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Hemolytic disease of the newborn

Hemolytic disease of the newborn (HDN) used to be a major cause of fetal loss and death
among newborn babies. The frst description of HDN is thought to be in !"# by a $rench
midwife who deli%ered twins&one baby was swollen and died soon after birth' the other
baby de%eloped jaundice and died se%eral days later. $or the ne(t )"" years' many
similar cases were described in which newborns failed to sur%i%e.
*t was not until the #+"s that the underlying cause of HDN was clarifed, namely' the
newborn-s red blood cells (./0s) are being attac1ed by antibodies from the mother. The
attac1 begins while the baby is still in the womb and is caused by an incompatibility
between the mother-s and baby-s blood.
/y the #!"s' trials in the 2nited 3tates and the 2nited 4ingdom tested the use of
therapeutic antibodies that could remo%e the antibodies that cause HDN from the
mother-s circulation. The trials showed that gi%ing therapeutic antibodies to women
during their pregnancy largely pre%ented HDN from de%eloping (). /y the #5"s' routine
antenatal care included screening of all e(pectant mothers to fnd those whose
pregnancy may be at ris1 of HDN' and gi%ing pre%entati%e treatment accordingly. This
has led to a dramatic decrease in the incidence of HDN' particularly se%ere cases that
were responsible for stillbirth and neonatal death.
This chapter will discuss the causes of HDN and how the disease can be treated or
minimi6ed' if not pre%ented entirely.
Maternal antibodies cross the placenta and attack
fetal red blood cells
During pregnancy' some of the mother-s antibodies are transported across the placenta
and enter the fetal circulation. This is necessary because by the time of birth' newborns
ha%e only a primiti%e immune system' and the continuing presence of maternal
antibodies helps ensure that they sur%i%e while their immune system matures. 7
downside to this protection is that by targeting fetal ./0s' maternal antibodies can also
cause HDN.
7 major cause of HDN is an incompatibility of the .h blood group between the mother
and fetus. 8ost commonly' hemolytic disease is triggered by the D antigen' although
other .h antigens' such as c' 0' 9' and e' can also cause problems.
:regnancies at ris1 of HND are those in which an .h D;negati%e mother becomes
pregnant with an .hD;positi%e child (the child ha%ing inherited the D antigen from the
father). The mother-s immune response to the fetal D antigen is to form antibodies
against it (anti;D). These antibodies are usually of the *g< type' the type that is
transported across the placenta and hence deli%ered to the fetal circulation.
HDN can also be caused by an incompatibility of the 7/= blood group. *t arises when a
mother with blood type = becomes pregnant with a fetus with a di>erent blood type
(type 7' /' or 7/). The mother-s serum contains naturally occurring anti;7 and anti;/'
which tend to be of the *g< class and can therefore cross the placenta and hemolyse
fetal ./0s.
HDN due to 7/= incompatibility is usually less se%ere than .h incompatibility. =ne
reason is that fetal ./0s e(press less of the 7/= blood group antigens compared with
adult le%els. *n addition' in contrast to the .h antigens' the 7/= blood group antigens are
e(pressed by a %ariety of fetal (and adult) tissues' reducing the chances of anti;7 and
anti;/ binding their target antigens on the fetal ./0s.
?ess common causes of HDN include antibodies directed against antigens of the 4ell
blood group (e.g.' anti;4 and anti;1)' 4idd blood group (e.g.' anti;@1a and anti;@1b)' Du>y
blood group (e.g.' anti;$ya)' and 8N3 and s blood group antibodies. To date' antibodies
directed against the : and ?ewis blood groups ha%e not been associated with HDN.
Sensitization occurs during the frst pregnancy
3ensiti6ation to an antigen occurs when the immune system encounters an antigen for
the frst time and mounts an immune response. *n the case of HDN caused by .h
incompatibility' an .h D;negati%e mother may frst encounter the D antigen while being
pregnant with an .h D;positi%e child' or by recei%ing a blood transfusion of .h D;positi%e
blood. =nce a mother has been sensiti6ed to the D antigen' her serum will contain anti;
D. The direct 0oombs test (see below) confrms the presence of anti;D and hence that
the mother has been sensiti6ed.
=nly a small amount of fetal blood need enter the mother-s circulation for sensiti6ation to
occur. Typically' this occurs during the deli%ery of the frst;born .h D;positi%e child. $etal;
maternal hemorrhage is common during labor and is increased during a prolonged or
complicated labor' which in turn increases the ris1 of sensiti6ation. 3ensiti6ation can also
occur earlier in the pregnancy' for e(ample during a prenatal bleed or a miscarriage. *t
may also occur during medical procedures' such as a termination of pregnancy or
chorionic %illus sampling.
The ris1 of sensiti6ation to the .h D antigen is decreased if the fetus is 7/=
incompatible. This is because any fetal cells that lea1 into the maternal circulation are
rapidly destroyed by potent maternal anti;7 andAor anti;/' reducing the li1elihood of
maternal e(posure to the D antigen.
HDN occurs in subsequent pregnancies
*nitially' the maternal anti;D that is formed at the time of sensiti6ation is of the *g8 type'
which can not cross the placenta. *n subseBuent pregnancies' a repeat encounter with
the .h D antigen stimulates the rapid production of type *g< anti;D' which can be
transported across the placenta and enter the fetal circulation. =nce in the fetal
circulation' anti;D attaches to the .h D antigens found on the fetal ./0s' mar1ing them
to be destroyed.
The rate of hemolysis determines whether the nature of HDN is mild' moderate' or
se%ere. *n mild cases' the small increase in the rate of hemolysis is tolerated by the
fetus. 7t birth and during the newborn period' symptoms include a mild anemia and
jaundice' both of which may resol%e without treatment.
*n cases where there is a greater increase in the rate of hemolysis' the le%el of bilirubin
may still remain low during the pregnancy because of the ability of the placenta to
remo%e bilirubin from the fetal circulation. Howe%er' after birth the neonate-s immature
li%er is unable to metaboli6e the increased amount of bilirubin that instead accumulates
in his or her blood. Cithin D4 hours of birth' the le%el of bilirubin may rise dramatically. *f
le%els continue to rise' bilirubin may enter the brain to cause 1ernicterus' a potentially
fatal condition that lea%es permanent neurological damage in the babies that sur%i%e.
7n e%en greater rapid and prolonged destruction of ./0s leads to se%ere anemia in the
fetus. The li%er' spleen' and other organs increase their production of ./0s to
compensate for their loss. The dri%e to produce ./0s causes the li%er and spleen to
increase in si6e (hepatosplenomegaly)' and li%er dysfunction can occur. *mmature ./0s
(erythroblasts) spill into the circulation' gi%ing rise to the alternati%e name of this
disease' erythroblastosis fetalis. 7 complication of se%ere HDN is hydrops fetalis' in which
the fetal tissues become swollen (edematous). This condition is usually fatal' either in
utero or soon after birth.
The oombs test detects !h incompatibility between
mother and fetus
To detect HDN' the presence of maternal anti;.h *g< must be identifed. In vivo' these
antibodies destroy .h D;positi%e fetal ./0s' but in vitro' they do not lyse cells or e%en
cause agglutination' ma1ing them diEcult to identify. Therefore' the 0oombs test is used.
This test uses antibodies that bind to anti;D antibodies. The test is named for .obin
0oombs' who frst de%eloped the techniBue of using antibodies that are targeted against
other antibodies.
Direct oombs test" diagnoses HDN
The direct 0oombs test detects maternal anti;D antibodies that ha%e already bound to
fetal ./0s.
$irst' a sample of fetal ./0s is washed to remo%e any unbound antibody (*g). Chen the
test antibodies (anti;*g) are added' they agglutinate any fetal ./0s to which maternal
antibodies are already bound.
This is called the direct 0oombs test because the anti;*g binds FdirectlyF to the maternal
anti;D *g that coats fetal ./0s in HDN.
#ndirect oombs test" used in the pre$ention of HDN
The indirect 0oombs test fnds anti;D antibodies in the mother-s serum. *f these were to
come into contact with fetal ./0s they would hemolyse them and hence cause HDN. /y
fnding maternal anti;D before fetal ./0s ha%e been attac1ed' treatment can be gi%en to
pre%ent or limit the se%erity of HDN.
$or this test' the mother-s serum is incubated with .h D;positi%e ./0s. *f any anti;D is
present in the mother-s serum' they will bind to the cells. The cells are then washed to
remo%e all free antibodies. Chen anti;*g antibodies are added' they will agglutinate any
./0s to which maternal antibodies are bound.
This is called the indirect 0oombs test because the anti;*g fnds FindirectF e%idence of
harmful maternal antibodies' reBuiring the addition of fetal ./0s to show the capacity of
maternal anti;D to bind to fetal ./0s.
:re%enting HDN
Determine .h status of the mother
7s part of routine prenatal or antenatal care' the blood type of the mother (7/= and .h) is
determined by a blood test. 7 test for the presence of atypical antibodies in the mother-s serum
is also performed. 7t present' .h D incompatibility is the only cause of HDN for which screening
is routine.
*n the 2nited 3tates' the freBuency of .h D;negati%e status %aries from about 5G in 0aucasians
to about 5G in Hispanics and /lac1s. The freBuency is much lower in people of 7sian descent
(including people from 0hina' *ndia' and @apan)' a%eraging about DG (D).
*f the mother is not sensiti6ed' reduce the ris1 of future
To fnd out whether a pregnant .h D;negati%e mother has been sensiti6ed to the .h D antigen'
an indirect 0oombs test is done (see abo%e). *f anti;D is not found in the mother-s serum' it is
li1ely that she has not been sensiti6ed to the .h D antigen.
The ris1 of future sensiti6ation can be greatly reduced by gi%ing all unsensiti6ed mothers anti;D
*g' which Fmops upF any fetal ./0s that may ha%e lea1ed into the maternal circulation' reducing
the ris1 of frst;time e(posure to the D antigen.
2sually' .h D;negati%e mothers recei%e on injection of anti;D *g at about DH wee1s gestation'
which is about the time when fetal ./0s start to e(press the D antigen' and mothers recei%e
another dose at about )4 wee1s' a few wee1s before labor begins during which the ris1 of
fetomaternal hemorrhage is high. 7 fnal dose of anti;D *g is gi%en after the baby has been
deli%ered. *n addition' anti;D *g is gi%en to co%er other e%ents during the pregnancy that may
lead to sensiti6ation' e.g.' antepartum bleeds and pre;eclampsia.
This prophyla(is regime against .h D sensiti6ation is e>ecti%e. Howe%er' currently' there is no
routine prophyla(is for HDN caused by incompatibility of other blood group antigens.
*f the mother is sensiti6ed' determine whether the fetus is at
ris1 and monitor accordingly
=nce the presence of maternal anti;D has been confrmed' the ne(t step is to determine whether
the fetal ./0s are a target' i.e.' confrm the .h status of the fetus. *f the father is homo6ygous for
the D allele (DAD)' the fetus will be D positi%e. *f howe%er the father is hetero6ygous (DAd)' there
is a +"I+" chance that the fetus is D positi%e' and the only way to 1now the blood type for sure is
to test a sample of fetal cells ta1en from the amniotic Juid or umbilical cord.
*f the fetus is .h D;positi%e' the pregnancy is carefully monitored for signs of HDN. 8onitoring
includes regular ultrasound scans of the fetus and monitoring of the amount of anti;D in the
mother-s serum. 7cti%e hemolysis is indicated by a rise in anti;D. *f a fetal blood test confrms
fetal anemia' depending upon its se%erity' a blood transfusion can be done in utero to replace
the lysed fetal ./0s.
/lood transfusions may also be needed to correct anemia in the newborn period. During this
period there may also be a sharp rise in the le%el of bilirubin in the neonate' which can be
lowered by phototherapy and e(change transfusions.