ArticlePDF Available

Abstract and Figures

Haemolytic disease of the newborn (HDN) is a condition in which the lifespan of the fetal/neonatal red cells is shortened due to maternal alloantibodies against red cell antigens inherited from the father. Maternal IgG can cross the placenta, thus IgG red cell alloantibodies can gain access to the fetus. If the fetal red cells contain the corresponding antigen then binding of antibody to red cells will occur. When the antibody is of clinical significance (e.g. anti-D, -c, -E, -K, -Jka), and of sufficient potency, the coated cells will be prematurely removed by the fetal mononuclear phagocytic system. The effects on the fetus/newborn infant may vary according to the characteristics of the maternal alloantibody. The antibodies giving rise to HDN most commonly belong to the Rh or ABO blood group systems. The morbidity of Rh HDN is explained by the great immunogenicity of the D antigen; HDN due to anti-c is also important and its incidence comes second amongst the cases of severe HDN closely followed by the non-Rh antibody, anti-K. (The anaemia caused by anti-K is more properly called alloimmune anaemia of the fetus and newborn as it is due to direct inhibition of erythropoiesis by the antibody and haemolysis is not a feature.) Antibodies against antigens in almost all the blood group systems (e.g. Duffy, Kidd, etc.) and against the so-called ‘public’ and ‘private’ antigens, have also been responsible for HDN. However, IgM cannot cross the placenta and Lewis and P1 antibodies, which occur frequently during pregnancy, are usually IgM and do not lead to HDN. Furthermore, the Lewis antigens are not fully developed at birth. Key words: Haemolytic disease of the newborn, Epidemiology, History
No caption available
Content may be subject to copyright.
Inter. J. of Pharmacotherapy / 5(1), 2015, XX-XX.
Obeagu Emmanuel Ifeanyi
Diagnostic Laboratory Unit, University Health Services, Michael Okpara University of Agriculture,
Umudike, Abia State, Nigeria.
Although the Rh antibody was and still is the
most common cause of severe hemolytic disease of the
newborn, 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 hemolytic
disease of the newborn [1].
Frequency of Rh negativity is higher in whites
(15%) than in blacks (5%) and Hispanics (8%) and is rare
in Eskimos, Native Americans, Japanese and Asians,
especially in Chinese individuals. The paternal
heterozygosity determines the likelihood of an Rh-
positive child being born to an Rh-negative mother.
Pathophysiology The exposure of the Rh-
negative mother to Rh-positive red cells occurs as a result
of asymptomatic fetomaternal hemorrhage during
pregnancy. 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. Fetomaternal hemorrhage has been documented
in 7%, 16%, and 29% of mothers during their first, second
and third trimesters, respectively. 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 the transplacental
hemorrhage is less than 0.1 mL in most pregnancies, most
women are sensitized as a result of small, undetectable
fetomaternal hemorrhage.
Corresponding Author:- Obeagu Emmanuel Ifeanyi E mail:
International Journal of Pharmacotherapy ISSN 2249 - 7765
Print ISSN 2249 - 7773
Haemolytic disease of the newborn (HDN) is a condition in which the lifespan of the fetal/neonatal red cells is
shortened due to maternal alloantibodies against red cell antigens inherited from the father. Maternal IgG can cross the
placenta, thus IgG red cell alloantibodies can gain access to the fetus. If the fetal red cells contain the corresponding
antigen then binding of antibody to red cells will occur. When the antibody is of clinical significance (e.g. anti-D, -c, -E, -
K, -Jka), and of sufficient potency, the coated cells will be prematurely removed by the fetal mononuclear phagocytic
system. The effects on the fetus/newborn infant may vary according to the characteristics of the maternal alloantibody.
The antibodies giving rise to HDN most commonly belong to the Rh or ABO blood group systems. The morbidity of Rh
HDN is explained by the great immunogenicity of the D antigen; HDN due to anti-c is also important and its incidence
comes second amongst the cases of severe HDN closely followed by the non-Rh antibody, anti-K. (The anaemia caused
by anti-K is more properly called alloimmune anaemia of the fetus and newborn as it is due to direct inhibition of
erythropoiesis by the antibody and haemolysis is not a feature.) Antibodies against antigens in almost all the blood group
systems (e.g. Duffy, Kidd, etc.) and against the so-called ‘public’ and ‘private’ antigens, have also been responsible for
HDN. However, IgM cannot cross the placenta and Lewis and P1 antibodies, which occur frequently during pregnancy,
are usually IgM and do not lead to HDN. Furthermore, the Lewis antigens are not fully developed at birth
Key words: Haemolytic disease of the newborn, Epidemiology, History.
Inter. J. of Pharmacotherapy / 5(1), 2015, XX-XX.
After the initial exposure to a foreign antigen, B-
lymphocyte clones that recognize the RBC antigen are
established. The maternal immune system initially
produces antibodies of the immunoglobulin M (IgM)
isotype that do not cross the placenta and later produces
antibodies of the IgG isotype that traverse the placental
barrier. Predominant antibody subclass appears to be
IgG1 in one third of individuals whereas a combination of
IgG1 and IgG3 subclasses are found in the remaining
IgG3 is more efficient in binding to
reticuloendothelial cells and causing hemolysis because of
its longer hinge region. This is termed the primary
response and is dose dependent (documented in 15% of
pregnancies with 1 mL of Rh-positive cells in an Rh-
negative individual compared with 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.
The risk of Rh immunization after the 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 the fetus is 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 compared with 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 are independent of the activation
of the complement system.
Reticulocytosis is noted when fetal Hb deficit
exceeds 2 gm/dl compared with gestational age norms.
Tissue hypoxia develops as fetal anemia becomes severe.
When the hemoglobin (Hb) level drops below 8 g/dL, a
rise in umbilical arterial lactate occurs. When the Hb level
drops below 4g/dL, increased venous lactate is noted.
Hydrops fetalis occurs when fetal Hb deficit exceeds 7
g/dL and starts as fetal ascites and evolves into pleural
effusions and generalized edema. The various
mechanisms responsible for hydrops are
hypoalbuminemia secondary to depressed liver function,
increased capillary permeability, iron overload secondary
to hemolysis, and increased venous pressures due to poor
cardiac function [2].
Prolonged hemolysis leads to severe anemia,
which stimulates fetal erythropoiesis in the liver, spleen,
bone marrow, and extramedullary sites, such as the 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. Hemolytic disease of the newborn
due to Kell sensitization results in hemolysis and
suppression of erythropoiesis because the Kell antigen is
expressed on the surface of erythroid progenitors. This
leads to severe fetal disease at a lower maternal antibody
titer than in Rhesus disease.
Hemolysis associated with ABO incompatibility
exclusively occurs in type-O mothers with fetuses who
have type A or type B blood, although it has rarely been
documented in type-A mothers with type-B infants with a
high titer of anti-B IgG. In mothers with type A or type B,
naturally occurring antibodies are of the IgM class and do
not cross the placenta, whereas 1% of type-O mothers
have a high titer of the antibodies of IgG class against
both A and B. They cross the placenta and cause
hemolysis in fetus.
Hemolysis due to anti-A is more common than
hemolysis due to anti-B, and affected neonates usually
have positive direct Coombs test results. However,
hemolysis due to anti-B IgG can be severe and can lead to
exchange transfusion. Because A and B antigens are
widely expressed in various tissues besides RBCs, only a
small portion of antibodies crossing the placenta are
available to bind to fetal RBCs. Recent analysis of IgG
subclass in ABO incompatible direct coombs positive
neonates showed IgG2 was predominent antibody which
is poorly transferred across placenta and less efficient in
causing hemolysis while IgG1 was noted in 22% of
neonates and as a group had similar rate of hemolysis and
severity of hyperbilirubinemia [3].
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. This results in
hyperbilirubinemia as a predominant manifestation of
incompatibility (rather than anemia), and peripheral blood
film frequently reveals a large number of spherocytes and
few erythroblasts, unlike what is seen in Rh
incompatibility (erythroblastosis fetalis), in which blood
film reveals a large number of nucleated RBCs and few
spherocytes [4].
Frequency: United States
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 has declined from 45 cases
Inter. J. of Pharmacotherapy / 5(1), 2015, XX-XX.
per 10,000 births to 10.2 cases per 10,000 total births,
with less than 10% requiring intrauterine transfusion.
Alloimmunization due to Kell antigen accounts for 10%
of severely affected fetuses. The most recent data from
review of 2001 birth certificates in the United States by
the Centers for Disease Control and Prevention (CDC)
indicates that Rh sensitization affects 6.7 newborns per
1000 live births [5].
Currently, anti-D is still one of the most common
antibodies found in pregnant women, followed by anti-K,
anti-c, and anti-E. Of those fetuses who require
intrauterine transfusions, 85%, 10%, and 3.5% were due
to anti-D, anti-K, and anti-c, respectively [6]. 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. Less than 1% of births are associated with
significant hemolysis.
Almost 50 different red cell surface antigens
have been found to be responsible for hemolytic disease
of fetus and newborn. Only 3 antibodies are associated
with severe fetal disease: anti-RhD, anti-Rhc, and anti-
Kell (K1). Nearly 50% of the affected newborns do not
require treatment, have mild anemia and
hyperbilirubinemia at birth, and survive and develop
normally. 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 [7].
Exchange Transfusion
A study by Smits-Wintjens et al indicated that
exchange transfusion in neonates increases the risk of
sepsis, severe thrombocytopenia, leukocytopenia,
hypernatremia, and hypocalcemia in neonates with
hemolytic disease of the newborn (HDN) [8].
Race Incompatibility involving Rh antigens (anti-D or
anti-c) occurs in about 10% of all pregnancies among
whites and blacks; in contrast, it is very rare in Asian
Sex Fetal sex plays a significant role in the degree of
response to maternal antibodies. An apparent 13-fold
increase is observed in fetal hydrops in RhD-positive
male fetuses compared with female fetuses in similarly
sensitized pregnancies [9].
History Two usual patterns of Rh isoimmunization
severity are noted. The disease may remain at the same
degree of severity or may become progressively worst
with each pregnancy. A history of hydropic birth
increases the risk of fetal hydrops in the next pregnancy to
90%; the fetal hydrops occurs at about the same time or
earlier in gestation in the subsequent pregnancy. Women
at risk for alloimmunization should undergo an indirect
Coombs test and antibody titers at their first prenatal visit.
If results are positive, obtain a paternal blood type and
genotype with serologic testing for other Rh antigens (C,
c, E, e). Obtaining serial maternal titers is suggested if
the father is homozygous. If the father is heterozygous,
determine fetal Rh genotype using PCR for the RHD gene
on fetal cells obtained at amniocentesis [10] or on cell-
free DNA in maternal circulation [11]. The sensitivity and
specificity of PCR typing on amniotic fluid is 98.7% and
100%, respectively. However, obtaining maternal blood
to rule out a maternal RHD pseudogene (in a Rh-positive
fetus) and obtaining paternal blood to rule out RHD gene
locus rearrangement (in a Rh-negative fetus) is important
to improve the accuracy. Determining fetal Rh genotype is
also possible by performing cordocentesis, which is also
called fetal blood sampling (FBS). FBS is associated with
a more than 4-fold increase in perinatal loss compared
with amniocentesis.
Indicators for severe hemolytic disease of the
newborn (HDN) include mothers who have had previous
children with hemolytic disease, rising maternal antibody
titers, rising amniotic fluid bilirubin concentration, and
ultrasonographic evidence of fetal hydrops (eg, ascites,
edema, pleural and pericardial effusions, decreasing
hemoglobin [Hb] levels).
An infant born to an alloimmunized mother
shows clinical signs based on the severity of the disease.
The typical diagnostic findings are jaundice, pallor,
hepatosplenomegaly, and fetal hydrops in severe cases.
The jaundice typically manifests at birth or in the first 24
hours after birth with rapidly rising unconjugated
bilirubin level. Occasionally, conjugated
hyperbilirubinemia is present because of placental or
hepatic dysfunction in those infants with severe hemolytic
disease. Anemia is most often due to destruction of
antibody-coated RBCs by the reticuloendothelial system,
and, in some infants, anemia is due to intravascular
destruction. The suppression of erythropoiesis by
intravascular transfusion (IVT) of adult Hb to an anemic
fetus can also cause anemia. Extramedullary
hematopoiesis can lead to hepatosplenomegaly, portal
hypertension, and ascites.
Inter. J. of Pharmacotherapy / 5(1), 2015, XX-XX.
Anemia is not the only cause of hydrops.
Excessive hepatic extramedullary hematopoiesis causes
portal and umbilical venous obstruction and diminished
placental perfusion because of edema. Increased placental
weight and edema of chorionic villi interfere with
placental transport. Fetal hydrops results from fetal
hypoxia, anemia, congestive cardiac failure, and
hypoproteinemia secondary to hepatic dysfunction.
Commonly, hydrops is not observed until the Hb level
drops below approximately 4 g/dL (Hct < 15%) .
Clinically significant jaundice occurs in as many as 20%
of ABO-incompatible infants.
Causes In the absence of a positive direct Coombs test
result, other causes of pathologic jaundice svhould be
considered, including intrauterine congenital infections;
erythrocyte membrane defects (eg, hereditary
spherocytosis, hereditary elliptocytosis, hereditary
pyropoikilocytosis); RBC enzyme deficiencies (eg,
glucose-6-phosphate dehydrogenase [G6PD] deficiency,
pyruvate kinase deficiency, triosephosphate isomerase
deficiency); and nonhemolytic causes (eg, enclosed
hemorrhages, hypothyroidism, GI obstruction, and
metabolic diseases).
Similarly, hydrops can occur from nonimmune
hematologic disorders that cause anemia, such as
hemoglobinopathies (eg, α-thalassemia major), cardiac
failure due to dysrhythmia, congenital heart defects, and
infections (eg, syphilis, cytomegalovirus [CMV],
Common causes of hemolytic disease of the newborn
o Rh system antibodies
o ABO system antibodies
Uncommon causes - Kell system antibodies
Rare causes
o Duffy system antibodies
o MNS and s system antibodies
No occurrence in hemolytic disease of the newborn
o Lewis system antibodies
o P system antibodies
Differential Diagnoses
Anemia, Acute
Atrial Flutter
Cardiac Tumors
Cytomegalovirus Infection
Galactose-1-Phosphate Uridyltransferase Deficiency
Hydrops Fetalis
Parvovirus B19 Infection
Laboratory Studies
The following findings may be noted in hemolytic
disease of the newborn (HDN):
Hemolytic disease of the newborn is characterized by
one or more of the following clinical presentations:
Rapidly progressive severe hyperbilirubinemia or
prolonged hyperbilirubinemia
Positive maternal antenatal antibody findings and/or
diagnosis of anemia or fetal hydrops
Positive neonatal direct Coombs test (direct
antiglobulin test)
Hemolysis on blood film findings
The severity of hematologic abnormalities is directly
proportional to the severity of hemolysis and the extent of
hematopoiesis. The following abnormalities are observed
on CBC count findings:
Anemia: Measurements are more accurate using
central venous or arterial samples rather than capillary
Increased nucleated RBCs, reticulocytosis,
polychromasia, anisocytosis, spherocytes, and cell
o The reticulocyte count can be as high as 40% in
patients without intrauterine intervention.
o The nucleated RBC count is elevated and falsely
elevates the leukocyte count, reflecting a state of
o Spherocytes (< 40%) are more commonly observed
in cases of ABO incompatibility. Glucose does not correct
the autohemolysis in ABO incompatibility unlike
hereditary spherocytosis.
o In severe hemolytic disease, schistocytes and burr
cells may be observed, reflecting ongoing disseminated
intravascular coagulation.
o A low reticulocyte count is observed in fetuses
provided with intravascular transfusion in utero and with
Kell alloimmunization.
o Abnormally elevated mean cell hemoglobin
concentration (MCHC) and red cell distribution width
(RDW) values should prompt a diagnosis of hereditary
Neutropenia: This condition seems to be secondary to
stimulation of erythropoiesis in favor of myelopoiesis.
However, neutrophilia can be observed after intrauterine
transfusion because of an increase in circulating cytokines
(granulocyte-macrophage colony-stimulating factor).
Thrombocytopenia: This condition is common,
especially after intrauterine or exchange transfusions
because of platelet-poor blood product and suppression of
platelet production in favor of erythropoiesis.
Hypoglycemia is common and is due to islet cell
hyperplasia and hyperinsulinism. The abnormality is
thought to be secondary to release of metabolic
byproducts such as glutathione from lysed RBCs.
Inter. J. of Pharmacotherapy / 5(1), 2015, XX-XX.
Hypokalemia, hyperkalemia, and hypocalcemia are
commonly observed during and after exchange
Serologic test findings include the following:
Indirect Coombs test and direct antibody test results
are positive in the mother and affected newborn. Unlike
Rh alloimmunization, direct antibody test results are
positive in only 20-40% of infants with ABO
incompatibility. In a recent study, positive direct antibody
test findings have a positive predictive value of only 23%
and a sensitivity of only 86% in predicting significant
hemolysis and need for phototherapy, unless the findings
are strongly positive (4+). This is because fetal RBCs
have less surface expression of type-specific antigen
compared with adult cells. A prospective study has shown
that the titers of maternal immunoglobulin G (IgG) anti-A
or anti-B may be more helpful in predicting severe
hemolysis and hyperbilirubinemia. The sensitivity and
specificity of IgG titers of 512 or higher in predicting
need for invasive intervention was 90% and 73%,
Although the indirect Coombs test result (neonate's
serum with adult A or B RBCs) is more commonly
positive in neonates with ABO incompatibility, it also has
poor predictive value for hemolysis. This is because of the
differences in binding of IgG subtypes to the Fc receptor
of phagocytic cells and, in turn, in their ability to cause
IgG2 is more commonly found in maternal serum but
has weak lytic activity, which leads to the observation of
little or no hemolysis with a positive direct antibody test
result. On the other hand, significant hemolysis is
associated with a negative direct antibody test result when
IgG1 and IgG3 are predominant antibodies, which are in
low concentration but have strong lytic activity, crossing
to neonatal circulation.
In newborns with hemolytic disease due to anti-c or
anti-C antibodies, direct antibody test results may be
negative, and the diagnosis is established after indirect
Coombs testing.
Imaging Studies
High-resolution ultrasonography has been a
major advance in detection of early hydrops and has also
reduced the fetal trauma and morbidity rate to less than
2% during percutaneous umbilical blood sampling
(PUBS) and placental trauma during amniocentesis. High-
resolution ultrasonography has been extremely helpful in
directing the needle with intraperitoneal transfusion (IPT)
and intravascular transfusion (IVT) in fetal location.
Medical Care
Management of Maternal Alloimmunization
As a rule, serial maternal antibody titers are
monitored until a critical titer of 1:32, which indicates that
a high risk of fetal hydrops has been reached. At this
point, the fetus requires very intense monitoring for signs
of anemia and fetal hydrops. In Kell alloimmunization,
hydrops can occur at low maternal titers because of
suppressed erythropoiesis, and, thus, a titer of 1:8 has
been suggested as critical. Maternal titers are not useful in
predicting the onset of fetal anemia after the first affected
gestation. Large differences in titer can be seen in the
same patient between different laboratories, and a newer
gel technique produces higher titer results than the older
tube method. Therefore, standard tube methodology
should be used to determine critical titer, and a change of
more than 1 dilution represents a true increase in maternal
antibody titer. For all the antibodies responsible for
hemolytic disease of the newborn (HDN), a 4-fold
increase in any antibody titer is typically considered a
significant change that requires fetal evaluation.
When indicated, amniocentesis can be performed
as early as 15 weeks' gestation (rarely needed in first
affected pregnancy before 24 weeks' gestation) to
determine fetal genotype and to assess the severity.
Maternal and paternal blood samples should be sent to the
reference laboratory with amniotic fluid sample to
eliminate false-positive results (from maternal
pseudogene or Ccde gene) and false-negative results
(from a rearrangement at the RHD gene locus in the
father). Fetal Rh-genotype determination in maternal
plasma has become routine in many European countries
and is being offered in the United States. Fetal cell-free
DNA accounts for 3% of total circulating maternal plasma
DNA, is found as early as 38 days of gestation, and is
derived from apoptosis of the placental cytotrophoblast
layer. It is subjected to real-time PCR for the presence of
RHD genespecific sequences and has been found to be
accurate in 99.5% of cases. The SRY gene (in the male
fetus) and DNA polymorphisms in the general population
(in the female fetus) are used as internal controls to
confirm the fetal origin of the cell-free DNA.A panel of
92 SNPs is compared between maternal sample from
buffy coat and plasma. A difference of more than 6 single
nucleotide polymorphisms confirms presence of fetal
DNA and the validity of the test in a female fetus.
Unfortunately, cell-free fetal DNA testing for
determining the genotype for other red blood cell antigens
such as E and Kell is not yet available in United States.
Serial amniocentesis is begun at 10-14 day
intervals to monitor the severity of the disease in the
fetus. All attempts should be made to avoid transplacental
passage of needle which can lead to fetomaternal
hemorrhage (FMH) and a further rise in antibody titer.
Early ultrasonography is performed to establish correct
gestational age. Frequent ultrasonographic monitoring is
also performed to assess fetal well-being and to detect
moderate anemia and early signs of hydrops.
Inter. J. of Pharmacotherapy / 5(1), 2015, XX-XX.
During the period when intrauterine peritoneal
transfusion was the only means of treatment, newborns
were routinely delivered at 32 weeks' gestation. This
approach resulted in a high incidence of hyaline
membrane disease and exchange transfusions. With the
advent of intravascular transfusion (IVT) in utero, the
general approach to the severely affected fetus is to
perform IVT as required until 35 weeks' gestation, with
delivery planned at term. Establishment of lung maturity
is difficult in these fetuses because of contamination of
amniotic fluid with residual blood during transfusion;
however, if delivery is planned prior to 34 weeks'
gestation, maternal steroid administration to enhance fetal
lung maturity is indicated.
Recently washed maternal RBCs have been
successfully used as a source of antigen-negative RBCs in
the event of rare incompatibility but also have been
routinely used because of benefits such as decreased risk
for sensitization to new red cell antigens, a longer
circulating half-life being fresh and decreased risk of
transmission of viral agents. Mother can donate a unit of
red cells after the first trimester.
Extensive plasmapheresis with partial replacement using
5% albumin and intravenous immunoglobulin (IVIG) or
the administration of IVIG at 1 g/kg body weight weekly
has been shown to be moderately effective. The
mechanism of action appears to be blockage of Fc
receptors in the placenta, reducing antibody transport
across to the fetus, Fc receptors on the phagocytes in the
fetal reticuloendothelial system, and feedback inhibition
of maternal antibody synthesis.
Similar regimens of tests and treatment are used
in the management of pregnancies affected by nonRhD
alloimmunization, such as anti-Rhc, anti-K (K1), and anti-
M. Once the mother is diagnosed with an antibody
associated with hemolytic disease, an indirect Coombs
titer is performed, along with paternal testing for involved
antigen and zygosity. Maternal titers are repeated
(monthly until 28 weeks' gestation and then every 2 wk)
until a threshold for fetal anemia is reached (1:8 for Kell
and 1:32 for rest).
Management of the sensitized neonate
Mild hemolytic disease accounts for 50% of
newborns with positive direct antibody test results. Most
of these newborns are not anemic (cord hemoglobin [Hb]
>14 g/dL) and have minimal hemolysis (cord bilirubin < 4
mg/dL). Apart from early phototherapy, they require no
transfusions. However, these newborns are at risk of
developing severe late anemia by 3-6 weeks of life.
Therefore, monitoring their Hb levels after hospital
discharge is important.
Moderate hemolytic disease accounts for
approximately 25% of affected neonates. Moderate
hemolytic disease of newborn is characterized by
moderate anemia and increased cord bilirubin levels.
These infants are not clinically jaundiced at birth but
rapidly develop unconjugated hyperbilirubinemia in the
first 24 hours of life. Peripheral smear shows numerous
nucleated RBCs, decreased platelets, and, occasionally, a
large number of immature granulocytes. These newborns
often have hepatosplenomegaly and are at risk of
developing bilirubin encephalopathy without adequate
treatment. Early exchange transfusion with type-O Rh-
negative fresh RBCs with intensive phototherapy is
usually required. Use of IVIG in doses of 0.5-1 g/kg in a
single or multiple dose regimen have been able to
effectively reduce need for exchange transfusion [12].
Severe hemolytic disease accounts for the
remaining 25% of the alloimmunized newborns who are
either stillborn or hydropic at birth. The fetal hydrops is
predominantly caused by a capillary leak syndrome due to
tissue hypoxia, hypoalbuminemia secondary to hepatic
dysfunction, and high-output cardiac failure from anemia.
About half of these fetuses become hydropic before 34
weeks' gestation and need intensive monitoring and
management of alloimmunized gestation as described
earlier. Mild hydrops involving ascites reverses with IVTs
in only 88% of cases with improved survival but severe
hydrops causing scalp edema and severe ascites and
pleural effusions reverse in 39% of cases and are
associated with poor survival.
Management of ABO Incompatibility
Management of hyperbilirubinemia is a major
concern in newborns with ABO incompatibility. The
criteria for exchange transfusion and phototherapy are
similar to those used in Rh alloimmunization. IVIG has
also been very effective when administered early in the
course. Tin (Sn) porphyrin a potent inhibitor of heme
oxygenase, the enzyme that catalyzes the rate-limiting
step in the production of bilirubin from heme, has been
shown to reduce the production of bilirubin and reduce
the need for exchange transfusion and the duration of
phototherapy in neonates with ABO incompatibility.
Tin or zinc protoporphyrin or mesoporphyrins
have been studied in newborns. They must be
administered intramuscularly in a dose based on body
weight, and their effectiveness appears to be dose related
in all gestations.Their possible toxic effects include skin
photosensitization, iron deficiency, and possible
inhibition of carbon monoxide production. Their use in
Rh hemolytic disease of newborn has not been reported.
Their routine use cannot be recommended yet because of
lack of long-term safety data.
Further Inpatient Care
The following may be indicated in patients with
hemolytic disease of newborn (HDN):
Inter. J. of Pharmacotherapy / 5(1), 2015, XX-XX.
The stabilization of a hydropic newborn requires a
high level of intensive coordinated management by a
neonatal team well prepared for the possibly affected
In general, immediate intubation followed by
draining of pleural effusions and ascites results in
immediate improvement in respiratory gas exchange.
A cautious correction of anemia with packed RBCs
or by exchange transfusion is necessary to prevent
circulatory overload.
These neonates have normal blood volume but
elevated central venous pressure.
A close monitoring of metabolic status (eg, watching
for hypoglycemia, hypocalcemia, hyperkalemia, acidosis,
hyponatremia, renal failure) is absolutely essential to
achieve a successful outcome.
Despite of the first use of phototherapy by Cremer
and associates more than 40 years ago, no standard
method for delivering phototherapy is yet available.
Exchange transfusion removes circulating bilirubin
and antibody-coated RBCs, replacing them with RBCs
compatible with maternal serum and providing albumin
with new bilirubin binding sites. The process is time
consuming and labor intensive but remains the ultimate
treatment to prevent kernicterus. The process involves the
placement of a catheter via the umbilical vein into the
inferior vena cava and removal and replacement of 5- to
10-mL aliquots of blood sequentially, until about twice
the volume of the neonate's circulating blood volume is
reached (ie, double-volume exchange).
This process removes approximately 70-90% of fetal
RBCs. The amount of bilirubin removed directly varies
with the pretransfusion bilirubin level and amount of
blood exchanged. Because most of the bilirubin is in the
extravascular space, only about 25% of the total bilirubin
is removed by an exchange transfusion. A rapid rebound
of serum bilirubin level is common after equilibration and
frequently requires additional exchange transfusions.
The indications for exchange transfusion are
controversial, except for the fact that severe anemia and
the presence of a rapidly worsening jaundice despite
optimal phototherapy in the first 12 hours of life indicate
the need for exchange transfusion. In addition, the
presence of conditions that increase the risk of bilirubin
encephalopathy lowers the threshold of safe bilirubin
Exchange transfusion should be considered in newborns
born at more than 38 weeks' gestation with a bilirubin-to-
albumin ratio of 7.2 and in newborns born at 35-37 weeks'
gestation with a bilirubin-to-albumin ratio of 6.8.
Exchange transfusion is not free of risk, with the
estimated morbidity rate at 5% and the mortality rate as
high as 0.5%. Apnea, bradycardia, cyanosis, vasospasm,
and hypothermia with metabolic abnormalities (eg,
hypoglycemia, hypocalcemia) are the most common
adverse effects.
IVIG has been shown to reduce the need for
exchange transfusion in hemolytic disease of the newborn
due to Rh or ABO incompatibility. The number needed to
treat to prevent one exchange transfusion was noted to be
2.7 and was estimated to be 10, if all the infants with
strongly positive direct Coombs test were to receive the
medication [13,14]. In addition, it also reduced the
duration of hospital stay and phototherapy. Although it
was very effective as a single dose, multiple doses were
more effective in stopping the ongoing hemolysis and
reducing the incidence of late anemia.
Tin-mesoporphyrin in a dose of 4.5 mg/kg (6
µmole/kg) was used in an infant with persistent hemolysis
due to Rh alloimmunization to prevent need for further
phototherapy, without any adverse effects.
Consider the following in patients with hemolytic
disease of the newborn:
Rh immune globin (RhIG) was licensed in 1968 in
North America after several studies demonstrated its
effectiveness in preventing Rh alloimmunization when
administered to the mother within 72 hours of delivery.
The current standard is to administer RhIG to all
unsensitized Rh-negative women at 28 weeks' gestation
with an additional dose administered soon after birth if
the infant is Rh-positive, irrespective of the ABO status of
the baby. RhIG is not indicated for mothers with weak or
partial D status because most are not at risk for
The standard dose of RhIG is 300 mcg and is
increased (300 mcg for every 25 mL of fetal blood in
maternal circulation) based on the amount of fetomaternal
hemorrhage, which can be quantified using the Kleihauer-
Betke technique. Because only 50% of pregnancies with
excess fetomaternal hemorrhage can be identified by
clinical risk factors, routine screen for excess fetomaternal
hemorrhage (FMH) is undertaken in all Rh negative
women. However, if the incidence of excess FMH is
0.6%, the maximum risk of sensitization is 0.1%,
suggesting routine assessment for excess FMH may not
be justified.
Also administer RhIG to unsensitized Rh-negative
women after any event known to be associated with
transplacental hemorrhage such as spontaneous or elective
abortion, ectopic pregnancy, amniocentesis, chorionic
villous sampling, fetal blood sampling (FBS), hydatiform
mole, fetal death in late gestation, blunt abdominal
trauma, and external cephalic version. The indications for
first trimester threatened abortion and ectopic pregnancy
with no cardiac activity are not cost effective and are left
to the clinician.
Inter. J. of Pharmacotherapy / 5(1), 2015, XX-XX.
No more than 5 units of RhIG should be given by
intramuscular route in 24-hour period. An intravenous
preparation is now available for administration of large
doses. If RhIG was inadvertently omitted after delivery,
the protection can still be offered if given within first 4
weeks. A repeat dose is not needed if delivery occurs
within 3 weeks after administration of RhIG during
antenatal period. The current incidence of Rh
immunization stands at 0.1% with the above
Most RhIG is derived from human plasma obtained
from sensitized women or male donors sensitized with
RhD positive cells. Because it is a blood product, it has
risks of transmission of viral infections such as hepatitis C
and may not be acceptable in some religious
denomination. Hence 2 monoclonal anti-D antibodies
derived from recombinant technology, BRAD-1 and
BRAD-3, are being tested in clinical trials. A new novel
polyclonal recombinant antibody, rozrolimupab has also
been tested in phase I and II clinical trials with no adverse
The 2 major complications of hemolytic disease
of the newborn are bilirubin encephalopathy (kernicterus)
and late anaemia of infancy.
Bilirubin encephalopathy
o Before the advent of exchange transfusion,
kernicterus affected 15% of infants born with
erythroblastosis. Approximately 75% of these neonates
died within 1 week of life, and a small remainder died
during the first year of life. Survivors had permanent
neurologic sequelae and were thought to have accounted
for 10% of all patients with cerebral palsy (CP).
o The mechanism by which unconjugated bilirubin
enters the brain and damages it is unclear. Bilirubin enters
the brain as lipophilic free bilirubin unbound to albumin,
as supersaturated bilirubin acid that precipitates on lipid
membrane in low pH, or as a bilirubin-albumin complex
that transfers bilirubin to tissue by direct contact with
cellular surface. The blood-brain barrier is comprised of
ATP-dependent transport proteins and pumps free
bilirubin from the brain back into plasma and maintains
the concentration gradient of unconjugated bilirubin. A
damaged blood-brain barrier enhances the entry and fails
to remove all forms of bilirubin into the brain, which is
especially important in preterm neonates with respiratory
acidosis and vascular injury.
o Bilirubin has been postulated to cause neurotoxicity
via 4 distinct mechanisms [15]. (1) interruption of normal
neurotransmission (inhibits phosphorylation of enzymes
critical in release of neurotransmitters), (2) mitochondrial
dysfunction, (3) cellular and intracellular membrane
impairment (bilirubin acid affects membrane ion channels
and precipitates on phospholipid membranes of
mitochondria), and (4) interference with enzyme activity
(binds to specific bilirubin receptor sites on enzymes).
o The pathologic findings include characteristic
staining and neuronal necrosis in basal ganglia ,
hippocampal cortex , brainstem nuclei , and cerebellum .
The cerebral cortex is generally spared. About half of
these neonates also have extraneuronal lesions, such as
necrosis of renal tubular, intestinal mucosal, and
pancreatic cells.
o Clinical signs of bilirubin encephalopathy typically
evolve in 3 phases. Phase 1 is marked by poor suck,
hypotonia, and depressed sensorium. Fever and
hypertonia are observed in phase 2, and, at times, the
condition progresses to opisthotonus. Phase 3 is
characterized by high-pitched cry, hearing and visual
abnormalities, poor feeding, and athetosis.
o Long-term sequelae include choreoathetoid CP,
upward gaze palsy, sensorineural hearing loss, dental
enamel hypoplasia of the deciduous teeth, and, less often,
mental retardation. The abnormal or reduced auditory
brainstem response of wave I (auditory nerve) and wave
II and V (auditory brainstem nuclei), depicted as
decreased amplitudes, and increased interval I-III and I-V
characterize phase I of early, but reversible,
encephalopathy. Subtle bilirubin encephalopathy that
consists of either cognitive dysfunction, isolated hearing
loss, or movement disorder has been described in absence
of kernicterus and better correlates with free bilirubin
o Currently, the mortality rate stands at 50% in term
newborns, but mortality is nearly universal in the preterm
population who may simply appear ill without signs
specific for kernicterus. Research has indicated that
bilirubin production rates may be the critical piece of
information identifying jaundiced infants at risk of
neurotoxicity. A high bilirubin production rate is thought
to result in rapid transfer of bilirubin to tissue, causing
high tissue load, in which case any small further increase
has great potential to enter the brain. Because the total
serum bilirubin represents not only bilirubin production
but also distribution and elimination, it is not an absolute
indicator of risk of kernicterus. Techniques have been
developed to measure the bilirubin production
ratesaccurately and noninvasively using end-tidal carbon
monoxide measurement and percutaneous measurement
of carboxyhemoglobin.
Late anemia of infancy
o Infants with significant hemolytic disease often
develop anemia in the first month of life and frequently
(50%) require packed RBC transfusion. The anemia
appears to be due to several factors including suppression
of fetal erythropoiesis from transfusion of adult Hb during
intrauterine or exchange transfusion, resulting in low
erythropoietin levels and reticulocyte count.
Inter. J. of Pharmacotherapy / 5(1), 2015, XX-XX.
o Continued destruction of neonatal RBCs by high
titers of circulating maternal antibodies also contributes
the development of anemia. Weekly Hcts and reticulocyte
count need to be monitored after discharge until renewed
erythropoiesis is noted. Administration of recombinant.
Human erythropoietin (rh-EPO) has been shown to
minimize the need for transfusion in these newborns.
Potential complications of exchange transfusion
include the following
Cardiac - Arrhythmia, volume overload, congestive
failure, and arrest
Hematologic Over heparinization, neutropenia,
thrombocytopenia, and graft versus host disease
Infectious - Bacterial, viral (cytomegalovirus [CMV],
human immunodeficiency virus [HIV], hepatitis), and
Metabolic - Acidosis, hypocalcemia, hypoglycemia,
hyperkalemia, and hypernatremia
Vascular - Embolization, thrombosis, necrotizing
enterocolitis, and perforation of umbilical vessel
Systemic Hypothermia
Haemolytic Disease of the New Born(HDN) is
caused by alloimmune antibodies from the mother to the
foetus if there is incompatibility in the blood group of the
foetus inherited from the father and that of the
mother.This can be prevented by early premarital
counselling and proper antenatal care and
management.The titre of the antibodies should be
1. Van Der Schoot CE, Tax GH, Rijnders RJ, de Haas M, Christiaens GC. Prenatal typing of Rh and Kell blood group
system antigens, the edge of a watershed. Transfus Med Rev, 17(1), 2004, 31-44.
2. Moise KJ. Management of Rhesus Alloimmunization in Pregnancy. Obstet Gynecol, 112(1), 2008, 164-76.
3. Kaplan M, Na'amad M, Kenan A et al. Failure to predict hemolysis and hyperbilirubinemia by IgG subclass in blood
group A or B infants born to group O mothers. Pediatrics, 123(1), 2009, e132-7.
4. Luchtman-Jones L, Schwartz AL and Wilson DB..The Blood and Hematopoietic System. In, Fanaroff AA, Martin RJ,
eds. Neonatal-Perinatal Medicine-Diseases of the Fetus and Infant. Vol 2. 8th ed. St. Louis, Mo, Mosby, 2006, 1287-
5. Martin JA, Hamilton BE, Sutton PD et al. Births, final data for 2002. Natl Vital Stat Rep, 52, 2002, 1-116.
6. Eder AF. Update on HDFN, New Information on Long-Standing Controversies. Immunohematol, 22(4), 2006, 188-95.
7. Bowman JM. Hemolytic Disease (Erythroblastosis Fetalis). In, Creasy RK, Resnik R. Maternal-fetal medicine. 4th
edition. Philadelphia, WB Saunders, 1999, 736-767.
8. Van Der Schoot CE, Tax GH, Rijnders RJ, de Haas M, Christiaens GC. Prenatal typing of Rh and Kell blood group
system antigens, the edge of a watershed. Transfus Med Rev, 17(1), 2004, 31-44.
9. Moise KJ. Management of Rhesus Alloimmunization in Pregnancy. Obstet Gynecol, 112(1), 2008, 164-76.
10. Kaplan M, Na'amad M, Kenan A et al. Failure to predict hemolysis and hyperbilirubinemia by IgG subclass in blood
group A or B infants born to group O mothers. Pediatrics, 123(1), 2009, e132-7.
11. Luchtman-Jones L, Schwartz AL and Wilson DB..The Blood and Hematopoietic System. In, Fanaroff AA, Martin RJ,
eds. Neonatal-Perinatal Medicine-Diseases of the Fetus and Infant. Vol 2. 8th ed. St. Louis, Mo, Mosby, 2006, 1287-
12. Martin JA, Hamilton BE, Sutton PD et al. Births, final data for 2002. Natl Vital Stat Rep, 52, 2002, 1-116.
13. Eder AF. Update on HDFN, New Information on Long-Standing Controversies. Immunohematol, 22(4), 2006, 188-95.
14. Bowman JM. Hemolytic Disease (Erythroblastosis Fetalis). In, Creasy RK, Resnik R. Maternal-fetal medicine. 4th
edition. Philadelphia, WB Saunders, 1999, 736-767.
15. Smits-Wintjens VE, Walther FJ, Rath ME et al. Intravenous Immunoglobulin In Neonates With Rhesus Hemolytic
Disease, A Randomized Controlled Trial. Pediatrics, 127(4), 2011, 680-6.
16. Moise KJ. Hemolytic Disease of the Fetus and Newborn. In, Creasy R.K, Resnik, R. Maternal-fetal Medicine, Principles
and Practice. 6th edition. Philadelphia, WB Saunders, 2008, 477-503.
17. Bianchi DW, Avent ND, Costa JM and van der Schoot CE. Noninvasive Prenatal Diagnosis Of Fetal Rhesus D, Ready
For Prime(R) Time. Obstet Gynecol, 106(4), 2005, 841-4.
18. Rouillac-Le SC, Puillandre P, Gillot R et al. Large-Scale Pre-Diagnosis Study Of Fetal Rhd Genotyping By Pcr On
Plasma Dna From Rhd-Negative Pregnant Women. Mol Diagn, 8(1), 2004, 23-31.
19. Gottstein, R.and Cooke, R.W. Systematic review of intravenous immunoglobulin in haemolytic disease of the newborn.
Arch Dis Child Fetal Neonatal Ed, 88(1), 2003, F6-10.
20. Hammerman C, Vreman HJ, Kaplan M and Stevenson DK. Intravenous Immune Globulin In Neonatal Immune
Hemolytic Disease, Does It Reduce Hemolysis?. Acta Paediatr, 85(11), 1996, 1351-3.
Inter. J. of Pharmacotherapy / 5(1), 2015, XX-XX.
21. Elalfy MS, Elbarbary NS and Abaza HW. Early Intravenous Immunoglobin (Two-Dose Regimen) In The Management
Of Severe Rh Hemolytic Disease Of Newborn--A Prospective Randomized Controlled Trial. Eur J Pediatr, 170(4),
2011, 461-7.
22. Madan A, MacMahon JR and Stevenson DK. Neonatal Hyperbilirubinemia. In, Taeusch HW, Ballard RA, eds. Avery's
Diseases of the Newborn. 8th ed. Philadelphia, Pa, Elsevier Saunders, 2005, 1226-1256.
... Maternal alloimmunization occurs when the foetal and the maternal lymph combine due to rupture of placental barrier which often happens during delivery, although feto-maternal haemorrhage (FMH) may also result early in pregnancy. The instance of FMH has been observed in 7, 16, and 29% of mothers during their first, second and third trimesters, respectively [6]. Other maternal factors responsible for maternal sensitization involve factors such as Rh incompatibility, major surgical procedure, blood transfusion, multiparity, or operative removal of placenta [7]. ...
... It also consists of KIR2DL1*004 which is the most common inhibitory KIR2DL1 allele on the B haplotype, and is known to have a weak interaction with HLA-C2 allotype as compared to alleles present on KIR A haplotype [36]. On the contrary, mothers homozygous for KIR A haplotypes (KIR "AA" genotype), with foetus having an additional C2 copy as compared to mother (i.e., mother C1/C2 with foetus C1/C2 or mother C1/C2 with foetus C2/C2), that to when the extra copy is of paternal origin are at an increased risk of having a complicated pregnancy [6]. As mothers with KIR AA haplotype have two copies of inherited inhibitory KIR for HLA-C2 allotype i.e., KIR2DL1, thus when the mothers uterine NK cells possessing KIR AA genotype interact with foetal trophoblast cells expressing HLA-C2 allotype, it induces a strong inhibitory effect on NK cell which is one of the reasons for defective placentation and in turn for various pregnancy related complications [37] (Figure 2). ...
... Although over 50 different non-ABO red cell surface antigens are thought to be involved in leading to HDFN, but the most relevant and significant alloantibodies causing HDFN are anti-RhD [44], anti-Rhc, and anti-Kell (K1) [53]. HDN due to Kell alloimmunization results in haemolysis and direct inhibition of erythropoiesis by Kell antibodies, as the Kell antigen is expressed on the surface of erythroid progenitor [6,54]. Alloimmunization due to anti-Kell antibodies results in critical foetal disease even at lower maternal antibody titre than in Rhesus disease [6]. ...
... The deaths due to abortion might be higher than mentioned here as the deaths due to abortions are highly underreported [10][11][12]. One of the most important factors contributing to the maternal mortality and maternal death in low-and middle-income country is unsafe abortion [13][14][15][16][17]. Therefore, abortion accounts directly and indirectly in the increase in maternal mortality in low-and middle-income countries. ...
... Table 1 describes the demographic characteristics of the study population. Almost one-third of the women were in the young age group (20)(21)(22)(23)(24) year) and only 8% were in the youngest (15)(16)(17)(18)(19) year) age group. Forty four percent of the women had no education, while only 6% had the higher educational background. ...
Full-text available
Abortion is one of the major factors contributing to the high maternal mortality in the low-and middle-income countries. The aim of this study was to determine the prevalence of abortion its determinants among the women of the reproductive age (15-49 years) attending JRRH, Jinja district. A simple random sampling method was used to select 104 women who had at least one birth in the last five years. Abortion was measured on the basis of the reason provided by the women for having their last abortion. Likewise, unsafe abortion was measured on the basis of provider providing the service to women. Prevalence of abortion and the association of abortion and unsafe abortion with various factors were assessed using Odds Ratio (OR) with their 95% Confidence Interval (CI) using binary logistic regression models. The prevalence of abortion was found to be 4.8 percent among women with 20 percent of them conducted using unsafe methods. Women in the age group 30-34 were more likely (OR=4.59, 95% CI 1.8311.50) to perform abortions compared to women of the youngest age group (15-19 years). Women having secondary level of education were more likely (OR=2.58, 95% CI 1.62-4.09) to conduct abortions compared to illiterate women. Finally, richest women in urban settings were more likely (OR=2.97, 95% CI 1.71-5.17) to have abortions compared to women from rural settings. Also from the logistic regression models, women in the age group 30-34 were less likely (OR=0.08, 95% CI 0.01-0.89) to have unsafe abortions compared to the youngest age group (15-19 years) and the women from urban settings had lesser (OR=0.25, 95% CI 0.07-0.89) likelihood of conducting unsafe abortion compared to those from rural settings. From our study it was identified that one in every twenty women of reproductive age attending JRRH abort their child and nearly one in five of those are unsafe. Further studies should consider the relationship between the use of contraception and abortion to identify if women were aborting due to lack of access to contraception or due to other reasons.
... And also new born care reduces morbidity from infection and respiratory insufficiency [10][11][12][13][14]. One of the highest impact interventions for newborn survival and health is quality new born care. ...
Full-text available
In Uganda, newborn care remains poor since more than 75% of newborn deaths still results from preventable causes if appropriate newborn care practices are implemented. This study explored the knowledge and practices on newborn care among nurses in Kitagata hospital, Sheema Districts. A cross sectional study design was used to assess 40 nurses who were selected by simple random sampling and assessed by questionnaire, data was analyzed by SPSS and results presented by tables and figures. Results revealed that all 40(100%) nurses had ever heard of new born baby care, 40(100%) to identify preterm babies, 36(90%) had ever got extra training on baby care, 39(97.5%) knew hypothermia as a risk in new born babies while only a few 22(55%) knew that newborn babies are also at risk of hypoglycemia, 40(100%) nurses knew high temperatures as danger sign in newborns. 38(95%) of nurses had ever cared for new born baby during their professional nursing practice where 38(100%) suctioned newborn airway and did not touch newborn baby's cord with bare hands to avoid infections, , 38(100%) of nurses-maintained warmth by attachment of babies to the mothers' body, 30(78.9%) of nurses maintained premature glucose levels by maintenance fluids and 30(78.9%) ensured that newborn babies are also immunized yet only very few 2(5.3%) of nurses monitored for danger signs while they carried out newborn baby care. The nurse's knowledge on newborn care were generally fair and so were their practices.
... This haplotype consists of KIR2DS1 receptor which upon binding to its ligand (HLA-C2) stimulates NK cells to secrete chemokines such as GM CSF that support trophoblast invasion (Bari et al., 2009) (Fig. 1). In contrast, females with homozygous KIR A haplotype and heterozygous HLA-C1/HLA-C2 with fetal cells having homozygous C2 are at an increased risk of complicated pregnancy (Obeagu, 2015). This is because KIR AA genotype encodes two copies of the KIR2DL1, the inhibitory KIR for HLA-C2 that interacts with the fetal HLA-C2 allotype, inhibiting the NK cells and results in defective placentation (Hiby et al., 2004(Hiby et al., , 2014. ...
Full-text available
A successful pregnancy is a biological paradox as the maternal immune system accepts and tolerates the semi allogeneic fetus. Continued tolerance of the fetus relies on an optimal immune privileged environment that allows the developing fetus to avoid recognition and rejection. Any dysregulation in the crosstalk between the host’s immune system and the fetal allograft would result in rejection of the fetus, subsequently leading to miscarriages. The functioning of human leukocyte antigen (HLA) system at the maternal fetus interface plays a pivotal role in acceptance of the fetus. Alterations in the modulated activity of HLA system influence the fetal tolerance. Therefore, this review will provide an insight on how the working of HLA at the maternal fetal interface contributes towards recurrent pregnancy losses (RPL). Antigen hiding is a phenomenon that contributes towards immune evasion by the fetal cells as the placental barrier lacks HLA expression. However, the HLA molecules that are expressed by the extravillous trophoblast modulate maternal immune activity towards a protective function, leading to acceptance of the fetus. Further studies encompassing the functioning of HLA system at maternal fetal interface would prove to be beneficial for the affected couples.
... Dentro de las entidades que promueven la hemolisis de los glóbulos rojos, se encuentra la EHRN, la cual se presenta con mayor frecuencia en personas blancas con un 15%, seguido de personas hispanas con un 8% (15). Antes de implementarse la inmunoprofilaxis como tratamiento preventivo de la EHFRN, la incidencia era del 16% y la mortalidad atribuida a esta patología se presentaba en más de un 50% de los recién nacidos. ...
... As reported in the literature, reticulocyte count would fall almost to 0% by this postnatal age of four to seven days [14]. However, in the setting of this patient with alloimmune hemolytic disease, the patient failed to start reticulocyte production when the hemoglobin deficit exceeded 2 g/dL compared with gestational age norms [15]. By day seven of life, this patient with alloimmune hemolytic disease required its first RBC transfusion as the hemoglobin fell to 6.2 mg/dL, with a hematocrit of 18% and reticulocytes of 1.61% (Figure 2). ...
Full-text available
Rhesus hemolytic disease of the newborn is rarely found after the implementation of anti-D immunoglobulin prophylaxis. However, it may lead to cholestasis, elevated liver transaminases, hyperbilirubinemia, kernicterus, iron overload, and hyporegenerative anemia. Hyporegenerative anemia is characterized by low hemoglobin and reticulocyte count. It is typically recognized two to six weeks after birth. The etiology of this type of anemia is not identified yet, and treatment is controversial. We report a case of a neonate with rhesus hemolytic disease of the newborn with early hyporegenerative anemia that was noted on day seven of life. The available literature has described a similar age of onset, but after two weeks of life and not as early as on day seven of life as in our case. We treated this type of anemia with the standard of care management that includes phototherapy, intravenous immunoglobulin, and blood transfusions.
Objective: To determine the perinatal outcome of pregnancies complicated by Rh-alloimmunisation, requiring intrauterine blood transfusion. Study design: Observational study. Place and duration of study: Feto-maternal Unit of Gene Tech Laboratory, Lahore, from 2007 to 2019. Methodology: A retrospective analysis was done on the data of cases of intrauterine, intravascular blood transfusion given to at-risk foetuses to correct foetal anaemia due to Rh-alloimmunisation or parvovirus B19. All cases, who were eligible to receive IUBT were included in the study. Cases where historic data was not available have been excluded. Results: A total of 305 intrauterine blood transfusion (IUBT) procedures were performed on 127 foetuses. The gestational age ranged from 18-32 weeks at the time of referral. Infra-hepatic part of umbilical vein was preferred for transfusion, but in some cases of anterior placenta, the cord insertion was approached with exception of only two cases where intra-cardiac route was employed. In this study, 71.6% of the babies survived, 14.2% were loss to follow and 14.2% died. Conclusion: IUBT is a safe procedure, especially when performed by experienced hands, and helps save the foetuses at risk. Mothers with Rh-alloimmunisation should be referred before developing hydrops fetalis for better outcome. Key Words: Red cell alloimmunisation, Intrauterine intravascular blood transfusion, Foetal anaemia.
Full-text available
Despite limited data, international guidelines recommend the use of intravenous immunoglobulin (IVIg) in neonates with rhesus hemolytic disease. We tested whether prophylactic use of IVIg reduces the need for exchange transfusions in neonates with rhesus hemolytic disease. We performed a randomized, double-blind, placebo-controlled trial in neonates with rhesus hemolytic disease. After stratification for treatment with intrauterine transfusion, neonates were randomly assigned for IVIg (0.75 g/kg) or placebo (5% glucose). The primary outcome was the rate of exchange transfusions. Secondary outcomes were duration of phototherapy, maximum bilirubin levels, and the need of top-up red-cell transfusions. Eighty infants were included in the study, 53 of whom (66%) were treated with intrauterine transfusion(s). There was no difference in the rate of exchange transfusions between the IVIg and placebo groups (7 of 41 [17%] vs 6 of 39 [15%]; P = .99) and in the number of exchange transfusions per patient (median [range]: 0 [0-2] vs 0 [0-2]; P = .90) or in duration of phototherapy (4.7 [1.8] vs 5.1 [2.1] days; P = .34), maximum bilirubin levels (14.8 [4.7] vs 14.1 [4.9] mg/dL; P = .52), and proportion of neonates who required top-up red-cell transfusions (34 of 41 [83%] vs 34 of 39 [87%]; P = .76). Prophylactic IVIg does not reduce the need for exchange transfusion or the rates of other adverse neonatal outcomes. Our findings do not support the use of IVIg in neonates with rhesus hemolytic disease.
Full-text available
Direct antibody titer-positive, blood group A or B neonates who are born to group O mothers may be at risk for hemolysis and hyperbilirubinemia. Immunoglobulin G1 and immunoglobulin G3 subclasses are associated with increased hemolysis relative to immunoglobulin G2 and immunoglobulin G4. We investigated whether identification of immunoglobulin G subclass 1 or 3 may be predictive of hemolysis and hyperbilirubinemia. Direct antibody titer-positive, blood group A and B neonates born to group O mothers were tested for the presence of immunoglobulin G subclasses 1 and 3 in umbilical cord blood by using a commercially available gel testing technology. By inference, neonates in whom neither immunoglobulin G1 nor immunoglobulin G3 were detected were designated immunoglobulin G2 and/or 4. Mandatory plasma total bilirubin was measured at discharge, and additional measurements performed as clinically indicated. Hyperbilirubinemia was defined as any plasma total bilirubin value >95th percentile for hour of life. Blood carboxyhemoglobin and total hemoglobin concentrations were also measured on the predischarge sample. Measured carboxyhemoglobin, expressed as percentage of total hemoglobin, was corrected for ambient carbon monoxide to derive "corrected carboxyhemoglobin," a sensitive index of heme catabolism. The corrected carboxyhemoglobin/total hemoglobin ratio was calculated to correct for any differences in total hemoglobin mass between groups. Eighty-two infants were studied, 18 of whom were designated as immunoglobulin G1, 0 as immunoglobulin G3, and 64 as immunoglobulin G2 and/or 4. The incidence of plasma total bilirubin >95th percentile was similar between the subgroupings. Corrected carboxyhemoglobin values and corrected carboxyhemoglobin/total hemoglobin ratio were also similar between the subgroupings. Immunoglobulin G1 was found in 22% of direct antibody titer-positive, group A and B neonates who were born to group O mothers, whereas immunoglobulin G3 was rare. Hemolysis and hyperbilirubinemia could not be predicted by this gel technique that enabled identification of these immunoglobulin G subclasses.
Full-text available
To assess the effectiveness of high dose intravenous immunoglobulin (HDIVIG) in reducing the need for exchange transfusion in neonates with proven haemolytic disease due to Rh and/or ABO incompatibility. To assess the effectiveness of HDIVIG in reducing the duration of phototherapy and hospital stay. Systematic review of randomised and quasi-randomised controlled trials comparing HDIVIG and phototherapy with phototherapy alone in neonates with Rh and/or ABO incompatibility. Significantly fewer infants required exchange transfusion in the HDIVIG group (relative risk (RR) 0.28 (95% confidence interval (CI) 0.17 to 0.47); number needed to treat 2.7 (95% CI 2.0 to 3.8)). Also hospital stay and duration of phototherapy were significantly reduced. HDIVIG is an effective treatment.
Full-text available
The routine prenatal determination of fetal RhD blood group would be very useful in the management of pregnancies in RhD-negative women, as up to 40% of these pregnancies bear a RhD-negative fetus. The fetal DNA present in maternal plasma offers an opportunity for risk-free prenatal diagnosis. This study focused on the feasibility and accuracy of large-scale RhD fetal diagnosis in non-immunized and anti-D immunized RhD-negative women. Plasma DNA was extracted from 893 RhD-negative pregnant women and amplified in exons 7 and 10 of the RHD gene using conventional and real-time PCR. The results were then compared with the RHD fetal genotype determined on amniotic cells and/or the RhD phenotype of the red blood cells of the infants at birth. After exclusion of 42 samples from women exhibiting a nonfunctional or rearranged RHD gene, fetal RhD status was predicted with a 99.5% accuracy. A strategy is also proposed to avoid the small number of false-positive and -negative results. Fetal RHD genotyping from maternal plasma DNA in different clinical situations may be used with confidence.
Hemolytic disease of the newborn secondary to rhesus alloimmunization was once a major contributor to perinatal morbidity and mortality. Today, rhesus immune globulin has markedly decreased the prevalence of this disease so that only one to six cases occur in every 1000 live births. The rarity of this condition warrants consideration of consultation or referral to a maternal-fetal medicine specialist. Once sensitization occurs, rhesus immune globulin is no longer effective. Evaluation for the presence of maternal anti-D antibody should be undertaken at the first prenatal visit. First-time sensitized pregnancies are followed with serial maternal titers and, when necessary, serial amniocenteses to detect fetal bilirubin by DeltaOD(450). In cases of a heterozygous paternal genotype, new deoxyribonudeic add techniques now make it possible to diagnose die fetal blood type through amniocentesis or even from plasma/serum deoxyribonudeic acid analysis. When there is a history of an affected fetus or infant, maternal titers are no longer diagnostic as a screening test. Serial peak middle cerebral artery velocities using Doppler ultrasound can be used in these pregnancies to detect fetal anemia. In some situations, intrauterine transfusion is necessary through ultrasound-directed puncture of the umbilical cord with the direct intravascular injection of red cells. Perinatal survival rates of more than 90% have been reported; hr drops fetalis reduces the chance for a viable outcome by up to 25%. Immediate neonatal outcome is complicated by the need for repeated transfusions secondary to suppressed erythropoiesis. Long-term studies have revealed normal neurologic outcomes in more than 90% of cases. Future therapy will involve selective modulation of the maternal immune system making the need for intrauterine transfusions a rarity. (C) 2002 by The American College of Obstetricians and Gynecologists.
Phototherapy is the standard treatment in moderately severe hemolytic disease of newborn (HDN), whereas exchange transfusion (ET) is the second line in progressive cases. Intravenous immunoglobin (IVIG) has been suggested to decrease the need for ET. We aimed at assessing the efficacy of early two-dose regimens of IVIG to avoid unnecessary ET in severe Rh HDN. The study included 90 full-term neonates with Rh incompatibility unmodified by antenatal treatment and not eligible for early ET and which were randomly assigned into one of three groups: group (I), treated by conventional method; groups IIa and IIb received IVIG once at 12 h postnatal age if PT was indicated, in a dose of 0.5 and 1 g/kg, respectively. Analysis revealed 11 neonates (22%) in the conventional group and 2 (5%) in the intervention group who administered low-dose IVIG at 12 h, while none in group IIb required exchange transfusion (p = 0.03). Mean bilirubin levels were significantly lower during the first 96 h in the intervention group compared to the conventional group (p < 0.0001). Shorter duration of phototherapy (52.8 ± 12.39 h) and hospital stay (3.25 ± 0.71 days) in the IVIG group compared to conventional group (84 ± 12.12 h and 4.72 ± 0.78 days, p < 0.0001, respectively) were observed. We conclude that IVIG administration at 12 h was effective in the treatment of severe Rh HDN; the low-dose IVIG (0.5 g/kg) was as effective as high dose (1 g/kg) in reducing the duration of phototherapy and hospital stay, but less effective in avoiding exchange transfusion.
We studied the effect of intravenous immune globulin (IVIG) on hemolysis in term, hyperbilirubinemic, Coomb's positive infants utilizing measurement of carboxyhemoglobin fraction corrected for inhaled carbon monoxide (COHbc), a sensitive indicator of hemolysis. COHbc values were determined before and after IVIG infusion. In those babies who responded with a decrease in serum total bilirubin (n = 19), no exchange transfusions were required and COHbc levels decreased significantly by 24 h post-IVIG from 1.37 +/- 0.31 to 1.12 +/- 0.26% tHb (p < 0.0001). There were no corresponding decreases in COHbc levels (1.989 +/- 0.54 to 1.82 +/- 0.48% tHb; p > 0.05) among those whose serum bilirubin levels did not decrease in response in to IVIG (n = 7), and all of these infants required exchange transfusions. Furthermore, the extent of the decrease in COHbc was related to the degree of decrease in serum bilirubin levels, such that the percentage decrease of bilirubin at 24 h was directly correlated with the percentage decrease of COHbc at 24 h (p = 0.007). We conclude that IVIG, when successful, inhibits hemolysis in these infants.
Knowledge of the molecular basis of the blood group systems has enabled the development of assays for blood group genotyping. At this time, polymerase chain reaction (PCR)-based assays validated on fetal material obtained by invasive means (chorionic villus sampling or amniocentesis) are available for all clinically relevant fetal blood groups, However, only Rh typing (D, C, c, E, and e) and K1 genotyping assays are discussed in this review. Importantly, one must remember that results of genotyping assays will not always be concordant with serological typing. Thus, the RhD genotyping assays have to be modified in response to increased understanding of the molecular biology of this blood group system. RhD typing assays should produce negative results when tested on the black RhD-negative RHD alleles, RHDpsi and r's. PCR-based assays can be used to determine paternal zygosity. For RhD zygosity testing, the real-time quantitative PCR approach and the direct detection of the hybrid Rhesus box, which is the result of the deletion of the RHD gene are available. Recently, methods for noninvasive prenatal genotyping have been investigated. The use of fetal cells circulating in the maternal circulation has been explored; however, the scarcity of circulating fetal cells has limited the use of this approach. More promising are the results obtained with RhD typing assays with cell-free fetal DNA, which is present in the maternal circulation in a concentration of 25 genomic equivalents per milliliter of maternal blood in early pregnancy increasing to 100 copies per milliliter in the third trimester, which is cleared from the circulation within a few hours of delivery. The positive predictive value of this approach is virtually 100%, but false-negative results are (infrequently) encountered. Therefore, this assay can at present only be used for screening of RhD-negative women to make the use of antenatal prophylaxis more targeted and hence more cost-effective. For the clinical management of the pregnancies of alloimmunized women, the development of a control for the presence and the amplification of fetal DNA is needed, which is at present only available in male pregnancies. Assays for the genotyping of the other Rh antigens or Kell antigens with cell-free fetal DNA have not yet been described.