Human Reproduction Update 2000, Vol. 6 No. 2 pp. 177–189 © European Society of Human Reproduction and Embryology

Haemodynamic evaluation of the first trimester fetuswith 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 developingfetus. In this overview dealing with Colour and Power Doppler ultrasound findings in the first trimester of pregnancyand its pathophysiological background, we aim to report on the methodological aspects, normal blood flow waveformpatterns, normal reference values for haemodynamic parameters and potential clinical applications for both arterialand venous flow information (umbilical artery, descending aorta, middle cerebral artery, umbilical vein, inferiorvena cava, ductus venosus) and atrioventricular valves. Particular emphasis is devoted to the venous return to theheart. Alterations in venous waveforms, particularly in the ductus venosus, are correlated with the pathophysiologyof some fetal diseases and are suggested as a promising tool for the screening of cardiac impairment and as analternative method for fetal biophysical surveillance.

Key words: Colour flow mapping/Doppler/fetal circulation/first trimester pregnancy/venous return

TABLE OF CONTENTS

Introduction 177Ultrasound for fetal haemodynamic evaluation in the first

trimester 178Ultrasound bioeffects and safety issues 178Anatomical and physiological background of fetal

haemodynamics and ultrasound Doppler findings 178Concluding remarks 186References 186

Introduction

Fetal cardiovascular performance is dependent on thephysiological determinants of cardiac function: the systolicfunction, primarily determined by the amount of blood distendingthe ventricles before contraction (preload), the combinedresistance of the blood, ventricular mass, and central andperipheral vascular beds (afterload), the intrinsic ability of themyocardial fibres to contract (contractility), rate of contraction(heart rate) and the diastolic function. In spite of describing eachvessel individually, for the sake of clarity, none of the cardiacdeterminants act in an isolated way and therefore will not causeindependent effects in each vessel.

All these determinants should be considered in the light of thefetal environment peculiarities: in the fetus there are centralcommunications between the two ventricles, although eachchamber 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 byrecruiting the Frank–Starling mechanism, implying that the lengthof the cardiac muscle fibres (i.e. the extent of the preload) isproportional to the end-diastolic volume. This limitation ispartially caused by immaturity and increased stiffness of themyocardium (Romero et al., 1972; Friedman, 1973). From the latefirst trimester onwards, the very compliant umbilical–placentalunit absorbs much of the increase in circulating volume. Inaddition, fetal ventricles are very sensitive to changes in afterload,so that modest increases in afterload will determine a markeddecrease in output (Thornburg and Morton, 1983). The fetalmyocardium cannot generate the same force as the adultmyocardium due to structural and functional immaturity of thecontractile apparatus of the fetal heart (Kenny et al., 1986; Reedet al., 1986).

Studies in the human fetus are limited by the methods availablefor investigation. Pressure and volume flow measurements in thefetal cardiovascular system require invasive techniques that areethically inadvisable. The earliest experience with visualization ofthe fetal heart in utero was reported in 1968 (Winsberg, 1968).Since then, improvements in two-dimensional image resolutionand the introduction of Doppler techniques have made it possibleto examine the human fetal heart and vessels non-invasively andto determine normal and abnormal cardiovascular physiology. Inthe last decade, cardiovascular research in the human fetus hasfocused on the study of arterial, cardiac and venous return to theheart, providing crucial information on fetal circulatoryperformance 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 andpathophysiological concerns shifted haemodynamic curiosity toearlier phases of pregnancy, disclosing a diverse physiologicalenvironment worthy of exploration: in the first trimester ofpregnancy, fetal heart rate changes and beat-to-beat variationappears, fetal movement patterns differentiate, intervillous flowappears 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 forfetal haemodynamics in the first trimester of gestation.

Ultrasound for fetal haemodynamic evaluation in thefirst trimester

In terms of obstetric diagnosis, FitzGerald and Drumm were thefirst to succeed in demonstrating a blood flow spectrum in theumbilical artery and vein by means of a continuous-wave Dopplertechnique (FitzGerald and Drumm, 1977). The next step was todisplay Doppler information in two dimensions and to relate thisinformation to the anatomy of the vascular structures. This giantstep was achieved when the combination of an ultrasound probeoperating with pulsed Doppler and the linear transducer of arealtime scanner was made possible (Eik-Nes et al., 1980, 1981).Although Doppler-derived blood flow velocity is not identical toblood flow volume (McDicken, 1991), from clinical experience itbecame obvious that the velocity waveform reflects thecirculatory state (Gosling and King, 1975; Pourcelot, 1984). Morerecently, a new technique has been proposed (Rubin et al., 1994)to overcome the limitations from colour Doppler, providingPower Doppler which is not limited by vessel-beam angledependence, aliasing and noise, and is much more sensitive tolow-flow states.

In early phases of pregnancy, transvaginal imaging undermatched conditions is superior in quality to transabdominalsonograms. Several factors contribute to this improved resolutionof images: using a transvaginal transducer, the ultrasound beamcrosses less amount of overlying tissue, allowing a closerapproach to the fetus; it is possible to use higher emissionfrequencies and more strongly focused beams (Schats, 1991;Kossoff et al., 1991), the possibility of associating colour andPower Doppler in a transvaginal probe proved helpful as apathfinder for fetal vessels, defining their calibre and course,decreasing the examination time and fetal exposure to acousticenergy.

Ultrasound bioeffects and safety issues

So far, the known bioeffects of ultrasound energy seem fairlyreassuring. Nevertheless, it is a matter of consensus that scannersare capable of warming tissue in vivo (thermal effect) (Barnettet al., 1997; Miller and Nyborg, 1999), applying waves of stress totissue (‘acoustic streaming’) (Duck, 1999a) and, under somecircumstances, damaging fragile tissues adjacent to gas (cavitationeffect) (Barnett, 1998). Therefore, it is essential that, in theenthusiastic search for improved diagnostic efficacy, continuousvigilance is implemented to evaluate physical, biophysical andteratological viewpoints (Duck, 1999b).

The first trimester is known to be particularly vulnerable toexternal influences and a critical period for organogenesis.However, at this time, bone ossification is still immature and heatdeposition tends to be considered rather insignificant. On the otherhand, the relatively higher amount of amniotic fluid contributes toa decrease in the warming effect on the embryo.

Concurrently, special care taken by the operator concerning thetime of exposure of a fixed ultrasound beam and the help providedby colour and Power Doppler in the identification of the structureto insonate, should minimize the hazardous effects of pulsedDoppler. Finally, the total exposure time in the experimentalstudies is typically of several minutes, exceeding by far the normalexamination time.

Energy output levels from the transvaginal Doppler transducerare clearly situated in the safe region for acoustic output ofdiagnostic ultrasound equipment (Ide, 1989) and the energyexposure on the surface of the fetus (ISPTA = 1.2–1.9 mW/cm2) iswell within the recommendations of the Food and DrugAdministration (ISPTA = 94 mW/cm2) (Hussain et al., 1992).However, the widely adopted realtime display of safety indices(thermal and mechanical energy output) (American Institute ofUltrasound in Medicine, 1998) is safer. In our study, and accordingto the manufacturer (Aloka, Tokyo, Japan), the maximum thermalindex (TI) and mechanical index (MI) produced by the scanner usedwere automatically maintained at <1.0.

No epidemiological evidence of hazard is available on the use ofhigh energy devices in the first trimester of pregnancy. One studyshowed no physical or psychomotor development harassment inexposed children to transvaginal ultrasound (Gershoni-Baruchet al., 1991). Wisdom and the ALARA principle (as low asreasonably achievable) should continue to be a main concern untilsafety judgements become more reliable.

Anatomical and physiological background of fetalhaemodynamics and ultrasound Doppler findings

Arterial vessels

By 4 weeks gestation, a pair of dorsal aortae bend ventrally toform the first aortic arches (Larsen, 1993). Eventually theybecome connected to the umbilical arteries that develop in theconnecting stalk at the same time, and are thus, together withvitelline vessels, among the earliest embryonic arteries to arise.During the fifth week these connections are obliterated, and theumbilical arteries develop a new and definitive junction with theinternal iliac arteries.

The ventricle must eject blood against its own inertia and that ofblood, the impedance of central vessels, and the resistance ofperipheral vessels. Examination of this factor (afterload), has beenattempted with Doppler studies on the fetal descending aorta andumbilical artery in the second half of the pregnancy (Marsàl et al.,1984; Trudinger et al., 1985, 1987; Tonge et al., 1986; Arabinet al., 1987a,b; Arbeille et al., 1987). The systematic presence offorward end-diastolic flow velocities in umbilical and fetal arterialvessels 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 thetransvaginal approach enabled a more detailed visualization of

Colour Doppler and fetal circulation in the first trimester 179

fetal structures early in pregnancy and Doppler recording of bloodflow in first trimester vessels (Wladimiroff et al., 1991a,b,1992a,b). A completely different scenario exists before thetrophoblastic invasion of the spiral arteries (Brosens, 1964; Hustinand Schaaps, 1987; Hustin et al., 1988), determining a diversehaemodynamic behaviour.

Umbilical artery and fetal descending aorta

Flow velocities in the umbilical artery were obtained in the free-floating loop of the umbilical cord, in a straight section to allowdetermination of the vessel interrogation angle, which shouldalways be kept at <20°. Recordings of flow in the descendingaorta were obtained from a sagittal cross-section through the fetaltrunk, displaying a major section of the fetal spine (Wladimiroffet al., 1991a, 1992a,b). This latter recording can be difficult toachieve in most situations, as the longitudinal fetal position isparallel to the transducer.

First trimester studies revealed a high pulsatility index (PI) inboth umbilical artery and fetal aorta, expressed in the absence ofend-diastolic flow velocities at 6–13 weeks gestation andreflecting 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 isa slight increase in PI values from 7 weeks until 11–12 weeksfollowed 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 aresurgence of endovascular trophoblast migration with a secondwave of cells moving into the muscular layer of spiral arteries anda process of angiogenesis in the placenta (Jauniaux et al., 1992).This will eventually result in the destruction of the medialmusculo–elastic tissue, transforming thick-walled spiral arteriesinto flaccid utero–placental vessels and establishing directconnections between terminal villi and fetal stem cells (Brosenset al., 1967; de Wolf et al., 1973; Benirschke and Kaufmann,1990). In other terms, an initially high resistance territory isconverted in a low pressure conductance system that is ready toaccommodate the increased blood flow volume of the developingfetus.

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.

Figure 2. Normal ranges (mean ± SD) for umbilical artery pulsatility index at 7–13weeks gestation (based on crown–rump length measurement) (adapted fromMontenegro et al., 1995).

Figure 3. Transverse cross-section through the lower part of the fetal brain, in aheart-shaped cross-section, in a 12-week fetus. Note the presence at this stage ofend-diastolic flow, for the middle cerebral artery, as can be seen in the pulsedDoppler spectrum.

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Occasionally reverse end-diastolic flow in the umbilical arterieshas been recorded in the late first trimester of pregnancy inassociation with ulterior fetal demise (Ariyuki et al., 1993) andwith chromosomal abnormalities (Montenegro et al., 1995;Martinez et al., 1996a,b; Comas et al., 1997). Some groups haveproposed the use of increased resistance in the umbilical artery asa marker for chromosomal anomalies in early gestation and as anindication for fetal karyotyping (Martinez et al., 1996b, 1997), butrecently Brown et al. (1998) have proven the PI in the umbilicalartery is useless in screening for chromosomal defects.

Middle cerebral artery

In the late first trimester, it is usually quite difficult to differentiateflow in the carotid artery and its middle and anterior cerebralbranches. The presence of intracerebral forward end-diastolicflow in the normal blood flow waveform pattern, as opposed toabsent end-diastolic flow in the descending aorta and umbilicalartery, reflects comparatively lower vascular resistance in the fetalcerebrum (Figure 3). End-diastolic frequencies have beenrecorded in 66% of 39 cases assessed at 10–11 weeks, 2–3 weeksearlier than in the umbilical artery (Montenegro et al., 1994). Themiddle cerebral artery resistance index (RI) falls at 10–13 weeks,coinciding with a decrease in mean fetal heart rate, and the meanintracerebral PI value is only marginally higher at 11–13 weeksgestation (Wladimiroff et al., 1992a) than that established in latesecond trimester pregnancies (van den Wijngaard et al., 1989).The PI in the middle cerebral artery compares with the PI in thedescending aorta and umbilical artery by a factor of 1.4 and 2.0respectively (Wladimiroff et al., 1992a), probably due to the rapidgrowth of the fetal head in early pregnancy.

Venous vessels

It is noticeable that most published reports have concentrated onthe physiology of the arterial vascular system. Little is knownabout the preload factor and the haemodynamics of the venousreturn to the fetal heart, which differs considerably from the adultcharacteristics, since it depends on the presence of three shunts(foramen ovale, ductus arteriosus and ductus venosus) and theplacenta as a third circulation. In the fetus, under normalconditions, venous return is mainly controlled by: (i) right atrialpressure (which exerts a backward force on the veins to drawblood flow into the right atrium); (ii) mean systemic fillingpressure (which forces systemic blood flow towards the heart andis related to blood volume); (iii) muscular movement (inassociation with the venous valves, it enables the return of bloodfrom the extremities); (iv) negative intrathoracic pressure during‘inspiration’ (breathing-like movements have been recognized infetuses as early as 11 weeks gestation); (v) peripheral resistance orafterload (in the fetus the placental circulation is located betweenthe arterial and the venous system); and (vi) vein physicalproperties (the large cross-sectional area and the significantcompliance of veins yield a low resistance territory).

The understanding of such special features and its influence onfetal haemodynamics has changed with time. Previously, it hadbeen shown that almost all the blood returning to the heart wasdirected across the tricuspid valve to the right ventricle, while anegligible amount would cross the foramen ovale (Heymannet al., 1977). However, studies performed in the fetal lambclarified the venous streamlining and explained the differences in

oxygen saturation in the upper and lower portions of the body inthe fetus (Edelstone and Rudolph, 1979; Reuss and Rudolph,1981; Rudolph, 1983). Of umbilical venous blood, ~50% bypassesthe liver through the ductus venosus circumventing the rightatrium, as a well-oxygenated stream in the posterior left portion tothe foramen ovale (via sinistra) (Amoroso et al., 1942; Rudolph,1983; Kiserud et al., 1992a,b). A right anterior functionalpathway, delivering less oxygenated blood into the right atriumthrough the proximal inferior vena cava (IVC), streamspreferentially through the tricuspid valve into the right ventriclewhich ejects into the pulmonary trunk, and is then directedthrough the ductus arteriosus to the descending aorta and lowerbody organs (via dextra) (Amoroso et al., 1942; Rudolph, 1983;Kiserud et al., 1992a,b).

The primitive venous system consists of three majorcomponents, all of which are initially bilaterally symmetrical: thecardinal system, which drains the head, neck, body wall, andlimbs; the vitelline veins, which initially drain the yolk sac; andthe umbilical veins, which develop in the connecting stalk and willsoon carry oxygenated blood from the placenta to the embryo(Montenegro et al., 1999). All three undergo extensivemodifications during development as systemic venous return isshifted to the right atrium: the right umbilical vein obliteratesduring the second month, whereas the left umbilical vein persistsand establishes a new connection with the ductus venosus (Larsen,1993).

Umbilical vein

Waveform velocities in the umbilical vein (UV) have beenobtained 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 theumbilical vein (Gill and Kossoff, 1984; Griffin et al., 1985;Erskine and Ritchie, 1985; Lingman et al., 1986) in latepregnancy. In the first trimester, in order to avoid interferencewith the arteries in the vulnerable free-floating part of the cord, themost reliable technique is to obtain a transverse cross-section ofthe fetal abdomen at the level of the cord insertion and to place thesample volume over the intra-abdominal part of the UV 1–2 mmfrom the cord insertion. Besides considering determinant aspectsto ensure reproducible and high quality waveforms, such as theexact location of the Doppler sample volume, the sample size andinterrogation angle, special care is needed to obtain Doppler bloodflow waveforms during fetal apnoea.

At 12–15 weeks gestation, Huisman et al. (1993a,b) determinedthe normal pattern of flow velocity waveforms in the UV with acharacteristically low blood velocity (15–25 cm/s). Additionally,they investigated the reproducibility of Doppler recordings at thisstage of pregnancy, stating a reliability of 91–99 % for all therecordings and parameters studied (Huisman et al., 1993c,d).

Doppler blood flow waveforms in the umbilical vein (UV) andthe porta circulation are, in contrast to the systemic venouscirculation, even and without fluctuation, with a continuousforward pattern (Figure 4). A heart synchronous pulsatile patterncan occasionally be recorded in early pregnancy, but tends todisappear at 9–12 weeks gestation (Rizzo et al., 1992; Matiaset al., 1996). The physiological presence of such pulsations seemsto be related to IVC flow patterns. An abnormal pulsating pattern

Colour Doppler and fetal circulation in the first trimester 181

of the UV has also been reported in an otherwise normalpregnancy, presenting with a knot on the cord. Characteristic lowfrequency fluctuation, non-related to the heart rate, can also beapparent in this vessel during fetal breathing movements. Later inpregnancy, the presence of pulsations in the UV, with a decreasein velocity by >15% from the basal state, has a completelydifferent meaning and has been described in association withcongestive heart failure in fetuses with non-immune hydrops andimminent asphyxia (Gudmundsson et al., 1996).

The mean UV blood velocity recorded from the intra-abdominalpart of the vein was 12.6 (3.1 cm/s, without notorious changesthroughout pregnancy (Huisman et al., 1993a; Matias et al.,1996). The value (mean ± SD) for the ductus venosus/umbilicalvein was 3.2 ± 0.8 and the time-averaged velocity in the UV was9.7 ± 2.9 cm/s at 12–15 weeks gestation (Huisman et al., 1993a).Interestingly, no statistically significant correlation could beestablished between the UV velocities and cardiac cycle length(r = –0.45) (Huisman et al., 1993a).

Ductus venosus

Ductus venosus (DV) is a tiny vessel with a central role asdistributor of well-oxygenated umbilical venous blood,functionally arterialized and behaving as a different vein (Kiserud,1997). This branchless vessel is the sole direct connectionbetween the umbilical vein and the inferior atrial inlet, shuntinghalf the umbilical blood directly to the left atrium through theforamen ovale (Figure 5) (Rudolph, 1983; Kiserud et al., 1991;Schmidt et al., 1996). These preferential pathways for umbilicalvenous and distal IVC flow contribute not only to ensure higheroxygen saturation and higher glucose concentration in ascendingaorta as compared with descending aortic blood.

The DV connects the intra-abdominal umbilical vein (umbilicalsinus) to the IVC, running from anterior to posterior, upward andslightly towards the left side to join the IVC in a rather steepcourse (Figure 5) (Chinn et al., 1982; Champetier et al., 1989;Kiserud et al., 1992a; Montenegro et al., 1997a). Throughoutpregnancy the DV develops a trumpet-like shape and remains anarrow isthmic structure, barely >2 mm in diameter. This unusualarchitecture for a vein accelerates the blood jet crossing the leftside of the IVC directly towards the right atrium, with the highestvelocities being reached at the isthmic portion. Computationalsimulations developed in order to study the influence ofanatomical features of the DV on the haemodynamics of thevessel, 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 relatedwith the presence of a sphincter, but even though neural andmuscular elements were isolated (Pearson and Sauter, 1969;Chacko et al., 1953), no agreement was reached.

DV blood flow waveforms can be obtained from either atransverse or longitudinal fetal view, since the DV bends as ittraverses the fetal abdomen. In the late first trimester ofpregnancy, 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 4. Identification of the umbilical vein with Power Doppler and therespective blood flow waveform obtained by pulsed Doppler at 11 weeks gestation.

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 ascendingaorta 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). Lessoxygenated blood from the IVC predominantly enters the right atrium (ra), and the well oxygenated umbilical blood is preferentially directed through the DV to the leftatrium (la) (adapted from Kiserud and Eik-Nes, 1995).

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para–sagittal plane should be the one recommended to insonatethe DV and the transvaginal approach gives a higher rate ofsuccessful velocity recordings (Montenegro et al., 1997a). Theoblique transection of the abdomen is, however, less suitable forestimating the angle of interrogation, since the DV has its steepestcourse in the sagittal plane (Kiserud and Eik-Nes, 1995). Theexamination is done during fetal quiescence and apnoea, due tothe substantial impact of respiratory movements on the velocities(Huisman et al., 1993b). Reliability studies of DV waveformrecording ranged at 94.5–98.5% (Huisman et al., 1993c,d).

Blood flow waveform in the DV is clearly pulsatile, with threecomponents (Figure 6). Flow velocities are highest duringventricular systole (S-wave) and ventricular diastole (D-wave),the two forward components. The third component iscontinuously anterograde and the lowest velocities are observedduring atrial contraction (A-wave). Therefore, in relation to theother precordial veins, two important differences should be noted:the velocity in the ductus venosus is particularly high (time-averaged flow velocity is 3.2- and 2.7-fold higher than in the UVand IVC respectively) (Huisman et al., 1993a,e), and ananterograde velocity is maintained during atrial contraction. Thislatter aspect may well be the consequence of the placental pressuregradient over the DV and UV (Wladimiroff and Huisman, 1994).Special care should be taken to avoid examining the wrong vesseland to include neighbouring vessels in the sample volume: thepositioning of the sample volume too distally will overestimateatrial contraction velocities by ‘contamination’ from the UVspectrum, whereas when it is placed too proximally the‘contamination’ by the IVC will underestimate the A-wavevelocity (Figure 7) (Montenegro et al., 1997a).

Pioneering studies to characterize flow velocity waveforms inthe DV were performed at 10–15 weeks gestation (Huisman et al.,

1992, 1993a; Montenegro et al., 1997a). Peak S and D wavesshowed a significant correlation with gestational age (r = +0.66and +0.58, P < 0.001 respectively) and peak systolic/diastolicvelocity (S/D) ratio remained constant throughout pregnancy inthe DV (1.1 ± 0.1) (Huisman et al., 1992). The various parametersfrom the DV waveforms obtained at 10–14 weeks gestationrevealed a normal mean velocity for the peak systolic and diastolicvelocities in the DV of 24.8 ± 10.0 cm/s and 18.6 ± 8.4 cm/srespectively (Montenegro et al., 1997a). The normal valuesdefined for the A-wave trough were 4.5 ± 0.9 cm/s and none ofthese parameters were affected by fetal heart rate (Montenegroet al., 1997a).

Until recently, late diastolic reversal of DV flow had beenobserved 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 cardiacperformance. In-vivo evidence of heart failure was provided byour group by the demonstration of abnormal flow in the DVduring atrial contraction at 10–14 weeks gestation inchromosomally abnormal fetuses with increased nuchaltranslucency 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 DVwas also recorded in a high proportion of fetuses with increasednuchal translucency and normal karyotype displaying a cardiacdefect (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 resultssuggest that assessment of DV blood flow is likely to be a helpfulmethod of selecting for invasive testing those pregnanciesconsidered to be at high risk after first trimester screening and

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 venosusDoppler 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 thefar left demonstrates contamination by the umbilical vein, and the waveform on the far right shows contamination by the inferior vena cava.

Colour Doppler and fetal circulation in the first trimester 183

defining the group of chromosomally normal fetuses at risk ofhaving a major cardiac defect (Matias et al., 1998a, 1999).

Inferior vena cava

IVC blood velocity at the entrance of the right atrium can givevarying velocity patterns. This may be due to blood entering thearea from at least five vessels (sub-diphragmatic vestibulum)(Huisman et al., 1992): IVC, ductus venosus, and three hepaticveins. In order to obtain non-contaminated and reproduciblewaveforms, the sample volume should be placed between the DVand renal veins. However, obtaining optimal blood velocity signsin the IVC can be difficult due to the large angle of insonation. Atan angle of >45°, parts of the IVC blood flow waveform can beinvisible under the filter level. As an alternative to the IVCrecording, 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 bloodvelocity in the flow towards the heart: the first corresponds to thefilling of the atria during ventricular systole (S-wave) (Reed et al.,1990). This might be explained by reduced pressure in the atriacaused by atrial wall relaxation and resulting from the downwardmovement of atrio–ventricular valve (AV-valve) annulus duringventricular contraction. The second peak of blood flow velocity(D-wave) occurs at the onset of diastole and corresponds to the

early filling of the ventricles or to the early diastole (E) peak ofblood 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 flowpattern, corresponding to atrial contraction (A-wave). The degreeof 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 ofretrograde 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 gestationmay be ascribed to a relatively low cardic ventricular compliancein the late first and early second trimesters of pregnancy (Romeroet al., 1972; Friedman et al., 1968; Nakanishi and Jarmakani,1984; Reed et al., 1986).

Moreover, as for the other vessels, consideration should betaken regarding fetal movements, especially breathingmovements, and large variations on fetal heart rate. Blood flowtowards the heart can be increased by 20-fold during theinspiratory phase of fetal breathing movements, compared withthe apnoeic state (Marsál et al., 1984; Chiba et al., 1985; van derMooren et al., 1991b; Huisman et al., 1993b), with a non-significant alteration in the percentage of reverse flow duringatrial contraction (Huisman et al., 1993b). This increase in IVCvelocities may be explained by a raised pressure differencebetween thorax and abdomen resulting in a reduction in IVCvessel diameter and an increase of blood volume directed to theright atrium. Extra blood could originate from the hepatic vascular

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 = rightatrium. (Middle) Normal pattern of a ductus venosus blood flow waveform obtainedat 10 weeks gestation using pulsed Doppler. (Bottom left) Anomalous pattern ofductus venosus blood flow waveforms (reversal of flow during atrial contraction) ina 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).

Figure 9. On the left hand side of the image, progression of nuchal translucencythickness (NT) in a case with increased NT at 10 weeks (NT = 5.9 mm) and 12weeks gestation (NT = 2.9 mm) is shown. At the bottom, a B-mode imageillustrates a transposition of the great arteries suspected in this fetus. On the righthand side, abnormal flow in the ductus venosus, with reversed flow during atrialcontraction, was recorded at 12 weeks gestation (top), along with normal bloodflow waveforms in the inferior vena cava (middle) and umbilical artery (bottom).Karyotyping revealed a normal male fetus. An echocardiographic examinationperformed at 20 weeks gestation confirmed the transposition of the great vessels.

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bed as it is squeezed into the IVC during the temporary increase ofintra-abdominal pressure (van Eyck et al., 1991; Huisman et al.,1993b). Therefore, recording of venous blood flow velocitiesshould be performed during fetal quiescence.

Concerning fetal heart rate, a rise in the percentage of reverseflow during fetal bradycardia (<120 bpm) and tachycardia (>160bpm) has been found (Reed et al., 1990), suggesting less optimalatrial contraction under these circumstances. The absence of acorrelation between heart rate and percentage of reverse flow inthe IVC suggests that the heart rate is independent of thepercentage of reverse flow changes observed at 11–16 weeksgestation (Wladimiroff et al., 1992b).

The S and D peak velocities normally increase with gestationalage (Huisman et al., 1991; Wladimiroff et al., 1992b; Matiaset al., 1996). The S/D ratio, however, remains unchangedthroughout gestation, being 1.62 ± 0.2. The nearly two-foldincrease in time-averaged velocity in the IVC may be caused by ahigher volume flow in this vessel, increased cardiac contractilityand physiological decrease in placental vascular resistance withreduced afterload during the second half of pregnancy (den Oudenet al., 1990).

A statistically significant negative correlation with gestationalage was established for the percentage of reverse flow duringatrial contraction (r = –0.80; P < 0.0001) (Waldimiroff et al.,1992a,b) and a positive correlation (r = +0.58; P > 0.0001) wasdocumented between time-averaged velocity and gestational age.Absolute values for percentage reverse flow in the fetal IVC at11–12 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 fourtimes 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 isnormally >1. Similarly, peak S/D (1.13 ± 0.05) and time velocityintegral S/D did not significantly change with gestation.

Cardiac contractility

Again the fetal cardiac load has peculiar characteristics in the firsttrimester of pregnancy: during this period the maturation of thevagal system is established with the lowering of the fetal heart ratebaseline (Joupilla et al., 1971; Hertzberg et al., 1988; Montenegroet al., 1994, 1998; Wisser and Dirschedl, 1994) and theappearance of beat-to-beat variation (Wladimiroff and Seelen,1972a,b). Simultaneously, a relatively high placental vascularresistance characterizes this early stage of pregnancy (den Oudenet al., 1990). These high afterload conditions are reflected byabsent end-diastolic flow in the umbilical artery and aorta until12–13 weeks gestation (den Ouden et al., 1990; Wladimiroffet al., 1992a; Montenegro et al., 1994).

It is well known that flow velocities at the cardiac level areinfluenced by preload, contractile function, afterload and heartrate. Despite the limitations of non-invasive Doppler techniques,which are unable to measure confidently fetal and venous andarterial volume flow in the late first trimester accurately,transvaginal Doppler echocardiography can be used to study earlyhuman fetal cardiac function indirectly. Several attempts havebeen made to quantify cardiac stroke volume and force at the levelof the outflow tracts and atrioventricular valves, by means ofDoppler flow (Maulik et al., 1984; Kenny et al., 1986; Reed et al.,

1986; Allan et al., 1987; Matias et al., 1996). However, the resultswere disappointing due to the poor reproducibility (Beeby et al.,1991).

A more successful approach to indirectly evaluating cardiaccontractility is the assessment of diastolic function in the fetus.Doppler blood flow velocities across the tricuspid and mitral valvehave been used as indicators of ventricular filling. In contrast withthe adult heart, in which the peak velocity during early diastole(peak E velocity) is significantly higher than the peak velocity inlate diastole (peak A velocity), the relationship between bothwaves is inverted in the fetus. At this stage, fetal ventricles areexquisitely sensitive to afterload but unable to cope successfullywith changes in loading conditions (Gilbert, 1982).Atrioventricular tracings were obtained in the first studies in thesecond half of pregnancy (Reed et al., 1986; Allan et al., 1987;van der Mooren et al., 1991a). For both the tricuspid and mitralvalves, the peak A velocity exceeded the peak E velocitythroughout pregnancy and in the first 3 weeks postnatally (Areiaset al., 1992). The A/E ratio tended to decrease with advancinggestational age. For the tricuspid valve, the decreasing A/E ratiowas caused by an increase in peak E velocity with increasinggestational age with unchangeable A wave. For the mitral valve,the decreasing A/E ratio resulted from a decrease in A wavevelocity whereas E wave did not change with advancinggestational age. When comparing tricuspid and mitral velocityvalues, both tricuspid peak E and A velocities systematicallyexceeded the mitral peak E and A velocities. From this study wecan infer the striking impairment of ventricular relaxation in thefetus.

These results agree well with the results of experimentsperformed in fetal lambs (Romero et al., 1972) that demonstrateda much less compliant fetal ventricle than a neonatal ventricle.Studies in isolated fetal muscle strips have clearly demonstratedthat fetal myocardium cannot generate the same force as adultmyocardium (Friedman, 1968; Nakanishi and Jarmakani, 1984;Reed et al., 1986). This well established impairment of ventricularcontractility has been ascribed to multiple factors: decreasedsympathetic innervation and decreased β-adrenoceptorconcentration (Chen et al., 1979), immaturity of sarcoplasmicreticulum in both structure and function (Maylie, 1982; Nassaret al., 1987; Page and Buecker, 1981), and decreasedconcentration and function of myofibrils (Friedman, 1968; Nassaret al., 1987). Ultimately, the different contributions of the earlyand late filling phases to the decrease in A/E ratio observed inhuman fetuses probably reflect differences in function andmaturation of the two ventricles before birth.

The availability of transvaginal Doppler techniques has openedthe possibility of studying the fetus in greater detail in earlierphases of pregnancy (Timor-Tritsch, 1988). Preliminary results onfetal cardiac flow velocities in the late first trimester of pregnancyappeared in the literature in 1991 (Wladimiroff et al., 1991a,b;Huisman et al., 1992; Matias et al., 1996) and reproducibilityissues were addressed (van der Mooren et al., 1992). Peakvelocities during atrial contraction were nearly twice as high asthose during early diastolic filling, reflecting again a restrictedventricular compliance, i.e. a more pronounced stiffness of thefetal ventricles in early gestation. Therefore, the Frank–Starlingmechanism is greatly impaired or even not operating, at least in

Colour Doppler and fetal circulation in the first trimester 185

early phases of pregnancy, and as a result, the fetal ventricles arelimited in their ability to increase stroke volume in response toincreased heart rate or decreased afterload.

Flow velocity waveforms at the fetal atrioventricular valves arerecorded following a strict methodology, similarly applied later inpregnancy: a four-chamber view should be obtained and theDoppler sample volume placed immediately distal to theatrioventricular valves (Matias et al., 1996). Because mitral andtricuspid valve structures are situated close to each other on a fourchamber cross-sectional view in such a small fetus, distinctionbetween trans-mitral and trans-tricuspid blood flow velocitywaveforms can be a major hindrance. The presence of a fluid-filled stomach can help in establishing the left side of the heart.Mean flow peak velocities for trans-atrioventricular blood flowwere 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 and38.6 ± 4.7 cm/s. E/A ratio was 0.53 ± 5.4. The right ventricle is thedominant ventricle, ejecting the highest proportion of thecombined ventricular output into the descending aorta. Thesevelocities were shown to increase with advancing gestation,probably due to functional and structural maturation of theventricles and decreased peripheral vascular resistance (denOuden et al., 1990).

Fetal heart rate

Heart rate is relatively easy to obtain from the early phases ofpregnancy. The detection of fetal heart activity in the firsttrimester using pulsed ultrasound with time–motion mode wasfirst described by Robinson in 1972. In 1973, the detection of ahuman fetal heart rate between 44 days and 15 weeks after the firstday of the last menstrual period was reported (Robinson andShaw-Dunn, 1973). Since then, there are multiple studiesevaluating the course of heart rate, e.g. in one of the papers(Wisser and Dirschedl, 1994), embryonic heart rate (EHR) (Figure10, left) in dated embryos is described as showing an increase upto 63 post-menstrual days (or 22 mm of greatest length); inanother study (Deaton et al., 1997), the prognostic value of fetalheart 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 ofthe embryonic heart was completed. Thereafter a steady decreaseof EHR was noted at 10–14 weeks gestation (Joupilla et al., 1971;Hertzberg et al., 1988; Montenegro et al., 1994, 1998; Wisser andDirschedl, 1994) (Figure 10, right). The initial increase in EHRmay be explained by the morphological development of the heartand the predominance of intrinsic myogenic activity (Andersonand Taylor, 1972; Davies et al., 1983; Veenstra and DeHaan,1988). The subsequent decrease may be the result of the functionalmaturation of the parasympathetic system (Robinson and Shaw-Dunn, 1973; Wisser and Dirschedl, 1994; Wladimiroff andSeelen, 1972a,b), to the expansion of the vascular bed and to theestablishment of secondary connections among chorionic,vitelline, umbilical and embryonic vessels (O’Rahilly and Müller,1987).

In a recent study, we demonstrated that reliable andreproducible information concerning the embryonic/fetal heartrate, during the first trimester of pregnancy, could be obtainedfrom a single measurement (Montenegro et al., 1998). The intra-individual 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 themore important physiological variation found after 9 weeks,contrasting with the more preponderant autonomic neurogenicactivity expected before.

Low fetal heart rate in the first trimester of pregnancy has beenshown to be a good predictor of embryonic death or impendingfetal demise (Laboda et al., 1989; Rempen, 1990; May andSturtvant, 1991; Merchiers et al., 1991; Montenegro et al., 1994).These studies provide direct support for the hypothesis thatcardiovascular competence is crucial during embryogenesis(Clark and Hu, 1990). More recently, other authors (Hyett et al.,1996) have demonstrated the importance of including themeasurement of fetal heart rate as part of the first trimester routineultrasound. In fact, the sensitivity of the screening for fetalchromosomal abnormalities reached 76% by a combination ofmaternal age and nuchal translucency thickness, but was notably

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 heartrate (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 fromRempen et al., 1990).

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 mayotherwise be risen in the first trimester by an abnormal fetal heartrate (bradycardia in trisomy 18 and triploidy; tachycardia infetuses with trisomy 21, trisomy 13 or Turner syndrome) (Hyettet al., 1996; Martinez et al., 1998).

Finally, studies have shown that as a result of the restrictedFrank–Starling mechanism in the fetus, fetal heart rate changeswithin the normal heart rate range do not seem to considerablyinfluence fetal cardiac output (Kenny et al., 1987; van der Moorenet al., 1991a).

Concluding remarks

Non-invasive assessment of fetal haemodynamics in early phasesof human pregnancy can be achieved, preferentially by usingtransvaginal Doppler ultrasound. Considering the limitationimposed by the diminished dimensions of the vessels to beexplored, the contribution of Colour and Power Doppler turnedout to be essential in early haemodynamic studies. More recently,this latter technique became the method of choice to localize thefetal vessels and to facilitate the ulterior quantification of flowparameters by pulsed Doppler, due to its angle-independence andhigher sensitivity to low velocity flows. Consequently, theexamination time could be reduced as well as the embryonic–fetalexposure to acoustic energy.

Information yielded by the arterial compartment has been ofparamount importance to the knowledge of the physiologicalaspects in early phases of human pregnancy. However, the clinicalutility of arterial blood flow assessment in the late first trimesterhas recently been challenged.

In contrast, the importance of venous system evaluation in thehaemodynamic assessment of the fetus is gaining supporters and itseems wise to consider this information from the early phases ofpregnancy. Owing to the characteristics of the venous system (lowpressure, low velocity and compliant walls), it easily reflectschanges in central circulation. Thus it may provide the clinicianwith a promising screening or even diagnostic tool that mayanticipate serious alterations in fetal wellbeing at a very earlystage, and prove to be an alternative tool in fetal surveillance.

It is becoming recognized that venous waveform alterationsmay be useful in disclosing deviations in fetal physiology, as anearly manifestation of myocardial compromise. The mostsystematic alterations have been identified in the ductus venosus,in which alterations of flow during atrial contraction canconstitute the earliest sign of cardiac impairment and identify thefetuses at risk of chromosomal abnormality and/or heart failure.

Studies on fetal venous return are still insufficient and itsclinical potential is not fully explored. This should not deter theclinician from applying the ‘venous’ approach, provided resultsare interpreted cautiously. However, new studies on venousparameters are still needed to clarify the physiopathologicalmeaning of such alterations. In many situations, e.g. hypoxaemia,placental insufficiency, anaemia, cardiac diseases etc, the ductusvenosus seems to respond differently from other veins. It may wellbe 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