IACC Vol . Is, No. 2
AUgovl 1991'532-5
532
PEDIATRIC CARDIOLOGY
Doppler Echocardiography of Fetal Ductus Arteriosus Constriction
Versus Increased Right Ventricular Output
GERA!-D TULZF-R, MD, SAEMUND(IR GUDMUNDSSON, MD . PHD,
ANGELA M . SHARKEY . M D . DENNIS C. WOOD. RDMS. RCI'f . ARNOLD W . COHEN . MD,`
JAMES C . HUH'FA, MD . FACCt
rieaarer5err,, ~,a...r.r,a .eiaa
A prospclive longitudinal study from 121 examination of 41
normal pregnant wiener showed that fetal ductal flow velocities
tncrcvred with geslational Pge .'fhose normal data were compared
with data in three groups of fetuses with altered duel lbw
vetacilies: 22 fetuses (man geslalioaal age 31 .3 woks) had ductal
constriction due in maleroal indomethacia lrealmenp 10 felltues
(mean gestationat age 27 .9 weeks! had aeon exposed to lorbnlaline, a pntilive Inntropte agent end 14 fetuses Intense gestatlonal
age 33.3 weeksi had hypoplastic lea hear syndrome.
1. normal fetuses maximal systolic, mean and end-dlaslolic
ductal flow velocities increased linearly (p < 0 .0001) . The pulsaVity index did nut change (mean t 2 SD ; 2,46 t 0.52) . Fetuses
.
with iuclal constrician had higher maximal, mean and end
diastoli .
Sow
tic leer heart syndrome had increased maximal lbw velocity, but
normal or only mildly iterated man Sow velocity. The palsadl!ty
index in Manes during terbutahne therapy and with h ;poWaslk
lea hear syndrome was significantly highs thin in normal fetus m
(3
.11 t 0 .46 and 3 .09 t 0.7. respectively, vs . 2 .46 t 0.52; p <
0 .01105).
Fetal ductal wvveform analysis was necessary to distinguish
fetal dorsal constriction from increased Tight ventricular output .
These measurements may be helpful in the diagnosis or WOW
outflow obstruction and assessment of fetal hemodynamk data .
(J Am Coll Cordiol 1991;!8:532-6)
velocities and a significantly lower pulsatf€lty index
Doppler echocardiography provides an excellent noninvasive tool for assessing blood flow velocity and pressure
gradients across the fetal dOClus arteriosus II Constrirrtion
of the fetal ductus arterosus may occur during maternal
therapy with indomethacin lot premature labor (2-4) . 11 has
been demonstrated in animals that chroalc fetal doctat
constriction and occlusion affect lore fetal right ventricle and
Lad to morphologic changes in the pulmonary vasculature .
resulting in Persistent pulmonary hypertension in the newborn 15-81 . Thus, echocardiography of the fetus is used to
detect fetal ductal constriction during indometharin therapyIt has been shown that maximal ductal blood flow velocity
increases during weeks 25 to 32 of gestation, but normal
values with defined confidence limits arc not currently
available ()). Furthermore, the fetus whose mother is being
From the Deparsmenl e l Pediatrics. tnivenayot Pennsylvania School of
Medkine, the Disision of Cardiology, the Children s Hosplml of Philadelphh
and 'Ihc Dcpartrecat I Obstetrics and Gynccotogy. Diyismn of Fetal.
Mammal Medicine, Hospital of the Unisersity V N-11 , 4, Fhi:tdelphia .
Penmylvams . This study ass supposed in pan by ngmnt entitled "Doppler
Corrlaws of Fetal Cardiovascular Disease" from the N'itminn_ron . Delan-me
Affiliate of the Arnencah Heart Ass-aulon.
Manuuripr received N .v- ember 12, 1989, revised ,neusedlx realised
January It, 1991 . accepted February 6. 1991.
funentaddre , s and address for reprints : James C. Huhra . MD . Perinatal
Cardi .dog, . P-,,Io oa Hospital, 800 Spruce Srre0L PAlladelphia, Penreylvania 1910?.
.eaw
than did normal fetuses 4' .5 ar 0,76; p < 0.0005). Six of 10
looses of the lerhuniine group and 8 of 14 fetuses with hypoplas-
by me Pmedcan
college ..f C rd,omay
treated with terbutaline to induce tecolysis has increased
cardiac output (9) : we have noted markedly increased maximad ductal flow velocities in this setting, in increased fetal
right ventricular output may simulate ductal constriction .
The alms of this study were 1) to investigate the changes
in ductus arteriosus flow velocities during the last 2 trimesters of human gestation, and 21 to compare fetus,,, with
normal versus altered ductus arteriosus flow .
Methods
Normal group . A total of 121 studies were performed on
41 normal pregnant women who were recruited as volunteers
from the staff of the Children's Hospital of Philadelphia. The
study protocol was approved by the Human Studies Committee and informed consent was obtained from each
woman. Fetuses were initially examined after the 14th week
of gestation and then at 4 week intervals throughout pregnancy, Women who were taking drugs other than vitamins,
or who had complications of pregnancy including premature
labor, were excluded . Gestarional age was assessed by
measurements of bipariesal diameter, head circumference,
abdominal circumference and femur length (10). All fetuses
had a complete postnatal echocardiographic examination
witbio the I at 3 weeks of postnatal life to exclude congenital
heart disease. Gestational age at birth ranged from 38 to 42
eras-Imnnlo; su
1ACC V0. Ix, N, 2
Auauu 1991 552 .5
TULZER ET AL.
DOPPLER ECHOCARDIOGRAPHY OF FETAL DEC T US ARTERIOSUS
weeks (mean 40 .3) and birth weighs ranged from 3 .300 to
5,170 g (mean 3,8101 .
Ductal constriction group . With use of the criteria of
Huhla et al . (I l . fetal ductal constriction due to indomethacin
therapy for preterm labor was detected in 22 fetuses with a
structurally normal hear[ igeslalional age 27 to 14 weeks .
mean 31 .31 referred from the Department of Obstetric , All
had peak systolic and diastolic flow velocities in the duclus
>t40 and >3t1 emls, respectively- as previously reported for
the gestational age range of 26 to 32 weeks . All women were
receiving drug therapy for ?Ik h before the examination
The dose of indomethacin ranged from 10G to 150 mg daily at
divided doses . Serial studies demonstrated the change in
ductal flow velocity during Iseatment, but only the esamination with the highest flow velocity was used for analysis .
Findings of constriction including increased systolic and
diastolic flow velocities were present in all misses and
resolved within I to 5 days after discom .nuatiun of indomethoein therapy .
Terbutalinegroup, Ten Fetuses with asartaclurallynormal
533
each value- Waveforms were analyzed for maximal, enddias4oltc and mean flow velocity, respectively . The pulsatility index was calculated with use of the formula (Maximal
velocity - End-diastolic veloeity('Mean velocity .
Statistics . The normal data were analyzed to obtain normal charts with 95f1, confidence intervals far duclus arteriosos flow velocities during gestation . A simple linear random
effects mndel was used of the form Y, = t, + p5, + ey ,
where Y„ - measure
I
value, t, -= random hetween-stthject
variability . Ox, = fixed effect of increasing gestational age
and e, = random within-subject variability . It was assumed
that t, and e, are independent identically distributed normal
random variables, the classic assumptions for random effects
medals t Ll . 1 he pulsatility indexes of the indomethacin and
terhutaline groups were compared with values in the normal
group using a two tailed unpaired Student's r test with a
signilicance level at p < 0 .05 . All values are presented as
mean values _ 2 SD.
heart. (gestational age 20 to 33 weeks . mean .1 7,91 were
examined while the mothers were being treated for premature labor with terbutatine . 30 mg'duyl in 6 doses for =24 h
before examiamiuo. Because of the urgency of treai •nent .
fetuses exposed to terbutaline did not have pretrcatn .ent
cehocardiographic examinations .
Hypoplaslie left hear, syndrome group . Fouriten fetuses
tgestational age 21 to 39 weeks. mean 33 .31 seer diagnosed
in oiero as having hypoplastic left heart syndrome . manifested by mitral atresia or slenosis . aortic atresia or stenosts
and a hypoplastic aortic arch . Three fetuses had more than
one prenatal study . All diagnoses were confirmed by systolic
and diastolic reversal in the aortic isthmus on a postnatal
echocardiogram [Bash et al . 411)J, which howcd that the
systemic circulation was entirely dependent on the ducms
artetiosas . and thus the prenatal dstctal flow was equal to the
combined cardiac output in these fetuses .
Equipment. An Acuson 123 scanner was used in cnmhin,lion with 5-MHz and 3.5-MHz Iransducers for all examinations. Doppler interro_iexi,ons were performed with use of
either i-MHz or 3.5-MHz image-directed coninuous ware
Doppler echucardiography . The power output seas maim
twined at <100 mWlcm` spatial peak temporal average at all
times. Each study was recorded on standard VHS iiS in .(1 .27 call ideolapc.
Technique . Aflerevalualtona t heearcliacanatomy.co m
tinuous wave Doppler intcrroualiun of the flow through the
ducms aneriosuv was performed in a wgicial plan : chaos ing
the pulmonary artery . duet arlcriusus and descending
aorta simultancou,I~, as previously described Ill . All Doppler recordings acre uhtuined in the ihcence of fetal hreathinc
mnvvacals at an angle of -.31) to flow, and color floss
mapping vas used Io align the Doppler beam, Mcusurcments
were take.
, either on-line or off-line from o hard cups of the
4,Doppler tracing with use of
g usm, •utcr snstem
IDigisonicstaverage of 3 beats was used to establish
Results
Doppler recordings of the dectus arteriosus flow of feiuscs with normal and altered blood flow v eloci-.es are
shown in Figure I .
Normal fetuses. From 14 weeks of gestation to term there
v-as a star ica-it increase in maximal systolic, mean and
end-dias€olic flow velocities ip < 0.00011 . There was no
cigars^anI change in the pulsatility index during toil period
(mean 2,46 -0.52) .
Fetuses with altered duclus arlericsus flow velocities .
Figure 2 cam, area data in the three groups of fetuses with
altered data= arteriosus flow velocities with data in normal
(closes. The mar :mal flu . velocity was increased above the
99 F confidence limits is all letuses in the group with ductal
eu,i,i i eliun . i n 6 of 10 fetuses in the group affected by
terbutaline therapy and ,n 8 of 14 fetuses in the group with
the hypoplastic left heart s •,•n dromc The mean. ductal flow
vuluciin was >2 SD in all fetuses with ductal constriction
and wnhm the normal confidence limits in all felus .s in the
terhutaline croup, four of 14 fetoses with the hypoplastic
left heart syndrome had a mean doctal flow velocity slightly
abuse the normal range . The end-diastolic how velocity was
within the normal limits in both the terbutaline and the
hypoplastic left heart syndrome group and >2 9D in nil
fetuses with ductal constriction . Compared with values in
normal fetuses . the pulsatility index was significantly lower
in fetuses in the ductal constriction group (mean 1 25 w 0 .76 ;
p <. II-1ky119I and significantly higher in fetuses during terbutaliac therapy (3 .11 - 0.46 ; p < 0.90051 and in fetuses with
the by pnpl case left heart syndrome (3 .09 = 0.7 ; p < 0 .0005).
There seas no significant difference between the pulsmility
index, of the terbutaline and hypoplastic left heart syndrome groups .
534
TUL/ER Ir€ AL
OOPi-ERECHOCARnIOGRAVHVI> FFTAt .FILCTUSART LRtOSUS
)ACC Vot . tx. 00.2
. 1441 :532- 6
Aura
Discussion
Normal ductal flow vdlxllies. In the 2nd and 3rd trimesters. fetuocs ehowvd an increase in ductal flow velocities
with increasing gesational age, in agreement with previous
da!a. This increased ductal flow vekority is a function of
mukcnle variabt. ; . including ductal diameter and wall compliance, systolic and diastolic : uactal flow and right ventricular function, Therefore, flow velocities of the fetal ductus
aneriosus must always he related to gestational age for
correct intersretatkon .
Cunstrlcliot. versus increased right antricular output .
Fetal ductal cunshiatinn was characterized by increased
maximal and diastolic d'tclal flow velocities, resulting in a
Doppler waveform similar to that seen postnataliy across
cuurctatiun of the aorta (1). In our study. elevated maximal
ductal velocity was also found in h6° of the fetuses exposed
to terbutaline . Both terbutaline tlterapy :nd premature labor
have a positive inonopic effect on the fetal heart (9).
Increased right veal riculer output causes a greater volume of
blood to be pumped from the main pulmonary artery to the
descending aorta- resulting in an increased maximal ductal
flow velocity . The group with increased ductal flow had
ductus-dependent hypoplastic left heart syndrome . This
lesion can be seen as a model of increased right ventricular
output, because the aortic valve was either atretic or severely hypoplastic . We found elevated maximal flow velocities in 5730 of these fetuses and the shape of the ductal
Doppler waveforms was nearly identical to those seen in
fetuses with terbutaline therapy, thus supporting the hypoth-
Figures . Doppler rccurdingsafFetal ductpsaneriosus .Iop .normal
fetus at 28 weeks of gestation . Middle, fetus ut 29 weeks ofgestation
exposed to terbutaline, there are increased maximal but normal
cod-diastolic and mean r.- rdsxaics fpulsntility index >1t . Fetuses with the hypoplastic left heart syndrome have a similar
pattern . Boapm, fetal ductal constriction at 31 weeks of gestation
with increased maximal . end-diastolic and mean flow vducitics
ipulsahlity index c21 .
Maximal velocity
End-diastolic Velocity
aaa
ao
FT:_
r.uW
d Gmsssrm .
o
D.oSal em.Hm.
e
• rare
100
~o
6 une
ao
6e
e
j L1
ew-
M
a
a2
2.
3B
3.
Ba
Mean Velocity
•
ono r
E
"'Bo
G
•
34
'B
42
26
00
Pulsatllity Index
0 ,,nww„
1-
10
la 22 26 30
50
a&
GA
34 36
31
36
Figure 2. Ductus aneriosus flow velocity and posatility index in feseses
exposed in terbutaline to - 101. fetuses with constriction of the ductus
anerosus in = 221 and fetuses with
the hypoplastic left heart syndrome
IHLHSI in = 141 computed with values in normal fetuses . CA = gestational age in weeks. Bray and light
tires = mean normal values e 2 SD .
re=spectively.
JACC Vol. la . Nu'_
Augmi '"L5115
TULcER El' AL.
t#1PPLER it-iiiAKDIOCIr 0PHx OF FETAL DUc'TUS AerratoSUS
esis that increased flow , volume may cause elevated It- Imal
ductal flow velocity .
When lerbutaline therapy fails to stop premature labor .
mdomethacin is frequently added as a second drug. Increased maximal fetal ductal flow velocity in these cases
could be due to indomethacin-induced ductal constriction or
the effect ufterbutaline-induced increased right ventricular
Output_ Ifonly maximal ductal flew velocity is measured . the
latter effect may be misinterpreted as fetal ductal constriclion and aneffeclive tocolysis regimen may he discontinued .
The shape of the Doppler waveform, h owever. i s different
from that seen during ductal cnnstriairtn . In dueud cooslric-
5
flow velocities are, to a certain degree . related ace Iieht
ventricular output . they may be used as pan of an assessment of Fetal hemodynamic data .
Application to congenital heart disease . Focuses soot the
hypuplaslic left heart syndrome may hate increased maximal ductal flow velocities even early ht gestation . and this
increase combined with disproportion in the ventricular and
great artery sizes may be an additional indicator of fetal left
ventricular outflow obstruction and must not he interpreted
as ductal constriction .
Constriction of the duct as arteriosuv is the normal fetus
with two ventricles appears to he well tolerated "hen it is
short-term, and it can he recognized by assessing the ductal
flow velocities with Doppler echocardiography, When there
is only one pumping c hamber. as in the hypoplasuc left heart
syndrome, the entire cardiac output of the fetus most pass
through the ductus artenosus . and ductal conduction could
dramatically increase the "ark of the right vemricie and
decrease the fetal and placental perfusion . For alas reason.
when premature labor occurs in a monart whose fetus is
being monitored for ductus'dependenl congenital heart disease . frequent monitoring of the ductal flm%' velocities is
neccssary if prostaglandin-inhibiting drugs are to be used . In
the sating of postnatal management of the hypoo!astic left
hear. syndrome a cardinal crmciple is avoidance of myocardial hypertrophy and this principle also applies here .
Pulsatility index as an indiratar of obstruction . The r III-
atility index in peripheral vessels is thought to reflect
peripheral impedance . In the ductus arteriosus it i, used only
as an aid in the differential diagnosis of increased maximal
Incrsaeed RV Output
4
a
pl
NRrmal
a
t
DWGW CumilIt6dYn .
0
10
20 30
Getdatlonal Age
40
lwoshul
lion flow velocity tans the JuLIUS aiterioxus slowly de-
creases from its maximum to end-diastole. but increased
flow through a wide open duets anerosus shrnss a very
pulsatile Doppler pattern . with a rapid decrease after peak
velocity to the baseline or near to it, and once again an
Increment diastole and a decrease toward end-diastole . This
difference in shape •a n be appreciated by measuring mean
flow velocity, or even better, by calculating the pulsalility
index . which takes maximal. end-diastolic and mean velocities into account . A flow pattern of a mildly constricted
ductus and a wide open duca us with increased Sow may have
the same maximal systolic and erd-diastolic velocities . but
there are significant differences in mean velocity and pulsa .
tility index that clearly differentiate each cause . As ductal
535
Figure 3 . flu .rulity index [Pit of the fetal ductus attenosus and
feud gcstair nal age- This chart gives the normal range versas the
ranges for increased right ventricular (RV) output and ductal con .
,mct .onn
flow vet city. Ductal constriction causes decreased pulsalility and higher than normal flow velocities indicating obstruclion . whereas an increased right ventricular stroke volume
cause, increased pulsalility and elevated maximal but normal or only slightly elevated mean and end-diastolic flow
velocities (Fig. 31 . in the umbilical circulation . for example.
decreased pulsalility is at low velocity, indicating increased
floss- and lower impedance f 131. Mean ductal flow velocity
alone may he able to distinguish ductal constriction from
other causes of elevated maximal flow velocity . but it must
he interpreted in relation togestatinnal age. Pulsatility index .
In eonlrasl . did not change with gestation: age and may
therefore be a more useful variable in clinical practice.
Conclusions . Fetal ductal waveform analysis is necessary
it, differentiate fetal ductal constriction and increased fetal
note ventricular output . Flit mean flow velocity and tire
pulsalility index are the most useful variables in the analysis
of Doppler waveforms . These measurements may he helpful
in the diagnosis of left-sided outflow obstruction and as , essmcnt of fetal hemodynamics .
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TULAER Ll AL .
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