Written by practicing physicians specializing in pediatric
hematology, neonatology, immunology, pediatric infectious
disease, and transfusion medicine, this is a practical guide to
the pathogenesis, recognition, and management of
hematologic problems in the neonate. The focus is on clinical
issues encountered by pediatric specialists. There are chapters
devoted to disorders of leukocytes, platelets, procoagulant and
anticoagulant proteins, and disorders of red blood cells.
Neonatal transfusion, malignant disorders in the newborn,
neonatal hemoglobinopathy screening, and harvesting and
storage of umbilical-cord stem cells are also covered, and
practical approaches to diagnosis and treatment are given.
Pedro de Alarc´ on is a Member of St Jude Children’s Research
Hospital, Professor of Pediatrics at the University of Tennessee.
Eric Werner is Professor of Pediatrics and Director of the
Division of Pediatric Hematology/Oncology at the Eastern
Virginia Medical School and Co-Director of the Division of
Pediatric Hematology/Oncology, Children’s Speciality Group,
Children’s Hospital of the King’s Daughters.
Pedro A. de Alarc´ on
St Jude Children’s Research Hospital
Eric J. Werner
Eastern Virginia Medical School and
Children’s Hospital of the King’s Daughters
Cambridge, New York, Melbourne, Madrid, Cape Town, Singapore, São Paulo
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Dedication to Dr Frank A. Oski
Our journey to the creation of this book in neonatal
hematology began with a challenge from Dr Oski to
cian, Dr Oski’s special love was neonatal hematol-
ogy. We both were attracted to Syracuse, New York,
not because of the wonderful weather in that sunny
city of eternal snow but because of the program that
Dr Oski had built both in pediatrics and in pedi-
atric hematology. As Fellows, we had the privilege
and unusual experience of making neonatal hema-
tology rounds once a week. Dr Oski attended in the
search yields 80 publications by Dr Oski in the field
of neonatal hematology. Three editions of Hemato-
logic Problems in the Newborn, co-edited with his
of us maintain an interest in neonatal hematology.
Inspired by Dr Diamond’s contributions, Drs Oski
and Naiman established neonatal hematology as a
field worth devoting a career to. Dr Oski contributed
basic information to the field of neonatal red-cell
a natural sequence of study in an attempt to under-
stand why newborns became “anemic” at birth. The
role of iron, transfusions of red cells, and vitamin E
lowed suit, culminating with Dr Oski’s logical next
step, nature’s solution, breast milk, became areas to
which Dr Oski contributed throughout his career. It
is with respect and a deep felt thanks that we dedi-
cate this book to our mentor Dr Oski. We also want
to thank Dr Naiman for writing the foreword to this
book. He also deserves credit and gratitude for his
contributions to the field of neonatal hematology
and his role in establishing this discipline.
pedro de alarc ´ on and eric werner
Dedication to Dr Maureen E. Andrew
Dr Maureen Andrew (1952–2001) died suddenly
during the preparation of this chapter. Dr Andrew
clinicians of our time. A past president of the
Society for Paediatric Research, she worked actively
in research until her death, introducing the con-
cept of developmental hemostasis and leading the
field of thromboembolic disease in children with
an evidence-based approach. As founder of the
1-800-NO-CLOTS service, she directly helped thou-
sands of babies as a source of clinical expertise.
Dr Andrew trained numerous pediatricians in the
art of pediatric haematology. She will be remem-
bered by many as a brilliant scientist, a caring doc-
tor, a thoughtful mentor, and, for those of us lucky
enough to know her well, as a warm and wonderful
List of contributors
1Neonatal hematology: a historical
Howard A. Pearson, M.D.
2 Disorders of the fetomaternal unit
Eric J. Werner, M.D.
3 Erythropoiesis, red cells, and the
approach to anemia
Pedro A. de Alarc´ on, M.D., M. Cris Johnson, M.D.
and Eric J. Werner, M.D.
4Anemia of prematurity and indications
for erythropoietin therapy
Pamela J. Kling, M.D.
5 Hypoplastic anemia
Gary Kupfer, M.D.
6 Hemolytic disease of the fetus
Peter E. Waldron, M.D. and William J. Cashore,
7 Neonatal hemolysis
Bertil Glader, M.D., Ph.D. and Geoffrey Allen,
8Neonatal screening for
Peter A. Lane, M.D.
9 Polycythemia and hyperviscosity in
Ted S. Rosenkrantz, M.D. and
William Oh, M.D.
10Newborn platelet disorders
Pedro A. de Alarc´ on, M.D.
11Neutrophil function and disorders of
neutrophils in the newborn
E. Stephen Buescher, M.D.
12 Immunodeficiency diseases of
Matthew A. Saxonhouse, M.D. and John W.
Manuela Albisetti, M.D., Maureen Andrew,
M.D., F.R.C.P.C. and Paul Monagle, M.B.B.S.,
M.Sc., F.R.A.C.P., F.R.C.P.A.
Jayashree Ramasethu M.D. and Naomi L. C.
Joanne Kurtzburgh, M.D.
16 Neonatal oncology
Thomas D. Lamkin, M.D. and
Alan S. Gamis, M.D.
17Normal values and laboratory methods
Pedro A. de Alarc´ on, M.D. and Eric J. Werner,
Pedro A. de Alarc´ on
St. Jude Children’s Research Center
Danny Thomas, Founder
Mail stop #103
332 N. Lauderdale St.
Memphis, TN 38105-3991, USA
University Children’s Hospital
Geoffrey A. Allen
Department of Pediatrics
University of North Carolina
418 MacNider Building, CB#7220
Chapel Hill, NC 27599-7220, USA
E. Stephen Buescher
Center for Pediatric Research
Eastern Virginia Medical School
855 W. Brambleton Ave
Norfolk, VA 23510, USA
William J. Cashore
101 Dudley Street
Providence, RI 02905, USA
xList of contributors
Alan S. Gamis
Division of Hematology / Oncology /
Bone Marrow Transplantation
Children’s Mercy Hospital &
2401 Gillham Road
Kansas City, MO 64108-9898, USA
Stanford University Medical Center
300 Pasteur Drive
Stanford, CA 94305-5208, USA
Children’s Hospital Central California
9300 Children’s Place
Madera, CA 93638, USA
Pamela J. Kling
University of Wisconsin and
202 S. Park St.
Madison, WI, 53715, USA
Division of Pediatric Hematology and Oncology
Box 441 Jordan Hall
University of Virginia
Charlottesville, VA 22908, USA
Duke University Medical Center
Durham, NC 27710, USA
Thomas D. Lamkin
Doernbecher Children’s Hospital
3181 Sam Jackson Park Road, CDRCP
Portland, OR 97239, USA
Peter A. Lane
Children’s Healthcare of Atlanta
2040 Ridgewood Dr, Suite 100
Atlanta, GA 30322, USA
Naomi L. C. Luban
Children’s National Medical Center
111 Michigan Avenue, NW
Washington, DC 20010, USA
Department of Pediatrics
The George Washington University
Washington, DC, USA
Prof Paul Monagle
Women’s & Children’s Health
Royal Children’s Hospital
Flemington Road, Parkville
Victoria, Australia 3052
Women and Infants’ Hospital
101 Dudley St.
Howard A. Pearson
Department of Pediatrics
Yale University School of Medicine
333 Cedar Street, New Haven
CT, 06520, USA
Division of Neonatology
Georgetown University Hospital
3800 Reservoir Road, NW, Suite # M3400
Washington, DC 20007, USA
Ted S. Rosenkrantz
University of Connecticut Health Center
Division of Neonatal-Perinatal Medicine
263 Farmington Ave
Farmington, CT 06030, USA
Matthew A. Saxonhouse
Division of Neonatology
Shands Children’s Hospital
University of Florida
1600 SW Archer Road
PO Box 100296
Gainesville, FL 32610, USA
John W. Sleasman
Department of Pediatrics
801 6th St. South
All Children’s Hospital Box 9350
St Petersburg, FL 33701, USA
List of contributors xi
Eric J. Werner
Children’s Specialty Group, Children’s
Hospital of The King’s Daughters,
601 Children’s Lane, Norfolk,
VA 23507, USA
Peter E. Waldron
Department of Pediatrics
University of Virginia Health System
PO Box 800386
Charlottesville VA 22908-0386, USA
Oski, with whom I coauthored three editions of the
monograph Hematology of the Newborn from 1966
to 1982, would echo this sentiment. And he would
be delighted that his former fellows Drs Werner and
de Alarc´ on shared our interest in the importance of
this subject sufficiently to bring it up to date in an
expanded textbook rich with information of great
scientific and practical value.
As expected, there have been many important
advances in the field of neonatal hematology in the
past 20 years – new diseases, new ways of diagnos-
ing, treating, and preventing old diseases. These are
covered thoroughly in the chapters written by the
tors for his or her expert knowledge and experience.
With progress, diseases that virtually established
neonatal hematology as a distinct discipline have
largely come under control, reducing the space
ple of this than in the section devoted here to
hemolytic disease of the fetus and newborn (for-
merly referred to as erythroblastosis fetalis), one
that represented the largest chapter in our earlier
monograph. All this resulted from the successful
implementation in 1968 of Rh immunoglobulin to
prevent Rh alloimmunization and hemolytic dis-
ease of the newborn. In its place, we now see
chapters devoted to subjects hardly known then,
such as hemoglobinopathy screening, immunology,
practices, and umbilical-cord stem-cell harvest and
What started as a practical monograph to
assist clinicians dealing with hematologic problems
encountered in the newborn has grown into a com-
prehensive reference source for everyone interested
in the unique aspects of blood and neoplastic dis-
orders seen at this age – and a useful guide to those
directly responsible for care of these patients.
Books such as the present one and that by Dr Oski
and myself serve also to stimulate others to investi-
gate unsolved problems and develop new therapies.
I was reminded of this by a chance meeting several
years ago with Dr Pablo Rubinstein, who developed
the first public cord blood bank (Placental Blood
Program) at the New York Blood Center and made
these products available for hematopoietic stem-
cell transplant programs worldwide. At this, our first
meeting together, he attributed his interest in the
potential of cord blood for transplantation to state-
ments in our book about cord blood being a rich
our book, we had no idea that statements like that
might have led to a major development such as the
use of cord blood for transplantation. But it encour-
book by Drs Werner and de Alarc´ on will provide the
seed for advances by others that were not at all con-
ceived at the time this text went to press. And this is
how the tree of knowledge grows.
J. Lawrence Naiman, M.D.
There is no time in life when human physiology
changes more rapidly than in the neonatal period.
The blood is very much affected by the transition
from the intrauterine to the extrauterine environ-
abnormalities from physiologic variations. Further-
more, remarkable advances in perinatal/neonatal
medicine have led to dramatic improvements in
infant survival – now extending to the extremely
low-birthweight infant. Many previously fatal con-
genital disorders are no longer universally so, due
both to advances in basic and clinical research
and to the hard work of perinatologists, neonatol-
ogists, pediatricians, pediatric subspecialists, and
great experience, would refer to textbooks as either
“How come?” books or “How to” books. It is the goal
of this textbook to be a “How to” book, with some
discussion of the pathophysiology of the hemato-
logic problems while focussing on practical aspects
most of the hematologic disorders of the newborn,
we have chosen to be inclusive of the discussions
prepared by each of the contributors.
The contributors to this text bring a wealth of
knowledge and expertise to each of the chapters.
We are so fortunate to have readily acknowledged
neonatologists, pediatric hematologists, pediatric
immunologists, pediatric transfusion medicine spe-
These authors took time from their very busy activi-
ties to review the state of the art in their fields, often
dealing with repeated questions and requests from
the editors. In particular, we, and the entire medi-
cal world, will greatly miss Dr Maureen Andrew. In
addition to her extensive research into hematologic
problems of the newborn, especially in the area of
ment of difficult clinical problems.
We thank Dr J. Lawrence Naiman for his continu-
ous support through the production of this text and
insightful comments and criticisms. Lastly, but cer-
tainly not the least, we wish to thank our wives (Jill
and Alice), our children (Alessandro, Tessa, Jacob,
were limited by their dedication to completing this
Neonatal hematology: a historical overview
Howard A. Pearson, M.D.
University School of Medicine, Yale New Haven Hospital, New Haven, CT, USA
Ancient concepts of the blood were described by
Hippocrates and Galen 2000 years ago in their doc-
trine of “humors.” It was believed that the body was
made up of four humors – blood, phlegm, black
bile, and yellow bile – and that these four compo-
moist, and dry. The Galenic concept of the blood
prevailed through the Middle Ages. Health or dis-
ease was a result of a balance or imbalance, respec-
tively, between these humors, and this was the basis
of the practice of therapeutic blood-letting (which,
through the mid nineteenth century as a way to rid
the body of the abnormal humors believed to cause
a wide variety of diseases.
The hematology of the fetus and newborn is a
relatively recent area of study whose development
tology and, especially, upon methods to study the
blood and its elements. As Wintrobe has pointed
out, the development of the field of hematology has
of hematology into two general areas: morphology,
The invention of the microscope enabled identifi-
cation of the blood cells. Antonj van Leeuwenhoek,
working in Delft, Holland, constructed a primitive
microscope from a minute biconcave lens mounted
between two metal plates attached to a screw that
permitted focussing. Leeuwenhoek’s publication in
1674 contained the first accurate description of the
red blood corpuscles :
The blood is composed of exceedingly small particles, named
globules, which in most animals are red in color . . . These par-
ticles are so minute that 100 of them placed side by side would
not equal the diameter of a common grain of sand.
In the centuries following, the development of
compound microscopes with two lenses greatly
increased magnification and minimized spherical
aberration, permitting more accurate descriptions
of the blood cells. William Hewson, who has been
designated as one of the “fathers of hematology,”
noted that the red cells were flat rather than glob-
ular and also described the leukocytes for the first
time . The last of the formed elements of the
blood, the platelet, was recognized independently
by several investigators. The most definitive early
work on the platelet was done by Julius Bizzozero.
His monograph, published in 1882, clearly recog-
“Pl¨ attchen.” He also assigned a hemostatic func-
tion to the platelet . William Osler, early in his
although he believed that they might be infectious
agents, perhaps analogous to bacteria .
With improvements in microscopy, the morphol-
ogy of the fixed blood cells began to be examined
using thin films of blood, spread and dried on glass
slides, which were then stained with analine dyes
that stained differentially the nuclei and granules of
2Howard A. Pearson
the leukocytes. Staining of peripheral blood smears
was developed by Paul Ehrlich in 1877, while he
was still a medical student, and became practical
in the early twentieth century by the work of James
Homer Wright of Boston, who formulated the poly-
chromatic Wright stain that is still used today for
morphologic examination of the blood and bone
vided a method for assessment of erythropoiesis
by reticulocyte counts. These techniques permitted
blood diseases such as the leukemias and the vari-
ous types of anemia were described on the basis of
typical morphological findings.
Hematology as a quantitative discipline began
ods to quantify accurately the numbers of the
various blood cells. These methods used gridded
chambers of uniform depth (hematocytometers)
into which precisely diluted suspensions of blood
were placed. The numbers of cells in the chamber
were counted and, when combined with the known
dilutions, the actual numbers of cells per cubic
milliliter in the patient’s blood could be calculated.
Hemoglobin levels were estimated by comparing
the density of color in fixed dilutions of hemolyzed
blood with colorometric standards and, later, by
spectroscopy. For many years, hemoglobin values
were reported as “% of normal;” because the defini-
tion of “normal” was often different, however, there
was considerable variability from study to study. In
1929, Maxwell Wintrobe described his method for
obtaining the hematocrit or packed red-cell vol-
ume (PCV) by centrifugation of blood in a glass
tube . He then defined so-called red-cell indices,
the mean corpuscular volume (MCV), mean cor-
hemoglobin concentration (MCHC), which proved
anemia . The latest advance in blood-cell quan-
titation began in the 1950s with the introduction
of increasingly more complicated and sophisticated
computer-driven electronic instruments that mea-
sure very accurately hemoglobin, the numbers of all
now also provide automated differential counts of
atric textbooks gave scant attention to hematologic
problems of the neonate. Dewees’s 1825 A Trea-
tise on the Physical and Medical Treatment of Chil-
and Job Lewis Smith’s 1869 A Treatise on the Dis-
eases of Infancy and Childhood gave only passing
notice to blood conditions of the neonate, such as
neonatal jaundice and hemorrhage from improper
ligature of the umbilical cord [9, 10]. However, the
monumental text of L. Emmett Holt, The Diseases
of Infancy and Childhood, first published in 1897,
contained a section on “the Diseases of the Newly-
Born,” including the hemorrhagic disease, and a 17-
page section on “the Diseases of the Blood,” which
included the normal blood findings in the new-
studies published in the German literature, and his
descriptions are reasonably consistent with modern
The percentage of haemoglobin is highest in the blood of the
newly born . . . At this time the number of red blood corpuscles
a much greater variation is seen in the red cells of the neonate.
In the blood of the foetus there are present nucleated red cor-
puscles or erythroblasts. These diminish in number toward the
end of pregnancy. These are always found in the blood of pre-
matures, but in infants born at term, they are seen only in small
numbers. The number of leukocytes in the blood of the newly
18,000 per cubic millimetre.
In 1921, W.P. Lucas and associates from the Uni-
described their extensive studies of the blood of
150 infants at birth and during the first two months
of life . Their samples were obtained from
serial punctures of the longitudinal sinus! The poly-
cythemia of the newborn and changes in the leuko-
cytes were defined clearly.
In 1924, H.S. Lippman from the University of
Minnesota published detailed studies of the blood
Neonatal hematology: a historical overview3
of newborn infants . He noted (without further
details) that “Denis published the first observations
the newborn. Most of these studies were published
in European, especially German, journals. Although
there was considerable variability because of differ-
ent methods and standards, the consensus of these
early studies was that “hemoglobin values at birth
are higher than at any other period in the child’s
life.” Some of these studies described reticulocyto-
declined rapidly in the first week of life. Lippman
conducted serial studies of capillary blood over the
changes in the leukocytes during this period.
It has been known for 100 years that the red
blood cells of the fetus and newborn are large com-
pared with those of adults, as determined by micro-
scopic measurement of red-cell diameter. Newer
that the mean MCV of the neonate’s red blood cells
averages 110fl, compared with the 90fl of adults.
The red cells of midgestational fetuses are even
In 1856, Korber, in an inaugural dissertation, is
reported to have described his experiments that
tions and maintained a red color, while hemoglobin
solutions from adults treated in the same way were
rapidly denatured and decolorized . The prop-
of fetal hemoglobin (Hb F), as well as the Apt test,
used to differentiate fetal from swallowed maternal
nal tract [16, 17]. Fetal hemoglobin is also resistant
to acid denaturation, which is the basis for the red-
of fetomaternal transfusions .
The understanding of the protein structure of
hemoglobin advanced rapidly in the 1950s when it
was shown that adult hemoglobin, Hb A, (α2β2) is
a tetramer of alpha (α) and beta (β) polypeptide
chains and that Hb F (α2?2) contains a different
pair of polypeptide chains designated as gamma (?)
chains [19, 20]. During fetal development, synthe-
sis of ? chains predominates, but with approach-
ing term there is a fall-off of ?-chain synthesis and
a simultaneous reciprocal increase in β-chain syn-
thesis. The regulatory mechanisms that govern this
“β/? switch” remain to be elucidated. The blood of
the newborn contains large amounts of Hb F, aver-
aging 60–80%. The affinity of Hb F for oxygen is
greater than that of Hb A, because of poor bind-
ing of 2-3-diphosphoglycerate. This results in a shift
of the oxygen dissociation curve to the left, which
is favorable for oxygen transport to the fetus in the
relative hypoxia of intrauterine existence but which
may be disadvantageous after birth . The high
level of Hb F at birth offers temporary protection
from hemoglobinopathies such as sickle cell ane-
mia and may hamper their diagnosis in the new-
born. Roland Scott, using the classical “sickle cell
prep,” demonstrated a much lower frequency of
“sicklemia” in black newborns than was found in
older children from the same community . The
development of techniques such as acid agar gel
electrophoresis has permitted genotypic diagnosis
of most hemoglobinopathies at birth, and neona-
routinely in 47 states of the USA .
The only somewhat common hemoglobinopa-
thy that produces symptoms in the newborn is
homozygous α-thalassemia resulting from deletion
of four α-globin genes . In parts of Southeast
Asia, fetal hydrops is caused much more frequently
by α-thalassemia than by Rh immunization. The
recent immigrations of large numbers of South-
eastern Asian people into the USA have resulted
in increasing numbers of affected infants. Some of
these have survived after intrauterine transfusions
but are transfusion-dependent .
Since the turn of the twentieth century, a large
number of studies of the hematology and blood
diseases of the newborn have been reported.
Much of this information has been incorporated
into textbooks of hematology. Maxwell Wintrobe’s
4Howard A. Pearson
monumental Clinical Hematology, which was first
published in 1943, contained sections on normal
blood values, anemias, and hemorrhagic disease of
neonatal hematological conditions were described.
In 1960, Carl Smith published Blood Diseases of
Infancy and Childhood, the first American textbook
of pediatric hematology/oncology, which had sev-
logic problems in the neonatal period.
In 1966, Frank Oski and Laurie Naiman published
the first textbook devoted solely to the hematology
and hematological problems of the newborn .
The authors’ stated purpose was
ing both the abnormal and abnormal hematologic processes
of the first month of life and the effects of prenatal factors on
them . . . And to provide a useful guide to all who care for the
newborn infant – those who are continually confronted with
infants who are bleeding, anemic or jaundiced.
The Oski–Naiman text had two subsequent re-
editions in 1972 and 1982. Subsequently, there have
been a plethora of texts and handbooks on pediatric
hematology, most of which devote chapters to the
The history of neonatal hematology and the pro-
cess of understanding hematologic diseases based
on clinical and laboratory observations that stim-
ulate investigation of basic mechanisms and then
therapeutic interventions are illustrated well by two
quintessential neonatal blood diseases: erythroblas-
As recently as 1946, erythroblastosis fetalis, or
hemolytic disease of the newborn, affected between
0.5% and 1.0% of fetuses and newborns in the USA.
It had a 50% mortality as well as significant neu-
rologic morbidity in many survivors . Prior to
1936, four seemingly distinct neonatal syndromes
had been identified: fetal hydrops; fetal erythro-
blastosis with massive red-cell proliferation in fetal
organs; icterus gravis familiaris, a severe neona-
tal jaundice that often affected subsequent infants;
and severe anemia in surviving infants who had not
had edema or striking jaundice, which was simply
called anemia of the newborn. Based on histological
and hematological similarities and the familial
occurrence, Diamond, Blackfan, and Baty put forth
their unifying hypothesis that these four syndromes
lying disease process. They designated all of these
neonatal syndromes “erythroblastosis fetalis” .
In 1938, Ruth Darrow, a pathologist, several chil-
a brilliant inductive hypothesis about its cause.
Assembling all of the available information, as well
usual sparing of the first child and the involvement
of most subsequently born children. She also recog-
hemolysis. She concluded that the disease resulted
component of them . . . The antibodies formed in the maternal
organism may then pass to the child through the placenta .
The elusive offending antibody and its red-cell
antigen were discovered in 1940 by Karl Landsteiner
sus factor) because the antibody was produced by
injection of red blood cells of rhesus monkeys into
rabbits. This antibody agglutinated the red cells of
85% of normal individuals . Interestingly, Land-
plished almost 50 years after he had discovered the
ABO blood groups . Philip Levine described a
transfusion reaction in a postpartum woman who
was given a transfusion of her husband’s blood
fetalis. Levine was able to demonstrate Rh anti-
bodies in the mother’s circulation, defining clearly
the pathophysiology of erythroblastosis fetalis
Neonatal hematology: a historical overview5
gressed slowly. The treatment of icterus gravis by
“exsanguination transfusion” was first reported in
1925 by A.P. Hart at Toronto’s Hospital for Sick
Children . With the discovery of the Rh factor,
exchange transfusion evolved rapidly as a way to
remove circulating antibody, sensitized red blood
cells, and bilirubin. This treatment was spear-
headed by Harry Wallerstein and Alexander Weiner
in New York and Louis K. Diamond in Boston.
Wallerstein’s method involved aspiration of blood
from the sagittal sinus and infusion of Rh negative
blood into a peripheral vein . Weiner’s method
employed heparinization and surgical cannulation
at a time long before institutional review boards for
research, he first evaluated the technique in a non-
erythroblastotic “mongolian idiot” . Diamond’s
much more practical method utilized the umbili-
cal vein to alternately remove and infuse blood, and
world . Diamond developed practical guidelines
for the prenatal and postnatal management of Rh-
sensitized mothers and their erythroblastotic new-
borns. These reduced neonatal mortality from 50%
to 5% and intrauterine death from 20% to less than
10%, and kernicterus associated with severe hyper-
bilirubinemia was virtually eliminated .
Implicit in the pathogenesis of Rh erythroblasto-
sis is that small numbers of fetal erythrocytes gain
entrance into the maternal circulation, where they
evoke maternal immunization and Rh antibody for-
mation. The possibility of large fetomaternal trans-
fusion was first hypothesized by Weiner and later
proven definitively by Bruce Chown, who used dif-
ferential agglutination to demonstrate fetal red cells
in the maternal circulation in a case of neonatal
anemia [39, 40]. It is now recognized that acute,
pallor and hypovolemic shock resembling asphyxia
pallida, while chronic hemorrhage may be associ-
ated with well-compensated congenital microcytic
hypochromic anemia due to iron deficiency .
The penultimate important developments in
erythroblastosis fetalis were provided by A.W.
Liley of New Zealand, who devised a method of
spectroscopic analysis of amniotic fluid. This iden-
tified immunized fetuses at high risk of intrauterine
toneal blood transfusion to carry them to delivery
[42, 43]. Development of percutaneous umbilical
blood sampling under ultrasonographic guidance
assess the severity of anemia in immunized fetuses
and to treat them with simple or exchange transfu-
sions in utero. Finally, Clark in Liverpool and Freda
and associates in New York showed independently
ers by the Rh-positive red cells of their fetuses could
istration of potent anti-Rh gamma globulin to the
mother [44, 45]. In most of the developed world,
erythroblastosis fetalis has become a rare disease of
have become a lost skill.
Hemorrhagic disease of the newborn
Newborn infants may bleed seriously from several
rence of severe bleeding following ritual circumci-
sion of boys, who doubtless had hemophilia, was
It has been reported of four sisters at Sapphoris; the first one
circumcised her son, and he died; the second, and he died; the
be Ganalied who said to her; abstain from circumcision . . . for
there are families whose blood is loose; while in others it coag-
ulates. (Babylonian Talmud, tractate Yehamot, fol. 64, p. 2 )
Armand Quick, in a 1942 review of the history of
coagulation, noted that possible cases of a neona-
tal hemorrhagic disease, distinct from hemophilia,
had been reported from time to time as far back as
1682. Quick also postulated that the delay of ritual
circumcision by Jews until the eighth day of life may
neonatal bleeding symptoms have largely waned by
that time .
6Howard A. Pearson
However, the first definitive description of “the
by C.W. Townsend in Boston in 1894. Townsend
described a generalized, not local, bleeding disor-
der, beginning on the second or third day of life.
About 0.6% of newborns were affected with clini-
cal hemorrhage, chiefly into the skin, gastrointesti-
nal tract, and central nervous system. There was a
62% mortality rate, but if not fatal, the disease was
self-limited, with most cases recovering within five
of transient bleeding only in the first few days of
life, as well as the involvement of girls, clearly differ-
entiated hemorrhagic disease of the newborn from
Lucas and associates performed clotting times, a
measure of the entire coagulation mechanism, and
showed that during the first four days of life, “there
coagulation time which favors the so called hemor-
rhagic condition of the new born” . Whipple in
1912 found that the plasma of a newborn with hem-
orrhagic disease was deficient in prothrombin; this
colleagues in 1937 [49, 50].
Treatment of hemorrhagic disease of the new-
including local compression when possible .
More than half of affected babies died of intracra-
nial hemorrhage or hemorrhagic shock. Lambert in
1908 was able to rapidly reverse the bleeding of an
affected baby by a transfusion in which the father’s
vein. In 1923, J. B. Sidbury, a practicing pediatri-
volemic shock and bleeding disorder of an affected
newborn by giving a blood transfusion through the
umbilical vein. Sidbury stated that “human whole
blood has acted as a specific in this condition” .
In the 1920s, and continuing into the 1940s, the
standard treatment of hemorrhagic disease of the
newborn, and in some centers the prophylaxis of
the condition, was the intramuscular injection of
before the discovery of the Rh factor, and led to the
Rh immunization of some girls and erythroblastosis
in their offspring .
Understanding of the pathogenesis of hemor-
rhagic disease of the newborn was made possible in
1929, when Dam and associates showed that chicks
ing tendency that could be prevented by feeding
They named the correcting factor “Koagulations-
vitamin,” or vitamin K [54, 55]. The nature of the
bleeding defect in vitamin K-deficient chicks was
soon localized to a deficiency of prothrombin and
defined clearly by Brinkhaus and colleagues and
Dam and colleagues in normal babies and those
ciates showed that vitamin K administration could
Synthesis of vitamin K was accomplished in 1939
. Routine vitamin K prophylaxis (0.5–1.0mg) for
all newborns was recommended by the Committee
on Nutrition of the American Academy of Pediatrics
in 1961, and vitamin K-associated hemorrhagic dis-
ease of the newborn has virtually disappeared in the
developed world . It should be mentioned, how-
ever, that the incidence of hemorrhagic disease of
the newborn had decreased markedly in the USA
even before vitamin K prophylaxis became a rou-
tine; this decrease was probably a consequence of
the declining incidence of breast feeding from the
1930s through the 1960s. The vitamin K content of
breast milk is much lower than that of cows’ milk,
and hemorrhagic disease of the newborn occurs
almost exclusively in breast-fed infants who, delib-
erately or inadvertently, do not receive prophylac-
tic vitamin K [60, 61]. The biochemical basis of the
action of vitamin K has been shown to relate to
the gamma-carboxylation of glutamic acid residues
in the vitamin K-dependent coagulation factors,
including prothrombin .
This review of the history of neonatal hematology
makes clear that study of the blood of the fetus and
Neonatal hematology: a historical overview7
newborn has captured the attention of many pedi-
atricians and hematologists over many years. It is
surprising how large their contributions were and
that “there is little new under the sun.” The sagas of
erythroblastosis fetalis and hemorrhagic disease of
recognition and description, to definition of patho-
genesis, to empiric and then specific therapy, and
finally to prevention.
tologists. However, we are now seeing a generation
of hematologists who have been trained in neona-
tology, who work in newborn special care units,
and who have made hematology their clinical and
As we examine neonatal hematology today, the
tology have been succeeded by modern eras of bio-
chemical and genetic investigation of the processes
of many of the blood diseases that affect the new-
born. Discoveries in these areas will revolutionize
neonatal hematology and will make a wonderful
story for another historical overview in the twenty-
second century, or perhaps even sooner.
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8Howard A. Pearson
22 Scott, R. B. Screening for sickle cell in newborn infants. Am
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Yang, M. M. Routine screening of umbilical cord blood
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29 Darrow, R. R. Icterus gravis neonatorum: an examination of
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32 Levine, P., Katzin, E. M., Burnham, L. Isoimmunization in
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1946; 2: 922–924.
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38 Allen, F. H., Diamond, L. K. Erythroblastosis Fetalis. Boston,
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40 Chown, B. Anaemia from bleeding of the fetus into the
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42 Liley, A. W. Liquor amni analysis in the management of the
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49 Whipple, G. H. Hemorrhagic disease. Arch Intern Med 1912;
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Neonatal hematology: a historical overview9
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Disorders of the fetomaternal unit
Eric J. Werner, M.D.
Eastern Virginia Medical School and Children’s Hospital of The King’s Daughters, Norfolk, VA, USA
the interface between the maternal and fetal circu-
lations, providing nutrition, oxygen, fluid, and elec-
trolytes and removing fetal waste and carbon diox-
the presence of pathogens or toxins that can cross
the placental barrier, can adversely affect the fetus.
This chapter will discuss disorders of the maternal–
the fetus and/or newborn infant.
Hemorrhagic disorders of the fetoplacental unit
The average blood volume of the fetoplacental cir-
culation is roughly 110ml/kg , and hence a rel-
atively small amount of blood loss can be a siz-
able proportion of the fetal blood volume. Placental
abnormalities causing fetal blood loss are shown in
Table 2.1. Such blood loss can be visible, as with pla-
suspect fetal blood loss if the neonate presents with
shock and pallor. The placenta and cord should be
inspected for pallor, a hematoma, or other anoma-
lies. As discussed below, maternal blood should be
studied for the presence of fetal cells.
Abruptio placenta and placenta previa
also occur [2, 3]. The frequency of neonatal anemia
requiring transfusion increases with the severity of
fetal erythrocytes using the Kleihauer–Betke stain,
which identifies cells containing hemoglobin F.
Placental or umbilical-cord damage can cause
rupture may occur, especially with traumatic deliv-
ery, the presence of velomentous cord insertion, or
significant fetal blood loss.
Infants who have experienced acute hemorrhage
during fetal life present with clinical features of
acute anemia; pallor, hypovolemia, and hypoten-
A hemoglobin measurement immediately following
birth often does not reflect accurately the severity of
the bleeding. Furthermore, because capillary blood
counts are generally higher than central measure-
ments, especially in the acidotic infant, they may
ally with volume expanders such as Ringer’s lactate
indicated for large fetal blood loss.
Small quantities of fetal erythrocytes pass into the
maternal circulation in the majority of pregnancies
. In approximately 98% of pregnancies, less than
2ml of fetal cells are found in the maternal blood
Disorders of the fetomaternal unit11
Table 2.1 Causes of fetal blood loss
Placenta previa (if fetal vessels are torn)
Placental laceration at operative delivery
Umbilical-vessel injury during amniocentesis
Fetofetal transfusion (twin–twin transfusion)
. However, in about 0.3% of pregnancies, this vol-
ume exceeds 30ml, roughly equivalent to 10% of
the blood volume of a 3-kg infant. The presence of
pregnancy complications, abortion, pre-eclampsia,
Cesarian section, or complicated delivery increases
sive fetomaternal hemorrhage, e.g. over 30–50 ml,
anemia is dependent upon both the amount of and
the time course of the hemorrhage, i.e. a large acute
bleed presents with hypovolemic shock, whereas
tive heart failure.
The usual approach is to examine maternal blood
lost into the maternal circulation, especially if there
is a blood-group incompatibility between the infant
and mother. False-positive results can occur if the
mother has an increased percentage of hemoglobin
F in her own cells, as may occur with the hereditary
persistence of fetal hemoglobin, aplastic anemia, or
use of cancer chemotherapy . Fetal ultrasound
ably sensitive to the identification of fetal anemia
but, as discussed in Chapter 6, Doppler studies of
fetal middle cerebral artery-flow velocity may be a
useful technique to identify fetal anemia [14, 15].
indicate fetomaternal transfusion .
As with acute hemorrhage, the initial management
for acute severe fetomaternal bleeding is volume
expansion using isotonic crystalloid solutions and
possibly red-blood-cell transfusion. Chronic bleed-
ing, not resulting in severe or symptomatic anemia,
can be managed with iron supplementation.
Twin–twin transfusion syndrome
Twin–twin transfusion syndrome (TTS) is the result
monozygotic, monochorionic twins. Dickinson and
1 per 4000 births and 1 per 58 twin births in West-
ern Australia. Vascular anastomoses can be arterio-
arteriolar, veno-venous, or arterio-venous. The inci-
dence of TTS is higher if there is a velamentous
cord insertion . Postnatally, the diagnosis can be
confirmed by injecting milk or other fluids into the
TTS may be acute or chronic. With chronic twin–
twin transfusion, the recipient twin becomes hyper-
volemic, stimulating increased fetal urination and
polyhydramnios. The donor twin becomes ane-
mic and develops oligohydramnios. Acute TTS usu-
ally occurs at delivery. The donor twin typically
has symptoms of hypovolemia while the recipi-
ent twin is at risk for polycythemia/hyperviscosity
called into question. In a recent study of 97 pairs
of monochorionic twins, Wenstrom and colleagues
 identified 35 pairs with this size discordance.
12Eric J. Werner
Half were concordant for hemoglobin concentra-
tion. In 18%, the smaller twin had the higher
hemoglobin, while in 32%, the smaller twin had the
lower hemoglobin. Furthermore, 36% of the size-
concordant twins were discordant for hemoglobin
concentration. In a study of 178 consecutive twin
onic twins and in seven dichorionic twins. Only one
of five twins with both a >5-g/dl hemoglobin and
a 20% birthweight difference was monochorionic
. Diagnosis of TTS is now often made by pre-
natal ultrasonography. Criteria include discordant
fetal abdominal circumference, polyhydramnios in
one twin and oligohydamnios in the other, and an
increased intertwin difference of systolic/diastolic
plications of prematurity. In addition to plethora
in the recipient twin, a number of other systems
may be involved in the recipient. Cardiac find-
cythemia can result in vascular occlusion [22, 23].
muffin rash) [24, 25] or neutropenia  may be
present in the donor twin. The donor twin may also
suffer renal failure [27, 28].
Many advances have come about recently in
the obstetric management of TTS. Transplacental
digoxin therapy for hydrops fetalis, amnioreduc-
tion, and endoscopic laser coagulation of placen-
tal vascular anastomoses may improve survival [29–
31]. Postnatally, the donor twin may require vol-
ume expansion. If the twin is severely hypovolemic
and/or anemic, then red-blood-cell transfusion is
indicated. Glucose infusions may be necessary for
hypoglycemia in the donor twin. Long-term iron
supplementation should be administered to the
donor twin. The recipient twin should be eval-
uated for complications of the polycythemia/
hyperviscosity syndrome, such as respiratory dis-
tress, jitteriness, seizures, hypocalcemia, hypo-
glycemia, and hyperbilirubinemia. The affected
twin may require partial exchange transfusion.
The complications and management of the poly-
Hematologic consequences to the fetus
of maternal diseases
development. Maternal diabetes may predate the
pregnancy or can develop during pregnancy (gesta-
and 1–5% are affected by gestational diabetes .
Reported problems in infants of diabetic mothers
tional age (SGA) and large for gestational age (LGA),
although the LGA group predominates. Insulin does
not cross the placenta, and hence maternal hyper-
glycemia causes fetal hyperglycemia and resultant
fetal hyperinsulinemia. This increased fetal insulin
of congenital malformations and fetal macrosomia.
There are several hematologic complications in the
IDM, most notably increased rates of polycythemia
Polycythemia in infants of diabetic mothers
IDMs have an increased incidence of polycythemia
. Mimouni and colleagues  found that the
Disorders of the fetomaternal unit13
≥65% at two hours of age) in IDMs was 29% ver-
of delivery, and Apgar scores. The hematocrit of the
infant did not correlate with maternal glycosylated
hemoglobin levels but did correlate with neonatal
found that the hematocrit of IDMs correlated with
maternal glycosylated hemoglobin levels at term
cose control in late gestation has the greatest influ-
ence on the incidence of polycythemia.
Several factors may contribute to polycythemia in
the IDM. Insulin itself may promote erythropoiesis.
Insulin infusion causes increased red cell mass in
stimulate the growth of late erythroid progenitors
in tissue culture . Widness and colleagues 
found that the umbilical-vein erythropoietin con-
centrations were elevated in IDMs and correlated
with maternal HbA1c levels taken the month before
delivery. Fetal erythropoietin concentrations corre-
late with fetal insulin levels . Shannon and col-
leagues  did not find increased erythropoietin
concentrations in IDMs whose mothers had tight
glycemic control throughout pregnancy. Nucleated
red-blood-cell (RBC) levels, which may be a marker
production in the IDM [43, 44].
hyperviscosity syndrome such as hypocalcemia,
hypoglycemia, and hyperbilirubinemia should be
expected and managed (see Chapter 9).
Thrombosis in infants of diabetic mothers
The incidence of thrombosis, especially renal-vein
thrombosis, is increased in IDMs [33, 45]. Clinical
shock, vomiting, hematuria, and a palpable kidney.
IDM. While reported cases of peripartum gangrene
of the limb are rare, 22% of one series were reported
to be in IDMs .
It is likely that the increased incidence of throm-
bosis in the IDM is multifactorial. Polycythemia
causes increased blood viscosity. Birth trauma, in
part caused by macrosomia, may lead to ves-
sel damage. Both platelet and plasma factors
place the IDM at increased risk for thrombosis.
Hathaway and colleagues suggested that there is
increased platelet consumption . Stuart and
tivity and platelet endoperoxide formation in dia-
ical arteries from IDMs born to mothers with
elevated HbA1c values produce significantly less
prostacyclin, a potent inhibitor of platelet aggre-
gation, than those obtained from control infants
or IDMs of mothers with normal values for HbA1c
. Easa and Coen  failed to find a differ-
ence in the prothrombin time, activated partial
thromboplastin time, fibrinogen, factors V, X, or XII,
or von Willebrand antigen. Ironically, they found
slightly lower levels for factor VIII and increased lev-
. Recently, elevated levels of homocysteine, a
in IDM .
Thrombocytopenia in infants of diabetic
Mild thrombocytopenia is seen in IDM [47, 50]. The
mean platelet count in IDMs was shown to be lower
than in matched controls and did not correlate with
maternal glycemic control . Usually, no specific
therapy is indicated.
Hypertension is a well-recognized and potentially
serious complication of pregnancy. Several predis-
posing maternal factors, including age (young or
old), parity, twin gestation, lower socioeconomic
14Eric J. Werner
status, genetic factors, and diabetes, have been
in some women.
In their classic paper defining the normal neona-
tal neutrophil count, Manroe and colleagues 
demonstrated a high incidence of neutropenia in
the infant of the hypertensive mother (IHM). Since
that time, other studies have demonstrated a 40–
50% incidence of neutropenia in the IHM, using
Manroe’s data for the normal range [55–57]. Doron
normative data developed for premature infants. In
contrast, Gray and Rodwell  failed to find an
increased incidence of neutropenia in premature
IHMs compared with matched controls also using
normative data developed for premature infants.
gestational age), and/or Cesarian-section-delivered
IHMs are more likely to have neutropenia. The inci-
dence of neutropenia increases with the severity of
maternal hypertension [56, 58]. Koenig and Chris-
tensen  identified decreased neutrophil produc-
tion, perhaps due to an inhibitor of myelopoiesis, as
the cause of neutropenia in the IHM. Some stud-
ies have shown this neutropenia to last for less
than 72 hours [55, 57], while another study reported
more prolonged neutropenia . Compared with
infants with sepsis-induced neutropenia, the neu-
tropenia in IHMs occurs earlier in life and does
not have an increased ratio of immature to total
neutrophils . The neutropenia in the IHM may
result in an increased risk of infection. Doron and
colleagues  reported an increased rate of bac-
terial infection in the first 48 hours of life in neu-
tropenic compared with non-neutropenic IHMs.
Other studies have shown an increased incidence
of late-onset infection, usually after the neutro-
penia had resolved [56, 57]. Neutropenia in IHMs
may respond to granulocyte colony stimulating fac-
of this medication in the neutropenic IHM is not
Thrombocytopenia in infants of hypertensive
While thrombocytopenia is seen in 15–36% of
IHMs [55–57, 61], it is generally mild. Thrombo-
cytopenia appears to be more common in infants
of mothers with more severe hypertension or
HELLP syndrome [57, 61]. Disseminated intravas-
cular coagulation (DIC) has been reported in IHMs
whose mothers’ platelet counts were less than
50 000 per ?l .
Polycythemia in infants of hypertensive
been reported . Brazy and colleagues  found
The recommendations regarding the management
of polycythemia are outlined in Chapter 9.
Cancer complicates approximately 1 in 1000 preg-
nancies. The most common cancers in pregnant
women are of the uterus, breast, lymphatic system
and ovaries . The potential effect of treatment
can also occur in pregnant women, the usual sur-
gical treatment does not typically affect either the
pregnancy or the fetus.
Antineoplastic agents used to treat cancer can
cross the placenta . The ability of the fetal liver
and kidney to metabolize these agents is not well
studied. There are differences in both the fetal and
maternal physiology that might affect the toxicity of
these agents [66, 67]. An increase in fetal malforma-
trimester . Congenital anomalies are produced
and colleagues  reported that of 13 women
Disorders of the fetomaternal unit 15
receiving chemotherapy in the first trimester, four
underwent elective abortion, four had a spon-
taneous abortion, and two gave birth to infants
with major malformations. The relative risk of
after the first trimester. The incidence of stillbirth
after intensive chemotherapy for leukemia is 25% in
the first trimester  and falls to about 13% in the
second and third trimesters . Infants exposed
to chemotherapy during the second and third
trimesters may be at increased risk for intrauterine
growth retardation . Idarubicin-induced fetal
cardiotoxicity has been reported . Myelosup-
pressive chemotherapy administered near to the
time of delivery may cause neonatal pancytopenia
, and hence some authors have recommended
trying to avoid myelosuppressive chemotherapy
within three weeks of delivery .
There is limited long-term follow-up of chil-
dren whose mothers were treated with chemother-
apy. One study found no long-term hematologic,
immunologic, or cytogenetic problems among 43
children aged 3–19 years whose mothers received
chemotherapy for malignancies during pregnancy
. A national registry has been established to fol-
Each year, approximately 4000 women undergo
radiation therapy during pregnancy. The topic
of radiation administered during pregnancy has
recently been reviewed . Intrauterine growth
retardation, microcephaly, eye, and central nervous
system (CNS) abnormalities are the predominant
complications of intrauterine exposure to ionizing
radiation in humans . Hematopoietic, hepatic,
renal, and cutaneous effects of radiation therapy
ation late in gestation.
Maternal malignancy rarely spreads to the fetus
or the placenta. Malignant melanoma is the most
common malignancy to metastasize to products of
conception . Dildy and colleagues  reviewed
53 cases of maternal cancer metastatic to the prod-
ucts of conception. Twelve involved the fetus, of
which seven were malignant melanoma and four
further in Chapter 16.
Neonatal lupus erythematosus
The neonatal lupus erythematosus (NLE) syndrome
is believed to be due to the transplacental passage
of autoantibodies, usually anti-Ro (SS-A) or anti-La
(SS-B). Irreversible congenital heart block arising in
cation of the NLE syndrome. Cutaneous manifesta-
tions include hepatitis and occasionally neurologic
manifestations, including seizures.
Transient thrombocytopenia has been noted in
10% of infants with NLE . Antiplatelet anti-
body studies were negative in two infants with
leagues reported a case of NLE-associated micro-
angiopathic anemia with severe thrombocytopenia
that responded to intravenous gamma globulin and
corticosteroid treatment .
Antiphospholipid antibody syndrome
An association between the presence of anticardi-
olipin antibodies and recurrent fetal loss has been
body and/or the lupus anticoagulant is associated
bosis. The cause of the increased thrombosis is not
certain, but it appears to be related to platelet acti-
vation. The IgG isotype of the anticardiolipin anti-
body can cross the placenta . The presence of
for intrauterine growth retardation . There have
been numerous case reports of fetal and neonatal
culature, vena cava, and aorta . The presence
of the anticardiolipin antibody in the newborn is
transient, and thrombosis should be managed as
described in Chapter 13.
16Eric J. Werner
Hematologic effects of maternal
Despite extensive publicity about the medical com-
plications of smoking, maternal cigarette usage
remains common worldwide . In 1994, approxi-
mately 15% of pregnant women, as opposed to 23%
of all women, smoked cigarettes. The prevalence of
ity and maternal education . In Ottawa, approx-
imately 25% of pregnant women used cigarettes,
but a decreasing percentage reported using greater
than one pack/day as the pregnancy progressed
. Although cigarette smoke contains numerous
toxins, the majority of the literature has addressed
the impact of carbon monoxide and nicotine. Mea-
surement of fetal or maternal levels of the nicotine
metabolite cotinine is a better marker of maternal
Infants of smoking mothers have lower birth
weights . In Finland, infants exposed to nicotine
in utero weighed 188g less and measured 10 mm
less than unexposed infants . Maternal cigarette
use is associated with increased rates of placenta
previa, abruptio placenta, ectopic pregnancy, and
premature rupture of membranes (PROM) but with
decreased rates of pre-eclampsia .
Polycythemia with maternal tobacco usage
Cigarette usage increases the concentration of car-
bon monoxide in the mother’s blood. Hemoglobin
has a 200-fold greater affinity for carbon monox-
ide than oxygen. In addition, the presence of carbon
boxyhemoglobin is significantly higher in the new-
 found that, compared with control infants,
F and that their hemoglobin has an increased oxy-
hemoglobin concentrations in infants of smoking
leagues failed to show this relationship , the
degree of maternal tobacco exposure was relatively
low in their study.
Erythropoietin concentrations are higher in
infants of smoking mothers . As erythropoietin
does not cross the placenta, the increased levels are
and to fetal cotinine levels . In a large consec-
utive series, there was no correlation between the
number of neonatal nucleated RBCs and maternal
smoking history , but, ironically, Dollberg and
colleagues  found that infants whose moth-
ers were exposed to passive smoking had increased
numbers of nucleated RBCs in their cord blood.
Hence, multiple factors place the infants of moth-
ers who smoke cigarettes at increased risk for poly-
cythemia and tissue hypoxia.
Bleeding with maternal tobacco usage
While platelet counts are similar in infants of smok-
ing and non-smoking mothers [97, 99], Spinillo and
between heavy maternal smoking and intraventric-
study did not show an excessive activation of the
coagulation or fibrinolytic pathways in the infants
of smoking mothers .
Effects on hemostasis
Vitamin K deficiency is seen in 10–66% of newborns
whose mothers have been treated with anticonvul-
sants, including phenobarbital, phenytoin, and car-
bamazepam [106–108]. Hemorrhagic disease of the
reported. The coagulopathy can be reversed with
Disorders of the fetomaternal unit 17
severe bleeding can also be caused by maternal
Aspirin irreversibly acetylates platelet cyclo-
oxygenase, leading to platelet dysfunction. Prepar-
tum maternal aspirin ingestion within five days of
delivery can cause platelet function abnormalities
in the newborn  and has been associated with
clinical bleeding in the fetus and neonate, including
intracranial hemorrhage . Antenatal exposure
rate of intraventricular hemorrhage in infants deliv-
ered at under 30 weeks gestational age .
As described above, cancer chemotherapeutic
agents can cause neonatal thrombocytopenia.
Thrombocytopenia has been noted in women
treated with thiazides for hypertension, but it is
unclear whether the reduction in platelets is due
to the medication or the underlying pregnancy-
thrombocytopenia (HIT) occurs in a small per-
centage of individuals treated with heparin. It
is manifested by mild thrombocytopenia and,
paradoxically, an increased risk for thrombosis.
HIT is caused by an antibody directed against the
heparin–platelet factor 4 complex. HIT occurs in
pregnant women; since the HIT antibody is an IgG
antibody that is transported transplacentally, it has
been found in cord blood .
Effects on red blood cells
ciency is by far the most prevalent genetically trans-
mitted erythrocyte enzymopathy, with millions of
individuals affected. As the gene is transmitted in
an X-linked recessive manner, the disorder is far
more common in males than females, but females
may be affected if they are homozygous or by the
X chromosomes, as per the Lyon hypothesis. Fetal
hemolysis in G-6-PD deficient fetuses can be trig-
gered by maternal ingestion of compounds known
to induce hemolysis in deficient RBCs, includ-
ing naphthalene, fava beans (broad beans), and
the medications as listed in Table 7.2 [112, 114].
The neonatal manifestations of G-6-PD deficiency
are described in Chapter 7. Cancer chemotherapy
administered to pregnant women can interfere with
erythropoiesis in the newborn.
Effects on leukocytes
Barak and colleagues  reported that infants
whose mothers received antenatal administration
of betamethasone within 36 hours of delivery had
higher leukocyte and neutrophil counts than con-
days. Leukemoid reactions have been noted in a
natal dexamethasone . In a small trial, granu-
locyte colony stimulating factor was administered
to mothers with a pregnancy of <30 weeks’ gesta-
tional age and imminent delivery. Two infants who
their absolute neutrophil counts while no increase
in neonatal neutrophil counts was noted for infants
delivered <30 hours after maternal administration
of this agent .
Maternal nutritional deficiencies
worldwide, with billions of people affected by iron
deficiency and iron deficiency anemia . Iron
11% and 5%, respectively, of non-pregnant women
aged 20–49 years , with nearly identical rates in
women . In the developing world, estimates of
least half being due to iron deficiency .
The diagnosis of iron deficiency can be difficult,
because many standard diagnostic measures can be
affected by pregnancy. Ferritin is an acute-phase
18Eric J. Werner
(iron-saturation ratio) can be affected by inflamma-
able iron in the bone marrow, but marrow sampling
is neither practical nor necessary in most instances.
Some studies have used a hemoglobin concentra-
below the World Health Organization (WHO) crite-
ria for the diagnosis of anemia and factors such as a
serum ferritin <12 ng/ml or an iron saturation ratio
of <15% in adult women to identify iron deficiency.
The serum transferrin receptor level is elevated in
erythropoiesis . The reticulocyte hemoglobin
content is reduced in iron deficiency, but this has
not been well studied in the newborn . Mea-
surements of iron sufficiency and nutrition in the
neonate are discussed in greater detail in Chapter 4.
needs of the growing fetus place an exceptional bur-
den on the iron stores of the mother. The average
daily requirement for absorbed iron during preg-
nancy is 4.4 mg/day and increases from 0.8 mg/day
in the first ten weeks to 7.5 mg/day in the last ten
weeks . The fetal iron endowment is 75 mg/kg
nancy is over 1000mg to cover the needs of the
fetus and the increased maternal red cell volume.
Iron deficiency may be caused by inadequate nutri-
of preceding pregnancies, or a combination of these
The effect of maternal iron deficiency on mater-
nal and fetal health has been reviewed . The
fetus is remarkably effective at extracting iron from
its mother, even when her iron stores are depleted.
There is no correlation between the maternal and
neonatal hemoglobin concentrations at birth .
Studies of the effect of maternal iron stores dur-
ing pregnancy on neonatal iron stores at birth (as
estimated by ferritin levels) have yielded conflicting
results. For instance, Choi found that ferritin con-
iron deficiency (as determined by a ferritin concen-
mothers with normal ferritin levels, but that neona-
anemic . However, serum transferrin receptor
levels were increased significantly in the infants of
iron-deficient mothers. Using elevated zinc proto-
in non-anemic mothers, Harthroon-Lasthuizen and
colleagues  failed to find a significant effect
on neonatal hemoglobin, ferritin, or zinc proto-
porphyrin levels. Iron supplementation adminis-
tered to non-anemic mothers improved measures
of iron stores and lowered erythropoietin levels in
the mother but did not affect measures of iron suf-
ficiency in cord blood . Mild maternal anemia
likely has little impact on fetal growth or measur-
was associated with the lowest incidence of low-
birth-weight infants. Severe anemia, however, can
increase the risk of an adverse outcome, such as low
birth weight or premature delivery [126, 130].
While the newborn’s hemoglobin concentration
maternal iron supplementation during pregnancy
may improve the infant’s hemoglobin levels later in
life. In a population at high risk for iron deficiency,
Preziosi and colleagues  found that infants of
mothers supplemented with iron late in pregnancy
had higher serum ferritin levels at three months of
Folate is a required cofactor in many one-carbon-
the purine and thymidine synthetic pathways and,
hence, affect DNA synthesis. Because this step is
critical for hematopoiesis, folate deficiency can be
a cause of anemia, thrombocytopenia, and neutro-
penia. Folates are also important in the degradation
of histidine and homocysteine. Folate is found in
many foods, especially leafy vegetables, fruits, and
yeast. It is also found in human and cows’ milk, but
Disorders of the fetomaternal unit19
it is absent in goats’ milk. In addition to diet, sev-
eral other factors can affect maternal folate levels.
Excessive cooking inactivates folate. Methotrexate,
pyrimethamine, and trimethoprim inhibit dihydro-
5,6,7,8-tetrahydrofolic acid, the active form of folate
decrease folate absorption from the intestine .
Ethanol, aspirin, smoking, and oral contraceptives
of maternal folate deficiency.
Folate deficiency in unsupplemented pregnant
tant iron deficiency. Megaloblastic changes are seen
in the bone marrows of 25% of pregnant women
. Folate supplementation will improve birth
weight in deficient but not sufficient populations
. Maternal folate deficiency is associated with
an increased risk for neural-tube defects, prematu-
rity, and growth retardation to the fetus . Cur-
rent recommended daily intake for women of child-
bearing age for folate is 400?g/day . Folate is
transported against a gradient in the placenta .
Ek  compared serum and RBC folate levels in
unsupplemented mothers and their infants. At all
gestational ages studied (22–43 weeks), the infants
had higher RBC and plasma folate levels. The infant
weeks but then increased significantly while mater-
nal levels decreased near term, suggesting transfer
to the infant. A high-affinity folate-binding protein
is present in umbilical-cord serum .
Because of the preferential transport of folate
to the fetus, deficiency in the immediate new-
born period is unlikely. Neonates of mothers with
even severe megaloblastic anemia have normal
hemoglobin concentrations . Postnatal events
and liver disease increase the likelihood of folate
deficiency in the neonate. The diagnosis should be
suspected in the malnourished infant with persis-
bocytopenia and/or neutropenia. Bone-marrow
examination may reveal megaloblastic hemato-
poiesis, and hypersegmented neutrophils may be
seen on the peripheral blood smear. The diagnosis
is confirmed by reduced serum or erythrocyte folate
concentrations. Erythrocyte folate levels would be
expected to decline more slowly than serum folate
levels, although whole-blood folate levels have been
of age in term newborn infants of mothers with an
omnivorous diet . Total plasma homocysteine
levels may be elevated in folate deficiency. Cobal-
amin deficiency should also be considered in mega-
loblastic anemia in infants, as cobalamin deficiency
causes reduced erythrocyte folate concentrations
with normal to elevated serum folate levels .
Infants with folate deficiency will respond to folate
supplementation. Often doses as low as 200–500 ?g
may be sufficient, but higher doses may be neces-
added to hyperalimentation solutions.
Cobalamin, or vitamin B12, is a cofactor in the con-
malonyl coenzyme A to succinyl coenzyme A. The
former reaction is critical for creation of intracellu-
lar polyglutamated tetrahydrofolate, the functional
anemia, a peripheral neuropathy with degeneration
of the lateral and posterior columns of the spinal
cord develops. Cobalamin is present only in foods
of animal origin. A complex series of reactions leads
to the absorption and distribution of cobalamin in
tor in the ileum. The complex is then absorbed,
20Eric J. Werner
metabolized, and transported through the blood by
In adults, most cases of cobalamin deficiency are
caused by pernicious anemia (i.e. an absence or
defect in intrinsic factor) or as a result of a strict
vegan diet. Deficiency in pregnancy is rare, as per-
nicious anemia is usually a disorder of older adults
and cobalamin deficiency causes infertility .
In infants, congenital disorders of transport pro-
teins such as transcobalamine II or of cobalamine
metabolism are more common than nutritional dis-
Adult stores of cobalamin total approximately
3000?g . Since the daily cobalamine require-
ment is 3?g/day, it should take years for a
cobalamin-sufficient individual to become dep-
leted. There is preferential transport of cobalamin
from the mother to the fetus. While this causes a
decline in maternal serum cobalamine levels dur-
is but a small fraction of the usual maternal stores.
Neonatal serum cobalamin levels are higher than
age . Maternal cobalamin levels correlate with
neonatal levels in infants of mothers with omniv-
orous diets . Vitamin B12 deficiency is rare in
infants, but cases caused by maternal deficiency
Diagnosis of cobalamin deficiency may be made
by documentation of a low serum vitamin B12 level,
although this does not explain the etiology of the
deficiency. Significant cobalamin deficiency results
bocytopenia and/or neutropenia. The peripheral
blood smear may reveal macrocytes and hyper-
segmented neutrophils. Bone-marrow findings of
megaloblastic hematopoiesis may precede the pres-
ence of anemia. Nonspecific findings of cobalamin
deficiency include elevation of the serum lactate
dehydrogenase (LDH), hyperbilirubinemia, and an
elevated transferrin saturation ratio. Evidence of
functional cobalamin deficiency, such as increased
plasma levels of methylmalonic acid or total homo-
cysteine, may precede anemia .
The treatment of the infant with cobalamin defi-
ciency depends in part on the degree of anemia.
Severe anemia should be treated with slow trans-
fusion, as rapid response to cobalamin is unlikely.
Rapid transfusion in the severely anemic child may
initial doses, e.g. 0.2 ?g/kg, of cyanocobalamin may
be given subcutaneously . Serum potassium
develop, especially if large doses of cobalamin are
administered. Unless there is documentation of a
infant should be studied for a defect in cobalamine
absorption, transport, or metabolism .
On occasion, the fetus can acquire bacterial, viral,
or protozoal infections transplacentally from the
mother (Table 2.2). This section will focus on the
diagnosis and hematologic manifestations of peri-
natal infections. Anemia, thrombocytopenia, leuko-
cyte abnormalities, and coagulation abnormalities
As it is not yet possible to rapidly differentiate viral
from bacterial infection in the newborn, the initial
empirical antibiotics. Unless specifically stated, the
management of the hematologic problems found in
is referred to other references, such as the Red Book:
2003 Report of the Committee on Infectious Diseases
from the American Academy of Pediatrics, for spe-
cific recommendations regarding the treatment of
infants with congenital infections .
Toxoplasma gondii is a protozoal feline parasite that
can infect humans and other animals. In almost all
cases of fetal infection, the susceptible mother has
Disorders of the fetomaternal unit21
Table 2.2 Intrauterine infections
Human immunodeficiency virus
vated disease to the fetus. Maternal primary infec-
infection, but the consequences of late-gestation
fetal infection are fewer . Antibiotic treatment
of the mother decreases the likelihood of fetal infec-
tion . Toxoplasma infection in the newborn has
been reviewed [144, 145].
The frequency of seropositivity in pregnant
women varies from 22% and 32% in New York and
London, respectively, to 84% in Paris, where inges-
tion of uncooked meat is believed to increase the
infection rate . In France, from 1970–1980 the
prevalence of congenital infection was estimated to
ital toxoplasmosis was found by neonatal screening
in 52 of 635 000 infants in two US states .
Clinical manifestations in symptomatic patients
include seizures, hydrocephalus, chorioretinitis,
fever, hepatomegaly, splenomegaly, and jaundice.
CNS. Generalized disease appears to be limited to
majority of infants with congenital toxoplasmosis
The diagnosis of congenital toxoplasmosis can be
based on demonstration of the organism, serologic
plished on several tissues or fluids, including the
placenta and amniotic fluid . Serologic tests
glutination, the indirect fluorescent antibody test,
enzyme-linked immunosorbent assay (ELISA) tests,
and others. The sensitivity and availability of these
are several issues to consider when using humoral
responses to diagnose congenital toxoplasmosis.
Specific IgG in neonatal serum can be acquired
transplacentally from the mother; hence, in the first
few months of life, a single positive test for IgG does
not confirm neonatal infection. Persistent or rising
IgG titers in the infant are considered diagnostic but
require serial testing over the first several months
of life. Immunoglobulin A (IgA) may be more sensi-
tive than IgM . While a positive immunoglob-
ulin M (IgM) or IgA serologic test for Toxoplasma
in the newborn should be considered diagnostic for
congenital toxoplasmosis, the fetus does not begin
to make specific antibody until after the fifteenth to
very high sensitivity and specificity for Toxoplasma
. PCR testing of amniotic fluid was shown to
the prenatal diagnosis of congenital toxoplasmosis
. Often, a combination of tests is necessary to
Hematologic manifestations of congenital
Anemia has been reported in 4–64% of infants with
congenital toxoplasmosis and is present in most
to only 10% of infants identified through serologic
screening [144, 152]. The presence of increased
22 Eric J. Werner
anemia is due to hemolysis . Congenital toxo-
plasmosis can cause non-immune hydrops .
Thrombocytopenia can be seen in symptomatic
infection. Alford and colleagues found thrombo-
cytopenia in 10% of prospectively identified infants
. Hohlfeld and colleagues found thrombo-
mosis studied by fetal-blood sampling .
Leukocyte abnormalities have been described
in congenital toxoplasmosis. Eighteen percent of
infants with generalized disease had eosinophilia
. Hohlfeld and colleagues found leukocytosis
and eosinophilia in 7% and 9%, respectively, of
els of CD4 lymphocytes and a lower ratio of CD4 to
CD8 lymphocytes than uninfected infants of moth-
ers with gestational toxoplasmosis .
Congenital syphilis caused by the spirochete Tre-
ponema pallidum was one of the first recognized
perinatal infections. In the USA, risk factors for
congenital syphilis include young maternal age,
low socioeconomic status, parental drug use, sex-
There was a transient increase in the incidence of
congenital syphilis in the late 1980s and early 1990s
in the USA. In the UK, low maternal infection rates
the UK included being born abroad, nonwhite eth-
has been noted in the newly independent states of
the former Soviet Union . High rates of gesta-
tional syphilis have also been reported from Bolivia
Australia (28%) .
infection in mothers of stillbirths is significantly
greater than in mothers of live births. Syphilis is a
cause of stillbirth, non-immune hydrops  and
intrauterine growth retardation. Many organs can
(snuffles) can be profuse and, occasionally, bloody.
Other features include a maculopapular skin rash,
other skin rashes. X-rays may reveal osteochon-
dritis, osteomyelitis, and/or periostitis of the long
bones. Congenital syphilis has been reviewed [156,
The diagnosis of congenital syphilis may require a
high index of suspicion in the absence of obvious
cres appear, they may be non-painful and hidden
early in pregnancy will miss infection later in ges-
tation. Placental abnormalities, such as the pres-
ence of plasma cells, may suggest the diagnosis of
be discharged from the hospital without determina-
tion of the mother’s serologic status for syphilis and
for screening .
inations, tests for the organism, serologic tests, and,
recently, PCR assays. Non-treponemal tests have
long been used as screening tests for syphilis. The
venereal disease research lab (VDRL) and rapid
plasma regain (RPR) identify antibody against car-
diolipin. The RPR may be the more sensitive test for
tion in the CSF . If the infant’s serum antibody
tant to use the same assay performed in the same
laboratory. Problems with non-treponemal assays
include a relatively high false-negative rate in early,
latent, and tertiary syphilis, a potential for a false-
negative reaction with very high titers of antibody,
and false-positive results caused by autoimmune
Disorders of the fetomaternal unit23
disorders, other infections, hepatitis, and lym-
phoma. Wharton jelly contamination can cause a
false-positive non-treponemal antibody test from
cord blood . Testing cord-blood sera may be
less sensitive than testing neonatal serum at two to
three days of age . Non-treponemal antibody
titers decrease over time with successful treatment
Specific treponemal antibody tests are also used;
these include the fluorescent treponemal antibody
absorption test (FTA-ABS) and the microhemagglu-
diagnosis . Because these tests usually remain
positive, even in treated patients, the presence of
a positive test does not prove active disease and
Unless the disease is early, a negative test excludes
the diagnosis. Because false-positive tests can be
a non-treponemal test.
Several tests for the organism or antigen have
been used. Organisms can be seen on darkfield
microscopy of placenta and discharge from snuffles
ism, although this is a technically difficult test. Use
compared well to the rabbit infectivity test .
Hematologic features of congenital syphilis
with congenital syphilis. Eight had anemia. They
observed that infants with the largest spleens had
the most severe anemia, but splenectomy failed
to resolve the anemia in one of these infants.
Infants presenting in the first week of life have
typical features of hemolysis, i.e. hyperbilirubine-
mia, increased reticulocyte counts, and periph-
eral blood-smear findings of polychromasia and
increased numbers of nucleated RBCs. The hemoly-
Hemoglobin levels generally became normal after
three months of age. While hyperbilirubinemia is
common, most infants have elevation of both the
direct and indirect fractions of bilirubin.
Thrombocytopenia was found in 28% of South
African infants with congenital syphilis .
Whitaker and colleagues  documented throm-
counts were performed. Platelet counts as low as
17000–20000/?l were seen in both series. Neu-
vacuolization of the granulocytes and 5% peripheral
Hemophagocytosis has also been described .
Congenital viral infections
Approximately 1% (range 0.2–2.2%) of newborns are
infected by cytomegalovirus (CMV) [168–170]. Most
symptomatic intrauterine infections occur with pri-
mary infection in the mother; however, congeni-
tal infection occasionally may occur in infants of
seropositive mothers . Maternal seropositivity
rates vary with location and socioeconomic status.
Females in developing countries or of lower socio-
economic status are more likely to become infected
with CMV early in life and to be seropositive before
pregnancy . Despite this lower susceptibility
rate for primary infection, women of low socioeco-
tion during pregnancy . Stagno and colleagues
found that 52% of infants born to mothers with pri-
mary CMV contracted the infection as opposed to
<1% of infants born to mothers who were seroposi-
tive before pregnancy .
Infants can also be infected during delivery from
exposure to maternal secretions, and postnatally
from breast milk of infected mothers, via blood
transfusion, or from exposure to infected individu-
can be similar to those of congenital CMV .
24Eric J. Werner
Fig. 2.1 Dermal hematopoiesis in a newborn. Courtesy of
Dr Evan Farmer, with permission.
with congenital CMV, only 18% of infants showed
signs of the disorder, and all of these were born to
mothers with primary infection . Symptomatic
congenital CMV infection has been described in
infants of mothers who were seropositive for CMV
CMV may be born prematurely or have intrauter-
with congenital CMV have profound involvement,
with findings that include petechiae, hepatomegaly,
splenomegaly, and jaundice . Neurologic prob-
lethargy, poor suck, and seizures [173, 174]. Intra-
cerebral calcifications are a sequel of congenital
infection. Ophthalmologic findings include chorio-
retinitis, optic neuritis, cataracts, and colobomas.
Multiple other organs, including the kidneys, liver,
gastrointestinal tract, lungs, thyroid, and pituitary,
can be affected . Infants may present with
the classic “blueberry-muffin rash” due to dermal
hematopoiesis (Fig. 2.1) . Survival and/or long-
term outcome of these infants is very poor.
Most infants with congenital CMV infection are
asymptomatic at birth, but sequelae may appear in
ital CMV infection who are asymptomatic at birth
develop significant mental retardation or hearing
deficit within the first five years of life .
The recent demonstration of symptomatic CMV in
nal IgG cannot be used to exclude perinatal CMV
infection . Diagnosis in the fetus can be chal-
lenging. While ultrasound abnormalities consistent
with CMV combined with positive maternal serolo-
gies strongly support the diagnosis of intrauterine
infection, a normal ultrasound does not exclude
either congenital infection or sequelae . Early
in gestation, infants are incapable of producing IgM
. Furthermore, if the infected fetus does pro-
delivery. The most sensitive techniques for prena-
tal diagnosis are viral culture from amniotic fluid
and detection of CMV DNA via PCR, although this
may be less sensitive in fetuses under 21 weeks’ ges-
tation . Culture of CMV and PCR from amni-
otic fluid have similar sensitivity, specificity, and
positive predictive value . Postnatally, tech-
niques for diagnosing congenital infection include
culturing of the virus from blood or urine and
detecting CMV antigen in the urine or peripheral
Hematologic manifestations of congenital
Thrombocytopenia and petechiae are common
in symptomatic infants . Hohlfeld and col-
leagues found that 36% of infants with congeni-
tal CMV had thrombocytopenia, and that 38% of
these had a platelet count below 50000/?l .
Several observations suggest that there is accel-
erated platelet destruction with congenital CMV.
Consumptive coagulopathy and thrombosis have
been noted in infants with congenital CMV [182,
183]. Apparent immune thrombocytopenia follow-
ing congenital CMV infection has been reported
. Hypersplenism may also contribute to the
shortened platelet lifespan. However, human CMV
infection can also impair megakaryocyte viability
. Hence, decreased platelet production may
contribute to the thrombocytopenia.
Disorders of the fetomaternal unit25
Hemolytic anemia is a common finding in infants
chromasia, and abnormal RBC morphology may be
seen in the peripheral blood of infants with con-
genital CMV [170, 186]. Contributing factors include
RBC membrane damage and hypersplenism .
infantile CMV . CMV has been shown to infect
throcyte production may play a role .
Leukocyte abnormalities are common. Atypical
lymphocytosis can be seen . Prolonged neu-
tropenia following congenital CMV infection has
been reported .
Rubella is a member of the togavirus family. It has
a worldwide distribution, but vaccination has dra-
matically decreased the prevalence of viral infection
in the developed world. Maternal infection is usu-
ally confirmed serologically . Positive rubella-
infection, but false-positive tests may be seen with
compromised women may occur, but the risk of
damage to the fetus from such reinfections is small
have been reported in women who have been vac-
cinated or who have serologic documentation of
immunity before pregnancy [194, 195]. The trans-
mission rate from an infected mother to the fetus
is highest in the first and last trimesters; however,
the development of fetal embryopathic changes is
limited to infection in the first 15 weeks of gestation
The diagnosis in the newborn is often suspected
on clinical grounds. The common manifestations
of congenital rubella syndrome include intrauter-
congenital heart disease (such as patent ductus
arteriosus and peripheral pulmonary artery steno-
sis), meningoencephalitis, mental retardation, bony
stitial pneumonitis, and ophthalmologic findings,
including cataracts, retinopathy, and/or cloudy
corneas [192, 196]. These infants may also present
with the blueberry-muffin rash of dermal erythro-
poiesis (Fig. 2.1) .
Viral culture should be attempted from urine and
from throat swabs. Viral shedding may persist for
months, and virus may be cultured from the CNS
of infants with encephalitis . Virus can also be
cultured from blood, urine, throat, and nasal speci-
mens . Rubella-specific IgM from the infant is
a strong indicator of congenital rubella, but false-
positive tests can occur with rheumatic factor or
incomplete removal of IgG in the preparation of the
specimen . Rubella-specific IgM persists for a
genital infection . PCR has been used to diag-
nose rubella in the fetus of infected mothers .
Hematologic manifestations of congenital rubella
Decreased platelet counts are commonly seen in
the congenital rubella syndrome (CRS) [200, 201].
infants [202, 203]. Cooper and colleagues reported
that 17% of infants with congenital rubella had
platelet counts below 20000/?l . Bone marrow
studies from thrombocytopenic infants with con-
genital rubella showed decreased megakaryopoiesis
with a shift to more juvenile megakaryocytes [202,
205]. Splenic sequestration may be a contributing
factor. DIC has been reported .
Anemia is common and may be present at birth
or develop over the first month [202, 204]. There
are several features that suggest hemolysis. Periph-
ogy and increased numbers of normoblasts. The
reticulocyte count is increased. The bone marrow
usually shows accelerated erythropoiesis with an
increased erythroid:myeloid ratio . Decreased
RBC survival has been documented . One
26Eric J. Werner
report, however, described a transient bone marrow
Leukopenia and leukocytosis have been noted in
patients with congenital rubella . Lymph-
mately 20% of patients. Hepatomegaly and/or
splenomegaly are common in symptomatic infants
Herpes simplex virus (HSV), like most of the her-
pesvirus family, has the ability to remain latent after
with symptoms. There are two distinct antigenic
types of HSV. HSV 1 usually infects the oral region
while HSV 2 typically involves the genital region.
Acquisition generally occurs through intimate con-
tact. Seropositivity to HSV 2 parallels the onset of
tests do not distinguish reliably between HSV 1 and
HSV 2. Unless the exposure was recent, a negative
serologic test should exclude prior exposure in the
mother . PCR of active lesions can be used
for diagnosis. Viral culture has been the gold stan-
dard but is limited to times of active viral shedding
. Most infants with congenital HSV are born to
asymptomatic mothers . Factors that increase
nal infection during gestation, infection late in ges-
specific antibody to the fetus), and prolonged rup-
ture of membranes .
The incidence of perinatal HSV in the USA is
tion of the neonate can occur in utero, during
delivery, or postnatally. Intrauterine transmission is
ilar to those of other congenital infections, such as
toxoplasmosis and CMV. More commonly, the new-
during delivery . Perinatal HSV presents in the
in the first week . HSV 2 is responsible for 70%
of neonatal HSV infection . Infection may also
mothers, fathers , and other providers. Perina-
eyes, mouth, and/or skin, CNS disease with or with-
out involvement of the eye, mouth, and skin, and
disseminated disease . Disseminated disease is
often fatal and may involve the liver, lungs, heart,
CNS, skin, and other organs.
In the absence of skin vesicles, the diagnosis of dis-
seminated neonatal HSV is clinically indistinguish-
able from many other congenital infections. Rapid
diagnosis can be attempted with direct fluorescent
antibody staining of scrapings from viral lesions.
The gold standard is viral culture, which may be
obtained from the infant’s CSF, stool, conjunctivae,
urine, and/or oropharynx. Recently, the PCR has
been shown to be effective in the diagnosis of CNS
HSV in the newborn .
Hematologic manifestations of congenital herpes
infection [183, 211, 213–215]. In 1970, Miller and
colleagues  reviewed the available literature on
fatal neonatal HSV. Abnormal bleeding was noted
in 22 of 54 cases and abnormal coagulation studies
were reported in seven of ten studied cases. Hep-
atic disease can contribute to the coagulopathy. The
presence of DIC increases the infant’s risk of dying
from neonatal HSV . Neutropenia may also be
The enterovirus family, including coxsackie virus,
echovirus, poliovirus, and enterovirus, consists of
causes of illness in humans. In the immunocompe-
tent host, infections are generally self-limited and
Disorders of the fetomaternal unit27
summer and the fall.
While most cases of enteroviral infection in the
newborn are self-limited, serious infection may
occur . Infection can occur through transpla-
cental passage, contact with the virus in the passage
eral nursery epidemics have been reported with dif-
ferent enteroviruses .
Symptoms of neonatal enterovirus infection vary
widely. An extensive review of these potential symp-
toms by organ system and by virus has been writ-
ten . Abzug et al.  identified 29 infants
with culture-proven enterovirus in the first 14 days
of life. Fever, irritability, lethargy, and anorexia were
noted in over half, while decreased perfusion, res-
piratory abnormalities, jaundice, and rash were also
common. CNS involvement was found in 53% of the
infants in whom CSF cultures were obtained. Severe
thy, meningitis, and pneumonitis, may occur. These
comparative data are lacking, echovirus 11 has been
reported frequently to present with severe disease
Virus isolation has been the gold standard for diag-
nosis of enteroviral infections. Proper handling of
the specimen is critical. It is recommended that
specimens be taken from multiple sites, including
CSF, blood, urine, and other body fluids. Swabs
from mucosal surfaces need to be sent in trans-
port medium . The large number of potential
serotypes makes antibody detection impractical.
Recently, PCR studies on serum and CSF of new-
borns infected with enterovirus have been shown to
than viral culture .
Hematologic manifestations of congenital
DIC is a common feature of enteroviral hepatitis
with multiorgan involvement. In a series of patients
who, by definition, had hepatitis and coagulopa-
boplastin and thrombin times were seen in 100%,
and prolonged prothrombin times, elevated fibrin
split products, and decreased fibrinogen concentra-
tions were seen in over 85%. Two-thirds had ane-
mia and 60% had peripheral leukocytosis . In
another series of infants diagnosed with enterovirus
in the first 14 days of life but not limited to those
with hepatitis and coagulopathy, 17% were noted
to have thrombocytopenia . Bleeding is often
a cause of death in infants with enterovirus hepati-
tis and coagulopathy . Intraventricular hemor-
rhage may result . Leukocytosis, neutrophilia,
and increased numbers of band forms are often
From the hematologic perspective, supportive care
management of DIC is outlined in Chapter 13.
Human parvovirus B19
Human parvovirus B19 is a small DNA non-
enveloped virus that propagates in the human ery-
throcyte precursor. It enters the cell through the P
P antigen are not susceptible to infection. The com-
mon childhood illness erythema infectiosum, also
known as fifth disease, is caused by parvovirus B19.
Parvovirus B19 is transmitted mainly by respi-
ratory droplets, although percutaneous exposure
to blood or blood products and vertical maternal-
Infection is often asymptomatic. Common symp-
toms include fever, rash, and arthralgia. Symptoms
of the joints may be difficult to distinguish from
rheumatoid arthritis, especially in adults. In rare
instances, vasculitis, myocarditis, and neurologic
disease have been reported . In immunocom-
mia may result.
28Eric J. Werner
In immunocompetent individuals, acute par-
eral days. Because the usual erythrocyte lifespan is
120 days, this should not cause symptomatic ane-
mia. However, in individuals with hemolytic disor-
ders, e.g. sickle cell disease or hereditary spherocy-
tosis, severe anemia may result.
ing parvovirus during pregnancy is estimated to
be 1 in 400 . Despite multiple case reports
of non-immune hydrops and other complications,
most prospective studies have shown a low rate of
complications in the offspring of mothers with pri-
instance, Rodis found 37 of 39 infants of infected
mothers were healthy, with no cases of hydrops
. In Spain, a prospective study identified 1 of 60
infants with perinatal parvovirus infection to have
parvovirus-related fetal loss . In contast, Miller
first 20 weeks of pregnancy. In this group, there were
seven cases of fetal hydrops, all in weeks 11–18 of
gestation. There was no increased risk of adverse
outcomes for women infected after the twentieth
immune hydrops as a result of maternal parvovirus
infection is small, especially after 20 weeks of gesta-
tion. There do not appear to be adverse long-term
effects in surviving infants [231, 232].
Diagnosis of parvovirus B19 infection can be made
serologically through a four-fold increase in IgG
titers or by the presence of parvovirus-specific IgM.
Parvovirus-specific IgM is available commercially
and has a sensitivity of 90–97% with a specificity
of 88–96% in adults . Alternatively, PCR can be
used to identify parvovirus DNA . IgM may be
absent, especially if the infant is infected early in
gestation. Koch and colleagues  studied infants
from 43 women with primary parvovirus B19 infec-
tion during pregnancy. Using a combination of IgG,
IgM, and 11 were positive by PCR. Only 22% of the
IgM. Giant pronormoblasts may be identified in the
marrow of individuals infected with parvovirus B19
Hematologic manifestations of congenital
parvovirus B19 infection
While it is uncommon, fetal hydrops has been
reported as a complication of maternal infection
with parvovirus B19 [236–239]. Fetal demise may
occur up to 14 weeks after infection. The manage-
ment of non-immune hydrops in such fetuses is
unclear. While intrauterine transfusions have been
utilized to treat affected fetuses ; spontaneous
resolution has also been noted [241, 242]. In a retro-
hydrops fetalis treated with intrauterine transfusion
. There are no prospective controlled trials to
answer this question. Forestier and colleagues 
found that 11 of 13 infants with hydrops secondary
having platelet counts below 50000/?l.
The long-term outlook, however, is quite good.
In a long-term follow-up study of 129 congeni-
tally infected infants, Miller and colleagues found
two instances of transient iron deficiency, one case
of transient idiopathic thrombocytopenic purpura,
and one case of transient eosinophilia . While
described in three infants from whom parvovirus
DNA was recovered from the bone marrow .
Red blood cell transfusions may be necessary in the
newborn with parvovirus-induced anemia. Chronic
hypoproliferative anemia may respond to intra-
venous gammaglobulin .
Disorders of the fetomaternal unit29
Human immunodeficiency virus
deficiency virus (HIV) infection remains a problem
of massive worldwide proportions. Perinatal trans-
to 40% and appear to be higher in Africa than in
Europe or the USA . The transmission rate can
be decreased by over 50% with maternal zidovudine
Hematologic manifestations of human
HIV infection affects virtually every aspect of
hematology in the infected host. While hep-
atomegaly and/or splenomegaly may be present,
most neonates are asymptomatic and the clinical
The hematologic aspects of HIV in older infants
and children have been reviewed elsewhere .
The clinical and immunologic effects of congeni-
tal HIV infection are discussed in Chapter 12. The
majority of infants infected with HIV are asymp-
tomatic, but the current use of antiretroviral ther-
apy in the mother can affect the hematologic status
of the infant. In a randomized trial of zidovudine
in pregnant HIV-infected women, Connor and col-
leagues  reported lower initial hemoglobin lev-
els in infants of treated mothers, although the mean
hemoglobin at birth was still 16g/dl. The maxi-
mal difference between the infants of zidovudine-
treated versus untreated mothers was 1g/dl at three
weeks of age. The mean hemoglobin nadir at six
weeks of age was 10g/dl, which was still slightly
lower than that in infants of untreated mothers. By
12 weeks of age, both groups were similar, at about
11g/dl. Sperling and colleagues  followed 30
infants whose mothers were treated with zidovu-
dine during pregnancy. The mean hemoglobin at
birth was 15.0±2.3g/dl. Seven infants had ane-
mia, three with hemoglobin values below 12g/dl.
Of these seven, three were under 28 weeks’ gesta-
tional age. A 28-week gestational age infant (one
of twins) had thrombocytopenia but also congen-
ital sepsis and CMV. One infant also exposed to
aciclovir and trimethoprim-sulfamethoxazole had
neutropenia. Mandelbrot and colleagues  eval-
uated infants of 29 thrombocytopenic women with
HIV who received different antiretroviral regimens
during pregnancy. Of 28 infants, only two had
mildly reduced platelet counts. One had concomi-
tant group B streptococcus (GBS) sepsis and a
platelet count above 100000/?l while the other had
a platelet count of 74000/?l. Combined antiretro-
viral therapy may have a greater effect on neona-
in the infant can cause anemia and neutropenia
The general and antiviral management of the infant
with congenital HIV is complex and beyond the
scope of this chapter; it is discussed in Chapter 12. A
bone-marrow examination should be considered in
HIV-infected infants with depressed hematopoiesis
to rule out marrow invasion or infection by oppor-
Erythropoietin may help increase hemoglobin in
children treated with zidovudine. Iron supplemen-
tation of 6mg/kg/day of elemental iron is usually
necessary to see an optimal effect from erythro-
poietin. Red blood cell transfusion may be neces-
Anemia due to chronic infection may be amelio-
rated with appropriate antimicrobial therapy. Intra-
infected patients with chronic human parvovirus
B19 infection . Relatively low doses of gran-
ulocyte colony-stimulating factor can increase the
neutrophil count to normal in children with HIV-
induced neutropenia (253).
Severe thrombocytopenia can cause clinical
bleeding. Microangiopathic changes on the periph-
eral blood smear suggest the diagnosis of hemolytic
uremic syndrome/thrombotic thrombocytopenic
purpura or DIC. The management of DIC begins
with appropriate therapy for the underlying cause.
30Eric J. Werner
Platelet and/or plasma transfusion may be neces-
anti-D, and corticosteroids have all been shown to
improve the platelet count in thrombocytopenic
children with HIV .
Goldberg and colleagues  described a term
hypotonia, micronathia, cataracts, cryptorchidism,
and metaphyseal bone changes. Over the next 20
months, the infant had hypotonia, lymphadenopa-
thy, and hepatosplenomegaly. The hematologic pic-
ture at birth revealed thrombocytopenia and a large
number of atypical lymphocytes. The infant had
serologic and viral culture evidence for perinatal
Epstein–Barr virus (EBV) infection. Another infant
with hepatosplenomegaly, petechiae, thrombocyto-
penia, and intraventricular calcifications had sero-
conversion to both CMV and EBV in the first three
months of life . Horwitz and colleagues 
described an infant with recurrent emesis, diarrhea,
and failure to thrive. The infant died on day 57,
despite aggressive therapy. Serologic studies sug-
gested acute EBV infection, and DNA hybridiza-
tion studies demonstrated EBV in the lymphocytes.
primary EBV in the first trimester of pregnancy. All
three products of these pregnancies were normal
of intrauterine infection . Despite these case
reports, one of which may have been attributed
to congenital CMV, the incidence of perinatal EBV
appears to be very low. The susceptibility rate for
EBV is low. Le and colleagues  found only 58 of
1729 pregnant women to be susceptible to primary
during pregnancy. Fleisher identified three serocon-
versions to EBV in 4063 pregnant women .
There were no readily identified hematologic
effects in these infants. Two infants had thrombo-
cytopenia: one had classic pathologic and clinical
features of congenital CMV  while the other
infant’s mother had significant hypertension .
None of the three infants described in Fleisher’s ser-
but CBC results were not noted .
cinctly by Dr Frank Oski: “It is apparent that disease
in the newborn infant can only be interpreted after
careful questioning and study of the mother. Appar-
ently insoluble diagnostic problems often become
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