AMER. ZOOL., 32:343-354 (1992)
Physiology of Placental Transfer in Mammals1
J. JOB FABER, KENT L. THORNBURG, AND NANCY D. BINDER
Departments of Physiology and Pediatrics, School of Medicine,
Oregon Health Sciences University, Portland, Oregon 97201
SYNOPSIS. Almost all substances that are passively transferred fall into two classes. Their
transfer is either purely "flow limited" or purely "diffusion limited," with few in between.
Diffusion limited transfer (most lipid insoluble materials) is determined by the diffusion
permeability of the interhemal membrane. In the epitheliochorial placenta, this permeability
declines precipitously with increasing molecular weight and with the presence of electric
charge. In the various hemochorial placentas, molecular weight is not discriminated, except
to the extent that it affects the coefficient of free diffusion in water and electric charge is of
little or no consequence. Flow limited transfer applies to those substances (lipid soluble)
whose concentrations in maternal and fetal blood equilibrate in a single pass through the
placenta. Transfer of oxygen is flow limited or nearly so. The effectiveness of flow limited
transfer depends on vascular geometry. The "counter current" labyrinthine placentas of the
rabbit and the guinea pig are highly efficient, whereas the villous placentas of sheep, monkey
and man, which appear to allow end venous equilibration, are much less so. The price of
efficient flow limited transfer may be less reserve when one of the blood flows declines.
Maternofetal water flow per unit surface area of the placenta may be much greater in the
embryo than in the fetus. If so, ultrafiltration may play more than a negligible role in the
embryo in the transfer of lipid insoluble solutes and species differences may be less pronounced than in the fetus. A relation between placental transfer regime and evolutionary
pressure is not yet apparent.
INTRODUCTION
There is no other mammalian organ
whose structure and functions are so species
diverse as those of the placenta. This is curious since the "purpose" of the placenta, presumably, is the same in all species.
The simple minded reductionism of the
physiologist leads to a view in which the
placenta is no more than a system of maternal blood vessels, a barrier between the
maternal and fetal (or embryonic) bloods
and a system of fetal vessels. Even this generalized form of the placenta exercises a
variety of functions: endocrine, immune and
biochemical that fall outside our spheres of
expertise. We will restrict ourselves to a
review of the passive transfer properties of
the placenta, i.e., those that depend on convection through the blood spaces and on
diffusional or electrical processes or on filtration for transport through the barrier.
PLACENTAS AS EXCHANGERS
It is necessary to first introduce the concepts of diffusion limited and flow limited
1
From the Symposium on Evolution ofViviparity in
Vertebrates presented at the Annual Meeting of the
American Society of Zoologists, 27-30 December 1990,
at San Antonio, Texas.
transfers since the transfer of inert materials
is rather sharply divided between these two
classes. The expression diffusion limited
transfer means a regime of transfer from
mother to fetus or vice versa that is only
limited by the diffusion permeability of the
barrier, i.e., that is not limited by the blood
flows through either the maternal or the fetal
vessel systems. The expression flow limited
transfer means not limited by the diffusion
permeability of the barrier. Figure 1A shows
what the concentrations in the maternal and
fetal microvessels would look like in a case
offlowlimited transfer between parallel systems of maternal and fetal exchange vessels
that are perfused in the same direction.
(Unless excepted, all substances will be considered to be inert, that is, not consumed or
produced by the placenta.) It follows from
Fick's principle of" the conservation of mass
that the rate at which a substance crosses
the barrier is the product of the arteriovenous difference in concentration and the flow
(at the same side of the barrier). Since the
maternal and fetal flow rates in Figure 1A
are assumed to be the same, it follows that
the arteriovenous differences are the same
also; in this case, they are one half of the
arterial maternofetal concentration difference because the venous concentrations are
343
344
J. JOB FABER ET AL.
CONCURRENT
FETAL
COUNTERCURRENT
CAPILLARY
MATERNAL CAPILLAR'
B
DISTANCE ALONG VESSELS
DISTANCE ALONG VESSELS
FIG. 1. The diagrams show the concentrations of an inert solute along the exchange vessels in a placenta with
parallel maternal and fetal vessels that are perfused at the same rates. Diffusion from maternal to fetal blood
requires that everywhere along the barrier the concentration in maternal blood exceeds that in fetal blood. 1A
shows that the concentrations of highly diffusible solutes equilibrate during a single passage through the placenta.
Choosing a still more diffusible, or slightly less diffusible, solute would only make equilibration occur earlier or
slightly later during transit. Small changes in diffusibility, therefore, do not affect the artenovenous differences;
this is flow limited transfer. IB shows that the concentrations of very impermeable solutes do not change
significantly during transit from arteries to veins. Thus, the average concentration difference across the barrier
is almost constant and does not change much when flows are changed. This represents diffusion limited transfer.
1C and ID show corresponding diagrams for parallel vessels that are perfused in opposite directions.
PHYSIOLOGY O F PLACENTAL TRANSFER
345
TABLE 1. Glossary of symbols, superscripts and subscripts.
Superscripts
M
maternal
F
fetal
Subscripts
s
solute
50
(P50) oxygen pressure at which hemoglobin is half saturated
Symbols
a
radius of a molecule of diffusing solute
C
concentration
d
permeability of the placental barrier divided by the square root of the product of fetal and maternal blood flows
D
coefficient of free diffusion in water at body temperature
f
ratio of total blood content (bound and free) and the concentration of the unbound form of the
solute of interest
influx of solute across 1 cm2 of placental barrier
Js
N
Avogadro's number
P
diffusion permeability of 1 cm2 of placental barrier
R
gas constant
S
surface area of placental barrier
T
absolute temperature
T
(with superscript) arteriovenous concentration difference divided by the concentration difference
between maternal and fetal arterial blood
AF
fetal arteriovenous concentration difference
AM
maternal arteriovenous concentration difference
AA
difference in concentration between maternal and fetal arterial bloods
AV
difference in concentration between maternal and fetal venous bloods
aratio of circumference and diameter of circle
n
viscosity of extracellular fluid
a
reflection coefficient (ratio of observed osmotic pressure and osmotic pressure predicted by van 't
HofTs law)
the same. The arteriovenous concentration for s, see below, and CSM and CSF are the
differences are constant and the process is average concentrations of s in the maternal
not diffusion limited because small changes and fetal vessels. The rate of transfer is indein diffusion permeability make a difference pendent of the flow rates because small
only in how soon along the vessels equili- changes in flow rates do not greatly affect
bration is achieved. Since (essentially) com- the venous maternofetal concentration difplete equilibration occurs, the transfer rate ference. Hence the mean concentration difis equal to one half of the arterial concen- ference across the barrier (CSM - C ^ does
tration difference (AA) multiplied by the not change by much either and J S S remains
blood flow on the corresponding side. Thus the same.
the process is flow limited.
Figures 1C and ID show the correspondFigure IB shows an example of diffusion ing diagrams when the bloods flow through
limited transfer. Here the arteriovenous the maternal and fetal vessels in opposite
concentration differences are so small that directions (countercurrent). In the case of
the venous maternofetal concentration dif- flow limited transfer, this reversal of flow
ference (AV) is nearly equal to the arterial polarities leads to a doubling of the exchange
maternofetal difference. The rate of transfer efficiency since the arteriovenous differof a solute s (J S S) in Figure IB is governed ences (AM and AF) are now nearly equal to
by Fick's law of diffusion (see glossary of the arterial concentration difference (AA).
symbols in Table 1):
In the case of diffusion limited transfer, flow
TO
/^M
VIATIC
i/
/ i \ polarity is of no consequence (compare Figs.
J.-S = (CM - CO-P.-S mol/sec, (1) \B aJ m ) T h u s a M use f u l generalization
where P s -Sis the permeability of the barrier is that blood vessel arrangement is of no
346
J. JOB FABER ET AL.
importance in diffusion limited transfers but
may greatly affect flow limited transfers.
FLOW LIMITED TRANSFER AS OPPOSED TO
DIFFUSION LIMITED TRANSFER
Variables that are involved in the transfer
of inert solutes include 4 concentrations
(fetal and maternal arterial and venous), two
blood flows, the diffusion permeability of
the membrane and, for some solutes, such
as oxygen, the binding constants of the
transferred solute to blood protein. Relations between nine variables cannot be
entrusted to untutored intuition and it is
here that a mathematical tool of the engineers, dimensional analysis, proves helpful.
In short, dimensional analysis is a mathematical process in which all variables are
replaced by compound variables that consist of dimensionless combinations of the
original variables (Langhaar, 1951). "Dimensionless" means that when one calculates the dimension (or the units) of the
compound variable, one finds that they all
cancel out. One of the great advantages of
this form of analysis is that the number of
required dimensionless variables can be far
less than the number of original variables;
in the present case 3 instead of 9 suffice for
a complete representation of the process.
Since all concentration differences as well
as the transfer rates are proportional to the
concentration difference (AA) between arterial maternal and arterial fetal bloods, we
should divide all concentrations by AA. This
division normalizes the maternal (AM) and
fetal (AF) arteriovenous differences, which
will be denoted with the letter T (for transport), as TM (=AM/AA) and T F (=AF/AA).
Clearly, both variables have the useful
property of being dimensionless (numbers
without units).
Equation 1 already implied that the total
permeability of the placental barrier for a
solute s, P S S, is the permeability for that
solute, Ps (which is expressed per cm2 of
membrane area), multiplied by the surface
area of the membrane, S (in cm2). The product P S S has the dimensions of volume per
unit time, just like flow. One can, therefore,
construct a third dimensionless parameter,
d, a "flow normalized diffusion permeabil-
ity," by dividing P S S by flow but the question arises: which flow? For this reason, we
use the product of maternal (QM) and fetal
flow (QO and take the square root of that
product to obtain the correct dimension.
Thus we define d by d = P . S ^ Q M - Q T 5 - If
there is protein binding and the ratio of total
(bound + free) and free material is equal to
f, then the flow, Q, is replaced by the product of Q and fin the definition of d: P S S/
(Q M f M Q F f F ) 0 5 . Engineering theory says
that the exchange process is completely
described in terms of a relationship between
the three dimensionless variables TM, TF and
d (Langhaar, 1951), which is a vast simplification of the interrelationship between the
original nine variables, well worth the effort
of using normalized AV differences and a
normalized placental permeability instead
of the original uncomplicated measurements.
The relationships between the normalized AV differences on the fetal and maternal sides and the normalized permeability
are shown in Figure 2, not only for the counter- and concurrent exchangers but for some
other possible models as well. One of us
devised this form of representation (Faber,
1969, 1977) because a plot of experimentally obtained data on flow limited transfer
shows at a glance whether one is dealing
with an efficient type of exchanger (with, for
instance, countercurrent or cross current
vessel arrangements) or with one of the less
efficient models (such as concurrent and pool
flow exchangers).
Although one would imagine that information on vessel arrangement could be
obtained just as well by anatomical methods, this has proven to be more difficult and
less reliable than the use of physiological
methods, except in one classical case, the
placenta of the rabbit (Mossman, 1926).
The diagrams remain useful when, as is
the usual situation, maternal and fetal blood
flows are not equal to each other. In this
case, the AV differences are inversely proportional to the corresponding flows, since
Fick's principle demands that the products
of flow and AV differences are the same on
both sides. As a fringe benefit, the flow ratios
(Qp/QM) can be read from the graphs (Fig.
2). It is also possible to incorporate com-
347
PHYSIOLOGY OF PLACENTAL TRANSFER
UNTER CURRENT
A,
CROSS CURRENT
MIXED CROSS CURRENT
FIG. 2. The normalized maternal AV difference, TM, as a function of the normalized fetal AV difference, TF,
for various values of the normalized diffusion permeability, d, in exchangers with a variety of vessel arrangements.
Ratios of fetal and maternal blood flows (QF/QM) are indicated by straight lines through the origin and are
labelled at the top and the right edge of each diagram. Maternal and fetal flows are equal on the diagonals. On
the diagonals, the normalized AV differences approach the perfect value of 1.0 when d is very large in countercurrent and cross current vessel arrangements only; in less efficient types of exchangers the limits of the
normalized AV differences are only 0.5. Reproduced from Faber (1977) with permission of Federation Proceedings.
plications such as the presence of shunts
(Faber, 1969, 1977). For these reasons, we
prefer to depict results from experiments
with flow limited transfers in the form of
the diagrams used in Figure 2.
Figure 2 shows that, in general, transfer
is flow limited when the flow normalized
permeability, d, is greater than 30 {i.e., when
the total permeability is more than 30 times
greater than the flows) and nearly so when
d > 10. Transfer is diffusion limited when
d < 0.1. For values of d in between 0.1 and
10, the rate of transfer is affected both by
changes in flow or changes in permeability.
In practice, inert materials fairly cleanly
separate into flow limited (lipid soluble) solutes and diffusion limited (hydrophilic) solutes, with only a few exceptions; Figure 3
explains why.
Oxygen, although not truly an inert mate-
rial, is almost (Faber and Thornburg, 1983;
flow limited, whereas carbon monoxide,
because of its much tighter binding to
hemoglobin (f « 10,000) is diffusion limited; this follows from the definition of d
and explains the great usefulness of carbon
monoxide for determining the diffusion
capacity of the placenta (Longo et ai, 1967;
Bissonnette and Wickham, 1977). Experiments with tracers whose transfer is flow
limited (nitrous oxide, 3H2O, ethyne, antipyrine, etc.) have shown that the discoid
labyrinthine placentas of the rabbit (hemodichorial) and the guinea pig (hemomonochorial) belong in the efficient class of
exchangers (Fig. 4) and anatomic studies
confirm a countercurrent vessel system
(Mossman, 1926; Kaufmann and Davidoff,
1977). The discoid villous placenta of Rhesus monkey and, presumably, also the
348
J. JOB FABER ET AL.
T
FIG. 3. Artist's view of placental exchange. Lipid insoluble (hydrophilic) materials, such as Na+, cannot easily
cross cell membranes and are restricted to the extracellular spaces, which are long, narrow and tortuous. Their
permeabilities are low. Lipid soluble solutes, such as oxygen, ethyne, anesthetics, easily cross cell membranes.
Their diffusion area includes all of the placental surface area and their diffusion paths are no longer than the
thickness of that barrier. Their diffusibility is three or four orders of magnitude greater than the diffusibility of
hydrophilic solutes. The flow normalized diffusion permeability of oxygen is less than that of other gases because
of its binding to hemoglobin (value of f of the order of 100). Even so, its transfer appears to be close to flow
limited (d » 1).
human placenta (both hemomonochorial),
and the villous cotyledonary epitheliochorial placenta of the sheep (and presumably
the goat) belong in the inefficient category
(Figs. 4, 5), in spite of some anatomical evidence that argued for a more efficient type
(Barcroft and Barron, 1946).
The biological advantage of an efficient
placenta has its price. Figure 6 shows that
the rate of flow limited transfer diminishes
much more steeply in the countercurrent
exchanger than in the concurrent exchanger
when one (but not both!) of the flows, either
fetal or maternal, diminishes. After a flow
reduction of 50%, exchange in the countercurrent system has fallen by half but that in
the concurrent system by only one third. In
this respect, the rabbit and the guinea pig
have little reserve. This may explain an
observation that workers who experiment
with pregnant animals are familiar with.
Rabbit and guinea pig pregnancies are fragile, as opposed to the robust pregnancy of
the sheep.
The very limited extent of our knowledge
does not permit any form of classification
of placentas according to their exchange efficiencies. Exchange efficiency is important,
mostly, for the transfer of oxygen. In this
context we may add (Meschia et al., 1969)
that the much discussed difference between
the half saturation pressures (P5Os) of maternal and fetal hemoglobins is not as obviously beneficial to the fetus as is sometimes
assumed, and that here, also, there is neither
rhyme nor reason to the few species differences that are known (Faber and Thornburg, 1983, pp. 69-73). In fact, low fetal
P5Os may serve to keep fetal blood oxygen
tension low rather than oxygen saturation
high (Faber and Thornburg, 1983).
ELECTRICAL POTENTIAL DIFFERENCES
An electrical potential difference across
the placental barrier would affect the diffusional transfer of all charged species. Table
2 shows that electrical potential differences
have been found between the fetus and the
mother of a number of species. It was originally assumed that these fetomaternal
potential differences were potential differences across the placental barrier (Meschia
349
PHYSIOLOGY OF PLACENTAL TRANSFER
U S E D ON 0 A M FROM HESCHU *t oL 1967;
•UKOVSKI d oL t968; BLECKNER cl ol (969; SUSS
<t t t 1973; THORN0UR6 «*d FABER. «M«Mid«d.
BASED ON (MIA FROM SCHRODER « d I E (CUT WEISS,
1977; THO, GUINEA PIG PLACENTA (PERFUSED)
BASEO ON DATA FROU 6EHRM
oxl D t L M M i r , I96S
FIG. 4. The center panel shows experimental data obtained on artificially perfused guinea pig placentas. When
the circulations of this placenta are perfused in their physiologic directions, it behaves as an (imperfect) countercurrent exchanger since the normalized AV differences are greater than 0.5. When one of the flows is reversed
(perfusion from vein to artery), it is turned into a concurrent exchanger with a corresponding decrease in efficiency.
The left panel (sheep) and right panel (Rhesus monkey) show that these other placentas, normally, are of an
inefficient vessel arrangement. The lines are model predictions for various values of d, and with the presence
or absence of small shunts or unevenly distributed bloodflows.Sources of data quoted in Faber (1977); reproduced
with permission of Federation Proceedings.
et al, 1958) but the existence of a near
equality of the concentrations of most electrolytes in fetal and maternal plasmas made
that assumption unlikely. It has since been
found that a number of exogenous ions also
equilibrate in fetal and maternal plasmas in
guinea pigs and sheep; for that reason the
hypothesis that the large potential differences between fetus and mother were transplacental potential differences must be
rejected, at least for these species (Binder et
al., 1978; Thornburg et al., 19796). This is
not to say that a potential difference of a
BASED OH DATA FROM BOOS «l cl. 1940:
GAHLENBECK >! ol. 1968'. mil COULINE • ! ol. 1974
few millivolts could not exist across the placental barrier (Thornburg et al., 1979a);
presently available techniques are not sufficiently sensitive to determine the magnitude of small transplacental differences in
potential. But the origin of the large fetomaternal potential differences must be found
outside the placenta, possibly in the allantoic membrane (Thornburg et al., 1979b) or
in uterine epithelium outside the placenta
(Dale et al., 1990). The placenta of the pig
may be an exception (Faber et al., 1987;
Boyd et al., 1989) and may generate a fairly
BASEO ON DATA FROM BARRON, 1931; KAISER
I I ol. 1950: 0«) HETCALFE • ! ol. 1962
BASEO ON DATA FROM BARRON, 1955/56; S1TMO.IA
I t ol. 1965; BARTELS el ol, 1967; MRER • ! OL 8 6 7 ;
BEHRHAN, 1968 end BEKRUAN t l ol. 1969
'/•
FIG. 5. Oxygen, being consumed by the placenta, is not an inert substance. But the differences in the efficiencies
of countercurrent and less efficient placentas are so enormous that it is revealing to plot the experimental data
as normalized AV differences. Original sources in Faber (1977); reproduced with permission of Federation
Proceedings.
350
J. JOB FABER ETAL.
of the placental barriers to the permeabilities of the same solutes in a layer of stationary water. The latter permeability is
defined by the permeability of a unit cube
of water, the "coefficient of free diffusion,"
Ds. The Stokes-Einstein equation relates the
coefficient of free diffusion, D5, to the molecular radius, as, of the diffusing solute (s), the
viscosity of water, rj, and the usual physical
constants N, R, and T (Table 1):
UJ
1=1
2
BO
Ds = (R-T)/(as-6-7r-N-77) cm2-sec"1. (2)
It follows that D is inversely proportional
to molecular radius (in the case of ions, the
FLOW IN'/.OF IDERL
radius of the hydrated particle). Thus, if the
FIG. 6. Decrease in transfer rates, as % of the rate nature of the placental barrier is that of a
under perfect conditions (equal fetal and maternal blood stationary layer of water, permeabilities of
flows) when either the maternal or the fetal blood flow different solutes should be proportional to
is reduced. The initial fall off in the countercurrent their coefficients of diffusion and inversely
exchanger is much steeper than that in the concurrent
proportional to their molecular radii. To
exchanger.
compare the placental barrier to a layer of
stationary water is not as far fetched as it
large transplacental potential difference. might seem since materials that are excluded
Again, the extent of our knowledge is pitiful from cell interiors are restricted to interstiand no obvious organizational principle is tial fluid spaces, the so called "paracellular
evident.
pathways" in the placenta (Fig. 3).
Placental permeabilities have been meaDIFFUSION LIMITED TRANSFER
sured for a large number of hydrophilic
For materials that diffuse slowly across (extracellular) materials in a number of spethe barrier the AV differences are so small cies. The results are compiled in the graphs
that the average concentration difference of Figure 7.
The permeabilities of the hemochorial
across the placenta is approximated by the
difference in the arterial plasma concentra- placentas of man, the guinea pig (both
tions (Fig. 1). The total permeability of the hemomonochorial), the rabbit (hemodibarrier can be calculated from equation 1, chorial) and the rat (hemotrichorial) obey
if the rate at which a substance of interest the expected inverse relationship with
accumulates in the conceptus is measured molecular radius reasonably well, although
in a simple tracer experiment (Thornburg they are not identical. (Permeabilities measured with iodinated albumin, at the far right
etal., 1988).
Since animal tissues are mostly water, it of the graphs, are somewhat suspect due to
is instructive to compare the permeabilities problems with loose label.) But the rela20
40
60
80
100
TABLE 2. Fetomaternal potentials in different species.
Species
Placental histology and type
Guinea pig
Human
Rabbit
Rat
Sheep
Goat
Pig
Hemomonochorial, labyrinthine
Hemomonochorial, villous
Hemodichorial, labyrinthine
Hemotrichorial, labyrinthine
Epitheliochorial, villous
Epitheliochorial, villous
Epitheliochorial, villous
From summary in Faber and Thornburg (1983) and Boyd et al. (1989).
Potential difference
(maternal = 0, mV)
= -25
0
0
+ 12
-51
= -70
both positive and negative
values have been reported
PHYSIOLOGY OF PLACENTAL TRANSFER
HUMAN PLACENTA
351
GUINEA PIG PLACENTA
10000
1000
P-S/WI
•
1 0 0
nl/(s-g)
•
P-SVWI
nl/(s-g)
1
MOLECULAR RADIUS (A)
MOLECULAR RADIUS (A)
RABBIT PLACENTA
RAT PLACENTA
P-S/WI
nl/(s-g)
P-S/Wt , „ „
nl/(s-g)
10
100
10
100
MOLECULAR RADIUS (A)
MOLECULAR RADIUS (A)
SHEEP PLACENTA
10000
N
• \
etliy
«
o ycol
\
\
100
P-S/WI
nl/(s-g)
10
rl
B
tit'
•
•
\
piytht
A
\
•
itnl
l-glu
nann I L o l
\
1
-I-DT.
0.1
1
io
ioo
MOLECULAR RADIUS (A)
FIG. 7. Experimentally determined permeabilities for hydrophilic solutes in the mature placenta of a number
of different species. The permeabilities (expressed per gram placental weight) are plotted as a function of molecular
radius, both on logarithmic scales. The straight lines (intentionally displaced from the data) indicate the slopes
of the the relationships between permeability and molecular radii, if the two are inversely proportional to each
other. Data from Bain et al. (1988), Faber et al. (1971), Hedley and Bradbury (1980), Illsley et al. (1985),
Robinson et al. (1988), Schneider et al. (1985), Stulc and Stulcova (1986), Thomburg and Faber (1977), Thornburg et al. (1979a, 1988) and Willis et al. (1986).
352
J. JOB FABER ET AL.
tionship for the epitheliochorial placenta of
the sheep does not obey the inverse relationship at all, except perhaps for very small
solutes. The sheep placenta behaves as if its
paracellular pathways are so narrow that the
passage of all but the smallest molecules is
impeded. In the limiting case, in which the
diameter of the molecule is equal to or
greater than the diameter of the passages,
the permeability falls to zero. From a relationship like that shown in Figure 7, Boyd
and co-workers (1976) calculated that the
passages of the sheep placenta are only 0.45
nm wide. There is at present only scarce
information on placental membranes with
histological structures other than those of
the placentas in Figure 7.
There is a second anomaly in the placenta
of the sheep in that the permeabilities for
the electrolytes Na + and Cl~ are two orders
of magnitude less than those expected for
uncharged tracers of similar coefficients of
diffusion. Apparently the sheep placenta,
unlike the hemochorial placentas, discriminates the presence (but not the polarity!) of
charge. The biophysical basis for this kind
of discrimination is unknown. The sodium
permeability of the placenta of the goat is
as low as that of the sheep placenta (calculated from data by Flexner and Gellhorn,
1942); discrimination of the presence of
electric charge may, therefore, be a general
property of the epitheliochorial placenta.
Protein transfer is another topic in which
there are enormous differences between species. Some transfer gamma globulins by
means of a yolk sac {e.g., rabbit, guinea pig),
some through the (chorioallantoic) placenta
(man), and some not at all (sheep, goat); this
will be dealt with elsewhere in the symposium.
What evidence there is on diffusion limited transfer points to a modification of
Flexner's principle (Flexner and Gellhorn,
1942) that stated that the placental permeability for hydrophilic solutes (in his case
Na + ) diminishes as the number of cell layers
of the placenta (counted before the advent
of the electron microscope) increases. Present evidence suggests that hemochorial placentas, whether consisting of two cell layers
(hemomonochorial), three (hemodichorial)
or four (hemotrichorial) do not discriminate
molecular size, except to the extent that a
molecule's size affects its coefficient of free
diffusion in water, and do not discriminate
the presence of electric charge. The opposite
is true for the four layered epitheliochorial
placenta of the sheep (and the goat).
FILTRATION AND ULTRAFILTRATION
Sometimes a small calculation yields a big
surprise. Barcroft (1946) calculated that in
the course of gestation the placenta supplies
a greater mass of water to the conceptus
than it does of oxygen. One may well ask
how water gets there.
It seems safe to assume that water is
transferred by a combination of hydrostatic
and osmotic pressures. The hydrostatic
pressure differences across the barrier are
not yet known because of technical difficulties and the osmotic pressure differences
are not yet known because solutes that are
somewhat permeable in a membrane do not
exert their full (van't Hoff) osmotic pressure
but only a fraction thereof, usually designated by the letter a. With few exceptions,
the values of these "reflection coefficients,"
which can vary from 0 to 1 and which are
different for each solute, have not yet been
determined. We are, therefore, at present
poorly informed about the forces that transfer water to the conceptus.
This brings up the matter of ultrafiltration. There are, in reality, at least two forces
that transfer solutes across the barrier. The
diffusional force was dealt with above. The
second force is the ultrafiltration force, the
force that sweeps solutes along with the
stream of water through the barrier. Near
the end of gestation the fetal sheep grows at
3.5% per day. About 80% of its soma, and
therefore of its growth, is water. The diffusion permeabilities, above, were calculated on the assumption that the ultrafiltration forces were negligible. The reason for
this is that in those experiments the maternofetal concentration ratios were enormous
and diffusion of the tracers overwhelmed
their transport by ultrafiltration. However,
the normal ratios of maternal and fetal
plasma solute concentrations are generally
close to 1 and even near the end of gestation,
when water flow is low, ultrafiltration may
account for as much as 20% of the influx of
PHYSIOLOGY OF PLACENTAL TRANSFER
(non tracer) NaCl (Thornburg et al, 1979a).
It is likely that in this respect also there are
enormous species differences.
Early in gestation, ultrafiltration may play
a far greater role. For instance, the rabbit
embryo at 0.5 of gestation (15 days) grows
at about 100% per day and about 95% of
that embryo is water. At the same time, the
diffusion permeability of the early placenta,
per unit mass of the conceptus, is some 10
times less than near the end of gestation
(unpublished). Thus, early in gestation, the
relative importance of diffusion and ultrafiltration for supplying inert materials to the
conceptus is shifted towards the latter process, which is likely to be a major one. If
other species show comparable gestational
changes, supply early in gestation may be
less species specific than near the end of
gestation.
EPILOGUE
The medical physiologists take a dim view
of species differences, which prevent the use
of animal placentas as a guide to the human
placenta. As two amateur comparative
physiologists and one zoologist, we are fascinated, however, and we hope that our
colleagues will find redeeming zoological
principles in the small collection of heterogeneous data that we have been able to present here.
ACKNOWLEDGMENTS
The work in our laboratory would not
have been possible without the help of Tom
Green, Pat Renwick, Kim Saunders and Bob
Webber. It was financially supported by
various grants from the National Institute
of Child Health and Human Development,
lately HD27452, the Medical Research
Foundation of Oregon and the Oregon Affiliate of the American Heart Association.
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