Placental Gas Exchange and the Oxygen Supply

to the Fetus
Anthony M. Carter*1

ABSTRACT
The oxygen supply of the fetus depends on the blood oxygen content and flow rate in the uterine
and umbilical arteries and the diffusing capacity of the placenta. Oxygen consumption by the
placenta is a significant factor and a potential limitation on availability to the fetus. The relevance
of these several factors as well as responses to acute or sustained hypoxia has been explored
in the sheep model. In addition, much has been learned in the context of hypobaric hypoxia
by studying human populations that have resided at high altitude for varying periods of time.
Embryonic development occurs under anaerobic conditions and even the fetus is adapted to a
low oxygen environment. Nevertheless, there is a reserve capacity, and during acute hypoxia the
fetus can counter a 50% reduction in oxygen delivery by increasing fractional extraction. During
sustained hypoxia, on the other hand, fetal growth is slowed, although oxygen consumption is
unaltered when corrected for fetal mass. Similarly, birth weight is reduced in humans living at
high altitude even if the effect is tempered in those with a long highland ancestry. Placental mass
changes little during sustained hypoxia in sheep or humans at high altitude. This conceals the fact
that there are structural changes and that placental oxygen consumption is reduced. The underlying
mechanisms are a current focus of research. One intriguing possibility is that increased anaerobic
metabolism of glucose in the placenta spares oxygen for the fetus but reduces its supply of substrate
and thereby limits fetal growth. © 2015 American Physiological Society. Compr Physiol 5:1381-
1403, 2015.

Introduction In contrast, human pregnancy at high altitude offers an

An acute reduction in fetal oxygen supply can have serious
consequences. Monitoring of fetal heart rate and oxygen status
during delivery is therefore standard clinical practice. The aim
is to reduce the incidence of perinatal death and of patholo-
gies such as cerebral palsy. Chronic hypoxia, where the oxy-
gen supply is limited over time, may result in fetal growth
restriction with long-term consequences for health, includ-
ing a higher incidence of cardiovascular disease in adult life.
Because placental gas exchange and fetal oxygen supply play
critical roles for obstetric and pediatric outcomes, a wealth
of experimental data has accumulated about the factors that
determine them.
A major source of information stems from experiments
in sheep, where sophisticated techniques have been devel-
oped to study the ewe and her fetus. The heyday for such
research was 25 to 40 years ago and there are several com-
prehensive reviews (35, 125, 218). It is commonly assumed
that the sheep data can be translated to human pregnancy. As
an example, textbooks of physiology often give values for
oxygen saturation in the fetal circulation without acknowl-
edging that the data derive from sheep. However, clinical
correlates can be hard to find. Although uterine and umbilical
blood flows can be estimated noninvasively by Doppler ultra-
sound, it is difficult to pair them with values for blood oxygen
content.
interesting natural experiment in chronic maternal hypoxia.
Although the first observations date back 60 years (114),
research on high-altitude hypoxia continues to offer new
insights. It represents our second major source of informa-
tion and here is treated accordingly. Populations that have
been resident in the highlands for many generations (e.g.,
Andeans and Tibetans) have fewer pregnancy complications
and higher birth weights than recent immigrants (e.g., Euro-
peans and Han). Comparison of these groups continues to
improve our understanding of the role of the placenta in fetal
oxygenation. As an example, the ability of the placenta to
downregulate its own oxygen consumption in favor of the
fetal oxygen supply is now better understood because of
work on high-altitude placentas. Additionally, this body of
work supports the assumption that the physiology of placen-
tal gas exchange is similar in ovine and human pregnancies
at term.
* Correspondence to acarter@health.sdu.dk
1 Cardiovascular and Renal Research, Institute of Molecular Medicine,
University of Southern Denmark, Odense, Denmark
Published online, July 2015 (comprehensivephysiology.com)
DOI: 10.1002/cphy.c140073
Copyright © American Physiological Society.

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Placental Gas Exchange Comprehensive Physiology

Some Basic Concepts and Animal Models Table 1 Values Pertinent to Arterial Oxygen Transport in the Term
Fetus, Male High-Altitude Climbers at 8400 m on Mount Everest and a
Typical Adult Male
The oxygen environment of the fetus
In the first trimester of human pregnancy, the fetus and pla- Climbers at
centa need to be protected from exposure to high oxygen Term fetus 8400 m Adult male
levels. The danger to the developing embryo stems from the
threat posed by reactive oxygen species (ROS) such as the PaO2 , (kPa (mmHg)) 2.5-3.5 (19-26) 3.28 (25) 13.3 (100)
superoxide (O. 2 − ) and hydroxyl (OH. ) anions and their non-
SaO2 (%) 65 54 98
radical intermediates such as hydrogen peroxide (33). Conse-
PaCO2 , (kPa (mmHg)) 5.3-6.6 (40-50) 1.77 (13) 4.7-6.0 (35-45)
quently, the supply of maternal blood to the intervillous space
is sluggish or even absent during the first 10 weeks of ges- pH 7.25-7.35 7.53 7.35-7.45
tation (90). On the fetal side, embryonic hemoglobins with Hb (g dL−1 ) 16.6 19.3 15.0
high oxygen affinity (29, 108) act to sequester oxygen rather P50 , (kPa (mmHg)) 2.5 (19) 3.6 (27) 3.5 (26)
than transport it to the tissues.
CaO2 , (mL L−1 ) 150 145 200
The low oxygen levels endured by the early embryo make
sense when viewed in an evolutionary perspective. The atmo- Reproduced from (138) © 2010 Biomed Central Ltd.
sphere and the oceans were devoid of oxygen during most
of earth’s history. This changed during the Great Oxidation
Event 2.4 to 2.0 billion years ago, but for long after the oxy- Oxygen delivery to the fetus (mmol min−1 ) is given by the
gen content of the atmosphere was a fraction of present day product of umbilical blood flow (mL min−1 ) and the oxygen
levels (73, 179). Although atmospheric oxygen rose intermit- content ([O2 ]) of umbilical venous blood (mmol L−1 ):
tently 850 to 540 million years ago, oxygenation of the oceans
remained low in the Cryogenian Period when the first traces of Fetal O2 delivery = Umbilical blood flow × [O2 ]umbilical vein
sponges appear (134). Interestingly, present day sponges can (1)
maintain respiration, feeding, and growth at equivalent levels
of oxygenation (0.5%-4.0% of present atmospheric levels) Oxygen uptake by the fetus is the product of umbilical
(149). Returning to the first trimester human fetus, it thrives blood flow and the difference in oxygen content across the
in a low oxygen environment by relying on the phylogenet- fetal placental circulation:
ically ancient polyol pathway. That enables it to metabolize
glucose and regenerate NAD+ and NADP+ under anaerobic Fetal O2 uptake = Umbilical blood flow
conditions without producing lactate. This was confirmed by
× ([O2 ]umbilical vein − [O2 ]umbilical artery ) (2)
analysis of amniotic and celomic fluid from the first trimester
human fetus (89), but the pathway may be maintained by the
placenta later in gestation as indicated by the transplacental The values obtained in Eqs. (1) and (2) frequently are
gradients for polyols in sheep (201). Blood flow through the corrected for fetal mass and given in mmol min−1 kg−1 . In
intervillous space starts to rise around 12 to 14 weeks and steady state, fetal oxygen uptake is equal to fetal oxygen
this change is accompanied by increased expression in the consumption.
placenta of ROS scavengers such as superoxide dismutase Fetal oxygen extraction is the ratio of oxygen uptake to
(90, 212). oxygen delivery and often is expressed as a percentage:
Even after the increase in maternal placental blood flow,
PO2 in the umbilical vein (the most highly oxygenated fetal Fetal O2 extraction = Fetal O2 uptake∕Fetal O2 delivery × 100
blood) is as low as 30 mmHg (4.0 kPa) with an oxygen satu- (3)
ration of around 85% (218). Despite the physiological shunts
offered by the ductus venosus and foramen ovale, blood reach- Oxygen delivery to the gravid uterus is given by:
ing the heart and brain has a PO2 of 25 mmHg (3.3 kPa) and
a saturation of at most 65%. Thus what might be considered Uterine O2 delivery = Uterine blood flow × [O2 ]uterine artery
hypoxia in postnatal life is normoxia to the fetus. This led (4)
Sir Joseph Barcroft to coin the concept of “Everest in utero”
(138, 220) (Table 1). Uterine oxygen uptake is obtained by:

Oxygen delivery, oxygen uptake, and oxygen
extraction
It is important to distinguish between fetal oxygen delivery
and uptake, on the one hand, and oxygen delivery to the
uteroplacental unit (including the fetus), on the other.
Uterine O2 uptake = Uterine blood flow
× ([O2 ]uterine artery − [O2 ]uterine vein ) (5)
Analogous with Eq. (3), uterine oxygen extraction is the
ratio of oxygen uptake to oxygen delivery.

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The difference between uterine and fetal oxygen uptake
gives oxygen uptake by the placenta and uterine wall:
Placental O2 uptake = Uterine O2 uptake − Fetal O2 uptake
(6)
Some studies use Eq. (6) to calculate placental oxygen
uptake and do not distinguish between oxygen usage by the
placenta and uterine wall. This is an approximation given that
about 15% of uterine blood flow supplies the endometrium
and myometrium (137).
Animal models
Some of the variables in the above equations can be deter-
mined acutely at Cesarean section, but the oxygen content of
uterine venous blood cannot and some would dispute whether
maternal placental or uterine blood flow can be measured
accurately by current imaging techniques (198). Certainly,
there is no scenario where these variables can be altered
to examine the acute and chronic responses of the system.
Therefore, much of our knowledge of placental gas trans-
fer is based on experimental work in sheep. The model was
pioneered by Sir Joseph Barcroft, Donald H. Barron, and
Geoffrey Dawes [reviewed by (126)]. An important break-
through came in the 1970s when techniques were developed
for the chronic catheterization of the umbilical and uterine
blood vessels (142). This enabled studies to be made in the
unstressed ewe and her fetus without the confounding effects
of anesthesia and surgical stress (12). Representative values
for the principal factors affecting placental oxygen transfer in
midgestation and late gestation sheep are given in Table 2. To
model high-altitude pregnancy, the techniques developed in
sheep have been adapted for studies in unstressed llamas and
their fetuses, the llama being an inhabitant of the altiplano
(21, 120, 121).
Table 2 Reference Values for the Principal Factors Affecting Placental Oxygen Transfer in the Ewe and Fetal Sheep in
Midgestation (71-81 days) (19) and Late Gestation (133 ± 1 days) (219)
Variable
Uterine blood flow (mL min−1 )
Maternal hemoglobin concentration (mmol L−1 )
Maternal arterial oxygen saturation (%)
Umbilical blood flow (mL min−1 )
Umbilical blood flow (mL min−1 kg−1 fetus)
Fetal hemoglobin concentration (mmol L−1 )
Umbilical venous oxygen saturation (%)
Fetal oxygen uptake (mmol min−1 )
Fetal oxygen uptake (mmol min−1 kg−1 fetus)
Oxygen uptake by myoendometrium and placenta (mmol
All values are mean ± SEM.
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Placental Gas Exchange
A minor drawback of the sheep as a model is the occur-
rence of two types of hemoglobin with different affinities for
oxygen. Thus the P50 of maternal blood depends on whether
the ewe is homozygous for type A hemoglobin (P50 = 31.3
mmHg), homozygous for type B (P50 = 40.7 mmHg), or
heterozygous (AB; P50 = 35.7 mmHg) (135). A careful com-
parison of pregnant ewes that were either AA or BB found
that the difference in maternal blood oxygen affinity was com-
pensated to the extent that their fetuses had similar levels of
oxygenation (219).
Data obtained in sheep have been used for mathematical
modeling of placental gas exchange. This is a useful approach
that allows predictions to be made about the impact of altering
a single variable or set of variables. The principles of placental
modeling are embodied in the work of Hill, Power, and Longo
(71, 130) and are reviewed elsewhere (125).
One advantage of the sheep is its size and the fact that like
humans it gives birth to a highly developed neonate. Placen-
tation in the sheep is, however, different in several respects
from human placentation (Table 3). While a human placenta
is discoid with an intervillous space and a hemochorial pla-
cental barrier, the ovine placenta is cotyledonary, lacks an
intervillous space, and has an epitheliochorial barrier (43).
There are more layers of tissue in an epitheliochorial than a
hemochorial placenta. However, several adaptations result in
a diffusion distance from maternal to fetal blood that is not
much greater in ovine than in human placenta. Techniques
have been developed for the baboon (59,96,199), which has a
placenta similar to our own (Table 3), and although the body
of data is much smaller, it suffices to support the assertion
that the sheep is an adequate model to study placental gas
exchange (38).
Placentation in rodents differs in several respects from
human placentation (Table 3). The chorioallantoic placenta
is labyrinthine rather than villous and there is an additional
yolk sac placenta that functions throughout gestation. The
Midgestation Late gestation
657 ± 77 1132 ± 83
7.3 ± 0.3 6.6 ± 0.2
92.8 ± 0.6 89.4 ± 0.6
100 ± 12 571 ± 40
468 ± 57 189 ± 10
5.7 ± 0.3 7.1 ± 0.3
89.6 ± 1.1 79.7 ± 2.0
0.11 ± 0.01 1.02 ± 0.09
0.486 ± 0.027 0.329 ± 0.006
min−1 ) 0.57 ± 0.07 0.63 ± 0.06
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Table 3 Comparison of Placentation in the Human and Some Common Animal Models

Baboon and rhesus

Human macaque Mouse Guinea pig Sheep and llama

Implantation Primary interstitial Superficial Secondarily Secondarily interstitial Superficial

interstitial
Decidualization Spontaneous Spontaneous Induced Induced Absent
Placental shape Discoid Discoid Discoid Discoid Cotyledonary
Internal structure Intervillous space Intervillous space Labyrinthine Labyrinthine Interdigitating villi
Interhemal barrier at Hemomono-chorial Hemomonochorial Hemotrichorial Hemomonochorial Epitheliochorial
term
Trophoblast invasion Interstitial and Interstitial to decidua Interstitial to decidua Interstitial and Absent
endovascular to inner endovascular at least to
third of myometrium myometrium
Yolk sac Never forms a Never forms a placenta Permanent inverted Permanent inverted yolk Temporary yolk sac
placenta yolk sac placenta sac placenta placenta
Gestation length 268 days 160 days 19 days 64 days Sheep 148 days;
llama about 350
days
Litter size Usually one Usually one 4-12 About 4 1-2
Neonate Precocial Precocial Altricial Precocial Precocial

mouse and most other murine rodents have short gestations
and poorly developed (altricial) neonates. Placental oxygen
transfer may be critical only in the last few days making
them less satisfactory as models of fetal oxygenation (38,44).
In addition, most of the relevant variables are difficult to
measure in these species, although progress has been made
in measuring flow velocities in the uterine, umbilical, and
vitelline arteries of the mouse (163). Guinea pigs have a longer
gestation and deliver mature (precocial) young. Some work
has been done on placental oxygen transfer in this species
although mainly in acute experiments and under anesthesia
(36).
Modeling fetal growth restriction in sheep
Currently there is a strong focus on fetal growth restriction and
its implications for future health (64). The placenta is increas-
ingly seen to play a key role in what is generally defined as
developmental programming (34, 113). Much of the relevant
research concerns the nutrient supply to mother and fetus and
is beyond the scope of this overview.
There are, however, animal models of fetal growth restric-
tion that target variables important for placental gas exchange.
One of these, developed by Alexander (4), relies on the
fact that the ovine placenta is made up of numerous placen-
tomes (approx. 60-100) formed at preexisting structures in the
endometrium called caruncles. The number of placentomes
formed can be reduced by excising most of the caruncles
prior to pregnancy. This procedure, known as carunclectomy,
affects uterine and umbilical blood flows and oxygen delivery
to the gravid uterus and fetus (167, 168).
Embolization of the umbilical circulation by repeated
injection of microspheres targets umbilical blood flow and
fetal oxygen delivery (61). This model has been used mainly
to explore fetal endocrine responses to hypoxia (40, 62) and
remodeling of fetal blood vessels (204).
Vascular Architecture and Placental
Blood Flows
Labyrinthine and villous placentas
In many mammals, the exchange area of the placenta is a
labyrinth in which fetal and maternal capillaries (maternal
blood channels in hemochorial placentas) run parallel to one
another. The direction of blood flow is opposite in the fetal
and maternal circuits, allowing for countercurrent exchange
(147). This is an efficient system when exchange is flow-
dependent as is the case for oxygen. Interestingly, neither the
sheep nor the human placenta conforms to the countercurrent
pattern. Concurrent flow is assumed in mathematical models
of the ovine placenta (125). However, recent work employ-
ing microvascular corrosion casting and scanning electron
microscopy has shown there is a mix of concurrent, cross-
current, and countercurrent flow in the sheep placenta (66). In
human placenta, the fetal capillaries are found at the tips of
the villous trees whilst maternal blood flows through the inter-
villous space. This is best approximated as crosscurrent flow,
although clearly there will be concurrent and countercurrent
components, a pattern sometimes referred to as “multivillous
flow.”

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Does this entail that oxygen transfer is less efficient in
the human placenta than that of the mouse or guinea pig? A
stringent analysis by Metcalfe et al. (144) showed the advan-
tage of countercurrent over “multivillous” flow is not as great
as sometimes thought. In the human placenta, it likely is over-
ridden by the greater volume flow that can be achieved in the
low-resistance intervillous space (39).
Uterine and placental vasculature
Maintenance of an adequate blood flow through the mater-
nal placental circulation requires far reaching changes in
the upstream vessels, especially the uterine arteries and their
branches. Responses to pregnancy include increases in vessel
diameter, remodeling of the vessel wall and changes in vasore-
activity [reviewed by (206)]. One current focus of research
is the role played by potassium channels in uterine vascu-
lar adaptation to pregnancy, including the response to sex
hormones (226). We are also gaining information about the
importance of intercellular communication through gap junc-
tions as it pertains to the regulation of smooth muscle tone by
endothelium-derived factors like nitric oxide and prostacyclin
(5). In human pregnancy, there is extensive remodeling of the
uterine spiral arteries that supply the intervillous space; both
maternal factors and invasive trophoblast are important for
this process (67, 178).
Uterine blood flow
The diameter of the uterine artery and the rate of uterine blood
flow both increase in linear fashion during human pregnancy
(203). Accurate and reproducible measurements of uterine
blood flow in pregnant women are, however, difficult to obtain
(14). The oxygen saturation of uterine venous blood at term
is about 80% (60). With this as a starting point, Battaglia and
Meschia (14) recently estimated a uterine blood flow of about
800 mL min−1 or 270 mL min−1 kg−1 fetal mass, which is at
the high end of the range of values obtained by ultrasound.
Uterine blood flow was reduced in pregnancies with fetal
growth restriction compared to those where the fetal weight
was appropriate for gestational age (109). The reproducibility
of measurements purporting to reflect blood flow through
the intervillous space has been called into question (198).
Fortunately, there are reliable measurements in sheep under a
range of experimental conditions.
Oxygen uptake by the ovine fetus was shown to be insensi-
tive to variations in uterine blood flow (217). A 45% reduction
in fetal oxygen delivery led to a fall in fetal arterial oxygen
content from 4 to 2 mmol L−1 . But this did not cause any
appreciable change in fetal oxygen uptake because of a com-
pensatory increase in fractional oxygen extraction. In contrast,
a marked reduction in fetal oxygen uptake occurred when oxy-
gen delivery was decreased by more than 55% (to <0.5 mmol
min−1 kg−1 ). Thus, under normal physiological conditions,
the oxygen supply to the fetal lamb is approximately twice
that needed to maintain an adequate fetal oxygen uptake.
Volume 5, July 2015
Placental Gas Exchange
It seems unlikely, therefore, that fetal oxygenation is much
affected by the reductions in uterine blood flow that occur
during uterine contractions. This view is supported by a study
where uterine oxygen uptake was measured during uterine
contraction on a moment-to-moment basis (128). The system-
atic changes in uterine blood flow and oxygen uptake during
spontaneous or oxytocin-induced contractions were no greater
than the random variations seen during uterine quiescence.
The ovine fetus can maintain its oxygen consumption dur-
ing even a 24-h reduction in uterine blood flow (25, 75). Pro-
longed reductions of uterine blood flow can, however, impact
on fetal growth. Thus, when a reduction in uterine blood flow
was maintained for 7 days, by partial occlusion of the aorta,
the linear growth rate of the fetus decreased by 38% over
controls and growth rate was correlated to oxygen delivery
(27). Interestingly, fetal uptake of glucose and oxygen was
sustained, despite a sizeable decrease in oxygen delivery. Pla-
cental mass was 20% smaller in occluded animals compared
to controls and this was interpreted as an adaptive response
(27). In a more recent study (111, 112), uterine blood flow
was clamped at 750 mL min−1 from day 113 of gestation to
day 138, a week before term. Over the same period uterine
blood flow in control animals rose to 1409 mL min−1 . The
procedure led to asymmetric growth restriction with a 32%
reduction in fetal body weight, but no significant decrease in
brain weight. There was a 27% decrease in placental weight
(111).
Umbilical blood flow
Reviewing estimates of umbilical blood flow in human preg-
nancy, Battaglia and Meschia (14) concluded that some stud-
ies were biased by large systematic errors in the calculation of
blood flow. On physiological grounds, they were inclined to
accept estimates at the high end of the range (about 120 mL
min−1 kg−1 fetal mass). Umbilical blood flow is increased
in term human fetuses as compared to preterm ones (118).
Calculated per unit of fetal mass, however, umbilical blood
flow is seen to decrease with advancing gestation (118).
Umbilical blood flow in sheep was seen to vary widely
without any significant change in fetal oxygen uptake at low
or high rates of flow (46). When umbilical blood flow was
reduced, by occluding the cord for 3 to 4 min, the resultant
decrease in oxygen delivery was accompanied by a progres-
sive increase in fetal oxygen extraction (80). Umbilical blood
flow could be reduced by almost half without influencing fetal
oxygen uptake. Indeed, due to the high oxygen affinity of fetal
hemoglobin, the fetus was capable of a remarkable increase
in fractional oxygen extraction, which rose from 34% to 68%
when umbilical blood flow was reduced by 75%. This degree
of cord compression was, however, associated with a fall in
fetal oxygen uptake (Fig. 1).
The interval within which fetal oxygen uptake was main-
tained could be extended by allowing the ewe to breathe 100%
oxygen rather than room air (57). During this treatment, oxy-
gen delivery improved because of a 15% to 20% rise in the
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14 1 blood flow (6). There did not appear to be a threshold level for
y = –276.80 X
+ 8.49
umbilical blood flow above which fetal oxygen uptake was
r = 0.84
O2 consumption (mL min–1 kg–1)

P < 0.001 maintained at control levels. This may partly explain why
fetal growth fell from 4% per day to 2% per day when reduc-
10 tions in umbilical blood flow were maintained for several days
or weeks (6). Commenting on the subtle difference between
the results of short-term and long-term reduction of umbilical
blood flow, Anderson et al. (8) suggested that fetal oxygen
6 consumption can be turned down only slowly in response to
a reduced oxygen supply.

2 Mismatching of maternal and fetal placental blood

–75% –50% –25% C flows
Mathematical modeling indicates that placental gas exchange
40 120 200 280
will be most efficient when fetal and maternal blood flows are
Umbilical blood flow (mL min–1 kg–1)
perfectly matched. This has been looked at in sheep by inject-
ing radionuclide-labeled microspheres into both circulations
and measuring their distribution in small samples of placenta
80 (cubes about 2-3 mm on edge). The maternal:fetal blood flow
y = –58.18 log X + 173.44 ratio was <0.5 in 9% of the samples, 0.5 to 1.5 in 70% and
r = –0.91 >1.5 in the remaining 21%. When these numbers were fed
P < 0.001 into a mathematical model of placental gas exchange, it was
O2 extraction (%)

60 found that mismatching of flows reduced the predicted PO2

of umbilical venous blood by ca. 6 mmHg (181).

40
20
–75% –50% –25%
40 120 200
Umbilical blood flow (mL min–1 kg–1)
Figure 1 Effect on fetal oxygen consumption (upper panel) and oxy-
gen extraction (lower panel) of reducing umbilical blood flow in the
fetal lamb by partial cord occlusion. Error bars are SD. Reproduced,
with permission, from (80); Copyright © 1983 with permission from
Elsevier.
oxygen content of umbilical venous blood and fetal oxygen
uptake was maintained over a significantly wider range of
umbilical blood flows than in experiments where the ewe
breathed room air. A second study confirmed the beneficial
effect of 100% oxygen, although noting it was less effective at
severe degrees of blood flow reduction (172). Together these
studies suggest that there is a wide margin of safety in pla-
cental oxygen transfer during acute reductions in umbilical
blood flow lasting a few minutes, which may be of clinical
relevance in the context of cord compression in labor.
A rather different picture emerged during long-term
reduction of fetal placental blood flow, achieved by inflat-
ing an occluder around the distal aorta. In experiments where
computer-controlled restriction of flow was maintained for
10 days, fetal oxygen uptake was linearly related to umbilical
Blood Oxygen Capacity and Affinity
Embryonic and fetal hemoglobins
Hemoglobin is a heterotetramer comprised of two alpha and
C two beta globin chains each with an associated heme group.
There are multiple isoforms of the alpha and beta chains
280 encoded by separate cassettes of genes located on differ-
ent chromosomes. Importantly, gene expression is develop-
mentally regulated, resulting in embryonic, fetal, and adult
hemoglobins. The principal hemoglobins expressed during
human development are listed in Table 4. The nomenclature
used for the globin genes is that proposed by Aguileta et al.
(2) with traditional nomenclature given in parentheses.
Gower I expression begins coincident with the production
of nucleated red cells in the yolk sac. This hemoglobin has a
P50 of 4 mmHg and a very low sensitivity toward modulation
of oxygen affinity, properties reminiscent of myoglobin (29).
Its function may be to sequester oxygen rather than transport
it to the tissues. This could also be the case with Portland
I, the intermediate embryonic hemoglobin. Gower II, on the
other hand, has a somewhat lower oxygen affinity (72) (Fig. 2)
and shares properties with fetal hemoglobin (29). The oxygen
affinity of embryonic hemoglobin in other species is likely to
be high based on findings in the mouse (17), rabbit (74, 91),
and pig (214).
The high oxygen-binding affinity of fetal blood facilitates
placental oxygen transfer (Fig. 3). If, for example, maternal
and fetal bloods equilibrate at a PO2 of 30 mmHg, the mater-
nal hemoglobin will be about 50% saturated whilst the fetal

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Table 4 Human Embryonic, Fetal, and Adult Hemoglobins

Hemoglobin Ontogeny Alpha chain Beta chain P50 (mmHg)

Gower I Embryonic (predominant days 15-37) HBZ-T1 (ζ) HBE (ε) 4

Portland I Embryonic (from 4 weeks) HBZ-T1 (ζ) HBG-T1 (γ1 ) 6
Gower II Embryonic (from 4 weeks) HBA-T1, HBA-T2 (α2 , α1 ) HBE (ε) 12
Fetal (HbF) Fetal and early postnatal HBA-T1, HBA-T2 (α2 , α1 ) HBG-T1, HBG-T2 (γ1 , γ2 ) 20
Adult (HbA) Late fetal and adult HBA-T1, HBA-T2 (α2 , α1 ) HBB (β) 26
Adult (HbA2 ) Adult (3%) HBA-T1, HBA-T2 (α2 , α1 ) HBD (δ) 26

hemoglobin will have achieved an oxygen saturation of about by developmental regulation of two enzymes associated with
80%. DPG metabolism (92).
However, whilst all mammals have embryonic
hemoglobins (108), not all have a fetal hemoglobin. Human Oxygen affinity of fetal blood
fetal hemoglobin is the result of a gene duplication that
The oxygen affinity of hemoglobin is inversely proportional
occurred in the lineage of anthropoid primates (182). The
to the concentration of its three other ligands: hydrogen
sequence in which beta globin genes are expressed is a func-
ion, carbon dioxide, and DPG. Human hemoglobin F has a
tion of their distance from a common locus control region.
lower affinity for DPG than hemoglobin A and a correspond-
Tandem gene duplication resulted in a copy of an embryonic
ingly higher affinity for oxygen (16). During placental gas
gene that was further from the locus control region and came
exchange, the PCO2 of maternal blood rises, and the pH falls,
to be expressed later in development (95). In an interesting
which diminishes the oxygen affinity of maternal hemoglobin
example of convergence, a fetal hemoglobin was evolved in
(the Bohr Effect). The reverse process occurs in fetal blood,
the bovid family of ruminants, which includes the sheep and
increasing the oxygen affinity of fetal hemoglobin. The dou-
goat. In this instance, it arose by tandem duplication of the
ble Bohr Effect enhances the difference in oxygen affinity
HBB gene (117).
between maternal and fetal blood and it accounts for an esti-
In most other mammals, including murine rodents, fetal
mated 8% of placental oxygen transfer (71, 144).
and maternal blood contain the same type of hemoglobin (32).
To evaluate the importance of the difference in oxygen
Fetal blood nevertheless has a higher oxygen affinity due to
affinity, Itskovitz et al. (79) raised the P50 of fetal blood from
a the low 2,3-diphosphoglycerate (DPG) content of the fetal
20 to 41 mmHg, an oxygen affinity corresponding to that
red cells (39). It has been shown in the rat that this is achieved
of adult sheep hemoglobin, by exchange transfusion of the
fetus with maternal blood. Secondary to the reduced oxygen
affinity, there was a fall in the oxygen saturation of umbil-
100 ical venous blood, resulting in a decrease in oxygen con-
tent from ca. 4 to 2 mmol L−1 . Umbilical blood flow also
80 decreased following the exchange transfusion, and oxygen
delivery to the fetus fell by 64%. Fetal oxygen uptake fell
by 44% and metabolic acidosis developed, causing a further
Saturation (%)

60
rightward shift of the oxygen dissociation curve. The right-
ward shift limited the efficiency of oxygen unloading to the
40 fetal tissues and thus the ability of the fetus to compensate
for reduced oxygen delivery by increasing oxygen extraction.
20 Therefore, mean fetal oxygen extraction was only 51% fol-
lowing exchange transfusion with maternal blood (79).
The long-term effects on fetal oxygenation and develop-
0
0 10 20 30 40 50 ment of replacing fetal blood with adult blood are not com-
PO2 (mmHg)
pletely known. Human fetuses given transfusions of adult red
cells to treat hemolytic disease of the fetus and newborn have
Figure 2 Oxygen binding to human embryonic hemoglobins. The survived with normal growth indices and fairly normal acid-
saturation of hemoglobin with oxygen as a function of PO2 is shown for base values at birth (166, 193, 211). The effect of exchange
adult hemoglobin (black circles) and embryonic hemoglobins Gower I transfusion may be less pronounced in humans than in sheep
(black inverted triangles), Portland (open circles), and Gower II (open
squares). Reproduced, with permission, from (29); Copyright © 2002 as the difference between fetal and maternal P50 is smaller
with permission from Elsevier. (79).

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Placental Gas Exchange Comprehensive Physiology

24

10
22

9
20

8 18 Fetus

16 v

4.6 mL . dL–1
7 A
*
O2 content (mL . dL–1)
O2 content (mmol L–1)

5 mL . dL–1
6 14
Mother
12
5 a

10 *
V
4
8
3
6
2
4

1 2

0 0
0 10 20 30 40 50 60 70 80 90 100
Oxygen tension (mmHg)

Figure 3 Blood oxygen content as a function of PO2 for human maternal and near term fetal blood. A and V,
maternal arterial and venous values; a and v, umbilical arterial and venous values. Reproduced, with permission,
from (125); Copyright © 1987 The American Physiological Society.

Oxygen affinity of maternal blood if an increase in oxygen capacity were achieved at the expense
of a drop in umbilical blood flow.
Maternal hyperventilation in labor causes a fall in PCO2 and
Chronic intrauterine hypoxia stimulates the secretion of
rise in pH of maternal blood and this leads to a reduction in
erythropoietin, resulting in increased red cell production (52).
fetal PO2 (148, 209). In part, the response can be attributed to
In addition to the fetal kidneys, human placenta is a potential
the resultant increase in maternal oxygen affinity, since closer
source of erythropoietin (51, 52). Polycythemia is associated
approximation of the maternal and fetal oxygen dissociation
with fetal growth restriction and may reflect an attempt at
curves entails that equilibrium between the blood of mother
compensation (202). Note, however, that polycythemia may
and fetus is reached at a lower PO2 .
in itself impede growth because the associated increase in
Women with high-affinity blood (hemoglobinopathies)
blood viscosity can have a negative impact on oxygen delivery
have successful pregnancies (157, 170), however, indicating
(200).
that a difference in oxygen affinity between maternal and
The effect of raising or lowering fetal hematocrit has been
fetal blood is not a prerequisite for fetal survival. There is,
evaluated in sheep by isovolemic exchange transfusion with
nonetheless, a higher incidence of perinatal morbidity and
packed red blood cells or plasma from a donor fetus (55). Fetal
small-for-gestational-age babies in mothers with sickle cell
oxygen delivery was maximal at a hematocrit of 33% (Fig. 4).
disease (45, 76).
When fetal hematocrit was increased above the optimal value,
oxygen delivery decreased because the reduction in umbili-
cal blood flow was proportionately greater than the rise in
Oxygen capacity of fetal blood umbilical venous oxygen content. Fetal oxygen uptake was,
The oxygen-carrying capacity of blood is largely a function however, relatively constant at hematocrits between 16% and
of hematocrit, since the intraerythrocytic hemoglobin con- 48%, because fractional oxygen extraction increased to com-
centration is rather constant and the contribution of dissolved pensate for the reduction in oxygen delivery. At hematocrits
oxygen is negligible. The hematocrit is higher in fetal than <16% or >48%, corresponding to a fetal oxygen delivery
maternal blood so it is worth noting that hematocrit also is a <0.6 mmol min−1 kg−1 , oxygen uptake by the fetus decreased.
major determinant of blood viscosity and influences the rate This was associated with a fall in base excess, confirming that
of blood flow. Clearly, no advantage would accrue to the fetus oxygen delivery to some fetal tissues was inadequate to meet

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Comprehensive Physiology Placental Gas Exchange

40 isovolemic exchange transfusion with plasma or packed red

cells from pregnant donor sheep (initial hematocrit 27%).
DO2 fetus (mL O2 min–1 kg–1)

y = –19.7 + 2.59x – 0.039x2 Uterine blood flow did not alter and oxygen delivery to the
30
uterus decreased linearly with decreasing hematocrit. Oxygen
consumption by the uterus, placenta, and fetus decreased only
20 slightly, however, because of increased oxygen extraction. On
the fetal side, both umbilical venous oxygen content and oxy-
10 gen delivery to the fetus fell with decreasing maternal hema-
tocrit. But even when fetal oxygen delivery was reduced by
50%, oxygen uptake was kept constant by a compensatory
0 increase in fetal oxygen extraction. When maternal hemat-
100 ocrit and fetal oxygen delivery were decreased by more than
y = 124 – 5.9x + 0.09x2 50%, fetal oxygen uptake fell, because the increased extrac-
80 tion did not fully compensate for the additional reduction in
fetal oxygen delivery. An oxygen delivery of >6 mmol min−1
Fetal O2 extraction (%)

kg−1 was required to maintain oxidative metabolism. At lower

60 rates there was a decrease in the base excess of fetal arterial
blood.
40 When maternal anemia (hematocrit 14%) was maintained
for 6 days, there was a compensatory increase of 35% in utero-
placental blood flow. There was still a net reduction in oxygen
20
delivery to the gravid uterus, but its oxygen uptake was main-
tained through an increase in fractional oxygen extraction
0 (54).
10 y = 3.23 + 0.23x – 0.0035x2
Changes in maternal oxygen capacity, for which mother
VO2 fetus (mL O2 min–1 kg–1)

and fetus can compensate in the short term, are nevertheless

capable of stunting fetal growth, as shown by observations
in chronically anemic sheep (161). In that study, fetal oxygen
5 delivery was reduced sufficiently to affect not only fetal oxida-
tive metabolism but also fetal growth. A sustained reduction
in maternal hematocrit from day 115 of gestation to day 138,
a week before term, led to a 40% reduction in fetal weight
0 (161).
.

0 10 20 30 40 50 60
Fetal hematocrit (%)

Figure 4 Effect on fetal oxygen delivery (DO2 fetus), oxygen extrac-
tion and oxygen uptake (VO2 fetus) of varying the hematocrit of the
fetal lamb by exchange transfusion. Reproduced from (55); Copyright
© 1985 with permission from Elsevier.
their demands. At first inspection these findings suggest that
placental oxygen transport is little affected by variations in
fetal hematocrit. Therefore it is important to note the close
correspondence between the normal fetal hematocrit (32%)
and the hematocrit that ensured optimal oxygen delivery to
the fetus. The reduction in oxygen delivery during anemia and
polycythemia could help to explain why higher morbidity and
mortality rates are associated with these conditions in infants.
This provides a rationale for treatment of hemolytic and other
forms of anemia by intrauterine transfusion (78, 115).
Oxygen capacity of maternal blood
To examine short-term responses to maternal anemia, Paulone
et al. (173) varied hematocrit between 8% and 30% by
Maternal Arterial PO2
Maternal hypoxia
Hypoxic hypoxia at high altitude is discussed below. Other
than at altitude, hypoxic hypoxia is rare in clinical obstetrics,
but it is a potential cause of reduced oxygen delivery to the
gravid uterus (136). Fetal responses to maternal hypoxia were
studied by Parer (171), who reduced maternal arterial PO2
to about 35 mmHg by allowing the ewe to breathe a gas
mixture low in oxygen. After about 30 min, umbilical blood
flow was unchanged, but umbilical venous oxygen content
fell from 4.3 to 1.9 mmol L−1 with a resultant 57% decrease
in oxygen delivery to the fetus. Despite a rise in fractional
oxygen extraction, fetal oxygen uptake fell by 43%. There was
gradual development of metabolic acidosis during maternal
hypoxia that could be attributed to the accumulation of lactic
acid. This could further compromise fetal oxygenation. In a
setting where maternal hypoxia was maintained for 7 to 8 h,
the progressive fall in fetal vascular pH was accompanied by
a decrease in umbilical blood flow and led to a reduction in
fetal oxygen uptake (191).

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Placental Gas Exchange
Oxygen supplementation
The opposite situation, maternal hyperoxia, will hardly
improve oxygen delivery to the uterus. Maternal arterial blood
is fully saturated whether the fraction of oxygen in inspired
air is 21% or 100% (the change in dissolved oxygen amounts
to ca. 0.8 mmol L−1 , an increase of only 10% in blood oxygen
content). There may, nevertheless, be an improvement in fetal
oxygen supply. This is because fetal blood does not normally
become fully saturated in the placenta. Therefore, if umbilical
and uterine venous bloods equilibrate at a higher PO2 , there
can be a considerable improvement in oxygen delivery to the
fetus (82).
Supplementary oxygen is routinely given during general
anesthesia for elective Cesarean section, although current
evidence suggests it is unnecessary (102). A randomized
double-blind study did show an increase in umbilical arterial
and venous PO2 and oxygen content when anesthesia was
administered with 100% oxygen (164), confirming a previous
report (177). Although this was in agreement with theoretical
considerations, the difference was small. The effect of
supplemental oxygen has also been assessed noninvasively
by Blood Oxygen Level Dependent magnetic resonance
imaging. Preliminary findings in healthy pregnancies indi-
cated an increase in oxygenation of placental tissue (194)
and some fetal organs, although with no improvement in
oxygenation of the brain (195).
Could hypoxic, growth-restricted human fetuses benefit
from supplemental oxygen? In one study the value of giving
humidified 55% oxygen to the mother was explored by mea-
suring PO2 in umbilical arterial and venous blood obtained
by cordocentesis (165). In four of five fetuses, PO2 values
rose to within the normal range at the end of 10 min of
maternal hyperoxygenation. Later, however, a double-blind
randomized control trial failed to find any beneficial effect of
chronic administration of 40% humidified oxygen (116). A
recent review by an author of the original study did not rec-
ommend supplemental oxygen as an effective treatment for
fetal growth restriction (3).
The oxygen content of umbilical venous blood can be
raised by administering hyperbaric oxygen to the mother. In
sheep, administration of 100% oxygen to the ewe at 3 atmo-
spheres pressure was found to result in pulmonary vasodila-
tion and constriction of the ductus arteriosus (10). Neverthe-
less, placental oxygen transfer and fetal oxygen consumption
were maintained (104). Hyperbaric oxygen therapy has been
recommended for the treatment of carbon monoxide poison-
ing in pregnancy (210). A recent French study found no dif-
ference in psychomotor development between children born
following such treatment and matched controls exposed nei-
ther to carbon monoxide nor to hyperbaric oxygen (213). It
should be noted, however, that a fresh Cochrane review failed
to find sufficient evidence that hyperbaric oxygen was benefi-
cial in the treatment of carbon monoxide even in nonpregnant
adults (31).
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Comprehensive Physiology
Placental Factors
Placental diffusing capacity for oxygen
Placental diffusing capacity is defined as the amount of gas
diffusing across the placental membranes per unit of time per
unit of partial pressure difference between fetal and mater-
nal blood. It is dependent on the surface area, thickness
and solubility properties of the membranes, the diffusivity
of the gas, and the volume of blood in the fetal and mater-
nal placental capillaries (124, 132). The standard experimen-
tal approach is to determine placental diffusing capacity for
carbon monoxide (Table 5). Placental diffusing capacity for
oxygen is about 21% higher than the values obtained for car-
bon monoxide (132). The resistance of the interhemal mem-
brane contributes about 60% of the total resistance (132).
The diffusing capacity of the membrane is directly propor-
tional to the surface area and inversely proportional to the
mean diffusion distance, i.e. mean membrane thickness. Thus,
surface area can be estimated from the diffusing capacity
of the interhemal membrane and mean membrane thickness
(132).
An alternative approach is to estimate surface area, mem-
brane thickness, and vascular volumes by appropriate mor-
phometric techniques and use those values to estimate overall
diffusing capacity and the contributions of each compartment
in the diffusion pathway (139).
The interhemal membrane
The diffusion distance between fetal and maternal blood
is a limiting factor for oxygen transfer. Across mammals
distance is decreased by a reduction in the number of tis-
sues in the interhemal membrane and thinning of those that
remain (42). Thus, in human placenta, potential tissue lay-
ers include the maternal-facing syncytiotrophoblast; cytotro-
phoblasts (Langhans’ layer); connective tissue; and fetal cap-
illary endothelium. At term, however, cytotrophoblasts are
excluded from the exchange areas and a very thin layer of con-
nective tissue cytoplasm separates syncytiotrophoblast from
capillary endothelium (Fig. 5). In the epitheliochorial pla-
centa of sheep, there are three additional layers of tissue,
that is, uterine epithelium, connective tissue, and maternal
capillary endothelium. The diffusion distance is not greatly
increased, however, because the connective tissue layer is thin,
whilst maternal capillaries indent the uterine epithelial cells
and fetal capillaries indent the trophoblast (42). Indeed, diffu-
sion capacities for the epitheliochorial placenta of the sheep,
endotheliochorial placenta of the dog and hemochorial pla-
centa of the rhesus monkey are of the same order of magnitude
(Table 5).
As discussed below, a reduction in the thickness of the
interhemal membrane, which should increase diffusing capac-
ity, is one of the adaptations that occur in high altitude preg-
nancy (139, 185).
Volume 5, July 2015
Comprehensive Physiology Placental Gas Exchange

Table 5 Placental Diffusing Capacity for Carbon Monoxide and Placental Type

Diffusing capacity [mL

Internal structure of min−1 mm Hg−1 kg−1 fetal
Species placenta Interhemal barrier mass (mean ± SEM)] Reference

Rhesus macaque Intervillous space Hemomonochorial 0.65 ± 0.06 (24)

Guinea pig Labyrinth Hemomonochorial 3.27 ± 0.10 (63)
Rabbit Labyrinth Hemodichorial 2.3 ± 0.2 (186)
Rat Labyrinth Hemotrichorial 1.73 ± 0.33 (125)
Dog Interdigitating villi Endotheliochorial 0.57 ± 0.8 (131)
Sheep Interdigitating villi Epitheliochorial 0.55 ± 0.02 (127)

Placental surface area Human pregnancies complicated by fetal growth restric-

Unexpectedly, values for placental diffusing capacity vary
greatly among species with various types of hemochorial pla-
centa (Table 5). Values are higher in guinea pig, rat, and rabbit,
all of which have labyrinthine placentas with a large counter-
current component. The implication is that the labyrinthine
type of internal structure allows a greater area for placental
exchange (24), which may depend on the compact arrange-
ment of the exchange vessels shown by Mossman (160).
Fetal capillary
Endothelium
Syncytiotrophoblast
Intervillous space
Figure 5 The interhemal barrier of the human placenta. The intervil-
lous space is separated from blood in the fetal capillary by syncytiotro-
phoblast and fetal capillary endothelium with their basal membranes.
A very thin layer of connective tissue cytoplasm is interposed between
the two basal membranes. Courtesy of Dr. Allen C. Enders.
tion are associated with reductions in villous tree elaboration
affecting the surface area of the terminal villi (87). This repre-
sents a reduction in diffusing capacity, but opinions differ as
to whether it is the cause or effect of fetal growth restriction
(37, 103).
Placental oxygen consumption
Easily overlooked is the high rate of oxygen consumption
by the placenta itself. Although data on human pregnancy is
sparse, it has been determined that the placenta accounts for
40% of the combined fetal and placental oxygen consumption
at term (26). Fetal oxygen consumption in that study was 6.8
mL min−1 kg−1 , which agrees well with a more recent calcu-
lation of 6.58 mL min−1 kg−1 based on direct measurement
of umbilical blood flow and the difference in the umbilical
venous and arterial oxygen content (1).
In agreement, oxygen consumption by the ovine placenta
accounts for 40% of total oxygen uptake by the gravid uterus
(217). In midgestation sheep (71-81 days gestation), where
fetal oxygen consumption is smaller, uteroplacental oxygen
uptake accounts for more than 80% of the total (Table 2) (19).
Extrapolating from those experiments, we may expect the
placenta to account for the major part of the combined oxygen
consumption in the second trimester of human pregnancy.
In the ovine placenta, most oxygen is used for oxida-
tive phosphorylation of glucose (141); the remainder likely
is utilized for non-mitochondrial processes. The ATP yield
is expended mainly in protein synthesis and cation transport.
Protein synthesis is estimated to account for 30% of placental
oxygen uptake, reflecting the high rates of synthesis of peptide
and steroid hormones. The Na+ -K+ -pump likely accounts for
a further 20% to 30% of placental oxygen use; it serves to
maintain the sodium gradient that is the basis for secondary
active transport of amino acids and other substances (37).
Placental oxygen consumption remains remarkably con-
stant following acute alterations in uterine oxygen supply.
This is true both when the oxygen supply is reduced, by par-
tial occlusion of the uterine artery (65, 217), and when it is

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Placental Gas Exchange Comprehensive Physiology

1600 (A)

1200

800
Oxygen uptake (μmol min–1)

400

0
Fetus Placenta Fetus Placenta
Control Arterial occlusion
2400
(B)
2000

1600

1200

800

400

0
Fetus Placenta Fetus Placenta
Normal growth Growth restricted

Figure 6 Effects of acute and chronic hypoxemia on fetal and placen-

tal oxygen uptake in the sheep. (A) Effect of an acute 60-min reduction
in uterine blood flow on oxygen uptake of the fetus and placenta. Pla-
cental oxygen consumption is maintained at the expense of the fetus.
Data adapted, from (65). (B) Effect of long-term restriction in uterine oxy-
gen and substrate supply (following carunclectomy) on oxygen uptake
of the fetus and placenta. Placental oxygen consumption is reduced to
a greater extent than that of the fetus. Data adapted, from (168). Error
bars are SEM. Reproduced, with permssion, from (37); Copyright ©
2000 with permission from Elsevier.
increased, by raising the oxygen saturation of maternal arterial
blood (15). Thus, a reduction of uterine blood flow by 30%
to 50% for 60-min depressed fetal oxygen uptake, because
oxygen consumption by the placenta was maintained at the
expense of the fetus (65) (Fig. 6A). At the same time, fetal
glycogen stores were mobilized to supply the placenta with
glucose and lactate (65).
Fetal supply of nutrients to the placenta cannot be sus-
tained indefinitely. Thus, some form of adaptation can be
expected during long-term reductions in uterine blood flow.
In the carunclectomy model of fetal growth restriction, where
the supply of oxygen and nutrients is restricted throughout
gestation, uteroplacental oxygen consumption was reduced
to a greater extent than fetal oxygen consumption (168)
(Fig. 6B). Consequently, it accounted for a smaller propor-
tion of total uterine oxygen uptake (28%) than during normal
growth (53%). Uteroplacental consumption of glucose was
also reduced compared to normal growth controls (168). Pos-
sible mechanisms for limiting placental oxygen consump-
tion are discussed below in the context of high altitude
hypoxia.
Figure 7 Principal pathways of the fetal circulation and representa-
tive values for oxygen saturation of the blood. Well oxygenated blood
from the umbilical vein (UV) is directed through the ductus venosus (DV)
(or left lobe of the liver) across the inferior vena cava (IVC), through the
foramen ovale (FO), left atrium (LA), and ventricle and up the ascending
aorta (AO) toward the common carotid arteries (CCA). Deoxygenated
blood from the superior vena cava (SVC) and IVC passes through the
right atrium (RA), right ventricle, pulmonary artery (PA), and ductus arte-
riosus (DA). FOV, foramen ovale valve; LHV, left hepatic vein; MHV,
medial hepatic vein; PV, pulmonary vein; RHV, right hepatic vein. Repro-
duced, with permission, from (105); Copyright © 2004 John Wiley &
Sons, Ltd.
Oxygen Delivery to Fetal Organs
The oxygen content of umbilical venous blood is relatively
low, but the oxygenated blood is sent preferentially to the
fetal heart and brain because it is shunted through the ductus
venosus and foramen ovale (Fig. 7). Rates of blood flow in the
principal vessels have been measured by ultrasound imaging
(105). Our knowledge of oxygen saturations in the human
fetus is necessarily sparse, but they are assumed to be similar
to those reported for the fetal lamb by Dawes et al. (53).
Textbooks of human physiology often repeat their estimates
without specifying that the data were obtained in sheep.
As much as 56% of umbilical venous return passes
through the ductus venosus of the fetal lamb (58, 188). How-
ever, estimates of the shunt in human pregnancy, made by
Doppler ultrasonography, are 28% to 32% at 18 to 20 weeks
falling to 18% at 31 weeks (107); a second study found a drop
from 40% at 20 weeks to 15% near term (20). The smaller

1392 Volume 5, July 2015

Comprehensive Physiology
role of the human ductus venosus should not be overempha-
sized as the remainder of the umbilical venous return passes
through the fetal liver, which extracts rather little oxygen; the
oxygen content of hepatic venous blood is quite high (28).
Some species, such as the horse (11) and guinea pig (41),
have disposed of the ductus altogether. The second link in the
shunt is the foramen ovale. Despite anatomical differences
between sheep (7) and human (106), the foramen ovale plays
a similar role in ovine and human fetuses (106, 146).
The distribution of combined right and left ventricular car-
diac output and organ blood flows can be determined in the
fetal lamb using microspheres (189). There was a redistribu-
tion of cardiac output during acute hypoxia in favor of blood
flow to the brain, myocardium and adrenal glands (47, 190).
Oxygen delivery to the brain, heart, and adrenals was also
maintained during acute reductions in uterine blood flow
(93, 184) or umbilical blood flow (81). There were regional
differences within the brain with a redistribution of blood
flow in favor of critical brain stem areas during acute hypoxia
(9, 174). The neural and endocrine regulation of the fetal cir-
culation, including responses to hypoxia, is the subject of a
separate overview (162).
Placental Transfer of Carbon Dioxide
The fetus produces 0.8 to 0.9 moles of carbon dioxide for
each mole of oxygen consumed (144). In the blood, about
8% of the carbon dioxide is in solution, 30% is bound to
hemoglobin as carbaminohemoglobin and the remainder is
transported as bicarbonate ion. Carbon dioxide, not bicar-
bonate, is the major species that crosses the placenta, since
transfer is scarcely affected by inhibition of carbonic anhy-
drase, the intraerythrocytic enzyme that catalyzes conver-
sion of carbon dioxide and water through carbonic acid to
hydrogen ion and bicarbonate (129). Because carbon dioxide
is highly lipid soluble, it diffuses rapidly across biological
membranes.
Pregnant women hyperventilate, as first was shown by
the Danish physiologist Karl Albert Hasselbalch (68). There-
fore, arterial PCO2 is lower in pregnant than in nonpregnant
individuals. In the placenta, oxygenation of fetal hemoglobin
results in decreased affinity for carbon dioxide and PCO2
tends to rise (the Haldane Effect). The opposite occurs dur-
ing deoxygenation of hemoglobin on the maternal side. The
double Haldane Effect thereby magnifies the PCO2 gradi-
ent and it accounts for some 46% of carbon dioxide transfer
(71). Therefore, it is counterintuitive that across species the
PCO2 of umbilical venous blood is 4 to 5 mmHg higher
than that of uterine venous blood (13, 49, 50). This would not
be expected from the venous equilibration model of placen-
tal gas exchange and indeed the gradient exists even in the
guinea pig, a species where there is evidence of a substantial
countercurrent component (13). Seeking an explanation by
mathematical modeling, Hill et al. (71) showed the difference
could not be explained by placental metabolism, but could be
Volume 5, July 2015
Placental Gas Exchange
accounted for by vascular shunts, including those produced
by mismatching of maternal and fetal placental blood flows.
Human Pregnancy at High Altitude
Oxygen availability decreases at high altitude because of the
decrease in barometric pressure. At 3100 m (10,200 ft.), the
PO2 of the inspired air (PI O2 ) is 98 mm Hg or two-thirds of
that at sea level. The highest permanent human habitations are
at about 5000 m, where the PI O2 is 75 mmHg (150). High-
altitude populations, therefore, offer singular insights about
the effects of hypoxia and the physiological adaptations that
maintain the oxygen supply to the fetus.
Human studies at low and high altitude offer valuable
information on the physiology of placental oxygen trans-
fer and fetal oxygen consumption. They offer some of the
most complete data sets yet available for human pregnancy
(Table 6).
Study populations
Pioneering studies showing an effect of altitude on birth
weight (114) and infant mortality (140) were conducted in
Lake County, Colorado, which includes the city of Leadville
3100 m above sea level. This population continues to be a
valuable research asset (94). The main control population has
been Denver, Colorado, at an elevation of 1600 m, but for
some recent studies control placentas were collected at sea
level in the United Kingdom (48, 221).
As many as 140 million people live at altitudes above
2500 m (153). Some have lived at high altitude for millen-
nia; Tibetans for as many as 25,000 years, Andeans for per-
haps 13,000 years (151). It has proven particularly instruc-
tive to compare these native populations with recent settlers,
Table 6 Some Factors Relevant to Placental Oxygen Transfer in Term
Human Pregnancy Measured in a Bolivian Population of European
Ancestry Residing at 400 m Above Sea Level (180, 223)
Variable Value
Uterine blood flow (mL min−1 ) 638 ± 37∗
Maternal arterial oxygen saturation (%) 97.6 ± 0.1
Maternal arterial oxygen content (mL L−1 ) 157 ± 2
Uterine oxygen delivery (mL min−1 kg−1 fetal mass) 29.7 ± 2.1∗
Umbilical blood flow (mL min−1 ) 325 ± 14∗
Umbilical venous oxygen saturation (%) 52 ± 2
Umbilical venous oxygen content (mL L−1 ) 103 ± 4
Fetal oxygen delivery (mL min−1 kg−1 fetal mass) 9.6 ± 0.5
Fetal oxygen uptake (mmol min−1 kg−1 fetus) 6.1 ± 0.3∗
∗ Extrapolated from the figures.
All values are mean ± SEM.
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Placental Gas Exchange
that is, Tibetans with Han Chinese and Andeans with peo-
ple of European, mainly Hispanic, descent. The latter studies
have been made in both Bolivia and Peru. It is now possi-
ble to test whether individuals have been correctly assigned
to their group using ancestry-informative single nucleotide
polymorphisms (23, 180). This is desirable as surnames can
be misleading (196). Bolivia has a substantial population of
Japanese ancestry for which data is available on birth weights
at high and low altitude (100). There is also a small number of
studies of high-altitude populations elsewhere, for example,
Kirghizstan (185) and Nepal (192).
The genetic basis for adaptation to life at high alti-
tude shows similarities and differences between popula-
tions. There is evidence for positive selection of EGLN1,
a gene known to be important for oxygen-sensing, in both
Tibetans and Andeans (23, 133). EGLN1 encodes PHD2, an
enzyme involved in degradation of hypoxia-inducible factor
1α (HIF1α). In contrast, a variant allele of EPAS1, the gene
that encodes HIF2α , is found only in Tibetans and has been
linked to a blunted erythropoietic response to low ambient
oxygen (18, 77). Single nuclear polymorphisms of EPAS1
in Andeans do not associate with hemoglobin concentration
(23). In Andeans, a further two genes associated with oxygen
sensing and vascular control show single nucleotide polymor-
phisms that associate with birth weight (22); EDNRA codes
for endothelin receptor type A while PRKAA1 codes for a sub-
unit of adenosine monophosphate-activated protein kinase.
Birth weight, placental weight, and gestational
hypertension
Not all babies born at high altitude are small. However,
when corrected for socioeconomic and other risk factors, birth
weight decreases by 102 g for each 1000 m gain in altitude
(94). The critical altitude at which this sets in is 2000 m
(159). The decline is steeper in recent residents than in those
with a high-altitude ancestry (Table 7) (97, 153). Birth length
decreases with altitude and here there is no protective effect
of highland ancestry (196). Placental weight does not change
with altitude (84, 180, 208).
Table 7 Effect of Ancestry and Altitude on Birth Weight in Four
Populations
Decline in Birth weight at 4000 m
birth weight compared to sea level
Population (g 1000 m−1 ) average (g)
Tibetan (including 88 −296
Sherpa)
Han 153 −723
Andean 89 −338
European 119 −439
Data are from Moore et al. (2011) (153) and were derived by regres-
sion analysis of data for 4,690,093 newborns.
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Comprehensive Physiology
There normally is a fall in maternal blood pressure during
the second trimester. This does not occur at high altitude even
in women who remain normotensive (169). Preeclampsia, a
gestational disease defined in most studies by high blood
pressure and proteinuria, is more common at high altitude.
In Colorado the incidence was 16% at 3100 m compared to
3% at 1260 m (169) and in Bolivia 18% at 3600 m versus
11% at 300 m (101). In both studies, the rates were even
higher in primiparous women. Many preeclamptic newborns
are small for gestational age and preeclampsia can account for
about half the fall in birth weight at high altitude (153). Fetal
distress is more frequent at high altitude (101) and gestational
hypertension no doubt contributes to the high infant mortality
that was the impetus for the early studies in Leadville (140)
and persists at troubling levels in Bolivia (101) and elsewhere.
Maternal and fetal adaptations
Minute ventilation
Maternal hyperventilation helps preserve arterial oxygena-
tion during high altitude pregnancy (154). In a comparison
between mothers of smaller babies (<2.9 kg) and mothers of
larger babies (>3.5 kg), all born at Leadville, Moore et al.
(155) found that the smaller babies were delivered by women
in whom minute ventilation failed to increase from early to
late gestation. During pregnancy in Andeans, the isocapnic
hypoxic ventilatory response (HVR) increased nearly four-
fold and accounted for a 25% rise in resting ventilation (152).
There are differences between Andeans and Tibetans that
may affect their ventilatory responses to pregnancy. Tibetans
ventilate more than Andeans at similar altitudes, but whether
there is a difference in HVR remains unresolved (151). Non-
pregnant Tibetans have an HVR similar to that of acclimatized
Han (151) and during pregnancy show a similar rise in minute
ventilation and HVR (156).
Hemoglobin concentration
The decrease in maternal blood hemoglobin concentration
that occurs during pregnancy at low altitude was retained in
native Tibetans, whereas in Han at similar altitude hemoglobin
did not change. As a result arterial oxygen content was lower
in Tibetan than in Han women (154 vs. 174 mL −1 ) (156). It is
plausible to link the response of Tibetans to the EPAS1 variant
described above. Hemoglobin concentration and arterial oxy-
gen content increased to similar levels in pregnant Andeans
and Europeans at high altitude (CaO2 178 vs. 187 mL L−1 )
(223).
Uterine blood flow and oxygen delivery
Uterine artery blood flow can be estimated by measuring bilat-
eral vessel diameters and flow velocities. An early attempt
comparing women at Leadville and Denver showed a decrease
in arterial diameter, increased flow velocity and overall a
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Comprehensive Physiology Placental Gas Exchange

(A) Low altitude (B) High altitude

Uterine artery blood flow (mL min–1)

Uterine artery blood flow (mL min–1)

900 900
Time, P < 0.001 (both groups) Time, P < 0.001 (both groups)
800 Ancestry, p = NS 800 Ancestry, P < 0.001 Andean
700 Interaction (time*ancestry), NS 700 Interaction (time*ancestry), NS †
600 600 *
500 500
European *
400 400
300 300 European
200 Andean 200
*
100 100
0 0
Non pregnant 20 weeks 36 weeks Non pregnant 20 weeks 36 weeks
Week of pregnancy Week of pregnancy

Figure 8 Uterine artery blood flow at low and high altitude in women of European and Andean descent. (A) At low altitude, the pregnancy-
associated rise in uterine blood flow was similar in Andean and European women. (B) At high altitude, the pregnancy-associated rise in uterine
blood flow was greater in Andeans than in Europeans, resulting in blood flows that were more than one-third larger at 20 or 38 weeks in Andean
women. Error bars are SEM. Asterisks, P < 0.05. Reproduced, with permission, from (98); Copyright © 2009 The American Physiological Society.

decrease in uterine blood flow at the higher elevation (222).
In a similar context remodeling of the uterine spiral arter-
ies was found to be reduced at the higher altitude (208).
When Andeans and Europeans were compared at low alti-
tude, there was no difference in uterine blood flow (98). At
high altitude, however, Andeans were able to increase uterine
artery blood flow and uteroplacental oxygen delivery at 20
and 36 weeks whereas Europeans did not (Fig. 8); in part this
could be explained by the greater uterine artery diameter of
Andeans (98). Therefore, it is of interest that one genotype
of the PRKAA1 gene, which occurred at higher frequency
in Andeans than Europeans, was associated with increased
uterine artery diameter (22). A comparison of Tibetan and
Han pregnancies at high altitude reinforces the notion that
increased uterine artery diameter and flow velocity are impor-
tant adaptations that serve to maintain uteroplacental oxygen
delivery in populations with highland ancestry (156).
In contrast, another recent study found that uterine artery
diameter, flow velocity, and uterine blood flow decreased at
high altitude both in Andeans and Europeans (223). This was
partly compensated by increased hemoglobin concentration
and arterial oxygen content; in relation to fetal mass, uteropla-
cental oxygen delivery (mL min−1 kg−1 ) was not different at
altitude (223). Differences between the findings may depend
on study design [discussed in (196)].
Umbilical blood flow and oxygen delivery to the
fetus
Ultrasound can be used to estimate umbilical venous blood
flow. When paired with measurement of blood oxygen content
in the umbilical artery and vein, made at Cesarean section,
oxygen delivery to and consumption by the fetus can be cal-
culated. This was done in conjunction with the above study
on Andean and European pregnancies at low and high alti-
tude (180). The most pronounced difference, which occurred
in both groups at high altitude, was a reduction in umbilical
vein diameter and blood flow. This was largely compensated
by increased fetal hemoglobin concentration and a leftward
shift in the oxygen dissociation curve contingent on a lower
PCO2 (Bohr Effect). As a result fetal oxygen delivery did
not change with altitude in either Andeans or Europeans, nor
did fetal oxygen consumption when calculated as mL O2
min−1 kg−1 fetal mass. In both groups, however, there was
the expected decrement in birth weight.
Placental adaptations
Interhemal membrane and placental diffusing
capacity
A reduction in placental weight with increasing altitude
was seen in a material from Kirghizstan (185), but not in
more extensive studies from Colorado (208) and the Andes
(84, 180). A comprehensive morphometric study of placen-
tas from Bolivia found effects related to altitude irrespective
of ancestry (Andean versus European or Mestizo) or sex of
the newborn. At high altitude there was a reduction in vil-
lous volume and surface area (83). The mean thickness of the
interhemal membrane was reduced, due in part to the greater
proximity of fetal capillaries to the overlying trophoblast; this
reduced the effective diffusion distance (85,86,139). A reduc-
tion in the thickness of the interhemal membrane, resulting
in increased morphometric diffusing capacity, was also found
in Kirghizstan and interpreted as a placental adaptation to
high-altitude pregnancy (185).
Placental oxygen consumption
Several recent studies sought for an explanation of the
reduced villous volume in high-altitude placentas in terms of
endoplasmic reticulum stress and reduced protein synthesis.
These papers compared placentas from Leadville (elevation

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Placental Gas Exchange Comprehensive Physiology

3100 m) with others collected in Cambridge and London (sea (A)

level). At sea level, placentas collected after vaginal delivery P < 0.0001
showed evidence of hypoxic stress compared to those from 4 Venous

Umbilical plasma glucose

Cesarean section. This difference was not seen at altitude P < 0.0001 Arterial
and its lack was interpreted as evidence of hypoxic precondi- 3

(mmol L–1)
tioning (207). Further experiments indicated the presence of
2
endoplasmic reticulum stress in high altitude placentas (221).
It was then shown that expression of the HIF-1α-responsive 1
microRNA-210 (miR-210) was increased in high altitude pla-
centas; miR-210 has been implicated in downregulation of 0
mitochondrial oxygen consumption. It was further suggested,
based on work with cell lines, that inhibition of protein syn- 400 3600 m
(B)
thesis altered mitochondrial function by suppressing com-
plexes I and IV of the electron transport chain (48). Protein

Umbilical ΔFV-FA glucose

1.0
synthesis has been estimated to account for about 30% of
placental oxygen uptake (37). Thus, overlapping mechanisms 0.8

(mmol L–1)
may act on the hypoxic placenta to suppress its oxygen con- 0.6
sumption at the level of the mitochondrial electron transport
0.4
chain (48).
Although the placenta may adapt to spare available oxy- 0.2
gen for fetal use, this could have a negative effect on fetal 0.0
growth. The aforementioned studies of Andean and European
pregnancies at low- and high-altitude included measurements 400 3600 m
of blood glucose concentration and fetal glucose uptake (224). (C)
Changes at altitude were similar in Andeans and Europeans. P < 0.01
(μmol min–1 kg–1 birth weight)

Although uteroplacental glucose delivery seemed not to be

Fetal glucose consumption

compromised, glucose concentrations were lower in umbili-
cal venous and arterial blood and fetal glucose uptake reduced
by 28% (Fig. 9). It was suggested that anaerobic consumption
of glucose by the placenta limited glucose availability to the
fetus. There was also a reduction in expression of the glucose
transporter GLUT1 at the basal membrane of the syncytiotro-
phoblast, which was seen as a secondary effect (224).
Overall, current thinking points to high altitude hypoxia
acting primarily at the level of the placenta, reducing mito-
chondrial respiration and protein synthesis and thus passing
more of the available oxygen to the fetus. Conversely, the pla-
centa maintains a high consumption of glucose, restricting its
availability to the fetus and leading ultimately to restriction
of fetal growth.
Animal models of high-altitude pregnancy
Sheep
Pioneering studies on sheep indigenous to Andean pastures
(4500 m) found they had raised fetal hematocrits whilst umbil-
ical venous and arterial PO2 were similar to sea level values
(145, 183). The logistics of performing more sophisticated
studies at altitude are demanding and usually involve bring-
ing the sheep to a lower altitude laboratory. Fetal responses to
high-altitude hypoxia were studied in this way by comparing
sheep that had been kept at the White Mountain Research Sta-
tion in California (elevation 3820 m) with those kept through-
out at sea level (99,175). In these studies, there was no effect of
sojourn at high altitude on fetal or placental weight although
80
60
40
20
0
400 3600 m
Figure 9 Plasma glucose concentrations in umbilical vessels and
fetal glucose uptake in term human pregnancies at low (400 m) and
high (3600 m) altitude. (A) Umbilical arterial and venous plasma glu-
cose concentrations were lower at high than at low altitude. (B) The
fetal venous-to-arterial plasma glucose concentration difference (ΔFV-
FA) was similar at low and high altitude. (C) Fetal glucose consumption
(corrected for birth weight) was greater at low than at high altitude.
Error bars are SEM. Reproduced, with permission, from (224); Copy-
right © 2010 Zamudio et al.
changes occurred in placentome shape and vessel branch-
ing and were interpreted as placental adaptations to hypoxia
(110, 176). More recent studies have revealed that chronic
hypoxia can adversely affect vascular tone in upstream vessels
by inhibiting the steroid-mediated upregulation of potassium
channels in uterine artery smooth muscle cells (225, 226).
An alternative approach is to keep pregnant sheep in a
hypobaric chamber. When ewes were kept at an ambient pres-
sure of 429 mmHg (equivalent to an altitude of 4572 m) from
30 to 135 days gestation, average fetal weight was 21% lower
than for control pregnancies (88). During hypobaric hypoxia

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of shorter duration, from 120 to 141 days gestation, fetal arte-
rial oxygen saturation remained low, but this was compen-
sated by a gradual rise in hemoglobin concentration. There
was nevertheless a 17% reduction in fetal body weight (88).
Thus the long-term effect of hypobaric hypoxia in sheep is to
slow fetal growth.
Llama
South American camelids with a long history of residence
on the Andean altiplano include the llama (Lama glama).
Adaptations to high altitude include a higher blood oxygen
affinity that is conserved in pregnant animals both at high
altitude [4500 m (143)] and when they are brought closer
to sea level (158) (Fig. 10). In contrast, fetal llamas have
a higher hemoglobin concentration than fetal lambs (158)
and thus a higher blood oxygen capacity (21). The estimated
oxygen uptake by the llama fetus (4.8 mL min−1 kg−1 ) is
close to the range of values reported for the sheep fetus (21).
Cardiac output and organ blood flows are relatively low in
the llama fetus but oxygen extraction is more efficient (121).
When pregnant animals were moved from sea level to 4400
m, PO2 in the descending aorta of the fetus dropped from 21
to 15 mmHg with no change in blood pressure or heart rate
but a considerable increase in blood flow to the heart (122).
Similarly, when pregnant llamas at sea level were allowed to
breathe a gas mixture with a low oxygen fraction, myocardial
blood flow tripled (119). In contrast to the fetal lamb, however,
there was no change in blood flow to the brain (119). A
decrease in oxygen delivery to the cerebral hemispheres was
largely compensated by increased extraction, although after
60 min of hypoxia there was also a fall in cerebral oxygen
consumption (123).

Guinea pig
(A)
100 The laboratory guinea pig (Cavia porcellus) stems from a
species domesticated in the Andes (C. tschudii) and imported
to Europe in the 17th Century (197). Pregnant guinea pigs have
been kept in a hypobaric chamber simulating high altitude
Hemoglobin saturation (%)

75
(3962 m) and compared with those kept at 1600 m in Denver
(215). These experiments focused on the impact of hypobaric
Fetal IIamas hypoxia on the adaptation of the uterine arteries to pregnancy
50
Maternal IIamas and revealed alterations at both the structural and functional
level (187, 215, 216). As in several human studies, simulated
high altitude in guinea pigs led to a decrease in fetal weight
25 with no change in placental weight (187).

0
0 10 20 30 40 50 60 70 80 90 100 Conclusion
Po2 (Torr)
The fetus is adapted to a low-oxygen environment. Umbilical
(B) venous PO2 is about 30 mmHg and PO2 is even lower in the
100
blood reaching the tissues. Blood oxygen content is higher
than these values imply because of the high hematocrit and
greater oxygen affinity of fetal hemoglobin. Perhaps surpris-
Hemoglobin saturation (%)

75
ingly, the normally grown fetus has a large reserve capacity.
The experiments summarized in Table 8 show that fetal oxy-
Fetal sheep gen uptake is maintained when oxygen delivery is reduced by
50 half. Fractional oxygen extraction is increased with a resul-
Maternal sheep
tant drop in oxygen content of umbilical arterial blood and
there is a corresponding increase in oxygen uptake across the
25 placenta. As a further example, reduction of uterine blood
flow, and thus of uteroplacental oxygen delivery, led to a 54%
decrease in fetal oxygen delivery; fetal oxygen uptake was
0 maintained, however, with a drop in the oxygen content of
0 10 20 30 40 50 60 70 80 90 100 umbilical arterial blood from 4 to 2 mmol L−1 (217). It must
Po2 (Torr) be stressed that these are short term responses to hypoxia.
They are nevertheless indicative of fetal resilience to acute
Figure 10 Blood oxygen dissociation curves of maternal and fetal
episodes of hypoxia such as those occurring during labor.
blood of llamas (upper panel) and sheep (lower panel). Maternal blood
has a relatively high oxygen affinity in the llama. Reproduced, with per- A reduction in oxygen delivery greater than 50% is not
mission, from (158); Copyright © 1996 with permission from Elsevier. so well tolerated. When fetal oxygen delivery falls below a

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Placental Gas Exchange Comprehensive Physiology

Table 8 Effect on Fetal Oxygen Delivery, Fractional Oxygen Extraction and Fetal Oxygen Uptake of a Short-Term 50%
Reduction in Some Parameters of Importance for Placental Gas Exchange

Change (% control value)

Fractional O2
Variable Fetal O2 delivery extraction Fetal O2 uptake Reference

Umbilical blood flow −46% +55% −18% (80)

Umbilical blood flow −50% +55% −23% (57)
Fetal hematocrit −49% +92% −14% (55)
Maternal hematocrit −50% +41% −27% (173)
Fetal blood O2 affinity1 −64% +57% −44% (79)

1 Umbilical blood flow fell by 33%.

critical level, aerobic metabolism can no longer be maintained 10

and the fetus becomes acidemic (Fig. 11) (56).
A quite different picture emerges when hypoxia is main-

Fetal O2 consumption
(mL O2 min–1 kg–1)
tained for longer periods of time (Table 9). Typically, this
leads to reduction in the rate of fetal growth. Fetal acidemia is
slight or absent, suggesting the fetus is able to maintain aer- 5
obic metabolism. It was shown in the carunclectomy model
that while fetal oxygen uptake decreased in the small fetuses
(from 1.1 to 0.6 mmol min−1 ), it was unchanged when cor-
rected for fetal mass (0.395 to 0.355 mmol−1 min−1 kg−1 )
(168). Placental weight was little affected except in the carun- 0
clectomy and embolization models where it was the object of
the insult (Table 9). The results of these sheep experiments 10
are in agreement with what is known from human pregnancy
at high altitude. Moreover, they have broader implications for
human pregnancy. Maintenance of an adequate oxygen deliv-
ery to the intervillous space of the placenta depends on the
Base excess (mEq L–1)

0
physiological transformation of the uterine spiral arteries by
the extravillous trophoblast (67, 178). When this process is
defective, a number of pregnancy complications can ensue,
most notably fetal growth restriction and preeclampsia (30). –10
The most promising scientific developments of recent date
concern the central role of the placenta. It has been clear for
some time that the placenta has a high oxygen consumption
that is maintained during acute hypoxia (Fig. 6A). Conversely, –20
during long-term reduction in oxygen delivery to the gravid
uterus, placental oxygen consumption is reduced in favor of 0
the fetus (Fig. 6B). Moreover, as discussed above, the more 0 10 20 30
moderate impact of hypoxia on placental mass belies the Fetal O2 delivery (mL O2 min–1 kg–1)
fact that there are structural and functional changes in the
placenta of sheep and at high altitude in human pregnancy. Figure 11 Fetal oxygen consumption (upper panel) and arterial
blood base excess (lower panel) as a function of fetal oxygen delivery
Changes in villus development are associated also with fetal in sheep. Fetal oxygen uptake remained constant until oxygen delivery
growth restriction and preeclampsia (103). It now appears that was reduced below ca. 13 mL min−1 kg−1 fetal mass (0.6 mmol min−1
hypoxia can directly impact the placenta, causing endoplas- kg−1 ). There was then an increase in anaerobic metabolism with a resul-
tant fall in arterial base excess. Data are from experiments in which both
mic reticulum stress, inhibition of protein synthesis, and sup- oxygen affinity (hemoglobin type) and oxygen capacity (hemoglobin
pression of oxygen consumption in the mitochondrial electron concentration) were varied. Circles: fetal hemoglobin; squares: adult
transport chain (48, 221). The evidence is convincing in rela- hemoglobin; filled circles and squares: normal hematocrit; half-filled cir-
cles and squares: moderate anemia; open circles and squares: severe
tion to high altitude hypoxia [“preplacental hypoxia” (103)] anemia. Reproduced, with permission, from (56); Copyright © 1989
and should stimulate further research in the context of reduced with permission from Elsevier.

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Comprehensive Physiology Placental Gas Exchange

Table 9 Effect on Fetal and Placental Weights of Long-Term Reductions in Oxygen Delivery to the Fetus

Duration Change (% control value)

Method Total (days) Gestation (days) Fetal weight Placental weight Reference

Umbilical blood flow reduced by embolization 10 Late gestation −13% (NS) −22% (61)
Uterine blood flow clamped 25 113-138 −21% −9% (112)
Maternal anemia 28 110-138 −40% N/A (161)
Hypobaric hypoxia 105 30-135 −21% −23% (NS) (88)
Carunclectomy 130 0-130 −31% −51% (168)

intervillous blood flow and fetal growth restriction [“uteropla-
cental hypoxia” (103)]. Another interesting hypothesis, aris-
ing from high altitude studies, is that the placenta increases
anaerobic consumption of glucose and deprives the fetus of
substrate, thereby slowing fetal growth (224). A good deal is
known about placental and fetal handling of glucose in sheep
(69,70) and this topic deserves to be revisited in the context of
hypoxia, not least because the resultant fetal responses may
impact adult health (205).
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