Download Fetal Imaging - Circulation: Cardiovascular Imaging

Fetal Imaging
Reference Ranges of Blood Flow in the Major Vessels
of the Normal Human Fetal Circulation at Term by
Phase-Contrast Magnetic Resonance Imaging
Milan Prsa, MD; Liqun Sun, MD; Joshua van Amerom, BASc; Shi-Joon Yoo, MD;
Lars Grosse-Wortmann, MD; Edgar Jaeggi, MD; Christopher Macgowan, PhD; Mike Seed, MD
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Background—Phase-contrast MRI with metric-optimized gating is a promising new technique for studying the distribution
of the fetal circulation. However, mean and reference ranges for blood flow measurements made in the major fetal vessels
using this technique are yet to be established.
Methods and Results—We measured flow in the major vessels of the fetal circulation in 40 late-gestation normal human
fetuses using phase-contrast MRI (mean gestational age, 37 [SD=1.1] weeks). Flows were indexed to the fetal weight,
which was estimated from the fetal volume calculated by MRI segmentation. The following mean flows (in mL/min per
kilogram; ±2SD) were obtained: combined ventricular output, 465 (351, 579); main pulmonary artery, 261 (169, 353);
ascending aorta, 191 (121, 261); superior vena cava, 137 (77, 197); ductus arteriosus, 187 (109, 265); descending aorta,
252 (160, 344); pulmonary blood flow, 77 (0, 160); umbilical vein, 134 (62, 206); and foramen ovale, 135 (37, 233).
Expressed as percentages of the combined ventricular output, the mean flows±2 SD were as follows: main pulmonary
artery, 56 (44, 68); ascending aorta, 41 (29, 53); superior vena cava, 29 (15, 43); ductus arteriosus, 41 (25, 57); descending
aorta, 55 (35, 75); pulmonary blood flow, 16 (0, 34); umbilical vein, 29 (11, 47); and foramen ovale, 29 (7, 51). A strong
inverse relationship between foramen ovale shunt and pulmonary blood flow was noted (r=−0.64; P<0.0001).
Conclusions—Although too small a sample size to provide normal ranges, these results are in keeping with those predicted
in humans based on measurements made in fetal lambs using radioactive microspheres and provide preliminary reference
ranges for the late-gestation human fetuses. The wide range we found in foramen ovale shunting suggests a degree of
variability in the way blood is streamed through the fetal circulation. (Circ Cardiovasc Imaging. 2014;7:663-670.)
Key Words: magnetic resonance imaging ◼ pediatrics ◼ regional blood flow
P
hase-contrast cine MRI (PC-MRI) is the current gold
standard for the noninvasive measurement of vessel blood
flow and is widely used in the hemodynamic assessment of
children with congenital heart disease.1 However, the application of PC-MRI to the measurement of human fetal blood flow
has only recently become possible with the development of
alternatives to conventional ECG gating. Potential approaches
to achieving triggered fetal cardiac imaging include self-gating and cardiotocographic gating, which have both recently
been shown to be feasible in fetal lambs, with the latter used
to make PC-MRI measurements.2–4 Metric-optimized gating
(MOG) is a retrospective technique that acquires temporally
oversampled data and then iteratively sorts the data using
hypothetical ECG trigger times until artifact in the associated images is minimized.5,6 PC-MRI with MOG has been
shown to be feasible in the late-gestation human fetus and
validated using an in vivo simulation of fetal vessels.7 It has
been used successfully to make preliminary observations of
redistribution of the fetal circulation in human fetuses with
left-sided congenital heart disease, transposition, and lateonset intrauterine growth restriction.8–10
Clinical Perspective on p 670
However, to identify changes in regional blood flow in conditions such as congenital heart disease and placental insufficiency, it is essential first to define reference physiological
ranges of fetoplacental flow using this technique. This report
details PC-MRI measurements made in each of the major fetal
blood vessels in 40 late-gestation human fetuses and provides
preliminary means and reference ranges of the distribution of
the normal fetal circulation at term.
Methods
A single-center prospective cross-sectional study was conducted to
establish normative ranges of blood flows in the late-gestation human
fetus using PC-MRI with MOG.
Received October 16, 2013; accepted May 23, 2014.
From the Division of Pediatric Cardiology, Department of Pediatrics (M.P., L.S., L.G.-W., E.J., M.S.), Department of Diagnostic Imaging (J.v.A., S.-J.Y.,
M.S.), and Department of Physiology and Experimental Medicine (C.M.), University of Toronto and Hospital for Sick Children, Toronto, Canada.
The Data Supplement is available at http://circimaging.ahajournals.org/lookup/suppl/doi:10.1161/CIRCIMAGING.113.001859/-/DC1.
Correspondence to Mike Seed, MD, Division of Pediatric Cardiology, Department of Pediatrics, Hospital for Sick Children, 555 University Ave, Toronto,
Ontario M5G 1X8, Canada. E-mail [email protected]
© 2014 American Heart Association, Inc.
Circ Cardiovasc Imaging is available at http://circimaging.ahajournals.org
663
DOI: 10.1161/CIRCIMAGING.113.001859
664 Circ Cardiovasc Imaging July 2014
Study Participants
The study was performed with the approval of the institutional review board, and subjects gave informed consent. Pregnant women
with a family history of congenital heart disease were screened with a
detailed echocardiogram at around 20 weeks’ gestation according to
guidelines published by the American Society of Echocardiography.11
Subjects with normal studies were invited to attend for a second echocardiogram and MRI at term. Pregnancies complicated by maternal
chronic illnesses, including diabetes mellitus, hypertension, and maternal autoantibody disease, as well as fetuses with any complication such as intrauterine growth restriction, multiple gestations, and
known or expected aneuploidy, were excluded.
Imaging Protocol
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Fetal MRI was performed according to a previously published
technique using a 1.5T MRI system (Avanto; Siemens, Erlangen,
Germany).3 Briefly, the fetal weight was calculated using segmentation of a 3-dimensional steady-state free precession acquisition of
the whole fetus to measure the fetal volume (Mimics; Materialise
Group, Leuven, Belgium). The weight was derived from the volume
using the previously published conversion: fetal weight (g)=fetal
volume (mL)×1.03+120.12 After localization of the fetus, steadystate free precession surveys were performed in 3 orthogonal planes
to the fetal thorax. These were used to prescribe the PC-MRI acquisitions, which were aligned perpendicular to the long axis of
the main pulmonary artery (MPA), ascending aorta (AAo), superior vena cava (SVC), ductus arteriosus (DA), descending aorta
(DAo), umbilical vein (UV), right pulmonary artery (RPA), and
left pulmonary artery (LPA) based on 2 orthogonal views. The UV
was targeted in its mid-intrahepatic section, distal to the umbilical insertion to avoid complex flow behavior but proximal to any
portal vein branches. The image parameters used for PC-MRI acquisitions were as follows: slice thickness, 5 mm; field of view, 240
mm; phase field of view, 100%+33% phase oversampling; matrix
size, 192×192; voxel size, 1.25×1.25×5 mm; echo time, 2.92 ms;
repetition time, 6.55 ms; flip angle, 20°; 1 average and 4 views per
segment. This results in a temporal resolution of ≈50 ms giving
≈10 true cardiac phases, which were interpolated to 15 calculated
phases. A velocity sensitivity of 150 cm/s was used for AAo, MPA,
DAo, DA; 100 cm/s for SVC, RPA, and LPA; and 50 cm/s for UV.
A typical scan time for each vessel was 34 seconds, with a total
scan time of ≈30 minutes. Using software created in our laboratory (MATLAB; MathWorks), the correct R–R intervals for each
acquisition were determined retrospectively by MOG using raw
data acquired at an R–R interval of 545 ms to ensure fetal heart
rates down to 110 beats per minute were adequately oversampled
for correct reconstruction. The details of MOG are given in previous publications.5,7 The reconstructed images were postprocessed
on a commercial software package for flow quantification (Q-flow
5.2; Medis Medical Imaging Systems, Leiden, the Netherlands).
The total postprocessing time for each study including fetal weight
estimation was ≈90 minutes.
The morphology of the fetal hearts was assessed at the initial echocardiogram using a segmental sequential analysis of the anatomy.13 At
follow-up echocardiography, we measured the mitral, tricuspid, aortic, and pulmonary valve dimensions and the end-diastolic diameters
of the right ventricles (RVs) and left ventricles (LVs) according to
previously published techniques.14 Z scores were calculated for each
of these structures. The morphology of the interatrial septum was assessed and size of the foramen ovale (FO) measured. Each subject
underwent Doppler assessment of the umbilical artery, UV, middle
cerebral artery, and ductus venosus. As newborns, the study subjects
were examined by a pediatrician, who checked the oxygen saturations
using a pulse oximeter.
In a subset of subjects, we attempted to assess the reproducibility of the MRI measurements by repeating them in each vessel.
We also compared the MRI flows with ultrasound measurements
made in the AAo and MPA. Ultrasound flows were measured using
pulsed Doppler tracings from a sample volume at the fetal aortic
and pulmonary valves. The mean velocity time integral of these
traces was multiplied by the fetal heart rate and vessel area (calculated from vessel diameter measured by 2-dimensional ultrasound)
to calculate flow.15,16 The MRI flows were also assessed for internal
validation by comparing pulmonary blood flow (PBF) measured
directly (sum of RPA and LPA flows) and indirectly (difference
between MPA and DA flow. Interobserver variation was assessed
for the MRI flow measurements, with the second reader blinded to
the first reader’s results.
Statistical Analysis
The collected flows for each vessel were confirmed to be normally
distributed using the Kolmogorov–Smirnov test, and means, SDs,
and references ranges were calculated using 2 SDs either side of
the mean for the reference range. Pearson correlation was used to
investigate the relationships between the different measurements of
flow, and Bland Altman plots were used to assess bias in comparisons
of flows measured by different techniques or observers. Significant
relationships between all measured parameters were sought using
multiple regression analysis. Statistical analysis was performed using MATLAB and Graphpad Prism. P values <0.05 were considered
statistically significant.
The combined ventricular output (CVO) was calculated as the
sum of the MPA and AAo flows plus 3% to allow for coronary
blood flow, based on previous fetal lamb data.17 PBF was calculated as the sum of the RPA and LPA flows. The FO shunt could
not be directly measured using PC-MRI. However, because PBF
and FO shunt are the 2 exclusive sources of LV filling, FO flow
can be calculated as the difference between the LV output, which
comprises the AAo plus coronary blood flow and PBF. Although
the calculated mean percentages of the distribution of the CVO required minimal adjustment to conform to a principle of conservation
of flow across the fetal circulation, a model was extrapolated from
measured flows using constrained nonlinear optimization, where
the active set algorithm attempts to find a constrained minimum of
the scalar function MPA+AAo−SVC−PBF−DAo, starting at an initial estimate based on measured values, subject to MPA−PBF≥0,
MPA+AAo−SVC−PBF−DAo=0, and MPA+AAo=97.18–20 Once
MPA, AAo, SVC, PBF, and DAo are established, the remaining flows
are calculated as DA=DAo+SVC−AAo=AAo−SVC+DA−DAo and
FO=AAo+CA−PBF.
Results
Fifty subjects with normal second-trimester fetal echocardiograms who met the inclusion criteria were enrolled between
2012 and 2014. Ten fetuses were excluded from the analysis: 3 for fetal weights below the tenth percentile by MRI, 3
because of incomplete MRI data sets resulting from vigorous
fetal motion, 1 for an abnormally high middle cerebral artery
peak velocity, and 1 for an abnormally low middle cerebral
artery pulsatility index by Doppler. Two further subjects were
excluded based on follow-up echocardiography: 1 for an apical ventricular septal defect and 1 because no Dopplers were
recorded. Complete echocardiograms and a complete set of
MRI flow measurements were obtained in all of the remaining 40 subjects. All 40 of these fetuses were subsequently
born at term with normal birth weights, and there were no
significant perinatal complications or postnatal medical problems identified. MRI was performed at a mean gestational
age of 37 (SD=1.1) weeks with a mean fetal weight of 3.0
(SD=0.5) kg.
The first 5 fetuses had repeat PC-MRI measurements
made in each of the vessels. The comparison reveals good
reproducibility with no significant bias (r=0.96; P<0.0001;
bias=−10.8; SD of bias=71.3 mL/min) as shown in Figure 1.
Measurements made in the last 10 fetuses were examined
Prsa et al Normal Fetal Flows by PC-MRI 665
Measurement 1 - Measurement 2
Measurement 2
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for interobserver correlation and showed good agreement
with no significant bias (r=0.97; P=0.0001; bias=−21.2;
SD of bias=48.3 mL/min; Figure 2). In this same group of
10 fetuses, the MRI measurements correlated reasonably
well with ultrasound measurements of flow in the MPA and
AAo (r=0.77; P=0.0001), with a small bias of 26 mL/min
for higher flows by ultrasound (SD of bias=98.6 mL/min;
Figure 3). The assessment of internal validation between
MRI flow measurements through comparison of direct and
indirect measurements of PBF for the whole study group
also revealed reasonable agreement with no significant bias
(r=0.43; P=0.004; bias=10.5; SD of bias=56.0 mL/min per
kilogram) as shown in Figure 4.
The results of the flow measurements are shown in Table 1
and Figures 5 and 6, with a full table of individual flows
and cardiac morphology included in the Data Supplement.
The mitral, tricuspid, aortic, and pulmonary valves and
RV and LV diameters were all with 2 SDs of the mean. A
significant inverse correlation was found between FO flow
and PBF (r=−0.64; P<0.0001) as shown in Figure 7. We
found a moderate correlation between the ratio of MPA to
AAo flow by MRI and the ratio of RV to LV end-diastolic
diameter (r=0.54; P=0.0003; Figure 8), with a weaker correlation between MPA to AAo flow and tricuspid valve to
mitral valve ratio (r=0.31; P=0.05). There was no relationship between the ratio of the pulmonary and aortic valves
diameters to MPA/AAo flow, and there was no correlation
between FO size and magnitude of FO shunt. There was no
correlation between the fetal weight and any of the vessel
flows or cardiac output by MRI. We could not demonstrate
a significant relationship between the flow in any vessel by
MRI and the pulsitility index in the middle cerebral artery
or umbilical artery by Doppler, although there were trends
toward inverse correlations between umbilical artery pulsatility index and PBF (r=−0.24; P=0.38) and UV flow
(r=−0.20; P=0.47). We found no other significant correlation between measured parameters.
Discussion
Accuracy of PC-MRI and Comparison With
Previous Measurements
PC-MRI flow measurements made in adult blood vessels are
more accurate than flow measurements made using ultrasound, with PC-MRI flows in the AAo and MPA agreeing to
<3% in normal volunteers.21 Flow turbulence and small vessel
size affect the fidelity of the technique, although turbulence
was not a particular concern in our study, and even the smallest vessels we interrogated had >8 voxels across the vessel
area, which has been shown to be the lower limit of spatial
resolution for accurate flow measurement.22 We previously
attempted to establish the accuracy of PC-MRI for fetal MRI
using an in vivo fetal vessel simulation and demonstrated good
agreement between conventionally gated and MOG measurements.7 The reproducibility, internal validation, and comparison with ultrasound obtained in the current study suggest the
technique is at least reasonably reliable. However, inspection
of the individual flows reveals some discrepancies between our
results and the expected distribution of flow. These include 3
fetuses with higher LV outputs than that of RV despite having
larger RV than LV by echocardiography; a fetus with higher
SVC flow than AAo flow, which would imply the presence of
retrograde flow across the aortic isthmus; and some variation
in the proportion of DAo flow reaching the UV. These findings raise concerns about the accuracy of the technique and,
therefore, its utility for clinical decision making. However, the
dramatic redistribution of flow we have demonstrated in some
fetuses with congenital heart disease and placental insufficiency is unlikely to be attributable to errors in phase-contrast
measurement.8–10 Furthermore, our study suggests that when
PC-MRI measurements are collected from several fetuses, the
averaged results are similar to experimental animal data. The
most comprehensive studies of the distribution of the fetal
circulation were performed in fetal lambs using a radioactive
microsphere technique.23 Based on their lamb measurements,
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Figure 1. Reproducibility in repeated flow
measurements in 5 fetuses showing good
agreement between the consecutive
measurements with no significant bias
(bias=−10.8 mL/min; SD of bias=71.3;
95% limits of agreement from −150.5
to 128.9). Analysis did not account for
multiple paired observations within each
fetus, leading to possible incorrect estimates of correlations, standard errors, P
values, etc.
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Figure 2. Interobserver variation between
flow measurements in 10 fetuses showing
good agreement between observers with
no significant bias (bias=−21.2 mL/min;
SD of bias=48.1; 95% limits of agreement
from −115.5 to 73.2 mL/min). Analysis did
not account for multiple paired observations within each fetus, leading to possible incorrect estimates of correlations,
standard errors, P values, etc.
666 Circ Cardiovasc Imaging July 2014
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PBF MPA-DA (ml/min/kg)
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these investigators made estimations of the absolute and relative proportions of the CVO directed to the various parts of
the human fetal circulation.17 A comparison of these estimations with the mean flows we obtained by MRI is shown in
Table 2. There is generally good agreement between these
2 sets of results. The most striking difference between their
estimates and our findings is the mean UV flow, estimated at
180 mL/min per kilogram by Rudolph24 and measured at 129
mL/min per kilogram by MRI. However, in the more recent
edition of Rudolph’s24 textbook, the estimate of UV flow has
been modified to be more in line with human ultrasound data
to 115 mL/min per kilogram. Our own measurements of UV
flow are most in keeping with the ultrasound measurements of
Van Lierde et al,25 with a mean UV flow of 117 and 140 mL/
min per kilogram (one third of CVO) found by Sutton et al.26
Other modifications in the human estimates reported in the
more recent edition of Rudolph’s24 textbook result in significant differences compared with the MRI results, including
lower DA, FO, and DAo flows and higher PBF. The modifications are reportedly an attempt to accommodate subsequent human ultrasound results. However, as acknowledged
by Rudolph,24 ultrasound measurements of flow are prone to
potential inaccuracies arising from problems with vessel diameter measurement, flow alignment, and inability to account for
the different velocities across the lumen of the vessel.15 In our
study, the ultrasound flow measurements were consistently
slightly higher than the MRI measurements, which may be
because of the fact that our ultrasound technique assumed a
constant flow velocity across the vessel lumen, where in reality flow was likely slower around the vessel periphery than
in the middle of the vessel where it was sampled. In addition
to intrinsic inaccuracies in our ultrasound and MRI measurements, we are also aware of the possibility that although the
2 techniques were performed on the same day, changes in the
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Average MR & US Flow measurement
physiological state of the fetus during and between the MRI
and ultrasound could have affected their agreement.
Differences in sampling techniques may explain the wide
variation in results obtained in different human ultrasound
studies. For example, Rasanen27 found an RV/LV output ratio
of 1.5 in late-gestation fetuses, compared with a ratio of 1.08 at
term in De Smedt’s study.28 Our results indicate a ratio of 1.27,
in keeping with the 1.28 found by Kenny.16 Estimates of mean
CVO range from 425 to 553 mL/min per kilogram, although
most estimates are ≈450 mL/min per kilogram, which is in
keeping with the MRI result of 465 mL/min per kilogram.29
The good correlation we found between the ratio of MPA by
AAo flow by MRI with echocardiographic measurements of
the ratio of the RV and LV end-diastolic dimensions was a
reassuring demonstration of congruent physiological and
morphological parameters of the relative dominance of each
ventricle with respect to the CVO by 2 different imaging
modalities.
Previous ultrasound measurements of mean fetal PBF range
from 47 mL/min per kilogram or 11% of CVO in Mielke’s30
large cohort to 25% of CVO in third-trimester fetuses in
Rasanen’s27 study. One reason for the wide range of PBF
found by different authors might be the different measurement
techniques used, because in the majority of studies, the PBF
is calculated by subtraction of the DA flow from the MPA.
Rasanen27 used direct ultrasound measurements of PBF and
found that PBF increased from 13% at 20 weeks to ≈25% of
CVO at 30 weeks and then dropped again to ≈20% of CVO by
38 weeks. Rasanen’s27 results indicate that the increase in PBF
seen in the third trimester was associated with a reduction in
FO shunt but no change in AAo flow. This inverse relationship between PBF and FO shunt was also seen in our study,
although in our case the variation in PBF and FO flow was seen
in fetuses of the same gestational age. In Rasanen’s27 study,
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LPA+RPA & PBF MPA-DA measurement
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Figure 3. Validation of MRI flow measurements against ultrasound flow measurements made in the ascending aorta
and main pulmonary artery of the last
10 fetuses scanned showing reasonable
correlation between flow measurements
with a small bias for higher flows by
ultrasound (bias=25 mL/min; SD of bias:
98.6 ml/min; 95% limits of agreement
from −167.4 to 219.2 mL/min). Analysis did not account for multiple paired
observations within each fetus, leading to
possible incorrect estimates of correlations, standard errors, P values, etc.
Figure 4. Internal validation of flow measurements for all 40 fetuses comparing
pulmonary blood flow measured directly
as the sum of right and left pulmonary
arterial flows versus an indirect measurement: the difference between main
pulmonary artery and ductus arteriosus
flows showing reasonable agreement
between the 2 measures with no significant bias (bias=10 mL/min per kg; SD of
bias=57.3; 95% limits of agreement from
−102.4 to 122.4 mL/min per kg).
Prsa et al Normal Fetal Flows by PC-MRI 667
Table 1. Means, SDs, and Reference Ranges (mean±2SD) of Flows in 40 Normal Late-Gestation Human Fetuses
Measured by Phase-Contrast MRI (mL/min per kilogram) and as Percentages and as Modeled Mean Percentages
of the Combined Ventricular Output
CVO
Mean flow, mL/min per kg
AAo
SVC
DA
PBF
DAo
UV
465
261
191
137
187
74
252
134
57
46
35
30
39
43
46
36
SD
Mean±2 SD
MPA
351, 579
169, 353
Mean flow, % CVO
77, 197
109, 265
0, 160
160, 344
62, 206
135
49
37, 233
56
41
29
40
16
55
29
6
6
7
8
9
10
9
11
44, 68
29, 53
15, 43
25, 57
35, 75
11, 47
7, 51
56
41
SD
Mean±2 SD
121, 261
FO
Modeled mean flow, % CVO
28
41
0, 34
15
54
29
29
29
AAo indicates ascending aorta; CVO, combined ventricular output; DA, ductus arteriosus; DAo, descending aorta; FO, foramen ovale; MPA,
main pulmonary artery; PBF, pulmonary blood flow; SVC, superior vena cava; and UV, umbilical vein. FO flow was calculated as the difference
between the left ventricular output and PBF.
study, the lowest FO shunt was just 29 mL/min per kilogram
or 5% of the CVO, with a 10-fold increase to the largest FO
shunt of 283 mL/min per kilogram or 54% of the CVO. We
found a strong inverse correlation between FO shunt and PBF.
The physiological mechanism behind this finding is not yet
clear. Our results would not support anatomic restriction at
the FO as a likely cause, although accurate measurements of
the FO orifice are difficult to obtain.32 One potential explanation is normal variation in fetal pulmonary vascular resistance.
Evidence for this is provided by the wide range of pulmonary arterial wall thickness in Naeye’s33 histological studies of
perinatal subjects and ultrasound studies showing variation in
shunting at the DA in newborns at birth.34 Variation in PVR,
and therefore PBF, could be the driver behind the inverse
variation we found in FO flow. Konduri et al35 showed that
an increase in pulmonary arterial PaO2 of 7 mm Hg resulted
in a 3-fold increase in PBF and increase in left atrial pressure
from 4 to 8 mm Hg. It seems feasible, therefore, that PVR is
an important determinant of the relative contributions to LV
filling from the pulmonary circulation and FO shunt. The
inverse relationship between fetal PVR and the oxygen content of the blood in the pulmonary arteries was initially shown
by Rudolph17 using flow probes around the pulmonary arteries
of fetal lambs during variation of the concentration of inspired
oxygen of the ewes. Rasanen36 has since demonstrated human
fetal pulmonary vasodilation in response to maternal hyperoxygenation using Doppler. Normal variation in the pulmonary
arterial oxygen content in the human fetus is perhaps to be
expected when the normal variation in umbilical venous blood
oxygen content is taken into account. Blood gas analysis of
Variation in PBF and FO Shunting
As in Rasanen’s27 study, there was no correlation between PBF
and AAo flow measured by MRI, with AAo remaining fairly
constant between patients. Because PBF and FO shunt are the
2 sources of LV filling, a wide range of FO shunt and inverse
relationship with PBF should, therefore, be anticipated. In our
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there was ≈2- to 3-fold range in PBF at 37 weeks, whereas
in our own study, the range of PBF was higher with at least
a 10-fold difference between the subject with the lowest PBF
of 13 mL/min per kilogram or 2% of CVO and the highest
PBF of 187 mL/min per kilogram or 30% of CVO. The reason
for this discrepancy is not clear. Rasanen27 reports a higher
level of agreement between direct and indirect measurements
of PBF using ultrasound than we obtained using MRI, raising the possibility that inaccuracy of the MRI measurements
could have resulted in the discrepancy. The pulmonary arteries
are certainly the smallest vessels we measured by MRI and are
at the lower limit of size for established criteria for PC-MRI
accuracy.22 However, it is also possible that the sample size had
an influence, because although Rasanen’s27 study included 63
patients, these were evenly distributed across a gestational age
range of 18 to 40 weeks, whereas our own 40 subjects were
concentrated around the same gestational age of 37 weeks.
The wider range of PBF found by our study might, therefore,
be expected based on the larger number of patients studied
at this gestation. This conclusion is supported by the similar
range in right and left cardiac outputs and CVO at term found
in our study compared with other ultrasound studies with large
numbers of late-gestation subjects.28,30,31
Figure 5. Plots of individual vessel flows
measured by phase-contrast MRI in 40
late-gestation normal human fetuses
expressed in mL/min per kg (left) and
converted to percentages of the combined
ventricular output (right). The boxes show
median and interquartile ranges, and whiskers show ranges of flows for each vessel.
AAo indicates ascending aorta; CVO, combined ventricular output; DA, ductus arteriosus; DAo, descending aorta; FO, foramen
ovale; MPA, main pulmonary artery; PBF,
pulmonary blood flow; SVC, superior vena
cava; and UV, umbilical vein.
668 Circ Cardiovasc Imaging July 2014
cordocentesis samples has revealed a normal range of oxygen
saturation from 60% to 80% in term fetuses.37 This hypothesis is supported by the fact that although we were not able to
demonstrate any statistically significant relationships between
Doppler parameters of placental function, we did observe
trends suggesting that umbilical artery pulsatility index was
inversely proportional to PBF and UV flow. This result would
be in keeping with the concept that higher placental resistance
might result in a reduction in UV flow and PBF because of
reduced fetal oxygen delivery. However, contrary to this conclusion, we found no relationship between UV flow and PBF.
We were also unable to demonstrate any evidence of a relationship between cerebral vascular resistance and pulmonary
or placental blood flow by Doppler or MRI in the fetuses in
this study. This would suggest that none of the fetuses in the
current group were approaching the brain-sparing physiology
we have seen in fetuses with established intrauterine growth
restriction in which we have demonstrated SVC flows >300
mL/min per kilogram and >50% of the CVO.10 In future, new
techniques for MR oximetry may be helpful for investigating
the relationship between oxygen transport and the distribution
of blood flow in the fetal circulation and provide a technique
to measure fetal oxygen delivery and consumption.38,39 A
combination of PC-MRI and MR oximetry may also provide
useful information regarding the streaming of the umbilical
venous return, which by convention is preferentially directed
through the ductus venosus and left lobe of the liver to form
a high-velocity stream in the leftward posterior aspect of the
IVC, which is directed toward the FO.17 In fetal lambs, this
mechanism maintains a higher oxygen content of the blood in
the left heart than the right, although the wide variation in the
FO shunt seen in our study suggests this mechanism may be
subject to some variation.
Strengths and Limitations
Although this study establishes provisional reference ranges
for MRI flows, the sample size of 40 is too small to establish
normal ranges. However, one strength of our study compared
with previous ultrasound studies is that flow was measured in
each of the large vessels. This allows for characterization of
distribution of the whole fetal circulation, which has been a
conceptually helpful aspect of the fetal lamb research and permits internal validation of the measurements. Our reference
ranges are indexed by fetal weight rather than gestational age.
This allows for comparison with the lamb measurements and
is made possible by the high accuracy of fetal weight measurement by MR segmentation at term.40 Our study differs from
the majority of ultrasound studies, because all of the subjects
300
3.0
200
100
0
r = - 0.64
P < 0.0001
0
100
200
300
PBFLPA+RPA Flow (ml/min/kg)
Figure 7. Scatter plot showing inverse relationship between pulmonary blood flow and foramen ovale shunt in 40 late-gestation
fetuses by phase-contrast MRI.
PC MR MPA / AAo Flow
FOLVO- PBF Flow (ml/min/kg)
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Figure 6. Distribution of the
normal human fetal circulation
measured by phase-contrast
MRI in 40 late-gestation fetuses
expressed as mean flows
(left) and converted to modeled mean percentages of the
combined ventricular output
(right). Coronary blood flow
estimated based on fetal lamb
findings,9 FO flow calculated
as the difference between LV
output and PBF. AAo indicates
ascending aorta; DA, ductus
arteriosus; DAo, descending
aorta; FO, foramen ovale; LA,
left atrium; LV, left ventricle;
MPA, main pulmonary artery;
PBF, pulmonary blood flow; RA,
right atrium; RV, right ventricle;
SVC, superior vena cava; UA,
umbilical artery; and UV, umbilical vein. Courtesy of Luke Itani,
The Hospital for Sick Children,
Toronto, Canada.
2.5
2.0
1.5
1.0
0.5
r = 0.54
p = 0.0003
1.0
1.5
2.0
US RVED / LVED
Figure 8. Comparison between ratio of main pulmonary artery to
ascending aortic flow by MRI with ratio of right ventricular to left
ventricular end-diastolic diameter by echocardiography.
Prsa et al Normal Fetal Flows by PC-MRI 669
Table 2. Comparison of the Distribution of the Fetal Circulation in the Late-Gestation Human Measured by MRI With Estimates for
the Human Based on Fetal Lamb Radioactive Microsphere Measurements17
Mean flows,
Human MRI
mL/min per kg
Lambs
Mean flows,
% of CVO
CVO
MPA
AAo
SVC
DA
PBF
DAo
UV
FO
465
261
191
137
187
74
252
134
135
450
250
185
140
175
75
220
180
125
Human MRI
56
41
28
41
15
54
29
29
Lambs
56
41
31
39
17
49
39
28
AAo indicates ascending aorta; CVO, combined ventricular output; DA, ductus arteriosus; DAo, descending aorta; FO, foramen ovale; MPA, main pulmonary artery;
PBF, pulmonary blood flow; SVC, superior vena cava; and UV, umbilical vein.
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were studied during a short-gestational age window. Although
this might be regarded as a limitation, we would argue that
it results in a more homogeneous study group, focusing on
a period of pregnancy when PC-MRI is less prone to movement artifact but when sonographic windows are more limited. However, we wish to emphasize that our results can only
be applied to the late-gestation human fetus. Furthermore,
our technique is not currently suitable for studying fetuses
at younger gestational ages because of the inherent difficulties encountered with imaging small moving structures using
MRI. The vulnerability of MRI to movement artifact resulting from fetal motion represents a significant drawback of the
technique compared with ultrasound.
Conclusions
This study provides a comprehensive set of measurements of
blood flow in the major vessels of the late-gestation human
fetal circulation. The results are consistent with a previous
estimate of human fetal flows based on detailed measurements made in fetal lambs using radioactive microspheres
and provide a preliminary set of reference data for future MRI
and ultrasound measurements of the fetal circulation. A new
observation was the wide range and inverse relationship of
PBF and FO shunt among fetuses of the same gestational age.
We propose that the mechanism and implications of this finding deserve further investigation.
Acknowledgments
We thank Luke Itani for his illustration for Figure 6.
Sources of Funding
This research was funded by a grant awarded by the Labbatt Family
Innovations Fund.
Disclosures
None.
References
1. Fratz S, Chung T, Greil GF, Samyn MM, Taylor AM, Valsangiacomo
Buechel ER, Yoo SJ, Powell AJ. Guidelines and protocols for cardiovascular magnetic resonance in children and adults with congenital heart
disease: SCMR expert consensus group on congenital heart disease. J
Cardiovasc Magn Reson. 2013;15:51.
2.Yamamura J, Frisch M, Ecker H, Graessner J, Hecher K, Adam G,
Wedegärtner U. Self-gating MR imaging of the fetal heart: comparison
with real cardiac triggering. Eur Radiol. 2011;21:142–149.
3. Yamamura J, Kopp I, Frisch M, Fischer R, Valett K, Hecher K, Adam
G, Wedegärtner U. Cardiac MRI of the fetal heart using a novel triggering method: initial results in an animal model. J Magn Reson Imaging.
2012;35:1071–1076.
4.Schoennagel BP, Remus CC, Yamamura J, Kording F, de Sousa MT,
Hecher K, Fischer R, Ueberle F, Boehme M, Adam G, Kooijman H,
Wedergartner U. Fetal blood flow velocimetry by phase-contrast MRI using a new triggering method and comparison with Doppler ultrasound in a
sheep model: a pilot study. MAGMA. 2014;27:237–244.
5. Jansz MS, Seed M, van Amerom JF, Wong D, Grosse-Wortmann L, Yoo
SJ, Macgowan CK. Metric optimized gating for fetal cardiac MRI. Magn
Reson Med. 2010;64:1304–1314.
6. Roy CW, Seed M, van Amerom JF, Al Nafisi B, Grosse-Wortmann L, Yoo
SJ, Macgowan CK. Dynamic imaging of the fetal heart using metric optimized gating. Magn Reson Med. 2013;70:1598–1607.
7. Seed M, van Amerom JFP, Yoo SJ, Al Nafisi B, Grosse-Wortmann L,
Jaeggi E, Jansz MS, Macgowan CK. Feasibility of quantification of the
distribution of blood flow in the normal human fetal circulation using
CMR: a cross-sectional study. J Cardiovas Magn Reson. 2012;26:14.
8. Al Nafisi B, van Amerom JF, Forsey J, Jaeggi E, Grosse-Wortmann L, Yoo
SJ, Macgowan CK, Seed M. Fetal circulation in left-sided congenital heart
disease measured by cardiovascular magnetic resonance: a case-control
study. J Cardiovasc Magn Reson. 2013;15:65.
9. Porayette P, van Amerom JFP, Yoo SJ, Macgowan CK, Seed M. MRI
shows limited mixing between systemic and pulmonary circulations – a
potential cause of in utero pulmonary vascular disease. Cardiol Young.
In press.
10. Van Amerom JFP, Roy CW, Prsa M, Kingdom, JC, Macgowan CK, Seed
M. Assessment of late-onset fetal growth restriction by phase contrast MR.
Abstract. Proc Intl Soc Mag Reson Med. 2013;21:4129.
11.Lai WW, Geva T, Shirali GS, Frommelt PC, Humes RA, Brook MM,
Pignatelli RH, Rychik J; Task Force of the Pediatric Council of the
American Society of Echocardiography; Pediatric Council of the
American Society of Echocardiography. Guidelines and standards for performance of a pediatric echocardiogram: a report from the Task Force of
the Pediatric Council of the American Society of Echocardiography. J Am
Soc Echocardiogr. 2006;19:1413–1430.
12. Baker PN, Johnson IR, Gowland PA, Hykin J, Harvey PR, Freeman A,
Adams V, Worthington BS, Mansfield P. Fetal weight estimation by echoplanar magnetic resonance imaging. Lancet. 1994;343:644–645.
13. Yoo SJ, Lee YH, Cho KS, Kim DY. Sequential segmental analysis of fetal
congenital heart disease. Cardiol Young. 1999;9:430–444.
14. Schneider C, McCrindle BW, Carvalho JS, Hornberger LK, McCarthy KP,
Daubeney PE. Development of Z-scores for fetal cardiac dimensions from
echocardiography. Ultrasound Obstet Gynecol. 2005;26:599–605.
15. Gill RW. Measurement of blood flow by ultrasound: accuracy and sources
of error. Ultrasound Med Biol. 1985;11:625–641.
16. Kenny JF, Plappert T, Doublilet P, Saltzman DH, Cartier M, Zollars L,
Leatherman GF, St John Sutton MG. Changes in intra-cardiac blood flow
velocities and right and left ventricular stroke volumes with gestational
age in the normal human fetus: a prospective Doppler echocardiographic
study. Circulation. 1986;60:338–342.
17. Rudolph AM. Congenital Diseases of the Heart: Clinical-Physiological
Considerations. 2nd ed. Chichester: Wiley Blackwell; 2001.
18.Han SP. A globally convergent method for nonlinear programming.
J Optimiz Theory App. 1977;22:297–309.
19. Powell MJD. A fast algorithm for nonlinearly constrained optimization
calculations. Lect Notes Math. 1978;630:144–157.
20. Mangasarian OL, Meyer RR, Robinson SM. The convergence of variable
metric methods for nonlinearly constrained optimization calculations. In:
Mangasarian OL, Meyer RR, Robinson SM, eds. Nonlinear Programming
3. London and New York: Academic Press; 1978.
21. Lotz J, Meier C, Leppert A, Galanski M. Cardiovascular flow measurement with phase-contrast MR imaging: basic facts and implementation.
Radiographics. 2002;22:651–671.
670 Circ Cardiovasc Imaging July 2014
Downloaded from http://circimaging.ahajournals.org/ by guest on June 18, 2017
22. Hofman MB, Visser FC, van Rossum AC, Vink QM, Sprenger M, Westerhof N.
In vivo validation of magnetic resonance blood volume flow measurements with
limited spatial resolution in small vessels. Magn Reson Med. 1995;33:778–784.
23.Rudolph AM, Heymann MA. The circulation of the fetus in utero.
Methods for studying distribution of blood flow, cardiac output and organ
blood flow. Circ Res. 1967;21:163–184.
24. Rudolph AM. Congenital Diseases of the Heart: Clinical-Physiological
Considerations. 3rd ed. Chichester: Wiley Blackwell; 2009.
25. Van Lierde M, Oberweis D, Thomas K. Ultrasonic measurement of aortic and
umbilical blood flow in the human fetus. Obstet Gynecol. 1984;63:801–805.
26. Sutton MG, Plappert T, Doubilet P. Relationship between placental blood
flow and combined ventricular output with gestational age in normal human fetus. Cardiovasc Res. 1991;25:603–608.
27. 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.
28. De Smedt MC, Visser GH, Meijboom EJ. Fetal cardiac output estimated by Doppler echocardiography during mid- and late gestation. Am J
Cardiol. 1987;60:338–342.
29. Sutton MS, 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.
30. Mielke G, Benda N. Cardiac output and central distribution of blood flow
in the human fetus. Circulation. 2001;103:1662–1668.
31. Kiserud T, Ebbing C, Kessler J, Rasmussen S. Fetal cardiac output, distribution to the placenta and impact of placental compromise. Ultrasound
Obstet Gynecol. 2006;28:126–136.
32. Phillipos EZ, Robertson MA, Still KD. The echocardiographic assessment
of the human fetal foramen ovale. J Am Soc Echocardiogr. 1994;7(3 Pt
1):257–263.
33.Naeye RL. Arterial changes during the perinatal period. Arch Pathol.
1961;71:121–128.
34. Noori S, Wlodaver A, Gottipati V, McCoy M, Schultz D, Escobedo M.
Transitional changes in cardiac and cerebral hemodynamics in term neonates at birth. J Pediatr. 2012;160:943–948.
35. Konduri GG, Gervasio CT, Theodorou AA. Role of adenosine triphosphate and adenosine in oxygen-induced pulmonary vasodilation in fetal
lambs. Pediatr Res. 1993;33:533–539.
36. 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.
37. Gregg AR, Weiner CP. “Normal” umbilical arterial and venous acid-base
and blood gas values. Clin Obstet Gynecol. 1993;36:24–32.
38. Wedegärtner U, Kooijman H, Yamamura J, Frisch M, Weber C, Buchert
R, Huff A, Hecher K, Adam G. In vivo MRI measurement of fetal blood
oxygen saturation in cardiac ventricles of fetal sheep: a feasibility study.
Magn Reson Med. 2010;64:32–41.
39.Sun L, Al-Rujaib M, van Amerom JFP, Macgowan CK, Seed M.
Comprehensive assessment of late gestation human fetal circulation by
phase contrast MRI and T2 mapping. Abstract. Proc Intl Soc Mag Reson
Med. 2014;22:0857.
40. Zaretsky MV, Reichel TF, McIntire DD, Twickler DM. Comparison of
magnetic resonance imaging to ultrasound in the estimation of birth
weight at term. Am J Obstet Gynecol. 2003;189:1017–1020.
CLINICAL PERSPECTIVE
This paper establishes a preliminary set of reference ranges for blood flow in the major vessels of the normal human fetal
circulation at term by phase-contrast MRI. The results are in keeping with previous estimates based on invasive measurements made in fetal lambs and noninvasive measurements made in humans using ultrasound. The results also reveal that
a wider range of pulmonary blood flow and foramen ovale shunt may be present in normal late-gestation fetuses than was
previously appreciated. These reference ranges should be useful to researchers interested in investigating the use of MRI to
examine the distribution of blood flow in the setting of fetal cardiovascular diseases such as congenital heart disease or placental insufficiency. Although there are currently no established clinical indications for performing fetal cardiovascular MRI,
preliminary experience indicates that the technique may provide new insights into fetal cardiovascular physiology. Furthermore, preliminary work using new MRI techniques for performing oximetry in fetal vessels suggests that a combination of
phase-contrast MRI and MR oximetry may be used to measure such basic parameters of fetal cardiovascular physiology as
fetal oxygen delivery and consumption. We wish to emphasize that the results are only applicable to late-gestation fetuses
and that this technique is currently only feasible close to term.
Reference Ranges of Blood Flow in the Major Vessels of the Normal Human Fetal
Circulation at Term by Phase-Contrast Magnetic Resonance Imaging
Milan Prsa, Liqun Sun, Joshua van Amerom, Shi-Joon Yoo, Lars Grosse-Wortmann, Edgar
Jaeggi, Christopher Macgowan and Mike Seed
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Circ Cardiovasc Imaging. 2014;7:663-670; originally published online May 29, 2014;
doi: 10.1161/CIRCIMAGING.113.001859
Circulation: Cardiovascular Imaging is published by the American Heart Association, 7272 Greenville Avenue,
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