Raina Raquel Flores, M.D. 3/7/14 Hemolytic Disease of the Fetus/Newborn and Intrauterine RBC Transfusion Raina Raquel Flores, M.D. 3/7/14

Outline Brief review: Hemolytic disease of the fetus and newborn (HDFN) Intrauterine RBC transfusion Indications Blood product selection Transfusion technique Volume to transfuse Complications Fetal IVIG Therapy

HDFN Destruction of fetal/newborn RBCs by antibodies (IgG) produced by the mother Maternal antibodies to ABO antigens are most common cause of HDFN (mild) Majority of severe HDFN due to anti-Rh(D) antibodies Anti-c, E, and C antibodies also clinically significant Of the non-Rh system antibodies, anti-Kell is most common cause of HDFN So technically, any IgG antibody could cause HDFN, but only Dramatic decrease in Rh(D) HDFN with advent of RhIG The D antigen is the most antigenic of all RBC antigens Little c, E, and C are immunogenic, but less so than D antigen

Active IgG transport (2nd trimester) Pathogenesis Active IgG transport (2nd trimester)

Pathogenesis Fetal anemia Marrow stimulated to release immature RBCs – erythroblastosis fetalis Fetal RBCs coated in maternal IgG Extravascular hemolysis in spleen High output cardiac failure with ascites, effusions, edema – hydrops fetalis Decreased hepatic plasma protein production Extramedullary hematopoiesis in liver

Hydrops Fetalis Hydrops fetalis is defined as = edema involving at least 2 fetal components This condition used to be universally fatal; with the use of intrauterine transfusions, the survival in cases of hydrops fetalis has improved.

Sir William Liley (1929 - 1983) In 1961, demonstrated that amniotic fluid bilirubin corresponds to degree of fetal anemia → Liley curve Observed improved anemia in sickle cell patients after peritoneal infusion with RBCs In 1963, Liley reports first successful intrauterine transfusion for HDFN “Intrauterine Transfusion of Foetus in Haemolytic Disease” RBCs absorbed through lymphatics RBCs migrate into intravascular space and correct anemia Br Med J 1963;5365:1107e9. 7

Intrauterine RBC Transfusion Gold standard for treatment of severe fetal anemia RBC alloimmunization Anti-D, anti-Kell, and anti-c Parvovirus infection Chronic fetomaternal hemorrhage Inherited RBC disorders Congenital dyserythropoietic anemia, alpha thalassemia Complications after twin-twin transfusion syndrome Anemia seen in the setting of parvovirus infection is due to arrest of maturation of bone marrow precursors

Assessing Fetal Anemia Assessing severity of fetal anemia: Middle cerebral artery-peak systolic velocity (MCA-PSV) Anemic fetus preserves O2 delivery to the brain by increasing cerebral flow Fetal blood sampling 1-2% risk of fetal loss Reserved for cases with increased MCA-PSV Amniotic fluid spectral analysis (Liley curve) Other than observing fetal movements, heart tones, and BPP, we can very accurately assess the severity of fetal anemia MCA-PSV is the gold standard in assessing anemia; it is accurate, sensitive (100%), and non-invasive Fetal blood sampling: blood taken from the cord or the placental disk Study looked at a couple of hundred babies and looked at correlation between the MCA peak systolic velocity and the Hgb in the cord blood Mari et al35 first reported in 1995 that middle cerebral artery peak systolic velocity (MCA-PSV) was increased in anaemic fetuses. In a subsequent study, investigating 111 fetuses at risk of anaemia secondary to rhesus sensitisation, it was possible to predict moderate to severely anaemic fetuses with a sensitivity of 100% for a false-positive rate of 12%.36 In this study they used a cut-off for peak systolic velocity of 1.5.multiples of the median (MoM) for gestational age. In addition, they confirmed that this technique was a strong predictor of moderate-to-severe anaemia irrespective of whether or not hydrops was present. The test did not perform well in the prediction of mild anaemia, but from a clinical perspective this is not a problem because mildly anaemic fetuses do not require in-utero therapy. Also, the false-positive rate of the test increases after 35 weeks gestation. N Engl J Med. 2000;342(1):9.

When to Initiate Intrauterine Transfusion (IUT) Indications: Cordocentesis blood sample with: Hgb < 10 g/dL Hgb level > 7 below the mean for GA Hgb < 2 SD below the mean for GA Hct <30% or < 2 SD below the mean for GA Fetal hydrops noted on ultrasound Amniotic fluid ΔOD 450 nm results in high zone II or zone III Normal fetal hemoglobin concentration increases linearly during pregnancy, from about 10 to 11 at 17 weeks to about 14 to 15 at term, one standard deviation is approximately 1 All of these criteria are used in conjunction with BPP, or decreased fetal movement, etc. Performed at 18 to 35 weeks gestation Some centers have found that it may be wise to intervene sooner because transfusion/outcome is more complicated with fetus is hydropic N Engl J Med. 2000;342(1):9

RBC Product Selection Requirements: Considerations: Type O Rh(D)-, antigen negative, crossmatch compatible CMV seronegative Leukoreduced Irradiated Hemoglobin S negative Fresh (less than 7 days old) Washed and tightly packed Hct 75-85% Considerations: Donor vs. maternal RBCs? Normal fetal hemoglobin concentration increases linearly during pregnancy, from about 10 to 11 at 17 weeks to about 14 to 15 at term, one standard deviation is approximately 1 Performed at 18 to 35 weeks gestation Hct of usual RBC unit that we use in adults has hematocrit of approx 65% Seminars in Fetal & Neonatal Medicine (2007) 12, 432e438

Am J Obstet Gynecol. 1997;177(4):753. Donor vs. Maternal RBCs 25% of mothers undergoing IUT produce additional RBC antibodies due to exposure to antigens on donor blood Use of autologous blood from mother decreases risk of sensitization Donation may be limited by Hgb status of the mother Possible decrease in frequency of IUT in neonates who receive maternal blood Hgb must be above 12.5 g/dL One study performed at Ohio State University looked at the difference in transfusion requirements between neonates receiving maternal blood and neonates receiving donor blood; the difference in the two groups was significant only in late gestation Am J Obstet Gynecol. 1997;177(4):753.

Routes of Administration Intrauterine transfusion Intraperitoneal Intravascular Umbilical cord Intrahepatic umbilical vein Direct cardiac puncture Historically, peritoneal infusion was performed due to limitations in imaging ability; it was easier to target the peritoneum vs. vascular sites NOTE: The various methods and points of access for IUT have not been compared in randomized trials [21]. For this reason, many centers have developed their own preference for a specific methodology.

Intraperitoneal Transfusion Indirect access to fetal circulation RBCs slowly absorbed through diaphragmatic lymphatic system (over 7 to 10 days) Least effective in the hydropic fetus May be preferred if fetal vasculature inaccessible In babies less than 18-20 weeks gestation, the anatomy may be very small and difficult to target if the fetus is less than 18 weeks; or positioning of the baby may complicate the procedure Fetal Diagn Ther. 2008;23(2):159.

Direct Vascular Access Correction of fetal anemia is rapid More effective than IPT in the hydropic fetus Intravascular transfusion (IVT) improves survival two-fold in the hydropic fetus Overall, higher rate of survival with IVT compared to IPT A case control comparison from Canada looked at hydropic and nonhydropic fetuses (macthed for gestational age, severity of anemia, and placental location). This was best illustrated in a study of hydropic and nonhydropic fetuses matched for severity of disease, placental location, and gestational age at the first transfusion that compared outcomes with IPT and IVT Am J Obstet Gynecol. 1991;165(4 Pt 1):1020.

Umbilical Cord Transfusion Preferred method in North America Target: umbilical vein at site of cord insertion into placenta Stable Less fetal bradycardia Cord near the fetus has vagal innervation= if aiming for cord, may cause bradycardia The higher incidence of bradycardia with umbilical artery puncture (21 versus 3 percent) is probably due to spasm of the muscularis [28,29]. The cord proximate to the fetal umbilicus appears to have vagal innervation [30], which might account for the increased the risk of fetal bradycardia. Am J Anat. 1971;132(1):53.

Intrahepatic Umbilical Vein Transfusion Preferred method in Europe Target: intrahepatic portion of the umbilical vein Low incidence of fetal bradycardia Fetal pain → fetal movement → organ trauma Some clinicians may administer a drug to induce fetal paralysis--- Lancet. 1994;344(8915):77. Am J Obstet Gynecol. 2005;192(1):171

Combined Approach IPT followed by IVT IVT followed by IPT If transfusion is required prior to 18-20wks gestation IVT followed by IPT More stable fetal hematocrit between procedures Slow absorption of RBCs from intraperitoneal reservoir Longer interval between procedures → fewer total IUTs One study performed at BCM looked at 20 fetus who underwent a combined total of Fetal Ther. 1989;4(2-3):126

IUT Volume Determination Target Hct depends on gestational age Less than 24 weeks gestation: 1st IUT → Hct ≤ 25% 2nd IUT (48 hours later) → Hct ~ 40% 3rd IUT (7 to 10 days later) → Hct ~ 40% Greater than 24 weeks gestation: Hct 40 to 50% Intraperitoneal transfusion (IPT) volume: Volume to transfuse (ml) = (GA in weeks – 20) x 10 ml Intravascular transfusion volume: Fetoplacental volume (FPV) (ml) = fetal weight (g) x 0.14 Volume to transfuse (ml) = [FPV x (Goal Hct – Initial Hct)] / Donor unit Hct In young fetus (less than 24 weeks old), do not want to correct fetal anemia too quickly = increased blood viscosity leads to increased afterload and increased cardiac output Obstet Gynecol. 1992;79(3):390

Timing of Transfusion in Alloimmunization After 1st IUT, Hct will drop by 1% per day if not hydropic and 1.88% per day if hydropic Fetal erythropoiesis suppressed after 2 to 3 transfusions → lengthened time interval between subsequent procedures Can empirically transfuse. . . 10 days after 1st transfuion 2 weeks after 2nd transfusion 3 weeks after 3rd transfusion Transfusions should continue up to 34-35 weeks gestation

Complications of IUT Most common complication of IPT is infusion in the wrong location For intravascular transfusions Procedure-related (PR) fetal loss = 1 to 2% per procedure Overall risk of PR complications = 3% per procedure Emergency c/s Infection Bleeding from puncture site Premature rupture of membranes Arterial puncture Bradycardia or tachycardia The complications seen in this procedure are a direct consequence of the fact that the fetus is not fully visualized or the baby is really small Cohort study out of the Netherlands that looked at 254 fetus with a combined 740 intravascular transfusions for RBC alloimmunization at one institution from 1988 to 2001 American Journal of Obstetrics and Gynecology (2005) 192, 171e7

Outcomes of IUT Survival: Neurologic: 89% survival after one IUT Survival of hydropic fetus is lower than non hydropic fetus Lower survival if IUT needed at less than 20 weeks Neurologic: Normal neurologic outcome expected in 90% of surviving infants, regardless of hydropic status at time of 1st IUT Hydropic fetus more likely to severe developmental delay or cerebral palsy This percentage varies with the severity of disease, age of gestation, experience of the physician, etc The LOTUS study is the largest study to assess the incidence and risk factors for neurodevelopmental impairment in children with hemolytic disease of the treated with IUT [83]. Alloimmunization was related to Rh(D) in 80 percent of cases, 26 percent of the fetuses were hydropic, the mean gestational age at first transfusion was 26 weeks, the mean number of transfusion was 3, and all of the pregnancies were delivered between 35 and 37 weeks of gestation. Major findings at follow-up at median age 8.2 years (range 2 to 17 years): looked at cerebral palsy, severe neurologic deficit, severe developmental delay + CP, deafness, blindness Obstet Gynecol. 1996;88(1):137 Am J Obstet Gynecol. 2012;206(2):141.e1

IVIG Therapy In Rh(D) and ABO HDFN babies, postnatal IVIG reduces need for exchange transfusion for hyperbilirubinemia IVIG may block antibody receptors on RBCs Maternal IVIG administration during pregnancy for management of alloimmune HDFN Expensive Questionable efficacy This findings is supported by two studies Mechanism is unknown Indication: increasing Tbili despite phototherapy Maternal IVIG is expensive- product expensive, mom needs to be frequently injected, no guarantees of how much is actually getting to fetus Arch Dis Child Fetal Neonatal Ed. 2003;88(1):F6

Direct Fetal Immunoglobulin Administration?? “Fetal Intravenous Immunoglobulin Therapy in Rhesus Hemolytic Disease” 4 cases of severe Rh(D) HDFN treated with fetal IVIG Decreased frequency of IUT and eliminated need for postnatal transfusion “Fetal intraperitoneal injection of immunoglobulin diminishes alloimmune hemolysis” Case of anti-M HDFN successfully managed with 4 IG treatments (2 g per-kg fetal body weight) Healthy baby delivered at 38 weeks without IUT, exchange transfusion, or phototherapy J Perinatol. Apr 2011; 31(4): 289–292. Gynecol Obstet Invest 2007;63:176–180

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