(Circulation. 1998;97:257-262.)
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports |
Reactivity of the Human Fetal Pulmonary Circulation to Maternal Hyperoxygenation Increases During the Second Half of Pregnancy
A Randomized Study
Juha Rasanen, MD;
Dennis C. Wood, RDMS;
Robert H. Debbs, DO;
Jose Cohen, MD;
Stuart Weiner, MD;
; James C. Huhta, MD
From the Sections of Perinatal Cardiology and Maternal-Fetal-Medicine,
Department of Obstetrics and Gynecology, Pennsylvania Hospital, Philadelphia,
Pa.
 |
Abstract
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Background—The aims of the
present study were to determine whether maternal
hyperoxygenation affects human fetal pulmonary
circulation and whether there is a gestational age-related response in
the fetal pulmonary circulation to maternal
hyperoxygenation during the second half of
gestation.
Methods and Results—Twenty women between 20 and 26 weeks of
gestation and 20 women between 31 and 36 weeks of gestation with normal
singleton pregnancies were randomized to receive either 60% humidified
oxygen or medical compressed air (room air) by a face mask. Fetal
aortic and pulmonary valve; ductus arteriosus (DA); and right
(RPA), left (LPA), and distal (DPA) pulmonary artery blood
velocity waveforms were obtained by Doppler ultrasound before,
during, and after maternal administration of either 60% oxygen or room
air. Left and right ventricular cardiac outputs, DA volume
blood flow, and RPA and LPA volume blood flows (QP) were
calculated. Foramen ovale volume blood flow (left
ventricular cardiac output-QP) was estimated.
Pulsatility index (PI) values of DA, RPA, LPA, and DPA were calculated.
Maternal hyperoxygenation did not change any of the
measured fetal parameters between 20 and 26 weeks, whereas
between 31 and 36 weeks, the PI values of RPA, LPA, and DPA decreased
(P<.0001) and the PI of DA increased
(P<.0001). In addition, QP increased
(P<.001), and DA volume blood flow
(P<.01) and foramen ovale volume blood flow
(P<.03) decreased. Left and right
ventricular cardiac outputs were unchanged. All changes
returned to baseline after maternal hyperoxygenation
was discontinued.
Conclusions—Reactivity of the human fetal pulmonary
circulation to maternal hyperoxygenation increases with
advancing gestation; this suggests that fetal pulmonary
circulation is under acquired vasoconstriction at least after 31 to 36
weeks of gestation.
Key Words: blood flow • echocardiography • hemodynamics • oxygen • physiology
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Introduction
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Fetal lamb studies
have suggested that fetal pulmonary vascular responses to
hyperoxemia and hypoxemia as well as vasoactive agents change with
advancing gestational age.1 2 In the beginning of
the third trimester, the fetal lamb pulmonary circulation does
not respond to changes in the oxygen tension or to
intravenous acetylcholine injection, whereas at term, a
rise in the fetal lamb oxygen tension can induce an increase in
pulmonary blood flow similar to that seen with the onset of
breathing at birth.2 Similarly, reductions in the
fetal oxygen tension cause a decrease in the pulmonary blood
flow and an increase in the pulmonary vascular resistance at
near-term gestation. Likewise, the sensitivity of the pulmonary
circulation to acetylcholine is increased in older
fetuses.1
In the human fetus, the branch pulmonary
arterial vascular impedance decreases significantly during
the second half of pregnancy until 34 to 35 weeks of gestation, and
thereafter it remains unchanged, even though lung growth
continues.3 In addition, human fetal
weight–indexed pulmonary vascular resistance decreases
significantly from 20 to 30 weeks of gestation and increases again
significantly from 30 to 38 weeks of gestation.4
All these findings suggest that the pulmonary
arterial circulation in the human fetus is under acquired
vasoconstriction during the latter part of the third trimester.
To evaluate whether oxygen tension has a role in the regulation of the
human fetal pulmonary arterial circulation during
the second half of gestation, we asked two questions in this study:
Does maternal hyperoxygenation affect human fetal
pulmonary vascular impedance and pulmonary blood flow?
Does the reactivity of the fetal pulmonary circulation to
maternal hyperoxygenation change during the normal
growth and development of the fetal lung?
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Methods
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Forty women with uncomplicated singleton pregnancies were
included in this randomized study, which was approved by the Research
Review Committee of our institution. Before the study, each patient
signed a written informed consent form. Each fetus was appropriate for
gestational age in size (between 10th and 90th percentile growth curve)
according to fetal biometry. Fetal standard anatomic survey did not
reveal any abnormalities, and all the newborns were normal on the basis
of physical examination.
Twenty fetuses were studied between 20 and 26 weeks of gestation, and
20 fetuses were studied between 31 and 36 weeks of gestation.
Image-directed pulsed and color Doppler equipment (Acuson 128XP)
with a 5-MHz sector probe was used to obtain blood velocity waveforms
at the level of the AoV and PV, proximal RPA and LPA (immediately after
the bifurcation of the main pulmonary artery), DPA (beyond the
first bifurcation of the branch pulmonary artery), and DA. The
lowest high-pass filter level was used (100 Hz), and the spatial peak
temporal average power output for color and pulsed Doppler was kept
at <100 mW/cm.2 An angle of 
15° between the
vessel and Doppler beam as assessed by color Doppler was
accepted for later analysis. After the baseline Doppler
study, randomization was performed with the use of sealed envelopes.
Ten patients received medical compressed air (room air) and 10 patients
received 60% humidified oxygen via face mask in each gestational age
group. Room air and 60% oxygen, which were delivered from the wall
units, were administered 
5 minutes before and during the second
Doppler ultrasound study, which was identical to the baseline
study. The wall units were covered to keep the investigator performing
the ultrasound examinations unaware of the randomization. After the
second Doppler study, the face mask was removed, and 5 minutes
recovery time was allowed before the last Doppler ultrasound
examination was started. All the Doppler studies, which were
videotaped for later analysis, were performed and
analyzed by one investigator (J.R.). The randomization was
unsealed after the analysis of all the Doppler studies was
completed.
From Doppler tracings, we calculated FHR (bpm) and TVI (cm). The
TVI calculation, which is considered to be a measure of the length of
the column of ejected blood, was performed by planimetering the area
underneath the Doppler spectrum. Three consecutive cardiac cycles
were analyzed, and their mean value was used for further
analysis. The AoV and PV annuli, DA, RPA, and LPA diameters
were measured from frozen real-time images during systole by using the
leading edge–to–leading edge method. Three separate measurements of
the vessel diameters were made, and the mean values were calculated.
Calculation of the CSA (cm2) of the vessel was
based on the assumption that the cross-sections of the vessels were
circular. Volumetric blood flow at the level of the AoV, PV, DA, RPA,
and LPA was assessed by using the formula Q=FHRxCSAxTVI. The volume
blood flow through AoV equals LVCO, and the volume blood flow through
PV equals RVCO. Total QP is the sum of the RPA
and LPA volume blood flows. QFO was estimated by
subtracting QP from LVCO. The PI values of DA,
RPA, LPA, and DPA were calculated [(peak systolic
velocity-end-diastolic velocity)/mean velocity during the
cardiac cycle]. All the Doppler measurements were done during
fetal apnea and in the absence of fetal body movements.
To analyze the intraobserver reproducibility of the Doppler
measurements, room air groups (n=20) were combined. We calculated the
correlation and intraobserver variability of the measurements,
expressed as difference (in percent) between the three study points. To
test the validity of the volume blood flow assessment, all the groups
were combined (n=40), and the correlation between two independent RVCO
calculations (blood flow across the PV and the sum of
QDA and QP) was established
at three different study points.
Statistical comparison of the measured parameters within
the group between three different study points was performed by one-way
ANOVA for repeated measurements, and if statistical significance was
reached, further analysis was made with the Fisher PLSD test.
Comparisons between different groups were done with Student's
t test. A value of P<.05 was selected as the
level of statistical significance.
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Results
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Between 20 and 26 weeks of gestation, the mean gestational age was
23.5 weeks in the oxygen group (group I; n=10) and 22.7 weeks in the
room air group (group II; n=10). Between 31 and 36 weeks of gestation,
the mean gestational age was 33.6 weeks in the oxygen group (group III;
n=10) and 33.4 weeks in the room air group (group IV; n=10). The
gestational ages did not differ significantly between groups I and II
or between groups III and IV.
The baseline values of the measured parameters did not
differ significantly between groups I and II or groups III and IV. FHRs
remained unchanged in all the groups during the study period. The PI
values of RPA, LPA, DPA, and DA did not change significantly in groups
I and II during the study period (Fig 1
).
On the other hand, in group III, the PI values of RPA, LPA, and DPA
decreased significantly (P<.0001) during maternal
hyperoxygenation (Figs 2 and 3). The mean decrease in the PI
values was 18.0% from the baseline value for RPA, 19.6% for LPA, and
21.2% for DPA (see Fig 7). At the same time, the PI value of DA
increased significantly (P<.0001) (Figs 2 and 3). The mean
increase was 14.4% from the baseline values (see Fig 7). After
maternal hyperoxygenation was discontinued, all PI
values returned to the baseline level (Figs 2 and 3). In group IV, the
PI values of RPA, LPA, DPA, and DA remained unchanged throughout the
study period (Fig 2).
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Figure 1. PI values of RPA, LPA, and DPA and DA before
(study I), during (study II), and after (study III) maternal
administration of 60% humidified oxygen (group I) and room air (group
II) between 20 and 26 weeks of gestation. All values are expressed as
mean±SD.
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Figure 3. Individual data points demonstrate the changes in
PI values of RPA and DA and in QP and
QDA before (study I), during (study II), and after (study
III) maternal administration of 60% humidified oxygen in group
III.
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Figure 7. QP, QFO, and
QDA; combined RVCO and LVCO; RPA and LPA (Proximal PA); DPA
(Distal PA); and DA PI value changes during maternal
hyperoxygenation between 31 and 36 weeks of gestation.
Values are given as a mean percentage change from baseline.
*Statistically significant change between baseline and maternal
hyperoxygenation values.
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CSAs and TVIs of AoV, PV, DA, RPA, and LPA in different groups are
presented in Tables 1 and 2. In groups I and II, LVCO, RVCO,
QDA, and QP did not change
significantly during the study period (Fig 4). In group III, maternal
hyperoxygenation increased QP
significantly (P<.001) and decreased
QDA significantly (P<.01) (Figs 3
and 5). The mean increase in the
QP was 24.5% from the baseline value, and the
mean decrease in the QDA was 17.1% (Fig 7). One
fetus at 36 weeks of gestation developed a reverse (from the aorta to
the pulmonary artery) diastolic blood flow in the
DA during maternal hyperoxygenation. All these changes
returned to the baseline level after maternal
hyperoxygenation was discontinued (Figs 3 and 5). LVCO
and RVCO were unchanged during maternal
hyperoxygenation (Fig 5). In group IV, there were no
statistically significant changes in LVCO, RVCO,
QDA, or QP between the
three study points (Fig 5). The estimated QFO
remained stable in groups I, II, and IV during the study period (Fig 6). In group III, maternal
hyperoxygenation decreased QFO
significantly (P<.03) (Fig 6). The mean decrease in the
QFO was 16.0% (Fig 7).
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Figure 4. RVCO and LVCO, QDA and QP
before (study I), during (study II), and after (study III) maternal
administration of 60% humidified oxygen (group I) and room air (group
II) between 20 and 26 weeks of gestation. All values are expressed as
mean±SD.
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Figure 6. QFO before (study I), during (study
II), and after (study III) maternal administration of 60% humidified
oxygen (group I, 20 to 26 weeks of gestation; group III, 31 to 36 weeks
of gestation) and room air (group II, 20 to 26 weeks of gestation;
group IV, 31 to 36 weeks of gestation). All values are expressed as
mean±SD. *P<.03 compared with study I.
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In the combined room air group (group II plus group IV), the PI values
and volumetric blood flow calculations did not change significantly
during the study period. The intraobserver variability was <4% for PI
values and <9% for volumetric blood flow calculations. The
correlation between different study points was significant for PI
values (P<.0001), with correlation coefficient values of
.89, and for volumetric blood flow calculations
(P<.0001), with correlation coefficient values of .96.
Two independent RVCO calculations (n=40) demonstrated a significant
correlation at every study point with an R value of .95
(P<.0001).
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Discussion
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Maternal hyperoxygenation with 60% oxygen did not
affect the human fetal pulmonary arterial vascular
impedance and QP between 20 and 26 weeks of
gestation, whereas between 31 and 36 weeks of gestation, the
pulmonary arterial vascular impedance decreased and
QP increased significantly. After maternal
hyperoxygenation was discontinued, pulmonary
arterial impedance increased and QP
decreased to the baseline level. Invasive lamb studies have
demonstrated that in late gestation, the increase in the fetal oxygen
tension decreases pulmonary vascular resistance and increases
QP, whereas the effects of decreased fetal oxygen
tension are the opposite.1 2 5 6 However, the
fetal lamb pulmonary vascular bed does not react to changes in
oxygen tension in the beginning of the last trimester of
pregnancy.1 2 The findings of this study support
the concept that in the human fetus, the reactivity of the
pulmonary arterial bed to changes in the fetal
oxygen tension develops after 21 to 26 weeks of gestation and is
detectable by noninvasive Doppler ultrasound techniques between 31
and 36 weeks of gestation. Our results show that the human fetal
pulmonary circulation is under acquired vasoconstriction at
least after 31 to 36 weeks of gestation, and in this way blood flow is
directed from the pulmonary circulation to the systemic
circulation. Fetal oxygen tension has a role in the regulation of the
pulmonary circulation and the distribution of fetal cardiac
output during the latter part of the third trimester. In this study,
DPA and proximal pulmonary arteries showed a similar decrease
in the PI values during maternal hyperoxygenation,
suggesting that the two sampling sites give the same information about
the pulmonary vascular reactivity. The development of the
reactivity of the pulmonary arterial circulation to
oxygen with advancing gestation has been explained by an increasing
amount of smooth muscle in small pulmonary
arteries.7 The decrease in the pulmonary
vascular resistance is mainly caused by the release of
endothelium-derived nitric oxide, which leads to
vasodilatation of the pulmonary arterial
bed.8 9
The decrease in the pulmonary vascular impedance and the
increase in the QP by maternal
hyperoxygenation between 31 and 36 weeks of gestation
was accompanied by opposite changes in the fetal DA. The PI values
increased and the QDA decreased significantly;
all these changes returned to the baseline values after maternal
hyperoxygenation was discontinued. The decrease in the
DA PI has been associated with the constriction of the DA, and the
increase in the DA PI has been found in the cases with increased
RVCO.10 This study shows that the changes in the
DA PI may also reflect fetal pulmonary vascular impedance. The
decrease in the pulmonary vascular impedance directs blood flow
from the systemic circulation to the pulmonary circulation;
mainly, this affects the diastolic flow component in the DA
by decreasing it or even reversing the direction of the blood flow
during diastole. This leads to increased PI in the DA
because the end-diastolic velocity and the mean velocity
during the cardiac cycle decrease. Under normal circumstances, the
direction of the blood flow in the human fetal DA during the
diastole is from the pulmonary artery to the aorta.
This study supports previous animal data2 5 6
that the increase in the QP and the decrease in
the pulmonary vascular impedance during maternal
hyperoxygenation are not caused by the constriction of
the DA. In the presence of the ductal constriction, peak
systolic, end-diastolic, and mean velocities across
the DA are increased in the human fetus, leading to decreased PI value.
Our findings also agree with the results of Burchell et
al,11 who found in children and adults with
patent DA and pulmonary hypertension that breathing of a low
oxygen mixture either initiated or increased the blood flow from the
pulmonary artery to the aorta and that breathing of 100%
oxygen caused opposite changes.
During maternal hyperoxygenation, both the RVCO and
LVCO remained unchanged. Rizzo et al12 found that
maternal hyperoxygenation with 60% oxygen between 34
and 36 weeks of gestation did not affect the TVIs of the mitral and
tricuspid valves, suggesting that the RVCO and LVCO remained unchanged.
Maternal hyperoxygenation at 31 to 36 weeks of
gestation causes redistribution of the RVCO from the systemic
circulation to the pulmonary circulation. Morin et
al2 found in fetal lambs that at near-term
gestation, maternal hyperoxygenation decreased the
proportion of RVCO distributed to the organs of the lower body and
placenta without changing the RVCO.
Blood flow across the foramen ovale is technically very difficult to
measure directly. However, we can indirectly estimate the
QFO by subtracting the QP
from the LVCO. Our findings suggest that the QFO
decreases during maternal hyperoxygenation at 31 to 36
weeks of gestation because the QP increases
significantly without any change in the LVCO. In fetal lambs, the
QFO decreases by an average of 50% during
maternal hyperbaric oxygenation at near-term
gestation.5
Immediately after birth, pulmonary vascular resistance
decreases and QP increases. The increase in the
alveolar oxygen tension with the beginning of breathing is an important
factor in this process.13 At least between 31 and
36 weeks of gestation, we can simulate by maternal
hyperoxygenation the changes in the central
hemodynamics occurring after birth. We speculate that
this noninvasive technique may allow us to estimate prenatally whether
the changes in the fetal pulmonary circulation will occur in a
normal fashion during the postnatal period. Before the acquisition of
increasing pulmonary vascular reactivity, the pulmonary
blood velocity pattern should be useful for assessing fetal lung
development and may be a tool for the assessment of lung hypoplasia.
After the acquisition of pulmonary vascular reactivity, we
speculate that fetuses with lung hypoplasia do not demonstrate similar
vasodilatation in the pulmonary circulation as seen in normal
fetuses during maternal hyperoxygenation.
Theoretically, one limitation of this study is that maternal
physiological responses to oxygen may be different
late in pregnancy and other factors, in addition to fetal
hyperoxygenation, could have a role in the changes in
human fetal central hemodynamics during maternal
hyperoxygenation.
Maternal hyperoxygenation with 50% oxygen for 5
minutes increased maternal transcutaneous oxygen partial pressure about
threefold.14 After 5 minutes of maternal
hyperoxygenation with 100% oxygen, intervillous space
oxygen tension rose 
41% from the baseline
values.15 Transcutaneously measured fetal oxygen
partial pressure has been found to increase during maternal
hyperoxygenation.16 17 In
addition, maternal administration of 55% humidified oxygen has been
shown through fetal umbilical cord blood sampling to increase human
fetal oxygen partial pressure.18 Based on these
findings, our study protocol was sufficient to demonstrate the effects
of increased fetal oxygen tension on fetal central
hemodynamics.
This study, in which half of the patients were randomized to receive
room air and the investigator who performed the Doppler ultrasound
studies was unaware of the randomization, allows us to evaluate the
methodological limitations related to both the calculation of vascular
impedance and volume blood flow. In the combined room air group, all
the measured parameters remained unchanged between the
three study points. PI values are angle independent, and the
variability among the PI calculations between different study points
was the least, being <4%. In addition, the calculations of the volume
blood flows showed good repeatability, and the intraobserver
variability was <9%. Volume blood flow measurements based on
Doppler ultrasound have been demonstrated to be valid in in vivo
animal studies as well as in in vitro
studies.19 20 21 The human fetal cardiac output
measurements at the level of atrioventricular and
semilunar valves have been shown to correlate
significantly.22 To minimize the methodological
problems related to volume blood flow calculations, the angle between
the vessel and the Doppler beam was kept at 15° as assessed by
color Doppler and the vessel diameters were measured by using the
well-established leading edge–to–leading edge technique. In the study
of Kenny et al,23 the correlation coefficient
between two observers for pulmonary arterial and
aortic diameters was .98. Reed et al24 showed
that maximal velocity tracings across cardiac valves could be obtained
with a variation of <10%. To test the validity of the volume blood
flow calculations, we correlated two independent RVCOs (blood flow
across PV and QP+QDA) and
showed a good correlation between these two independent calculations.
These findings with previously published studies confirm that
measurement of vascular impedance and calculation of the volumetric
blood flow can be done accurately in the human fetus during the second
half of gestation with the use of current ultrasound technology.
In conclusion, this study demonstrates that maternal
hyperoxygenation decreases human fetal
pulmonary arterial vascular impedance and increases
QP between 31 and 36 weeks of gestation. Earlier
in pregnancy, between 20 and 26 weeks of gestation, maternal
hyperoxygenation does not alter human fetal
pulmonary circulation. This finding shows that the reactivity
of the human fetal pulmonary circulation to oxygen develops
between these two study periods and that oxygen tension in the fetus
has a role in the regulation of the fetal pulmonary
circulation. During the latter part of the third trimester, the human
fetal pulmonary arterial bed is under acquired
vasoconstriction, directing RVCO from the pulmonary circulation
to the systemic circulation. Maternal hyperoxygenation,
at least between 31 and 36 weeks of gestation, mimics the changes in
the fetal central hemodynamics that occur after birth.
Finally, all the changes in the fetal central
hemodynamics returned to baseline level after maternal
hyperoxygenation was discontinued.
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Selected Abbreviations and Acronyms
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| AoV |
= |
aortic valve |
| CSA |
= |
cross-sectional area |
| DA |
= |
ductus arteriosus |
| DPA |
= |
distal pulmonary artery |
| FHR |
= |
fetal heart rate |
| LPA |
= |
left pulmonary artery |
| LVCO |
= |
left ventricular cardiac output |
| PI |
= |
pulsatility index |
| PV |
= |
pulmonary valve |
| QDA |
= |
ductus arteriosus volume blood flow |
| QFO |
= |
foramen ovale volume blood flow |
| QP |
= |
pulmonary volume blood flow |
| RPA |
= |
right pulmonary artery |
| RVCO |
= |
right ventricular cardiac output |
| TVI |
= |
time-velocity integral |
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Footnotes
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Dr Huhta's present address: Tampa Children's Hospital, 3001 W Dr Martin Luther King Jr Blvd, Tampa, FL 33607.
Requests for reprints to Juha Rasanen, MD, Department of Obstetrics and Gynecology, Thomas Jefferson University, 834 Chestnut St, Suite 400, Philadelphia, PA 19107.
Received June 4, 1997;
revision received September 29, 1997;
accepted September 30, 1997.
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Top
Abstract
Introduction
P<.001 and 
P<0.0001 compared
with study II.
