HYDROPS FETALIS FETAL HYDROPS
Category: Child Health
Abstract : Hydrops fetalis (ie, fetal hydrops) is usually defined as the presence of fetal
subcutaneous tissue edema accompanied by serous effusion(s) in 1 or more body
cavities. As the effects of gravity are blunted in the relatively weightless
fetus, the edema is generalized, not dependent. The fetus may accumulate a much
greater excess of fluid than is possible after birth because of key differenc
Hydrops fetalis (ie, fetal hydrops) is usually defined as the presence of fetal
subcutaneous tissue edema accompanied by serous effusion(s) in 1 or more body
cavities. As the effects of gravity are blunted in the relatively weightless
fetus, the edema is generalized, not dependent.
The fetus may accumulate a much
greater excess of fluid than is possible after birth because of key differences
between fetal and postnatal circulations (eg, parallel flow vs serial flow,
low-resistance systemic circuit) and differences between the organs of gas
exchange (placenta vs lungs). The degree of edema observed in the fetus or
newborn with hydrops is thus massive and may appear grossly bloating and
deforming to the clinician who is more accustomed to children or adults.
Placental edema invariably accompanies fetal edema, and hydramnios is usually
present.
Massive edema of the newborn infant has been recognized for at
least 3 centuries. While fetal hydrops was considered idiopathic a century ago,
a causal relationship with maternal-fetal blood group incompatibilities was
recognized soon after red cell antigens were identified. During the mid years of
this past century, fetal hydrops was considered to be primarily the consequence
of severe maternal isoimmunization to fetal blood group antigens foreign to the
mother, most commonly those in the Rhesus (Rh) family. More recent recognition
of factors other than isoimmune hemolytic disease that can cause or be
associated with fetal hydrops led to the use of the term nonimmune hydrops to
identify those cases in which the fetal disorder was caused by factors other
than isoimz.
In the 1970s, the major cause of immune hydrops (ie, Rh D
antigen) was conquered with the use of immunoglobulin (Ig) prophylaxis in
at-risk mothers. This conquest was quickly followed by recognition that the
nonimmune causes of hydrops were, in fact, more common than had been suspected.
Arbitrarily classifying fetal hydrops into these categories is probably no
longer clinically useful since so few current cases are immune, so many are
nonimmune, and so many causes for nonimmune hydrops are currently
recognized.
Pathophysiology:
Until recently, many speculations but few
facts existed about the pathophysiologic events leading to fetal hydrops. The
bewildering heterogeneity of conditions causing or associated with the syndrome
added to the confusion. Studies in sheep, most of which occurred in the past
decade, provide a much clearer picture of fetal hydrops. Hydrops has been
produced in the ovine fetus by anemia, tachyarrhythmia, occlusion of lymphatic
drainage, and obstruction of cardiac venous return. Hypoproteinemia and
hypoalbuminemia are common in human hydrops, and reduced intravascular oncotic
pressure has been speculated to be a primary cause for the disorder. However, in
the sheep model, a 41% reduction in total serum protein accompanied by a 44%
decline in colloid osmotic pressure failed to produce fetal hydrops.
Furthermore, normal concentrations of serum proteins are found in a sizable
proportion of human hydrops. A closer look at the animal studies provides the
clues necessary to piece together the puzzle of the pathophysiology of
hydrops.
In one study, profound anemia was induced in fetal sheep; the
hydrops that resulted was unrelated to hematocrit levels, blood gas levels,
acid-base balance, plasma proteins, colloid oncotic pressure, or aortic
pressure. A difference was found in central venous pressure (CVP), which was
much higher in persons with hydrops. The hematocrit level was reduced by 45% in
a study of particular notation; however, CVP was maintained unchanged, and no
fetus developed hydrops under these conditions.
Induced fetal
tachyarrhythmia has led to fetal hydrops in several studies. Key to the
development of fetal hydrops in these studies was an elevation in CVP; the
anemia was only of indirect importance. CVP was elevated markedly, with a range
of 25-31 mm Hg in one study. In other reports, hydrops induced by sustained
fetal tachycardia was unrelated to blood gases, plasma protein, or albumin
turnover; however,a 75-100% increase in CVP was observed in the fetuses that
developed hydrops.
Excision of major lymphatic ducts produces fetal
hydrops in the sheep model. A related study demonstrates an exquisite, linear,
inverse relationship between lymphatic outflow pressure and CVP; a rise in CVP
of 1 mm Hg reduces lymph flow 13%, and flow stops at a CVP of 12 mm Hg. These
results are confirmed by other observations of linear decline in lymph flow when
CVP exceeds 5 mm Hg and a cessation of flow at CVPs greater than 18 mm
Hg.
Placement of an inflatable tissue expander in the right chest,
designed to mimic the effects of a space-occupying chest mass, has been
demonstrated to produce hydrops in fetal sheep. Of particular note is the 400%
rise in CVP, which accompanied both inflation of the expander and development of
fetal hydrops, as well as the parallel decline in CVP and resolution of hydrops
when the expander was deflated. Just how sensitive the fetus can be to
obstruction of venous return is demonstrated in another study in which fetal
hydrops was induced by cannulation of 1 carotid artery and 1 jugular vein or by
catheter placement in a single jugular vein in the midgestation ovine
fetus.
Also of note is a computer simulation model in which
cardiovascular and fluid electrolyte disturbances (eg, severe anemia, lymphatic
obstruction, excess fluid and electrolyte loads, elevation in angiotensin
levels) and compensating homeostatic mechanisms have been examined. This model
demonstrated that "...fetal cardiac failure constituted the strongest stimulus
for the formation of fetal edema..." (Shinbane, 1997), thus further
substantiating the pivotal role of CVP in the development of fetal
hydrops.
Many other physiologic disturbances are associated with human
fetal hydrops. Elevations in aldosterone, renin, norepinephrine, and angiotensin
I levels are likely to be secondary consequences. While infusion of angiotensin
I led to fetal hydrops in nephrectomized sheep, the 4-fold rise in CVP was
probably the primary cause of the hydrops. An elevation in erythropoietin has
been observed after 24 weeks' gestation in humans; however, this is likely a
normal response to the fetal anemia in the observed cases. The meaning of
increased levels of coenzyme Q10, placental vascular endothelial growth factor,
and endothelin and decreased cytokine interleukin-3 levels is unclear at this
time.
However, of particular interest is the 3- to 5-fold increase in
atrial natriuretic peptide (ANP) that accompanies both human fetal hydrops (with
cardiac anomaly or isoimmunization) and ovine hydrops (induced by obstruction of
venous return, sustained tachycardia, or induced anemia). A return of ANP levels
to normal parallels the resolution of hydrops. These observations and the
observations that vascular permeation of albumin is enhanced and cardiovascular
and renal homeostatic adaptations are influenced by this peptide suggest an
important role for ANP in fetal hydrops. Recent evidence of low fetal plasma
levels of cyclic guanosine monophosphate suggests that reduced nitric oxide
production due to injury of fetal vascular endothelial cells may be involved in
the development of fetal hydrops. This isolated observation requires
confirmation and further study.
Frequency:
• In the US: An attempt to
provide a precise incidence figure would be misleading. Recent estimates of the
frequency of fetal hydrops depend, among other factors, on date (more common in
recent reports because of earlier and more precise fetal diagnoses), season of
the study reported (differences in exposure and immunity to viral infections),
and ethnicity of the population studied (differences in genetic instructions for
hemoglobin alpha-chain production). Variations in the use of sensitive,
specific, and sophisticated prenatal, neonatal, and postmortem diagnostic tools
also differ greatly among studies. The best estimate for how common hydrops
fetalis is in the United States is approximately 1 in 600 to 1 in 4000
pregnancies.
• Internationally: Hydrops fetalis is much more common in
Southeast Asia. The best figures come from Thailand, where the expected
frequency of hydrops, from homozygous alpha-thalassemia or Bart hydrops alone,
is 1 in 500 to 1 in 1500 pregnancies. Accurate figures from the Mediterranean
region are not available; however, the commonness of glucose-6-phosphate
dehydrogenase (G-6-PD) deficiency and of defects in alpha-chain hemoglobin
production in several populations from this region lead to the suspicion that
the incidence of hydrops in that region is much higher than it is in the United
States.
Mortality/Morbidity: Estimates of mortality also vary widely,
from nearly zero to virtually 100%. Most case series report 60-90% mortality,
although some improvements are notable in more recent reports. Many causes for
these variations exist, not the least of which include the sophistication of
diagnostic methods used and the complexity and costs of treatment. However, the
most important single factor is the cause of the hydrops. A significant
proportion of these cases are caused or accompanied by multiple and complex
congenital malformations of genetic and/or chromosomal origin, which by
themselves are fatal at an early age. Many other causes are accompanied by
masses or fluid accumulations, which compress the developing fetal lung and
preclude its normal development. Thus, the presence or absence and potential
prevention of pulmonary hypoplasia are of crucial importance.
Another
highly important factor is the very premature delivery of most babies with
hydrops, consequent to conditions, which distend the uterus and provoke early
labor (fetal fluid accumulations and/or hydramnios), or to therapeutic
interventions (fetal thoracentesis, paracentesis, and/or complex fetal surgical
procedures). Generally, the earlier in gestation that fetal hydrops is
recognized, the poorer the prognosis.
Race: Ethnic influences are related
almost entirely to cause. Selected examples include the importance of genetic
variations in the alpha-chain structure of hemoglobin in Asian and Mediterranean
populations in addition to the more serious nature of the hemolytic disease in
the African American fetus affected by maternal ABO-factor
isoimmunization.
Sex: Sex influences in incidence or outcome of hydrops
fetalis are related largely to the cause of the condition. A significant
proportion of hydrops is caused by or associated with chromosomal abnormalities
or syndromes. Many of these are X-linked disorders.
Since most
individuals with hydrops fetalis are delivered quite prematurely, and since
fetal pulmonary maturation takes place earlier in female than in male fetuses,
male preterm infants are at greater risk for the pulmonary complications of very
preterm delivery. They are also at greater risk for infections (nosocomial or
otherwise), which are so common in the very preterm infant. A striking example
of greater male risk is the nearly 13-fold increase in the odds ratio for
development of hydrops in the male fetus with Rh D hemolytic disease. While a
single precise risk figure is not available for the heterogenous collection of
cases that comprise hydrops fetalis, saying that the male fetus is at greater
risk for occurrence, morbidity, and mortality appears to be safe.
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