Hydrops

DOI: 10.1542/neo.
5-1-e5
2004;5;e5 Neoreviews
Janet H. Murphy
Nonimmune Hydrops Fetalis
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Janet H. Murphy, MB,
ChB*
Objectives After completing this article, readers should be able to:
1. Describe the common causes of nonimmune hydrops fetalis (NIHF).
2. Characterize the primary steps in antenatal investigation of NIHF.
3. Describe the clinical interventions required for in utero management of NIHF.
4. Delineate the procedures required for ongoing postnatal management of the neonate
who has NIHF.
5. Describe the role of postmortem studies in NIHF.
Introduction
Hydrops fetalis has been a well-recognized fetal and neonatal condition throughout
history. Until the latter half of the 20th century, it was believed to be due to Rhesus blood
group isoimmunization of the fetus, although Potter described infants who had nonim-
mune causes of fetal hydrops. The advent of Rho (D) immune globulin resulted in a
decline in the incidence of isoimmune fetal hydrops and increasing prominence of
nonimmune causes of this severe and highly lethal fetal and neonatal condition.
Diagnostic Criteria
Nonimmune hydrops fetalis (NIHF) is as pathologic accumulation of uid in the skin and
one or more other body compartments of the fetus, including the pleural space, peritoneal
cavity, pericardial sac, or placenta. Some authors dene NIHF as edema of the skin plus
uid accumulation in two other compartments of the fetus, but the former denition is
more common.
Incidence
NIHF is estimated to occur in 1 in 2,500 to 1 in 4,000 pregnancies, but the incidence
varies with the ethnic population studied. For example, in Southeast Asia, NIHF is seen in
1 in 500 to 1 in 1,500 pregnancies. In this population, homozygous alpha thalassemia is
common, accounting for 57% to 81% of cases of NIHF in some series, although a more
recent study from Taiwan showed that homozygous alpha thalassemia accounted for only
31% of NIHF. Variations in the incidence of NIHF have been documented when an
infectious epidemic occurs, such as with parvovirus B19 (erythema infectiosum).
General Pathophysiology
Fluid accumulates within fetal tissues or body cavities when the production of interstitial
uid exceeds its rate of reabsorption and removal by the capillary and lymphatic circula-
tions. The production of interstitial uid is a function of the hydrostatic and oncotic
pressures within the capillary and interstitial space and of the integrity of the capillary
endothelium. This relationship is expressed in the Starling equation for the balance of uid
across a membrane as adapted for a capillary:
Filtration of fluid k [(Pcap Ptiss) r ( Oplas Otiss)]
Where k is the ltration coefcient across the capillary wall, Pcap is the hydrostatic pressure
in the capillary, Ptiss is the hydrostatic pressure in the tissue, r is the reection coefcient
*Associate Professor of Pediatrics, University of Washington, Seattle, WA.
Article nephrology
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of a solute, Oplas is the osmotic pressure of plasma, and
Otiss is the osmotic pressure of tissue uid.
If the ltration coefcient k was 1, the capillary would
be freely permeable to water, but this does not occur
naturally. Certain factors, such as hypoxia, endotoxins,
and inammatory mediators, may increase capillary per-
meability to water, resulting in capillary uid leak.
Hydrostatic pressure within the capillary (Pcap) rises
when there is an increase in central venous pressure, an
obstruction to venous drainage, or a rise in arterial pres-
sure. Hydrostatic pressure in the tissue (Ptiss) rises with a
decrease in lymphatic drainage caused by obstruction of
lymphatic duct drainage due to high central venous
pressure, malformation of the lymphatic drainage chan-
nels, or rapid interstitial uid production that exceeds the
capacity for lymphatic drainage and capillary reabsorp-
tion. Given the expansile nature of this compartment,
Ptiss rises slowly.
The reection coefcient r is the degree of permeabil-
ity of the capillary to a given solute. When r 1, the
capillary is impermeable to the solute that would exert
maximum osmotic effect across the capillary wall. Large
molecules, such as albumin, have a high reection coef-
cient and exert greater osmotic pressure within the
capillary. Conditions such as infection or asphyxia in-
crease the permeability of the capillary wall to albumin,
thus decreasing its reection coefcient and, thereby,
increasing edema formation.
A decrease in plasma oncotic pressure (Oplas), such as
occurs in hypoproteinemic states, results in an increase in
tissue uid production. This can occur when hepatic
synthetic function is impaired, as in hepatic infection or
congestion; when plasma protein is lost in the urine, as in
nephrotic syndrome; or when a generalized capillary leak
of protein occurs due to impaired capillary integrity, as in
asphyxia or infection.
Tissue osmotic pressure (Otiss) is lower than capillary
osmotic pressure, but it does rise when osmotically active
solutes such as plasma proteins leak into the interstitial
compartment, as occurs in asphyxial injury or infection.
In the fetus and neonate, all factors in the Starling
equation may be affected to varying degrees by the
underlying pathophysiologic process causing NIHF. The
edema of NIHF is the nal common pathway for a
multitude of multifactorial disease processes that inu-
ence edema formation in the fetus. Isolated hypopro-
teinemic states may be insufcient to cause NIHF, as
demonstrated by the low incidence of NIHF in the
hypoalbuminemia of congenital (Finnish) nephrosis or in
analbuminemia. For any specic precipitating cause of
NIHF, one factor in the equation may predominate. For
example, raised central venous pressure resulting in in-
creased capillary hydrostatic pressure is a major factor in
cardiac causes of NIHF, whether they are disorders of
cardiac structure, function, or rhythm.
Etiologic and Diagnostic Categories of NIHF
A multitude of fetal diseases can precipitate NIHF, and
the list of causes continues to expand as more genetic
conditions associated with NIHF are identied. Causes
of NIHF can be divided into six broad categories: 1) car-
diac, including arrhythmias and anatomic abnormalities;
2) genetic abnormalities; 3) malformations; 4) hemato-
logic disorders; 5) infections; and 6) idiopathic. Current
texts provide comprehensive lists of fetal conditions as-
sociated with NIHF.
Depending on the trimester of pregnancy in which
NIHF is diagnosed, one of the diagnostic categories may
predominate in a series of patients. Published series of
NIHF diagnosed in the rst trimester showthat chromo-
somal abnormalities (genetic) predominate; NIHF iden-
tied in the latter half of the second trimester and the
third trimester is associated with a high percentage of
cardiac disorders. As previously noted, hematologic
problems predominate in some Southeast Asian studies.
In all published series of NIHF, the idiopathic category
remains appreciable, responsible for 5% to 40% of cases in
recent series. More sophisticated fetal diagnostic tech-
niques as well as expanded studies in cytogenetics and
molecular biology are reducing the incidence of the
idiopathic NIHF.
Cardiac causes of NIHF can be divided into structural
malformations, arrhythmias, and myocardiopathies.
A composite of these cardiac factors occurs in some
patients. Structural cardiac anomalies of the right heart
associated with NIHF are those lesions that result in
right heart congestion, elevation of central venous pres-
sure, and right heart failure, such as pulmonary valve
atresia or incompetence and abnormalities of the tricus-
pid valve (eg, Ebstein anomaly). Abnormalities of the left
heart associated with NIHF include aortic valve stenosis
or atresia, hypoplastic left heart, coarctation of the aorta,
truncus arteriosus, endocardial broelastosis, and non-
compacted myocardium. Fetal premature closure of the
foramen ovale or ductus arteriosus is associated with
NIHF, as are absence of the ductus venosus or obstruc-
tion of the superior or inferior vena cava.
Supraventricular tachycardia (SVT) is the predomi-
nant tachyarrhythmia causing NIHF. Heart rates of
220 to 260 beats/min result in inadequate ventricular
lling in diastole with consequent elevation of central
venous pressure. Decreased systolic ejection volume is a
nephrology hydrops fetalis
e6 NeoReviews Vol.5 No.1 January 2004
further result of decreased ventricular lling, and there is
poor perfusion and oxygenation of fetal tissues. Hepatic
venous congestion can result in decreased hepatic syn-
thetic function and hypoalbuminemia. The myocardium
fails because of the sustained increased work load caused
by the tachycardia. These combined factors result in
accumulation of uid in the fetal tissues and NIHF.
Bradyarrhythmia, as occurs in fetal congenital heart
block (usually with heart rates of 65 beats/min), can
result in fetal hydrops due to venous congestion and
elevation of the central venous pressure as well as de-
creased cardiac output and poor tissue perfusion and
oxygenation. Hepatic congestion and impaired synthesis
of albumin can contribute to the NIHF. Fetal bradycar-
dia is difcult to treat, and the resulting NIHF is usually
fatal. When congenital heart block is associated with
maternal collagen diseases, particularly systemic lupus
erythematosus or anticardiolipin syndromes, anticardio-
lipin can cross the placenta and affect the atrioventricular
node, resulting in impaired conduction or even brosis.
Attachment of anticardiolipin to myocardial cells also has
been documented by some investigators and may con-
tribute to cardiomyopathy in the fetus.
Cardiomyopathy associated with NIHF may be pri-
mary, as in endocardial broelastosis and noncompacted
myocardium, or secondary, as in infection due to herpes-
virus, cytomegalovirus, and coxsackievirus infections. It
also may be due to hypoxia and high cardiac output, as in
severe fetal anemia.
Inherited Disorders
Inherited disorders associated with NIHF encompass
chromosome abnormalities, inborn errors of metabo-
lism, and genetic disorders.
Chromosome abnormalities represent the largest sin-
gle category in published series of cases of NIHF diag-
nosed in the rst trimester. Turner syndrome (45XO)
and trisomy 21 are the most common, although trisomy
of chromosomes 18, 13, 15, and 16 all have been asso-
ciated with NIHF. In most of these syndromes, NIHF is
associated with a congenital cardiac malformation of a
type previously described. However, other conditions
associated with the trisomy may contribute to the NIHF.
For example, an atrioventricular septal defect is a com-
mon cardiac malformation in trisomy 21, but chylotho-
rax and disorders of lymphatic drainage also occur, not
necessarily in association with a cardiac defect. Hypoto-
nia and decreased motility associated with this trisomy
also may contribute to the edema, as may polycythemia
and, rarely, congenital leukemia. Congenital cardiac dis-
ease is common with Turner syndrome, but disordered
lymphatic drainage and lymphedema also occur in this
trisomy in the absence of a cardiac abnormality.
Genetic syndromes associated with NIHF usually are
autosomal recessive. Autosomal dominant disorders in-
clude Noonan syndrome, tuberous sclerosis, and myo-
tonic dystrophy. Tuberous sclerosis presenting as NIHF
frequently is seen with rhabdomyoma of the heart, con-
sequent cardiac compromise, and resulting fetal hydrops;
such patients may provide the index case for retrospective
diagnosis within the kindred of the propositus. Among
other associated disorders are certain types of achondro-
genesis and chondrodysplasia; in these conditions, ab-
normal rib growth and decreased thoracic volume may
be contributing factors to NIHF.
Inborn errors of metabolism associated with NIHF
include glycogen storage disease type IV, lysosomal stor-
age diseases, hyperthyroidism, hypothyroidism, and car-
nitine deciency. New lysosomal storage diseases are
being identied, and many cases of NIHF previously
identied as idiopathic may have been caused by a lyso-
somal storage abnormality.
Malformations and Tumors
A variety of congenital malformations associated with
NIHF have been documented. Among the intrathoracic
lesions are congenital diaphragmatic hernia, congenital
cystic adenomatoid malformation of the lung, congenital
pulmonary lymphangiectasia, and bronchopulmonary
sequestration. Congenital malformations associated with
NIHF are often complex, and some include cardiac
malformations as part of the cause of the hydrops.
Congenital diaphragmatic hernia (CDH) is illustra-
tive of a complex malformation in which many factors
may contribute to the development of fetal hydrops.
Abdominal organs displaced through the diaphragmatic
defect cause an intrathoracic mass effect with mediastinal
shift that not only contributes to the pulmonary hypopla-
sia, but also compresses the heart, impairs cardiac func-
tion, and reduces venous return. Displacement of the
liver into the chest could result in impaired hepatic
venous drainage by compression of the portal and he-
patic veins. In left-sided diaphragmatic hernia, there may
be associated left ventricular hypoplasia or other complex
heart disease. Any or all of these factors may contribute to
NIHF in a patient who has CDH.
Congenital cystic adenomatoid malformation of the
lung (CCAM) has been associated with NIHF. The mass
effect of the tumor may raise intrathoracic pressure and
displace the mediastinum and the heart, leading to im-
paired venous return to the heart and an increase in
central venous pressure, with consequent edema, ascites,
and pleural effusions.
Fetal tumors are associated with NIHF. Most notable
are large cystic hygromas of the neck and chest, arterio-
venous malformations, teratomas (especially sacrococcy-
geal lesions), and large hemangiomas or lymphangiomas.
Polycystic renal disease also can be a cause of NIHF.
Sacrococcygeal teratomas may include a vascular malfor-
mation, and bleeding into the teratoma has been associ-
ated with fetal anemia and hydrops. These malformations
also may result in high-output cardiac failure and conse-
quent fetal hydrops.
Arteriovenous malformations may occur within the
fetus, most commonly in the brain and liver, and may
cause fetal hydrops due to high-output cardiac failure.
Hemorrhage associated with the malformation may lead
to anemia and hydrops.
The placenta in a monochorionic twin pregnancy may
be the site of an arteriovenous communication between
the two fetal circulations, leading to twin-twin transfu-
sion and fetal hydrops. Vascular communications within
the placenta of twins are common. Venovenous commu-
nications or arteriovenous communications with addi-
tional vascular communications within the placenta that
permit equilibration of circulating blood volume be-
tween the two fetuses do not pose a severe problem.
However, an arteriovenous communication between the
two fetuses, with the rst twins circulation feeding the
arterial side and its venous drainage entering the circula-
tion of the second twin, has severe hemodynamic and
hematologic consequences dened as twin-twin transfu-
sion syndrome. The recipient twin has an increase in
circulating blood volume and increased venous return to
the heart, resulting in high-output cardiac failure with
myocardiopathy and fetal hydrops. The associated poly-
cythemia also may contribute to overload of the heart,
and renal impairment is common. The donor twin occa-
sionally develops hydrops due to severe anemia and
cardiac failure. Other lesions of the placenta associated
with NIHF include severe fetomaternal hemorrhage, in
which the fetus develops severe anemia and hydrops.
Chorioangioma and choriocarcinoma of the placenta
also can lead to NIHF.
Hematologic Disorders
Anemia that results in cardiac failure is the usual mecha-
nismby which hematologic disorders lead to NIHF. The
anemia is due to hemolysis, hemorrhage, or failure of red
blood cell production.
Intrinsic red blood cell abnormalities due to hemo-
globinopathy or red blood cell enzyme or membrane
abnormality result in hemolysis and anemia. Homozy-
gous alpha thalassemia is a common cause of NIHF in
Southeast Asia and the Eastern Mediterranean. Red
blood cell enzyme abnormalities associated with NIHF
include glucose-6-phosphate dehydrogenase (G-6-PD),
pyruvate kinase, and glucosephosphate isomerase de-
ciencies. Hemolysis also is associated with fetal heman-
giomas in Kasabach-Merritt syndrome. Anemia and
NIHF occur in severe acute fetomaternal hemorrhage,
twin-twin transfusion syndrome, or hemorrhage into
arteriovenous malformations or other fetal tumors.
The production of red blood cells is reduced in clinical
syndromes in which abnormal material is deposited in the
bone marrow. Transient myeloproliferative disorders or
congenital leukemia result in anemia and fetal hydrops.
A few cases of transient myeloproliferative disorder have
been reported in association with trisomy 21, with reso-
lution of the disorder within months of birth. This dis-
order must be differentiated from a leukemoid reaction
associated with congenital infection and severe hemoly-
sis. Parvovirus B19 is tropic for erythroid progenitors
that are lysed, and infection with this virus has been
associated with a transient severe anemia and NIHF.
Infections
A number of infectious diseases have been associated
with NIHF, including those caused by viral, bacterial,
spirochetal, and parasitic agents (Table 1). The most
Table 1. Common Infectious
Causes of Nonimmune
Hydrops Fetalis
Viruses
Human parvovirus B19
Cytomegalovirus
Other herpesviruses (Type I)
Coxsackievirus
Rubella
Parasites
Toxoplasma gondii
Trypanosoma
Spirochetes
Treponema pallidum
Leptospira
Bacteria
Listeria monocytogenes
common infectious causes of NIHF are cytomegalovirus
infection, toxoplasmosis, syphilis, and parvovirus B19
infection.
Human parvovirus B19 initially was reported as a
cause of NIHF in 1984. Fully 50% of the adult popula-
tion has antibodies to this parvovirus, making the re-
maining 50% of pregnant women vulnerable to infection.
However, there is seasonal variation in parvovirus infec-
tions in the community, and the infection rate in the
susceptible adult is 25% to 50%. The virus is not always
transmitted to the fetus, which may not develop anemia
or hydrops. The net result is that few fetuses exposed to
parvoviral infection develop NIHF.
Syphilis always should be a concern in the differential
diagnosis of NIHF, particularly with the resurgence in
congenital syphilis in recent decades. Serology may be
false-negative due to the prozone phenomenon in which
a high antibody level in the tested sera prevents the
occulation of the positive rapid plasma reagin (RPR)
test. Serum dilutions should be a routine procedure
when the initial RPR is negative in a patient who has
NIHF.
Antenatal Investigation of NIHF
NIHF frequently presents based on ultrasonography for
a rapid increase in fundal height due to polyhydramnios
or as an incidental nding on routine ultrasonography.
Currently, increasing attention is turning to the occur-
rence of nuchal edema in the fetus because it may be the
early herald sign of fetal abnormalities, including those
associated with NIHF. Techniques for early identica-
tion of a prodromal stage of NIHF are needed to permit
early, disease-specic therapeutic intervention before
catastrophic fetal hydrops occurs. The nding of a fetus
that has evidence of edema requires a comprehensive
evaluation of mother and fetus to determine the under-
lying cause and the appropriate clinical management.
The evaluation of NIHF requires a well-coordinated
obstetric, genetic, and laboratory investigation. The eval-
uation usually is conducted in a tertiary obstetric facility
where the expertise of a perinatologist, geneticist, pedi-
atric cardiologist, neonatologist, pathologist, and social
worker may be needed for evaluation of the fetus and
counseling of the family.
Presentations in the rst trimester or early in the
second trimester often have chromosomal or other ge-
netic causes of fetal hydrops. Prompt identication of the
cause of the NIHF before fetal viability is reached is
necessary to permit the family the option of pregnancy
termination where appropriate.
Table 2 outlines a protocol for evaluation of mother
and fetus. Amniotic uid testing is common, but evalu-
ation by chorionic villus sampling may be undertaken
instead early in gestation. Because the quantity of fetal
Table 2. Antenatal Investigation
of Nonimmune Hydrops Fetalis
History
1. Maternal past medical and obstetric history
2. Details of current pregnancy and reason for referral
3. Results of previous ultrasonography and laboratory
studies
4. Family history of metabolic or genetic disorders,
consanguinity, ethnic origins
5. History of recent infection or exposure risk to same
Maternal
1. Complete blood count
2. Maternal blood group and antibody testing
3. Infection screening tests: hepatitis, syphilis,
cytomegalovirus, herpesvirus, Toxoplasma, human
immunodeciency virus, group B Streptococcus,
rubella, parvovirus B19, coxsackievirus
4. Autoantibody screen for systemic lupus
erythematosus, antiRo La
5. Evaluation for diabetes mellitus
6. Hemoglobin electrophoresis of both parents if
possible alpha thalassemia carriers
7. Kleihauer-Betke test for fetomaternal hemorrhage
Fetal
1. Detailed level III fetal ultrasonography of all fetal
structures, especially the brain, heart, lungs, liver,
intestine, kidneys, and skeleton. Doppler ow studies
of the umbilical vessels and middle cerebral arteries
2. Fetal echocardiography, including M-mode with
heart rate and rhythm and cardiac dimensions
3. Placental thickness and morphology
4. Amniotic uid index
Amniotic Fluid
1. Amniotic uid cells for karyotype and uorescent in
situ hybridization (FISH) for specic chromosome
defects
2. Amniotic uid for cell count and viral polymerase
chain reaction
3. Optical density
Percutaneous Umbilical Blood Sampling
(where clinically indicated)
1. Fetal complete blood count, including reticulocytes
2. Fetal blood group and Coombs antibody testing
3. Hemoglobin electrophoresis (if indicated)
4. Glucose-6-phosphate deciency screen (males in
at-risk ethnic group)
5. Fetal karyotype and FISH studies if not already
obtained on amniotic uid
blood obtained by percutaneous umbilical blood sam-
pling (cordocentesis) is limited to a few milliliters, the
priority of planned tests must be established. In cases of
suspected fetal anemia, blood group O-negative blood
should be available for umbilical transfusion.
In Utero Management
NIHF presenting in the rst trimester of pregnancy is
associated with a high incidence of chromosome or other
genetic anomalies. Rapid, denitive diagnosis of the
cause is essential, and the family requires extensive ob-
stetric, genetic, and social work counseling regarding the
current and future pregnancies. If the pregnancy is con-
tinued, fetal mortality is extremely high.
Presentation of NIHF in the second or third trimester
offers some hope for effective therapeutic intervention if
a treatable cause is found. Often intervention is directed
toward palliation and maintenance of the fetus until
viability and lung maturity are achieved, but delivery
before 34 weeks gestation remains associated with a
high neonatal mortality rate. Spontaneous preterm labor
and delivery is common and usually related to polyhy-
dramnios. Accordingly, repeated amnioreduction can
help to maintain the pregnancy until fetal viability is
achieved. Following are a fewspecic examples of clinical
interventions.
Fetal tachycardia requires fetal echocardiography to
evaluate fetal cardiac anatomy and function. Fetal heart
rates of 200 beats/min or greater in SVT can be man-
aged with digoxin or other agents. A return to sustained
normal fetal cardiac rates usually results in resolution of
the NIHF. Administration of digoxin to the mother to
the threshold of toxicity has been effective, but fetal
venous congestion and associated placental edema may
interfere with transfer of digoxin to the fetus. In some
cases, direct infusion of a loading dose of digoxin into the
fetal umbilical vein has converted the SVT, and adminis-
tration of subsequent doses to the mother has main-
tained control. If digoxin alone is insufcient, other
agents such as propanolol or ecainide have been used
with success, but pediatric cardiology consultation is
necessary before these drugs are used.
NIHF due to anemia has been treated effectively with
direct transfusion of packed red blood cells into the fetal
umbilical vein. The presence of fetal hydrops and a
sinusoidal fetal heart rate pattern indicates fetal anemia.
Diagnostic PUBS usually is combined with transfusion of
blood group O-negative red blood cells if anemia is
conrmed.
Human parvovirus B19 infection with anemia can be
treated successfully with intrauterine transfusion. Not all
infected fetuses become anemic, but when anemia does
occur, it is usually within 8 weeks of infection, although
many authorities recommend monitoring the fetus for
12 weeks after documented maternal parvovirus infec-
tion during pregnancy. One to three transfusions of red
blood cells may be required before the fetal bone marrow
recovers erythropoietic function. Cases that present in
the third trimester may require only a single transfusion
to correct the fetal hydrops, followed by elective delivery
once lung maturity is assured by amniocentesis and the
possible use of antenatal betamethasone.
Fetal persistent pleural effusions occurring before
26 weeks gestation are associated with restriction of fetal
lung growth and result in pulmonary hypoplasia. This, in
turn, is associated with a high neonatal morbidity and
mortality. Intrauterine centesis of fetal pleural effusions
has been attempted, but often pleural uid reaccumu-
lates within 24 hours of the procedure. Placement of
pigtail pleuroamniotic drains has met with some thera-
peutic success in reducing pleural effusions and allowing
improved fetal lung growth.
Fetal surgery for resection of fetal tumors, such as
sacrococcygeal teratomas or congenital cystic adenoma-
toid malformation (CCAM) of the lung, has been under-
taken in specialized fetal surgery centers with some doc-
umented successes. Spontaneous arrest of tumor growth
or even remission has occurred in some patients who
have CCAM. However, it is intriguing to note that
Harrisons group in San Francisco documented three
instances of prompt resolution of CCAMwhen antenatal
steroids were administered to fetuses awaiting planned
surgical resection. This lesion is considered a disorder of
pulmonary differentiation, which suggests that the re-
sponse to antenatal steroid therapy may be more than
coincidence.
Interventions for twin-twin transfusion have included
amnioreduction for polyhydramnios and fetal transfu-
sion if the donor twin has anemia, but these procedures
have met variable success. Identication of feto-fetal
vascular communications within the placenta and abla-
tion of the abnormal vascular channels has been success-
ful in correcting twin-twin transfusion in some reports.
Neonatal Diagnosis
Neonatal diagnostic testing is a continuum of the inves-
tigation that begins during pregnancy. In most instances,
the neonatal intensive care team has time to prepare for
delivery of a fetus that has NIHF. An important aspect of
preparation is to outline resuscitative measures and neo-
natal diagnostic studies. Frequently it is necessary to
remove ascitic uid from the abdomen or pleural uid to
improve ventilation during resuscitation. This ascitic or
pleural uid should be obtained in a sterile procedure
and placed in sterile containers; if fetal infection is a
concern, the uid is sent for culture and viral PCR
studies. The uid should be analyzed for total protein
and albumin. Chylothorax is characterized by a cell count
of 80% to 90% lymphocytes, underlining the importance
of differential analysis of cells in pleural or ascitic uid.
The presence of profound anemia may necessitate
immediate packed red blood cell transfusion with washed
O-negative cells, but it is essential to obtain samples of
the infants blood prior to transfusion. A complete blood
count and reticulocyte count, blood typing, measure-
ment of serum albumin and total protein, immunoglob-
ulin (Ig) Mand IgGstudies, fetal chromosome studies, a
sample for G-6-PD studies or hemoglobin electrophore-
sis, and routine newborn metabolic screening are impor-
tant to obtain prior to transfusion of donor cells in the
delivery roomor neonatal intensive care unit. During the
resuscitation or immediately thereafter, it is important to
begin monitoring fetal blood gases and correct any met-
abolic or respiratory acidosis.
Detailed macroscopic, microscopic, and electron mi-
croscopic evaluation of the placenta can provide impor-
tant diagnostic information and review of placental pa-
thology such as chorioangioma or vascular abnormalities
that may be the primary causes of NIHF.
Once resuscitation is complete, a comprehensive
physical examination is conducted for evidence of fetal
anomalies, but edema may obscure many physical fea-
tures in the infant who has profound hydrops.
M-mode echocardiography is obtained to evaluate
cardiac structure and function, including chamber size
and myocardial contractility. Small pericardial effusions
are common in NIHF, but an effusion may be of suf-
cient magnitude to impair myocardial function and
prompt ultrasonographically guided pericardiocentesis.
Electrocardiography is important to evaluate disorders of
rate and rhythm.
Radiographic evaluation of the chest for evidence of
pleural effusions and pulmonary hypoplasia is an impor-
tant initial step. Ultrasonography of the lung is helpful in
evaluating CCAM of the lung, if computed tomography
cannot be obtained immediately. A radiographic skeletal
survey is obtained to look for anomalies associated with
genetic or chromosomal syndromes. Cranial ultrasonog-
raphy for structural abnormalities should include Dopp-
ler owstudies for possible arteriovenous malformations,
as should abdominal ultrasonography of the liver. Ab-
dominal ultrasonography identies the presence of ascitic
uid as well as anomalies of the kidneys and urinary tract,
liver, and other abdominal organs or masses.
Finally, genetic consultation is important in the plan-
ning of the neonatal diagnostic evaluation.
Neonatal Management
Delivery Room Resuscitation
In preparing for delivery of an infant who has known
NIHF, the obstetric staff alerts the neonatologist of the
impending delivery. In most instances, the neonatologist
will have been involved in antenatal counseling of the
family and will have reviewed with the family potential
problems for the infant and the planned delivery room
management.
A skilled neonatal resuscitation team is essential, and
personnel should be assigned tasks prior to the delivery.
Fluid sample tubes and equipment for planned diagnos-
tic studies of blood and pleural or ascitic uid are assem-
bled, and umbilical catheters are prepared for emergency
insertion. Establishment of ventilation is a priority, and
prompt intubation and ventilation often are necessary.
Other team members are responsible for paracentesis
abdominis for removal of ascitic uid and bilateral tho-
racentesis for removal of pleural uid to permit adequate
lung expansion. Placement of an umbilical venous line
may be necessary for administration of sodiumbicarbon-
ate or blood transfusion after blood is drawn for planned
diagnostic studies. Anemia may be corrected by simple
packed red blood cell transfusion or partial exchange
transfusion.
Ongoing Management
Once an airway is established and the infant is stabilized,
arterial and central venous access via the umbilical vessels
or peripheral vessels is obtained for blood sampling and
uid administration. Placement of a double-lumen um-
bilical venous line permits both uid administration and
monitoring of central venous pressure. Therapeutic in-
tervention includes both respiratory and cardiac support
in addition to treatment specic to the precise diagnosis
of the cause of hydrops.
SURFACTANT
Many infants who have NIHF are delivered preterm
because of fetal distress or premature labor due to poly-
hydramnios. Once the intubated preterm infant is stabi-
lized, surfactant administration is appropriate. Adminis-
tration of surfactant to the term infant is controversial,
but it should be considered in the presence of severe lung
disease.
MECHANICAL VENTILATION
Mechanical ventilation usually is required in infants who
have hydrops, but published studies comparing conven-
tional and high-frequency ventilation have not docu-
mented any difference in outcome or survival with use of
either mode of ventilation. Because pleural effusions
occurring prior to 26 weeks gestation frequently are
associated with pulmonary hypoplasia, low peak pres-
sures are used for mechanical ventilation, thereby reduc-
ing the risk for pneumothorax.
CHEST TUBE PLACEMENT
Recurrent pleural effusions require placement of pleural
catheters for continuous drainage. It can be difcult to
place a catheter in the face of massive chest wall edema,
but a coiled pigtail catheter may be retained better than a
conventional Argyll catheter.
FLUID AND ELECTROLYTE MANAGEMENT
The infant who has hydrops is in sodium and free water
excess and represents a challenge in uid and electrolyte
management. Sodium and uid restriction and frequent
monitoring of serum and urine electrolytes and total
output are necessary. Diuretic therapy with furosemide
should be used with caution, but it may be effective in
combination with inotropic drugs in cardiac failure.
A combination of furosemide and albumin or intrave-
nous immunoglobulin may help mobilize uid from the
tissues, but 5% albumin approximates a sodium load
equivalent to an equal volume of normal saline. Because
uid losses from pleural drainage can reach 300 to
400 mL/d, careful uid replacement is important. The
high protein and lymphocyte content of pleural uid
necessitates frequent monitoring of serum albumin, Ig
levels, and white blood cell counts. Ongoing replace-
ment of pleural or ascitic uid drainage may be necessary
if these volumes are large and lead to intravascular deple-
tion. Fluid losses may be replaced with 0.5 to 1.0 mL of
normal saline or 5% albumin for each milliliter of uid
drained. Profound hypoalbuminemia may be managed
with 0.5 to 1 g/kg infusions of 25% albumin to attempt
to correct the hypoalbuminemia and optimize renal per-
fusion and function.
INFECTION
Because primary infection may be the cause of NIHF,
bacterial and viral studies should be obtained if not
included in the fetal evaluation. It may be necessary to
continue antenatal antiviral or antibacterial treatment.
Acquired infection is a common problem for the infant
who has hydrops. Broad-spectrum antibiotic therapy
usually is initiated at birth following blood culture, and
the duration of therapy is based on culture results. In-
dwelling arterial and central venous catheters and pleural
catheters increase the risk for infection. Continuing
losses of lymphocytes and gamma globulin in pleural
drainage also increase the risk of infection; Wy and
associates found a 44% infection risk with the presence of
pleural effusion and a case fatality rate of 64%. Close
monitoring of gamma globulin levels and infusion of
intravenous gamma globulin are important consider-
ations for the infant who experiences continuing pleural
or peritoneal drainage.
CARDIAC EVALUATION AND SUPPORT
Complete cardiac evaluation and diagnosis-specic treat-
ment are vital components of medical management, and
a cardiology consultation is essential to the ongoing
management of any infant who has hydrops. A primary
cardiac malformation may be the cause of the NIHF, and
prostaglandin E1 is required for duct-dependent lesions.
Interventional cardiology may be necessary for a stenotic
or atretic valve or vessel. Inotropic and pressor support
often is required for the infant who has hydrops, and
dopamine and dobutamine are used frequently. Digoxin
may be used for inotropic support in the well-oxygenated
infant or in conjunction with other agents for ongoing
management where fetal tachycardia is the cause of the
hydrops. There are complex interactions between many
of the cardiotonic agents and other drugs used in this
clinical setting. Therefore, it is vital for a pediatric cardi-
ologist and a pediatric pharmacist to collaborate in the
management of these patients. Elevated central venous
pressure is a feature of NIHF in many infants that re-
quires monitoring of central venous pressure and careful
uid and electrolyte management, as noted previously.
CARNITINE
Carnitine deciency has been documented as a cause of
NIHF. Accordingly, following measurement of the
blood carnitine level, empiric carnitine therapy should be
considered for infants who have myocardiopathy and
infants requiring long-term total parenteral nutrition
support.
USE OF STEROIDS
Intravenous hydrocortisone may be effective in correct-
ing intractable hypotension unresponsive to pressors
such as dopamine and dobutamine. Adrenocortical in-
sufciency due fetal and neonatal distress requires corti-
costeroid replacement therapy. The use of dexametha-
sone for severe lung disease and prevention of potential
bronchopulmonary dysplasia in preterm infants is very
controversial, as it is in infants who have hydrops.
OCTREOTIDE
Octreotide is long-acting synthetic octapeptide analog of
somatostatin that binds to G-protein receptors and in-
hibits adenylate cyclase activity, thereby decreasing
cyclic-AMP production. Octreotide has been used suc-
cessfully to treat persistent chylothorax and chylous as-
cites in adults, and there are anecdotal reports of its use in
infants. It is administered either subcutaneously or by
intravenous infusion. Subcutaneous administration of
20 mcg/kg of body weight per day divided every 8 hours
or intravenous administration of 1 mcg/kg per minute
has been effective. If chylous drainage persists, the dose
may be increased to a maximum of 40 mcg/kg per day.
Octreotide decreases splanchnic blood ow, gastrointes-
tinal motility, and gastric emptying as well as gallbladder
contraction. It decreases production of gastrointestinal
peptides and pancreatic enzymes and reduces insulin
secretion. The latter effect is the basis for its use in the
treatment of nesidioblastosis. Described adverse effects
are hypoglycemia, delayed gastric emptying, and intesti-
nal ileus. Elevation of liver enzymes has been docu-
mented, and prolonged use is associated with cholestasis
and cholelithiasis. Thrombocytopenia has been docu-
mented with the use of octreotide, and there has been a
single case report of induced pulmonary hypertension.
Persistent chylous drainage has been associated with an
increase in morbidity and mortality. Therefore, oct-
reotide has been reserved for infants who have severe
persistent pleural or peritoneal chylous drainage where
the benets of success outweigh the risk of adverse
effects.
Pathology
Detailed postmortem study of fetal and neonatal deaths
due to NIHF remains extremely important, particularly
for those cases described as idiopathic, and parental
consent for autopsy always should be requested. Any
planned laboratory investigation listed in Table 2 should
be completed. A complete radiographic survey of the
skeleton is obtained to look for skeletal anomalies and
thoracic dysplasia. Detailed macroscopic, microscopic,
and electron microscopic studies are required of the
placenta and the infant organs, including brain, heart,
lungs, liver, kidneys, and any masses or tumors. Any
concerns for underlying genetic disease, such as lysoso-
mal storage disease, should prompt harvesting of DNA
for analysis and for comparison with fetal DNA in the
mothers future pregnancies. Preservation of DNA for
further study is especially important in those cases classed
as idiopathic; fetal cells can be grown to conuence,
harvested, and frozen for future reference.
Mortality and Outcome
Despite advances in fetal diagnosis and fetal and neonatal
therapy, the mortality for NIHF remains extremely high
in most case series. Liveborn infants who have NIHF
have a mortality of approximately 50%. Diagnosis of
NIHF before 24 weeks gestation with subsequent later
delivery is associated with a very lowsurvival rate of 4% to
6%.
The cause of the NIHF has a profound inuence on
infant outcome. Homozygous alpha thalassemia is asso-
ciated with virtually 100% mortality. SVT has the best
prognosis for survival and has been controlled success-
fully with digoxin or other agents. In North America,
NIHF due to congenital syphilis has a good prognosis for
survival if treated early and effectively with antibiotics,
but the same disease has a very poor prognosis for sur-
vival in Africa. Red blood cell transfusion for the fetus
that has anemia due to parvovirus has improved fetal and
neonatal survival. Poor prognosis has been associated
with lethal genetic conditions, presence of pleural effu-
sions, and pretermdelivery. Carlton and associates noted
that 90% of affected infants dying within 24 hours of
birth had pleural effusions. The diagnosis of persistent
pleural effusions before 26 weeks gestation is associated
with a higher mortality, which likely is due to disease
severity and underlying pulmonary hypoplasia. Massive
fetal pleural effusions at any point in the gestation have a
poor prognosis for survival.
Fetal prognostic indicators include cardiac biventricu-
lar outer diameter (BVOD) on M-mode echocardiogra-
phy. Carlton and colleagues found that a BVOD greater
than 95% of normal had a 100% predictive value for
death, and a normal BVOD had an 86% predictive value.
Wy and coworkers found that proven infection or two
uid-lled body cavities were associated with a worse
outcome. In a comparison of patients from 1990
through 1993 with patients from 1994 through 1997,
use of steroids, surfactant, or high-frequency ventilation
did not inuence ultimate survival outcome but did
prolong the interval to death (6.5 days and 20.5 days,
respectively). The average length of stay for survivors was
28 days (range, 7 to 90 days).
Therapy continues to be directed toward close fetal
monitoring, diagnosis, and intense, complex neonatal
management. Individual perinatal and neonatal care cen-
ters have too fewpatients to permit statistical comparison
of treatment and outcome, but with the advent of in-
creasing opportunities for multicenter collaborative
studies, more data may be available in the future. Data on
neurologic outcome for survivors are sparse, but any
individual survivor of NIHF should receive close neuro-
developmental follow-up.
Suggested Reading
Apkon M. Pathophysiology of hydrops fetalis. Semin Perinatol.
1995;19:437446
Buettiker V, Hug MI, Burger R, Baenziger O. Somatostatin: a new
therapeutic option for the treatment of chylothorax. Intensive
Care Med. 2001;27:10831086
Carlton DP, McGillivray BC, Schrieber MD. Nonimmune hydrops
fetalis: a multidisciplinary approach. Clin Perinatol. 1989;16:
844851
Cheung YF, Leung M, Yip MM. Octreotide for treatment of
postoperative chylothorax. J Pediatr. 2001;139:157159
Heikenen JB, Pohl JF, Werlin SL, Bucuvalas JC. Octreotide in
pediatric patients. J Pediatr Gastroenterol Nutr. 2002;35:
600609
Heinonen S, Ryynanen M, Kirkinen P. Etiology and outcome of
second trimester non-immunologic fetal hydrops. Acta Obstet
Gynecol Scand. 2000;79:1518
Jauniaux E. Diagnosis and management of early non-immune
hydrops fetalis. Prenat Diag. 1997;17:12611268
Jones DC. Nonimmune fetal hydrops: diagnosis and obstetrical
management. Semin Perinatol. 1995;19:447461
Norton ME. Nonimmune hydrops fetalis. Semin Perinatol. 1994;
18:321332
Potter EL. Universal edema of the fetus unassociated with erythro-
blastosis fetalis. Am J Obstet Gynecol. 1943;46:30
Rodriguez MM, Chaves F, Romaguera RL, Ferrer P, De la Guardia
C, Bruce J. Value of autopsy in nonimmune hydrops fetalis:
series of 51 stillborn fetuses. Pediatr Dev Pathol. 2002;5:
365374
Swain S, Cameron AD, McNay MB, Howatson AG. Prenatal diag-
nosis and management of nonimmune hydrops fetalis. Aust NZ
Obstet Gynaecol. 1999;39:285290
Tsao KJ, Hawgood S, Vu L, et al. Resolution of hydrops fetalis in
congenital cystic adenomatoid malformation after prenatal ste-
roid therapy. J Pediatr Surg. 2003;38:508510
Wafelman LS, Pollock BH, Kreutzer J, Richards DS, Hutchison
AA. Nonimmune hydrops fetalis: fetal and neonatal outcome
during 19831992. Biol Neonate. 1999;75:7381
Wraith JE. Lysosomal disorders Semin Neonatol. 2002;7:7583
Wy CAW, Sajous CH, Loberiza F, Weiss MG. Outcome of infants
with a diagnosis of hydrops fetalis in the 1990s. Am J Perinatol.
1999;16: 561567
Yang Y-H, Teng R-J, Tang J-R, Yau K-I T, Huang L-H, Hsieh F-J.
Etiology and outcome of hydrops fetalis. J Formos Med Assoc.
1998;97:1620
NeoReviews Quiz
1. Anemia resulting in heart failure is the usual mechanism by which hematologic disorders result in
nonimmune hydrops fetalis. Of the following, the most common hematologic disorder that results in
nonimmune hydrops fetalis in Southeast Asia is:
A. Alpha thalassemia.
B. Congenital leukemia.
C. Glucose-6-phosphate dehydrogenase deciency.
D. Polycythemia.
E. Pyruvate kinase deciency.
2. The production of interstitial uid is a function of hydrostatic and osmotic pressures within the capillary
and interstitial space as well as the integrity of the capillary endothelium. This relationship is expressed
best by the Starling equation, in which Pcap is hydrostatic pressure in the capillary, Ptiss is hydrostatic
pressure in the interstitial tissue, Oplas is osmotic pressure of plasma, Otiss is osmotic pressure of
interstitial tissue uid, k is ltration coefcient, and r is reection coefcient. Of the following, the most
accurate expression of the Starling equation for uid ltration (FF) is:
A. FF k [ (Oplas Otiss) r (Pcap Ptiss)].
B. FF k [ (Pcap Ptiss) r (Oplas Otiss)].
C. FF k [ (Pcap Ptiss) r (Otiss Oplas)].
D. FF k [ (Ptiss Pcap) r (Oplas Otiss)].
E. FF k [ (Ptiss Pcap) r (Otiss Oplas)].
3. Fetal ultrasonography at 32 weeks of estimated gestational age reveals bilateral pleural effusions and
ascites. Previous ultrasonography performed at 20 weeks had normal results. Of the following, the most
likely cause of hydrops fetalis in this patient is:
A. Cardiac abnormality.
B. Genetic malformation.
C. Hepatic dysfunction.
D. Parvovirus infection.
E. Renal anomaly.
4. Fetal chromosomal abnormalities often are associated with nonimmune hydrops fetalis. Of the following,
the most common chromosomal abnormality associated with nonimmune hydrops fetalis is:
A. Trisomy 13.
B. Trisomy 15.
C. Trisomy 16.
D. Trisomy 18.
E. Trisomy 21.
5. Despite advances in fetal diagnosis and fetal/neonatal therapy for nonimmune hydrops fetalis, the mortality
in this disease remains extremely high in most case series. Of the following, the best prognosis for survival
in nonimmune hydrops fetalis is associated with:
A. Alpha thalassemia.
B. Chondrodysplasia.
C. Congenital syphilis.
D. Parvovirus infection.
E. Supraventricular tachycardia.
DOI: 10.1542/neo.5-1-e5
2004;5;e5 Neoreviews
Janet H. Murphy
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