Unit 11 Neonatal and Obstetrical Transfusion Practice Terry Kotrla, MS, MT(ASCP)BB

Introduction Neonatal period – birth to 4 months. Indications for transfusion DIFFERENT Weight Gestational age Circumstances of delivery Maturation

Introduction Ill infants most transfused patients in hospital. Iatrogenic blood loss carefully monitored. Once significant, transfuse Transfusion service must provide specialized service Minimize donor exposure if possible. Use one unit with satellite bags Use sterile docking device

Sterile Docking Original bag on left, aliquot bag on right. Tubing inserted in device and welds the two together, maintains CLOSED system. Blood squeezed over.

Fetal and Neonatal Erythropoiesis Appropriate transfusion practice requires knowledge of neonatal physiology and careful clinical observation. As embryo develops predominant sites of hematopoiesis change: at about the 9th week of gestation shifts from wall of yolk sac to liver. at about the 24th week from liver to bone marrow. Hematopoiesis regulated by gradually increasing erythropoietin levels stimulated by low oxygen tensions during intrauterine life. At 40 weeks (full term), normal infants have cord blood hemoglobin of 19 +/- 2.2 g/dL. Neonates of lower birth weight have lower normal hemoglobin levels.

Fetal and Neonatal Erythropoiesis Fetal red cells have life span of 45-70 days, 53-95% hemoglobin F Physiologically adapted to low intrauterine oxygen tensions High oxygen affinity allow red cells to acquire oxygen from maternal RBC throughout pregnancy and release tissues. High oxygen affinity results in poor tissue oxygenation after birth. Hemoglobin A replaces hemoglobin F after birth Oxygen delivery to tissues remains satisfactory despite a physiologic fall in hemoglobin concentration. Oxygen dissociation curve shifts to the right, reflecting improving oxygen delivery to the tissues. Premature infants have lower hematocrits and greater percentage of hemoglobin F in their RBC than term newborns.

Fetal and Neonatal Erythropoiesis As tissue oxygenation improves, erythropoietin decline and erythropoiesis diminishes. Decline in RBC produces a "physiologic anemia of infancy“. Normally developing infant maintains adequate tissue oxygenation despite lower hemoglobin levels.

Unique Aspects of Neonatal Physiology Differences between newborns and adults dictate differences in transfusion practice. Newborns are small and physiologically immature. Those requiring transfusion are often premature, sick and unable to tolerate minimal stresses.

Unique Aspects of Neonatal Physiology Infant size Full-term newborns blood volume approximately 85 ml/kg Premature infants average blood volume of 100 ml/kg. Survival rates continue to improve for infants weighing 1000 g (2.2 lbs) or less at birth Transfusion service must provide blood components for patients whose total blood volume is less than 100 mLs. Small blood volumes and need for frequent laboratory test makes replacement of iatrogenic blood loss most common indication for transfusion.

Unique Aspects of Neonatal Physiology Infants do not compensate for hypovolemia well. Results in diminished cardiac output, resulting in poor tissue perfusion, low tissue oxygenation and metabolic acidosis. Bone marrow responds more slowly to anemia. If hemolysis occurring due to maternal antibody may be no increased erythropoiesis for 2-3 weeks.

Unique Aspects of Neonatal Physiology Cold stress (hypothermia) causes exaggerated effects: increased metabolic rate hypoglycemia metabolic acidosis tendency to apneic episodes that may lead to hypoxia, hypotension and cardiac arrest. Blood for transfusion should be warmed if given in large amounts, small amounts reach RT in about 20 minutes and does not need to be warmed.

Unique Aspects of Neonatal Physiology Immunologically immature, antibodies present in plasma originate almost entirely from maternal circulation. IgG only immunoglobulin class that crosses the placenta. Passively acquired antibody conserved during the neonatal period due to slow catabolism by the fetus. Infants exposed to an infectious process in utero or shortly after birth may produce small amounts of IgM detectable by sensitive techniques, but rarely form RBC antibodies of either class during the neonatal period.

Transfusion Associated Graft versus Host Disease (TA-GVHD) TA-GVHD reported in newborns receiving intrauterine transfusion followed by postnatal exchange transfusion. Lymphocytes given during intrauterine transfusion may have induced host tolerance, so that lymphocytes given in subsequent exchange transfusion were not rejected in the normal way. GVHD not felt to be significant clinical problem for immunologically normal newborns who receive multiple exchange transfusions.

Transfusion Associated Graft versus Host Disease (TA-GVHD) Irradiation of blood kills immunologically competent lymphocytes. Irradiated blood given to low birth weight, low gestational age or septic premature neonates such infants are immunologically more vulnerable to TA-GVHD. Blood for intrauterine transfusion should be irradiated. Any directed donor blood from a relative should be irradiated.

Unique Aspects of Neonatal Physiology – Metabolic Problems Immature kidneys have reduced glomerular filtration rate and concentrating ability, the newborn may have difficulty excreting potassium, acid and/or calcium loads. Acidosis or hypocalcemia may also occur postransfusion because immature liver metabolizes citrate in banked blood inefficiently. Studies have shown older units do not affect the infant for routine transfusion purposes.

Cause of Hemolytic Disease Maternal IgG antibodies directed against an antigen of paternal origin present on the fetal red blood cells. IgG antibodies cross the placenta to coat fetal antigens, cause decreased red blood cell survival which can result in anemia. Produced in response to previous pregnancy with antigen positive fetus OR exposure to red blood cells, ie transfusion.

Unique Aspects of Neonatal Physiology – 2,3-DPG Tissue oxygenation poor due to high percentage of hemoglobin F. Hemoglobin F does not release oxygen to the tissues like adult hemoglobin. Respiratory distress syndrome (RDS) or septic shock have decreased levels of 2,3-DPG, alkalosis and hypothermia can further increase the oxygen affinity of hemoglobin. 2,3-DPG levels decrease in stored blood, newborns should be given freshest blood available, less than 5 days old if possible. Controversy in the field about the practice of using fresh blood. Greater importance to decrease donor exposures rather than give fresh blood. Allow CPD donor units to be put on hold for infant for 21 days. Exception is for massive transfusion

Cytomegalovirus (CMV) Infection Infection by CMV may occur in the perinatal period, either in-utero or during birth, by breast feeding or by close contact with mothers or nursery personnel. CMV mays also be transmitted by transfusion, virus seems to be associated with leukocytes in blood and components. Infection in newborns is extremely variable in its manifestations, ranging from asymptomatic seroconversion to death. Symptomatic infection may produce pulmonary, hepatic, renal, hematologic and/or neurologic dysfunction.

Cytomegalovirus (CMV) Infection This neonate was found to have respiratory distress, an extensive rash and hepatomegaly. Results of CMV IgM and IgG tests and both serum and plasma DNA polymerase-chain-reaction assays were positive.

Cytomegalovirus (CMV) Infection Epidemiology and prevention of post transfusion CMV in neonatal patients have been under intense investigation. The following observations have been noted: Where CMV rate is high, symptomatic infection is low. Babies of seropositive moms unlikely to develop CMV. Premature infants born of seronegative mothers, weigh less than 1200 grams and require multiple transfusions at risk for symptomatic postransfusion infections. The risk of CMV increases with number of donor exposures. Risk of transmission decreases by using seronegative donors or components depleted of leukocytes.

Cytomegalovirus (CMV) Infection Standards states that in geographic areas where postransfusion CMV transmission is a problem, blood with minimal risk of transmitting CMV be used for: newborns weighing less than 1200 g, born to mothers who lack CMV antibodies or whose antibody status is unknown. Most blood banks make it standard practice to transfuse all infants with CMV negative blood.

Hemolytic Disease of the Fetus and Newborn - HDFN HDFN, red cells of fetus coated with IgG alloantibody of maternal origin, directed against antigen of paternal origin present on fetal cells. IgG coated cells undergo accelerated destruction, both before and after birth. Clinical severity of the disease is extremely variable, ranging from intrauterine death to a condition that can be detected only by serologic tests on blood from an apparently healthy baby.

HDFN - Pathophysiology Shortened RBC survival causes fetal hematopoietic tissue increase production of RBCs, causes increase in nucleated red cells (NRBCs). Organs containing hematopoietic tissue increase in size, particularly liver and spleen (hepatosplenomegaly). If increased hematopoiesis cannot compensate for the immune destruction, anemia becomes progressively more severe.

HDFN - Pathophysiology Severely affected fetus may develop high output cardiac failure with generalized edema, a condition called hydrops fetalis, death may occur in utero. If live-born, severely affected infants exhibit heart failure and profound anemia. Less severely affected infants continue to experience accelerated red cell destruction, which generates large quantities of bilirubin.

HDFN - Pathophysiology In-utero fetal bilirubin processed by maternal liver. After birth neonatal immature liver takes over. Deficient in uridine diphosphoglucoronyl transferase, bilirubin rises. Bilirubin 20mg/dL> results in mental retardation or death, condition known as kernicterus.

Kernicterus Kernicterus (bilirubin encephalopathy) results from high levels of indirect bilirubin (>20 mg/dL in a term infant with HDN). Kernicterus occurs at lower levels of bilirubin in the presence of acidosis, prematurity, hypoalbuminemia and certain drugs (e.g., sulfonamides).

Kernicturus Affected structures have bright yellow color. Unbound unconjugated bilirubin crosses blood-brain barrier and, because it is lipid soluble, penetrates neuronal and glial membranes. Bilirubin is thought to be toxic to nerve cells Mechanism of neurotoxicity and reason for topography of lesions are not known. Patients surviving kernicterus have severe permanent neurologic symptoms (choreoathetosis, spasticity, muscular rigidity, ataxia, deafness, mental retardation).

Three Classifications of HDN ABO “Other” – unexpected immune antibodies other than anti-D – Jk, K, Fy, S, etc. Rh Immune anti-D alone Immune anti-D along with other Rh antibodies – anti-C, -c, -E or –e.

Maternal Immunization Fetal cells possessing paternal antigen mother does not possess enter her circulation and stimulate antibody production. D antigen most immunogenic but other blood group antigens may also immunize. Fetal cells enter maternal circulation during pregnancy. Biggest exposure during birth.

Maternal Immunization Can occur with exposure to <0.1mL Immunization to D correlates with  volume of RBCs entering D neg mom’s circulation.

Maternal Immunizing Events Other than birth can be due to: Amniocentesis Miscarriage Abortion Chorionic villus sampling Cordocentesis Blunt trauma to the abdomen Rupture of an ectopic pregnancy

Maternal Immunization - Transfusion Severe HDFN in D neg women transfused with D pos RBCs and develop anti-D Must give D neg RBC and platelet products to females. If D pos platelets or granulocytes given must give Rh prophylaxis, i.e., RhIg Avoid directed donation from husband to wife

ABO Hemolytic Disease Mother group O, baby A or B Group O individuals have anti-A, -B and –A,B in their plasma, fetal RBCs attacked by 2 antibodies Can occur in any ABO incompatible pregnancy Occurs in only 3%, is severe in only 1%, and <1:1,000 require exchange transfusion. The disease is more common and more severe in African-American infants.

HDFN Other Than ABO If this pregnancy is the immunizing event first baby is not affected or only mildly affected. Primary immune response – IgM During pregnancy IgG may not be produced in sufficient quantity to cause problems. Severity of HDFN in future pregnancies due to “other” immune antibodies variable. If anti-D future pregnancies severely affected.

Prenatal Serologic Tests ABO/D type and antibody screen. If antibody screen positive Identify antibody Determine clinical significance If clinically significant patient history important, previously affected infant. IgM antibodies are not of concern

Prenatal Serologic Tests In primary immune response IgM antibodies may demonstrate high thermal amplitude. Treat serum with 2ME or DTT to determine if IgG is present. Antibody may be present but fetus may be antigen negative. If anti-D test father to determine zygosity of D antigen.

Amniotic Fluid Analysis Assess probable severity of HDFN. Based on history of antibody AND maternal history with previous pregnancies. Monitor antibody titer, perform if rising. Measure bile pigments at 450 nm Level correlates with severity of hemolysis. Result will determine action plan.

Amniotic Fluid Analysis Maternal titer greater than 32 for anti-D and 8 for anti-K OR four fold increase in titer indicates need for analysis of amniotic fluid. Amniocentesis Perform at 28 wks if HDN in previous child Perform at 22 wks if previous child severely affected Perform if maternal antibody increases before 34th wk. High values of bilirubin in amniotic fluid analyses by the Liley method or a hemoglobin concentration of cord blood below 10.0 g/mL. Type fetus -recent development in fetal RhD typing involves the isolation of free fetal DNA in maternal serum. In the United Kingdom, this technique has virtually replaced amniocentesis for fetal RhD determination in the case of a heterozygous paternal phenotype Maternal plasma exchange may be instituted if the fetus is too young for intrauterine transfusion.

Amniocentesis

Amniotic Fluid Analysis Zone 1- unaffected or mildly affected Zone 2 – Deliver at 36-38 weeks based on fetal lung maturity. Zone 3 – Seriously affected, intrauterine transfusion and preterm delivery indicated.

Amniotic Fluid Analysis

Amniotic Fluid Analysis Weigh risks in severely affected pregnancy Respiratory Distress Syndrome (RDS) Due to inadequate surfactant and lecithin Determine fetal lung by L/S ratio and phosphotidylcglycerol (PG) in amniotic fluid. If lungs not mature, intrauterine transfusion.

Amniotic Fluid Analysis and Fetal Blood Sampling Amnio can cause fetomaternal hemorrhage (FMH) If amnio done for other reasons and woman unsensitized D neg, give RhIg D type of fetus is unknown, prevent immunization Cordocentesis – draw blood from umbilical cord for laboratory analysis Use non-invasive procedures when possible.

Intrauterine Transfusion (IUT) Performed after careful evaluation due to high risk to fetus. Given to prevent hydrops fetalis and fetal death. Rarely feasible before 20th week gestation. Once started administer every 2 weeks.

Intrauterine Transfusion (IUT) Blood must be: Less than 5 days old Low risk of CMV (CMV neg or safe) Hematocrit 80% or higher O negative and COMPATIBLE WITH MOM Lack antigens which antibody(ies) are directed. Irradiated 75-175mLs determined by fetal size and age

Intrauterine Transfusion (IUT) After multiple IUTs RBC testing will not be accurate: Will type as O neg as 90% of circulating RBCs will be donor cells. Direct Antiglobulin test will be negative Indirect Antiglobulin Test will be positive. Cord bilirubin not an accurate indicator of rate of hemolysis or of likelihood of need for exchange transfusion after birth.

Intrauterine Transfusion (IUT) Done in the hospital Ultrasound to determine the position of the fetus and placenta. Local anesthetic to numb site. Medicate fetus to stop or slow movement. Ultrasound used to guide needle through abdomen into fetus's abdomen or umbilical cord vein. Peritoneal cavity versus cord vein.

Intrauterine Transfusion (IUT)

Intrauterine Exchange Transfusion Replace fetal blood with donor blood. Use ultrasound to cannulate umbilical vein. Take blood sample H&H and verification of catheter location in the fetal circulation. Small volume donor blood transfused, wait, small volume removed. EXCHANGE fetal blood with donor blood.

Intrauterine Transfusion - Risks Fetal Loss - risk variable depending on condition of fetus, overall 1-2%, range <1% - 50%. Bradycardia - common but usually transient Bleeding - usually transient and mild Preterm Labor

End of Unit 11 Part 1