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Cardiac Output and Central Distribution of Blood Flow
in the Human Fetus
Gunther Mielke, MD; Norbert Benda, PhD
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Background—The objectives of this study were to establish reference ranges for left and right cardiac output and to
investigate blood flow distribution through the foramen ovale, ductus arteriosus, and pulmonary bed in human fetuses.
Methods and Results—A prospective study was performed in 222 normal fetuses from 13 to 41 weeks of gestation with
high-resolution color Doppler ultrasound. Cardiac output and ductal flow were calculated by use of vessel diameter and
the time-velocity integral. Pulmonary blood flow was expressed as the difference between right cardiac output and
ductal flow. Foramen ovale flow was estimated as the difference between pulmonary flow and left cardiac output.
Gestational age–specific reference ranges are given for left, right, and biventricular output and volume of ductal blood
flow, showing an exponential increase with gestational age. Median ratio of right to left cardiac output was 1.42 and
was not associated with gestational age. Right cardiac output was 59% and left cardiac output was 41% of biventricular
cardiac output. Median biventricular cardiac output was estimated to be 425 mL · min⫺1 · kg⫺1 fetal weight. Ductal blood
flow was 46%, estimated pulmonary flow was 11%, and estimated foramen ovale flow was 33% of biventricular output.
Conclusions—The study establishes reference ranges for fetal cardiac output and offers insights into the central blood flow
distribution in human fetuses from 13 weeks to term. There is a clear right heart dominance. The estimated ratio of
pulmonary blood flow to cardiac output is higher than in fetal lamb studies. (Circulation. 2001;103:1662-1668.)
Key Words: cardiac output 䡲 ductus arteriosus, patent 䡲 fetal heart 䡲 circulation
C
ardiac output and the distribution of blood flow have
been well studied in animal experiments demonstrating
the fetal right heart dominance.1 Doppler studies in human
fetuses have also suggested a right heart dominance. However, the reported ratio of right to left cardiac output ranges
from 1.0 to 1.5.2–7 The very few studies that have focused on
blood flow through the ductus arteriosus and through the
pulmonary circuit in the human fetus have given conflicting
results.4,7 For these reasons, a prospective cross-sectional
study that used high-resolution ultrasound equipment, including color Doppler imaging, was performed to establish
gestational age–specific reference ranges for left and right
cardiac output, combined cardiac output, and volume of
blood flow across the ductus arteriosus. Furthermore, the
ratio of right to left cardiac output ratio, distribution of right
cardiac output (ductus arteriosus to lungs), and foramen ovale
blood flow were calculated.
nancy, no malformation, size appropriate for gestational age, normal
amniotic fluid volume, fetal rest, fetal apnea, and healthy pregnant
women without hypertension, proteinuria, smoking, or use of drugs
such as tocolytics, prostaglandin synthetase inhibitors, or glucocorticoids that influence the cardiovascular system. Patients gave
informed consent.
Ultrasound Equipment
In all cases, high-resolution color Doppler ultrasound equipment
(ATL HDI 3000/ATL UM 9 HDI, Advanced Technology Laboratories) with 4 to 2, 5 to 3, and 7 to 4-MHz broadband transducer and
spatial peak temporal average intensities ⬍100 mW/cm2 was used.
Echocardiography
The (inner) diameter (trailing to leading edge method) of the aortic
valve annulus was determined from the long-axis view of the left
heart during systole. The diameters of the pulmonary valve annulus
(inner diameter during systole) and of the ductus arteriosus at its
middle (inner diameter) were obtained from the transverse scan of
the fetal thorax during systole with an insonation perpendicular to the
long axis.8,9 Doppler velocity waveforms of the aorta were obtained
from the 5-chamber view. Doppler velocity waveforms of the main
pulmonary artery and the ductus arteriosus were obtained from the
short axis of the fetal heart (sagittal scan of the fetus). All Doppler
recordings were obtained at an insonation angle ⬍10° to flow.9
Angle correction was not used. Doppler tracings were recorded with
the sample volume positioned just distal to the valve in the center of
the vessel9 –13; for Doppler recordings in the ductus arteriosus, the
Methods
Population
In this cross-sectional study, 2D and Doppler echocardiography was
performed by an experienced examiner (G.M.) in 222 normal
singleton fetuses from 13 to 41 weeks (median, 25 weeks) of
gestation. Criteria for inclusion in the study were as follows:
gestational age confirmed by sonographic biometry in early preg-
Received October 17, 2000; revision received December 8, 2000; accepted December 14, 2000.
From the Departments of Obstetrics and Gynecology (G.M.) and Medical Biometry (N.B.), University of Tuebingen, Tuebingen, Germany.
Correspondence to PD Dr Gunther Mielke, MD, Department of Obstetrics and Gynecology, Prenatal Medicine, University of Tuebingen,
Schleichstrasse 4, 72076 Tuebingen, Germany. E-mail [email protected]
© 2001 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
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Mielke and Benda
Fetal Circulation
1663
Figure 1. Individual values and calculated 5th, 10th,
50th, 90th, and 95th centiles of right ventricular
stroke volume.
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sample volume was placed in the distal ductal part.14,15 The sample
volume was set at 1 to 3 mm; the high-pass filter, at 100 to 200
Hz.5,9,16 At least 5 consecutive uniform Doppler velocity waveforms
with the highest velocities and a narrow band of frequencies (“clean”
signal) were recorded, and 1 cycle was analyzed.10
The following features were determined: fetal heart rate (FHR);
time velocity integral (TVI); stroke volume (TVI · ␲ · d2/4),9,10,17
where d is the diameter of the vessel; and output per minute (stroke
volume · FHR). The ratio of right cardiac output to left cardiac output
and the ratios of ductal blood flow to right and combined cardiac
output were determined. Pulmonary blood flow was expressed as the
difference between right cardiac output and ductus arteriosus blood
flow. Foramen ovale blood flow was calculated as the difference
between left cardiac output and pulmonary blood flow (right cardiac
output per minute minus volume of ductal blood flow per minute).
Combined cardiac output per 1 kg fetal weight was estimated with
the formulas for fetal weight estimation of Mielke et al18,19 (formula
1; 23 to 29 weeks of gestation) and Hansmann et al20 (30 to 41
weeks). Findings were documented on video prints or videotape.
Because of fetal presentation and duration of the examination, not all
measurements could be performed in all patients.
Statistical Analyses
Estimation of age-related quantiles followed a proposition of Altman21 (see also the work by Harris and Boyd22). Cubic regression on
log scale yielded the median curve y(t). Estimation of age-related SD
by quadratic regression of the absolute values of the residuals and
multiplying the predicted values by the square root of ␲/2 yielded an
estimation of age-related SD s(t). With the use of the statistical
program GAUSS 3.2.9, quantiles were estimated by exp[y(t)⫹u ·
s(t)], where u is the corresponding quantile of the standardized
normal distribution. The influence of gestational age on biventricular
output per 1 kg fetal weight and on the ratios of right to left cardiac
output and ductal blood flow to right cardiac output was analyzed by
means of linear regression after logarithmic transformation of the
outcome variables. Significance was set at ␣⫽0.05.
Results
Cardiac Output and Volume of Blood Flow
Through the Ductus Arteriosus
The calculated centiles for right and left ventricular stroke
volume (Figures 1 and 2) and output per minute (Figures 3 and
4) increased exponentially with advancing gestational age.
Median fetal heart rate derived from Doppler recordings in
the pulmonary trunk, ascending aorta, and ductus arteriosus
was 144 bpm (mean, 143.5 bpm; SD, 9.5 bpm; n⫽216), 148
bpm (mean,147.6 bpm; SD, 8.7 bpm; n⫽89), and 144 bpm
Figure 2. Individual values and calculated 5th, 10th,
50th, 90th, and 95th centiles of left ventricular
stroke volume.
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March 27, 2001
Figure 3. Individual values and calculated 5th, 10th,
50th, 90th, and 95th centiles of right ventricular output per minute.
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(mean,143.4 bpm; SD, 10.5 bpm; n⫽206), respectively.
Figures 5 and 6 demonstrate the increase in calculated
centiles for biventricular (combined) cardiac stroke volume
and output per minute with advancing gestational age. The
calculated 50th centile for biventricular output increased from
⬇40 mL/min at 15 weeks of gestation up to 1470 mL/min at
40 weeks.
Median biventricular output per 1 kg fetal weight was
estimated to be 425 mL · min⫺1 · kg⫺1 (mean, 429 mL · min⫺1
· kg⫺1; SD, 100 mL · min⫺1 · kg⫺1; n⫽37; gestational age:
range, 23 to 40 weeks; median, 34.9 weeks; mean, 33.1
weeks; SD, 5.2 weeks), which was not associated with
gestational age (P⫽0.47, r⫽0.12). Median left cardiac output
per 1 kg fetal weight was estimated to be 179 mL · min⫺1 ·
kg⫺1.
In the ductus arteriosus, the calculated centiles for volume
of blood flow per cycle (Figure 7) and volume of blood flow
per minute (Figure 8) also increased exponentially with
advancing gestational age.
Distribution of Cardiac Output
The median ratio of right to left cardiac output was 1.42
(mean, 1.50; SD, 0.48; n⫽87), corresponding to a median
ratio of right to combined cardiac output of 0.59 and a median
ratio of left to combined cardiac output of 0.41. The ratio of
right to left cardiac output was not associated with gestational
age (P⫽0.94). The median ratio of the volume of ductal
blood flow per minute to right cardiac output per minute was
0.78 (mean, 0.80; SD, 0.31; n⫽197). The increase in this ratio
with advancing gestational age (factor, 1.002/wk; 95% CI,
0.916 to 1.040) was not significant (P⫽0.61). The median
ratio of the volume of ductal blood flow per minute to
combined cardiac output per minute was 0.46 (mean, 0.50;
SD, 0.19; n⫽85). The median ratio of estimated pulmonary
blood flow (right cardiac output per minute minus volume of
ductal blood flow per minute) to right cardiac output was 0.22
(n⫽187 cases in which right cardiac output per minute and
volume of ductal blood flow per minute were determined)
and 0.19 (n⫽85 cases in which right cardiac output per
Figure 4. Individual values and calculated 5th,
10th, 50th, 90th, and 95th centiles of left ventricular
output per minute.
Mielke and Benda
Fetal Circulation
1665
Figure 5. Individual values and calculated 5th,
10th, 50th, 90th, and 95th centiles of biventricular
stroke volume.
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minute, ductal blood flow per minute, and left cardiac output
per minute were determined). The median ratio of estimated
pulmonary blood flow to combined cardiac output was 0.11
(n⫽85).
Foramen ovale blood flow was expressed as the difference
between left cardiac output and pulmonary blood flow. The
median ratio of estimated foramen ovale blood flow to left
cardiac output was 0.76, and the median ratio of estimated
foramen ovale flow to combined cardiac output was 0.33. A
synopsis of the distribution of blood flow is given in the Table.
Discussion
Knowledge of fetal cardiac output and its distribution is based
predominantly on animal studies. In fetal lambs, biventricular
(combined) cardiac output in the second half of pregnancy is
⬇450 mL · min⫺1 · kg⫺1 fetal weight.1 About 60% to 65% of
cardiac output is ejected by the right ventricle and 35% to
40% by the left ventricle, corresponding to a ratio of right to
left cardiac output of 1.5 to 1.85.1,23,24
In fetal lambs, pulmonary blood flow is 6% to 8% of
combined cardiac output and ⬇10% of right cardiac output;
ductus arteriosus blood flow is 54% to 57% of combined
cardiac output and ⬇90% of right cardiac output.1,23–25 Lamb
experiments26 (n⫽44) have suggested an increase in pulmonary blood flow from 3.7% of combined cardiac output in
80-g to 450-g fetuses (n⫽7) to 7% of combined cardiac
output in near-term fetuses (n⫽10). In fetal lambs in the third
trimester of pregnancy, pulmonary blood flow did not change
relative to lung weight and right ventricular output at the
normal low oxygen tension of the fetus despite an increase in
pulmonary vessel density.27,28 In near-term fetuses, pulmonary blood flow was 35 to 40 mL · min⫺1 · kg⫺1 fetal weight.27
It has been demonstrated in animal experiments that
volumetric blood flow through the aortic and pulmonary
valves can be accurately determined through sonographic
measurements of vessel diameter and the time-velocity integral.8 However, previous Doppler studies in human fetuses
have resulted in conflicting data concerning fetal cardiac
Figure 6. Individual values and calculated 5th,
10th, 50th, 90th, and 95th centiles of biventricular
output per minute.
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March 27, 2001
Figure 7. Individual values and calculated 5th,
10th, 50th, 90th, and 95th centiles of volume of
blood flow per cycle in ductus arteriosus.
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output and its distribution. Very few studies have focused on
fetal cardiac output in the first half of pregnancy.
The present prospective cross-sectional study establishes
gestational age–specific reference ranges from 13 to 41
weeks of gestation for left and right cardiac output, biventricular (combined) output, and volume of blood flow across
the ductus arteriosus in the human fetus. Furthermore, the
data provide insights into the central blood flow distribution.
The calculated centiles for right and left ventricular stroke
volume and cardiac output per minute increased exponentially with advancing gestational age. Previous studies based
on smaller numbers of examinations show similar
results.2,3,5,7,17
The calculated 50th centile for biventricular output increased
from about 40 mL/min at 15 weeks of gestation up to 1470
mL/min at 40 weeks. Median combined (biventricular) output
per 1 kg fetal weight was estimated to be 425 mL · min⫺1 · kg⫺1,
which was not associated with gestational age. In fetal lambs,
reported values of combined cardiac output range from 377 to
549 mL · min⫺1 · kg⫺1, unrelated to body weight throughout
gestation.24,26 In the present study, median left cardiac output per
1 kg fetal weight was estimated to be 179 mL · min⫺1 · kg⫺1.
During postnatal circulatory changes,29 left cardiac output increases up to ⬇240 mL · min⫺1 · kg⫺1 within the first 2 hours of
birth because of increasing stroke volume.30 Then left cardiac
output falls to ⬇190 mL · min⫺1 · kg⫺1,30 reflecting an adaption
to the decreased demand on the left ventricle as the ductus
arteriosus constricts and ductal left-to-right shunt decreases from
62 mL · min⫺1 · kg⫺1 at 1 to 2 hours of age to 14 mL · min⫺1 ·
kg⫺1 at 12 hours of age.31,32
In human fetuses, the right heart dominance has been
discussed controversially.6 The reported ratio of right to left
cardiac output ranges from 1.0 to 1.5.2–7,16,17,33 Whereas De
Smedt et al3 reported a decreasing ratio of right to left cardiac
output with advancing gestational age, Rasanen et al7 found
this ratio to be increasing.
In the present study, the median ratio of right to left cardiac
output was 1.42 (mean,1.5; SD, 0.48; n⫽87), which was not
associated with gestational age, clearly supporting the conception of a right heart dominance in the human fetus.
Figure 8. Individual values and calculated 5th,
10th, 50th, 90th, and 95th centiles of volume of
blood flow per minute in ductus arteriosus.
Mielke and Benda
Fetal Circulation
1667
Distribution of Blood Flow Expressed as Percent of Combined (Biventricular) Cardiac Output
Near-Term
Fetal Lambs24
Human Fetuses,
Present Study
(13– 41 wk)
Human Fetuses7
(19 –39 wk)
Right cardiac output, %
60
59
53–60
Left cardiac output, %
40
41
47–40
Ductus arteriosus blood flow, %
54
46
32–40
Human Fetuses4
(18 –37 wk)
Human Fetuses39
(Age unknown)
Pulmonary blood flow, %
6
11
13–25
22
6
Foramen ovale blood flow, %
34
33
34–18
17–31
36
Biventricular output, mL 䡠 min⫺1 䡠 kg⫺1
462
425
470–503
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Because left ventricular output is distributed largely to the
upper carcass and brain of the fetus, the reduced ratio of right
to left cardiac output in the human fetus compared with the
values determined in the fetal lamb (ratio, 1.5 to 1.8) might be
explainable by the relatively larger human brain.34
In fetal life, blood shunts continuously right to left across
the ductus arteriosus. Doppler velocity waveforms of the
ductus arteriosus are characterized by high systolic and low
diastolic velocities.35,36 Reproducibility of the velocimetry of
peak systolic velocity and the time-velocity integral in the
ductus arteriosus has been demonstrated.37,38 In the present
study, volume of blood flow across the ductus arteriosus was
determined from examinations in 199 fetuses from 13 to 41
weeks of gestation. The calculated centiles show an exponential increase with advancing gestational age. Blood flow
across the ductus arteriosus was 78% (median) of right
cardiac output and 46% (median) of combined cardiac output.
Pulmonary blood flow was 11% (median) of combined
cardiac output. This fraction was not significantly associated
with gestational age. The volume of pulmonary blood flow
was estimated to be 47 mL · min⫺1 · kg⫺1 fetal weight (11%
of combined cardiac output). Thus, in this study of human
fetuses, pulmonary blood flow was a greater fraction of right
cardiac output and combined cardiac output than in fetal lamb
studies (6% to 8% of combined cardiac output).
Few other Doppler studies have been performed in human
fetuses to calculate the volume of blood flow across the
ductus arteriosus and through the pulmonary vascular bed. In
a study of 38 fetuses between 18 and 37 weeks of gestation,
the calculated pulmonary blood flow was 22% of combined
cardiac output and 48% of right ventricular output.4 There
was no association with gestational age. In a study of 39
fetuses (gestational age not mentioned), the calculated pulmonary blood flow was 6.4% of combined cardiac output and
⬇11% of right ventricular output.39 In a recent study of 63
fetuses, the calculated proportion of pulmonary blood flow
increased from 13% of combined cardiac output at 20 weeks
to 25% of combined cardiac output at 30 weeks; from 30 to
39 weeks of gestation, its proportion remained unchanged.7
Because foramen ovale blood flow is calculated as the
difference between left cardiac output and pulmonary blood
flow, Rasanen et al7 found that foramen ovale blood flow
decreased from 34% of combined cardiac output at 20 weeks
to 18% at 30 weeks, whereas from 30 to 38 weeks, the
proportions of foramen ovale blood flow and pulmonary
blood flow remained unchanged. In the present study, median
estimated foramen ovale blood flow was 76% of left cardiac
output and 33% of combined cardiac output. In fetal lamb
studies, foramen ovale flow was 34% of combined cardiac
output.24
Although animal experiments have demonstrated that the
echocardiographic Doppler method can accurately quantify
volumetric flow through the aortic and pulmonary valve,8
methodological problems have to be considered. Errors in
volumetric measurements arise from inaccuracies in vessel
diameter and Doppler recordings. In the present study,
volume of blood flow was calculated from the Dopplerderived time-velocity integral and the inner diameter of the
vessel (aortic and pulmonary valve annulus, lumen of the
ductus arteriosus at its middle) with the trailing to leading
edge method (from the inner, or trailing, edge of the anterior
vessel wall to the inner, or leading, edge of the posterior
wall). The accuracy of this noninvasive method has been
demonstrated in invasive animal experiments.8 However,
others have used the leading edge method (from the external
surface of the anterior wall to the internal surface of the
posterior wall), which overestimates the diameter and therefore the volume of blood flow by including 1 vessel wall
thickness. Vessel areas represent the most important source of
error in flow calculation. This error will be substantial
especially in vessels with a small diameter such as the ductus
arteriosus or the left and right pulmonary arteries. As modern
high-resolution ultrasound equipment makes accurate measurement of the inner vessel diameter possible, the trailing to
leading edge method may be more appropriate.
The use of color Doppler imaging optimizes positioning of
the pulsed-wave Doppler sample volume in the middle of the
vessel just distal to the valvular annulus, which is the
flow-limiting point in the outflow tract. Animal studies have
shown that the volumetric flow calculation is far more
accurate when the diameter of the aortic valve annulus is
used, as in the present study, than when the sino-tubular
junction diameter is used.8 Moreover, in the present study, the
pulsed-wave Doppler beam was aligned as parallel as possible to the direction of blood flow at an angle ⬍10° to flow to
avoid errors resulting from angle correction.9
In addition, the population of the study group is of great
importance. Fetal cardiac output and the distribution of blood
flow are influenced by maternal drug intake.36,40 Intrauterine
growth retardation is associated with reduced cardiac output
and a redistribution of blood flow with a reduced ratio of right
to left cardiac output.41 Therefore, only healthy women with
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Circulation
March 27, 2001
normal singleton pregnancies and gestational age confirmed
by sonographic biometry in early pregnancy were included
into the present study. For these reasons, we believe that the
results of this study represent the optimal data that can be
obtained.
Conclusions
Doppler investigations offer insights into fetal cardiovascular
physiology. The present study establishes reference ranges
for fetal cardiac output and ductus arteriosus blood flow and
describes the central blood flow distribution in the second and
third trimesters of pregnancy, confirming the conception of a
right heart dominance in the human fetus. The estimated
pulmonary blood flow is a greater fraction of right cardiac
output and of combined cardiac output than in fetal lamb
studies.
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Cardiac Output and Central Distribution of Blood Flow in the Human Fetus
Gunther Mielke and Norbert Benda
Circulation. 2001;103:1662-1668
doi: 10.1161/01.CIR.103.12.1662
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