NEONATAL JAUNDICE

Icteric staining of the skin (jaundice) in term infants occurs when the concentration of bilirubin in the blood
80-90 mmol/l (term infants)
> 120 mmol/l (pre-term infants)
> 35-40 mmol/liter (adults)
Causes of hyperbilirubinemia in newborns varies and are reflected in the classification outlined below.

Classification of neonatal jaundice

I. Unconjugated hyperbilirubinemia.
1. Transitory (physiological) jaundice.
2. Hemolytic anemia:
A. Hemolytic diseases of newborn
B. Drug-induced
C. Hereditary:
erythrocytic membranopathy (hereditary spherocytosis, or Minkowski-Chauffard disease)
haemoglobinopathies (sickle cell anemia, thalassemia)
erythrocytic fermentopathy (deficiency of glucose-6-phosphate dehydrogenase)
3. Polycythemia
4. Hematoma
5. Disorder of conjugated bilirubin without hemolysis and anemia:
A. Hereditary (Gilbert's syndrome, Kriegler-Nayar syndrome of types I and II)
B. Hormone deficiency (neonatal hypothyroidism, DM of the mother)
C. Neonatal hepatitis (usually of infectious origin)

II. Conjugated hyperbilirubinemia

1. Extrahepatic bile duct obstruction
2. Intrahepatic bile duct obstruction

Unconjugated hyperbilirubinemia
Accumulation of unconjugated bilirubin in the blood often associated with increased hemolysis or a lack of maturity of the enzyme
systems of hepatocytes. Most often in the neonatal period develops hemolytic disease of newborn.

HEMOLYTIC ANEMIA

Hemolytic Disease of Newborn

Hemolytic disease of newborn (HDN) - a disease, which is based on erythrocyte hemolysis of fetal and neonatal outcomes associated
with the incompatibility of blood between mother and fetus on erythrocytic Ag.

Etiology and Pathogenesis.

HDN develops mainly as a result of the incompatibility of blood between mother and fetus for rhesus-factor (Rh-factor) or group Ag, at
least - in other antigenic systems because of their lower immunogenosis.
Rh-conflict occurs if Rh-negative female fetus has Rh-positive blood.
ABO-conflict develops in the presence of 0(I) blood groups in women and the fetus - A(II) (in 2/3 of cases) or B (III) (in 1/3 of
cases).
When the incompatibility of blood between mother and fetus of AB0 or Rh-Ag HDN develops in 3-6%. It is believed that the HDN of ABO
system is developed, at least, but even more frequently than on Rh-factor, but occurs in most cases, easier, and it is often not
diagnosed. In recent years, increased the number of children with severe forms of HDN ABO system, especially if the newborn in B(III) of
blood.

Rh-factor, Ag A or B erythrocytes of fetus, pass through the placenta into mother's blood, causing the formation of Rh-AT or isoantitel
anti-A or anti-B, respectively, penetrating, in turn, through the placenta into the bloodstream of the fetus. Child is born patients in the
case of the previous sensitization of the mother. Rh-negative woman can be sensitized by transfusions Rh-positive blood, even in early
childhood. But more important is the immunization of mothers with previous fetal blood, including abortion, as the Rh-factor begins to
form at 5-6-th week of pregnancy and it can be found in the fetus at 10 - 14th week. The most pronounced trans placental transfusion
takes place during childbirth. In the development of HDN ABO system serial number of pregnancy does not matter, because in everyday
life sensitization to AB-Ag occurs frequently enough (with food, with some infections, vaccination).
Hemolysis of red blood cells the fetus and the newborn leads to hyperbilirubinemia and anemia. Unconjugated bilirubin neurotoxicity.
At a certain concentration (more than 340 mmol/l in term and more than 200 mmol/l in deep preterm), it can penetrate the BBB and
damage the structure of the brain in primarily subcortical nuclei and cortex, which leads to the development of bilirubin
encephalopathy (kernicterus). In addition to the concentration of unconjugated bilirubin on its passage through the BBB following the
factors influencing below:
The concentration of albumin in blood plasma (in the bloodstream of indirect bilirubin bound to albumin, losing their toxic
properties and the ability to pass through the BBB).
The concentration of nonesterified fatty acids that compete with bilirubin for liaison with albumin.
The concentration of glucose (glucose - the source material for the formation of glucuronic acid, in addition, hypoglycemia
increases the concentration of nonesterified fatty acids).
Hypoxia (the transition suppresses indirect bilirubin in the line).
Acidosis (reduces the strength of binding of unconjugated bilirubin and albumin).

Unconjugated bilirubin - a tissue poison, inhibiting the oxidative processes and causes in different organs, degenerative changes in the
cells until necrosis. As a result of damage to liver cells in the blood falls conjugated bilirubin. Ability to its excretion is reduced due to the
immaturity of the excretory system and the characteristics of the bile capillaries (narrow, small quantity). As a result, the bile ducts
occurs cholestasis, possibly the formation of reactive hepatitis.

As a result of the pathological destruction of red blood cells, anemia develops, which stimulates bone marrow
hematopoiesis. Significant anemia occur foci of extramedullary hematopoiesis in the peripheral blood erythroblasts appear in
connection with the disease than previously known as erythroblast.

In the spleen is phagocytosis of erythrocytes and their fragments. In the epithelial cells of the liver, kidney, pancreas and other organs is
the deposition of the decay products of erythrocytes. There is a shortage of iron, copper, zinc, cobalt. The liver and spleen were
increased mainly because of the foci of extramedullary hematopoiesis.

Clinical picture.
Divided into edematous (2%), yellow (88%), anemic (10%) form of the disease.
Edematous form - the most severe, develops in utero. In early immunologic conflict may occur miscarriage. When progress of
disease is massive intrauterine hemolysis of red blood cells leads to severe anemia, hypoxia, metabolic disturbances,
hypoproteinemia and edema of tissues. Formed in these cases, unconjugated fetal bilirubin enters the bloodstream and
cleared by mother's liver (in the blood of pregnant increases the concentration of bilirubin). Fetus dies before birth or are
born in critical condition with widespread edema. The skin is very pale, sometimes with subicteric shade, glossy. Newborn is
sluggish, muscle tone sharply reduced, reflexes are depressed, there are cardio-pulmonary insufficiency, marked
hepatosplenomegaly, big belly, tubby. The concentration of hemoglobin is less than 100 grams per liter.
Icteric form - the most common, medium mild, form of the disease. Its main symptoms - early emerging jaundice, anemia and
hepatosplenomegaly. Jaundice with orange hue appears at birth or in early, at least on the second day and is growing
rapidly. Growth in the liver and spleen. The sooner jaundice appears, the more severe the disease occurs. Due to the
development of bilirubin intoxication, children become lethargic and sleepy, appear hyporeflexia, hypotonia, the monotonous
cry, pathological yawning. At 3rd to 4th day, the concentration of unconjugated bilirubin can reach critical values. In this case,
nuclear jaundice symptoms: stiffness in the muscles of the neck, tonic-extensor muscle cramps, "brain" cry, a symptom of
"setting sun", a large bulging fontanelle. Kernicterus develops in 10% of full-term at a concentration of unconjugated bilirubin
in the blood above 340 mmol/l, 30% - higher than 430 mmol/l, 70% - higher than 520 mmol/l. Some children even at a
concentration of unconjugated bilirubin of about 650 mmol/l, kernicterus does not develop. By the end of the first week of life
against the backdrop of severe hemolysis decreases the secretion of bile in the intestine (a syndrome accumulation of bile),
and there are signs of cholestasis. The skin acquires a greenish tint, discolored feces, urine darkens, in blood content of
conjugated bilirubin. In severe cases of icteric staining of the skin persists for a long time. Icteric form of HDN is usually
accompanied by hyperchromic anemia. Duration of anemia depends on disease severity and type of treatment and may last
up to 2-3 months.
Anemic form - most benign. Clinically evident immediately after birth or during the first week of life. Sometimes pale skin did
not immediately evident. The disease progresses gradually, severe anemia diagnosed on 2-3rd week, and even later. The
general condition of the child changed little, increasing size of the spleen and liver. The concentration of unconjugated
bilirubin may be slightly increased. Favorable prognosis.

HDN during the conflict in ABO system occurs mainly in the more mild form, but possibly severe course of disease (especially
delayed diagnosis) with the outcome of bilirubin encephalopathy. With double incompatibility, HDN is usually caused by A-or B-Ag and
milder than in the isolated Rh-conflict.

Diagnosis.
Divided into antenatal and postnatal diagnosis.
 First of all we need antenatal diagnosis of possible immune conflict. Take into account the incompatibility of blood between
the parents of erythrocytic Ag, obstetric and maternal somatic anamnesis (previous abortions, stillbirths, miscarriages, birth of
sick children, blood transfusion without Rh-factor). During pregnancy, at least three times determine the titer pro-rhesus AT in
the blood of Rh-negative women. Titer value is the relative importance, as well as detection in the blood of pregnant AT can
only assume the probability of disease of the fetus. Type of curve changes titer Rh-AT in the dynamics ( "jumpy", ie, with sharp
fluctuations, titer) is of greater prognostic significance than the degree of its increase. In the case of determining the risk of
immune conflict, investigate amniotic fluid obtained by trans-abdominal amniocentesis in determining the optical density of
bilirubin, protein concentration, glucose, iron, copper, Ig, etc. In the development of HDN with ultrasound indicate a
thickening of the placenta, its rapid growth due to possible edema, polyhydramnios, increased abdominal size of the fetus at
the expense of hepatosplenomegaly.
Postnatal diagnosis of HDN is based primarily on clinical manifestations of the disease at birth or shortly thereafter (jaundice,
anemia, hepatosplenomegaly). Are very important laboratory data (increase the concentration of unconjugated bilirubin,
erythroblastosis, reticulocytosis, positive Coombs test for Rh-conflict). All figures take into account the complex and possibly
in the dynamics.

Treatment.
In severe cases, resorting to surgical treatment replacement blood transfusion, hemosorption, plasmapheresis. Replaced blood can
lead to unconjugated bilirubin and AT from the blood of the child and to fill the shortage of red blood cells. For the replacement of
blood transfusion usually used Rh-negative blood is the same group as the baby's blood. At present, no whole blood transfusion and Rh-
negative packed cells than mixed with fresh frozen plasma. If HDN is caused by group incompatibility, the use of packed cells than 0 (I)
group, and plasma or AB (IV) group, or of same group.

Absolute indications for replacement transfusion in the first day of life in term infants are as follows:
The concentration of unconjugated bilirubin in cord blood of more than 60 mmol / liter.
Hourly increase the concentration of unconjugated bilirubin of more than 6.10 mmol / liter.
The concentration of unconjugated bilirubin in peripheral blood of more than 340 mmol / liter.
Severe degree of anemia (Hb less than 100 g / l).

Often (if an hourly increase in bilirubin concentration exceeds 6-10 mmol / l) by replacing the blood must be carried out again (after 12h
after the first procedure). On the 3rd day of life has meaning only the absolute value of the concentration of bilirubin, as an hourly
increase is slowing due to the destruction of AT. When interpreting the results of laboratory investigations in each case they must be
weighed against the clinical data. Severe prematurity, abnormal pregnancy, the coincidence of the blood groups of mother and child
with Rh-conflict - risk factors for bilirubin encephalopathy. In this case, holding the replacement of blood transfusion at a lower
concentration of unconjugated bilirubin.

After surgical treatment, or with a lighter during the HDN use conservative methods to reduce hyperbilirubinemia: infusion of protein
drugs, glucose, which significantly reduces the likelihood of passage of unconjugated bilirubin across the BBB. In severe forms of HDN
immediately after birth can be assigned to prednisolone intravenously for 4-7 days.

Widely used phototherapy. After the introduction of this method need to replace blood transfusions decreased by 40%. At present,
instead of special lamps, located above the bed of the child, using a system consisting of a light source in the form of high intensity
tungsten halogen lamp with a built-in reflector and photo-optical cable in which the light passes from the lamp to fiber optic
cushion. The latter is a mattress of woven fiber in it. On the pillow put a protective coating that is in direct contact with the skin of the
newborn. Coating reduces the risk of contamination and infection. Pillow fastened to the body of a child with a special vest (Figure 6.3
inset). During phototherapy is photooxidation of unconjugated bilirubin, located in the skin, with the formation of dehydrobilirubin and
other water-soluble isomers that are excreted in the urine and feces.

For the treatment of HDN also use inducers of microsomal liver enzymes (eg, phenobarbital). Introduction of vitamins E, B, B 2, B 6, C,
cocarboxylase improves liver work and stabilizes the metabolism. In order to inhibit bilirubin absorption in the intestine, use cleaning
enema, activated charcoal in the first 12 hours of life. Syndrome thickening of bile cropped destination within cholagogue [magnesium
sulfate, allohola, Drotaverine (for example, No-Shpi, etc)]. In significant anemia, transfusion of packed red blood cells or washed
erythrocytes.

Previously believed that children with HDN should apply to the chest in 1-2 weeks after birth, as in the milk contains pro-rheseus AT. At
present, it is proved that early apposition to the chest does not lead to more severe disease, as well as AT, contained in milk are
destroyed with hydrochloric acid and digestive enzymes and does not have hemolysis action.

Prevention.
Outset of sensitization of women with Rh-negative blood.
Nonspecific prevention: conducting blood transfusions only from the Rh-factor, prevention of abortion, a set of social
measures to protect women's health.
 Specific prophylaxis: the introduction of Rh 0 (aHTH-D) Ig in the first 24 hours after the birth of a healthy Rh-positive child, and
after the abortion, which contributes to rapid elimination of red blood cells from fetal blood mother, preventing it, thus the
synthesis of Rh-AT.

The method of specific prophylaxis is highly effective, but its application possibility of failure, probably related to the late introduction of
the drug or its lack of dose (eg, by ingestion of a large amount of fetal blood in the mother's bloodstream). The level of perinatal
mortality in HDN correlated with the level of AT in Rh-sensitized women before pregnancy. Need to reduce their titers before the onset
of pregnancy, allowing the bearing with the titer AT 1:2-1:4.

Prevention in the identification of Rh-sensitization during pregnancy includes the following activities:
Nonspecific hyposensitization.
Specific hyposensitization: transplanted skin graft from her husband to commit to AT Ar transplant.
Hemosorbtion (from 1 to 8 operations), plasmapheresis.
3-4-fold replacement of intrauterine blood transfusion at gestational ages 25-27 weeks washed erythrocytes 0 (I) of Rh-
negative blood, followed by elective delivery from 29th week of pregnancy.

Prognosis depends on the severity of HDN. In severe forms of possible coarse delay psychomotor development, the development of
infantile cerebral palsy, with more light - moderate delay in the formation of static functions and psyche, hearing loss, strabismus. In the
group undergoing HDN higher overall morbidity, inadequate response to immunizations, the propensity to development of allergic
reactions, chronic damage of hepatobiliary system. In 2/3 of adolescents who have suffered HDN reveal a decline in physical
performance and psycho-vegetative syndrome, which can be attributed to high-risk violations of social adaptation.

Drug-induced Hemolytic Anemia

In the application of certain medications (eg, Salicylates, sulfonamides, nitrofuranov) possible development of hemolysis of red blood
cells and increase the concentration of bilirubin in the blood.

Hereditary Hemolytic Anemia

Erythrocytic membranopathy (hereditary spherocytosis, a disease or Minkowski-Chauffard). Hereditary spherocytosis, or
anemia Minkowski-Chauffard, often manifested in the age of 3-15 years (see "hemolytic anemia" in Chapter 8,
"Anemia"). Infantile picnocytosis may develop in the first days of life in preterm - to 3-4-th week, especially with a deficiency
of vitamin E. As a result of hemolysis developed transient hyperbilirubinemia. If you can prevent the development of
kernicterus, the prognosis is usually favorable.
Of the most common hemoglobin sickle cell anemia. To this group belong, and thalassemia. Hemoglobin arise from violations
of the synthesis of hemoglobin due to mutations in the genes globin chains. This group of diseases prevalent in tropical and
subtropical zones, develops usually by the end of the first year of life.
From erythrocytic fermentopathy most common hemolytic anemia due to deficiency of glucose-6-phosphate
dehydrogenase. Lack of this enzyme often revealed in the inhabitants of the Mediterranean, East, Asia and Africa. The disease
can occur in newborns.

Polycythemia
It can lead to hyperbilirubinemia because of the inability of the liver to metabolize excess bilirubin. Develops in 10-15% of infants with
low birth weight, with late cord clamping, delayed delivery, placenta praevia, feto-fetal and maternal-fetal transfusion, endocrine
disorders. Hematocrit in such children exceeds 0.65, the concentration of Hb - 220 g / liter.

Hematoma
The concentration of bilirubin in the blood can increase due to excess of its formation in chephalohematoma, intraventricular
hemorrhage.

Disorder of Conjugated Bilirubin in the Absence of Hemolysis and Anemia

Inherited disorders of conjugated bilirubin

Most common Gilbert Syndrome. This disease develops as a result of violations of the seizure of bilirubin hepatocytes and
the lack of activity of glucuronosyltransferase (SR). The concentration of unconjugated bilirubin in the blood increases slightly,
kernicterus does not develop. Often diagnosed in school age.
In the same group is a syndrome Kriegler-Nayar types I and II.
- Type I (p) takes place, usually with the development of kernicterus, as almost completely absent enzyme
glucuronosyltransferase. Prognosis is poor. Currently developing new treatments for this disease: transplantation
of liver, donor is usually the mother, the introduction of donors liver cells.
- Type II is characterized by a benign course. With this type is reduced activity glucuronosyltransferase.
Disorder of Conjugated Bilirubin with Hormone Deficiency
Hyperbilirubinemia arises from hypothyroidism in newborns, because thyroid hormones influence the maturation of
glucuronosyltransferase. Maturing of this enzyme is delayed and also in DM mother.

Disorder of Conjugated Bilirubin in Newborn Hepatitis

More likely to develop in such infections as Hepatitis B and C, Rubella, Listeria, Tauxe-plazmoz, as well as with cytomegalovirus,
mycoplasma, enterovirus infections (see above section on intrauterine infection). Hyperbilirubinemia usually of mixed origin, due both
to the defect of hepatocytes, and with increased hemolysis.

Conjugated Hyperbilirubinemia
Extrahepatic bile duct obstruction is usually associated with their atresia or hypoplasia in utero transferred from infectious
hepatitis. Obstruction due to accumulation of bile can occur when mucoresidual, severe forms of HDN, parenteral nutrition,
especially in preterm infants.
Intrahepatic bile duct obstruction develops in intrahepatic atresia of biliary tract, occurring as often after having suffered
intrauterine hepatitis.

Clinical picture.
When conjugated hyperbilirubinemia jaundice (with greenish tint) appears or increases in 5-7th day of life. Somewhat later, there are
constant or intermittent discoloration of feces, intense staining of urine. Developed hepatosplenomegaly, liver becomes very
dense. Expanded veins anterior abdominal wall, and later developed ascites, hemorrhagic syndrome, pancytopenia. These signs appear
earlier and more constant in extrahepatic cholestasis than in the intrahepatic atresia.

Treatment.
Necessary to removed cholestasis. Prescribe the enzymes of the pancreas, improve the digestion of fats, special nutrient mixture,
enriched polysaturated triglycerides and unsaturated fatty acids. In some forms of extrahepatic atresia of bile duct, use surgical
treatment. In recent years, surgical treatment and sometimes resorted intrahepatic atresia - producing liver transplantation, usually
over the age of 3-6 months.