Efficacy of High-dose Intravenous Immunoglobulin Therapy for Hyperbilirubinemia Due Rh Hemolytic Disease
Condition: Hyperbilirubinemia; Erythroblastosis, Fetal
MeSH terms: Erythroblastosis, Fetal; Hyperbilirubinemia
Study type: Interventional
Phase: Phase 4

Summary: 
      The use of intravenous immunoglobulin G (IVIG) therapy has been reported in
      hyperbilirubinemia of Rh hemolytic disease but we don't have enough evidences for it. Human
      Immunoglobulin is considered an alternative to delay the hemolytic process and consequently
      reduce the number of exchange transfusions and transfusions of red cells concentrate, thus
      diminishing the risk of transmitting transfusional therapies-related diseases. OBJECTIVE: To
      determine the effect of IVIG in decreasing the incidence and severity of neonatal immune
      hemolytic jaundice due to Rh hemolytic disease reducing the need for exchange transfusion as
      a primary goal in these babies. METHODS: This will be a randomized, double blind, clinical
      trial involving all newborns with risk of significant hyperbilirubinemia due to direct
      Coombs-positive Rh hemolytic disease. The primary goal will be need for exchange transfusion
      and others are: incidence of late anemia, kernicterus and deafness Babies were randomly
      assigned into two groups: group 1 (study group) received phototherapy plus IVIG (500 mg/kg);
      and group 2 (control group) received phototherapy and normal saline solution (10 ml/Kg) in
      the first 6 hours of life. Exchange transfusion was carried out in any group if at any time
      the bilirubin level reached 340 micromol/l (20 mg/dl) or more, or rose by 8.5 micromol/l per
      h (0.5 mg/dl per h). Adverse effects will be related in two groups. Parents informed consent
      will be asked in pre-natal time.
    

Detailed description: 
      The Hemolytic Anemia due to Rh alloimmunization is characterized by the hemolysis of Rh (D)
      fetal red cells caused by the action of anti Rh (D) maternal antibodies in the fetal
      circulation.

      The perinatal hemolytic disease due to Rh alloimmunization is almost extinct all over the
      world. The administration of Specific Human Immunoglobulin prevents the sensitization process
      and when introduced in the perinatal care of pregnant women, it reduces the incidence of
      cases of Rh alloimmunization.

      Unfortunately Brazil does not have effective policies geared to reducing the perinatal
      hemolytic disease and its consequences and thus the incidence of this condition continues to
      be high.

      The conventional treatment includes phototherapy and exchange transfusion. The advantages of
      the exchange transfusion in the Rh hemolytic disease are well defined but its risks remain
      high and the mortality rates related to the procedure range around 2% and the morbimortality
      (thrombocytopenia, thrombosis of the portal vein, necrotizing enterocolitis, metabolic
      disorders and infection) reach 12%. The procedure requires the availability of compatible
      blood, a team with appropriate training in the procedure and a neonatal ICU infrastructure
      prepared to prevent the admission of newborns whose mothers did not go through prophylaxis.

      The use of immunoglobulin associated to phototherapy may reduce the need for exchange
      transfusion, thus allowing for more sensitized newborns to receive treatment and therefore
      avoiding neurological damages associated with the hemolytic disease.

      If the high incidence of the disease, the difficulties and the risks involved in an exchange
      transfusion, the difficulties in obtaining Rh negative blood are taken into consideration, it
      becomes clear that it is important conducting studies to prove the effectiveness of the
      immunoglobulin in such cases.

      General Objective To determine the effect of IVIG in decreasing the incidence and severity of
      neonatal immune hemolytic jaundice due to Rh hemolytic disease reducing the need for exchange
      transfusion as a primary goal in these babies.

      Specific Objectives

        1. To asses if the administration of immunoglobulin in newborns with hyperbilirubinemia
           caused by alloimmunization Rh(D) hemolytic anemia:

             1. Reduces the need for phototherapy

             2. Reduces the length of the phototherapy treatment

             3. Reduces the need or number of exchange transfusion

             4. Reduces the time of hospitalization

        2. To evaluate the risk for those patients that received immunoglobulin and the side
           effects during its administration.

        3. To evaluate the incidence of late anemia and the sequelae of hyperbilirubinemia
           (deafness, development retardation, cholestasis and kernicterus) during the first year
           of life.

        4. To evaluate the Ig-G subclasses and the presence of anti-HLA antibodies of paternal
           blood cells in the groups of newborns studied and their relation with the clinical
           response to immunoglobulin.

      Methodology This will be a randomized and double-blind clinical trial essay . The mothers
      will be approached during the prenatal treatment, after being diagnosed as carriers of
      hemolytic disease due to Rh alloimmunization. The research will be presented and the
      mother/family will be invited to participate in the study. The informed consent term will be
      presented to the mother/family and they will be allowed some time to decide. If they are
      accepted in the study they will receive a questionnaire on the issues related to the possible
      reasons of sensitization.

      After obtaining the free and informed consent from the parents, the sensitized newborns will
      be randomized in 2 groups, in a 1:1 proportion. The study group will receive Human
      Immunoglobulin (Immunoglobulin® - 50mg/ml) with a dose of 500mg/kg, equivalent to 10ml/kg
      during the initial 6hours of life, through intravenous infusion for 2 hours; the control
      group will receive the same volume in saline solution at 0.09%.

      All newborns included in the study will be granted with conventional supplementary treatment
      that includes the indication of exchange transfusion and of phototherapy, according to
      specific criteria recommended by the American Academy of Pediatrics in 2004. The criteria
      apply equally to both groups. The study will be monitored individually and it will be allowed
      to be interrupted it if any important side effect occurs such as anaphylactic reaction or if
      the results of a given group are significantly better than those of the other before the
      inclusion of new subjects in the research, according to the size of the sample or in case the
      drug does not yield the desired beneficial effects.

      An independent neonatologist, previously chosen, will check the undesirable side effects and
      will partially monitor the results of the study. The report on undesirable effects will be
      conducted for each case; two intermediate evaluations on the results of the research are to
      be conducted. The Committee on Ethics on Research will be informed of every non-expected or
      undesired effect related to the medication under study or of the need to interrupt the
      research.

      Sample Size :

      The calculated size of the sample, considering a reduction of 30% on the indication of
      exchange transfusion, with a statistical significance of 95% and test power of 80% was 90
      newborns. An investigator will approach all pregnant women and/or parent/responsible for the
      babies potentially eligible for the study and he will deliver them a consent term.

      Randomization and blinding The randomization will be performed by drawing blocks of different
      sizes. In order to avoid that the health professionals in the nursery know which product is
      being infused into the newborns (Immunoglobulin or Saline Solution 0.9%) the syringes with
      the required volumes will be prepared in the pharmacy and wrapped in aluminum foil. The color
      of the products is similar. The newborns will be monitored and clinically followed-up before,
      during and after the two groups equally receive the infusion. All clinical changes such as
      cardiac and respiratory frequency and hemoglobin saturation will be recorded before and after
      the infusion in the two groups. All newborns, before and after the procedure, will be
      submitted to Glucose dosages by screening method (Blood sugar test).

      Complementary treatment

      The complementary treatment will be administered and secured to all newborns admitted into
      the study and will follow the protocols below:

      Indication for exchange transfusion

      The babies to whom an exchange transfusion at birth would be indicated will be excluded from
      the study. The indications for exchange transfusion at birth are:

        -  Bilirubin on the umbilical cord superior or equal to 4 mg%

        -  Fetal hydrops or congestive heart failure due to serious anemia.

      The exchange transfusion will be indicated to the following newborns after birth, according
      to the existing literature and presenting the following features:

        -  Bilirubin level is rising over 0.5mg/dl per hour despite phototherapy or

        -  Hyperbilirubinemia, according to APP directives.

      Indication of Phototherapy

      All newborns will receive phototherapy beginning in the first 6 hours of life The procedure
      adopted will be the triple phototherapy placed 50cms away from the newborns; the irradiance
      of the device will be measured every day.

      Indication for blood transfusion:

      The newborns that present the conditions mentioned below will be indicated to receive reed
      blood transfusion at the volume of 15ml/kg, according to criteria below:

        1. Hematocrit level under 25% with positive direct or indirect Coombs Hematocrit level
           under 21%, with negative direct and indirect Coombs

        2. Reticulocytes - less than 1%

        3. Hematocrit level under 30% accompanied by clinical signs of severe anemic. Auditory
           Evoked Potential All newborns involved in the study will undergo a non-invasive hearing
           test, at the occasion of hospital discharge or at the first time they go to the
           ambulatory for follow-up. The application of the hearing evoked potential is indicated
           to all isoimmunized newborns and is routinely performed at the local where the study is
           taking place.

      Follow-up after hospital discharge All newborns will be followed-up at the Follow-Up
      Ambulatory until the first year of life, during which the laboratorial follow-up will be
      conducted (Hematocrit/Coombs) as well as the complete physical and neurological examination.
      The Bayley method will be used for neurological evaluation, to be performed by a trained
      professional at the end of the first year of life. Every fact related to the clinical
      evolution during the first year of life will be recorded: the presence of cholestasis,
      nutritional situation (evaluation) through z-score at the time of hospital discharge, by the
      6th month and at the end of the first year, regarding weight, height and head perimeter,
      using NCHS as standard; hospital admittance for blood transfusion or other treatments,
      presence of infection that might be related to the use of blood derivates (hepatitis B and C
      , cytomegalovirus).

      Laboratorial Tests The laboratorial exams will be performed based on maternal samples, drawn
      during the pre-natal period and on samples of the newborn, drawn at birth (blood of the
      umbilical cord) and through heel puncture and withdrawal of 2 capillary tubes. These
      capillaries will be centrifuged and the total bilirubin will be measured by the Bilirubin
      Meter B105, ERMA INC.). The technicians to perform the exams will not be aware of the
      allocated group of the patient under examination.

        1. Determination of ABO blood groups of the mother- direct and reversal proof- a technique
           in the vial with BIOTEST reagents.

        2. Determination of the ABO blood group of the newborn -

        3. Determination of maternal and fetal Rho ( D) factor - Technique in vial using the anti-D
           monoclonal saline solution and BIOTEST Rh control saline solution.

        4. Research for irregular antibodies P.A I - in the phase of immediate reading, proteic
           phase at 37º - technique in the vial with BIOTEST reagents and sensitized red cell-test
           ( Coombs control) by BIOTEST

        5. Identification of Irregular Antibodies - technique performed with reagents in the
           albuminous Coombs vial and a Panel of phenotyped red cells and sensitized red cells (
           Combs Control) by BIOTEST

        6. Dosage of irregular antibodies in the maternal serum with phenotyped red cells of the
           newborn

        7. Research for anti-A and anti-B IgG in the blood serum of the Rh negative alloimmunized,
           blood type "O" positive mother.

        8. Direct test of human immunoglobulin (Direct Coombs) in samples of the NB - technique
           performed in a vial with BIOTEST reagents.

        9. Classification of IgG subclasses - immunoenzymatic test (ELISA)

       10. Research for anti-HLA antibodies against paternal blood cells.

      Data analysis:

      The data will be stored in the attached worksheet and analyzed using statistical methods to
      compare the results of laboratorial exams and the presence or absence of exchange transfusion
      during hospital stay among those children who were given intravenous immunoglobulin and those
      that were not. These tests will take into consideration that the sample has been randomized
      in blocks. The observations will also be conducted by stratifying both groups, as follows:
      premature babies, non-premature babies, babies that underwent intra-uterus transfusion and
      those that did not. The data will be examined by the statistical program SPSS 13.0, using the
      appropriate tests for quantitative and binary variables.
    

Intervention name(s): Intravenous Immunoglobulin; Normal saline solution
Intervention type(s): Drug; Drug
Intervention description(s): Intravenous Immunoglobulin; Normal saline solution 10 ml/Kg
Other intervention name(s): Immunoglobulin; saline solution
Intervention MeSH terms: Pharmaceutical Solutions; Immunoglobulins; Immunoglobulins, Intravenous; Antibodies; gamma-Globulins; Rho(D) Immune Globulin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Immunoglobulins, Intravenous; Hyperbilirubinemia; Erythroblastosis, Fetal; Exchange Transfusion, Whole Blood