AMER. ZOOL., 32:322-330 (1992)
Maternal-Fetal Oxygen Transfer in Lower Vertebrates1
R O L F L. INGERMANN
Department of Biological Sciences, University of Idaho, Moscow, Idaho 83843
SYNOPSIS. There exists a difference in oxygen affinity between fetal and maternal bloods
in almost all vertebrates examined and this difference in affinities probably facilitates oxygen
transfer to the fetus. It is likely that the high oxygen affinity of fetal blood represents a
biochemical pre-adaptation from an ancestral oviparous embryo for oxygen uptake in a
relatively hypoxic environment. In most cases, the maternal-fetal difference in blood oxygen
affinities is due to the characteristics of the fetal red cell and not due to any changes in the
adult red cell during pregnancy. These characteristics are based on the presence of a unique
fetal hemoglobin with an intrinsically high affinity for oxygen or on the absence of high red
cell concentrations of organic phosphates—allosteric modulators of hemoglobin function.
However, in several species of snake, representing different families, it appears that pregnancy
is associated with a pronounced decrease in the oxygen affinity of the adult red cell. This
suggests that the blood of the pregnant female is better able to unload oxygen to the fetus
than could the blood of the nonpregnant adult. The maternal-fetal difference in blood oxygen
affinities in these species is probably due to the characteristics of the fetal red cell as well
as to the change in the affinity of the adult cell during pregnancy. Nonetheless, although the
magnitude of the pregnancy-associated change in oxygen affinity of the adult cell in these
snakes suggests that it is physiologically significant, the actual significance remains to be
determined.
INTRODUCTION
Maternal-fetal oxygen transfer is dependent on numerous factors which include
blood oxygen carrying capacities, maternal
and fetal placental blood flows, placental
structure, and blood oxygen affinities (see
review by Carter, 1989). This paper, however, will be limited to a consideration of
the function, origin, and basis of the difference in oxygen affinity between maternal
and fetal bloods. The oxygen affinity of blood
is a reflection of the oxygen affinity of its
red cells and in almost all viviparous vertebrates which have been examined, fetal
red cells have a higher affinity for oxygen
than do those of the mother. Although controversial, it is likely that this maternal-fetal
difference in oxygen affinity facilitates the
transfer of oxygen to the fetus. I will use
mammalian data as a frame of reference to
examine this facilitation and will consider
the evolutionary origin of, and the fetal and
maternal contributions to, this difference in
blood oxygen affinities.
IMPORTANCE OF THE MATERNAL-FETAL
DIFFERENCE IN OXYGEN TRANSFER
No difference exists between the oxygen
affinity of maternal and fetal bloods of the
cat (Novy and Parer, 1969), and surprisingly, the blood oxygen affinity of the fetal
tammar wallaby is lower than that of the
mother (Tibben et al., 1991). Further,
human fetuses given transfusions of adult
red cells in utero for erythroblastosis fetalis,
and thus have blood with an oxygen affinity
similar to that of maternal blood, appear to
show normal growth (Novy et al., 1971).
These results indicate that a higher oxygen
affinity of fetal vs. maternal red cells is not
necessarily required for fetal growth and
development. Nonetheless, numerous
reports have suggested that a maternal-fetal
difference in blood oxygen affinity is important in facilitating oxygen transfer to, and
in the normal development of, the mammalian fetus. Hebbel et al. (1980) and Bauer
et al. (1981) found that fetal birth weight in
rats is reduced when the oxygen affinity difference is eliminated by increasing the affinity of maternal blood. Battaglia et al. (1969)
found that fetal sheep transfused in utero
1
From the Symposium on Evolution of Viviparity in with adult blood show lower oxygen tenVertebrates presented at the Annual Meeting of the
American Society of Zoologists, 27-30 December 1990, sions in umbilical blood. Furthermore, in
that study, of four sheep with twin pregat San Antonio, Texas.
322
MATERNAL-FETAL OXYGEN TRANSFER
nancies whose fetuses were transfused, three
suffered fetal death in utero. In similar
investigations, Itskovitz et al. (1984) transfused fetal sheep with maternal blood
thereby raising the fetal P50 (oxygen tension
required to half saturate the hemoglobin with
oxygen) from 20 to 41 mmHg (lmmHg =
0.133 kPa). As a result, there was a significant reduction of oxygen delivery to, and
oxygen consumption by, the fetus. These
findings are also consistent with the results
of studies by Edelstone et al. (1989) on fetal
sheep transfused with adult blood under
moderate anemia. In contrast, Meschia et
al. (1969) and Kirschbaum et al. (1971)
found no effects on fetal oxygen consumption when fetal blood was exchanged with
maternal blood. Nonetheless, as pointed out
by Edelstone et al. (1989), in each of these
studies, elimination of, or a decrease in, the
maternal-fetal difference in blood oxygen
affinities resulted in decreases in the quantity of oxygen delivered to the fetus (although
not necessarily in decreases of fetal oxygen
consumption). Finally, Soothill et al. (1988)
showed that replacement of fetal with adult
blood in human fetuses with erythroblastosis fetalis results in a decrease in oxygen
delivery to the fetus. These data suggest that
the relatively high oxygen affinity of most
fetal bloods is advantageous for normal
growth and development.
Several interesting interpretations have
been offered to explain the physiological
advantage of the relatively high oxygen
affinity of fetal blood. As indicated by Bartels et al. (1962) the pH of human fetal
plasma is about 7.2 while that of the mother
is about 7.4. The oxygen dissociation curves
of fetal and maternal blood at their respective in situ pH values occupy approximately
the same position. Thus, the higher oxygen
affinity of fetal vs. maternal blood may help
to ensure that fetal blood does not have a
lower oxygen affinity at normal, in vivo pH
values. Dawes (1967) and Faber and Thornburg (1983) indicated that the left shifted
oxygen dissociation curve of fetal blood
increases the maximal oxygen uptake at very
low fetal arterial Po2 tensions. They ask
whether low oxygen tensions may be necessary for normal fetal development. Alternatively, perhaps higher oxygen tensions are
323
simply unnecessary, especially considering
that pressure gradients required to supply
isolated cells with oxygen are very low (Wittenberg and Wittenberg, 1985). These interpretations and questions remain unresolved. Nonetheless, besides the cat and the
tammar wallaby, all viviparous vertebrates
which have been examined—lower vertebrates as well as mammals—show a difference in maternal-fetal blood oxygen affinities with fetal blood always having the higher
affinity. These results strongly suggest that
the higher oxygen affinity of fetal vs. maternal blood is physiologically advantageous
for most viviparous vertebrates.
PRE-ADAPTATION FROM AN
OVIPAROUS ANCESTOR
It is very likely that the ancestors of viviparous vertebrates were oviparous (Packard
et al., 1977; Shine, 1985). Further, as indicated by Manwell (19586), Metcalfe et al.
(1972), and Grigg and Harlow (1981), it is
likely that the high oxygen affinity of the
viviparous fetus is a pre-adaptation from
the embryo of the oviparous ancestor. It is
therefore reasonable to examine the affinity
characteristics of the avian embryo as a
model of the ancestor of the modern fetus.
The calcareous shell and the egg shell
membranes constitute an appreciable barrier to oxygen diffusion. As summarized by
Black and Snyder (1980), the oxygen tension at the blood vessels of the chick embryo
is about 85 mmHg at sea level. Thus, relative to gas exchange in the adult, the
embryo develops under conditions of hypoxia. Since oxygen is a nutrient which cannot be stored in the ovulated egg by the adult
female, the embryo must continuously deal
with the limited availability of oxygen. At
least one mechanism which appears to be
advantageous in oxygen acquisition is having a blood with a relatively high affinity for
oxygen (Fig. 1). That the high affinity of
embryonic blood is an adjustment to limited oxygen availability is indicated by the
substantial shift of the blood to a lower oxygen affinity when the embryo is incubated
under hyperoxia (60% O2) (Ingermann et al,
1983). Incubation of the chick embryo under
hypoxia (13.5% O2) results in a left shift of
the oxygen dissociation curve and an even
324
ROLF L. INGERMANN
0
10
20
30
40
SO
60
70
BO
90
100
PO2, mmHg
FIG. 1. Oxygen dissociation curves for blood from
the embryonic and adult chicken at 37°C. For Figures
1-3, the curves are approximations based on the Hill
equation. The curves in this figure were drawn with a
Hill coefficient of 2.5 and with P50 values of 34 and 49
mmHg for the embryo and adult, respectively (Metcalfe et al., 1972). The P50 is the oxygen tension at
which half of the oxygen binding sites are saturated
with oxygen and thus is an indicator of oxygen affinity:
the higher the Pso, the lower the oxygen affinity.
higher affinity for oxygen relative to the normoxic condition (Baumann et al., 1983).
Similarly, prior to the partial opening of the
egg case, the oxygen affinity of the embryonic red cell is measurably greater than that
of the adult red cell in the skate Raja binoculata (Manwell, 19586). Since the embryos
of turtles face similar problems of oxygen
diffusion across the shell and shell membranes, and in addition develop in somewhat hypoxic, buried nests (Prange and
Ackerman, 1974), it might be expected that
the blood of the turtle embryo has an appreciably higher oxygen affinity than the blood
of the adult. This appears to be the case with
the loggerhead turtle, Caretta caretta
(Isaacks et al., 1978). In contrast, in the green
sea turtle, Chelonia mydas, the blood of the
embryo has only a slightly greater affinity
for oxygen than does that of the adult at 44
and 50 days of embryonic development
(Isaacks et al, 1978). A difference in oxygen
affinity of bloods of embryonic and adult
diamond-back terrapin turtles {Malaclemys
centrata) may also be inferred from the data
of McCutcheon (1947) who showed the
presence of a unique, high oxygen affinity
hemoglobin in red cells from the embryo.
Retention of the egg for longer periods in
the reproductive tract of the female prior to
deposition appears to have been the devel-
opmental basis of viviparity. If the oviparous embryo already had a blood with a high
affinity for oxygen, or had the ability to biochemically acclimate to hypoxia, then this
embryo would be pre-adapted for the relatively hypoxic environment of the female
reproductive tract. Indeed, the mammalian
fetus is exposed in utero to hypoxia relative
to the adult; the umbilical venous oxygen
tension is about 30 mmHg (Faber and
Thornburg, 1983) in humans and about 40
mmHg in sheep (Soothill et al., 1986). It is
therefore likely, as Manwell (19586), Metcalfe et al. (1972), and Grigg and Harlow
(1981) have suggested that the fetus of the
viviparous vertebrate was biochemically
pre-adapted from its oviparous embryonic
ancestor to obtain oxygen from the mother.
MOLECULAR BASIS FOR THE
MATERNAL-FETAL DIFFERENCE IN
RED CELL OXYGEN AFFINITIES
The molecular basis of the difference in
oxygen affinities between maternal and fetal
red cells falls essentially into two categories.
In animals such as the teleost Zoarces viviparus (Weber and Hartvig, 1984) and the goat,
cow, and sheep (Blunt et al., 1971; Comline
and Silver, 1974; Hlastala et al., 1978), the
high oxygen affinity of fetal blood can be
accounted for by the presence of a unique
fetal hemoglobin with an intrinsically higher
affinity for oxygen than that of adult hemoglobin. Structurally and functionally different maternal and fetal hemoglobins are also
at least partially responsible for the maternal-fetal difference in blood oxygen affinity
in the chondrichthyan Squalus acanthias
(Manwell, 1958a, 1963).
A variation on this mechanism is found
in humans and other primates where structurally different maternal and fetal hemoglobins have different affinities for the
organic phosphates, 2,3-diphosphoglycerate (2,3-DPG) and adenosine triphosphate
(ATP). These organic phosphates bind to
and stabilize the deoxygenated state of
hemoglobin and therefore effectively lower
the oxygen affinity of the hemoglobin and,
thus, the red cell as well. Due to the difference in affinities for 2,3-DPG and ATP, the
oxygen affinities of adult and fetal human
hemoglobins are lowered unequally by the
MATERNAL-FETAL OXYGEN TRANSFER
presence of equal concentrations of these
organic phosphates (Bauer et ai, 1968;
Tyuma and Shimizu, 1969; Tomita, 1981).
This accounts for the higher oxygen affinity
of fetal than adult blood. A similar situation
appears to exist in the rhesus monkey (Metcalfe et ai, 1972) and in the Japanese monkey, Macaca fuscata (Takenaka and Morimoto, 1976).
In most viviparous animals which have
been examined, the hemoglobins of the adult
and fetus are structurally identical. However, the concentration of organic phosphates is lower in fetal than adult red cells
which results in the relatively high oxygen
affinity of fetal blood. This molecular strategy is found in the ectotherms: the caecilian
Typhlonectes compressicauda (Garlick et ai,
1979), the lizard Eulamprus (=Sphenomorphus) quoyii (Grigg and Harlow, 1981), and
the snakes Agkistrodon piscivorus (Birchard
et ai, 1984) and Thamnophis elegans (Berner and Ingermann, 1988). In these organisms, the primary organic phosphate appears
to be ATP. This strategy is also found in
most mammals, for example in the horse,
mouse, and the Weddell seal, Leptonychotes
weddelli (Bunn and Kitchen, 1973; Petschow et al., 1978; Qvist et al., 1981) where
the primary organic phosphate is 2,3-DPG
instead of ATP.
A difference in maternal-fetal oxygen
affinities also exists in the teleost, Embiotoca lateralis. In this species, the difference
appears to be due to lower concentrations
of ATP and to the presence of a high affinity,
unique hemoglobin in fetal red cells (Ingermann andTerwilliger, 198la, b; Ingermann
et ai, 1984). This situation is unusual as
most viviparous vertebrates appear to use
either different hemoglobins or different
concentrations of organic phosphate to
ensure that fetal blood has a higher oxygen
affinity for oxygen than does maternal blood.
325
ference does not appear to be due to changes
in the adult red cell in response to pregnancy. Nonetheless, changes in the properties of the adult red cell during pregnancy
have been documented in some mammals.
For example, Darling et al. (1941) and Ortner et al. (1983) documented slight decreases
in the oxygen affinity of the maternal red
cell associated with pregnancy in humans.
In contrast, Prystowsky et al. (1959) and
Lucius et al. (1970) were unable to discern
an influence of pregnancy on the oxygen
affinity of the adult red cell. Slight decreases
in the oxygen affinity of maternal blood have
also been reported in the goat (Barcroft,
1935; Hellegers et ai, 1959), and guinea pig
(Merlet-Benichou et ai, 1975) (Fig. 2). (In
the cow, pregnancy is associated with a slight
increase in red cell oxygen affinity of the
mother [Gahlenbeck et ai, 1968].) However, the maximum difference in oxygen
affinity between red cells of pregnant and
nonpregnant female, in any of these studies,
was less than about 3 ramHg. Although these
changes in oxygen affinity of the adult red
cell associated with pregnancy may have
been statistically significant, the physiological significance, if any, is not clear. Indeed,
Battaglia and Meschia (1986) have stated:
"There is no evidence that pregnancy
induces physiologically significant changes
in the oxygen affinity of maternal blood."
Recent findings suggest that pregnancy
may be associated with physiologically significant changes in the oxygen affinity of the
adult red cell in several reptiles. As shown
in Table 1, the red cell concentration of total
nucleoside triphosphate (NTP, primarily
ATP: Berner and Ingermann, 1988) is less
in the fetal than adult red cell of the garter
snake Thamnophis elegans. This difference
is associated with a higher oxygen affinity
of fetal vs. adult red cells (Fig. 3). Nonetheless, concentrations of NTP rise in red cells
of the mature female during pregnancy and
the 50% rise in red cell NTP is associated
INFLUENCE OF PREGNANCY ON THE OXYGEN with a 35-40% decrease in the oxygen affinAFFINITY OF MATERNAL BLOOD
ity of the adult cell at 20°C—an approximate
The difference in oxygen affinities between night-time temperature (Ingermann et ai,
fetal and maternal bloods is based primarily 1991a). Consistent with the findings of
on the characteristics of the fetal red cell, Benesch et al. (1969) and those summarized
that is, based on the presence of a unique by Pough (1980), an increase in temperature
hemoglobin or on low concentrations of is associated with a decrease in oxygen affinorganic phosphates in fetal cells. The dif-
326
ROLF L. INGERMANN
FIG. 2. Hypothetical oxygen dissociation curves for
blood from fetal, nonpregnant female (NPF), and pregnant female guinea pigs at 37°C. Fetal P50 is taken to
be 19 mmHg (Metcalfe et al., 1972) and nonpregnant
and pregnant adult female values are taken to be 26.3
and 27.0 mmHg, respectively (Merlet-Benichou et al.,
1975). The Hill coefficient is assumed to be 2.9 for
each curve.
ity of red cells from all groups of garter snake
examined (Table 1). However, at 34°C—an
approximate maximal daytime temperature—the red cell oxygen affinity of the pregnant female is not statistically different from
that of the nonpregnant female although it
is different from that of the adult male.
To examine whether such an effect of
pregnancy is restricted to a single species or
perhaps more widely distributed, Frances
Ragsdale and I examined the characteristics
of red cells from the fetal, pregnant female,
nonpregnant female, and male rattlesnake,
Crotalus viridis oreganus (Ragsdale and
Ingermann, 1991). As shown in Table 2,
NTP levels and P50 values are lower in fetal
than adult red cells. Consistent with the
findings for T. elegans, pregnancy appeared
to be associated with a 50% increase in red
cell NTP and a 30-35% reduction in the
oxygen affinity of the adult red cell at 20°C.
However, at 34°C, there are no differences
in red cell oxygen affinity among the three
adult groups. Thus, it appears that pregnancy is associated with a pronounced
increase in red cell NTP and an appreciable
decrease in the oxygen affinity of the adult
red cell at least at 20°C in the rattlesnake as
well as the garter snake.
Recently, Holland et al. (1990) reported
that pregnancy is associated with a decrease
in the blood oxygen affinity in the viviparous Australian snake, Pseudechis porphy-
FIG. 3. Hypothetical oxygen dissociation curves for
washed red cells in pH 7.4 buffer from fetal, nonpregnant female (NPF), and pregnant female garter snakes,
T. elegans. Pwvalues are those at 20°C taken from Table
1; the Hill coefficient is taken to be 2.3 for each curve.
riacus, at 30°C. They found that the P50 of
the blood of the pregnant female was 60 to
75 mmHg while that of the nonpregnant
female was about 45 mmHg. The fetal P50
value was about half of that of the nonpregnant female.
Therefore, in three species of viviparous
snake, representing three different families
(Colubridae, Viperidae, and Elapidae) from
two different continents (North America and
Australia), it appears that pregnancy is associated with an appreciable reduction in the
affinity of the red cell of the adult female.
Thus, the difference in oxygen affinity
between fetal and maternal bloods appears
due in part to a change in the adult red cell
in response to pregnancy and due in part to
the characteristics of fetal red cells. Furthermore, the data suggest that the effect of
pregnancy on red cell oxygen affinity makes
the blood of the pregnant female better able
to unload oxygen to the fetus than could the
blood of the nonpregnant adult.
This leaves some interesting questions.
First, what is the physiological advantage
of decreasing the oxygen affinity of adult
blood during pregnancy? One possible
explanation is that by shifting the blood
oxygen dissociation curve of the pregnant
female to the right it is possible for the fetus
to have a lower oxygen affinity than it would
otherwise have had. A potential advantage
of lowering the oxygen affinity of fetal blood
is that it would take less time to shift to the
nonpregnant adult value at birth and thus
327
MATERNAL-FETAL OXYGEN TRANSFER
TABLE 1. Total red cell nucleoside triphosphate concentration in mM and P!0 values in mmHg at 20 and 34XJ
for washed red cells from the garter snakeThamnophiselegsins (Ingermann et a\., 1991a). Values are mean ± SD
(n).
[NTP], mM
Fetus
Pregnant female
Nonpregnant female
Male
5.6
14.8
10.1
8.2
±
±
±
±
0.8"
1.4"
1.3'
0.9d
(11)
(11)
(19)
(17)
P»,20"C
±
±
±
±
P»,34-C
± 6 . 1 ' (5)
(5)
± 8.8J (5)
(5)
± 4.7k (5)
(5)
± 6.2' (5)
(5)
Significant differences in NTP data as indicated by ANOVA followed by Tukey test (all comparisons in Tables
1 and 2): P < 0.05, All. Significant differences in P50 data: P < 0.05, e:f, e:g, e:h, f:g, f:h, i:j, i:k, i:l, j:l; NS, g:h,
j k kl
hasten the onset of independent life. This
appears unlikely as the change to nonpregnant adult NTP levels and P50 values after
birth occurs so rapidly in T. elegans, within
6 hr (Ingermann et ai, 19916), that it does
not seem necessary for the mother to shift
her dissociation curve for this purpose. More
likely is the explanation that a low, as
opposed to high, oxygen affinity of fetal
blood should facilitate oxygen unloading to
fetal tissues—at relatively high tissue Po2
values. Also, the lower the maternal oxygen
affinity, the higher could be the NTP levels
in the fetal red cells and still maintain the
oxygen affinity difference between maternal
and fetal bloods. During metabolic depletion, the viscosity of red cell suspensions
increases and cell membranes become less
deformable (Weed et al, 1969). Since
organic phosphates promote partial dissociation of the red cell cytoskeleton and thus
promote red cell deformability (Sheetz and
Casaly, 1980), it is possible that the higher
the fetal cell NTP level, the easier would be
the passage of fetal cells through capillary
beds.
We do not see an appreciable lowering of
the oxygen affinity of adult blood associated
18.6
45.8
33.7
32.2
4.7'
5.6f
4.9«
6.8h
35.4
74.2
64.0
54.9
with pregnancy in other species; therefore,
might a reduction in adult oxygen affinity
have deleterious effects? Two possible effects
of a reduction in oxygen affinity are that the
blood may not load completely at the lungs
(or gills of fishes) and that oxygen might
dissociate from the hemoglobin too easily—
that excessive oxygen might be given off at
the beginning of a vascular bed with too
little remaining to supply the cells at the end
of that bed with sufficient oxygen. Therefore, the physiological costs and benefits of
a shift in oxygen affinity of the adult blood,
in terms of the mother as well as the fetus,
remain to be determined.
In addition, other interesting questions
remain. What is the pregnancy signal which
prompts a change in the adult red cell? How
do the regulatory mechanisms of the cellular
metabolic machinery change to allow a 50%
increase in steady state NTP levels? This
strategy appears either absent or physiologically unimportant in mammals, but does
it exist in other viviparous ectotherms?
Indeed, is it a cosmopolitan strategy among
viviparous ectotherms? Regardless, data
from these three species of snake appear to
have broadened our understanding of the
TABLE 2. Total red cell nucleoside triphosphate concentration in mM and Pso values in mmHg at 20 and 34°C
for washed red cells from the rattlesnake Crotalus viridis oreganus (Ragsdale and Ingermann, 1991). Values are
mean ± SD (n).
[NTP], mM
Fetus
Pregnant female
Nonpregnant female
Male
9.6
15.5
10.2
9.8
±2.0*
± 1.4"
± 0.7'
± 0.5d
PJTlcFc
(5)
(5)
(6)
(6)
25.5
48.3
36.8
35.8
±
±
±
±
7.9'
6.0r
5.5"
7.2"
P«h34»C
(5)
(6)
(6)
(6)
50.7
62.0
61.6
58.3
± 10.2'
± 5.4*
±6.0"
± 3.8'
(4)
(6)
(6)
(6)
Significant differences in N T P data: P < 0.05, a:b, b:c, b:d; NS, a x , a:d, c:d. Significant differences in Px data:
P < 0.05, e:f, e:g, f:g, f:h, i:j, i:k; NS, e:h, g:h, i:l, j:k, j:l, k:l.
328
ROLF L. INGERMANN
range of physiological strategies which can
successfully support fetal development.
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