Doppler Echocardiographic Studies of Deteriorating Growth-Restricted Fetuses

Intrauterine growth restriction (IUGR) is associated with significant perinatal mortality and morbidity [1, 2]. Adequate management of this condition re- quires early recognition of small-for-gestational-age (SGA) fetuses, a differential diagnosis of the factors that induce a delay in growth, monitoring the fetal condition, and determining the time of delivery.

The differential diagnosis between these etiologies is complex, but the introduction of noninvasive (i.e., high-resolution ultrasound imaging and Doppler ul- trasonography) and invasive (i.e., cordocentesis) tech- niques allows a differential diagnosis in most of the cases [3]. Doppler ultrasonography, by providing a unique tool with which to examine fetal and maternal circulations noninvasively, has greatly enhanced our knowledge of the circulatory adaptive mechanisms that occur with various complications of pregnancy including IUGR [4, 5]. In particular, the study of fetal intracardiac hemodynamics has clarified the patho- physiologic steps in progressive fetal deterioration, al- lowing better definition of the severity of fetal com- promise. Accurate assessment of the fetal condition may have favorable effects on perinatal mortality and morbidity, as fetuses can be delivered before irrever- sible damage occurs. In this chapter we outline the importance of Doppler echocardiography for antena- tal monitoring of IUGR fetuses, with special emphasis on the hemodynamic changes at the level of the fetal heart in the presence of progressive deterioration.

Pathophysiology

Although the pathophysiology underlying uteroplacen- tal insufficiency is poorly understood, it is assumed that various maternal, uterine, placental, and perhaps fetal abnormalities cause a reduction in the supply of nutrients provided to the fetus through the placenta [5±7]. This situation induces Doppler-detectable mod- ifications in various vascular districts. These changes may include increased impedance to flow at the level of the uterine arteries (believed secondary to failure or impairment of trophoblast invasion), which results

in poor uteroplacental blood perfusion [8, 9]. Similarly, impedance to flows is usually increased in the umbilical artery, which is considered an expression of high pla- cental vascular resistance due to a reduction in the number of small muscular arteries in the tertiary stem villi or their obliteration [10±12]. Other explanations, such as increased fetal blood viscosity or reduced arte- rial blood pressure, have not been excluded [13, 14]. Ir- respective of the underlying cause, the increased impe- dance in the uterine or umbilical arteries results in re- ducted delivery of oxygen and placental substrates to the fetus [5]. This condition causes differential changes of arterial vascular resistances in the fetal circulation with vasodilatation at the level of the brain and myo- cardium and constriction at the muscular and visceral level, resulting in the brain-sparing effect [15±17], a phenomenon long recognized in animal models [18].

Thus during the first stage of the disease, the supply of substrates and oxygen to vital organs is maintained at near-normal levels despite an absolute reduction of placental transfer.

The temporal sequence of Doppler-detectable mod- ifications during a pregnancy with developing IUGR is still unknown. Sometimes abnormal uterine artery velocity waveforms are the first Doppler-detectable sign [19]. IUGR may occur even in the presence of normal uterine artery velocity waveforms, suggesting an etiology primarily related to abnormal placental function. Similarly, there is no evidence as to whether the abnormalities in the umbilical artery occur ear- lier, simultaneously, or later than those in fetal vessels [20]. As already stated, despite the common denomi- nator of a reduced supply of nutrients, IUGR has multiple etiologies that may involve the uterine circu- lation, placenta, or fetal circulation.

Persistence of nutritional deprivation leads to pro- gressive deterioration of the fetal condition with further hemodynamic changes mainly affecting cardi- ac function [21, 22] and causing abnormalities in the venous system [23]. Additional modifications include abnormalities in fetal motor behavior and heart rate patterns [6, 24]. Finally, if the fetus is not delivered in due course, fetal death ensues.

Doppler Echocardiographic Studies

of Deteriorating Growth-Restricted Fetuses

Domenico Arduini, Giuseppe Rizzo

General Principles

of Doppler Echocardiography for Functional Study

of Fetal Cardiac Function

Fetal Circulation

Fetal cardiac hemodynamics differ from that seen postnatally. During fetal life blood is oxygenated in the placenta and returns to the fetal body via the um- bilical vein. Studies on chronically instrumented fetal lambs have shown that under physiologic conditions about 55% of umbilical venous blood bypasses the hepatic circulation, entering the inferior vena cava (IVC) directly via the ductus venosus [5, 25]. From the IVC this highly oxygenated blood preferentially streams through the foramen ovalis into the left at- rium, left ventricle, and descending aorta. In contrast, poorly oxygenated blood from the hepatic and superi- or vena cava circulations enters the right atrium and is almost completely directed through the tricuspid valve in the right ventricle and pulmonary artery [5, 25]. Because fetal blood is not oxygenated by the lungs an additional shunt (i.e., the ductus arteriosus) operates to bypass the pulmonary circulation, prefer- entially directing the right ventricular output to the descending aorta. As a consequence, both ventricles eject into the systemic circulation in parallel. The output of the left ventricle is directed through the as- cending aorta to upper body organs, making the most highly oxygenated blood available to the heart and brain. The right ventricle ejects through the patent ductus arteriosus and the descending aorta to the lower body and placenta.

Doppler Echocardiographic Technique The parameters used to describe fetal cardiac velocity waveforms differ from those used for fetal peripheral vessels. In the latter situation indices such as the pul- satility index (PI), resistance index (RI), and systolic/

diastolic (S/D) ratio are used. These indices are de- rived from relative ratios between the systolic, dia- stolic, and mean velocities and are therefore indepen- dent of the absolute velocity values and the angle of insonation between the Doppler beam and the direc- tion of the blood flow [5, 26].

Unlike measurements at the cardiac level, other measurements yield absolute values. Measurements of absolute flow velocities require knowledge of the angle of insonation, which may be difficult to obtain with ac- curacy. Errors in the estimation of the absolute velocity resulting from the uncertainty of angle measurement are strongly dependent on the magnitude of the angle itself. For angles less than 208 the error is reduced to practical insignificance. For angles greater than 208

the cosine term in the Doppler equation changes the small uncertainty in the measurement of the angle into a large error in the velocity equations [5, 26]. As a con- sequence, recordings should be obtained with the Dop- pler beam as parallel as possible to the bloodstream.

Moreover, all recordings with the estimated angle greater than 208 should be rejected.

Color Doppler sonography may solve many of these problems by showing in real time the flow di- rection, thereby allowing proper alignment of the Doppler beam with the direction of the blood flow.

To record velocity waveforms, pulsed-wave Doppler sonography is generally preferred to the continuous- wave Doppler technique because of its range resolu- tion. During recordings the sample volume is placed immediately distal to the location being investigated (e.g., distal to the aortic semilunar valves to record the left ventricular outflow).

Parameters Measured

The parameters most commonly used to describe the cardiac velocity waveforms are the following: peak ve- locity (PV), expressed as the maximum velocity at a given moment (e.g., systole, diastole) on the Doppler spectrum; time to peak velocity (TPV), or acceleration time, expressed by the time interval between the on- set of the waveform and its peak; and the time veloc- ity integral (TVI), calculated by planimetering the area underneath the Doppler spectrum.

It is possible also to calculate absolute cardiac flow from the atrioventricular valve and outflow tracts by multiplying the TVI ´ valve area ´ fetal heart rate (HR). These measurements are particularly prone to errors mainly because of inaccuracies in the valve area.

The area is derived from the valve diameter, which is near the limits of ultrasound resolution; this figure is then halved and squared during the calculation, there- by amplifying any potential error. The measurements can be used properly in longitudinal studies for a short time interval during which the valve dimensions are as- sumed to remain constant. Furthermore, it is also pos- sible to calculate accurately the relative ratio between the right and left cardiac outputs (RCO/LCO), thereby avoiding measurement of the cardiac valve: The relative dimensions of the aorta and pulmonary valves remain constant throughout the gestation in the absence of cardiac structural disease [27].

Recording Sites and Velocity Waveforms:

Characteristics and Significance

In the human fetus blood flow velocity waveforms

can be recorded at all cardiac levels, including venous

return, foramen ovalis, atrioventricular valves, out-

flow tracts, and ductus arteriosus. Various factors af-

fect the morphology of the velocity waveforms from different areas, among them preload [28, 29], after- load [29, 30], myocardial contractility [31], ventricu- lar compliance [32], and fetal heart rate [33]. It is not possible to obtain simultaneous recordings of pres- sure and volume, so we cannot fully differentiate be- tween these factors in the human fetus. However, be- cause each parameter and recording site can be spe- cifically affected by any one of these factors it is pos- sible to indirectly elucidate the underlying pathophys- iology by performing measurements at various cardi- ac levels.

Venous Circulation

Blood flow velocity waveforms may be recorded from the superior and inferior vena cava, ductus venosus, umbilical vein, and pulmonary veins. The vascular areas most intensively studied are the IVC, ductus ve- nosus (DV), and umbilical vein.

The IVC velocity waveforms, recorded from the segment of the vessel just distal to the entrance of the ductus venosus [34], are characterized by a triphasic profile with a first forward wave concomitant with ventricular systole, a second forward wave of smaller dimensions seen during early diastole, and a third wave with reverse flow during atrial contraction [23].

Several indices have been suggested for analyzing IVC waveforms, but the most frequently used is the per- cent reverse flow, which is quantified as the percent of TVI during atrial contraction (reverse flow) with respect to total forward TVI (first and second wave) [23]. This index is considered to be related to the pressure gradient between the right atrium and the right ventricle during end-diastole, which is a func- tion of both ventricular compliance and ventricular end-diastolic pressure [34].

Ductus venosus velocity may be recorded in a transverse section of the upper fetal abdomen, at the level of its origin from the umbilical vein [35, 36].

The ductus venosus velocity waveforms exhibit a bi- phasic pattern: a first peak concomitant with systole and a second peak during diastole, with a nadir dur- ing atrial contraction. The ratio between the maxi- mum systolic (S) peak velocity and the atrial nadir (A) (S/A ratio) and the preload index (S±A)/S are the most commonly employed indices to assess DV he- modynamics [37±39].

Umbilical venous blood flow is usually continuous.

However, in the presence of a relevant amount of re- verse flow, during atrial contraction in the IVC pulsa- tions occur with the heart rate in the umbilical ve- nous flow. During normal pregnancies these pulsa- tions occur only before the 12th week of gestation and are secondary to the stiffness of the ventricles at this gestational age, causing a high percentage of re-

verse flow in the IVC [40]. The presence of umbilical vein pulsations later in the gestation is considered a sign of impaired cardiac function. Only the qualita- tive venous Doppler waveform analysis seems to im- prove prediction of critical perinatal outcomes in pre- term IUGR fetuses and therefore should be incorpo- rated into the surveillance of these fetuses [40].

Atrioventricular Valves

Flow velocity waveforms at the level of mitral and tri- cuspid valves are recorded from the apical four-cham- ber view of the fetal heart. They are characterized by two diastolic peaks that correspond to early ventricular filling (E wave) and active ventricular filling during at- rial contraction (A wave). The ratio between the E and A waves (E/A) is a widely accepted index of ventricular diastolic function and is an expression of both cardiac compliance and preload conditions [28, 42].

Outflow Tracts

Flow velocity waveforms from the aorta and pulmo- nary artery are recorded, respectively, from the five- chamber and short-axis views of the fetal heart. PV and TPV are the most commonly used indices. The former is influenced by several factors, including valve size, myocardial contractility, and afterload [29, 30], whereas the latter is believed secondary to the mean arterial pressure [43].

At the level of the outflow tracts the PV values lin- early increase, and higher values are present in the aorta than in the pulmonary artery [33]. TPV values remain almost constant throughout gestation [44].

TPV values at the level of the pulmonary valve are lower than at the aortic level, suggesting slightly higher blood pressure in the pulmonary artery than in the ascending aorta [45]. Quantitative measure- ments have shown that the right cardiac output (RCO) is higher than the left cardiac output (LCO), and that from 20 weeks onward the RCO/LCO ratio remains constant at a mean of 1.3 [46, 47]. This value is lower than that reported in the fetal sheep (RCO/

LCO=1.8), a difference that may be explained by the higher brain weight in humans, which increases left cardiac output [48].

Longitudinal Hemodynamic Modifications in IUGR Fetuses

The timing of the delivery of IUGR fetuses is usually

based on the results of biophysical tests (e.g., fetal

heart rate monitoring or biophysical profile) or be-

cause there is an uncontrollable coexisting maternal

disease (e.g., preeclampsia). The time interval be-

tween the first Doppler abnormalities in the umbilical or fetal circulation (i.e., brain-sparing effect) and de- livery is usually wide. According to published data it may range from 1 to 9 weeks [49±52].

Knowledge of the temporal hemodynamic sequence in IUGR fetuses after establishment of the brain-spar- ing phenomenon has important clinical implications.

In fact, there are reports that IUGR fetuses that are acidotic during intrauterine life or that have antepar- tum abnormal heart rate tracings exhibit poor neurolo- gic development at 2 years [53, 54]. This finding has led some authors to suggest that IUGR fetuses should be delivered before the onset of abnormal fetal heart rate patterns (suggestive of fetal acidemia) in order to avoid the consequence of prolonged malnutrition and hypox- ia on the brain [24]. Moreover, gestational age should be taken into account, as the anticipation of the time of delivery may increase the risk of prematurity-related neonatal complications [50, 51].

At present, irrespective of the criteria for timing the delivery of these fetuses, knowledge of the pro- gressive hemodynamic changes in deteriorating IUGR fetuses may help to clarify their natural history and to predict the time left before the onset of abnormal heart rate patterns. Serial studies on IUGR fetuses followed from the diagnosis to the onset of heart rate late decelerations have allowed us to partly clarify the hemodynamic changes at various placental and fetal levels. A theoretic scheme of the temporal sequence of Doppler changes secondary to uteroplacental insuf- ficiency is outlined in Table 36.1.

Umbilical Artery

Experimental animal models in which obliteration of the placenta is achieved through embolization of the umbilical artery with microspheres have been used to show that only after 50% occlusion is there an in- crease in Doppler-measured vascular impedance [55].

This concept, validated in vitro [56, 57], suggests that wide damage of the placental vascular bed is already present at the time of diagnosis. However, further changes may occur, usually increasing progressively and dramatically around the onset of abnormal fetal heart rate patterns [16].

Fetal Peripheral Vessels

Doppler studies on the fetal descending thoracic aorta and fetal renal artery have shown that after establish- ment of the brain-sparing phenomenon further modi- fications of the PI occur with a behavior similar to that described for the umbilical artery [16] (i.e., a slight increase during the first stage of the disease followed by a rapid increase at the last stage of the disease). Of particular interest are the relations be- tween the fetal renal artery PI and fetal PO

, urine production, and amniotic fluid volume [58, 59].

Cerebral Vessels

After establishment of the brain-sparing effect, addi- tional changes occur in the cerebral circulation as as- sessed by the PI in the middle cerebral artery or in- ternal carotid artery, but the trend of these changes differs from that described for the umbilical artery and fetal peripheral vessels [16, 17, 51]. Indeed, the PI decrease is progressive during the first stage of the disease, reaching a nadir at least 2 weeks before the onset of abnormal fetal heart rate patterns [16, 60].

Furthermore, it has been shown that a few hours be- fore fetal death there is a loss of cerebral vasodilata- tion despite the persistence of high resistance in pe- ripheral vessels [61, 62]. These terminal changes are consistent with those reported in animal models [63].

However, Hecher et al. [51] found that in fetuses de- livered before 32 weeks' gestation, middle cerebral ar- tery PI became progressively abnormal until delivery, which is in contrast to the findings of Arduini et al.

[16], who found that PI of cerebral vessels did not change in the last week preceding fetal heart rate ab- normalities, and Weiner et al. [63], who even found a normalization of middle cerebral artery PI before the occurrence of abnormal fetal heart rate. Johnson et al. [65] demonstrated that increased middle cerebral artery PI may also occur in absence of premorbid fetal state, particularly in very preterm IUGR fetuses.

The significance of the different trends between ce- rebral vessels and peripheral or umbilical vessels is ob- Table 36.1. Suggested hemodynamic steps during dete-

rioration of IUGR fetuses and concomitant Doppler changes Hemodynamic steps Doppler findings

Brain-sparing phenomenon Increased UA/MCA Change of cardiac afterload Increased pulmonary ar-

tery TPV

Decreased aortic TPV Redistribution of cardiac

output Decreased RCO/LCO

Decreased cardiac output Decreased aortic PV Decreased pulmonary PV Increased venous pressure Increased percent reverse

flow in IVC Increased S/A in DV UVpulsations

Decompensation Abnormal FHR patterns

UA, umbilical artery; MCA, middle cerebral artery; TPV, time

to peak velocity; RCO/LCO, right/left cardiac output; PV,

peak velocity; IVC, inferior vena cava; S/A, systolic peak ve-

locity/atrial madir ratio; DV, ductus venosus; UV, umbilical

vein; FHR, fetal heart rate.

scure, but two hypotheses can be suggested. The first is related to different vascular sensitivities to fetal hypox- emia. The cerebral vessels may experience massive va- sodilatation in reaction to a mild to moderate level of hypoxemia, whereas profound changes in fetal periph- eral vessels may occur only after severe hypoxemia or acidosis [18]. This concept is validated by cordocentesis data showing that the relation between vasodilation in the middle cerebral artery and hypoxemia exists only if the hypoxemia is mild to moderate; with more severe hypoxemia and acidemia the reduction in PI reaches a nadir that has been suggested to represent maximal cerebral vessel dilatation [66]. Similarly, in fetal lamb models with progressively deteriorating fetal oxygena- tion, it has been shown that the modifications in cere- bral blood flow occur at an early stage of hypoxemia, whereas only minimal changes are present in peripher- al vascular areas [18]. With more severe hypoxemia vascular resistance and organ flow changes in peripher- al vessels occur abruptly, associated with further small increases or even reductions in cerebral blood flow [63].

An alternative explanation is based on the impair- ment of fetal cardiac function at the last stage of the disease, leading to decreased cardiac output [51, 66, 67]. Because the PI is highly and inversely dependent on input pressure and therefore on cardiac output [68], a decrease in cardiac contractility may explain the increase in peripheral and umbilical vessels.

Moreover, the autoregulatory mechanisms of the cere- bral circulation may maintain the nadir of cerebral vasodilatation until impending fetal death when the PI values may increase [66, 69].

The implications of changes in middle cerebral ar- tery blood flow on subsequent long-term neurodevel-

opment are unclear. Some follow-up studies have sug- gested that the brain-sparing effect is a benign adap- tation in IUGR fetuses [70, 71]; however, further long-term studies are required to establish the natural history of such cases.

Fetal Cardiac Flows

Uteroplacental insufficiency greatly affects fetal cardi- ac function. The brain-sparing effect induces selective changes in cardiac afterload that occur in IUGR fe- tuses (i.e., decreased left ventricle afterload due to ce- rebral vasodilation and increased right ventricle after- load due to systemic vasoconstriction). Furthermore, hypoxemia may impair myocardial contractility and polycythemia, which is usually present [72], may alter blood viscosity and therefore the preload. As a conse- quence, IUGR fetuses exhibit impaired ventricular filling properties [67, 73], lower peak velocities in the aorta and pulmonary arteries [21, 74] (Figs. 36.1, 36.2), increased aortic and decreased pulmonary TPV [44], and a relative increase in left cardiac output associated with decreased right cardiac output [67].

These hemodynamic intracardiac modifications are compatible with a preferential shift of cardiac output in favor of the left ventricle, leading to improved per- fusion to the brain; and they occur simultaneously with the changes in fetal peripheral vessels.

Serial recordings have allowed us to clarify the evolution of intracardiac modifications in IUGR fe- tuses [66]. TPV values and the ratio of right/left ven- tricular outputs remain stable during serial record- ings in such fetuses, suggesting that there are no other significant changes in outflow resistance or car- diac output redistribution after establishment of the

Fig. 36.1. Doppler tracing from

the aortic outflow tract in an

IUGR fetus at 29 weeks' gesta-

tion. The peak velocity is 48

cm/s (normal value for gesta-

tion is 64 cm/s)

brain-sparing mechanism. However, peak velocities and cardiac output progressively decline, rather than rise with gestation as expected. The ventricular ejec- tion force decreases in both ventricles and the differ- ent hemodynamic conditions in the vascular district (reduced cerebral resistance for the left ventricle and increased splanchnic and placental resistances for the right ventricle) can explain this decline in cardiac output. These changes may reflect decompensation of a normally protective mechanism responsible for the brain-sparing effect. According to this model, the fe- tal heart adapts to placental insufficiency in a manner that helps to maximize brain substrate and oxygen supply. With progressive deterioration of the fetal condition, this protective mechanism is overwhelmed by the decreased cardiac output, which may explain the reported changes in fetal peripheral vessels and the venous circulation.

Fetal Venous Flows

Studies of inferior vena cava blood flow velocities have demonstrated a characteristic pattern during fetal heart failure [75, 76]. Changes in venous blood velocity have been described during congestive heart failure with decreased diastolic blood velocity and increased reversal of flow during atrial contraction [76].

In IUGR fetuses an increase of reverse flow during atrial contraction may be present in the most severely compromised fetuses [23, 77] (Fig. 36.3). As a conse- quence of these abnormal venous flow patterns, the return of blood from the placenta to the heart is im- paired, further reducing the supply of oxygen and nu- trients. These findings are compatible with the de- crease in both cardiac output and aortic and pulmo- nary peak velocities in deteriorating IUGR fetuses [50, 66, 78]. These changes are an expression of the sample phenomenon (i.e., cardiac decompensation) that impairs both the filling and the output of the heart. Concomitant changes are present in the ductus

venosus of IUGR fetuses, where the velocity during atrial contraction is significantly reduced or reversed [50, 62, 79] (Fig. 36.4).

It seems that the blood velocity waveform in the hepatic vein is an earlier predictor of intrauterine death than that of the ductus venosus [78]. This might be due to the fact that the hepatic vein is nearer the heart and blood flow from the right liver lobe flows mainly to the right side of the heart, while that from the ductus venosus flows mainly to the left ventricle in the foramen ovale. The fetal left ventricle in IUGR fetuses usually has to work against a lower afterload than the right ventricle, due to brain spar-

Fig. 36.2. Doppler tracing from the pulmonary artery in an IUGR fetus at 29 weeks' gestation. The peak velocity is 37 cm/s (normal value for gestation is 57 cm/s)

Fig. 36.3. Doppler tracing from the inferior cava in an

IUGR fetus at 29 weeks' gestation. The percent reverse flow

in the inferior vena cava is 16.9% (normal value for gesta-

tion is 7.4%)

ing in chronic hypoxia. The differences in afterload might cause some differences in timing of signs of imminent heart failure in the two vessels. As flow from the right hepatic vein mainly enters the right ventricle, a compromised fetal state may therefore be expressed better in the hepatic vein than in the duc- tus venosus [79].

The presence of pulsations in the umbilical vein (Fig. 36.5) indicates severe cardiac compromise and imminent asphyxia. Double pulsation is known to be a more severe sign of fetal compromise and a direct reflection of pulsation in the central vein due to opening of the ductus venosus, either due to the hyp- oxia or increased central venous pressure [79, 80].

In IUGR fetuses the presence of pulsations in the umbilical vein is associated with a fivefold increase in perinatal mortality compared to IUGR fetuses with continuous umbilical flow [80, 81]. Actuarial analysis has demonstrated that of all the Doppler indices for IUGR fetuses, the pathological venous velocimetry in the vena cava, hepatic vein, and ductus venosus and the onset of umbilical vein pulsations are the events that best predict the onset of abnormal heart rate patterns [60, 79]. Hence, venous Doppler should be considered when timing delivery.

Conclusions

Examination of the fetal circulation by Doppler tech- niques provides evidence of some of the mechanisms of adaptation and decompensation of the IUGR fetus in response to uteroplacental insufficiency. At present, Fig. 36.4. Doppler tracing from

the ductus venosus in an IUGR fetus at 27 weeks' gestation.

(The PI normal value for gesta- tion is 0.55)

Fig. 36.5. Doppler tracing from the umbilical artery and

vein in an IUGR fetus at 27 weeks' gestation. Note the ab-

sence of end-diastolic velocity in the umbilical artery and

the end-diastolic pulsation in the umbilical vein

the condition of IUGR fetuses can be accurately as- sessed by sequential studies of Doppler waveforms from various vascular areas. Therefore the optimal timing of delivery to prevent intrauterine injury may be guided by combining multivessel Doppler ultra- sounds. Combining Doppler, composite biophysical profile, and/or computerized fetal heart rate analysis will provide significant early indication for action in the management of severe IUGR fetuses.

References

1. Dobson PC, Abell DA, Beisher NA (1981) Mortality and morbidity of fetal growth retardation. Aust NZ J Obstet Gynaecol 21:69±72

2. McIntire DD, Bloom SL, Casey BM, Leveno KJ (1999) Birth weight in relation to morbidity and mortality among newborn infants. N Engl J Med 340:1234±1238 3. Wladimiroff JW (1991) Review of the etiology, diagnos-

tic technique and management of IUGR, and the clini- cal application of Doppler in the assessment of placen- tal blood flow. J Perinat Med 19:11±13

4. Editorial (1992) Doppler ultrasound in obstetrics. Lan- cet 339:1083±1084

5. Nicolaides KH, Rizzo G, Hecher K (2000) Doppler studies in fetal hypoxemic hypoxia. In: Nicolaides KH (ed) Placental and fetal Doppler. Parthenon Publishing London NewYork, pp 67±88

6. Visser GHA, Bekedam DJ, Ribbert LSM (1990) Changes in antepartum heart rate patterns with progressive fetal deterioration. Int J Biomed Comput 25:239±246 7. Pardi G, Marconi AM, Cetin I (2002) Placental-fetal in-

terrelationship in IUGR fetuses ± a review. Placenta 23[Suppl A]:S136±141

8. Schulman H, Fleisher A, Farmakides G et al (1986) De- velopment of uterine artery compliance in pregnancy as detected by ultrasound. Am J Obstet Gynecol 155:1031±1036

9. Harrington K, Cooper D, Carpenter RG, Lees C, Hecher K, Campbell S (1996) Doppler ultrasound of uterine ar- teries: the importance of bilateral notching in the pre- diction of pre-eclampsia, placental abruption, or deliv- ery of small for gestational age baby. Ultrasound Obstet Gynecol 7:182±188

10. Giles WB, Trudinger BJ, Baird PJ, Cook CM (1985) Fetal umbilical artery flow velocity waveforms and pla- cental resistance: pathological correlation. Br J Obstet Gynaecol 92:31±36

11. Bracero LA, Beneck D, Kirshenbaum N et al (1989) Doppler velocimetry and placental disease. Am J Obstet Gynecol 161:388±393

12. Todros T, Sciarrone A, Piccoli E, Guiot C, Kaufmann P, Kingdom J (1999) Umbilical Doppler waveforms and pla- cental villous angiogenesis in pregnancies complicated by fetal growth restriction. Obstet Gynecol 93: 499±503 13. Steel SA, Pearce JM, Nash G et al (1991) Correlation

between the results of Doppler velocimetry with spec- tral analysis and the viscosity of cord blood. Rev Fr Gynecol Obstet 86:168±171

14. Fairle FM, Lang GD, Lowe GG, Walker JJ (1991) Umbil- ical artery flow velocity waveforms and cord blood viscosity. Am J Perinatol 9:250±253

15. Campbell S, Vyas S, Nicolaides KH (1991) Doppler in- vestigation of the fetal circulation. J Perinat Med 19:21±26

16. Arduini D, Rizzo G, Romanini C (1992) Changes of pulsatility index from fetal vessels preceding the onset of late decelerations in growth retarded fetuses. Obstet Gynecol 79:605±610

17. Harrington K, Thompson MO, Carpenter RG, Nguyen M, Campbell S (1999) Doppler fetal circulation in preg- nancies complicated by pre-eclampsia or delivery of a small for gestational age baby: 2. Longitudinal analysis.

Br J Obstet Gynaecol 106:453±466

18. Peeters LLH, Sheldon RF, Jones MD, Makowsky EI, Meschia G (1979) Blood flow to fetal organ as a func- tion of arterial oxygen content. Am J Obstet Gynecol 135:637±646

19. Harrington KF, Campbell S, Bewley S, Bower S (1991) Doppler velocimetry studies of the uterine artery in the early prediction of preeclampsia and intra-uterine growth retardation. Eur J Obstet Gynecol Reprod Biol 42[Suppl]:S14±S20

20. Severi FM, Bocchi C, Visentin A, Falco P, Cobellis L, Florio P, Zagonari S, Pilu G (2002) Uterine and fetal cerebral Doppler predict the outcome of third-trimester small-for-gestational age fetuses with normal umbilical artery Doppler. Ultrasound Obstet Gynecol 19:225±228 21. Groenenberg IA, Baerts W, Hop WC, Wladimiroff JW

(1991) Relationship between fetal cardiac and extra- cardiac Doppler flow velocity waveforms and neonatal outcome in intrauterine growth retardation. Early Hum Dev 26:185±192

22. Rizzo G, Arduini D, Romanini C (1992) Doppler echo- cardiographic assessment of fetal cardiac function.

Ultrasound Obstet Gynecol 2:434±445

23. Reed KL, Appleton CP, Anderson CF, Shenker L, Sahn DJ (1990) Doppler studies of vena cava flows in human fetuses: insights into normal and abnormal cardiac physiology. Circulation 81:498±505

24. Visser GHA, Stitger RH, Bruinse HW (1991) Manage- ment of the growth-retarded fetus. Eur J Obstet Gyne- col Reprod Biol 42:S73±S78

25. Reuss ML, Rudolph AM (1980) Distribution and recir- culation of umbilical and systemic venous blood flow in fetal lambs during hypoxia. J Dev Physiol 2:71±84 26. Burns PN (1987) Doppler flow estimations in the fetal

and maternal circulations: principles, techniques and some limitations. In: Maulik D, McNellis D (eds) Dop- pler ultrasound measurement of maternal-fetal hemo- dynamics. Perinatology Press, Ithaca, NY, pp 43±78 27. Comstock CH, Riggs T, Lee W, Kirk J (1991) Pulmo-

nary to aorta diameter ratio in the normal and abnor- mal fetal heart. Am J Obstet Gynecol 165:1038±1043 28. Stottard MF, Pearson AC, Kern MJ et al (1989) Influ-

ence of alteration in preload of left ventricular diastolic filling as assessed by Doppler echocardiography in hu- mans. Circulation 79:1226±1236

29. Gardin JM (1989) Doppler measurements of aortic blood velocity and acceleration: load independent indexes of left ventricular performance? Am J Cardiol 64:935±936 30. Bedotto JB, Eichorn EJ, Grayburn PA (1989) Effects of

left ventricular preload and afterload on ascending

aortic blood velocity and acceleration in coronary

artery disease. Am J Cardiol 64:856±859

31. Brownwall E, Ross J, Sonnenblick EH (1976) Mecha- nism of contraction in the normal and failing heart, 2nd edn. Little, Brown, Boston, pp 92±129

32. Takaneka K, Dabestani A, Gardin JM et al (1986) Left ventricular filling in hypertrophic cardiomyopathy: a pulsed Doppler echocardiographic study. J Am Coll Cardiol 7:1263±1271

33. Kenny J, Plappert T, Doubilet P, Saltzam D, St John Sut- ton MG (1987) Effects of heart rate on ventricular size, stroke volume and output in the normal human fetus:

a prospective Doppler echocardiographic study. Circu- lation 76:52±58

34. Rizzo G, Arduini D, Romanini C (1992) Inferior vena cava flow velocity waveforms in appropriate and small for gestational age fetuses. Am J Obstet Gynecol 166:

1271±1280

35. Kiserud T, Eik-Nes LR, Blaas HG, Hellevik LR (1991) Ultrasonographic velocimetry of the ductus venosus.

Lancet 338:1139±1145

36. Soregaroli M, Rizzo G, Danti L, Arduini D, Romanini C (1993) Effects of maternal hyperoxygenation on ductus venosus flow velocity waveforms in normal third tri- mester fetuses. Ultrasound Obstet Gynecol 3:115±119 37. Hecher K, Campbell S, Snijders R, Nicolaides K (1994)

References for fetal venous and atrioventricular blood flow parameters. Ultrasound Obstet Gynecol 4:381±390 38. Rizzo G, Capponi A, Arduini D, Romanini C (1994) Duc-

tus venosus velocity waveforms in appropriate and small for gestational age fetuses. Early Hum Dev 39:15±22 39. De Vore GR, Horenstein J (1993) Ductus venosus in-

dex: a method for evaluating right ventricular preload in the second trimester fetus. Ultrasound Obstet Gyne- col 3:338±342

40. Rizzo G, Arduini D, Romanini C (1992) Pulsations in umbilical vein: a physiological finding in early preg- nancy. Am J Obstet Gynecol 167:675±677

41. Baschat AA, Gembruch U, Weiner CP, Harman CR (2003) Qualitative venous Doppler waveform analysis improves prediction of critical perinatal outcomes in premature growth-restricted fetuses. Ultrasound Obstet Gynecol 22:240±245

42. Reed KL, Sahn DJ, Scagnelli S, Anderson CF, Shenker L (1986) Doppler echocardiographic studies of diastolic function in the human fetal heart: changes during ges- tation. J Am Coll Cardiol 8:391±395

43. Kitabatake A, Inoue M, Asao M et al (1983) Noninva- sive evaluation of pulmonary hypertension by a pulsed Doppler technique. Circulation 68:302±309

44. Rizzo G, Arduini D, Romanini C, Mancuso S (1990) Dop- pler echocardiographic evaluation of time to peak velo- city in the aorta and pulmonary artery of small for gesta- tional age fetuses. Br J Obstet Gynaecol 97:603±607 45. Machado MVL, Chita SC, Allan LD (1987) Acceleration

time in the aorta and pulmonary artery measured by Doppler echocardiography in the midtrimester normal human fetus. Br Heart J 58:15±18

46. Allan LD, Chita SK, Al-Ghazali W, Crawford DC, Tyna- na M (1987) Doppler echocardiographic evaluation of the normal human fetal heart. Br Heart J 57:528±533 47. De Smedt MCH, Visser GHA, Meijboom EJ (1987) Fetal

cardiac output estimated by Doppler echocardiography during mid- and late gestation. Am J Cardiol 60:338±

342

48. Rizzo G, Arduini D (1991) Cardiac output in anenceph- alic fetuses. Gynecol Obstet Invest 32:33±35

49. Bekedam DJ, Visser GHA, van der Zee AGJ, Snijders R, Poelmann-Weesjes G (1990) Abnormal umbilical artery waveforms patterns in growth retarded fetuses: rela- tionship to antepartum late heart rate decelerations and outcome. Early Hum Dev 24:79±90

50. Hecher K, Campbell S, Doyle P, Harrington K, Nico- laides K (1995) Assessment of fetal compromise by Doppler ultrasound investigation of the fetal circula- tion. Arterial, intracardiac, and venous blood flow ve- locity studies. Circulation 92:129±138

51. Hecher K, Bilardo CM, Stigter RH, Ville Y, Hackeloer BJ, Kok HJ, Senat MV, Visser GH (2001) Monitoring of fetuses with intrauterine growth restriction: a longitu- dinal study. Ultrasound Obstet Gynecol 18:564±570 52. Baschat AA, Gembruch U, Harman CR (2001) The se-

quence of changes in Doppler and biophysical param- eters as severe fetal growth restriction worsens. Ultra- sound Obstet Gynecol 18:571±577

53. Soothill PW, Ajayi RA, Campbell S et al (1992) Rela- tionship between acidemia at cordocentesis and subse- quent neurodevelopment. Ultrasound Obstet Gynecol 2:80±84

54. Todds AL, Trudinger BJ, Cole MJ, Cooney GH (1992) Antenatal tests of fetal welfare and development at age 2 years. Am J Obstet Gynecol 167:66±71

55. Copel JA, Schlafer D, Wentworth R et al (1990) Does the umbilical artery systolic/diastolic ratio reflect flow or acidosis? Am J Obstet Gynecol 163:751±756

56. Guiot C, Pianta PG, Todros T (1992) Modelling the feto-placental circulation. 1. A distributed network pre- dicting umbilical hemodynamics throughout pregnan- cy. Ultrasound Med Biol 18:535±544

57. Todros T, Guiot C, Pianta PG (1992) Modelling the feto- placental circulation. 2. A continuous approach to ex- plain normal and abnormal flow velocity waveforms in the umbilical artery. Ultrasound Med Biol 18:545±551 58. Vyas S, Nicolaides KH, Campbell S (1989) Renal flow-

velocity waveforms in normal and hypoxemic fetuses.

Am J Obstet Gynecol 161:168±172

59. Arduini D, Rizzo G (1991) Fetal renal artery velocity wa- veforms and amniotic fluid volume in growth-retarded and post-term fetuses. Obstet Gynecol 77:370±374 60. Arduini D, Rizzo G, Romanini C (1993) The develop-

ment of abnormal heart rate patterns after absent end diastolic velocity in umbilical artery: analysis of risk factors. Am J Obstet Gynecol 168:43±49

61. Mari G, Wasserstrum N (1991) Flow velocity wave- forms of the fetal circulation preceding fetal death in a case of lupus anticoagulant. Am J Obstet Gynecol 164:776±778

62. Rizzo G, Capponi A, Pietropolli A et al (1994) Cardiac and extra-cardiac flow changes preceding intrauterine fetal death. Ultrasound Obstet Gynecol 4:139±143 63. Richardson BS, Rurak D, Patrick JE, Homan J, Carmi-

chael L (1989) Cerebral oxidative metabolism during sus-

tained hypoxemia in fetal sheep. J Dev Physiol 11: 37±43

64. Weiner Z, Farmakides G, Schulman H, Penny B (1994)

Central and peripheral hemodynamic changes in

fetuses with absent end-diastolic velocity in umbilical

artery: Correlation with computerized fetal heart rate

pattern. Am J Obstet Gynecol 170:509±515

65. Johnson P, Stojilkovic T, Sarkar P (2001) Middle cere- bral artery Doppler in severe intrauterine growth retar- dation. Ultrasound Obstet Gynecol 17:416±420 66. Rizzo G, Arduini D (1991) Fetal cardiac function in in-

trauterine growth retardation. Am J Obstet Gynecol 165:876±882

67. Rizzo G, Capponi A, Rinaldo D, Arduini D, Romanini C (1995) Ventricular ejection force in growth retarded fetuses. Ultrasound Obstet Gynecol 5:247±255

68. Gosling RG, Lo PTS, Taylor MG (1991) Interpretation of pulsatility index in feeder arteries to low-impedance vascular beds. Ultrasound Obstet Gynecol 1:175±179 69. Al-Ghazali W, Chita SK, Chapman MG, Allan LD

(1989) Evidence of redistribution of cardiac output in asymmetrical growth retardation. Br J Obstet Gynaecol 96:697±704

70. Scherjon S, Smolders-DeHaas H, Kok J, Zondervan H (1993) The `brain sparing' effect: antenatal Doppler findings in relation to neurologic outcome in very pre- term infants. Am J Obstet Gynecol 169:169±175 71. Scherjon S, Oosting H, Smolders -DeHaas H, Zonder-

van H, Kok J (1998) Neurodevelopmental outcome at three years of age after fetal `brain sparing'. Human Dev 52:67±79

72. Soothill PW, Nicolaides KH, Campbell S (1987) Prena- tal asphyxia, hyperlactemia and erythroblastosis in growth retarded fetuses. BMJ 294:1051±1053

73. Rizzo G, Arduini D, Romanini C, Mancuso S (1988) Doppler echocardiographic assessment of atrioventric-

ular velocity waveforms in normal and small for gesta- tional age fetuses. Br J Obstet Gynecol 95:65±69 74. Ferrazzi E, Bozzo M, Rigano S, Bellotti M, Morabito A,

Pardi G, Battaglia FC, Galan HL (2002) Temporal se- quence of abnormal Doppler changes in the peripheral and central circulatory systems of the severely growth- restricted fetus. Ultrasound Obstet Gynecol 19:140±146 75. Reuss ML, Rudolph, AM, Dae MW (1983) Phasic blood

flow patterns in the superior and inferior venae cavae and umbilical vein of fetal sheep. Am J Obstet Gynecol 145:70±78

76. Gudmundsson S, Huhta JC, Wood DC, Tulzer G, Cohen AW, Weiner S (1991) Venous Doppler in the fetus with nonimmune hydrops. Am J Obstet Gynecol 164:33±37 77. Rizzo G, Caforio L, Arduini D, Romanini C (1992) Ef-

fects of sampling site on inferior vena cava flow veloc- ity waveforms. J Matern Fetal Invest 2:153±156 78. Severi FM, Rizzo G, Bocchi C, D`Antona D, Verzuri MS,

Arduini D (2000) Intrauterine growth retardation and fetal cardiac function. Fetal Diagn Ther 15:8±19 79. Hofstaetter C, Gudmundsson S, Hansmann M (2002)

Venous Doppler velocimetry in the surveillance of se- verely compromised fetuses. Ultrasound Obstet Gynecol 20:233±239

80. Hofstaetter C, Dubiel M, Gudmundsson S (2001) Differ- ent type of umbilical venous pulsation and outcome of pregnancy. Early Hum Dev 61:111±117

81. Indick JH, Chen V, Reed KL (1991) Association of um-

bilical venous with inferior vena cava blood flow veloc-

ities. Obstet Gynecol 77:551±557