 mmol/L per hour. In the phototherapy only group 22 neonates were treated with exchange transfusion whereas only 8 neonates in the IVIG group required exchange transfusion. Again the duration of phototherapy and hospital stay were significantly reduced in the IVIG group. No adverse effects of IVIG were reported. Similar results have been found in previous smaller studies assessing the use of
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IVIG in the treatment of HDN. Despite the positive benefits of IVIG suggested by these studies there are methodological difficulties and questions about the safety of IVIG that potentially limit the size of the role IVIG may have in the treatment of HDN. The preponderance of ABO HDN in the larger studies suggests that the neonates assessed are relatively well and the vast majority would be expected to respond to intensive phototherapy alone unless low thresholds for exchange transfusion (bilirubin 290340 mmol/L) are employed. There is also variation in the timing of administration and dose of IVIG between studies. Late anaemia may be more prevalent in those treated with IVIG, presumably because fewer neonates have exchange transfusion and therefore removal of maternal antibody. No major side effects have been reported in the neonates treated with IVIG but since IVIG is a pooled blood product the potential for transmission of blood borne infections remains. (Hayakawa F. et al.; 2002) (Quinti I. et al.; 2002)
Given these facts how should neonatal paediatricians approach the use of IVIG in patients with HDN. The current trial evidence clearly points to positive benefits, particularly the reduction in the need for exchange transfusion. Paediatricians are less experienced with this technique due to the reduction of ABO disease and so morbidity associated with this procedure may increase in the future. Therefore the use of a more straightforward but effective therapy should be considered in the limited number of patients where the likelihood of exchange transfusion is greatest. These would include neonates with red cell alloimmunisation unmodified by antenatal therapy or neonates with potential ABO HDN where a previous sibling has suffered from severe disease requiring exchange transfusion. Also the neonate with severe DAT-positive hyperbilirubinaemia readmitted from the community, where the serum bilirubin already exceeds local guidelines for exchange transfusion, but where initial therapy with IVIG is liable to be available more quickly than exchange transfusion. In these relatively rare circumstances
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adjuvant therapy with IVIG seems justified. A single dose of IVIG of 500 mg/kg appears to be as effective as any other regimen. (Irene A.G. Roberts., 2008)
Metalloporphyrins
Metalloporphyrins are heme analogs that competitively inhibit the activity of heme oxygenase, the rate-limiting enzyme in heme catabolism. This action reduces the formation of bilirubin and makes them potential agents for both the prophylactic and therapeutic reduction of hyperbilirubinaemia in the newborn. Tin (Sn) mesoporphyrins are the most fully studied compounds in this context.
In 1988 Kappas et al. reported the prophylactic use of Sn-Protoporphyrin (SnPP) in 122 term infants with DAT-positive ABO incompatability. At doses up to 2.25 mg/kg body weight, administered by 2 or 3 intramuscular injections, they demonstrated a significant reduction in the rate of rise of plasma bilirubin levels beginning at 48 h post SnPP administration that continued until 96 h. The only reported side effect in SnPP treated neonates was transient erythema during the concurrent use of phototherapy in two neonates.
In 1994 Valaes et al., reported the results of 5 sequential studies of the prophylactic use of Sn-Mesoporphyrin (SnMp) in preterm neonates between 30 and 36 weeks gestational age. SnMp was administered at doses up to 6 mg/ kg body weight by intramuscular injection beginning within the first 24 h of life. 517 neonates were studied over 4 years between 1988 and 1992. As the study population were preterm newborns prophylactic phototherapy was commenced at predetermined low levels and the main outcome of the study was a reduction in the requirement for phototherapy in SnMp treated neonates. This was most marked in those neonates
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receiving the highest dose of Sn- Mp (6 mg/kg) where mean peak incremental plasma bilirubin concentration was reduced by 41% and phototherapy requirements by 76%, compared to control neonates. Transient erythema was again noted in conjunction with phototherapy in SnMp treated neonates but no other adverse effects were noted during the study or at follow-up at 3 and 18 months.
More recently Martinez et al., have looked at the therapeutic effect of SnMp in healthy term neonates (without haemolytic disease) with moderate hyperbilirubinaemia (plasma bilirubin 256308 mmol/L) developing between 48 96 h of age. Despite being a population of relatively uncomplicated neonates a significant number of these would be expected to go on to be treated with phototherapy, often causing maternal anxiety and lengthening hospital stay. The study enrolled a total of 84 neonates, 40 of who received a single intramuscular dose of SnMp at 6 mg/kg body weight. In the control neonates 12 (27%) required phototherapy at a predetermined level of 333 mmol/L, whereas none of the SnMp treated neonates required phototherapy. SnMp treated neonates also required a shorter period of plasma bilirubin monitoring and a reduced number of plasma bilirubin measurements. No adverse effects of SnMp use were observed. Positive effects of SnMP in reducing peak plasma bilirubin concentrations have also been observed in neonates with glucose-6-phosphate dehydrogenase deficiency. In addition neonates of Jehovah's Witness parents have been given SnMP to reduce the likelihood of jaundiced neonates requiring therapy with exchange transfusion. (Kappas A. et al.; 2001)
Given these data there is good evidence to suggest that a single dose of SnMP in uncomplicated neonates reduces peak plasma bilirubin concentrations and reduces the need for phototherapy. As these are outcomes that themselves are not likely to result in harm it can be argued that SnMP therapy presents an unknown risk as the long-term consequences of such therapy are not yet fully known. However,
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phototherapy in relatively well neonates often provokes a high degree of maternal concern and prolongs hospital stay, both of which are unwanted outcomes in modern hospital-based medical practice. Further studies are underway to more fully assess the efficacy and safety of SnMP but the use of metalloporphyrins to reduce the medical burden of neonatal hyperbilirubinaemia may well find a role in the future as models of health care become increasingly community centred. (Irene A.G. Roberts., 2008)
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Mechanism
The two Coombs tests are based on the fact that anti-humanantibodies, which are produced by immunizing non-human species with human serum, will bind to human antibodies, commonly IgG orIgM. Animal anti-human antibodies will also bind to human antibodies that may be fixed onto antigens on the surface of red blood cells (also referred to as RBCs), and in the appropriate test tube conditions this can lead to agglutination of RBCs. The phenomenon of agglutination of RBCs is important here, because the resulting clumping of RBCs can be visualised; when clumping is seen the test is positive and when clumping is not seen the test is negative. Common clinical uses of the Coombs test include the preparation of blood for transfusion in cross-matching, screening for atypical antibodies in the blood plasma of pregnant women as part of antenatal, and detection of antibodies for the diagnosis of immune-mediated haemolytic anemias. Coombs tests are done on serum from venous blood samples which are taken from patients by venepuncture. The venous blood is taken to a laboratory (or blood bank), where trained scientific technical staff do the Coombs tests. The clinical significance of the result is assessed by the physician who requested the Coombs test, perhaps with assistance from a laboratory-based hematologist. (Geha R., et al 2008)
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Laboratory method
First stage Washed test red blood cells (RBCs) are incubated with a test serum. If the serum contains antibodies to antigens on the RBC surface, the antibodies will bind onto the surface of the RBCs.
Second stage The RBCs are washed three or four times with isotonic saline and then incubated with antihuman globulin. If antibodies have bound to RBC surface antigens in the first stage, RBCs will agglutinate when incubated with the antihuman globulin (also known Coombs reagent) in this stage, and the indirect Coombs test will be positive.
Titrations By diluting a serum containing antibodies the quantity of the antibody in the serum can be gauged. This is done by using doubling dilutions of the serum and finding the maximum dilution of test serum that is able to produce agglutination of relevant RBCs.
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Results
No clumping of cells (agglutination), indicating that there are no antibodies to red blood cells, is normal. Normal value ranges may vary slightly among laboratories. Talk to your doctor about the meaning of your specific test results. An abnormal (positive) direct Coombs' test means you have antibodies that act against your red blood cells. This may be due to: 1. Autoimmune hemolytic anemia without another cause 2. Chronic lymphocytic leukemia or other lymphoproliferative disorder 3. Drug-induced hemolytic anemia (many drugs have been associated with this complication) 4. Erythroblastosis fetalis (hemolytic disease of the newborn) 5. Infectious mononucleosis 6. Mycoplasmal infection 7. Syphilis 8. Systemic lupus erythematosus or another rheumatologic condition 9. Transfusion reaction, such as one due to improperly matched units of blood 10. The test is also abnormal in some people without any clear cause,
especially among the elderly. Up to 3% of people who are in the hospital without a known blood disorder will have an abnormal direct Coombs' test. An abnormal (positive) indirect Coombs' test means you have antibodies that will act against red blood cells your body views as foreign. This may suggest: 1. Autoimmune or drug-induced hemolytic anemia 2. Erythroblastosis fetalis hemolytic disease 3. Incompatible blood match (when used in blood banks) (Schrier SL. Et al.; 2010)
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Practical work
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Patients and method This prospective study took place on full term healthy newborns
admitted to neonatal intensive care unit at Menouf hospital and Benha university hospital started from January 2012 to September 2012 including about 106 babies of different gender [males and females]. Inclusion criteria: 1- Newborns with gestation ages ranged from (37 weeks-42 weeks) 2- Newborns whose weights greater than 2500 g. 3- Infant of blood group A or B was born to mother of blood group O 4- Jaundice observed clinically with in 1st 48 hours of birth (serum indirect bilirubin levels as follow :> 5 mg/dL at 12 hr,> 8mg/dL at 24 hr and>12.5 mg/dL at 48hr). 5-Patients who need exchange transfusion (serum indirect bilirubin concentration increasing by 0.5-1 mg/dL/hr or exceeding 20mg/dL). Exclusion criteria: 1-Newborns<37 weeks 2- Newborns<2.5 Kg 3-Newborns with Rh incompatibility 4-Sick Newborns: - Newborns with respiratory distress. - Newborns with perinatal asphyxia. - Newborns with congenital anomalies. - Newborns with neonatal sepsis. - Newborns with history or manifestations of congenital infections.
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3-The following laboratory investigations were done: Blood group of the mothers and their babies. Serum Total and Direct bilirubin levels at 6, 12, 24, 36 and 48 hours of baby age. Other tests for evaluating the condition as indicated: Complete blood count Liver enzymes Serum albumin level Reticulocytes count Indirect Combs test C-reactive protein and blood culture
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Statistical method
Using Microsoft Excel 2003 and SPSS v18.0 for Microsoft Windows 7 the clinical and laboratory data were statistically analyzed. Categorical variables were analyzed by chi-square, student t-tests or Mann-Whitney test.
Hypothesis
In our study, we conjectured that severity of jaundice in O-B infants more than that of O-A infants in ABO incompatibility HDN. The null hypothesis: There is no difference is tested. The alternative hypothesis: There is a difference between O-A infants and O_B infants in the severity of the disease. However, the data give rise to rejection of the null hypothesis and accept of the alternative hypothesis falsely suggesting that there is higher severity of ABO incompatibility HDN in O-B infant than O-A infants. NB: 1- P value less than 0.05 (P < 0.05) was considered significant. 2- P Value less than 0.01 (p < 0.01) was considered highly significant. 3- P value more than 0.05 (p > 0.05) was considered insignificant (Bland, 2000 and Kirkwood, 2003)
Some of data may appear incomplete due to defective registrations in some of the files.
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A total 106 patients admitted to hospital and included in present study. These patients divided
into O-A and O-B groups.
Table (1): distribution of cases of both groups (O-A and O-B groups) in our study
Groups
test
P value
A+ve B+ve
65 0
207.8
0.001 HS
Table (1) shows that patients in our study divided into 2 groups O-A group 65 cases (61.3%) and O-B group 41 cases (38.7%).
Group
X2 test
P value
0.512
0.474 NS
Table (2) shows the sex distribution of patients. In group A, 41cases (63.1%) were male patients while 24 cases (36.9%) were female patients. In group B, 23 cases (56.1%) were male patients while 18 cases (43.9%) were female patients.
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Table (3): Comparison between O-A and O-B patients regarding maternal risk factors in study group
Group A(n=65) B(n=41) Total x2 test P value
No Maternal Risk factors Mode of delivery NVD CS Gravidity 1 2 3 4 5 6 Previous blood No transfusion Yes Spontaneous abortion Maternal drug intake nitrofurantoin No Yes No Yes 33 32 15 16 19 8 4 3 62 3 49 16 45 20
No
No
50.7 49.3 23 24.6 29.2 12.3 6.2 4.7 95.4 4.6 75.4 24.6 69.2 30.8
18 23 8 11 5 7 10 0 41 0 29 12 28 13
44 56 19.5 26.8 12.2 17.1 24.4 0 100 0 70.7 29.3 68.3 31.7
51 55 23 27 24 15 14 3 103 3 78 28 73 33
48.1 51.9 21.7 25.4 22.7 14.2 13.2 2.8 97.2 2.8 73.6 27.4 86.9 31.1
0.475
0.49 NS
12.05
0.034 S
1.947
0.282 NS
0.28
0.597 NS
0.01
0.919 NS
Salicylates
No Yes
61 4 64 1
40 1 41 0
101 5 105 1
0.772
0.647 NS
Sulfonamide
No Yes
0.637
1.0 NS
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Group
x2 test
P value
No Yes No Yes
33 32 62 3
0.286
0.593 NS
1.947
0.282 NS
Table (3) shows maternal risk factors in group A and group B patients. Firstly patients delivered by normal vaginal delivery (NVD) 51 patients (48.1%) while 55 patients (51.9%) delivered by caesarian section (CS). Maternal gravida 1 were 23cases (21.7%), gravida 2 were 27 cases (25.4%), gravida 3 were 24 cases (22.7%), gravida 4 were 15 cases (14.2%), gravida 5 were 13 cases (13.2%) and gravida 6 were 3 cases (2.8%). Mothers with previous blood transfusion were 3 cases (2.8%). Mothers with spontaneous abortions were 28 cases (27.4%). The study showed 5 cases with maternal intake of salicylates (4.7%), 1 case with maternal intake of sulfonamide (0.9%), and 33 cases with maternal intake of nitrofurantoin (31.1%). Mothers with oxytocin intake in delivery were 50 cases (47.2%). Mothers with instrumental delivery were 3 cases (2.8%). Table (4): Risk factors affecting ABO incompatibility neonatal jaundice in study group Variable Groups Mean Serum SD bilirubin at admission 25.98 21.4 26.68 24.9 19.2 23.0 23.77 23.93 25.65 27.62
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Student t test
P value
3.31 0.463 0.0 4.03 1.174 1.57 1.2 0.0 0.78 2.39 1.06 3.59 0.257 NS 0.65 NS
Gravidity
F=1.68
0.214 NS
Variable
Groups
Mean Serum SD bilirubin at admission 26.71 24.6 26.05 23.2 27.6 25.79 23.90 19.2 3.53 1.89 3.82 1.42 3.26 0.0 0.0 3.3 2.56 2.33 1.07 0.77
P value
No Yes No Yes No
0.684
1.4 0.182 NS
Table (4) shows that higher mean serum bilirubin in positive cases with previous family history, oxytocin intake in delivery, poor feeding, sequestrated blood and hypoalbuminemia. It shows also higher mean serum bilirubin in NVD than in CS cases. As well as mean serum bilirubin level increases proportionally with gravidity. Table (5): Comparison between O-A and O-B groups regarding onset of jaundice in hours noted by mothers in study group Variable Groups A B Mean SD Range 36.6 32.78 8.36 2.202 9.22 0.03 S Student t-test P value
Onset of jaundice
Table (5) shows the age of onset of jaundice in patient noted by mother with ABO incompatibility, the most common age presented with jaundice (36.6) hours in group A patients (61%) while in group B patients (39%) presented with jaundice earlier at (32.7) hours with P value (0.03) which is significant .
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Table (6): Comparison between O-A & O-B according to family history in study group Group A(n=65) B(n=41) Total test P value
No Family history Sibling with jaundice No Yes Treatment of previous siblings with jaundice (78 cases) Phototherapy Phototherapy plus Exchange transfusion No Yes 18 47 44 3
No
No
27.7 10 72.3 31 94 6 27 4
24.4 75.6 87 13
28 78 71 7
26. 4 73. 6 91 9
0.141
0.707 NS
0.338
0.56 NS
62 3
95.4 40 4.6 1
97.6 2.4
102 4
96. 2 3.8
0.328
1.0 NS
Table (6) shows family history of jaundice in patients with Abo incompatibility. There were 47 cases of group A patients (72.3%) presented with previous family history of jaundice, about 44 cases (94%) treated with phototherapy only while 3 cases only (6%) treated with phototherapy plus exchange transfusion. There were 31 cases of group B patients (75.6%) presented with previous family history of jaundice, about 27 cases 87% treated with phototherapy while 4 cases (13%) treated with phototherapy plus exchange transfusion. There were 28 cases (26.4%) without family history of jaundice. Only 3 cases of group A and 1 case of group B presented with history of G6PD on maternal side.
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Table (7): Comparison between O-A & O-B according to neonatal history and Physical examination in study group
Group
A(n=65)
B(n=41)
Total
test
P value
No
No
No
Physical Ex.
No Yes
58 7
89.2 10.8
34 7
82.9 17.1
92 14
86.8 13.2
0.872
0.351 NS
No Yes
58 7
89.2 10.8
35 6
85.4 14.6
93 13
87.7 13.3
0.349
0.55 NS
Pallor
No Yes
42 23 63
22 19 41
53.7 46.3 100. 0 0.0 70.7 29.3 68.3 31.7 65.9 29.3 4.9
64 42 104
1.262
0.261 NS
Dark urine
No
1.286
0.521 NS
Yes
2 57 8 57 8 45 17 3
0 29 12 28 13 27 12 2
2 86 20 85 21 72 29 5
1.9 81.1 18.9 80.2 19.8 67.9 27.4 4.7 0.135 0.935 NS 5.96 0.015 S 4.73 0.03 S
Moro reflex
Normal Weak
73
Group
A(n=65)
B(n=41)
Total
test
P value
No.
No.
No.
Physical Ex.
Generalized ecchymosis No Yes Cephalhematoma Extremities ecchymosis No Yes No Yes Extremities bruises No Yes Extremities hematoma No Yes Abdominal hematoma No Yes Abdominal bruises No 65 0 65 0 65 0 65 0 64 1 64 1 65 100.0 0.0 100.0 0.0 100.0 0.0 100.0 0.0 98.5 1.5 98.5 1.5 100. 0 0.0 40 1 40 1 39 2 38 3 41 0 41 0 40 97.6 2.4 97.6 2.4 95.1 4.9 92.7 7.3 100.0 0.0 100.0 0.0 97.6 105 1 105 1 104 2 103 3 105 1 105 1 105 99.1 0.9 99.1 0.9 98.1 1.9 97.2 2.8 99.1 0.9 99.1 0.9 99.1 1.6 0.387 NS 0.637 1.0 NS 0.637 1.0 NS 4.895 0.055 NS 3.232 0.147 NS 1.6 0.387 NS 1.6 0.387 NS
Yes
2.4
0.9
Table (7) shows 13 patients (12.3%) with delayed 1st cry after delivery. These cases needed resuscitation after birth. In group A patients 8 cases (12.8%) with weak moro and suckling reflexes while in group B patients 12 cases (29.3%) presented with weak moro reflex and 13 cases (31.7%) presented with weak suckling reflex sequentially P value shows significant deference between A and B groups in moro and suckling reflexes. 20 cases (18.9%) presented with weak moro reflex at admission, while 21 cases (19.8%) presented with weak suckling at admission. 42 cases (39.6%) presented with pallor on examination and 2 cases (1.9%) presented with dark urine. 29 cases ( 27.4%) had once vomiting at admission while 5 cases only (4.7%) had twice vomiting at admission. There were 10 cases of sequestrated blood which include generalized ecchymosis, cephalhematoma, extremities hematoma, extremities bruises, extremities ecchymosis, abdominal hematoma and abdominal bruises.
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Table (8): Comparison between O-A & O-B according to level of serum bilirubin (total & direct) at admission at 6, 12, 24, 36 & 48 hours of admission in study group
Variable Groups A B Dsb at admission Tsb at 6 h. after admission Dsb at 6 h. after admission Tsb at 12 h. after admission Dsb at 12 h. after admission Tsb at 24 h. after admission Dsb at 24 h. after admission Tsb at 36 h. after admission Dsb at 36 h. after admission Tsb at 48 h. after admission Dsb at 48 h. after admission A B A B A B A B A B A B A B A B A B A B A B Mean 18.08 21.03 1.22 1.65 17.16 19.66 1.27 1.35 16.15 18.33 1.46 1.32 14.89 17.26 1.22 1.31 13.45 16.19 1.19 1.29 12.45 14.75 1.08 1.2 SD 3.23 4.13 0.47 1.74 2.39 4.03 0.46 0.45 2.28 3.43 1.77 0.59 2.33 3.77 0.35 0.79 2.7 3.22 0.41 0.66 2.31 3.29 0.39 0.596
*= Mann-Whitney test
Student t test
P value
Tsb at admission
4.073
0.001 HS
*1.84
0.065 NS
3.94
0.001 HS
0.863 3.9
0.39 NS 0.001 HS
*0.152
0.879 NS
3.98
0.001 HS
0.80
0.426 NS
4.718
0.001 HS
0.876
0.383 NS
4.198
0.001 HS
1.287
0.201 NS
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Table (8) shows high significant difference statistically between O-A and O-B groups in total serum bilirubin level at admission at 6, 12, 24, 36 & 48 hours of admission, while there is no significant difference between O-A and O-B groups in direct serum bilirubin level at admission at 6, 12, 24, 36 & 48 hours of admission. Table (9): Comparison between O-A & O-B according to mean number of hours for extensive phototherapy (double & triple) in study group Variable Extensive phototherapy D plus T Groups A B Mean no. of hrs. 34.06 45.66 SD 26.57 2.23 25.2 0.028 S Student t test P value
Table (9) shows there is significant difference between O-A and O-B groups in their need for extensive phototherapy.
N.B: unit of phototherapy was suggested by authors in order to make a standard that describe the total amount of phototherapy received by patients for easier comparing.
Table (10): Comparison between O-A & O-B according to mean number of time units of phototherapy (one unit of phototherapy = one hour of four lamps of
valid potency, about 50 cm distance from patient)
Groups A B
SD 62.02 64.98
P value
0.015 S
D2 = Double phototherapy for one hour T3 = triple phototherapy for one hour
Table (10) shows significant difference between O-A and O-B groups in time units needed for extensive phototherapy. We calculated the units for every patient with B & A groups to compare number of them for each group.
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Table (11): Comparison between O-A & O-B according to Duration of admission in study group Variable Duration of admission S+D+T Groups A B Mean no. of hrs. 93.42 98.93 SD 21.06 1.303 21.43 0.195 NS Student t test P value
Table (11) shows no statistical significant difference between O-A and O-B groups in the duration of admission. Table (12): Comparison between O-A & O-B according to number of exchange transfusion in study group Group A(n=65) B(n=41) Total test P value
N % o
No
No
(Exchange transfusion)
NO of Exchange ransfusion No Once Twice 5 9 6 0 90.8 9.2 0.0 28 11 2 68.3 26.8 4.9 87 17 2 82.1 16.0 1.9 9.57 0.008 HS
Table (12) shows highly significant difference statistically between O-A and O-B groups in need for exchange transfusion.
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Table (13): Comparison between O-A & O-B according to results of Indirect coombs test in study group Group A(n=65) B(n=41) Total test P value
No
% 58.5 41.5
No 51 55
41.5 24 58.5 17
Negative 38
Table (13) shows no significant difference between O-A and O-B groups in results of indirect combs test. Table (14): Comparison between O-A & O-B according to CRP in study
group
Group A(n=65) B(n=41) Total test P value
No
No
10.8 89.2
8 33
19.5 80.5
15 91
14.2 85.8
1.58
0.208 NS
Negative 58
Table (14) shows no significant difference between O-A and O-B groups in results of CRP.
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Table (15): Comparison between O-A & O-B according to level of serum bilirubin (total & direct) at admission at 6, 12, 24, 36 &48 hours in response to treatment with phototherapy in study group
Groups Admission 6h Tsb for group A 12h 24h 36h 48h Admission 6h 12h Dsb for group A 24h 36h 48h Admission 6h 12h 24h 36h 48h Admission 6h Dsb for group B 12h 24h 36h 48h
Tsb = total serum bilirubin
Mean 18.08 17.16 16.15 14.89 13.45 12.45 1.22 1.27 1.46 1.22 1.19 1.08 21.03 19.66 18.33 17.26 16.19 14.75 1.65 1.35 1.32 1.31 1.29 1.2
SD 3.23 2.39 2.28 2.33 2.7 2.31 0.47 0.46 1.77 0.35 0.41 0.39 4.13 4.03 3.43 3.77 3.22 3.29 1.74 0.45 0.59 0.79 0.66 0.596
Student t test
P value
45.182
0.001 HS
1.649
0.146 NS
16.34
0.001 HS
1.278
0.274 NS
Table (15) shows highly significant statistically in response to treatment in both A and B groups.
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Table (16): comparison between O-A and O-B regarding albumin level in study group Group A(n=65) B(n=41) Total test P value
% 75 25
No 11 6
% 64.7 35.3
No 20 9
% 69 31 0.033 0.86 NS
Table (16) shows non-significant difference between O-A and O-B grouped babies according to albumin level. Table (17): Comparison between O-A and O-B groups regarding gravidity and their mean serum bilirubin level Mean Serum SD Student P value bilirubin level t-test at admission A 15.8 2.455049 1 B 15.7 A 16.28 0.707107 2 B 15.1 A 18.52 2.874324 3 0.149406 B 21.68 0.88 NS Gravidity A 18.71 2.695022 4 B 21.1 A 20.95 4.414213 5 B 26.02 A 0 0.964365 6 B 25.3 Table (17) shows non- significant difference in mean serum bilirubin level of both groups according to gravidity.
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Variable
Groups
Table (18): Comparison between O-A & O-B according to blood picture in study group Variable A B A B A Platelets B A WBCs B Serum Albumin level A B A Reticulocytes B 9.3 4.16 15.83 3.98 3.72 6.88 4.61 0.185 2.66 0.296 2.56 3.72 0.001 HS 0.013 S 289.1 14.89 65.59 4.48 1.038 0.302 NS Groups Mean 12.59 12.0 34.62 30.35 297.45 SD 1.098 2.35 1.45 5.56 4.092 4.66 73.66 0.592 0.56 NS 0.001 HS 0.021 S Student t test P value
Hemoglobin level
Hematocrit value
Table (18) shows that there are highly statistically significant differences about values of reticulocytes and hematocrit and statistically significant differences about values of hemoglobin and serum albumin between O-A & O-B groups.
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Discussion
82
Discussion
Jaundice is a common clinical problem in the neonatal period. Many neonates develop
hyperbilirubinemia that requires intervention. It can progress to severe hyperbilirubinemia, resulting in kernicterus (Bhutani et al., 2004).
In a study conducted to Michael sgro, Douglas Campbell and vibhuti shah 2006 showed that the percentage of ABO incompatibility as a cause of severe neonatal hyperbilirubinemia is about (51%) followed by G6PD about (21.5%) other antibody incompatibility about (13%) and other causes about (14.5%). Therefore, ABO incompatibility is the most common cause of severe neonatal
hyperbilirubinemia. In the present study we documented 106 cases of hyperbilirubinemia due to ABO incompatibility between mothers and their babies randomly found that O-A group were about 65 cases (61.3%) and O-B group were about 41 cases (39.7%) in accordance with Moise KJ 2008 in that O-A incompatibility is more common than O-B incompatibility which can explained by higher frequency of A blood group than B blood group among population. Bhat YR and Kumar CG 2012 also made study including 878 deliveries, 151 (17.3%) neonates were ABO incompatible with their mothers. The proportions who were O-A and O-B incompatible were (50.4%) and (49.6%), respectively. The blood group of (59.2%) was A +ve and it was B +ve in (34.5%) of the babies and this is consistent with the studies of john a. et al; 1994 on ABO HDN. In our study we excluded other major risk factors like prematurity, low birth weight, Rh- incompatibility, respiratory distress, perinatal asphyxia, neonatal sepsis, congenital infections and congenital anomalies.
83
Table (2) illustrated that male patients were 1.5 times as like female patients, Numan N. Hameed et al; 2011 made study about 100 cases of ABO HDN with age range from 1-12 days. Fifty three percent were males and (47%) were females but Mohammad Irshad et al; 2011 studied about 45 cases of ABO incompatibility there were 33 (72%) males and 12 (28%) females. Table (3) showed maternal risk factors in group A and group B patients. Firstly, patients delivered by normal vaginal delivery (NVD) 51 patients (48.1%) while 55 patients (51.9%) delivered by caesarian section (CS). Secondly, Mothers with oxytocin intake in delivery were 50 cases (47.2%). In addition, table (4) showed that there are higher mean total serum bilirubin at admission in NVD babies and whose mothers took oxytocin in labor but without significant difference. Our findings were in accordance with Burgoes et al., 2008 stating that one of the factors associated with decreased likelihood of readmission for jaundice was cesarean section delivery, he found that bilirubin on days 1 and 2 were found to be higher in newborns delivered vaginally than caesarian section. As has been suggested neonates are stressed prior to birth and induce conjugative enzymes prior to vaginal delivery. Further newborns delivered by cesarean section are breast-fed relatively infrequently during 1st 48 hours of life than those born by vaginal delivery. In addition, our findings were in accordance with El-Shafie et al., 2003 stating that normal vaginal delivery was increased risk of hyperbilirubinemia this could be explained by the increased use of oxytocin infusion and the increased incidence of traumatic delivery with in normal delivery than cesarean section delivery. However Olcay et al., 2004 stated that mode of delivery did not influence levels of bilirubin
84
In agreement with us, Oral et al., 2003 reflected that there is no significant effect of oxytocin infusion on the incidence of neonatal hyberbilirubinemia, disagreeing with keren et al., 2005 and El-Shafie et al.,2003 who included that the oxytocin exposure as risk factor for hyperbilirubinemia. D'souza et al, 1979 stated that raised plasma bilirubin levels in cord blood, probably enhanced by breakdown of fetal red cells, appeared to be a dose dependent effect of oxytocin. Also, Buchan, 1979 stated that the vasopressin like action of oxytocin causes osmotic swelling of erythrocytes leading to decreased deformability and hence more rapid destruction with resultant hyperbilirubinemia in the neonates, these studies were done on venous cord blood of 95 healthy newborn infants, 15 were delivered by elective cesarean section, 40 after spontaneous labor and 40 after oxytocin use. There was no significant difference between the first two groups while infants born after oxytocin-induced labor showed clear evidence of increased hemolysis with resultant hyperbilirubinemia. Table (3) illustrated risk factors of ABO HDN severity, Firstly maternal gravida 1 were 23 cases (21.7%), gravida 2 were 27 cases (25.4%), gravida 3 were 24 cases (22.7%), gravida 4 were 15 cases (14.2%), gravida 5 were 13 cases (13.2%) and gravida 6 were 3 cases (2.8%) and table (4) appeared increased mean serum bilirubin with increased gravidity so as it with any previous pregnancy incident occurred within pregnancy in addition to labour itself increase antibody amount in the mother. Gitesh Dubal and Varsha Joshi; 2012 indicated strong influence of paragravida on neonatal jaundice and its TSB level. Zarrinkoub F. & Beigi A, 2007 found that there were statistically significant relationships between jaundice and parity (p>0.05).
85
Secondly, . Mothers with spontaneous abortions were 28 cases (27.4%). Valentin I. and Govallo, M.D; 1993 had a study about 85 women with ABOsensitization but only 31 cases had ABO-HDN. Nine of the women only (29%) had previous spontaneous abortions. Positive direct combs test and positive family history of neonatal jaundice or previous abortion are strongly predicted ABO incompatibility was documented in Ghasemi. N et al., 2011 The study showed 5 cases with maternal intake of salicylates (4.7%), 1 case with maternal intake of sulfonamide (0.9%), and 33 cases with maternal intake of nitrofurantoin (31.1%). Merck 2009 in his manual of pediatric stated certain drugs and agents in neonates with G6PD deficiency (e.g., acetaminophen, alcohol, antimalarial, aspirin, bupivacaine, oxytocin, corticosteroids, nitrofurantoin , penicillin, phenothiazine, sulfonamides) are oxidizing agents that lead to overproduction of bilirubin due to hemolytic anemia. Besides that, R. Brodersen 1974 stated that number of drugs if given to newborn babies with unconjugated hyperbilirubinemia might displace bilirubin from its binding sites to plasma albumin. Sulfonamides, salicylates and nitrofurantoin known to exert such an effect. Table (5) appeared that commonly our patients presented within the 2nd day of life (86%) compared with patients presented within the 1st day of life (14%) that life agreed with Barbara J. et al; 2004 who made study about 54 babies in the first 5 days and found that majority 23 babies (43%) presented with jaundice during the second day whereas, (35.2 %) of them presented in the first day of life and 12 cases (22.3%) presented after the second day of life.
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In other side, Pavan Kumar in an Indian study 2010 said that jaundice was detected within the first 24 hours in (47.8%)and also majority 30 (15%) presented on 1st day of life, followed by 6 (3%) on 2nd and 3rd day of life, followed by 3 (1.5%) day of life respectively, 2 (1%) on 4th day, and 01 (0.5%) on 5th day of life as stated in Mohammad Irshad et al; 2011 study Our study shows that 9 cases of O-B group (22%) in contrast with 6 cases of OA group (9%) presented in the 1st 24 hours of life which stated by Johnson l et al.; 2009 who appeared earlier jaundice in O-B incompatibility than O-A incompatibility. Also, Michael Kaplan et al.2010's results demonstrated that more O-B than O-A newborns developed hyperbilirubinemia at <24 hours and showed highly significance. (P-value <0.0001) Table (6) showed family history of jaundice in patients with Abo incompatibility. 78 cases of 106 cases (73.6%) presented with previous family history of jaundice and history of jaundice's treatment, Numan N. Hameed et al; 2011 illustrated that family history of neonatal jaundice, history of jaundice's treatment is negative in (54%) that agree with Mentzer WC & Glader BE, 1998 reported that majority presented with negative family history . This conflict may be due to low birth control in our society. Table (4) illustrated that higher mean serum bilirubin in neonates with previous sibling with jaundice in accordance with Zarrinkoub F. & Beigi A, 2007 found that there were statistically significant relationships between jaundice and previous siblings with jaundice (p>0.05).
87
Wennberg et al.; 2006 stated that family history of previously jaundiced baby as a child whose sibling needed phototherapy is 12 times more likely to also have significant jaundice in accordance with our study where (91%) of cases with previous family history of jaundice treated by phototherapy and (9%) of cases treated by phototherapy plus exchange transfusion presented with significant jaundice. Table (7) showed 21 patients (19.8%) developed neurological signs like poor feeding (include cases with poor suckling and vomiting). The Canadian Paediatric Surveillance Program recently reported 258 full-term infants over a two-year period (2002 to 2004) who either required exchange transfusion or had critical hyperbilirubinemia where twenty per cent of these infants had at least one abnormal neurological sign at presentation which stated by Sgro M. et al.; 2006. KJ Barrington; 2007 stated that acute encephalopathy does not occur in fullterm infants whose peak TSB concentration remains below 340 mol/L(19.5mg/dl) and is very rare unless the peak TSB concentration exceeds 425
mol/L(24,3mg/dl). Above this level, the risk for toxicity progressively increases. This supported our findings in table (4) which indicate that cases presented with poor feeding presented also with higher total serum bilirubin level at admission than those had no neurological signs at admission. In our study table (7) illustrated that there are eight cases only of O-A group (12.3%) had weak Moro and suckling reflexes but nearly 12 cases (29%) of O-B group had weak moro and suckling reflexes. This showed statistically significant difference between both groups that weak Moro and suckling reflexes occur more in O-B group. Penn AA, et al.; 1994 stated that these neurological signs occur with
88
severe hyperbillirubineamia (TSB more than340ummol/l), so this results indicate higher severity with O-B incompatibility jaundice than O-A. In our study table (7) illustrated that there are 10 cases only with sequestrated blood. Table (4) illustrated that total serum bilirubin at admissions higher in cases with sequestrated blood than others but without statistical significant difference. KJ Barrington; 2007 is in accordance with our study in that sequestrated blood as cephalhematoma, bruises, hematomas, ecchymosis has no statistical significance in ABO hemolytic disease of newborn. Therefore, sequestrated blood has no effect on ABO jaundice, which is supported by mean hemoglobin level at admission (11.8gm/dl). Table (8) showed high significant difference statistically between O-A and OB groups in total serum bilirubin level at admission and at 6, 12, 24, 36 & 48 hours of admission, while there is no significant difference between O-A and O-B groups regarding direct serum bilirubin level this indicate that O-B jaundice is more severe than O-A jaundice. Koura, H.M et al; 2009 stated that was no significant statistical difference between (Group I treated cases) and (Group II untreated cases) in (TSB) level on admission (p>0.05); while after 24 and 48 hours of therapy the (TSB) level was significantly lower in the treated group (Group I) than the untreated group (Group II) where the p value was 0.000 and 0.001 respectively. Table (15) showed that there is high statistical significant response to treatment regarding total serum bilirubin, which indicates that, the treatment is effective in both groups. Table (9) showed there is significant difference between O-A and O-B groups in their need for extensive phototherapy. Also, Table (10) shows significant difference between O-A and O-B groups in time units needed for extensive
89
incompatibility
phototherapy. We calculated the units for every patient with B & A groups to compare number of them for each group. These two tables show that O-B group needs more extensive phototherapy than O-A group. Sunita Bhandari, 2011 stated that extensive phototherapy used in maximizing energy delivery and maximizing the available surface area. As well as, Thor WR et al.; 2011 said that "Double" and "triple" phototherapy, which implies the concurrent use of 2 or 3 phototherapy units to treat the same patient, has often been used in the treatment of infants with very high levels of serum bilirubin. Thus, O-B cases had more severe jaundice than O-A cases, as they need more extensive phototherapy. For the same reason, O-B group need longer duration of admission than O-A group as shown in table (11). Table (12) showed highly significant difference statistically between O-A and O-B groups in need for exchange transfusion. In accordance with us, Bakkeheim et al; 2009 found a significantly increased rate of invasive treatments, including intravenous immune globulin therapy and exchange transfusion, in O-B infants compared with O-A. BRINK et al. 1969 stated that jaundice occurred in the O-B group it tended to be slightly more severe than in the O-A group. This was indicated by the observation that an exchange blood transfusion was required in 12 out of the 36 jaundiced cases in the O-B group, whereas it was needed in only 24 of the 80 O-A jaundiced cases which agree with our study. Table (13) showed no significant difference between O-A and O-B groups in results of indirect combs test. 51 cases (48.1%) presented with +ve indirect coombs test with more positive results in O-B cases, so that indicates that the amount of antibodies produced by immune system of the mothers against B antigen more than A antigen. Sameer Wagle 2011 stated that the indirect Coombs test
90
result (neonate's serum with adult A or B RBCs) is more commonly positive in neonates with ABO incompatibility; it also has poor predictive value for hemolysis. This is because of the differences in binding of IgG subtypes to the Fc receptor of phagocytic cells and, consequently in their ability to cause hemolysis. In 1990 Swinhoe D.J. proved that indirect Coombs test was negative in all the mothers of the patients and this means that this test is a weak marker for hemolysis. Table (14) showed only 15 (14.2 %) positive cases of CRP, which shows no significant difference between O-A and O-B groups in results of CRP. Results of CRP do not increase more than 12. In accordance with us, Minerva 1964, stated that there was some positivity of CRP caused by neonatal hyperbilirubinemia caused by maternal fetal incompatibility. In other side, Can Vet J. 2005 stated that increased bilirubin concentrations caused a significant decrease in CRP values. Even with +ve CRP cases our results showed negative blood culture and the total leukocyte count of < 25 000 without shift to left. So that we already excluded neonatal sepsis. Table (4) showed that there is increase in TsB with cases of hypoalbuminemia that agreed with Bhutani VK. et al.,2008 who implied that measurement of albumin concentration is recommended because a low albumin concentration is considered a risk factor for bilirubin neurotoxicity, resulting in lower TSB treatment thresholds or albumin infusion. Also, Sgro M. et al.; 2006 said that Bilirubin retention is increased by hypoalbuminemia due to decreased binding capacity of albumin to bilirubin. In addition to that KJ Barrington; 2007 stated that hypoalbuminemia is said to increase the risk of acute encephalopathy in the presence of severe hyperbilirubinemia.
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Table (16) showed that hypoalbumineamia (albumin level <3.5mg/ dl) is more common with O-B group. This is evident in table (18) where mean albumin level in B grouped patients is lower than A grouped patient. Hypoalbuminemia is caused by liver affection due to severe neonatal hyperbilirubinemia which decreases albumin synthesis. This indicates severity in O_B grouped babies. Table (17) showed that there are highly statistically significant differences about values of reticulocytes and hematocrit and statistically significant differences about values of hemoglobin and serum albumin between O-A & O-B groups.. Michael Kaplan, et al; 2010 stated that Hb values were somewhat lower for the O-B neonates, the difference between these and the O-A group was not significant (17.0 3.1 g/dl vs. 17.7 2.8 g/dl, p=0.2), in spite of our study showed significant difference between O-A and O-B group regarding hemoglobin level. In accordance with our study, Shu-Huey et al; 2012 stated that Mean Hb and RBC for the AO group were higher and nucleated RBC ratios were lower than for the BO group; however, these differences were also not statistically significant. Interestingly, the mean Hct value of the BO group was significantly lower than that of the AO group (p = 0.04). Faris B. alswaf et al; 2009 made study about 55 cases and stated that main investigations done to the patients with ABO-incompatibility includes, Total serum bilirubin >19mg/dl in 22 cases (40.8%), Hemoglobin level ranged from 100- 140g/l in 29 cases, regarding Reticulocyte percentage the majority of patients (34 cases) between 5-9 %. Our study showed that O-A group reticulocytes was about 6.88% but in O-B group was about 9.3% which is highly statistically significant.
92
A slight increase in reticulocytes is a common feature in HDN due to ABO incompatibility according to Rosenfield 1955. In the series of fairly severe cases collected by Crawford and co-workers 1953, the reticulocyte count exceeded 15% in 6 out of 11 cases. Michael Kaplan et al; 2010 showed that Several investigators were unable to show any difference in clinical severity between O-A and O-B hemolytic disease of the newborn, although in the former report there was a trend towards performing exchange transfusion during the first 24 hours more frequently in O-B compared with O-A infants. Similarly, Kanto 1978 made a retrospective analysis of ABO hemolytic disease did not find significant relationships between the infants blood type and clinical outcome. Sisson and Kaplan 1972 reported no significant differences in severity or response to therapy between the two blood types. An infant whose blood group was A was as likely to be affected by ABO hemolytic disease as a blood group B infant.
93
94
Conclusions
Neonatal jaundice is considered a major problem in the NICU. ABO HDN in NICU need close follow up and management.
: B grouped infants appeared to be more severe than A grouped infantsas like: (1) Weak moro and suckling reflexes are more in O-B infants. (2) There is earlier jaundice in O-B babies. (3) Sequestrated blood ocuured withj O-B babies more agreessive. . (4) Higher serum bilirubin levels at admissionand at 6, 12, 18, 24, 36 & 48 hours after admission appeared with O-B infants (5) More duration of phototherapy needed in O-B babies. (devil) Extensive phototherapy and Exchange transfusion needed in O-B infants more than in O-A infants. Our study showed that these risk factors appeared not significant, but caused increasing in the serum bilirubin levels: (1) +ve Family history of sibiling with jaundice (2) Poor feeding (3) Oxytocin intake to mother (4) Sequestrated blood found in diseased babies (5) Maternal intake of Nitrofurantion (devil) Hypoalbuminemia of the babies (7) Higher TSB in subsequent deliveries with ABO HDN. (music) Babies with normal Vaginal delivery showed higher TSB than babies delivered with caesarian section .Investigations ofABO jaundice include serological tests as indirec
95
Recommendations
Observation nd follow up of all infants with ABO HDN especially whose with risk factors such as babies delivered vaginally, babies with hypoalbuminemia, babies with poor feeding, babies with maternal intake of oxytocin or nitr furantoin and babies with sequestrated blood. Encourage taking good history from the mother including natal, postnatal, family and past history Screening for maternal and paternal blood group in antenatal period.rly management of ABO HDN patients especially who of O-B group infants. O-B grouped infants may need more to Extensive phototherapy and Exchange Transfusion.
96
Summary
Summary
ABO incompatibility between the mother and the baby occurs in 15-20% of all pregnancies, which produces HDN in 10% of these cases. The fact prevailed ABO incompatibility is not always a benign condition. Hence, the aim of this study was to identify maternal and neonatal factors affecting the course of ABO incompatibility neonatal jaundice and its severity and to compare between OA & O-B blood subgroups incompatibilities in incidence and severity in full term with gestational age equal or more than 37 week and weight equal or more than 2500 gm This prospective study took place on full term healthy newborns admitted to neonatal intensive care unit at Menouf hospital and Benha university hospital started from January 2012 to September 2012 including about 106 babies of different gender [males and female], excluding newborns<37 weeks, newborns<2.5 Kg , newborns with Rh incompatibility and sick newborns as who with respiratory distress, perinatal asphyxia, congenital anomalies, neonatal sepsis and congenital infections. The results of this study revealed that there are real risk factors of ABO HDN as like as mode of delivery, gravidity, oxytocin intake, sequestrated blood, instrumental delivery, poor feeding and hypoalbuminemia. Also the results of this study revealed that there is more severe symptoms and signs in B grouped infants than A grouped infants born to O grouped mothers in ABO HDN. The study showed earlier manifestations in B grouped babies. In addition to what said our study showed higher total Serum bilirubin levels in O-B group than O-A group and lower albumin level , Hb levels and Hct levels in O-B infants than O-A infants. Furthermore, O-B babies need more need to extensive phototherapy and/or exchange transfusion than A grouped infants.
97
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Arabic summary
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