HEMOLYTIC DISEASE OF NEWBORN
Category: Child Health
Abstract : Hemolytic Disease of Newborn A French midwife was the first to report
hemolytic disease of the newborn (HDN) in a set of twins in 1609. In 1932,
Diamond and colleagues described the relationship of fetal hydrops, jaundice,
anemia, and erythroblasts in the circulation, a condition later called
erythroblastosis fetalis. Levine later determined the cause after Landsteiner
and Weiner disc
Hemolytic Disease of Newborn
A French midwife was the first to report
hemolytic disease of the newborn (HDN) in a set of twins in 1609. In 1932,
Diamond and colleagues described the relationship of fetal hydrops, jaundice,
anemia, and erythroblasts in the circulation, a condition later called
erythroblastosis fetalis. Levine later determined the cause after Landsteiner
and Weiner discovered the Rh blood group system in 1940.
In 1953, Chown
subsequently confirmed the pathogenesis of Rh alloimmunization to be the result
of passage of Rh-positive fetal red blood cells after transplacental hemorrhage
into maternal circulation that lacked this antigen.
Pathophysiology:
Although the Rh antibody was and still is the most common cause of severe HDN,
other alloimmune antibodies belonging to Kell (K and k), Duffy (Fya), Kidd (Jka
and Jkb), and MNSs (M, N, S, and s) systems do cause severe HDN. Rh blood group
antigens are determined by at least 2 homologous but distinct
membrane-associated proteins. Two separate genes located on chromosome 1 encode
Rh proteins. Rh-negative phenotype represents absence of D protein on RBCs and
results from deletion of the RHD gene on both chromosomes. Rh antigens exist in
3 loci: Cc, Dd, and Ee. Expression is limited to RBCs, with an increasing
density during their maturation, unlike the ABH system, which exists in a wide
variety of tissues. Rh antigen is not expressed on RBC progenitors. Of
individuals who are Rh positive, 45% are homozygous and 55% are
heterozygous.
Frequency of Rh negativity is higher in whites (15%) than
in blacks (5%), and it is rare in Asians. The paternal heterozygosity determines
the likelihood of an Rh-positive child being born to an Rh-negative mother. The
Kleihauer-Betke acid elution technique that determines the proportion of fetal
RBCs in maternal circulation has shown the incidence of fetomaternal hemorrhage
to be 75% of all pregnancies. Incidence and degree of such hemorrhage appears to
increase with gestation. Risk is also increased in pregnancies complicated by
placental abruption, spontaneous or therapeutic abortion, and toxemia, as well
as after cesarean delivery and ectopic pregnancy.
Procedures such as
amniocentesis, chorionic villus sampling, and cordocentesis also increase the
risk of alloimmunization. Because in most pregnancies the transplacental
hemorrhage is less than 0.1 mL, most women are sensitized as a result of small
undetectable fetomaternal hemorrhage.
After the initial exposure to a
foreign antigen, the maternal immune system produces antibodies of the
immunoglobulin M (IgM) isotype that do not cross the placenta, and later it
produces antibodies of the IgG isotype that traverse the placental barrier. This
is termed the primary response, and it is dose dependent (documented in 15% of
pregnancies with 1 mL of Rh-positive cells in an Rh-negative individual versus
70% of pregnancies after 250 mL). A repeat exposure to the same antigen rapidly
induces the production of IgG. This secondary immune response can be induced
with as little as 0.03 mL of Rh-positive RBCs.
Risk of Rh immunization
after delivery of the first child to a nulliparous Rh-negative mother is 16% if
the Rh-positive fetus is ABO compatible with its mother, 2% if ABO incompatible,
and 2-5% after an abortion. The ABO-incompatible RBCs are rapidly destroyed in
the maternal circulation, reducing the likelihood of exposure to the immune
system. The degree of Rh sensitization of the mother is directly related to the
amount of fetomaternal hemorrhage (ie, 3% with <0.1 mL versus 22% with
>0.1 mL).
After sensitization, maternal anti-D antibodies cross the
placenta into fetal circulation and attach to Rh antigen on fetal RBCs, which
form rosettes on macrophages in the reticuloendothelial system, especially in
the spleen. These antibody-coated RBCs are lysed by lysosomal enzymes released
by macrophages and natural killer lymphocytes, and they are independent of the
activation of the complement system.
Prolonged hemolysis leads to severe
anemia, which stimulates fetal erythropoiesis in liver, spleen, bone marrow, and
extramedullary sites, such as skin and placenta. In severe cases, this can lead
to displacement and destruction of hepatic parenchyma by erythroid cells,
resulting in dysfunction and hypoproteinemia. Destruction of RBCs releases heme
that is converted to unconjugated bilirubin. Hyperbilirubinemia becomes apparent
only in the delivered newborn because the placenta effectively metabolizes
bilirubin. HDN due to Kell sensitization results in hemolysis and suppression of
erythropoiesis because the Kell antigen is expressed on the surface of erythroid
progenitors.
Hemolysis associated with ABO incompatibility is limited to
type O mothers with fetuses who have type A or B blood. In mothers with type A
and B blood, naturally occurring antibodies are of IgM class, which do not cross
the placenta, whereas in type O mothers, the antibodies are predominantly IgG in
nature. Because A and B antigens are widely expressed in a variety of tissues
besides RBCs, only small portion of antibodies crossing the placenta is
available to bind to fetal RBCs. In addition, fetal RBCs appear to have less
surface expression of A or B antigen, resulting in few reactive sites—hence the
low incidence of significant hemolysis in affected neonates.
Frequency:
In the US: Before the establishment of modern therapy, 1% of all pregnant women
developed Rh alloimmunization. Since the advent of routine prophylaxis of
at-risk women, incidence of Rh sensitization is reduced to 11 cases per 10,000
births with less than 10% requiring intrauterine transfusion. Alloimmunization
due to Kell antigen accounts for 10% of severely affected fetuses. ABO
incompatibility frequently occurs during the first pregnancy and is present in
approximately 12% of pregnancies, with evidence of fetal sensitization in 3% of
live births. Fewer than 1% of births are associated with significant
hemolysis.
Mortality/Morbidity: Nearly 50% of the affected newborns do
not require treatment. Approximately 25% are born near term but become extremely
jaundiced without treatment and either die (90%) or become severely affected by
kernicterus (10%). The remaining 25% of affected newborns are severely affected
in utero and become hydropic; about half of newborns are affected before 34
weeks' gestation, and the other half are affected between 34 weeks' gestation
and term. Before any interventions were available, the perinatal mortality rate
was 50%. Wallerstein introduced exchange transfusion in 1945 and reduced the
perinatal mortality rate to 25%. Later, Chown suggested the early delivery of
those severely affected nonhydropic fetuses by 34 weeks' gestation followed by
prompt exchange transfusion, and the mortality rate was further reduced to the
current rate of 16%.
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