1. 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

2. 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

3. 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

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

5. 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

6. 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.

7. Sir William Liley ( )
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

8. 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

9. 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.

10. 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

11. 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

12. 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.

13. 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.

14. 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 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.

15. 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.

16. 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.

17. 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

18. 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

19. 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

20. 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 weeks gestation

21. 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

22. 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

23. 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

24. 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

25. Questions?