doi:10.1111/jog.14402

J. Obstet. Gynaecol. Res. 2020

Ultrasound measurement of fetal arterial pulse pressureusing phased-tracking methods: A phantom study andclinical experience with antenatal corticosteroid therapy
Jin Muromoto1,2, Jun Murotsuki1,3, Susumu Miyashita4, Hideyuki Hasegawa5,
Hirofumi Taki6, Hiroshi Kanai7 and Nobuo Yaegashi81Department of Advanced Fetal and Developmental Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
Center for Maternal-Fetal, Neonatal and Reproductive Medicine, National Center for Child Health and Development, Tokyo,
Japan
3
Department of Maternal and Fetal Medicine, Miyagi Children’s Hospital, Sendai, Japan
4
Division of Maternal and Fetal Medicine Perinatal Medical Center, Dokkyo Medical University, Tochigi, Japan
5
Laboratory for Neural Information Technology, University of Toyama, Toyama, Japan
6
Graduate School of Biomedical Engineering, Tohoku University, Sendai, Japan
7
Department of Electronic Engineering, Tohoku University Graduate School of Engineering, Sendai, Japan
8
Department of Obstetrics and Gynecology, Tohoku University, Sendai, Japan
2

Abstract
Aim: This study aimed to compare the accuracy of fetal pulse pressure estimated with a vascular simulator
with that obtained by a manometer (reference) and evaluate the pulse pressure in normal human fetuses
and fetuses whose mothers received corticosteroids.
Methods: Fetal pulse pressure was estimated as the product of blood ﬂow velocity and pulse wave velocity,
based on the water hammer equation. Ultrasonic raw radiofrequency signals for blood ﬂow velocity were
captured from the fetal descending aortas at the diaphragm level, and pulse wave velocity was simultaneously measured from different directions using the phased-tracking method. First, the precision and accuracy of pulse pressure in the estimated method were veriﬁed by a circulatory phantom simulator, which
reproduced fetal blood ﬂow using a pulsating pump. Then, the pulse pressure of 98 normal human fetuses
after 17 weeks of gestation and the fetal pulse pressure in 21 mothers who received antenatal corticosteroids
for fetal maturation were measured.
Results: A signiﬁcant correlation between the estimated pulse pressure values and the actual values wasfound in the phantom simulation (r = 0.99, P < 0.01). The estimated pulse pressure was signiﬁcantly correlated with gestational age in normal fetuses (r = 0.74, P < 0.01). In steroid-treated pregnant women, fetal
pulse pressure was observed to increase signiﬁcantly on the second day of administration (P < 0.01).
Conclusion: A noninvasive and accurate estimation model of fetal pulse pressure could be established using
phased-tracking method, and this method has the potential to improve the assessment of human fetal
hemodynamics.
Key words: fetal pulse pressure, phased-tracking method, pulse wave velocity, vascular simulation model.

Received: April 4 2020.
Accepted: June 28 2020.
Correspondence: Dr Jin Muromoto, Center for Maternal-Fetal, Neonatal and Reproductive Medicine, National Center for Child Healthand Development, Tokyo 157-0074, Japan. Email: muromoto-j@ncchd.go.jp© 2020 Japan Society of Obstetrics and Gynecology

1J. Muromoto et al.

Introduction

Methods

Adequate blood ﬂow is necessary to facilitate sufﬁcient oxygen supply to all tissues in humans including
fetuses. Obstetricians focus on fetal blood pressure, as
pathological fetal hypotension (low blood pressure),
rather than hypoxemia, could lead to tissue hypoperfusion, which is a signiﬁcant causal factor of brain
damage in compromised fetuses.1 However, fetal
blood pressure monitoring is rarely a part of the clinical management of fetuses with critical conditions
because the standard monitoring methods used in
adults is too invasive for fetuses.
With recent advancements in ultrasound technology, noninvasive methods of fetal blood pressure
estimation have been sought.2–6 Several studies havereported a linear relationship between blood pressure and internal diameter or fractional area change
in the descending aorta in animal models.2–4
Although this method gives us meaningful parameters regarding blood pressure changes, it is notintended for the direct determination of the fetal
blood pressure. On the other hand, Struijk et al.5 andMiyashita et al.6 reported that fetal pulse pressure
could be calculated directly using the change in aortic diameter and pulse wave velocity (PWV) measurement, based on the Windkessel model. However,there is a discrepancy in the results between the twostudies regarding fetal pulse pressure values.5,6 Furthermore, both calculated values were markedly
higher than the invasively derived left ventricularpressures in human fetuses that have been previously reported.7
The aim of this study was to establish an estimation model of fetal pulse pressure using phasedtracking method based on the water hammer
equation, including blood ﬂow velocity and PWV in
the fetal descending aorta, in two phases: First, toperform experimental measurements using a vascular simulation model for pressure calibration and tocompare the values to those from previously
reported estimating equations, such as the water
hammer, Bramwell-Hill and Moens-Korteweg
models; then, to evaluate the ontogenic change inpulse pressure in normal fetuses and the vasopressor
effects of exogenous corticosteroid exposure for lungmaturation on fetuses who are at risk of preterm
birth to ensure the clinical signiﬁcance of the current
model and to thus provide a novel indicator for fetal
hemodynamics.

Ultrasonic phased-tracking method and PWVmeasurement2

An ultrasonic beam scanned different directions at aframe rate of 500 Hz using an ultrasonic diagnostic
equipment (Prosound F75; Hitachi-ALOKA) with a
5-MHz convex array probe (Hitachi-ALOKA). The
radiofrequency signals were sampled at 20 MHz forseveral pulsation cycles. For the in vivo measurements, the fetal descending aortas were identiﬁed in
the longitudinal direction at the diaphragm level inthe transabdominal B-mode plane. The radiofrequency signal in each scan line was captured
for 2–4 s.
The ultrasonic phased-tracking method was used toestimate the vibration velocities of the phantom andaortic walls. Before applying the phased-tracking
method, off-line quadrature demodulation wasapplied to the sampled radiofrequency signals. The
principles underlying phased-tracking method,
including the theoretical and in vivo evaluation of themeasurements, have been previously described.6 The
phased-tracking method was applied to the ultrasonicbeams from two different longitudinal positions in
the near wall of the descending aorta. A measuring
point was set at the upper side of the diaphragm, andanother point was set at the lower side. The crosscorrelation function between the velocity waveforms
at these two positions was obtained to estimate thepropagation time delay of the pulse wave between
these two positions. To estimate the time delay, whichis smaller than the frame interval, reconstructive interpolation was used to interpolate the cross-correlation
function.8 We conﬁrmed that the sampling frequency,
which corresponds to the frame rate, was highenough to include all frequency components of thevibration velocity in the phantom or fetal aortic wall
based on the Nyquist frequency. The PWV was
obtained by dividing the distance between the analyzed positions by the estimated time delay. The average time delay from several cardiac cycles was used
for the analysis.

Algorithm to estimate aortic pulse pressure
In the water hammer equation, pulse pressure is calculated as follows:
Δp = ρ × U × PWV ½Pað1Þ© 2020 Japan Society of Obstetrics and Gynecology

Ultrasonic fetal pulse pressure measurement

where Δp is the pulse pressure and ρ is the blood’s
density.9 This equation assumes that blood density isa constant number (1.05 g/mL) that is not dependent
on gestation age and that blood ﬂow velocity is halfof the maximum laminar ﬂow velocity, based on theHagen-Poiseuille law. Thus, fetal pulse pressure wasestimated from blood ﬂow velocity and PWV. Bloodﬂow velocity was measured using the same ultrasonography probe at the same level of the descending
aorta, the sample volume was assumed to be at thecenter of the vessel, and the maximum velocity wasrecorded for an average of ﬁve cardiac cycles. The
angle of insoniﬁcation was kept as low as possible (<30 ).
Struijk et al.5 and Miyashita et al.6 have reported
fetal pulse pressure measurements using the
Bramwell-Hill and Moens-Korteweg equations. However, these two equations require the measurement of
the aorta’s internal diameter change, instead of theblood ﬂow velocity:
Δp = ρ

D2max −D2min
D2min

× PWV 2 ½Pa Bramwell −Hill equation

ð2Þ

Dmax − Dmin
Dmax
2
× PWV ½Pa Moens − Korteweg equation

ð3Þ

Δp = 2ρ

In these equations, Dmin and Dmax are the internal
vessel diameters during diastole (measured using
M-mode) and systole, respectively. The D max -D min
term was measured using the phased-tracking
method.

Testing the algorithm using simulation-derived
pressure and ﬂow waveforms
Phantom simulation experiments were performed toevaluate the precision and accuracy of the pulse pressure measurements. The phantom consisted of a pulsatile ﬂow generator (TOBI HTJ-1000), a silicone tube
in a water tank, a manometer and simulated blood(model 046; Eastek Corporation) (Fig. 1). The pulsatile
ﬂow generator could create various pulse pressuresby changing the stroke volume from 10 to 50 mL ateach stroke. The radiofrequency signals were captured using the same settings used for pulse pressure
measurement, and the ultrasonography probe wasplaced downward in the water tank with thesilicone tube.
© 2020 Japan Society of Obstetrics and Gynecology

Figure 1 Experimental setup consisting of a pulsatile
ﬂow generator, a silicone tube with a water tank, amanometer, an ultrasound (US) probe, a pressure
monitor and simulated blood.

Testing the algorithm using clinical data
We prospectively recruited healthy women with singleton pregnancies at our hospital from June 2010 to
December 2017. Fetuses with apparent anomalies,
such as structural heart disease, arrhythmia, hydrops,
chromosomal abnormalities and congenital infection,
were excluded. Women with multiple pregnancy or
medical complications, such as diabetes, anemia, drug
abuse, alcoholic/smoking history, hypertension andsigniﬁcant heart, liver or renal disease, were also
excluded.
After applying the exclusion criteria, 119 womenwith singleton pregnancies (18–40 weeks of gestation)
were enrolled. Ninety-eight normal fetuses wereobserved to examine the normal ontogenic changes.
Twenty-one fetuses at 23–33 weeks of gestation were
tested to determine the pharmacological effects ofexogenous antenatal corticosteroids administered topregnant women at risk for preterm birth to facilitate
fetal lung maturity. A complete course of corticosteroids was deﬁned as two doses of 12 mg intramuscular
betamethasone
administered
24 hapart.
Measurements were performed before the initialadministration of betamethasone (day 0) and then ondays 2 and 8. The raw ultrasonic radiofrequency signals for blood ﬂow velocity were captured from thefetal descending aortas at the diaphragm level, andPWV was simultaneously measured from different
directions. The fetal pulse pressure was calculated
from the water hammer equation in clinical data.
This study complies with the policies and/or procedures of the Journal of Obstetrics and Gynecology
Research. This study was conducted in accordance
3

J. Muromoto et al.

with the Declaration of Helsinki and Good Clinicalpractice. This protocol was approved by the institutional ethics committee, and all measurements were
performed with written informed consent.

Statistical analysis
All measured data were analyzed using JMP version
10.0.2 (SAS). Both linear and nonlinear regression analyses were used to build the regression models. Oneway analysis of variance and the Tukey–Kramer
method were used to compare the pulse pressures atdays 0, 2 and 8 from fetuses exposed to antenatal
steroids.

Results
Experimental pressure calibration
In the phantom simulation experiment, the PWV
increased with increasing pulse pressure in the circuitas the pulsatile pump produced six levels of pressure(ranging from 40–90 mmHg). Figure 2 shows the correlation between the pulse pressure values, as measured using the manometer, and the estimated pulsepressure values from the different estimating equations. The pulse pressure values estimated from thewater hammer equation signiﬁcantly correlated withthe pulse pressure measured by the manometer, butthere were some conﬂicts between the two values on
the higher or lower pressure range. The estimatedpulse pressure values from the Moens-Korteweg and
Bramwell-Hill equations were markedly different
from the measured values. The equations for the
regression line were as follows: water hammer equation: y = 1.724 × G-40.978 (r2 = 0.99, P < 0.01); MoensKorteweg equation: y = 3.315 × G-134.07 (r2 = 0.79,
P = 0.054); Bramwell-Hill equations: y = 3.161 × G124.26 (r2 = 0.80, P < 0.01), where y is the estimatedpulse pressure and G is the generated pulse pressure.

Ontogenic change in normal fetuses
Altogether, 98 human fetuses were evaluated; thedata from 18 fetuses were excluded because of poor
recording due to fetal movements. The PWV andpulse pressure measurements from the remaining
80 fetuses are summarized in Figure 3. Among thenormal fetuses, gestational age was signiﬁcantly
related to blood ﬂow velocity (0.032 × GA + 0.097;
r = 0.74, P < 0.01), PWV (0.115 × GA–0.421; r = 0.7,
P < 0.01) and estimated pulse pressure (0.814 × GA–
11.371; r = 0.74, P < 0.01).

Effects of antenatal corticosteroids exposure
Twenty-one fetuses exposed to antenatal corticosteroids were available for analysis, and the fetal pulsepressures were evaluated on days 0, 2 and 8. One-

Figure 2 We compared the generated pulse pressure and estimated pulse pressures by each algorithm: (a) water hammer
equation, (b) Moens-Korteweg equation, (c) Bramwell-Hill equation. The pulse generator changed the pulse pressure
into six phases. The solid line is the regression line and the dashed diagonal line represents y = x. Regression line equations: water hammer equation: y = 1.724 × G-40.978 (r2 = 0.99, P < 0.01); Moens-Korteweg equation: y = 3.315 × G134.07 (r2 = 0.79, P = 0.054); Bramwell-Hill equation: y = 3.161 × G-124.26 (r2 = 0.80, P < 0.01), where y is the estimatedpulse pressure and G is the generated pulse pressure.

4© 2020 Japan Society of Obstetrics and Gynecology

Ultrasonic fetal pulse pressure measurement

Figure 3 (a) Pulse wave velocity and (b) estimated pulse pressure in relation to gestational weeks in normal fetuses. The
solid line represents the regression line, and the dotted lines indicate the 95% conﬁdence interval. Regression line equations: pulse wave velocity = 0.115 × GA-0.421 (r = 0.70, P < 0.01); estimated pulse pressure = 0.814 × GA-11.371(r = 0.74, P < 0.01), where GA is the gestational age (weeks).

way analysis of variance revealed a signiﬁcant timeeffect on the estimated fetal pulse pressures in
Figure 4 (P< 0.01). Although the fetal pulse pressuresincreased on day 2 (day 0, 15.02 ± 3.82 mmHg; day2, 18.75 ± 5.15 mmHg; P < 0.01), they subsequently
returned to baseline levels by day 8 (day0, 15.02 ± 3.82 mmHg; day 8, 12.90 ± 4.71mmHg; P = 0.57).

Figure 4 Pulse pressure evaluation in 21 fetuses who
received antenatal corticosteroid. Measurement was
performed before (day 0), 2 days after (day 2) and8 days after (day 8) drug administration. *P < 0.01,**P = 0.04, ***P = 0.57. The kite diagrams show themean (mid-lines) and 95% conﬁdence interval fordays 0, 2 and 8. The overall mean is the line acrossthe middle of the ﬁgure.

© 2020 Japan Society of Obstetrics and Gynecology

Discussion
In this study, we evaluated the precision and feasibility of a method for estimating the fetal pulse pressurein the descending aorta using PWV and the ultrasonicphased-tracking method as well as blood ﬂow velocity using the conventional pulse Doppler technique.
The precision and accuracy of the method were veriﬁed using a circulation simulation model. An agerelated increase in the pulse pressure in humanfetuses was found, and exposure to exogenous corticosteroids was determined to have short-term effects
on fetal pulse pressure. Our noninvasive approach isa feasible and clinically useful method for evaluating
fetal hemodynamics.
Noninvasive assessment of fetal hemodynamic
parameters, such as arterial pulse pressure from PWV
at the descending aorta, have attracted attention;
however, no studies have conﬁrmed the accuracy ofthe estimated values.5,6,10 Therefore, we designed asimulator of blood ﬂow and estimated pulse pressureusing each equation. The measured ﬁgures using thewater hammer equation exhibited a strong correlation
with the generated pulse pressures. Struijk et al.5 havereported that fetal pulse pressure can be derived
from measurements of PWV and vessel diameterchanges in the fetal descending aorta using the
Bramwell-Hill equation. They also estimated the distensibility and compliance of the fetal aortic wall,
which became the basis of the ﬁrst noninvasive estimation of arterial pulse pressure in human fetuses
5J. Muromoto et al.

using an echo-tracking system for detecting changes
in vessel diameter.11 However, their calculated fetal
pulse pressures were widely distributed and poorly
correlated with gestational age, which might berelated to the limited accuracy of conventional ultrasonography systems and algorithm. In contrast, we
employed ultrasonic phased-tracking method, whichallowed us to assess the arterial wall’s motion at the
micrometer level.12,13 The phased-tracking method
uses small differences in raw radiofrequency signals
to monitor these changes and provides greater precision (than that of conventional ultrasonography systems) by simultaneously recording radiofrequency
signals from different beam directions, which provides a more precise evaluation of fetal PWV.
We used the water hammer equation for the present study and created a basic simulation, which revealed that our estimated pulse pressures were tightly
correlated with the generated pressures in the phantom. The water hammer equation, which was derived
from Newton’s law of motion (as were the MoensKorteweg and Bramwell-Hill equations), relates thetime increment in blood ﬂow velocity to the timeincrement in pulse pressure.14 However, the water
hammer equation requires the blood ﬂow velocity(including PWV) measurement, while the MoensKorteweg and Bramwell-Hill equations rely on diameter measurements. Basic experimental studies haverevealed that the elastic behavior of the arterial wall
exhibits nonlinear pressure dependency, which might
introduce error in the diameter-dependent estimatesfrom the Moens-Korteweg and Bramwell-Hillequa.15,16 We previously reported on fetal pulse pressure estimations based on the Moens-Korteweg equation using ultrasonic phased-tracking method, but themeasured fetal pulse pressure (51.0 ± 6.8 mmHg) wasmuch higher than that expected in growth-restrictedfetuses and the calculated fetal pulse pressures poorly
correlated with gestational age.6 In addition, there
was a discrepancy between each non-invasive fetal
pulse pressure assessment and invasive study forhuman fetuses.5–7,10 Only the results of this study correlated with gestational age and were consistent withthe expected values from invasive study.7
Blood pressure and related factors were well studied in human adults.17 Arterial pressure is determinedby the volume ejected by the heart into the arteries,
arterial wall elasticity and systemic vascular resistance. If the arterial wall’s elastic properties remainunchanged, pulse pressure would exhibit a good correlation with systolic and mean blood pressures and6

stroke volume.18 In this regard, fetal pulse pressure isa function of the systolic and mean blood pressure
and is dependent on stroke volume and placental vascular resistance. Although fetal blood pressure could
not be directly measured, pulse pressure could be avery important clinical indicator of systolic and mean
blood pressure, stroke volume and placental vascular
resistance during fetal development.
Fetal pulse pressure measurement has the potential
to contribute to fetal care, such as decreasing the incidence of neurological damage among infants. The
brain has a high metabolic demand, and therefore,high cerebral blood ﬂow is required. Experimental
and clinical data suggest that hypoxemia alone does
not induce brain damage and that corresponding
cerebral ischemia is necessary for brain tissue injury.1
The cerebral vasculature responds to ischemia
through a hemodynamic protective process known as
cerebral autoregulation, which involves adaptation ofvascular resistance. The fetal cerebro-placental Doppler ratio and the middle cerebral artery Doppler,which reﬂect cerebral autoregulation, could predict
adverse outcome.19 However, routinely evaluating
cerebro-placental Doppler ratio and/or middle cerebral artery Doppler in low-risk population would leadto substantial number of false negatives; furthermore,
cerebral autoregulation may be impaired in patientswith intracranial hemorrhage and ischemic stroke,especially those with very low birthweights.19,20 Studies on premature neonates that focused on blood pressure suggested that systemic hypotension is anindependent risk factor for intraventricular hemorrhage, developmental delay and mortality.21-23 Therefore, not only cerebro-placental Doppler ratio andmiddle cerebral artery Doppler assessment but also
fetal pulse pressure monitoring would potentiallyenable the detection of pathological hemodynamics
leading to harmful events.
A study on isolated animal myocardium has revealed that fetal myocardium has less active tension
than adult myocardium, resulting in lower maximal
contractile force.24 A recent study on human
myocytes suggests that myoﬁbril force production
increases signiﬁcantly as gestation progresses becauseof the maturation of the sarcomeres and the changes
in contractile ﬁlament protein isoforms.25 An invasive
study determined that left and right ventricular pressures increase markedly as gestational progresses,7
and a noninvasive echocardiographic study used thestroke volume of both ventricles, and the combined
cardiac output, expressed as the sum of the left and© 2020 Japan Society of Obstetrics and Gynecology

Ultrasonic fetal pulse pressure measurement

right ventricular cardiac outputs, increases in a linear
fashion with advancing gestation in humanfetuses.7,26 These structural and functional development in the fetal myocardium may explain theincreases in blood pressure and stroke volume as
relating to the positive correlation of PWV and fetal
pulse pressure with gestational age in this study.
To our acknowledge, this study is the ﬁrst reportthat demonstrates a change in human fetal pulse pressure with antenatal steroid exposure. Antenatal steroid exposure increased the pulse pressure in animal
fetuses and human adults. The vasopressor effects ofcorticosteroids have been observed in a pregnant
sheep model, and several studies have identiﬁed similar vasopressor effects after short- and long-term corticosteroid use in adult humans.27-30 Those studies
found that corticosteroids increased cardiac output,
renal vascular resistance, glomerular ﬁltration rate,plasma volume, atrial natriuretic peptide concentrations and urinary kallikrein excretion as the cause ofelevated blood pressure. Therefore, human fetal pulsepressure would be raised with antenatal steroid exposure just as in animal fetuses and human adults. The
present study showed that fetal pulse pressure
increased signiﬁcantly on day 2 in response to maternal corticosteroid administration and that it returned
to near control levels on day 8. We might think that
our method is feasible for clinical practice and could
potentially be used to obtain pulse pressure change inhuman fetuses.
This study had several limitations. First, measurement of blood density is quite difﬁcult in fetuses. To
date, no study has reported the gestational agespeciﬁc reference range for blood density. Second, themeasurement of blood ﬂow velocity was based on theHagen-Poiseuille law. Theoretically, pulse pressure
measurement requires accurate stroke volume and/or
mean blood velocity in addition to PWV. The HagenPoiseuille law proves that the mean blood velocity ishalf of the maximum laminar ﬂow velocity in steadystate. However, it can be affected by blood viscosityand friction between the blood and the vessel walls.
Third, the phased-tracking method cannot measure
fetal PWV with any fetal or maternal movement. The
phased-tracking method assesses the motion at the
micrometer level, with even small movements leading tomeasurement error or misinterpretation. Hence, in the
future, more accurate blood density and velocity measurement will improve blood pressure assessment in fetus.
In conclusion, we created an estimation model ofpulse pressure using the water hammer formula,© 2020 Japan Society of Obstetrics and Gynecology

which consists of PWV and blood ﬂow velocity that
could precisely calculate the fetal pulse pressure. It
could be used to monitor the normal development offetal pulse pressure and determine the ﬂuctuations in
response to maternal corticosteroid administration.
This noninvasive assessment of fetal pulse pressure
would be a surrogate marker for fetal blood pressure
and could be useful for the hemodynamic evaluationof compromised fetuses.

Acknowledgments
This research did not receive any speciﬁc grant fromfunding agencies in the public, commercial or not-forproﬁt sectors.

Disclosure
None declared.

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© 2020 Japan Society of Obstetrics and Gynecology