Page 883 - Williams Hematology ( PDFDrive )

858 Part VI: The Erythrocyte Chapter 55: Alloimmune Hemolytic Disease of the Fetus and Newborn 859

for HDN as way to prevent the need for exchange transfusions. The neurodevelopmental impairment in children with HDFN treated with
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decreased bilirubin levels in infants treated with IVIG is attributed to IUT. The overall incidence of neurodevelopmental impairment was 4.8
reduction in hemolysis secondary to blockade of mononuclear phago- percent with severe developmental delay seen in 3.1 percent of children.
cyte Fc receptors. A Cochrane meta-analysis of the three largest studies Cerebral palsy was detected in 2.1 percent and bilateral deafness in
demonstrated that IVIG administration (0.5 to 1.0 g/kg) may prevent 1 percent of the children. Severe hydrops was identified as a strong
exchange transfusion for many term infants with HDN, which contrib- predictor for neurodevelopmental impairment. 125
uted to an AAP published recommendation that IVIG be considered in It is estimated that kernicterus, secondary to bilirubin encephal-
Rh HDN when TSB continues to rise despite aggressive phototherapy or opathy, is associated with at least 10 percent mortality and 70 percent
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126
when the TSB is within 2 to 3 mg/dL of the exchange level. However, long-term morbidity. Although the preponderance of kernicterus
a prospective randomized control trial showed that prophylactic IVIG cases occur in infants with bilirubin levels higher than 20 mg/dL, it has
(0.75 g/kg) did not decrease the duration of phototherapy, maximum been shown that when treated promptly with phototherapy or exchange
bilirubin levels, need for RBC transfusion or for exchange transfusion transfusion, peak bilirubin levels in the range of 25.0 and 29.9 mg/dL
in Rh HDN. Although, the majority of the infants included in this were not associated with adverse neurodevelopmental outcomes in
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study were treated with IUT, IVIG was not effective at reducing the term or near-term infants. 126,127 However, there was an adverse associa-
need for exchange transfusion in either the group treated with IUTs or tion with IQ among infants with a positive DAT and a TSB level equal
those who were not. Thus, there is no universal approach to the use of to or greater than 25 mg/dL, supporting the AAP recommendations to
IVIG in patients with HDN; it seems justified as a temporizing measure initiate treatment at lower bilirubin levels for jaundiced infants if they
to exchange transfusion in neonates with severe HDN unmodified by have a positive DAT. 27,110,127
IUT or neonates with HDN where a previous sibling had suffered from
severe disease requiring exchange transfusion. 109
Recombinant human erythropoietin (rHuEPO) given subcu- PREVENTION
taneously at a dose of 200 to 400 U/kg given three times weekly for Transfusion of blood phenotypically matched for D and for Kell anti-
2 weeks is sometimes administered to infants in an effort to reduce or gens has been advocated for all premenopausal women to prevent pri-
prevent transfusion for late-onset anemia from HDN. Some studies mary RBC alloimmunization. RhIg prophylaxis is very effective when
7,13
show its use to decrease the need for postnatal transfusions in infants administered to women exposed to RhD-positive RBCs either from
with late hyporegenerative anemia of Rh HDN and in neonates with Kell pregnancy or from transfusion; however, once alloimmunization has
HDN. 21,121,122 In one study of 103 patients with Rh HDN, administration occurred, RhIg is not effective for preventing or reducing the severity of
of 200 U/kg of rHuEPO, three times per week for 6 weeks, reduced the HDFN. Unlike RhD, there are no commercially available immune glob-
number of RBC transfusions to a mean of 1.5, and 55 percent of patients ulin products for prevention of alloimmunization to minor RBC anti-
121
did not require any transfusions. rHuEPO is more effective in decreas- gens (including non-D Rh antigens). If a nonpregnant woman is found
ing future transfusion needs in neonates that never received IUTs sug- to have a RBC alloantibody, counseling should be provided regarding
gesting that IUTs may decrease the neonatal response to rHuEPO. the potential effects of the antibody on future pregnancies. Interventions
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Despite encouraging reports in relatively small numbers of neonates, it which can be applied but are seldom offered to prevent HDFN in high
remains unclear whether rHuEPO, or the longer-acting analogue dar- risk maternal-paternal pairs include: artificial insemination with sperm
bepoetin, offer a distinct clinical benefit in regard to decreasing donor from an antigen-negative donor; pre-implantation genetic diagnosis
exposures or improvement of morbidity and/or mortality in this popu- selecting for antigen-negative embryos; and surrogate pregnancy. 128
lation. rHuEPO has been shown to lessen neurologic sequelae in term
infants with hypoxic ischemic encephalopathy, therefore it may have a
role as a potential treatment for perinatal brain injury in the future. 124 Rh IMMUNOGLOBULIN
Use of RhIg is the standard of care for the prevention of maternal D
OUTCOME immunization. Postpartum administration of RhIg to all nonsensitized
Rh-negative women who deliver an Rh-positive infant decreases the
Perinatal survival rates greater than 90 percent have been achieved with incidence of Rh isoimmunization from 12 percent to approximately 2
IUT in nonhydropic fetuses with severe HDFN. 98,105 The overall survival percent. Further reduction in the incidence of Rh-isoimmunization (to
rate for hydropic fetuses is lower (78 to 89 percent) despite IUTs. 105,107 0.1 percent) has been achieved by antepartum RhIg prophylaxis at 28
An 11-year study (from 1988 to 1999) which examined 80 fetuses with weeks’ gestation. This is the current standard recommendation in the
immune-mediated hydrops reported a survival rate for fetuses with United States. In the United Kingdom, routine antenatal anti-D pro-
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mild hydrops of 98 percent, and an intrauterine reversal of hydrops phylaxis can be given as two doses of anti-D immunoglobulin of 500
in 88 percent of the fetuses. The outcome in severe fetal hydrops was IU (one at 28 weeks’ and one at 34 weeks’ gestation), as two doses of
poor, with reversal of hydrops in 39 percent of cases, and a survival rate anti-D immunoglobulin of 1000 to 1650 IU (one at 28 weeks’ and one
of 26 percent for fetuses with persistent hydrops. This study under- at 34 weeks’ gestation), or as a single dose of 1500 IU at 28 weeks’ ges-
105
scores the importance of early diagnosis and treatment of fetal anemia, tation. Although the efficacy of RhIg is clear, its mechanism of action
130
before hydrops develops. Implementation of a nationwide first trimester is not. Some of the proposed mechanisms are accelerated clearance and
screening program for red cell antibodies in the Netherlands in 1998 destruction of D-positive red cells from the circulation, antibody-medi-
was associated with increased referrals for suspected fetal anemia, more ated immune suppression, and the production of immunomodulatory
timely referrals and an increase in perinatal survival in Kell HDFN from cytokines. 51
61 to 100 percent. 59 RhIg is prepared from plasma pools of screened, sensitized human
The neurodevelopmental outcome for infants saved by IUTs has donors; the plasma is tested using polymerase chain reaction (PCR) and
generally been good, with almost 90 percent of survivors being free of serologic methods for all known transfusion transmitted organisms.
disability, even when they have been profoundly anemic in utero. 25,107 Several steps are taken to further inactivate potential infectious organ-
The LOTUS study evaluated 291 children at a median age of 8.2 years isms, including solvent-detergent treatment, ion exchange chromatog-
(range: 2 to 17 years) to determine the incidence and risk factors for raphy, and nanofiltration. There are at least four formulations of RhIg,

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