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Reference Ranges of Blood Flow in the Major Vessels of the Normal Human Fetal
Circulation at Term by Phase Contrast Magnetic Resonance Imaging
Prsa et al: Normal Fetal Flows by PC MRI
Milan Prsa1, MD; Liqun Sun1, MD; Joshua van Amerom2, BASc;
Shi-Joon Yoo2, MD; Lars Grosse-Wortmann1, MD; Edgar Jaeggi1, MD;
Christopher Macgowan3, PhD; Mike Seed1,2, MD
1Division of Pediatric Cardiology, Department of Pediatrics, University of Toronto and Hospital
for Sick Children, Toronto, Canada
2Department of Diagnostic Imaging, University of Toronto and Hospital for Sick Children,
Toronto, Canada
3Department of Physiology and Experimental Medicine, University of Toronto and Hospital for
Sick Children, Toronto, Canada
Correspondence to Mike Seed Division of Paediatric Cardiology Department of Pediatrics, Hospital for Sick Children 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada Fax: 416-813-7547 Tel: 416-813-7654 ext. 204067 Email: mike.seed@sickkids.ca
DOI: 10.1161/CIRCIMAGING.113.001859
Journal Subject Codes: [6] Cardiac development, [30] CT and MRI, [41] Pediatric and
congenital heart disease, [156] Pulmonary biology and circulation.
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Abstract
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 have 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 weeks, 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/kg (± 2 SD) 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), foramen ovale 135 (37,233).
Expressed as percentages of the combined ventricular output, the mean flows ± 2 SD
were as follows: MPA 56 (44,68), AAo 41 (29,53), SVC 29 (15,43), DA 41 (25,57), DAo
55 (35,75), PBF 16 (0,34), UV 29 (11,47), FO 29 (7,51). A strong inverse relationship
between FO shunt and PBF 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 fetus. The wide range we found in FO shunting suggests a degree
of variability in the way blood is streamed through the fetal circulation.
Key Words: circulation, regional blood flow, pediatrics, magnetic resonance imaging
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Phase contrast cine MRI (PC MRI) is the current gold standard for the non-invasive
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 (2,3,4).
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
late onset intrauterine growth restriction (8,9,10).
However, in order to identify changes in regional blood flow in conditions like congenital
heart disease and placental insufficiency, it is essential first to define reference physiologic
ranges of feto-placental 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.
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Study participants
The study was carried out 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, 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
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 three-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). Following localization of the fetus, steady state free precession
surveys were performed in three 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 two orthogonal views. The UV was targeted in its mid
intrahepatic section, distal to the umbilical insertion in order to avoid complex flow behavior but
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proximal to any portal vein branches. The image parameters used for the PC MRI acquisitions
were as follows: slice thickness 5mm, 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 approximately 10 true cardiac phases, which were
interpolated to 15 calculated phases. A velocity sensitivity (VENC) of 150 cm/s was used for the
AAo, MPA, DAo, DA; 100 cm/s for the SVC, RPA and LPA; and 50 cm/s for the UV. A typical
scan time for each vessel was 34 seconds, with a total scan time of approximately 30 minutes.
Using software created in our laboratory (MATLAB, MathWorks, USA) the correct R-R
intervals for each acquisition were determined retrospectively by MOG using raw data acquired
at an R-R interval of 545ms to ensure fetal heart rates down to 110 bpm were adequately
oversampled for correct reconstruction. The details of MOG are given in previous publications
(5,7). The reconstructed images were post-processed on a commercial software package for flow
quantification (Q-flow 5.2, Medis Medical Imaging Systems, Leiden, Netherlands). The total
post-processing time for each study including fetal weight estimation was approximately 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 and left ventricles 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 measured. Each subject underwent Doppler assessment of the
umbilical artery, umbilical vein, middle cerebral artery and ductus venosus. As newborns, the
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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 (US) measurements made in the AAo and MPA. US 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 2D US) to calculate flow (15,16). The MRI flows
were also assessed for internal validation by comparing pulmonary blood flow measured directly
(sum of right and left pulmonary artery flows) and indirectly (difference between main
pulmonary artery and ductus arteriosus 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, standard deviations and references ranges were calculated
using two standard deviations either side of the mean for the reference range. Pearson’s
correlation was used to investigate the relationships between the different measurements of flow,
and Bland Altman plots used to assess for 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,
Mathworks, USA and Graphpad Prism, USA. P-values of less than 0.05 were considered
statistically significant.
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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).
Pulmonary blood flow (PBF) was calculated as the sum of the right and left pulmonary arterial
flows (RPA & LPA). The foramen ovale (FO) shunt could not be directly measured using PC
MRI. However, because PBF and FO shunt are the two exclusive sources of LV filling, FO flow
can be calculated as the difference between the left ventricular output (LVO), which is
comprised by 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, MPA + AAo = 97 (18,19,20). 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, three for
fetal weights below the 10th percentile by MRI, three because of incomplete MRI datasets
resulting from vigorous fetal motion, one for an abnormally high middle cerebral artery peak
velocity and one for an abnormally low middle cerebral artery pulsatility index by Doppler. Two
further subjects were excluded based on follow-up echocardiography, one for an apical
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ventricular septal defect and one 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 weeks (SD 1.1 weeks) with a
mean fetal weight of 3.0 kg (SD 0.5 kg).
The first five 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 ten fetuses
were examined for inter-observer 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 ten fetuses, the MRI measurements correlated reasonably well with US 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/kg), 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 supplementary information.
The mitral, tricuspid, aortic and pulmonary valves and right and left ventricular diameters were
all with two standard deviations 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 right to left
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ventricular 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 towards 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
within 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 at least eight 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 metric
optimized gated measurements (7). The reproducibility, internal validation and comparison with
ultrasound obtained in the current study suggest the technique is at least reasonably reliable.
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However, inspection of the individual flows reveals some discrepancies between our results and
the expected distribution of flow. These include three fetuses with higher left ventricular outputs
than right, despite having larger right ventricles than left 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 are unlikely to be attributable to
errors in phase contrast measurement (8,9,10). Furthermore, our study suggests that when PC-
MRI measurements are collected from a number of 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, 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 two sets of results. The most striking
difference between their estimates and our findings is the mean UV flow, estimated at 180
ml/min/kg by Rudolph et al. and measured at 129 ml/min/kg by MRI. However, in the more
recent edition of Rudolph’s textbook, the estimate of UV flow has been modified to be more in
line with human US data to 115 ml/min/kg (24). Our own measurements of UV flow are most in
keeping with the US measurements of of Van Lierde, with a mean UV flow of 117 ml/min/kg
and the 140 ml/kg/min (1/3 of CVO) found by Sutton (25,26).
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Other modifications in the human estimates reported in the more recent edition of
Rudolph’s text result in significant differences compared with the MRI results, including lower
DA, FO, and DAo flows and higher PBF flow. The modifications are reportedly an attempt to
accommodate subsequent human ultrasound results. However, as acknowledged by Rudolph,
ultrasound measurements of flow are prone to potential inaccuracies arising from problems with
vessel diameter measurement, flow alignment and the inability to account for the different
velocities across the lumen of the vessel (15). In our study, the US flow measurements were
consistently slightly higher than the MRI measurements, which may be due to 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 US and MRI measurements, we are also
aware of the possibility that although the two techniques were performed on the same day,
changes in the physiologic state of the fetus during and between the MRI and US could have
affected their agreement.
Differences in sampling techniques may explain the wide variation in results obtained in
different human ultrasound studies. For example, Rasenen 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 (27,28). 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 ml/min/kg to 553 ml/min/kg, although most estimates are approximately
450 ml/min/kg, which is in keeping with the MRI result of 465 ml/min/kg (29). The good
correlation we found between the ratio of MPA by AAo flow by MRI with echocardiographic
measurements of the ratio of the right and left ventricular end diastolic dimensions was a
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reassuring demonstration of congruent physiologic and morphologic parameters of the relative
dominance of each ventricle with respect to the CVO by two different imaging modalities.
Previous ultrasound measurements of mean fetal PBF range from 47 ml/min/kg or 11%
of CVO in Mielke’s large cohort to 25% of CVO in third trimester fetuses in Rasanen’s study
(27,30). One reason for the wide range of PBF found by different authors might be the different
measurement techniques used, as in the majority of studies the PBF is calculated by subtraction
of the DA flow from the MPA. Rasanen 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 (27). Rasanen’s 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’s
study, there was an approximately 2-3 fold range in PBF at 37 weeks, while in our own study,
the range of PBF was higher with at least a ten-fold difference between the subject with the
lowest PBF of 13 ml/kg/min or 2% of CVO and the highest PBF of 187 ml/min/kg or 30% of
CVO. The reason for this discrepancy is not clear. Rasanen reports a higher level of agreement
between direct and indirect measurements of PBF using US 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, as although Rasanen’s study included 63 patients,
these were evenly distributed across a gestational age range of 18 to 40 weeks, while our own 40
subjects were concentrated around the same gestational age of 37 weeks. The wider range of
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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 combined ventricular output at term found in our study compared with other
US studies with large numbers of late gestation subjects (28,30,31).
Variation in pulmonary blood flow and foramen ovale shunting
As in Rasenen’s study, there was no correlation between PBF and AAo flow measured by MRI,
with AAo remaining fairly constant between patients. As PBF and FO shunt are the two sources
of LV filling, a wide range of FO shunt and inverse relationship with PBF should therefore be
anticipated. In our study, the lowest FO shunt was just 29 ml/min/kg or 5% of the CVO, with a
10-fold increase to the largest FO shunt of 283 ml/min/kg or 54% of the CVO. We found a
strong inverse correlation between FO shunt and PBF. The physiologic mechanism behind this
finding is not yet clear. Our results would not support anatomical restriction at the foramen
ovale as a likely cause, although accurate measurements of the foramen ovale 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’s histological studies of perinatal subjects (33) and ultrasound studies showing
variation in shunting at the ductus arteriosus 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
showed that an increase in pulmonary arterial PaO2 of 7 mmHg resulted in a 3-fold increase in
PBF and increase in left atrial pressure from 4 to 8 mmHg (35). 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
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the blood in the pulmonary arteries was initially shown by Rudolph using flow probes around the
pulmonary arteries of fetal lambs during variation of the concentration of inspired oxygen of the
ewes (17). Rasanen has since demonstrated human fetal pulmonary vasodilation in response to
maternal hyperoxygenation using Doppler (36). 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
cordocentesis samples has revealed a normal range of oxygen saturation from 60-80% 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 umbilical artery pulsatility index was inversely
proportional to pulmonary blood flow and umbilical vein flow. This result would be in keeping
with the concept that higher placental resistance might result in a reduction in umbilical vein
flow and pulmonary blood flow due to reduced fetal oxygen delivery. However, contrary to this
conclusion, we found no relationship between umbilical vein flow and pulmonary blood flow.
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 intra-uterine growth restriction in
which we have demonstrated SVC flows in excess of 300 ml/min/kg and more than 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
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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 towards 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 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 were studied during a short gestational age
window. While this might be regarded as a limitation, we would argue that it allows for a more
homogeneous study group, focusing on a period of the 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
MRI flows, theheheeheee s
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fetal lamb research and permits internal validation of the me
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vulnerability of MRI to movement artifact resulting from fetal motion represents a significant
drawback of the technique compared with ultrasound.
Conclusion
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 amongst fetuses of the same gestational age. We propose that
the mechanism and implications of this finding deserve further investigation.
Acknowledgements
We would like to 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.
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ulations, in NoNoooooonnsssssss, 1919191919191978787878787878...Floow w w www w MeMeMeMeMeMeMeasasasasasasasururururururureme
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Table 1. Means, standard deviations and reference ranges (mean ± 2SD) of flows in 40 normal late gestation human fetuses measured by phase contrast MRI
expressed in ml/min/kg and as percentages and as modeled mean percentages of the combined ventricular output. CVO – combined ventricular output, MPA -
main pulmonary artery, AAo – ascending aorta, SVC – superior vena cava, DA – ductus arteriosus, PBF – pulmonary blood flow, DAo – descending aorta, FO –
foramen ovale. FO flow was calculated as the difference between the left ventricular output and pulmonary blood flow.
CVO MPA AAO SVC DA PBF DAO UV FO
Mean flow (ml/min/kg) 465 261 191 137 187 74 252 134 135
SD 57 46 35 30 39 43 46 36 49
Mean ± 2 SD (351,579) (169,353) (121,261) (77,197) (109,265) (0,160) (160,344) (62,206) (37,233)
Mean flow (% CVO) 56 41 29 40 16 55 29 29
SD 6 6 7 8 9 10 9 11
Mean ± 2 SD (44,68) (29,53) (15,43) (25,57) (0,34) (35,75) (11,47) (7,51)
Modeled mean flow(% CVO)
56 41 28 41 15 54 29 29
77
5 30 39 45 300000 333999 4
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Table 2. Comparison of the distribution of the fetal circulation in the late gestation human measured by phase contrast MRI and the late
gestation fetal lamb measured using radioactive microspheres (8). CVO – combined ventricular output, MPA - main pulmonary artery, AAo –
ascending aorta, SVC – superior vena cava, DA – ductus arteriosus, PBF – pulmonary blood flow, DAo – descending aorta, FO – foramen
ovale.
CVO MPA AAO SVC DA PBF DAO UV FO
Mean flows (ml/min/kg)
Human MRI 465 261 191 137 187 74 252 134 135
Lambs 450 250 185 140 175 75 220 180 125
Mean flows(% of CVO)
Human MRI 56 41 28 41 15 54 29 29
Lambs 56 41 31 39 17 49 39 28
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Figure Legends
Figure 1. Reproducibility in repeated flow measurements in five 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). N.B. analysis did not account
for multiple paired observations within each fetus, leading to possible incorrect estimates of
correlations, standard errors, P values, etc.
Figure 2. Interobserver variation between flow measurements in ten 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). N.B. analysis did not account for multiple
paired observations within each fetus, leading to possible incorrect estimates of correlations,
standard errors, P values, etc.
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, 95% limits of agreement from -167.4 to 219.2 ml/min). N.B. 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 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 two measures with no significant bias (bias: 10
ml/min/kg, SD of bias 57.3, 95% limits of agreement from -102.4 to 122.4 ml/min/kg).
Figure 5. Plots of individual vessel flows measured by phase contrast MRI in 40 late gestation
normal human fetuses expressed in ml/min/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. CVO – combined ventricular output, MPA –
main pulmonary artery, AAo – ascending aorta, SVC – superior vena cava, DA – ductus
arteriosus, DAo – descending aorta, PBF – pulmonary blood flow, UV – umbilical vein, FO –
foramen ovale.
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). MPA – main pulmonary artery, AAo –
ascending aorta, SVC – superior vena cava, DA – ductus arteriosus, DAo – descending aorta,
PBF – pulmonary blood flow, UV – umbilical vein, FO – foramen ovale, UA – umbilical artery,
RA – right atrium, LA – left atrium, RV – right ventricle, LV – left ventricle. Coronary blood
flow estimated based on fetal lamb findings (9), FO flow calculated as the difference between
LV output and PBF.
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Figure 7. Scatter plot showing inverse relationship between pulmonary blood flow and foramen
ovale shunt in 40 late gestation fetuses by phase contrast MRI.
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.
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Christopher Macgowan and Mike SeedMilan Prsa, Liqun Sun, Joshua van Amerom, Shi-Joon Yoo, Lars Grosse-Wortmann, Edgar Jaeggi,
at Term by Phase Contrast Magnetic Resonance ImagingReference Ranges of Blood Flow in the Major Vessels of the Normal Human Fetal Circulation
Print ISSN: 1941-9651. Online ISSN: 1942-0080 Copyright © 2014 American Heart Association, Inc. All rights reserved.
TX 75231is published by the American Heart Association, 7272 Greenville Avenue, Dallas,Circulation: Cardiovascular Imaging
published online May 29, 2014;Circ Cardiovasc Imaging.
http://circimaging.ahajournals.org/content/early/2014/05/29/CIRCIMAGING.113.001859World Wide Web at:
The online version of this article, along with updated information and services, is located on the
http://circimaging.ahajournals.org/content/suppl/2014/05/29/CIRCIMAGING.113.001859.DC1Data Supplement (unedited) at:
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