reference ranges of blood flow in the major vessels of the...

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: [email protected]

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.

vvvvvverersisisiisiitytyyyyyy ooooooof f ToToTooooorororororororonn

g k

s a

gnonoonon stic Imamamaaagigigingngnggng, UnUnUnUnUniviviviviveeeree sisisity ooof TTTorrrrroooono tototototo aandndn HHHHHossssspipipipipitatatatatalllll fofofoffor r rrr SiSiSiSiSickcccc

siologyyyy aaaaandndndndnd EEEEExpxxpxpx erererererimimimimimenenenenentaaaaal l lll MeMeMeMeMedididididicicicicicinenenen ,,,,, UnUnUnUnUnivivvvvererererersisisisisitytytytyty ooooof f f ff ToToToToTororrr nto a

by guest on April 22, 2018

http://circimaging.ahajournals.org/

Dow

nloaded from


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

2252525252525252 (((((((161616161616160,0,0,0,0,0,0,343434343434344)4)4)4)4)4)4),, ,, , , , ppppppp

ovalalallllleeeeee 131313131313135555555 (3(3(3(3(3(3(37,7,7,7,7,77 22

r s

(

e

n

rcecececeentntnntntageseseseses oofff ff the combined ventririricular ouuuutptptptptputttt, the mean flows

MMMMMPAPPP 56 (4444,68686 ), AAAAAo 414 ((2229,553)3)3))),,, , SVSVSVSVSVCC 2229 (1515155,4443),,, DADADDD 44111 (

16 (0,34), UUUUUV V VVV 29 (((1111111111,4,,, 7))))),,,,, FO 22229 (7((( ,5551))))). A sstrttrtt ong gggg inverse re

ntntnt aaandndnd PPPBFBFBF wwwasasas nnnotototededed (((r rr === 00-0 66.64,4,4,, pppp === <<<000.0000000101001).).).))



Dow

nloaded from


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.

hetical ECG trrigigigigigigigg

th MOMOMOMOMOMOMOG G GGGGG hahahahahahahasssssss bebebebebebebee

e o

e e

i

esesesesestatattatation hhhhumumumumumananananan fffffetetetetetususususus aaaaandndndndnd vvvvalalaaa idii atatteddddd uuuuusisisisisingngngngng aaan nnnn inininini vvvvivivivivivooooo ssssimimmimmulululululatatatatatio

eennnnn usususususededededed sususuuccccccesesesese sfss ululululullylylylyly ttttto mamamamamakekekekeke ppppprerererrelililililimimimimiminananananaryryryryry ooooobsbsbsbsbserrrrrvavavavavatititititionnnnnsss ofofofofof rrrrre

ininin hhhumumumananan fffeeetututusesesesss wiwiwiththth lllefefefttt sisisidedededdd cococongngngngngenenenitititalalal hhhheaeaeartrtrt dddisisiseaeaeasesese, trtrtraaa



Dow

nloaded from


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

o

m s

ormememememed dddd acacacacaccococoordrdrdddinininininggg gg toooo aaa ppppprevvvvvioioioioiousususususlylylylyly pppppububububublililililishshshshshededededed tttttecececee hnhnhnhnhniqiqiqiqiqueueueueue uuuuusisiiiingngnggn aaa

mmmenenensss, EEErlrlrlananangegegeg n,n,n, GGGererermamamanynynyyy)))) (3(3(3(( ).).).)) BrBrBrieieieeflflfly,y,y,yy ttthehehe fffetetetalalal wwweieieighghghg ttt wawawasss



Dow

nloaded from


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

s, USA) the cocoooooorrr

y MOGOGOGOGOGOGOG uuuuuusisisisisisisingngngngngngng rrrrrrrawa

f

r

c p

f 54545454545ms tototototo eeeeensnsnsssururururureeeee fefefefefetatatatatal l lll hehehehh arararrrt tt tt rarr tetees dododododownwnwnwnwn ttttoooo 11111111110 bpbpbpbpbpm m m m m wewewewewererererere aaaaad

reccccctt ttt rererererecococococonsnsnsstrtrtrucucuccctitititit onononn. TTTTThhehehehe dddddetetetetetaaaaailililillsssss ofofofofof MMMMMOGOGOGOGOG aaaaarerererere gggivvvvvenenenenen iiiiin ppppprerererrevivivivivioooo

ctctctededed iiimamamagegegegg sss wewewererere ppppposososttt-prprprocococesesesseseseddd onononnn aaa cccomomommememercrcrciaiaial ll sososoftftftwawawarerere ppp



Dow

nloaded from


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.

ry blood flowwww mmmmmmm

fferenennnnnncecececececece bbbbbbbetetetetetetetweweweweweweweene

d eddddd ddddductus sss ararararartetttt riririririosososososususususus ffffflololololow.ww.w.w InInInInntettt roobbbsererererervevevevever vavavavvaririiriiatatatata ion n n nn wawawawawas asasasasassesesesesessssss e

wititititith hhhh thththththeee ee seseseecococoondndndndnd reaeaeaeaadededededer bbbbblililililindndndndndededededd tttttoooo thththththee eee fifififfirsrsrsrsrst tttt rerereer adadadadadererererer’s’s’s’ss rrrrresesesssululululultststsss. r



Dow

nloaded from


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

odel was extraraaaaaappppppp

the acacacacacacctitititititit veveveveveveve-s-s-s-s-s-s-setetetetetetet aal

n _

e >

- ,

nnnnnstststttraineddddd mmmmminnnnnimimimimimumumumumum ooooofffff tttthehehehh ssssscaccc laarrr fufufuufuncncncncnctitttt onononoon fff MPMPMPMPMPA+A+A+A+A+AAAAAAAAAAo_o_ooo SVSVSVSVSVC_CCCC

esttttimimimimimatatataa eee ee babababaasesesed dddd ooonoo mmmmmeaeaeaeaeasuuuuurrrrrededededed vvvvvalalalala ueueueuues,ssss sssssubububububjejeejeectctctctct tttttooo MPMPMPMPMPA AAAA - PBPBPBPBPBF FFFF >>>>>

- DADADAooo === 0,0,0,, MMMPAPAPA +++ AAAAoAoAo === 999777 (1(1(1( 8,8,8,191919,2,2,20)0)0). OnOnOnO cecece MMMMMPAPAPA, ,,, AAAAAAOOO,



Dow

nloaded from


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

ents made in ththhhhhhee

greeeeeeeememememememementntntntntntt wwwwwwwititititititith h hhhhh n

0 h

R u

o (r = 0.77, p = 0.0001), with a small bias of 26 ml/min for h

000000000000010 , biiiiiasasasass ===== -----2121212121.2.2.222, , ,, , SDSDSDSDSD ooooof ff bibibibibiasaaa 4488.33333 mlmlmlmlml/mmmmmininini ))))) (F(((( igigigigigururururure e ee e 2)2)2)2)2). IIIIIn n n n n th

RRI IIII mememememeasasasasasurururremememmenenenenentstt cccccorrororrrrerrr laaaaateteteteted dddd rerererereasasasasasononononnababababablylylylyly wwwwwelelelelell l wwwititititithh hhh USUSUSUSUS mmmmmeaeaeae susususs

ooo (((rrr === 0.0.0.777777,,,, p p p p === 000.000000010101),),), wwwititithhh aaa smsmsmalalallllll bibibiasasas ooof fff 262626 mmml/l/l/mimiminnn fofoforrr hhh



Dow

nloaded from


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.

significant cooooooorrrrrrrrr

R

DiDiDiDiDiscscscscscususususussisisissionononono

RIRIRI aaandndnd cccomomompapapap riririsososonnn wiwiwiththth ppppprerereviviviououousss mememeasasasurururemememenenentststs



Dow

nloaded from


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).

study suggesstststststststs

veragagagagagagagededededededed rrrrrrresesesesesesesululululululultttttstst

f i

r t

dadadadadata. TTTTThehehehee mmmmososososost tt t t cococococompmpmpmpmprererereeheheheeensnsnsnn ivee sttttudududududieieieieiesssss ofofofo ttttthehehehehe dddddiiiiiststststs ririririribububububutititititiononononon o

formrmrmmmededededed iiiiin nn fefefefefetatataaall lallalal mbmbmbmbmbsss ss usininininingg ggg aaaaa rararaaadididididioaoaoaoao ctctctctctivivivivive eeee mimimimimicrcrcrososssosphphphphphereeee eee tttececececechnhnhnhnhni

rrremememenenentststs, ,,, thththeseseseee inininvevevestststigigiggatatatorororsss mamamadedede eeeestststimimimatatatioioionsnsns oooff ff thththeee abababsososolululuttt



Dow

nloaded from


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

e vessel lumennnnnnn, ,,, ,,, w

iddleleeeeee ooooooof f f ff ff thththththththe e e e e ee vevevevevevevesss

n

l

o S

n tototoo intriiiinsnsnsnssicicicicic iiiiinananananaccccccccccurururururacacacacacieieieeessss ininninn oooourr UUUUS S S SS ananananand dddd MRMRMRMRRIIIII mememememeasasasasasuruuuu emememememenenenenentstttt

lityyyyy ttttthahahahahat tttt alalalalalthththththouououuughghghgg tttthehehehehe tttttwo oooo tetetetetechchchchchnininnn quququququeseseseses wwwwwererererereee ee pepepepperfrfrfrfrforrrrrmememememeddd dd ononononon ttttthehehehehe

ololologogogicicic ssstatatatetete ooofff thththeee fefefetututusss dududuririringngnggg aaandndnd bbbbbetetetweweweenenen ttthehehe MMMMMRIRIRI aaandndnd UUUSSS



Dow

nloaded from


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

hat the increaasesesesesess

ut nooooooo ccccccchahahahahahahangngngngngngnge e e e e ee ininininininin

b o

e

a u

bbbbbetetettetweennnn PPPPPBFBFBFBFBF aaaaandndndndnd FFFFFOOOOO shshshshshununununt tt tt wawaww s alllllsososososo ssssseeeeeeen n n n inininnn ooourururrur ssstututututudydydydydy, alalalalalthththththo

andndndndnd FFFFFO OOOO fllflfllowowowo wwwwwasaa ssssseeeeeeeenn nnn innnnn fffffeeeeetututututusesesess sssss ofofofofof ttttthehehehehe sssssamamamammeee gegeeegestststststatatatatatioioioioionananananal lll agagaggge

apapapprprproxoxoximimimatatatelelely y y yy 222-333 fofofoldldld rrrananangegegegg iiinnn PBPBPBF F F FF atatat 3337 7 7 weweweekekeks,s,s,, wwwhihihilelele iiinnn ououou



Dow

nloaded from


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

with PBF shooululuuuuu d

n/kg g ororororororor 555555% % % % % % % ofofofofofofof tttttthh

h W

i

hhhhhee ee lllargesssst FOFOFOFOFO ssssshuhuhuhuhuntntntntnt oooooff f f f 28282822 3 mlmmmm /mmminnnn/k/k/k/k/kg gg gg orrrrr 55554%4%4%4%% of f f f f thththththe e ee e CVCVCVCVCVO.O.O.O.O. W

atitititiiononononon bbbbbetetetetetwewewew enenennn FFFFFOOO shshshshshuunuuu t ttt ananananand dddd PBPBPBPBPBFFF.FF ThThThThThee eee phphphphphysysysyysioioiooolooooogigigigigic cccc memememm chchchchchananannni

ararar. OOOururur rereresususultltltsss wowowoulululddd nononottt sususupppppppppporororttt anananaa atatatomomomiiicacacalll rererestststriririctctctioioionnn atatat ttt



Dow

nloaded from


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

oppler parametetetetetetetee

atiliitytytytytytyy iiiiiiindndndndndndndexexexexexexex wwwwwwwasa

m l

t m

,

monononononary blllllooooooooood dddd flflflflflowowowowow aaaaandndndndnd uuuuumbmbmbmbmbililiii icii aal veeeeeininininin ffffflooooow.w.w.w ThTTTT isisisss rrresesesesesululululult t t tt wowowowowouluuuu

t hihihihihighghghghgherererrr plalalalalacececentntntntntalaa rrrrresesesese isisisisistaaaaannnnncececeece mmmmmigigigigi hththththt rrresesesesesulululuu t tttt ininininin aaaa rrreddddducucucucuctititititionononnn iiiiin nnnn umumumuu

bbblololoododod ffflololowww dududueee tototo rrredededucucucededed fffeeetatatalll oxoxoxygygygygygenenen dddelelelivivivi ererery.y.y.yy HoHoHoweweweveveverrr,



Dow

nloaded from


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

h offfffff ooooooururururururu ssssssstututututututudydydydydydydy c

s l

o n

fetal lamb research and permits internal validation of the me

stststststuuuduu ies isisisii ttttthahahahahat tt t t flflflflflowowowowow wwwwwasasasasa mmmmeaeaeaeaasusss rereed ininininin eeeeeacacacacach h h hh ofoffofof thtttt e e ee lalalalalargrgrgrgrge eee vevevevevesssssssssseleeee

of fff dididididistststststririririribububububutitittt ononononon ooooof ff thththththeee whwhwhwhwholololololee eee fefefefefetatatataalll l cicicicicircrcrcrcrculululululatatatatatioioioioionnn,nn whwhwhwhwhicicicicich hhhh hahahahahasss bebebebebeenenenee

fefefetatatalll lalalambmbmb rrreseseseaeaearcrcrchhh ananand dd pepepermrmrmitititsss inininteteteeernrnrnalalal vvvalalallidididatatatioioiionnn ofofof ttthehehe mmmeee



Dow

nloaded from


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.

he wide rangeee aaaaaaan

estatattttttioioioioioioonanananananan l l l ll ll agagagagagagage.e.e.e.e.e.e. W

mmmmmppplpp icatioioioiionsnsnsnsns ooooof f f f f thththththisisisisis fffffininininindididididingngngng dddesererrveeeee fffffurururururththththhererere iiiiinvnnvnvn essessstititititigagagagagatitiititiononononon...

AcAcAcknknknowowowleleledgdgdgggemememenenenee tststs



Dow

nloaded from


References

1. Fratz S, Chung T, Greil GF, Samyn MM, Taylor AM, Valangiacomo Beuchel ER, Yoo S-J, Powell AJ. Guidelines and protocols for cardiovascular magnetic resonance in children and adults with congenital heart disease: SCMR expert group on congenital heart disease. J Cardiovas Magn Reson. 2013; 15:51.

2. Yamamura J, Frish M, Ecker H, Graessner J, Hecher K, Adam G, Wedegartner U. Self-gating MR imaging of the fetal heart: comparison with real cardiac triggering. EurRadiol. 2011;21:142-149.

3. Yamamura J, Kopp I, Frisch M, Fischer R, Valett K, Hecher K, Adam G, Wedergartner 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. 2013. doi: 10.1007/s10334-013-0397-0.

5. Jansz M, Seed M, van Amerom, 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 JFP, Al Nafisi B, Grosse-Wortmann L, Yoo S-J, 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 JFP, 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 Cardiovas 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 Int Soc Mag Reson Med 21. 2013.4129.

11. Lai WW, Geva T, Shirali GS, Frommelt PC, Humes RA, Brook MM, Pignatelli RC, Rychick J. 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, Mansfield P, Worthington BS. Fetal weight estimation by echo-planar 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.

mmmmmananananananann n n n n n n L,L,L,L,L,L,L, YYYYYYYoooooooooooooo SSSSSSSJ,JJ,J,J,J,J,son MMMMMMMededededededed...... 2020202020202010101010101010;

ed M, van Amerom JFP, Al N fisi B, Grosse-Wortmann L YC z

awa a;26:14

ed MMMMM, vavavavavan AmAAAA erom JFP, Al Naaaaafifififif si B, Grosseeeee-W---- ortmann L, YCK.K.K.KK. Dynanananamimmmm ccccc imimimimimagagagagaginininining g g gg ofofofoo thehehehh feetaaal heheheheheararararart tttt usususuu inininnng gggg mememememetrtrtrrricicicicic oooooptptptptptimimimimimiz

MMMMMedeeee . 2013;70:00 1555599989 -16007. AmAmAmAmmerererereromomomomom JJJJJFPFPFPFPFP, YoYoYoYoY o oooo SJSJSJSJSJ, AlAlAlAlAl NNNNNafafafafafisisiii iiiii BBBBB, GrGrGrGrGrososososossesesesee-W-WWWWorrrrrtmtmtmtmtmanananaa n nnnn L,LLLL JJJJJaaa

wan CK. Feeeeeasasasaasibibibibibilililili ititiii yyyy ofofofofof qqqqquauauauauantntntntntifififificicicaaaaatititititionoonono oooof ff f f thththththeeeee didididdistststststririririribubbbb tion of bananan fffetetetalalal cccirirircucuculalalatititiononon uuusisisinnng g g gg CMCMCMR:R:R: aaa cccrororooossssss ss-sececectititiionononalalall ssstututudydydyy. JJJ CaCaCa;2;2;26:6:6:141414



Dow

nloaded from


14. Schneider C, McCrindle BW, Carvalho JS, Hornberger LK, McCarthy KP, Daubeney PEF. 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 Bio. 1985;7:625-42.

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 edition. Chichester: Wiley Blackwell, 2001.

18. Han SP. A Globally Convergent Method for Nonlinear Programming. Journal of Optimization Theory and Applications. 1977;22:297-309.

19. Powell MJD. A Fast Algorithm for Nonlinearly Constrained Optimization Calculations. Lecture notes in mathematics. 1978;630:144-157.

20. Mangasarian OL, Meyer RR, Robinson SM. The Convergence of Variable Metric Methods for Nonlinearly Constrained Optimization Calculations, in 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.

22. Hofman MBM, Visser FC, Van Rossum AC, Vink GQM, 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 edition. 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, Plapper T and 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 the human fetal cardiac output during the second half of pregnancy. Circulation. 1996;94:1068-1073.

28. De Smedt MCH, Visser GHA, Meijboom, EF. Fetal cardiac output estimated by Doppler echocardiography during mid- and late gestation. Am J Cardiol. 1987;60:338-342.

29. St John Sutton M, Groves A and 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.

ulations, in NoNoooooonnsssssss, 1919191919191978787878787878...Floow w w www w MeMeMeMeMeMeMeasasasasasasasururururururureme

Imaging: Basi F t d I l t ti R di hi .

M, Visser FC, Van Rossum AC, Vink GQM, Sprenger M, Wou

M oof blood flow cardiac output and organ blood flow Circ Re

Immmmmagagagagaginininining:gggg BBBBBasic Facts and Implplplplp emeeee entation. RaRRRR diographics.

MMMMM, , , , Visser FFFC,,, VVVanananan Rossusuumm ACAAC,,, ViViViViVinknknknknk GGQMQQM, SpSpSpSprengngngnggerr M, Won ofofofofof mmmmmagagagaa nenenen tititititicccc rerrr sooooonanananananceee ee blblblblblooooooooood ddd vovoovovolululululumememememe ffffflololololow wwww memeeemeasasasasasuuuruu emememememenenennentstststtution in smalalalalall l l l vevevevev sssssssssselelllls.ss.s.s. MaMaMaMaMagngngngngn RRRResessssononononon MMMMededdeded... 19191919199595959595;3;3;33;33:3333 778-784.

MMM, HeHeHeymymymananannnn MAMAMA. ThThTheee cicicircrcrculululatatatioioionnn ofofofff thththeee fefefetututusss ininin uuuteteterororo::: mememethththooooooff blblooooooddddd flflflflowowow cacacardrdddiiacacac oooutututpupuputtt aaandndddd ooorgrgrgananan bbbblollol ododddd ffffflololl www CCCiririrccc ReReRe



Dow

nloaded from


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 Echocardiography. 1994;7:257-263.

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 and 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. Wedergartner U, Kooijman H, Yamamura J, Frisch M, Weber C, Buchert R, Huff A, Hecher K, Adam G. In vivo 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 Int Soc Mag Reson Med 22. 2014.8084.

40. Zaretsky M, Reichel TF, McIntire DD, Twickler DM. Comparison of magnetic resonance imaging to ultrasound in the estimation of birthwieght at term. Am J Obstet Gynecol.2003;189:1017-1020.

WWWWWWWebebebebebebebererererererer CCCCCCC, , ,,,,, BuBuBuBuBuBuBuchchchchchchcherererererererttttttoxygegegegegegegen n n n n nn sasasasasasasatututututututurararararararattitit o

fetal sheep: a feasibility study. M R M d 2010 64:u e

RbR al t17-1020

fetatatatatalllll shshshhheeeeee p:p:p:p:p: a feasibility studyyyyy.. MaMM gn Resonnnnn Med. 2010;64:ujajajajajaiiibii M, vavavavavan nnnn AmAmAmAmAmerererereromomomomom JJJJJFPFPFPFPF , MaMM cgcggowowowowowananananan CCCCCK,K,K,K SSSSSeed d d d d M.M.M.M.M CCCCComomomomomprpppp ef f ff f laaaaate gestaatttionnn humumumuman ffetettal cccirccuuulatatatatatioioioioionn bybyy phahaaseseses connntrttrtt asa t MRMMbstttttrararararactctctctct. PrPrPrPrProcococo IIIIIntntnttt Socococococ MMMMMaggggg RRRRResesesesesononononon MMMMMededededed 222222.2222 2020202020141414.8888808080808084.4444Reichel TF,,,,, McMcMcMMcInInInInIntitiiirerererere DDDDDD,D,D,D,D, TTTTTwiwiwwiw ckckkkklllllerereere DDDDM.M.MM.M CCCCComomomomompapapapaparirr son of maltltltrararasososounununddd ininin ttthehehe eeestststimimimatatatioioionnn ofofof bbbiririrthththwiwiwiww egegeggghththt aaattt tetetermrmrm. AmAmAm JJJ OOObsbsbsttt111777-101010202020



Dow

nloaded from


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



Dow

nloaded from


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

AAO SVC DA PBFAAAAAAAAAAOOO OO SVSVSVSVSVCCCCC DADADADADA PPPPPBFBFBFBFBF



Dow

nloaded from


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.

ten fffffffetetetetetetetususususususu eseseseseseses ssssssshohohohohohohow

o f

f f

w c

obbobbbssses rverrrrss s wiwwww ththththth nnnnnooooo sisisisisigngngngngnififififificicicii anananannt ttt biiiaaas (((((bibibibibiasasasaa :: -2-2-2-21.1.1..1.2 2222 mlmlmlmlml/m/m/m/m/mininiinin,,, SDSDSDSDSD ooooof

fromommmm -11111111115.55 55 tototooo 777773.22222 mlmlmlmlml/mmmmmininininin).)))) NNNNN BB.BBB. anananananalalalalalysysysysysisisisisis dddddidididdd nnnnnotoootot aaaaaccccccouououountntntnn fff

wiwiwithththininin eeeacacachhh fefefetututus,s,s,,, llleaeaeadididingngnggg tttooo pppppososossisisiblblbllleee ininincococorrrrrrecececttt esesestititimamamatetetesss ofofof ccc



Dow

nloaded from


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.

d interquartile e eee rarrrrrr

d venenenennnntrtrtrtrtrtrtricicicicicici ulululululululararararararar ooooooouu

e –

e c

errrrryyy,y AAoooo –––– aaaascscsccscenenenenendididididingngngngng aaaaaororororo tttta,aa SSSVCVCC –––– ssssupupupupupeereree ioioioi r rrrr vevvvv nanananana cccccavavavavava,a,a,aa DDDDDA AAAA –

escenenenenendididididingnnnn aaaaororortatatatt , PBBBBBFFFFF – pupuupuulllllmomomomomonananannaryryryryr bbbbblololololoododododod ffffflololololow,www UUUUUVV VVV – umumumumumbibibibibilililililic



Dow

nloaded from


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.



Dow

nloaded from




Dow

nloaded from


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:

http://circimaging.ahajournals.org//subscriptions/

is online at: Circulation: Cardiovascular Imaging Information about subscribing to Subscriptions:

http://www.lww.com/reprints Information about reprints can be found online at: Reprints:

document. Permissions and Rights Question and Answer this process is available in the

located, click Request Permissions in the middle column of the Web page under Services. Further information aboutnot the Editorial Office. Once the online version of the published article for which permission is being requested is

can be obtained via RightsLink, a service of the Copyright Clearance Center,Circulation: Cardiovascular Imaging Requests for permissions to reproduce figures, tables, or portions of articles originally published inPermissions:



Dow

nloaded from

http://circimaging.ahajournals.org/content/early/2014/05/29/CIRCIMAGING.113.001859

http://circimaging.ahajournals.org/content/suppl/2014/05/29/CIRCIMAGING.113.001859.DC1

http://www.ahajournals.org/site/rights/

http://www.lww.com/reprints

http://circimaging.ahajournals.org//subscriptions/


reference ranges of blood flow in the major vessels of the...

Documents