Pathophysiology of Hydrops Fetalis

Michael Apkon

Hydrops fetalis occurs when the rate of interstitial fluid production by capillary ultrafiltration
exceeds the rate of interstitial fluid return to the circulation via lymphatic vessels. Developmental
differences in the microcirculation and lymphatic system of the fetus, as compared with mature
subjects, renders the fetus susceptible to interstitial fluid accumulation. These differences include
greater capillary permeability, more compliant interstitial compartment, and greater influence of
venous pressures on lymphatic return. The balance between interstitial fluid production and
removal is most commonly disrupted as a consequence of homeostatic mechanisms serving to
preserve adequate systemic delivery of metabolic substrate when cardiocirculatory function is
impaired. The pathophysiology of two conditions of impaired cardiocirculatory function, atrial
tachycardia and severe anemia, serve as examples of the mechanisms by which these homeostatic
mechanisms perturb the balance of interstitial fluid movement.
Copyright 9 1995 by W.B. Saunders Company

H ydrops fetalis, the excessive accumulation
of interstitial fluid in the fetus, is a condi-
tion that results in considerable rates of morbidity
and mortality. The list of abnormalities associated
with hydrops is protean, encompassing congenital
malformations, infections, tumors, and acquired
disorders. Although many disorders have a clear
association with hydrops fetalis, in many cases,
the actual cause of excessive fluid accumulation
remains obscure. One might consider interstitial
fluid to be a transudate of plasma, which, via
lymphatic vessels, is eventually returned to the
vascular space (Fig 1). Accordingly, hydrops may
be considered a result of an imbalance between
the rate of interstitial fluid formation and the
rate at which this fluid is returned to the circu-
lation. Thus, hydrops might result from any con-
dition that accelerates the rate of transudation
from the vascular space or delays the return of
lymph to the circulation. This disrupted balance
of fluid accumulation and clearance from the in-
terstitial space may represent a primary distur-
bance in the mechanisms governing fluid flux, as
in the case of lymphatic malformations. More
frequently, however, the balance of fluid move-
ment is disrupted as a consequence of compen-
satory mechanisms invoked by the fetus to pre-
serve adequate delivery of oxygen and other vital
suhstrates to the tissues in the face of impaired
cardiocirculatory function. One approach in
planning a rational diagnostic and therapeutic
strategy in hydrops fetalis is to consider the
pathophysiological basis of interstitial fluid ac-
cumulation. Therefore, the author will develop
a physiological framework to examine the factors
governing fluid movement between the vascular
and interstitial spaces and will explore, in partic-
ular, the unique features of the fetal microcir-
culation that facilitates fluid movement in utero.
Additionally, the article discusses the compen-
satory mechanisms that preserve adequate oxy-
gen and nutrient delivery to the tissues at the
expense of increased interstitial fluid accumu-
lation. Finally, the pathophysiological mecha-
nisms in two experimental models of hydrops fe-
talis will be considered.
Regulation o f Fluid M o v e m e n t Between
Vascular and Interstitial Spaces
Transcapillary Filtration
The rate of interstitial fluid formation is deter-
mined by the balance of forces governing water
movement across the capillary endothelium, as
originally described by Starling I (Fig 1). The
driving forces for water extravasation from the
vascular space is the hydrostatic pressure within
the capillary (Pc) and the colloid oncotic pressure
of the interstitial fluid (a'i). Similarly, the forces
driving the return of water from the interstitial
From the Division of Critical Care, Departmentof Yale University
School of Medicine, New Haven, CT.
Address reprint requeststo Michael Apkon, MD, PhD, Department
of Pediatrics, Yale UniversitySchool of Medicine, PO Box 208064,
New Haven, CT 06520-8064.
Copyright 9 1995 by W.B. Saunders Company
0146-0005/95/1906-0009505.00/0

Seminars in Perinatology, Vol 19, No 6 (December), 1995: pp 437-446 437

488 Michael Apkon

Artery Interstitium
O0
0
0 00 o
(Pi)o
0 O00r 0

Capillary
(Pc) o 000 ~176
o o o
o

Oo~C~176
o
Vein
L Lymphatic

Figure 1. Interstitial fluid balance. Interstitial fluid is formed by ultrafiltration of plasma at the capillary. Capillary
ultrafiltration is driven by the difference between capillary (Pc) and interstitial (Pi) hydrostatic pressures. Fluid
reabsorption by the capillary is driven by the difference between the capillary 0re) and interstitial (Tri) colloid
oncotic pressures, measures of the concentrations of oncotically active molecules, or, the reflection coefficient,
and Lp, the hydraulic permeability, are intrinsic properties of the capillary wall that characterize the efficacy of
such driving forces to produce water flux (.Iv). Interstitial fluid is returned to the circulation via the lymphatic
system. The outflow pressure of the lymphatic pressure is the venous pressure. The "manometers" indicate the
relative pressures in each compartment.

space to the intravascular space is the hydrostatic Jv = CFC(Ap - ~A~r)

pressure o f the interstitium (Pi) and the plasma
colloid oncotic pressure (a'D. The colloid oncotic
pressure in the vascular and interstitial spaces
depends on the concentration o f osmotically ac-
tive particles in the compartment, and the efficacy
with which oncotic pressure differences influence
water m o v e m e n t depends on the extent to which
m o v e m e n t o f osmotically active molecules across
the capillary is restricted (as described by ~, the
colloid osmotic reflection coefficient). The less
p e r m e a b l e the e n d o t h e l i u m is to a particular
molecule (ie, the higher the tr), the greater the
effect o f colloid oncotic pressure differences. A
corollary of this relation is that a m o r e permeable
endothelium will allow a greater solute flux to
accompany, via solvent drag, water movement.
The net rate o f fluid m o v e m e n t depends on the
capillary surface area and its hydraulic conduc-
tivity (Lp). The p r o d u c t o f capillary surface area
and hydraulic conductivity, r e f e r r e d to as the
capillary filtration coefficient (CFC) provides a
measure of units o f volume translocated p e r unit
time per millimeters o f m e r c u r y driving force.
Thus, Jv, the fluid flux across the capillary, may
be described by the following equation:
where Ap is the net hydrostatic pressure gradient
(Pc - Pi) and ATr is the colloid osmotic pressure
gradient between the capillary and interstitial
fluid (Trc - 7ri).
Several features o f the fetal microcirculation
may facilitate transcapillary water m o v e m e n t
c o m p a r e d with adult subjects. 2 First, fetal cap-
illaries a p p e a r to be m o r e p e r m e a b l e to plasma
proteins, resulting in a lower reflection coeffi-
cient for oncotically active solute. The effect of
this enhanced solute permeability is that for any
given solute concentration difference across the
capillary endothelium, the colloid oncotic pres-
sure difference will drive water less effectively
f r o m the interstitium to the vascular space. Thus,
transcapillary flux and the distribution o f body
water will be less sensitive to alterations in plasma
or interstitial colloid osmotic pressure. This, in
part, explains the finding that plasma protein re-
duction in chronically instrumented fetal sheep
does not affect body water content. 3 Second, the
capillary filtration coefficient is fivefold higher
than that of adults. The increased capillary fil-
tration coefficient in the fetus results in an in-
 Pathophysiologyof Hydrops
creased water flux for a given driving force.
Third, the interstitial space o f the fetus is more
compliant than that of more mature subjects.
That is to say, that the interstitial space o f the
fetus is capable o f receiving a greater a m o u n t o f
fluid with a smaller increase in the interstitial hy-
drostatic pressure. Because it is the interstitial
hydrostatic pressure that opposes the capillary
hydrostatic pressure and drives water from the
capillary, a given increase in capillary hydrostatic
pressure may result in greater interstitial fluid
accumulation before it is checked by a corre-
sponding increase in interstitial hydrostatic pres-
sure.
In the short term, facilitated transcapillary
flow has important consequences in blood vol-
ume regulation. For example, transcapillary flow
from the interstitium is likely an import mecha-
nism restoring blood volume after acute hem-
orrhage. MeUander and others 4'5 have shown that
in adult cats, acute hemorrhage induces altera-
tions in microcirculatory pressures, which results
in reabsorption rather than filtration by the cap-
illaries. This "autotransfusion" probably con-
tributes to restoring the blood volume and
preserving cardiac output. In adult sheep, res-
toration o f full blood volume after a 30% hem-
orrhage requires 24 to 48 hours. 6 In contrast,
full blood volume o f fetal sheep is restored over
3 to 4 hours. 7 The more rapid recovery o f blood
volume in the fetal subjects is consistent with a
greater capillary filtration coefficient and a
greater interstitial compliance. Similarly, facili-
tated transcapillary flow contributes to blood
volume regulation during blood volume expan-
sion. For example, saline infusion results in blood
volume expansion. However, this expansion is
transient as fluid redistributes across the capil-
lary. In adult sheep, 30% o f administered saline
remains in the vascular space 30 minutes after
infusion. In fetal sheep, in contrast, only 6% o f
the infused saline remains in the vascular space, s
This suggests that for a given amount o f fluid
added to or retained by the fetus, a smaller frac-
tion will reside in the vascular space and a larger
fraction will reside in the interstitial space.
Lymphatic Return
Enhanced capillary filtration o f water to the in-
terstitial space predicts that lymphatic flow in the
fetus must be increased also. Indeed, Brace et
al 9A~ have shown that the thoracic duct lymph
439
flow (normalized for body mass) in fetal sheep is
four to five times greater than those o f adult
sheep. In addition to differences in lymphatic ca-
pacity between fetal and mature subjects, there
are differences in the regulation o f lymphatic
flow. For example, lymphatic flow rates d e p e n d
on the outflow pressure for the lymphatic system,
which is the venous pressure (Fig 2). In mature
subjects, lymphatic flow is relatively constant until
the outflow pressure increases to approximately
8 mm Hg. At greater pressures, lymphatic flow
falls and eventually ceases when the outflow
pressure nears 25 mm Hg. In contrast, fetal lym-
phatic flow begins to decrease when the outflow
pressure is greater than 0 m m H g and ceases
when the outflow nears 10 m m Hg. Because the
normal fetal central venous pressure is typically
greater than 0 mm Hg, basal lymph flow is limited
in the normal fetus and is expected to be limited
further whenever central venous pressure in-
creases. The factors governing lymphatic flow
through abnormal lymphatic structures are more
poorly understood.
Circulatory Failure as a Cause o f Hydrops
Although increases in capillary permeability, de-
creases in plasma colloid oncotic pressure, and
impaired lymphatic function may each contribute
to interstitial fluid accumulation in the hydropic
fetus, circulatory dysfunction with associated in-
creases in venous pressures may be a more com-
mon mechanism causing noninunune hydrops. ~~~4
Elevation in venous pressure is a manifestation
of several o f the normal homeostatic mechanisms
that preserve organ perfusion in the face o f a
critical imbalance between the supply and de-
mand for oxygen and other vital nutrients. An
understanding o f the pathophysiology o f hydrops
u n d e r such conditions o f supply-demand imbal-
ance requires examination o f the determinants
o f substrate delivery to the tissues as well as an
understanding o f the homeostatic mechanisms
contributing to elevations o f venous pressures.
Circulatory Failure as an Imbalance
Between Substrate Supply and Metabolic
Demand
Adequate delivery o f metabolic substrate to the
tissues depends not only on the overall cardiac
output, the concentration o f substrate within the
440 Michael Apkon

0.31 , , , I [ l I I I
i
[

!iiiiiiiiiiiii!iiiiiiiiiiiiiiiiiiiiiiiiiiiiiiii
.0~176 ... ..... ..............

,r
iiiiiii!i!iiiiii
iiiiiiii!!i
ili
.c:_ 0.2
E
Fetal
E

t~

0
0.1 Figure 2. Left thoracic
Q. duct lymph-flow in ovine
Adult

/
E fetus and adult. Measure-
._1 ments were made in animals
with chronically implanted
...........~176 , . . . - . . . . . . . . - . . . . . . . . . . . , lymphatic and vascular
catheters. The normal lym-
phatic outflow pressure is
the central venous pressure
0 k- which is typically 3 to 4 mm
-20 -10 0 10 20 30 40 Hg in the ovine fetus. Data
are mean -+2 X SE. (Re-
Outflow pressure (mmHg) printed with permission. 2)

blood and the appropriateness of the distribution cardiac o u t p u t is the p r o d u c t o f heart rate and
o f blood flow a m o n g various organs, but also on stroke volume. Furthermore, stroke volume is
the metabolic demands o f the tissue. Table 1 lists determined by the degree o f cardiac filling (ie,
examples o f clinical conditions that have been the end diastolic volume) and the effectiveness
associated with n o n i m m u n e hydrops and that o f contraction (ie, the ejection fraction). Thus
may decrease cardiac o u t p u t or increase the de- deficiencies in heart rate, cardiac filling, or con-
mand for blood flow. Conditions are g r o u p e d tractile function could impair cardiac output.
according to the primary mechanism by which I m p a i r m e n t o f cardiac filling may result from
supply-demand imbalance occurs. Recall that an inadequate intravascular volume, an impedi-

Table 1. Causes of Supply-Demand Imbalance for Metabolic Substrate Delivery

Disturbance Mechanism
Decreased cardiac output Inadequate cardiac filling
Inadequate or impeded ejection
Inadequate heart rate
Increased demand for flow Decreased oxygen content
Maldistribution of flow
Increased metabolic rate
Modified with permission)8
Examples
Decreased ventricular compliance,
pericardial effusion, tachyarrythmias,
hemorrhage, hepatitis or peritonitis
causing extravasation of fluid from
vascular space
Myocarditis, myocardial infarction, asphyxia,
polycythemia, premature closure of the
ductus arteriosus, valve dysfunction
Congenital heart block
Anemia, bypoxemia
Arteriovenous malfornaation
Thyrotoxicosis
 Pathophysiology of Hydrops
ment to venous return, or to a decrease in ven-
tricular compliance. A relative deficiency in in-
travascular volume may exist as a consequence
o f either fluid loss from the vascular space or
from an increase in vascular capacity. Fluid may
be lost from the vascular space to the interstitial
space if capillary filtration increases as a result
o f either an increase in capillary permeability or
a decrease in plasma colloid oncotic pressure as
discussed previously. Alternatively, blood may be
lost from the vascular space as a result o f fetal-
maternal or twin-twin transfusion. Furthermore,
fetal hemorrhage (ie, intracranial hemorrhage)
causes blood loss from the vascular space.
Even when intravascular volume is normal,
cardiac filling will be diminished if venous return
is impeded. Pericardial effusions, cardiac tumors,
and subendocardial fibroelastosis each decrease
the effective ventricular compliance, resulting in
a smaller end diastolic ventricular volume for a
given venous pressure. Tachyarrhythmias also
impart an impediment to cardiac filling by lim-
iting the duration o f diastole.
Given adequate cardiac filling, ejection o f
blood may be impaired by depressed cardiac
muscle function as may occur from in utero
myocarditis, myocardial infarction or hypoxemia.
Moreover, ejection may be impaired when ven-
tricular outflow is impeded. Thus, valvular mal-
formations such as calcified aortic valve or ab-
normalities of the puimonic valve compromise
the ability o f the ventricle to eject. Premature
closure o f the ductus arteriosus might also be
expected to compromise right ventricular ejec-
tion by forcing the total right ventricular o u t p u t
to be ejected through the high vascular resistance
of the fetal pulmonary circulation. In fetal lambs,
acute ductal occlusion caused a decrease in right
ventricular output (RV), increases in RV systolic
and diastolic dimensions, and tricuspid valve re-
gurgitation) 5 Interestingly, premature closure o f
the foramen ovale may also create a relative de-
ficiency in RV function by necessitating that the
RV discharge the total systemic venous return as
right to left transatrial flow is blocked) 6
Decreases in the concentration o f metabolic
substrate, particularly oxygen, in the blood cre-
ates a requirement for more blood flow to pro-
vide a constant amount o f substrate delivery.
Thus, decreases in hemoglobin concentration or
in hemoglobin saturation result in less oxygen
delivery per unit o f blood and hence a demand
441
for increased flow. Maldistribution o f blood flow,
as might occur in the presence o f an arteriove-
nous malformation, also creates a need for in-
creased total blood flow because a portion o f the
total cardiac o u t p u t is distributed to provide ex-
cessive flow to some tissues at the expense o f
flow to o t h e r tissues. Finally, increases in meta-
bolic rate, as may occur in metabolic disturbances
such as thyrotoxicosis, must be met by increases
in substrate delivery.
In the fetus as well as the mature subject, a
n u m b e r o f homeostatic responses are activated
locally and systemically by inadequate cardiac
output. 17.18 In addition to their beneficial effects,
these compensatory mechanisms may also be
maladaptive in so far as they contribute to fluid
retention by the fetus and extravasation o f fluid
from the vascular space, thereby contributing to
the development o f hydrops.
Compensatory Mechanisms
Local and systemic cardiovascular regulation
preserves homeostasis via three mechanisms.
First, local mechanisms enhance the efficiency o f
oxygen extraction and use by the tissues. Second,
systemic and local mechanisms act together to
redistribute blood flow to more metabolically ac-
tive organs such as the brain and heart. Third,
systemic mechanisms act to enhance cardiac out-
put by augmenting blood volume and myocardial
performance.
Local mechanisms enhance the efficiency o f
oxygen extraction in part by recruiting previously
closed capillaries. 19 In adult subjects, capillary
recruitment allows enhanced oxygen extraction
by increasing surface area for oxygen diffusion,
by decreasing the distance between the capillary
and tissue, and by increasing the transit time o f
blood cells within the tissues. It is not known to
what extent the capillary bed o f the fetus is fully
recruited at rest or if capillary recruitment is an
important homeostatic mechanism during de-
velopment.
At times o f insufficient cardiac o u t p u t for
metabolic demands, flow is redistributed by a
combination o f local and systemic mechanisms.
Many organs are able to locally regulate their
blood flow by varying the resistance o f the con-
ducting vessels. This regulation occurs as a result
of metabolic feedback from the tissues to the
conducting vessels and by direct effects o f per-
fusion pressure and blood flow on the blood ves-
442 Michael Apkon
sels themselves. As organs differ in their ability
to regulate flow in this manner, local mechanisms
will serve to redistribute blood flow to those or-
gans with m o r e potent autoregulation. Systemic
mechanisms involving neural and humeral factors
also serve to redistribute b l o o d flow. Specifically,
stimulation o f the sympathetic nervous system
via activation o f low pressure atrial stretch re-
ceptors and arterial b a r o r e c e p t o r s results in pe-
ripheral vasoconstriction. Similarly, plasma con-
centrations of vasopressin, angiotensin II, and
other n e u r o e n d o c r i n e factors are increased and
cause arteriolar constriction. As vascular beds
differ in their sensitivity to sympathetic stimula-
tion, blood flow is redistributed to those tissues
with a lower sensitivity such as the heart and
brain. In chronically i n s t r u m e n t e d fetal sheep, it
has b e e n possible to show that these mechanisms
function during gestation. The b a r o r e c e p t o r re-
flex, for example, a m e a s u r e o f autonomic ner-
vous system function, is active t h r o u g h o u t the
second half of gestation, 2~ although the sensitivity
o f the reflex to changes in mean arterial blood
pressure seems to increase with age. It is also
possible to show increases in fetal plasma con-
centrations of n o r e p i n e p h r i n e , renin, and vaso-
pressin in response to circulatory stress such as
hemorrhage. 7'21 That these mechanisms are im-
p o r t a n t to cardiovascular homeostasis is sup-
p o r t e d by the finding that blockade o f angioten-
sin II (whose formation is stimulated by increased
plasma renin activity) or vasopressin activity
magnifies the decrease in fetal m e a n arterial
pressure that occurs with h e m o r r h a g e . 22 The net
effect o f these regulatory mechanisms in the fetus
is that during times o f circulatory stress such as
hypoxia or h e m o r r h a g e , b l o o d flow and oxygen
delivery to the brain, heart, and adrenal glands
are preserved at the expense of that to the kidney,
gut, and m u s c l e . 23'24
The same systemic mechanisms that serve to
redistribute flow also act to enhance cardiac out-
put by augmenting blood volume and myocardial
performance. For example, renal arteriolar va-
soconstriction decreases renal perfusion. How-
ever, glomerular filtration may be maintained by
selective constriction o f the efferent arteriole. 25
The kidney responds to this decrease in perfusion
by increasing the proximal reabsorption o f the
glomerular filtrate. Additionally, vasopressin acts
to increase water r e a b s o r p t i o n and angiotensin
II stimulates aldosterone release f r o m the adrenal
cortex, which in turn p r o m o t e s sodium reab-
sorption. The effect o f these responses is that
fluid is retained by the kidneys, in p a r t aug-
menting the circulating blood volume.
Blood volume may also be a u g m e n t e d if trans-
capillary hydrostatic forces are altered to favor
fluid r e a b s o r p t i o n f r o m the interstitium. Mean
capillary pressure could decrease as a direct result
o f decreases in arterial or venous pressures. Al-
ternatively, m e a n capillary pressure could de-
crease even though arterial pressure is increased
if the arterial pressure is dissipated by arteriolar
constriction, as occurs with sympathetic nervous
system stimulation. It is likely that e n h a n c e m e n t
in transcapillary reabsorption by these mecha-
nisms contributes to the restoration o f fetal blood
volume after a c u t e h e m o r r h a g e . 26"27
Increases in blood volume result in increases
in myocardial filling as blood is distributed a m o n g
different c o m p a r t m e n t s (ie, arteries, capillaries,
veins, and cardiac chambers) according to the
relative compliance and capacitance o f each
c o m p a r t m e n t . Even if blood volume is not in-
creased, myocardial filling can be increased by
redistributing blood a m o n g these various com-
partments. The venous system has a large capac-
itance that is regulated by the sympathetic ner-
vous system. Increases in sympathetic tone cause
venoconstriction, which increases venous pres-
sures and redistributes blood f r o m the veins to
the heart. Such increases in fetal venous pressure
have b e e n shown during circulatory stress such
as hypoxia. 2s
Increases in myocardial filling are translated to
increases in cardiac output because of the Frank-
Starling mechanism, 29 which relates changes in
end-diastolic fiber length to changes in stroke
volume. T h e t e r m preload reserve has b e e n used
to describe the augmentation in cardiac output
that may be obtained with increases in myocardial
filling. In the fetal lamb, as in the adult, increases
in mean atrial pressure or end-diastolic pressure
result in increases in right and left ventricular
output 3~ (Fig 3). However, the increase in ven-
tricular o u t p u t for a given increase in filling
pressure is substantially diminished at filling
pressures greater than approximately 3 to 8 m m
Hg. W h e t h e r or not the Frank-Starling mecha-
nism provides preload reserve in the fetus de-
pends on the normal mean atrial pressure relative
to this inflection point in the output-pressure re-
lationship. It appears, at least in fetal lambs, that
 Pathophysiology of Hydrops
1.5
I
Figure 3. Ventricular stroke
volume as a function of mean
atrial pressure. These com-
posite left (LV) and fight
ventricular (RV) function
curves measured in ovine
fetuses were obtained by
measuring stroke volumes
ej
o.,//
during rapid blood rein- /
fusion after phlebotomy.
Lines represent the "best i t
fits" to the rising and pla-
teau segments of the curve. 0 5
(Reprinted with permission?~)
normal mean atrial pressures are sufficiently high
that preload reserve is limited.
Maladaptive Effects of Compensatory
Mechanisms
Although the c o m p e n s a t o r y mechanisms dis-
cussed previously preserve balance between
substrate supply and d e m a n d , at least in the
most metabolically active tissues, homeostasis
occurs at the expense o f increased venous
pressures, impaired organ function, and ulti-
mately interstitial fluid accumulation. Eleva-
tion in venous pressures has b e e n shown in
h u m a n I~'s~ and lamb s436 fetuses with hydrops
secondary to impaired circulatory function.
Increases in venous pressure may c o n t r i b u t e to
interstitial fluid accumulation by two mecha-
nisms, as discussed previously: (1) increasing
the mean capillary hydrostatic pressure, caus-
ing increased capillary filtration and, (2) in-
creasing the outflow pressure for lymphatic
return, causing a decrease in lymphatic flow.
Even if venous pressures are not increased,
mean capillary pressures can be increased as a
result o f local and systemic c o m p e n s a t o r y
mechanisms for insufficient circulation. For
example, precapillary vasodilation could ele-
vate mean capillary pressure by b e t t e r trans-
mitting arteriolar pressure to the capillaries and
could recruit previously closed capillaries,
contributing to an increase in capillary filtra-
443
. . - - - - - RV
_._...-- L V
t i I J * i i I i * * , I
10 15
Mean atrial pressure (torr)
tion surface area. Increases in venous resis-
tance that are p r o p o r t i o n a t e l y g r e a t e r than in-
creases in arteriolar resistance will also increase
mean capillary pressure. T h e s e increases in
mean capillary pressure are maladaptive in that
they result in extravasation o f fluid f r o m the
vascular space and interstitial fluid deposition.
Such decreases in blood volume have b e e n
shown experimentally in fetal lambs d u r i n g cir-
culatory stress such as o c c u r s in fetal hyp-
oxia.2S,s7
In addition to alterations in hydrostatic pres-
sure, colloid oncotic pressure has also been sug-
gested to be altered as a consequence o f circu-
latory compromise. In adults, for example,
venous congestion and decreased hepatic per-
fusion have been suggested to impair synthesis
o f albumin, ss the predominant oncotically active
plasma protein. Moreover, hepatic synthetic
function may be further reduced by increased
extramedullary hematopoeisis in response to
chronic fetal hypoxia.
Increases in capillary permeability could
also contribute to increased transcapillary fluid
m o v e m e n t at times o f circulatory compromise.
Capillary permeability may increase as a result
o f hypoxia-induced endothelial injury. Alter-
natively, capillary permeability may be m o d u -
lated by circulating n e u r o h o r m o n a l factors re-
leased via homeostatic mechanisms o r by the
host defense against infection. For example,
444 Michael Apkon
atrial natriuretic factor, released in response
to atrial distension, may directly increase cap-
illary permeability. 39
Experimental Models of Hydrops Fetalis
Atrial Tachycardia
Recognition o f i n t r a u t e r i n e supraventricular
tachycardia as a cause o f nonimmune hydrops
suggested that hydrops might be c r e a t e d in ex-
perimental subjects by atrial pacing. Stevens et
al 4~ adapted the chronically instrumented fetal
lamb preparation to electrically pace the left
atrium for prolonged periods o f time. Atrial pac-
ing at 300 bpm resulted in evidence o f fluid ac-
cumulation in all animals studied: 1 o f 13 study
animals developed massive edema (hydrops)~ Ev-
idence o f fluid accumulation was not observed
in a set o f control animals that did not receive
atrial pacing.
It is likely that these pathological changes re-
sult from the decrease in cardiac o u t p u t that ac-
companies rapid atrial pacing. In this regard, it
is important to distinguish between the conse-
quences o f abnormal rhythms with rapid atrial
rates, and the consequences o f tachycardia per
se. Anderson et al have distinguished between
the effects of sinus tachycardia and rapid atrial
pacing in chronically catheterized fetal lambs. 41'42
In fetal lambs, increases in spontaneous heart
rate were accompanied by increases in right ven-
tricular end-diastolic dimension and o u t p u t at a
constant stroke volume, but decreases in left
ventricular end-diastolic dimension and stroke
volume; left ventricular o u t p u t also increased.
However, when the heart rate was increased by
atrial pacing, a decrease in stroke volume and
end-diastolic dimension was observed for both
ventricles. Interestingly, ventricular o u t p u t only
decreased significantly in the ventricle ipsilateral
to the paced atrium. The alterations in myocar-
dial filling appear to result from an inadequate
diastolic intervalbecause the rate-related changes
were reversed during test beats introduced at
longer interbeat intervals. One reason t h a t the
cardiac o u t p u t is better preserved during spon-
taneous tachycardia is because the mechanisms
that normally accelerate the heart beat, such as
the sympathetic nervous system, also augment
cardiac filling (by increasing venomotor tone) and
the force o f contraction.
Given the decrease in cardiac o u t p u t during
pacing, it is not surprising that the arterial Po~
decreases somewhat from approximately 18 to
15 mm Hg. Decreases in arterial Po2 were not
observed in similar experiments by Gest et a l Y
It seems unlikely that this modest degree o f hyp-
oxia resulted in increases in capillary permeability
because plasma protein, albumin, and Na § con-
centrations do not change significantly with pac-
ing. Gest et a135 measured the turnover rate of
radiolabeled albumin in the plasma and found
no evidence for increased capillary permeability.
Stevens et al 4~ f o u n d that the histopathology
o f those fetuses who had received atrial pacing
suggested that edema formation is a result o f ve-
nous congestion: many animals had cardiomegaly
or hepatomegaly. Elevations in inferior vena cava
pressure were showed directly in the study by
Gest et al. 35 Interestingly, the increase in venous
pressures does not necessarily reflect an increase
in total blood volume. Plasma volume may ac-
tually decrease somewhat with a constant red
blood cell volume. This suggests that the com-
pensatory mechanisms preserving tissue perfu-
sion during tachycardia redistribute the blood
between the various vascular spaces and redis-
tribute fluid from the vascular to the interstitial
space. Furthermore, increases in venous pressure
must reflect increases in v e n o m o t o r tone and de-
creased venous compliance. This does not mean
that fluid accumulation by the fetus does not take
place. Rather, it suggests that if fluid retention
occurs it is poorly effective at increasing blood
volume and restoring circulatory function.
The elevation in venous pressure contributes
to edema not only by forcing fluid from the vas-
cular space, but also by impeding the return of
fluid via the lymphatics. Gest et a143 found that
if the thoracic duct lymph flow in fetal lambs was
collected against a pressure equal to the baseline
central venous pressure, then electrically induced
tachycardia caused a 50% increase in lymph flow.
If, however, the lymph flow outlet pressure was
increased to a pressure equal to the venous pres-
sures measured during atrial pacing, then lymph
flow decreased to baseline rates. Thus it appears
that in tachyarrhythmia-induced hydrops, edema
formation results from (1) increases in microcir-
culatory pressure resulting f r o m increased ven-
o m o t o r tone a n d / o r decreased ventricular com-
pliance, and (2) impairment o f lymphatic flow
resulting from increased venous pressure. Inter-
 Pathophysiologyof Hydrops
estingly, electrically induced tachycardia is par-
ticularly well suited for examining the time course
for the development and reversal o f hydrops, be-
cause the circulatory disturbance can be initiated
and terminated instantaneously. Hydrops ap-
pears to develop within several hours to a few
days after initiating pacing, and many o f the cir-
culatory disturbances are rapidly reversible after
returning to sinus rhythm. 34's6
Anemia
Anemia as a result o f alloimmunization, hemor-
rhage, or red blood cell dyscrasia is a c o m m o n
cause o f hydrops. Recently, Blair et al have suc-
cessfully produced anemia-associated hydrops in
fetal lambs by partial exchange transfusion. 44 This
experimental model is beginning to provide im-
portant insight into the pathogenesis o f fluid ac-
cumulation during anemia. As in electrically in-
duced tachycardia, hydrops in anemia seems to
be associated with an increase in venous pressure.
Plasma colloid oncotic pressure increased some-
what in all the anemic animals, suggesting that
extravasation o f fluid from the vascular space oc-
curs in anemia as well as in electrically induced
tachycardia. It is unlikely that these alterations
in oncotic forces contribute to water accumula-
tion in anemia, however, because the observed
increase in plasma oncotic pressure would be ex-
pected to impede water loss to the interstitium.
Interestingly, the likelihood o f developing hy-
drops was related to the rapidity with which ane-
mia was produced.
Sumnlal~
Interstitial fluid accumulates in the fetus when-
ever the rate o f fluid extravasation from the vas-
cular space is greater that the rate at which fluid
is returned to the venous system by the lym-
phatics. The fetus is particularly susceptible to
such interstitial fluid accumulation by virtue o f
developmental differences that facilitate fluid
extravasation and cause lymphatic return to be
more potently influenced by lymphatic outflow
pressure. The delicate balance between fluid en-
try and egress from the interstitium can be easily
upset as a result o f normal homeostatic mecha-
nisms that preserve organ nourishment in the
face of circulatory insufficiency. Given the num-
ber of independent parameters that determine
445
the rates o f transcapillary fluid movement, it is
not surprising that hydrops is a c o m m o n conse-
quence o f many different disease processes. Even
if one considers hydrops to be most commonly
a consequence o f circulatory insufficiency, the
specific entities leading to circulatory compro-
mise are numerous. Understanding the physiol-
ogy o f interstitial fluid accumulation and the
pathophysiology o f specific diseases aids in the
advancement o f diagnostic and therapeutic ap-
proaches to prenatal care. The challenge o f fu-
ture investigations is to develop therapeutic
strategies aimed not only at reversing the under-
lying disease, but also to ameliorate the conse-
quences o f interstitial fluid accumulation.
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