Download Haemodynamic evaluation of the first trimester fetus with special

Human Reproduction Update 2000, Vol. 6 No. 2 pp. 177–189
© European Society of Human Reproduction and Embryology
Haemodynamic evaluation of the first trimester fetus
with special emphasis on venous return
Alexandra Matias1, Nuno Montenegro1,*, José Carlos Areias2 and Luís Pereira Leite1
1Department
of Obstetrics and Gynecology, Porto Medical School, Hospital of S.João, 4200 Porto, and 2Pediatric Cardiology Unit,
Porto Medical School, Hospital of S.João, 4200 Porto, Portugal
Received on June 4, 1999; accepted on January 14, 2000
Knowledge of the fetal circulation is a prerequisite for understanding the physiological behaviour of the developing
fetus. In this overview dealing with Colour and Power Doppler ultrasound findings in the first trimester of pregnancy
and its pathophysiological background, we aim to report on the methodological aspects, normal blood flow waveform
patterns, normal reference values for haemodynamic parameters and potential clinical applications for both arterial
and venous flow information (umbilical artery, descending aorta, middle cerebral artery, umbilical vein, inferior
vena cava, ductus venosus) and atrioventricular valves. Particular emphasis is devoted to the venous return to the
heart. Alterations in venous waveforms, particularly in the ductus venosus, are correlated with the pathophysiology
of some fetal diseases and are suggested as a promising tool for the screening of cardiac impairment and as an
alternative method for fetal biophysical surveillance.
Key words: Colour flow mapping/Doppler/fetal circulation/first trimester pregnancy/venous return
TABLE OF CONTENTS
Introduction
Ultrasound for fetal haemodynamic evaluation in the first
trimester
Ultrasound bioeffects and safety issues
Anatomical and physiological background of fetal
haemodynamics and ultrasound Doppler findings
Concluding remarks
References
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Introduction
Fetal cardiovascular performance is dependent on the
physiological determinants of cardiac function: the systolic
function, primarily determined by the amount of blood distending
the ventricles before contraction (preload), the combined
resistance of the blood, ventricular mass, and central and
peripheral vascular beds (afterload), the intrinsic ability of the
myocardial fibres to contract (contractility), rate of contraction
(heart rate) and the diastolic function. In spite of describing each
vessel individually, for the sake of clarity, none of the cardiac
determinants act in an isolated way and therefore will not cause
independent effects in each vessel.
All these determinants should be considered in the light of the
fetal environment peculiarities: in the fetus there are central
communications between the two ventricles, although each
chamber performs the same primary function as postnatally
(Kenny et al., 1986; Reed et al., 1986). The fetus is greatly limited
in its ability to increase the combined ventricular output by
recruiting the Frank–Starling mechanism, implying that the length
of the cardiac muscle fibres (i.e. the extent of the preload) is
proportional to the end-diastolic volume. This limitation is
partially caused by immaturity and increased stiffness of the
myocardium (Romero et al., 1972; Friedman, 1973). From the late
first trimester onwards, the very compliant umbilical–placental
unit absorbs much of the increase in circulating volume. In
addition, fetal ventricles are very sensitive to changes in afterload,
so that modest increases in afterload will determine a marked
decrease in output (Thornburg and Morton, 1983). The fetal
myocardium cannot generate the same force as the adult
myocardium due to structural and functional immaturity of the
contractile apparatus of the fetal heart (Kenny et al., 1986; Reed
et al., 1986).
Studies in the human fetus are limited by the methods available
for investigation. Pressure and volume flow measurements in the
fetal cardiovascular system require invasive techniques that are
ethically inadvisable. The earliest experience with visualization of
the fetal heart in utero was reported in 1968 (Winsberg, 1968).
Since then, improvements in two-dimensional image resolution
and the introduction of Doppler techniques have made it possible
to examine the human fetal heart and vessels non-invasively and
to determine normal and abnormal cardiovascular physiology. In
the last decade, cardiovascular research in the human fetus has
focused on the study of arterial, cardiac and venous return to the
heart, providing crucial information on fetal circulatory
performance including pathological conditions.
* *To whom correspondence should be addressed at: Ultrasound Unit, University Hospital of S.João, Al. Prof. Hernâni Monteiro, 4200 Porto, Portugal.
Phone: +351 22550 5870; Fax: +351 22550 5870/2509 0371.
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In the 1990s, both technical improvements and
pathophysiological concerns shifted haemodynamic curiosity to
earlier phases of pregnancy, disclosing a diverse physiological
environment worthy of exploration: in the first trimester of
pregnancy, fetal heart rate changes and beat-to-beat variation
appears, fetal movement patterns differentiate, intervillous flow
appears in the placenta and the uterine artery blood flow increases.
In the present review we try to relate this special anatomical/
physiological background with ultrasound Doppler findings for
fetal haemodynamics in the first trimester of gestation.
Ultrasound for fetal haemodynamic evaluation in the
first trimester
In terms of obstetric diagnosis, FitzGerald and Drumm were the
first to succeed in demonstrating a blood flow spectrum in the
umbilical artery and vein by means of a continuous-wave Doppler
technique (FitzGerald and Drumm, 1977). The next step was to
display Doppler information in two dimensions and to relate this
information to the anatomy of the vascular structures. This giant
step was achieved when the combination of an ultrasound probe
operating with pulsed Doppler and the linear transducer of a
realtime scanner was made possible (Eik-Nes et al., 1980, 1981).
Although Doppler-derived blood flow velocity is not identical to
blood flow volume (McDicken, 1991), from clinical experience it
became obvious that the velocity waveform reflects the
circulatory state (Gosling and King, 1975; Pourcelot, 1984). More
recently, a new technique has been proposed (Rubin et al., 1994)
to overcome the limitations from colour Doppler, providing
Power Doppler which is not limited by vessel-beam angle
dependence, aliasing and noise, and is much more sensitive to
low-flow states.
In early phases of pregnancy, transvaginal imaging under
matched conditions is superior in quality to transabdominal
sonograms. Several factors contribute to this improved resolution
of images: using a transvaginal transducer, the ultrasound beam
crosses less amount of overlying tissue, allowing a closer
approach to the fetus; it is possible to use higher emission
frequencies and more strongly focused beams (Schats, 1991;
Kossoff et al., 1991), the possibility of associating colour and
Power Doppler in a transvaginal probe proved helpful as a
pathfinder for fetal vessels, defining their calibre and course,
decreasing the examination time and fetal exposure to acoustic
energy.
Ultrasound bioeffects and safety issues
So far, the known bioeffects of ultrasound energy seem fairly
reassuring. Nevertheless, it is a matter of consensus that scanners
are capable of warming tissue in vivo (thermal effect) (Barnett
et al., 1997; Miller and Nyborg, 1999), applying waves of stress to
tissue (‘acoustic streaming’) (Duck, 1999a) and, under some
circumstances, damaging fragile tissues adjacent to gas (cavitation
effect) (Barnett, 1998). Therefore, it is essential that, in the
enthusiastic search for improved diagnostic efficacy, continuous
vigilance is implemented to evaluate physical, biophysical and
teratological viewpoints (Duck, 1999b).
The first trimester is known to be particularly vulnerable to
external influences and a critical period for organogenesis.
However, at this time, bone ossification is still immature and heat
deposition tends to be considered rather insignificant. On the other
hand, the relatively higher amount of amniotic fluid contributes to
a decrease in the warming effect on the embryo.
Concurrently, special care taken by the operator concerning the
time of exposure of a fixed ultrasound beam and the help provided
by colour and Power Doppler in the identification of the structure
to insonate, should minimize the hazardous effects of pulsed
Doppler. Finally, the total exposure time in the experimental
studies is typically of several minutes, exceeding by far the normal
examination time.
Energy output levels from the transvaginal Doppler transducer
are clearly situated in the safe region for acoustic output of
diagnostic ultrasound equipment (Ide, 1989) and the energy
exposure on the surface of the fetus (ISPTA = 1.2–1.9 mW/cm2) is
well within the recommendations of the Food and Drug
Administration (ISPTA = 94 mW/cm2) (Hussain et al., 1992).
However, the widely adopted realtime display of safety indices
(thermal and mechanical energy output) (American Institute of
Ultrasound in Medicine, 1998) is safer. In our study, and according
to the manufacturer (Aloka, Tokyo, Japan), the maximum thermal
index (TI) and mechanical index (MI) produced by the scanner used
were automatically maintained at <1.0.
No epidemiological evidence of hazard is available on the use of
high energy devices in the first trimester of pregnancy. One study
showed no physical or psychomotor development harassment in
exposed children to transvaginal ultrasound (Gershoni-Baruch
et al., 1991). Wisdom and the ALARA principle (as low as
reasonably achievable) should continue to be a main concern until
safety judgements become more reliable.
Anatomical and physiological background of fetal
haemodynamics and ultrasound Doppler findings
Arterial vessels
By 4 weeks gestation, a pair of dorsal aortae bend ventrally to
form the first aortic arches (Larsen, 1993). Eventually they
become connected to the umbilical arteries that develop in the
connecting stalk at the same time, and are thus, together with
vitelline vessels, among the earliest embryonic arteries to arise.
During the fifth week these connections are obliterated, and the
umbilical arteries develop a new and definitive junction with the
internal iliac arteries.
The ventricle must eject blood against its own inertia and that of
blood, the impedance of central vessels, and the resistance of
peripheral vessels. Examination of this factor (afterload), has been
attempted with Doppler studies on the fetal descending aorta and
umbilical artery in the second half of the pregnancy (Marsàl et al.,
1984; Trudinger et al., 1985, 1987; Tonge et al., 1986; Arabin
et al., 1987a,b; Arbeille et al., 1987). The systematic presence of
forward end-diastolic flow velocities in umbilical and fetal arterial
vessels was settled for second and third trimesters pregnancies,
reflecting a low resistance feto–placental unit (Trudinger et al.,
1985).
The availability of high frequency probes in association with the
transvaginal approach enabled a more detailed visualization of
Colour Doppler and fetal circulation in the first trimester
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Figure 1. (Left) Power Doppler imaging of the umbilical artery at 11 weeks gestation. Note the absence of end-diastolic flow in the pulsed Doppler blood flow waveform
(high-pass filter = 50 Hz). (Right) Power Doppler imaging of the aorta at 12 weeks gestation. Note the low velocity of end-diastolic flow at this stage.
fetal structures early in pregnancy and Doppler recording of blood
flow in first trimester vessels (Wladimiroff et al., 1991a,b,
1992a,b). A completely different scenario exists before the
trophoblastic invasion of the spiral arteries (Brosens, 1964; Hustin
and Schaaps, 1987; Hustin et al., 1988), determining a diverse
haemodynamic behaviour.
Umbilical artery and fetal descending aorta
Flow velocities in the umbilical artery were obtained in the freefloating loop of the umbilical cord, in a straight section to allow
determination of the vessel interrogation angle, which should
always be kept at <20°. Recordings of flow in the descending
aorta were obtained from a sagittal cross-section through the fetal
trunk, displaying a major section of the fetal spine (Wladimiroff
et al., 1991a, 1992a,b). This latter recording can be difficult to
achieve in most situations, as the longitudinal fetal position is
parallel to the transducer.
First trimester studies revealed a high pulsatility index (PI) in
both umbilical artery and fetal aorta, expressed in the absence of
end-diastolic flow velocities at 6–13 weeks gestation and
reflecting the downstream impedance at the fetal placental level
(Wladimiroff et al., 1991a, 1992a,b; Huisman et al., 1993a;
Montenegro, 1993; van Splunder et al., 1996) (Figure 1). There is
a slight increase in PI values from 7 weeks until 11–12 weeks
followed by a decrease afterwards (Montenegro et al., 1994)
(Figure 2).
This reduction may be explained by a drop in umbilical–
placental resistance that coincides in the maternal side with a
resurgence of endovascular trophoblast migration with a second
wave of cells moving into the muscular layer of spiral arteries and
a process of angiogenesis in the placenta (Jauniaux et al., 1992).
This will eventually result in the destruction of the medial
musculo–elastic tissue, transforming thick-walled spiral arteries
into flaccid utero–placental vessels and establishing direct
connections between terminal villi and fetal stem cells (Brosens
et al., 1967; de Wolf et al., 1973; Benirschke and Kaufmann,
1990). In other terms, an initially high resistance territory is
converted in a low pressure conductance system that is ready to
accommodate the increased blood flow volume of the developing
fetus.
Figure 2. Normal ranges (mean ± SD) for umbilical artery pulsatility index at 7–13
weeks gestation (based on crown–rump length measurement) (adapted from
Montenegro et al., 1995).
Figure 3. Transverse cross-section through the lower part of the fetal brain, in a
heart-shaped cross-section, in a 12-week fetus. Note the presence at this stage of
end-diastolic flow, for the middle cerebral artery, as can be seen in the pulsed
Doppler spectrum.
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Occasionally reverse end-diastolic flow in the umbilical arteries
has been recorded in the late first trimester of pregnancy in
association with ulterior fetal demise (Ariyuki et al., 1993) and
with chromosomal abnormalities (Montenegro et al., 1995;
Martinez et al., 1996a,b; Comas et al., 1997). Some groups have
proposed the use of increased resistance in the umbilical artery as
a marker for chromosomal anomalies in early gestation and as an
indication for fetal karyotyping (Martinez et al., 1996b, 1997), but
recently Brown et al. (1998) have proven the PI in the umbilical
artery is useless in screening for chromosomal defects.
Middle cerebral artery
In the late first trimester, it is usually quite difficult to differentiate
flow in the carotid artery and its middle and anterior cerebral
branches. The presence of intracerebral forward end-diastolic
flow in the normal blood flow waveform pattern, as opposed to
absent end-diastolic flow in the descending aorta and umbilical
artery, reflects comparatively lower vascular resistance in the fetal
cerebrum (Figure 3). End-diastolic frequencies have been
recorded in 66% of 39 cases assessed at 10–11 weeks, 2–3 weeks
earlier than in the umbilical artery (Montenegro et al., 1994). The
middle cerebral artery resistance index (RI) falls at 10–13 weeks,
coinciding with a decrease in mean fetal heart rate, and the mean
intracerebral PI value is only marginally higher at 11–13 weeks
gestation (Wladimiroff et al., 1992a) than that established in late
second trimester pregnancies (van den Wijngaard et al., 1989).
The PI in the middle cerebral artery compares with the PI in the
descending aorta and umbilical artery by a factor of 1.4 and 2.0
respectively (Wladimiroff et al., 1992a), probably due to the rapid
growth of the fetal head in early pregnancy.
Venous vessels
It is noticeable that most published reports have concentrated on
the physiology of the arterial vascular system. Little is known
about the preload factor and the haemodynamics of the venous
return to the fetal heart, which differs considerably from the adult
characteristics, since it depends on the presence of three shunts
(foramen ovale, ductus arteriosus and ductus venosus) and the
placenta as a third circulation. In the fetus, under normal
conditions, venous return is mainly controlled by: (i) right atrial
pressure (which exerts a backward force on the veins to draw
blood flow into the right atrium); (ii) mean systemic filling
pressure (which forces systemic blood flow towards the heart and
is related to blood volume); (iii) muscular movement (in
association with the venous valves, it enables the return of blood
from the extremities); (iv) negative intrathoracic pressure during
‘inspiration’ (breathing-like movements have been recognized in
fetuses as early as 11 weeks gestation); (v) peripheral resistance or
afterload (in the fetus the placental circulation is located between
the arterial and the venous system); and (vi) vein physical
properties (the large cross-sectional area and the significant
compliance of veins yield a low resistance territory).
The understanding of such special features and its influence on
fetal haemodynamics has changed with time. Previously, it had
been shown that almost all the blood returning to the heart was
directed across the tricuspid valve to the right ventricle, while a
negligible amount would cross the foramen ovale (Heymann
et al., 1977). However, studies performed in the fetal lamb
clarified the venous streamlining and explained the differences in
oxygen saturation in the upper and lower portions of the body in
the fetus (Edelstone and Rudolph, 1979; Reuss and Rudolph,
1981; Rudolph, 1983). Of umbilical venous blood, ~50% bypasses
the liver through the ductus venosus circumventing the right
atrium, as a well-oxygenated stream in the posterior left portion to
the foramen ovale (via sinistra) (Amoroso et al., 1942; Rudolph,
1983; Kiserud et al., 1992a,b). A right anterior functional
pathway, delivering less oxygenated blood into the right atrium
through the proximal inferior vena cava (IVC), streams
preferentially through the tricuspid valve into the right ventricle
which ejects into the pulmonary trunk, and is then directed
through the ductus arteriosus to the descending aorta and lower
body organs (via dextra) (Amoroso et al., 1942; Rudolph, 1983;
Kiserud et al., 1992a,b).
The primitive venous system consists of three major
components, all of which are initially bilaterally symmetrical: the
cardinal system, which drains the head, neck, body wall, and
limbs; the vitelline veins, which initially drain the yolk sac; and
the umbilical veins, which develop in the connecting stalk and will
soon carry oxygenated blood from the placenta to the embryo
(Montenegro et al., 1999). All three undergo extensive
modifications during development as systemic venous return is
shifted to the right atrium: the right umbilical vein obliterates
during the second month, whereas the left umbilical vein persists
and establishes a new connection with the ductus venosus (Larsen,
1993).
Umbilical vein
Waveform velocities in the umbilical vein (UV) have been
obtained from either the free-floating loop (Eik-Nes et al., 1981;
Gudmundsson et al., 1991; Indik et al., 1991; St John Sutton et al.,
1991; Rizzo et al., 1992) or the intra-abdominal part of the
umbilical vein (Gill and Kossoff, 1984; Griffin et al., 1985;
Erskine and Ritchie, 1985; Lingman et al., 1986) in late
pregnancy. In the first trimester, in order to avoid interference
with the arteries in the vulnerable free-floating part of the cord, the
most reliable technique is to obtain a transverse cross-section of
the fetal abdomen at the level of the cord insertion and to place the
sample volume over the intra-abdominal part of the UV 1–2 mm
from the cord insertion. Besides considering determinant aspects
to ensure reproducible and high quality waveforms, such as the
exact location of the Doppler sample volume, the sample size and
interrogation angle, special care is needed to obtain Doppler blood
flow waveforms during fetal apnoea.
At 12–15 weeks gestation, Huisman et al. (1993a,b) determined
the normal pattern of flow velocity waveforms in the UV with a
characteristically low blood velocity (15–25 cm/s). Additionally,
they investigated the reproducibility of Doppler recordings at this
stage of pregnancy, stating a reliability of 91–99 % for all the
recordings and parameters studied (Huisman et al., 1993c,d).
Doppler blood flow waveforms in the umbilical vein (UV) and
the porta circulation are, in contrast to the systemic venous
circulation, even and without fluctuation, with a continuous
forward pattern (Figure 4). A heart synchronous pulsatile pattern
can occasionally be recorded in early pregnancy, but tends to
disappear at 9–12 weeks gestation (Rizzo et al., 1992; Matias
et al., 1996). The physiological presence of such pulsations seems
to be related to IVC flow patterns. An abnormal pulsating pattern
Colour Doppler and fetal circulation in the first trimester
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Ductus venosus
Figure 4. Identification of the umbilical vein with Power Doppler and the
respective blood flow waveform obtained by pulsed Doppler at 11 weeks gestation.
of the UV has also been reported in an otherwise normal
pregnancy, presenting with a knot on the cord. Characteristic low
frequency fluctuation, non-related to the heart rate, can also be
apparent in this vessel during fetal breathing movements. Later in
pregnancy, the presence of pulsations in the UV, with a decrease
in velocity by >15% from the basal state, has a completely
different meaning and has been described in association with
congestive heart failure in fetuses with non-immune hydrops and
imminent asphyxia (Gudmundsson et al., 1996).
The mean UV blood velocity recorded from the intra-abdominal
part of the vein was 12.6 (3.1 cm/s, without notorious changes
throughout pregnancy (Huisman et al., 1993a; Matias et al.,
1996). The value (mean ± SD) for the ductus venosus/umbilical
vein was 3.2 ± 0.8 and the time-averaged velocity in the UV was
9.7 ± 2.9 cm/s at 12–15 weeks gestation (Huisman et al., 1993a).
Interestingly, no statistically significant correlation could be
established between the UV velocities and cardiac cycle length
(r = –0.45) (Huisman et al., 1993a).
Ductus venosus (DV) is a tiny vessel with a central role as
distributor of well-oxygenated umbilical venous blood,
functionally arterialized and behaving as a different vein (Kiserud,
1997). This branchless vessel is the sole direct connection
between the umbilical vein and the inferior atrial inlet, shunting
half the umbilical blood directly to the left atrium through the
foramen ovale (Figure 5) (Rudolph, 1983; Kiserud et al., 1991;
Schmidt et al., 1996). These preferential pathways for umbilical
venous and distal IVC flow contribute not only to ensure higher
oxygen saturation and higher glucose concentration in ascending
aorta as compared with descending aortic blood.
The DV connects the intra-abdominal umbilical vein (umbilical
sinus) to the IVC, running from anterior to posterior, upward and
slightly towards the left side to join the IVC in a rather steep
course (Figure 5) (Chinn et al., 1982; Champetier et al., 1989;
Kiserud et al., 1992a; Montenegro et al., 1997a). Throughout
pregnancy the DV develops a trumpet-like shape and remains a
narrow isthmic structure, barely >2 mm in diameter. This unusual
architecture for a vein accelerates the blood jet crossing the left
side of the IVC directly towards the right atrium, with the highest
velocities being reached at the isthmic portion. Computational
simulations developed in order to study the influence of
anatomical features of the DV on the haemodynamics of the
vessel, showed similar findings, with lower systolic (S), diastolic
(D) and atrial (A) velocities at the outlet portion (Pennati et al.,
1997).
The narrowest portion of the DV has been insistently related
with the presence of a sphincter, but even though neural and
muscular elements were isolated (Pearson and Sauter, 1969;
Chacko et al., 1953), no agreement was reached.
DV blood flow waveforms can be obtained from either a
transverse or longitudinal fetal view, since the DV bends as it
traverses the fetal abdomen. In the late first trimester of
pregnancy, its tiny dimensions make it unlikely to be visualized,
without the concurrent help of colour or Power Doppler.
According to the anatomical disposition of this vessel, the right
Figure 5. (a) Power Doppler image of the venous return to the heart [note the trumpet-like shape of the ductus venosus (DV) with acceleration of blood into the ascending
aorta through the left atrium] in a 13-week fetus; (b) Schematic view of the relationship between the inlet of the inferior vena cava (ivc) and the foramen ovale (fo). Less
oxygenated blood from the IVC predominantly enters the right atrium (ra), and the well oxygenated umbilical blood is preferentially directed through the DV to the left
atrium (la) (adapted from Kiserud and Eik-Nes, 1995).
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A.Matias et al.
Figure 6. (a) Normal blood flow waveform pattern obtained in the ductus venosus of a 13-week fetus by pulsed Doppler. (b) Schematic representation of ductus venosus
Doppler blood flow waveform, depicting systolic (S)- wave, early diastolic (D)-wave and atrial contraction (A-trough).
Figure 7. Central image depicting an ideal blood flow waveform obtained in the ductus venosus of a 12-week old fetus using pulsed Doppler. The flow waveform on the
far left demonstrates contamination by the umbilical vein, and the waveform on the far right shows contamination by the inferior vena cava.
para–sagittal plane should be the one recommended to insonate
the DV and the transvaginal approach gives a higher rate of
successful velocity recordings (Montenegro et al., 1997a). The
oblique transection of the abdomen is, however, less suitable for
estimating the angle of interrogation, since the DV has its steepest
course in the sagittal plane (Kiserud and Eik-Nes, 1995). The
examination is done during fetal quiescence and apnoea, due to
the substantial impact of respiratory movements on the velocities
(Huisman et al., 1993b). Reliability studies of DV waveform
recording ranged at 94.5–98.5% (Huisman et al., 1993c,d).
Blood flow waveform in the DV is clearly pulsatile, with three
components (Figure 6). Flow velocities are highest during
ventricular systole (S-wave) and ventricular diastole (D-wave),
the two forward components. The third component is
continuously anterograde and the lowest velocities are observed
during atrial contraction (A-wave). Therefore, in relation to the
other precordial veins, two important differences should be noted:
the velocity in the ductus venosus is particularly high (timeaveraged flow velocity is 3.2- and 2.7-fold higher than in the UV
and IVC respectively) (Huisman et al., 1993a,e), and an
anterograde velocity is maintained during atrial contraction. This
latter aspect may well be the consequence of the placental pressure
gradient over the DV and UV (Wladimiroff and Huisman, 1994).
Special care should be taken to avoid examining the wrong vessel
and to include neighbouring vessels in the sample volume: the
positioning of the sample volume too distally will overestimate
atrial contraction velocities by ‘contamination’ from the UV
spectrum, whereas when it is placed too proximally the
‘contamination’ by the IVC will underestimate the A-wave
velocity (Figure 7) (Montenegro et al., 1997a).
Pioneering studies to characterize flow velocity waveforms in
the DV were performed at 10–15 weeks gestation (Huisman et al.,
1992, 1993a; Montenegro et al., 1997a). Peak S and D waves
showed a significant correlation with gestational age (r = +0.66
and +0.58, P < 0.001 respectively) and peak systolic/diastolic
velocity (S/D) ratio remained constant throughout pregnancy in
the DV (1.1 ± 0.1) (Huisman et al., 1992). The various parameters
from the DV waveforms obtained at 10–14 weeks gestation
revealed a normal mean velocity for the peak systolic and diastolic
velocities in the DV of 24.8 ± 10.0 cm/s and 18.6 ± 8.4 cm/s
respectively (Montenegro et al., 1997a). The normal values
defined for the A-wave trough were 4.5 ± 0.9 cm/s and none of
these parameters were affected by fetal heart rate (Montenegro
et al., 1997a).
Until recently, late diastolic reversal of DV flow had been
observed only in late pregnancy in cases of cardiac defects
(Kiserud et al., 1993) and severe intra-uterine growth retardation
(Kiserud et al., 1994), pointing out to an impaired cardiac
performance. In-vivo evidence of heart failure was provided by
our group by the demonstration of abnormal flow in the DV
during atrial contraction at 10–14 weeks gestation in
chromosomally abnormal fetuses with increased nuchal
translucency thickness (Figure 8) (Montenegro et al., 1997b;
Matias et al., 1997; Huisman and Bilardo, 1998; Matias et al.,
1998a; Borrell et al., 1998). Absent or reversed A-wave in the DV
was also recorded in a high proportion of fetuses with increased
nuchal translucency and normal karyotype displaying a cardiac
defect (Figure 9) (Areias et al., 1998; Matias et al., 1998b, 1999).
Such findings are probably the first expression of fetal distress,
indirectly reflecting cardiac diastolic function. These results
suggest that assessment of DV blood flow is likely to be a helpful
method of selecting for invasive testing those pregnancies
considered to be at high risk after first trimester screening and
Colour Doppler and fetal circulation in the first trimester
Figure 8. (Top) Two-dimensional B-mode imaging of the venous return to the heart.
UV = umbilical vein; DV = ductus venosus; IVC = inferior vena cava; RA = right
atrium. (Middle) Normal pattern of a ductus venosus blood flow waveform obtained
at 10 weeks gestation using pulsed Doppler. (Bottom left) Anomalous pattern of
ductus venosus blood flow waveforms (reversal of flow during atrial contraction) in
a case of trisomy 18 at 13 weeks (nuchal translucency = 10 mm) and (bottom right)
in a case of trisomy 21 at 10 weeks (nuchal translucency = 4.4 mm).
defining the group of chromosomally normal fetuses at risk of
having a major cardiac defect (Matias et al., 1998a, 1999).
Inferior vena cava
IVC blood velocity at the entrance of the right atrium can give
varying velocity patterns. This may be due to blood entering the
area from at least five vessels (sub-diphragmatic vestibulum)
(Huisman et al., 1992): IVC, ductus venosus, and three hepatic
veins. In order to obtain non-contaminated and reproducible
waveforms, the sample volume should be placed between the DV
and renal veins. However, obtaining optimal blood velocity signs
in the IVC can be difficult due to the large angle of insonation. At
an angle of >45°, parts of the IVC blood flow waveform can be
invisible under the filter level. As an alternative to the IVC
recording, blood velocities can be obtained in the hepatic veins,
since they can be recorded at an angle close to 0°.
Typically, the IVC blood waveform presents two peaks of blood
velocity in the flow towards the heart: the first corresponds to the
filling of the atria during ventricular systole (S-wave) (Reed et al.,
1990). This might be explained by reduced pressure in the atria
caused by atrial wall relaxation and resulting from the downward
movement of atrio–ventricular valve (AV-valve) annulus during
ventricular contraction. The second peak of blood flow velocity
(D-wave) occurs at the onset of diastole and corresponds to the
183
Figure 9. On the left hand side of the image, progression of nuchal translucency
thickness (NT) in a case with increased NT at 10 weeks (NT = 5.9 mm) and 12
weeks gestation (NT = 2.9 mm) is shown. At the bottom, a B-mode image
illustrates a transposition of the great arteries suspected in this fetus. On the right
hand side, abnormal flow in the ductus venosus, with reversed flow during atrial
contraction, was recorded at 12 weeks gestation (top), along with normal blood
flow waveforms in the inferior vena cava (middle) and umbilical artery (bottom).
Karyotyping revealed a normal male fetus. An echocardiographic examination
performed at 20 weeks gestation confirmed the transposition of the great vessels.
early filling of the ventricles or to the early diastole (E) peak of
blood velocity at the AV-valves of the heart (Reed et al., 1990).
Finally, at the end of diastole, a reduction in blood velocity occurs,
frequently resulting in a one-component reverse blood flow
pattern, corresponding to atrial contraction (A-wave). The degree
of reversion in blood velocity depends on the site of measurement
(most prominent near the heart) and on the gestational age (at 12–
16 weeks gestation there is a significantly higher percentage of
retrograde flow during atrial contraction than later in pregnancy)
(Huisman et al., 1991; Wladimiroff et al., 1992b; Matias et al.,
1996). This decrease of A-wave preponderance along gestation
may be ascribed to a relatively low cardic ventricular compliance
in the late first and early second trimesters of pregnancy (Romero
et al., 1972; Friedman et al., 1968; Nakanishi and Jarmakani,
1984; Reed et al., 1986).
Moreover, as for the other vessels, consideration should be
taken regarding fetal movements, especially breathing
movements, and large variations on fetal heart rate. Blood flow
towards the heart can be increased by 20-fold during the
inspiratory phase of fetal breathing movements, compared with
the apnoeic state (Marsál et al., 1984; Chiba et al., 1985; van der
Mooren et al., 1991b; Huisman et al., 1993b), with a nonsignificant alteration in the percentage of reverse flow during
atrial contraction (Huisman et al., 1993b). This increase in IVC
velocities may be explained by a raised pressure difference
between thorax and abdomen resulting in a reduction in IVC
vessel diameter and an increase of blood volume directed to the
right atrium. Extra blood could originate from the hepatic vascular
184
A.Matias et al.
bed as it is squeezed into the IVC during the temporary increase of
intra-abdominal pressure (van Eyck et al., 1991; Huisman et al.,
1993b). Therefore, recording of venous blood flow velocities
should be performed during fetal quiescence.
Concerning fetal heart rate, a rise in the percentage of reverse
flow during fetal bradycardia (<120 bpm) and tachycardia (>160
bpm) has been found (Reed et al., 1990), suggesting less optimal
atrial contraction under these circumstances. The absence of a
correlation between heart rate and percentage of reverse flow in
the IVC suggests that the heart rate is independent of the
percentage of reverse flow changes observed at 11–16 weeks
gestation (Wladimiroff et al., 1992b).
The S and D peak velocities normally increase with gestational
age (Huisman et al., 1991; Wladimiroff et al., 1992b; Matias
et al., 1996). The S/D ratio, however, remains unchanged
throughout gestation, being 1.62 ± 0.2. The nearly two-fold
increase in time-averaged velocity in the IVC may be caused by a
higher volume flow in this vessel, increased cardiac contractility
and physiological decrease in placental vascular resistance with
reduced afterload during the second half of pregnancy (den Ouden
et al., 1990).
A statistically significant negative correlation with gestational
age was established for the percentage of reverse flow during
atrial contraction (r = –0.80; P < 0.0001) (Waldimiroff et al.,
1992a,b) and a positive correlation (r = +0.58; P > 0.0001) was
documented between time-averaged velocity and gestational age.
Absolute values for percentage reverse flow in the fetal IVC at
11–12 weeks gestation (Huisman et al., 1991; Matias et al., 1996)
are twice the values found at 16 weeks (16.6 ± 6.2 cm/s;
Wladimiroff and Huisman, 1994; Matias et al., 1996) and four
times the values established during late trimester pregnancies
(5.2 ± 3.6 cm/s) (Wladimiroff and Huisman, 1994; Matias et al.,
1996). The D/A ratio is unrelated to gestational age and is
normally >1. Similarly, peak S/D (1.13 ± 0.05) and time velocity
integral S/D did not significantly change with gestation.
Cardiac contractility
Again the fetal cardiac load has peculiar characteristics in the first
trimester of pregnancy: during this period the maturation of the
vagal system is established with the lowering of the fetal heart rate
baseline (Joupilla et al., 1971; Hertzberg et al., 1988; Montenegro
et al., 1994, 1998; Wisser and Dirschedl, 1994) and the
appearance of beat-to-beat variation (Wladimiroff and Seelen,
1972a,b). Simultaneously, a relatively high placental vascular
resistance characterizes this early stage of pregnancy (den Ouden
et al., 1990). These high afterload conditions are reflected by
absent end-diastolic flow in the umbilical artery and aorta until
12–13 weeks gestation (den Ouden et al., 1990; Wladimiroff
et al., 1992a; Montenegro et al., 1994).
It is well known that flow velocities at the cardiac level are
influenced by preload, contractile function, afterload and heart
rate. Despite the limitations of non-invasive Doppler techniques,
which are unable to measure confidently fetal and venous and
arterial volume flow in the late first trimester accurately,
transvaginal Doppler echocardiography can be used to study early
human fetal cardiac function indirectly. Several attempts have
been made to quantify cardiac stroke volume and force at the level
of the outflow tracts and atrioventricular valves, by means of
Doppler flow (Maulik et al., 1984; Kenny et al., 1986; Reed et al.,
1986; Allan et al., 1987; Matias et al., 1996). However, the results
were disappointing due to the poor reproducibility (Beeby et al.,
1991).
A more successful approach to indirectly evaluating cardiac
contractility is the assessment of diastolic function in the fetus.
Doppler blood flow velocities across the tricuspid and mitral valve
have been used as indicators of ventricular filling. In contrast with
the adult heart, in which the peak velocity during early diastole
(peak E velocity) is significantly higher than the peak velocity in
late diastole (peak A velocity), the relationship between both
waves is inverted in the fetus. At this stage, fetal ventricles are
exquisitely sensitive to afterload but unable to cope successfully
with changes in loading conditions (Gilbert, 1982).
Atrioventricular tracings were obtained in the first studies in the
second half of pregnancy (Reed et al., 1986; Allan et al., 1987;
van der Mooren et al., 1991a). For both the tricuspid and mitral
valves, the peak A velocity exceeded the peak E velocity
throughout pregnancy and in the first 3 weeks postnatally (Areias
et al., 1992). The A/E ratio tended to decrease with advancing
gestational age. For the tricuspid valve, the decreasing A/E ratio
was caused by an increase in peak E velocity with increasing
gestational age with unchangeable A wave. For the mitral valve,
the decreasing A/E ratio resulted from a decrease in A wave
velocity whereas E wave did not change with advancing
gestational age. When comparing tricuspid and mitral velocity
values, both tricuspid peak E and A velocities systematically
exceeded the mitral peak E and A velocities. From this study we
can infer the striking impairment of ventricular relaxation in the
fetus.
These results agree well with the results of experiments
performed in fetal lambs (Romero et al., 1972) that demonstrated
a much less compliant fetal ventricle than a neonatal ventricle.
Studies in isolated fetal muscle strips have clearly demonstrated
that fetal myocardium cannot generate the same force as adult
myocardium (Friedman, 1968; Nakanishi and Jarmakani, 1984;
Reed et al., 1986). This well established impairment of ventricular
contractility has been ascribed to multiple factors: decreased
sympathetic innervation and decreased β-adrenoceptor
concentration (Chen et al., 1979), immaturity of sarcoplasmic
reticulum in both structure and function (Maylie, 1982; Nassar
et al., 1987; Page and Buecker, 1981), and decreased
concentration and function of myofibrils (Friedman, 1968; Nassar
et al., 1987). Ultimately, the different contributions of the early
and late filling phases to the decrease in A/E ratio observed in
human fetuses probably reflect differences in function and
maturation of the two ventricles before birth.
The availability of transvaginal Doppler techniques has opened
the possibility of studying the fetus in greater detail in earlier
phases of pregnancy (Timor-Tritsch, 1988). Preliminary results on
fetal cardiac flow velocities in the late first trimester of pregnancy
appeared in the literature in 1991 (Wladimiroff et al., 1991a,b;
Huisman et al., 1992; Matias et al., 1996) and reproducibility
issues were addressed (van der Mooren et al., 1992). Peak
velocities during atrial contraction were nearly twice as high as
those during early diastolic filling, reflecting again a restricted
ventricular compliance, i.e. a more pronounced stiffness of the
fetal ventricles in early gestation. Therefore, the Frank–Starling
mechanism is greatly impaired or even not operating, at least in
Colour Doppler and fetal circulation in the first trimester
185
Figure 10. (Left) B-mode image of a 7 week old embryo (left hand side) and M-mode register of valve motion in the same embryo, enabling the measurement of fetal heart
rate (142 bpm). (Right) Graphic representation of embryonic/fetal heart rate (bpm) in relation to gestational age (5–13 weeks) and review of the literature (adapted from
Rempen et al., 1990).
early phases of pregnancy, and as a result, the fetal ventricles are
limited in their ability to increase stroke volume in response to
increased heart rate or decreased afterload.
Flow velocity waveforms at the fetal atrioventricular valves are
recorded following a strict methodology, similarly applied later in
pregnancy: a four-chamber view should be obtained and the
Doppler sample volume placed immediately distal to the
atrioventricular valves (Matias et al., 1996). Because mitral and
tricuspid valve structures are situated close to each other on a four
chamber cross-sectional view in such a small fetus, distinction
between trans-mitral and trans-tricuspid blood flow velocity
waveforms can be a major hindrance. The presence of a fluidfilled stomach can help in establishing the left side of the heart.
Mean flow peak velocities for trans-atrioventricular blood flow
were defined at 11–13 weeks gestation (Wladimiroff et al., 1991b;
Matias et al., 1996): 20.5 ± 3.2 cm/s for peak E wave velocity and
38.6 ± 4.7 cm/s. E/A ratio was 0.53 ± 5.4. The right ventricle is the
dominant ventricle, ejecting the highest proportion of the
combined ventricular output into the descending aorta. These
velocities were shown to increase with advancing gestation,
probably due to functional and structural maturation of the
ventricles and decreased peripheral vascular resistance (den
Ouden et al., 1990).
Fetal heart rate
Heart rate is relatively easy to obtain from the early phases of
pregnancy. The detection of fetal heart activity in the first
trimester using pulsed ultrasound with time–motion mode was
first described by Robinson in 1972. In 1973, the detection of a
human fetal heart rate between 44 days and 15 weeks after the first
day of the last menstrual period was reported (Robinson and
Shaw-Dunn, 1973). Since then, there are multiple studies
evaluating the course of heart rate, e.g. in one of the papers
(Wisser and Dirschedl, 1994), embryonic heart rate (EHR) (Figure
10, left) in dated embryos is described as showing an increase up
to 63 post-menstrual days (or 22 mm of greatest length); in
another study (Deaton et al., 1997), the prognostic value of fetal
heart rate in the first weeks after conception was reported in
relation to the appearance of the yolk sac and maternal age.
Maximal EHR was reached when morphological development of
the embryonic heart was completed. Thereafter a steady decrease
of EHR was noted at 10–14 weeks gestation (Joupilla et al., 1971;
Hertzberg et al., 1988; Montenegro et al., 1994, 1998; Wisser and
Dirschedl, 1994) (Figure 10, right). The initial increase in EHR
may be explained by the morphological development of the heart
and the predominance of intrinsic myogenic activity (Anderson
and Taylor, 1972; Davies et al., 1983; Veenstra and DeHaan,
1988). The subsequent decrease may be the result of the functional
maturation of the parasympathetic system (Robinson and ShawDunn, 1973; Wisser and Dirschedl, 1994; Wladimiroff and
Seelen, 1972a,b), to the expansion of the vascular bed and to the
establishment of secondary connections among chorionic,
vitelline, umbilical and embryonic vessels (O’Rahilly and Müller,
1987).
In a recent study, we demonstrated that reliable and
reproducible information concerning the embryonic/fetal heart
rate, during the first trimester of pregnancy, could be obtained
from a single measurement (Montenegro et al., 1998). The intraindividual variation was lower than the inter-individual variation,
but the former was significantly lower at <10 weeks gestation.
Immature neurogenic control of the fetal heart rate can explain the
more important physiological variation found after 9 weeks,
contrasting with the more preponderant autonomic neurogenic
activity expected before.
Low fetal heart rate in the first trimester of pregnancy has been
shown to be a good predictor of embryonic death or impending
fetal demise (Laboda et al., 1989; Rempen, 1990; May and
Sturtvant, 1991; Merchiers et al., 1991; Montenegro et al., 1994).
These studies provide direct support for the hypothesis that
cardiovascular competence is crucial during embryogenesis
(Clark and Hu, 1990). More recently, other authors (Hyett et al.,
1996) have demonstrated the importance of including the
measurement of fetal heart rate as part of the first trimester routine
ultrasound. In fact, the sensitivity of the screening for fetal
chromosomal abnormalities reached 76% by a combination of
maternal age and nuchal translucency thickness, but was notably
186
A.Matias et al.
improved to 83% by the inclusion of fetal heart rate (Hyett et al.,
1996). Suspicion of a chromosomally abnormal fetus may
otherwise be risen in the first trimester by an abnormal fetal heart
rate (bradycardia in trisomy 18 and triploidy; tachycardia in
fetuses with trisomy 21, trisomy 13 or Turner syndrome) (Hyett
et al., 1996; Martinez et al., 1998).
Finally, studies have shown that as a result of the restricted
Frank–Starling mechanism in the fetus, fetal heart rate changes
within the normal heart rate range do not seem to considerably
influence fetal cardiac output (Kenny et al., 1987; van der Mooren
et al., 1991a).
Concluding remarks
Non-invasive assessment of fetal haemodynamics in early phases
of human pregnancy can be achieved, preferentially by using
transvaginal Doppler ultrasound. Considering the limitation
imposed by the diminished dimensions of the vessels to be
explored, the contribution of Colour and Power Doppler turned
out to be essential in early haemodynamic studies. More recently,
this latter technique became the method of choice to localize the
fetal vessels and to facilitate the ulterior quantification of flow
parameters by pulsed Doppler, due to its angle-independence and
higher sensitivity to low velocity flows. Consequently, the
examination time could be reduced as well as the embryonic–fetal
exposure to acoustic energy.
Information yielded by the arterial compartment has been of
paramount importance to the knowledge of the physiological
aspects in early phases of human pregnancy. However, the clinical
utility of arterial blood flow assessment in the late first trimester
has recently been challenged.
In contrast, the importance of venous system evaluation in the
haemodynamic assessment of the fetus is gaining supporters and it
seems wise to consider this information from the early phases of
pregnancy. Owing to the characteristics of the venous system (low
pressure, low velocity and compliant walls), it easily reflects
changes in central circulation. Thus it may provide the clinician
with a promising screening or even diagnostic tool that may
anticipate serious alterations in fetal wellbeing at a very early
stage, and prove to be an alternative tool in fetal surveillance.
It is becoming recognized that venous waveform alterations
may be useful in disclosing deviations in fetal physiology, as an
early manifestation of myocardial compromise. The most
systematic alterations have been identified in the ductus venosus,
in which alterations of flow during atrial contraction can
constitute the earliest sign of cardiac impairment and identify the
fetuses at risk of chromosomal abnormality and/or heart failure.
Studies on fetal venous return are still insufficient and its
clinical potential is not fully explored. This should not deter the
clinician from applying the ‘venous’ approach, provided results
are interpreted cautiously. However, new studies on venous
parameters are still needed to clarify the physiopathological
meaning of such alterations. In many situations, e.g. hypoxaemia,
placental insufficiency, anaemia, cardiac diseases etc, the ductus
venosus seems to respond differently from other veins. It may well
be that this tiny, inconspicuous vessel deserves far more attention,
as it can probably yield a great deal of valuable information.
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Received on June 4, 1999; accepted on January 14, 2000