Ultrasound Obstet Gynecol 2003; 22: 351–357

Published online 2 September 2003 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/uog.232

Retrograde aortic isthmus net blood flow and human

fetal cardiac function in placental insufficiency
K. MÄKIKALLIO, P. JOUPPILA and J. RÄSÄNEN
Department of Obstetrics and Gynecology, University of Oulu, Oulu, Finland

K E Y W O R D S: aortic isthmus; Doppler; fetal echocardiography; fetal growth restriction; placental insufficiency

ABSTRACT up the majority of LVCO. Fetuses with retrograde AoI net

Objective Retrograde aortic isthmus (AoI) net blood flow
has been associated with diminished oxygen delivery
to cerebral circulation. This study was designed to
characterize the cardiac function in human fetuses with
retrograde AoI net blood flow in pregnancies complicated
by placental insufficiency.
Methods The control group comprised 43 fetuses in
uncomplicated pregnancies. Study groups consisted of
fetuses with placental insufficiency, and either antegrade
(Group 1; n = 18) or retrograde (Group 2; n = 11) AoI
net blood flow. Volume blood flows (Q) of left (LVCO)
and right (RVCO) ventricles, ductus arteriosus (QDA ),
pulmonary arterial bed (QP ) and foramen ovale (QFO )
were calculated and their proportions (%) of combined
cardiac output (CCO) were determined. Ventricular
ejection forces were calculated. Blood velocity waveforms
of the mitral (MV) and tricuspid (TV) valves were
obtained. The proportion of left ventricular isovolumetric
relaxation time (IRT%) of the cardiac cycle, and index of
myocardial performance (IMP) were calculated.
Results In Group 1, QDA % was increased (P < 0.05) and
QP % decreased (P < 0.05) compared with the control
group, and QFO % was greater (P < 0.01) compared
with the control group and Group 2. In Group 2, the
distribution of CCO did not differ from that of the
control group. Ventricular ejection forces were similar
among the groups. In Group 2, the MV early filling/atrial
contraction time-velocity integral ratio was greater (P <
0.05) compared with those of the control group and
Group 1. In Groups 1 and 2, IRT% and IMP were
increased (P < 0.001) compared with the control group.
Conclusions In placental insufficiency, fetuses with
antegrade AoI net blood flow show a shift in RVCO from
the pulmonary to the systemic circulation, and QFO makes
blood flow fail to demonstrate these changes, suggesting a
relative drop in the oxygen content of the blood entering
the left ventricle. Copyright  2003 ISUOG. Published
by John Wiley & Sons, Ltd.
INTRODUCTION
In normal human pregnancies the fetal aortic isthmus
(AoI) may exhibit a short diastolic retrograde blood
velocity waveform component during the last trimester
of pregnancy. This may indicate a normal physiological
increase in the placental and fetal systemic vascular
resistances1 . In fetal lambs experimental studies under
acute conditions have shown that during stepwise increase
in the resistance to placental circulation the delivery
of oxygen to the brain is preserved as long as the
fetal AoI net blood flow is antegrade2 . Initial clinical
evidence suggests that in the human fetus the presence
of retrograde AoI net blood flow is associated with
non-optimal neurodevelopment of the child at least
between the ages of 2 and 4 years3 . Studies on fetal
lambs have demonstrated that an increase in placental
resistance affects the AoI blood flow profile before any
significant change in umbilical artery Doppler blood
velocity waveforms can be detected4 . In human fetuses
it has been shown that retrograde AoI net blood flow
can be present even with an apparently normal umbilical
artery blood velocity waveform profile5 .
In this study we tested the hypothesis that retrograde
AoI net blood flow is associated with changes in
human fetal cardiac function in pregnancies complicated
by placental insufficiency. The specific aims were to
investigate: 1) the distribution of fetal combined cardiac
output and 2) systolic and 3) diastolic functions of the
heart in fetuses with retrograde AoI net blood flow.

Correspondence to: Dr J. Räsänen, Department of Obstetrics and Gynecology, University of Oulu, 90220 Oulu, Finland
(e-mail: juharasa@cc.oulu.fi)
Accepted: 6 May 2003

Copyright  2003 ISUOG. Published by John Wiley & Sons, Ltd. ORIGINAL PAPER
352
METHODS
A total of 29 singleton pregnancies complicated by
placental insufficiency (fetal growth < 10th percentile
growth curve and/or abnormal umbilical artery blood
velocity waveform pattern6 ) were enrolled in this cross-
sectional study which was carried out between May 1998
and July 2000 in the University Hospital of Oulu, Finland.
The research protocol was approved by the local ethics
committee and all subjects gave written informed consent.
In all cases, gestational age was confirmed by sonography
prior to 20 weeks of gestation. Cases with structural or
chromosomal abnormalities were excluded.
Group 1 consisted of 18 fetuses which had antegrade
AoI net blood flow (Figure 1a) between 24 and 37 weeks
of gestation. According to ACOG guidelines7 , one mother
had pregnancy-induced hypertension, and 10 had severe
pre-eclampsia. In seven cases placental insufficiency
without a maternal hypertensive disorder was diagnosed.
Umbilical artery Doppler tracings revealed a normal blood
velocity waveform pattern in three cases, a decreased
diastolic blood velocity component in eight cases, and
a retrograde diastolic blood flow component in seven
cases. In 11 cases, neonatal birth weight was below
the 10th percentile growth curve. In every case with
neonatal birth weight above the 10th percentile growth
curve, umbilical artery Doppler tracings were abnormal,
indicating placental insufficiency. Cesarean delivery was
performed because of suspected fetal distress in six cases
as determined by abnormal non-stress tests and fetal
biophysical profiles, and in eight cases the indication
for Cesarean delivery was maternal hypertension and
severe headache. The time interval between the Doppler
sonographic examination and delivery ranged from 0 to
4 days with a median value of 0 days.
Group 2 consisted of 11 fetuses with retrograde
AoI net blood flow (Figure 1b) between 24 and
Figure 1 Antegrade net blood flow in the fetal aortic isthmus with
antegrade/retrograde time-velocity integral ratio of 2.0 (a), and
retrograde net blood flow in the aortic isthmus with the
corresponding ratio of 0.90 (b).
Copyright  2003 ISUOG. Published by John Wiley & Sons, Ltd.
Mäkikallio et al.
37 weeks of gestation. In two cases pregnancy-induced
hypertension was diagnosed; two patients suffered from
mild and two patients from severe pre-eclampsia. In five
cases placental insufficiency was not associated with a
maternal hypertensive disorder. Umbilical artery Doppler
recordings showed a normal blood velocity waveform
pattern in three cases, a decreased diastolic blood velocity
component in four cases and a retrograde diastolic
blood flow pattern in four cases. Cesarean delivery was
performed because of signs of fetal distress in non-stress
tests and in biophysical profile scoring, in all except
one case. Every neonate in this group had a birth
weight under the 10th percentile growth curve. The time
interval between the Doppler sonographic examination
and delivery ranged from 0 to 2 days with a median value
of 0 days.
The control group consisted of 43 cases with
uncomplicated pregnancy and labor that underwent
Doppler sonographic examination between 24 and
37 weeks of gestation. The birth weights of all the
neonates were between the 10th and 90th percentile growth
curves. Five fetuses were delivered by Cesarean section
because of fetopelvic disproportion, arrest of labor in the
first stage or previous Cesarean delivery. Perinatal data
on the groups are given in Table 1.
Image-directed pulsed and color Doppler equipment
(Acuson Sequoia 512, Mountain View, CA, USA) was
used, with a 4–8-MHz convex or a 5-MHz sector probe
to obtain blood velocity waveforms at the level of the
aortic (AoV) and pulmonary (PV) valves, ductus arteriosus
(DA), mitral (MV) and tricuspid (TV) valves and AoI. The
high pass filter was set at minimum. The acoustic output
of the system was controlled according to the ECMUS
guidelines8 . An angle of < 15◦ between the vessel and the
Doppler beam was accepted for analysis. From Doppler
tracings, fetal heart rate (FHR) was measured and time-
velocity integrals (TVIs) were calculated by planimetering
the area underneath the Doppler spectrum. In addition,
total TVIs, and TVIs of E- (early filling) and A- (atrial
contraction) waves were measured, and their ratio was
calculated from MV and TV blood velocity waveforms.
From AoI blood velocity waveform profiles, TVIs of
antegrade and retrograde components were measured and
their ratio was calculated. Net blood flow was considered
Table 1 Perinatal data of Group 1 (antegrade aortic isthmus net
blood flow), Group 2 (retrograde aortic isthmus net blood flow)
and controls
Control Group 1 Group 2
(n = 43) (n = 18) (n = 11)
Maternal age (years) 27.0 (6.1) 29.2 (3.2) 32.8 (6.7)
GA at study entry (weeks) 30.5 (4.0) 29.9 (5.9) 32.1 (3.8)
GA at delivery (weeks) 39.5 (1.4) 30.8 (4.0)‡ 32.5 (3.9)‡
Apgar at 5 min 9.0 (0.2) 7.8 (2.4)* 6.6 (3.2)†
Birth weight (g) 3267 (444) 1308 (724)‡ 1252 (540)‡
All values are mean (SD). *P < 0.05 vs. control group. †P < 0.01
vs. control group. ‡P < 0.0001 vs. control group. GA, gestational
age.
Ultrasound Obstet Gynecol 2003; 22: 351–357.
Fetal heart and aortic isthmus
antegrade if the ratio was ≥ 1, and retrograde when
the ratio was < 1 according to Fouron et al.2 . Three
consecutive cardiac cycles were analyzed and their mean
values were used for further analysis.
Using the four-chamber view, cardiac (CC) and thoracic
(TC) circumferences were determined and their ratio
was calculated. The diameters of the AoV and PV
annuli and the DA were measured from frozen real-time
images during systole by using the leading edge-to-leading
edge method9 . Three separate measurements of vessel
diameters were taken, and the mean value was used
for further analysis. Calculations of cross-sectional areas
(CSAs) of the arteries were based on the assumption
that the cross-sections of the vessels were circular.
Volume blood flow (Q) was calculated by the formula:
CSA × TVI × FHR.
Left ventricular cardiac output (LVCO) equals the
aortic valve volume blood flow (QAoV ) and right
ventricular cardiac output (RVCO) equals the pulmonary
valve volume blood flow (QPV ), and their sum is
the combined cardiac output (CCO). The pulmonary
volume blood flow (QP ) was estimated by the formula:
RVCO – QDA 10 , where QDA is the ductus arteriosus
volume blood flow. Foramen ovale volume blood flow
(QFO ) was estimated as LVCO – QP 9,10 . Weight-indexed
CCO, LVCO, RVCO, QDA , QP and QFO , and the
distribution (%) of CCO were calculated. Because the
time interval between the sonographic examination and
delivery was ≤ 4 days in Groups 1 and 2, the actual
birth weight was used for indexing purposes. In the
control group, fetal weight estimation was based on the
measurements of biparietal diameter, head and abdominal
circumferences and femur length, which is considered to
be the most reliable method with 7.5% SD11 .
Systolic function of the fetal heart was assessed by
calculating right (RVEFo) and left (LVEFo) ventricular
ejection forces using the formula: (1.055 × CSA ×
TVIac ) × (PSV/TTP), in which TVIac is the TVI during
the acceleration period of systole, PSV is the peak systolic
velocity and TTP is the time to peak velocity interval12 .
Both ventricular ejection forces were weight-indexed.
Fetal cardiac diastolic function was evaluated by cal-
culating the proportion of isovolumetric relaxation time
(IRT%) of the cardiac cycle13 . In addition, TV and MV
TVI E/A ratios were obtained. An index of myocardial
performance (IMP), which describes the combined systolic
and diastolic function of the heart, was calculated by the
formula: IMP = (ICT + IRT)/ET, in which ICT is the iso-
volumetric contraction time and ET is the ejection time14 .
In 12 patients, intraobserver variability of volumetric
blood flow calculations across AoV, PV and DA was
assessed. The reliability of the indirect calculation of
QP was documented by correlating it with direct QP
measurement in which right and left pulmonary artery
volume blood flows were calculated. The intraobserver
variability of direct QP measurement was also evaluated.
In addition, corresponding variabilities of MV and
TV TVI, and time-interval measurements, as well as
ventricular ejection force calculations, were assessed.
Copyright  2003 ISUOG. Published by John Wiley & Sons, Ltd.
353
Statistical analysis was performed by analysis of
variance when comparisons were made between the
three groups and the data were normally distributed. If
statistical significance was shown, the Scheffe F-test was
used for further analysis. If the data were not normally
distributed, the non-parametric Kruskal–Wallis test was
used. Between two groups, comparisons were made using
Student’s t-test if the data were normally distributed;
otherwise, the Mann–Whitney U-test was chosen. Linear
regression analysis was used to show the relationship
of measured parameters to gestational age. Difference in
frequency of Cesarean sections due to fetal distress was
compared by the chi-square test. A P-value of ≤ 0.05 was
selected as the level of statistical significance.
RESULTS
Maternal age, gestational age at delivery, birth weights
and Apgar scores of the neonates at 5 min in the different
groups are given in Table 1. No significant difference
in mean (SD) neonatal umbilical artery pH values was
observed between Groups 1 (7.24 (0.05)) and 2 (7.26
(0.06)). However, Cesarean section was performed due
to fetal distress more frequently (P < 0.01) in Group 2
(10/11) than in Group 1 (6/18). The CC/TC ratio was
greater (P < 0.001) in Group 1 (57.6% (3.7%)) than in
the control group (50.0% (1.9%)). In Group 2 (60.8%
(4.5%)), the CC/TC ratio exceeded that in Group 1
(P < 0.05).
The mean intraobserver variability of LVCO, RVCO,
QDA and direct QP calculation varied from 5.0% to
8.5% (95% CI, 2.9–11.1%). The correlation between
indirect and direct QP was good (R = 0.93, P =
0.0001). The mean intraobserver variability of MV
and TV TVI calculations ranged from 1.9% to 10.9%
(95% CI, 0.6–18.1%). In time-interval calculations, the
corresponding variability was from 7.9% to 9.6% (95%
CI, 4.2–14.2%). The mean intraobserver variability of
ventricular ejection force calculations was 7.3% (95%
CI, 3.5–11.0%).
In Groups 1 and 2, weight-indexed CCO, LVCO
and RVCO (P < 0.05) were less than they were in the
control group. In Group 1, weight-indexed QP was lower
(P < 0.05) than in the control group, while weight-
indexed QFO was higher (P < 0.05) than in Group 2
(Table 2, Figure 2). LVCO% and RVCO% did not differ
significantly between the groups. In Group 1, QDA % was
greater (P < 0.05), and QP % was less (P < 0.05) than in
the control group. Furthermore, in Group 1, QFO % was
higher (P < 0.01) than in Group 2 or the control group
(Table 3). The proportion of QFO of LVCO was greater
(P < 0.05) in Group 1 (71%) than in the control group
(49%) or in Group 2 (48%).
Weight-indexed RVEFo and LVEFo did not show
significant correlation with gestational age in the control
and study groups, and they did not differ between any of
the groups (Table 4). In addition, the ejection forces did
not differ between the right and left ventricles in any of
the groups.
Ultrasound Obstet Gynecol 2003; 22: 351–357.
354 Mäkikallio et al.

CCO RVCO LVCO

800
600 600
600
mL/min/kg

mL/min/kg

mL/min/kg
400 400
400
200 200
200

0 0 0
24 26 28 30 32 34 36 24 26 28 30 32 34 36 24 26 28 30 32 34 36

QDA QP QFO
400 400 400

300 300 300

mL/min/kg

mL/min/kg

mL/min/kg
200 200 200

100 100 100

0 0 0
24 26 28 30 32 34 36 24 26 28 30 32 34 36 24 26 28 30 32 34 36
Gestational age (weeks) Gestational age (weeks) Gestational age (weeks)

Figure 2 Weight-indexed combined cardiac output (CCO), right (RVCO) and left (LVCO) ventricular cardiac outputs and ductus arteriosus
(QDA ), pulmonary (QP ) and foramen ovale (QFO ) volume blood flows in fetuses with antegrade (◦) and retrograde (•) net blood flow in the
aortic isthmus, plotted against gestational age. Control group mean ± SD values are indicated by dashed and solid lines.

Table 2 Weight-indexed combined cardiac output (CCO), right
(RVCO) and left (LVCO) ventricular cardiac outputs and
pulmonary (QP ), foramen ovale (QFO ) and ductus arteriosus
(QDA ) volume blood flows in each group
Control Group 1
Table 4 Systolic and diastolic function of the fetal heart in control
and study groups: right (RVEFo) and left (LVEFo) ventricular
ejection forces, proportion of isovolumetric relaxation time (IRT%)
of the total cardiac cycle, time-velocity integrals (TVIs) of tricuspid
(TV) and mitral (MV) valves and TVI ratio of E- (early filling) and
A- (atrial contraction) waves, and index of myocardial performance
Group 2
(IMP)

CCO (mL/min/kg) 647 (113) 529 (141)* 549 (153)*

RVCO (mL/min/kg) 391 (74) 287 (57)* 317 (106)* Control Group 1 Group 2
LVCO (mL/min/kg) 298 (67) 242 (94)* 231 (59)*
QP (mL/min/kg) 150 (63) 99 (48)† 125 (74) Systolic function
QFO (mL/min/kg) 153 (74) 163 (79)‡ 105 (56) RVEFo (mN/kg) 7.1 (2.1) 5.5 (1.6) 6.4 (3.0)
QDA (mL/min/kg) 244 (50) 208 (49) 208 (77) LVEFo (mN/kg) 7.0 (2.4) 6.4 (3.7) 5.9 (2.3)
Diastolic function
All values are mean (SD). *P < 0.05 vs. control group. †P < 0.01 IRT% 8.8 (1.2) 13.4 (1.8)* 13.2 (1.9)*
vs. control group. ‡P < 0.05 vs. Group 2. TV TVI (cm) 6.5 (1.1) 4.9 (0.8)* 4.9 (0.8)*
TV TVI E/A 0.61 (0.17) 0.69 (0.24) 0.84 (0.87)
MV TVI (cm) 6.5 (1.1) 4.4 (0.8)* 4.9 (0.1)*
Table 3 Proportions (%) of right (RVCO) and left (LVCO) MV TVI E/A 0.71 (0.15) 0.76 (0.17) 1.08 (0.75)†
ventricular cardiac outputs and pulmonary (QP ), foramen ovale IMP 0.35 (0.06) 0.56 (0.09)* 0.57 (0.07)*
(QFO ) and ductus arteriosus (QDA ) volume blood flows of
combined cardiac output in control and study groups All values are mean (SD). *P < 0.001 vs. control group. †P < 0.05
vs. control group and Group 1.
Control Group 1 Group 2
(P < 0.05) was greater than it was in the control group
RVCO% 56.8 (4.7) 55.1 (5.2) 57.2 (6.3)
and Group 1. In Groups 1 and 2, IRT% and IMP values
LVCO% 43.2 (4.7) 44.9 (5.2) 42.8 (6.3)
QP % 23.4 (7.7) 17.8 (6.8)* 21.4 (10.5) were increased (P < 0.001) compared with the control
QFO % 23.5 (11.1) 32.0 (16.9)† 19.7 (10.8) group (Table 4).
QDA % 35.1 (6.8) 42.2 (18.3)* 37.4 (11.5)

All values are mean (SD). *P < 0.05 vs. control group. †P < 0.01
vs. control group and Group 2.
In the control group, TV and MV TVIs were
significantly greater (P < 0.001) than they were in Groups
1 and 2. The TV TVI E/A ratio did not differ significantly
between the groups. In Group 2, the MV E/A ratio of TVI
DISCUSSION
Placental insufficiency triggers compensatory mechanisms
in the fetus including redistribution of arterial circulation.
In the human fetus well-oxygenated blood entering from
the placenta flows through the ductus venosus and left
hepatic vein via the foramen ovale to the left atrium and
ventricle15 , while blood from the fetal lower body enters

Copyright  2003 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2003; 22: 351–357.
Fetal heart and aortic isthmus
the right atrium and ventricle through the inferior vena
cava and other hepatic veins. This parallel circulatory
system of the fetal heart ensures a highly oxygenated
blood supply to the coronary and cerebral circulations.
The AoI has a dynamic role in connecting these two
parallel circulatory systems in the fetus. In the acute fetal
lamb model, it has been demonstrated that AoI blood
flow changes precede impending cerebral hypoxemia.
It appears that oxygen delivery to the brain does not
decrease until the net blood flow through the AoI becomes
retrograde2 . In addition, studies on fetal lambs have
shown that an increase in placental vascular resistance
may change the fetal AoI blood flow profile prior to any
significant change in umbilical artery blood flow pattern4 .
This is in agreement with our finding which showed that
retrograde AoI net blood flow can be detected in the
presence of normal umbilical artery Doppler velocimetry.
On the basis of these data, the present study was designed
to investigate the cardiac function in human fetuses with
retrograde AoI net blood flow in pregnancies complicated
by placental insufficiency.
Our results demonstrate that human fetal weight-
indexed RVCO and LVCO are significantly reduced in
pregnancies complicated by placental insufficiency. There
was no difference in RVCO or LVCO with respect to
the direction of AoI net blood flow. In addition, the
CC/TC ratio was significantly increased in both study
groups, and in fetuses with retrograde net blood flow in
the AoI the increase was even greater than in fetuses with
antegrade net blood flow. This demonstrates an increase
in relative heart size in fetuses which suffer from placental
insufficiency.
The proportions of LVCO and RVCO of the total
cardiac output were similar in both study groups
compared with the control group. However, in fetuses
with antegrade net blood flow in the AoI, the proportion
of QDA was increased, and the proportion of QP
decreased. This demonstrates a shift in the distribution
of right ventricular cardiac output from the pulmonary
to the systemic circulation. It has been documented
that during the last trimester of pregnancy, human fetal
pulmonary circulation is under acquired vasoconstriction
which is affected by fetal oxygen tension16 . In placental
insufficiency, oxygen delivery from the placenta can be
impaired, leading to lower oxygen content of the blood.
In such cases, vasoconstriction of the pulmonary arterial
bed and a drop in QP could occur. In addition, the
proportion of QFO rises, thus increasing its role in making
up LVCO. In this way, in placental insufficiency, fetuses
with antegrade net blood flow in the AoI are able to ensure
highly oxygenated blood to the coronary and cerebral
circulations. Fetuses with retrograde net blood flow in
the AoI failed to reorganize the distribution of RVCO
and LVCO; in this group, the proportional distribution
of cardiac output did not differ from that in the control
group. Fetuses with placental insufficiency and retrograde
net blood flow in the AoI were unable to increase QFO to
the same magnitude as could fetuses with antegrade net
blood flow. This could lead to lower oxygen content of
Copyright  2003 ISUOG. Published by John Wiley & Sons, Ltd.
355
the blood entering the left ventricle, even in the presence
of similar pO2 values in the umbilical venous blood. Thus,
oxygen delivery to the coronary and cerebral circulations
is diminished compared with fetuses with antegrade net
blood flow in the AoI, predisposing these fetuses to
coronary and cerebral hypoxemia. In addition, placental
insufficiency is often associated with increased afterload of
the fetal heart leading to a rise in ventricular pressure and
wall tension. This may further increase oxygen demand
of the myocardium. This is supported by the fact that
fetuses with retrograde net blood flow in the AoI were
delivered more frequently by Cesarean section due to fetal
distress.
Systolic function of the fetal heart was assessed by
calculating ventricular weight-indexed ejection forces.
Ventricular ejection force estimates the energy transferred
from ventricular myocardial shortening to work done
by accelerating blood into the circulation. Ventricular
ejection force assessment does not require estimation of
ventricular volumes, and it is independent of ventricular
configuration12 . In addition, studies on animals have
suggested that early systolic flow is less affected by changes
in afterload and preload compared with flow during
late systole17,18 . In this study, we found no difference
between RVEFo and LVEFo in any of the groups. This
is in agreement with previous observations12,19 . The
weight-indexed RVEFo and LVEFo in the fetuses with
placental insufficiency and either antegrade or retrograde
net blood flow in the AoI did not differ from those
measured in control fetuses. Rizzo et al.19 demonstrated
that the ejection forces of both ventricles were significantly
and symmetrically decreased in growth-restricted fetuses.
Adverse obstetric outcome was observed in growth-
restricted fetuses in which the ejection forces of both
ventricles were below the 5th centile of the normal
limits for gestation. In addition, a relationship between
the severity of acidosis and diminished RVEFo and
LVEFo was demonstrated. The differences between the
observations in the present study and in that by Rizzo
et al.19 can be explained by a different study design. In
this study, we used weight-indexed ejection force values
because fetuses with placental insufficiency tend to be of
a lower weight. In addition, umbilical artery pH values at
delivery were similar among the study groups suggesting
that these fetuses were delivered prior to development
of severe fetal acidosis. Our findings show that the fetal
heart is able to preserve its systolic function even in the
presence of retrograde net blood flow in the AoI.
Fetuses with placental insufficiency had greater IRT%
with no difference as regards the direction of AoI net
blood flow. The IRT is the period between closure of
the semilunar valve and opening of the atrioventricular
valve. This time interval is needed for the ventricle to
drop its pressure from a systemic to an atrial level.
Relaxation of the myocardium is an active process
dependent on the ability of the myocytes to accelerate
calcium transport through sodium-calcium channels. Our
finding suggests that in placental insufficiency fetal cardiac
diastolic function is impaired, at least during the early part
Ultrasound Obstet Gynecol 2003; 22: 351–357.
356
of diastole. Another explanation for greater IRT% could
be an increased pressure gradient between systemic and
atrial levels, because fetuses with placental insufficiency
tend to be hypertensive20 . However, significantly higher
IMP values suggest impaired global cardiac function in
these fetuses compared with the control group, as shown
earlier by Tsutsumi et al.14 .
In both study groups, total TVIs of the MV and TV were
lower than those in the control group. This could be a
consequence of lower cardiac output in these fetuses. The
TV E/A ratio of TVI did not differ between the groups.
However, in fetuses with retrograde net blood flow in the
AoI, the MV TVI E/A ratio demonstrated a shift towards
the early filling period of the ventricle. With advancing
gestation, MV and TV TVI E/A ratios increase, which is
thought to reflect improvement in the diastolic function
of the fetal heart21 . However, loading conditions of the
heart may affect E/A ratios, and in children and adults
an increase in atrial pressure increases the E component
of the inflow velocity waveform. In fetuses with placental
insufficiency and retrograde net blood flow in the AoI,
MV E/A ratios were significantly greater than those in
the control group and in fetuses with antegrade AoI net
blood flow. This may indicate increased left atrial pressure
in fetuses with retrograde AoI net blood flow. Increased
left atrial pressure could also diminish the blood stream
through the foramen ovale.
The methodological problems concerning volumet-
ric blood flow measurements have been discussed
intensively22 . In experiments on animals, volumetric
blood flow measurements obtained by Doppler sonog-
raphy have been shown to be valid23,24 . In human fetuses,
an excellent correlation between two independent calcula-
tions of RVCO from PV and QP + QDA has been shown9 .
In addition, in a randomized blinded study, intraobserver
variability in volumetric blood flow measurements across
the PV, AoV, DA and pulmonary arterial bed has been
shown to be < 9%16 . In the present study, the angle
between the Doppler beam and the vessel was kept at
< 15◦ to minimize methodological errors. Vessel diam-
eters were measured using the well-established leading
edge-to-leading edge method. The intraobserver variabil-
ity of volumetric blood flow calculations was comparable
to those in previous reports. In addition, indirect esti-
mation of QP was found to correlate significantly with
direct QP calculation. In fetal studies, intraobserver vari-
ability in RVEFo calculations has been < 10%19,25 . In this
study, the corresponding variability of ventricular ejection
force calculations was 7–8%. These findings demonstrate
that calculations of volumetric blood flows can be accu-
rately assessed in the human fetus during the second
half of pregnancy with currently available sonographic
technology.
In conclusion, fetuses with placental insufficiency and
antegrade net blood flow in the AoI demonstrate a shift
in the distribution of RVCO from the pulmonary to the
systemic circulation. Furthermore, the proportion of QFO
increases, making up the majority of LVCO. However,
fetuses with retrograde net blood flow in the AoI fail
Copyright  2003 ISUOG. Published by John Wiley & Sons, Ltd.
Mäkikallio et al.
to demonstrate this rearrangement in the distribution of
cardiac output, and they have signs of increased left atrial
pressure. Thus, retrograde net blood flow in the AoI may
indicate a relative drop in the oxygen content of the blood
ejected from the left ventricle, and thus decreased oxygen
supplies to the coronary and cerebral circulations.
ACKNOWLEDGMENT
Financial support for the study was provided by The
Academy of Finland.
REFERENCES
1. Fouron JC, Zarelli M, Drblik P, Lessard M. Flow velocity
profile of the fetal aortic isthmus through normal gestation.
Am J Cardiol 1994; 74: 483–486.
2. Fouron JC, Skoll A, Sonesson SE, Pfizenmaier M, Jaeggi E,
Lessard M. Relationship between flow through the fetal aortic
isthmus and cerebral oxygenation during acute placental
circulatory insufficiency in ovine fetuses. Am J Obstet Gynecol
1999; 181: 1102–1107.
3. Fouron JC, Gosselin J, Amiel-Tison C, Infante-Rivard C,
Fouron C, Skoll A, Veilleux A. Correlation between prenatal
velocity waveforms in the aortic isthmus and neurodevelop-
mental outcome between the ages of 2 and 4 years. Am J Obstet
Gynecol 2001; 184: 630–636.
4. Bonnin P, Fouron JC, Teyssier G, Sonesson SE, Skoll A. Quan-
titative assessment of circulatory changes in the fetal aortic
isthmus during progressive increase of resistance to umbilical
blood flow. Circulation 1993; 88: 216–222.
5. Mäkikallio K, Jouppila P, Räsänen J. Retrograde net blood flow
in the aortic isthmus and human fetal arterial and venous
circulations. Ultrasound Obstet Gynecol 2002; 19: 147–152.
6. Hastie SJ, Danskin F, Neilson JP, Whittle MJ. Prediction of the
small for gestational age twin fetus by Doppler umbilical artery
waveform analysis. Obstet Gynecol 1989; 74: 730–733.
7. Committee on Technical Bulletins of the American College of
Obstetricians and Gynecologists. Hypertension in pregnancy.
1996 Jan. ACOG technical bulletin No.: 219 (replaces No.: 91,
1986 Feb). Int J Gynaecol Obstet 1996; 53: 175–183.
8. European Committee for Medical Ultrasound Safety (ECMUS)
1999. Thermal teratology. Eur J Ultrasound 1999; 9: 281–283.
9. Rasanen J, Wood DC, Weiner S, Ludomirski A, Huhta JC. Role
of the pulmonary circulation in the distribution of human fetal
cardiac output during the second half of pregnancy. Circulation
1996; 94: 1068–1073.
10. St John Sutton M, Groves A, MacNeill A, Sharland G, Allan L.
Assessment of changes in blood flow through the lungs and
foramen ovale in the normal human fetus with gestational age:
a prospective Doppler echocardiographic study. Br Heart J
1994; 71: 232–237.
11. Hadlock FP, Harrist RB, Carpenter RJ, Deter RL, Park SK.
Sonographic estimation of fetal weight. The value of femur
length in addition to head and abdomen measurements.
Radiology 1984; 150: 535–540.
12. Sutton MS, Gill T, Plappert T, Saltzman DH, Doubilet P.
Assessment of right and left ventricular function in terms of
force development with gestational age in the normal human
fetus. Br Heart J 1991; 66: 285–289.
13. Tulzer G, Khowsathit P, Gudmundsson S, Wood DC, Tian ZY,
Schmitt K, Huhta JC. Diastolic function of the fetal heart during
second and third trimester: a prospective longitudinal Doppler-
echocardiographic study. Eur J Pediatr 1994; 153: 151–154.
14. Tsutsumi T, Ishii M, Eto G, Hota M, Kato H. Serial evaluation
for myocardial performance in fetuses and neonates using a new
Doppler index. Pediatr Int 1999; 41: 722–727.
Ultrasound Obstet Gynecol 2003; 22: 351–357.
Fetal heart and aortic isthmus
15. Kiserud T, Eik-Nes SH, Blaas HG, Hellevik LR. Ultrasono-
graphic velocimetry of the fetal ductus venosus. Lancet 1991;
338: 1412–1414.
16. Rasanen J, Wood DC, Debbs RH, Cohen J, Weiner S, Huhta
JC. Reactivity of the human fetal pulmonary circulation to
maternal hyperoxygenation increases during the second half
of pregnancy: a randomized study. Circulation 1998; 97:
257–262.
17. Noble MIM, Trenchard D, Guz A. Left ventricular ejection in
conscious dogs: II. Determinants of stroke volume. Circ Res
1966; 19: 148–152.
18. Noble MIM. The contribution of blood momentum to left
ventricular ejection in the dog. Circ Res 1968; 23: 663–670.
19. Rizzo G, Capponi A, Rinaldo D, Arduini D, Romanini C. Ven-
tricular ejection force in growth-retarded fetuses. Ultrasound
Obstet Gynecol 1995; 5: 247–255.
20. Stale H, Marsal K, Gennser G, Benthin M, Dahl P, Lind-
strom K. Aortic diameter pulse waves and blood flow velocity
in the small, for gestational age, fetus. Ultrasound Med Biol
1991; 17: 471–478.
Copyright  2003 ISUOG. Published by John Wiley & Sons, Ltd.
357
21. Rizzo G, Arduini D, Romanini C, Mancuso S. Doppler echocar-
diographic assessment of atrioventricular velocity waveforms
in normal and small-for-gestational-age fetuses. Br J Obstet
Gynaecol 1988; 95: 65–69.
22. Eik-Nes SH, Marsal K, Kristoffersen K. Methodology and basic
problems related to blood flow studies in the human fetus.
Ultrasound Med Biol 1984; 10: 329–337.
23. Schmidt KG, Di Tommaso M, Silverman NH, Rudolph AM.
Doppler echocardiographic assessment of fetal descending aortic
and umbilical blood flows. Validation studies in fetal lambs.
Circulation 1991; 83: 1731–1737.
24. Meijboom EJ, Horowitz S, Valdes-Cruz LM, Sahn DJ, Lar-
son DF, Oliveira Lima CA. Doppler echocardiographic method
for calculating volume flow across the tricuspid valve: cor-
relative laboratory and clinical studies. Circulation 1985; 71:
551–556.
25. Rasanen J, Debbs RH, Wood DC, Weiner S, Weil SR, Huhta
JC. Human fetal right ventricular ejection force under abnormal
loading conditions during the second half of pregnancy.
Ultrasound Obstet Gynecol 1997; 10: 325–332.
Ultrasound Obstet Gynecol 2003; 22: 351–357.