Doppler Echocardiographic Assessment of Fetal Cardiac Failure

Introduction

In the fetus heart failure is the end stage of many pathological events that may lead to significant neo- natal morbidity or mortality. In the adult heart failure is defined as ªthe pathophysiological state in which an abnormality of cardiac function is responsible for the failure of the heart to pump blood at a rate commen- surate with the requirements of the metabolizing tis- sues and/or to be able to do so only from an elevated filling pressureº [1, 2]. In many instances this defini- tion also applies to the fetus, but differences in the anatomy and physiology of the fetal heart, when com- pared with the adult or neonatal heart, may not allow this definition to be fully applicable to the fetus.

Fetal Cardiac Anatomy and Physiology

Anatomical and physiological differences between the fetal and neonatal or adult heart call into question the ability to translate the knowledge of the patho- physiological events occurring during heart failure in the adult or neonate to the fetus. In the adult the two ventricular chambers of the heart work in series, with the right ventricle pumping deoxygenated venous blood into the pulmonary circuit and the left ventri- cle supplying oxygenated blood to the systemic circu- lation. The fetal heart, however, works in parallel with little of the right ventricular output going to the pulmonary circuit. Figures 35.1±35.3 review the nor- mal fetal intra-cardiac circulation.

Although there is some venous return to the fetal left atria via the pulmonary veins, the majority of venous return to the heart is through the superior and inferior vena cava and associated vessels [3±8]. Deoxygenated blood from the fetal head returns to the right atria from the superior vena cava and directly passes through the tricuspid valve into the right ventricle.

Studies in the fetal lamband other animal models have shown that oxygenated venous blood from the umbili- cal vein passes through the ductus venosus and prefer- entially enters the left heart via the foramen ovale [3±

8]. Studies on chronically instrumented fetal lambs have shown that, in physiological conditions, 50%±

60% of the umbilical venous blood bypasses the hepat- ic circulation and enters directly into the inferior vena cava via the ductus venosus [8]. From the inferior vena cava, this highly oxygenated blood preferentially streams through the foramen ovale to the left atrium, left ventricle, and ascending aorta. Figure 35.4 shows venous return in a 22-week fetus. Doppler flow (Fig.

35.4b) shows that, under normal conditions, there is always forward flow throughout the cardiac cycle in the ductus venosus.

Although there may be many anatomical variations in the venous return to the fetal heart, the following general anatomical relationships are noted [9]:

1. The inferior vena cava widens in the proximal por- tion and enters the atria in a slightly anterior direction. An extension of the inferior vena cava continues into the atria itself as a short tube-like

Doppler Echocardiographic Assessment of Fetal Cardiac Failure

William J. Ott

Fig. 35.1. Deoxygenated blood (1) enters the right atrium

from the superior and inferior vena cava. Oxygenated

blood (2) enters the right atrium primarily from the ductus

venosus

structure bounded on the right side by the Eusta- chian valve (or valve of the inferior vena cava) and on the left side by the foramen ovale flap. The atrial septum lies above the middle of the inferior vena cava in a crest-like structure known as the crista dividens (or septum secundum or limbus fossae ovalis). The inferior vena cava/foramen

ovale complex can be described as a Y-shaped unit with a long branch to the left atrium and a short branch to the right atrium.

2. This anatomical relationship results in two venous pathways for blood return to the fetal heart from the placental and lower body circulations. (a) A right inferior vena cava/right atrium pathway:

blood flow from the right hepatic vein and right portion of the proximal inferior vena cava is directed along this pathway. (b) A left ductus venosus/foramen ovale pathway: blood flow from the umbilical sinus, ductus venosus, and left por- tion of the proximal inferior vena cava is directed along this pathway. The left and medial hepatic Fig. 35.2. The oxygenated blood (2) is directed through

the foramen ovale into the left atria, while the deoxyge- nated blood (1) passes into the right ventricle

Fig. 35.3. Well-oxygenated blood (2) is then directed out the left ventricular outflow tract to the head and brain;

while the deoxygenated blood (1) is directed via the duc- tus arteriosus down the aorta to the umbilical arteries for oxygenation in the placenta

Fig. 35.4. a Gray-scale image of parasagittal scan of a 22-

week fetus using color Doppler. The aorta and inferior vena

cava (IVC) are shown. The arrow points to a segment of

the ductus venosus as it enters the inferior vena cava just

proximal to the right atria. b Doppler velocity flow in the

ductus venosus of the fetus in a. Note the triphasic pat-

tern, but that the flow is always forward throughout the

cardiac cycle

veins connect to this pathway. Blood flow in these two pathways has the proximal inferior vena cava in common but travels in different directions.

These anatomical and physiological relationships re- sult in different pathways for oxygenated and deoxy- genated blood returning to the fetal heart. Distal infe- rior vena cava blood with low oxygen saturation passes through pathway ªaº together with the right hepatic venous flow and is directed into the right at- ria where it joins the deoxygenated blood from the superior vena cava and passes into the right ventricle.

Oxygenated blood from the umbilical vein passed through the ductus venosus with some mixing with blood from the left and medial hepatic veins and is directed towards the foramen ovale and the left atria and hence to the left ventricle. These studies in nor- mal human fetuses are, in the main, consistent with previous studies in animal models.

The fetal anatomical shunt of the ductus arteriosus allows the fetal heart to function in parallel rather than in series, as in the adult heart [3]. The deoxygenated blood from the superior vena cava and the ªaº pathway blood from the inferior vena cava passes through the tricuspid valve and is ejected out the pulmonary artery.

Because of the ductus arteriosus shunt, this poorly oxy- genated blood is directed into the descending aorta to the lower carcass, and to the umbilical arteries for oxy- genation in the placental circulation. The left ventricle outflow is directed through the ascending aorta to the head and neck to supply the fetal brain with better oxy- genated blood derived primarily from the ªbº pathway via the foramen ovale. In the normal fetus right ventri- cular output is significantly greater than the left ventri- cular output in a ratio of 1.3 to 1.

A detailed evaluation of cardiac anatomy should always be undertaken in cases of suspected fetal heart failure. Normally the two ventricles should be of rela- tively similar size. Significant differences in ventricu- lar size can be related to structural anomalies (such as hypoplastic left or right heart) or heart failure.

Cardiomegaly is a common finding in fetal heart fail- ure. Figure 35.5 shows cardiomegaly in a 24-week fe- tus with both chronic and acute abruption. An evalu- ation of cardiac size can be made by comparing the anterior±posterior (AP) and transverse (trans.) diam- eters of the thorax with the AP and the transverse di- ameters of the heart in the axial view:

Ratio ˆ AP Hrt f ‰ … † ‡ Trans: Hrt … † Š=2 g=

AP Th … † ‡ Trans: Th … †

‰ Š=2

f g

This ratio ranges from 45% to 55% and is indepen- dent of gestational age [10]. Using M-mode, measure- ments of the pulmonary and aortic root diameters

can be obtained. Deng et al. have shown a consistent ratio between the pulmonary and aortic diameters of 1.09 (SD=0.06) with 5th and 95th percentile values of 1.06 and 1.11, respectively [11±13].

Fetal Cardiac Response to Stress

Because of the anatomical and physiological differences between fetal and adult circulations, the development of heart failure in the fetus may follow slightly different pathways than in the adult. In the adult alterations in myocardial function, and subsequent decrease in cardi- ac output, can be caused by alterations in one (or a combination) of three basic mechanisms: (a) preload, or ventricular filling pressure; (b) myocardial contrac- tility and heart rate; and (c) afterload or peripheral re- sistance [1, 2]. Alterations in any of these mechanisms can lead to decreased cardiac output and eventually to cardiac failure.

In the fetus the development of chronic stress and hypoxia results in alterations in fetal cardiovascular function. Both animal experimentation and Doppler evaluation of the human fetus have shown that chronic stress causes an alteration in the right/left heart dominance. During conditions of acute stress the primary fetal response is increased fetal heart rate. During conditions of chronic stress, however, al- terations in ventricular function lead to redistribution of cardiac output and preferential perfusion of the fe- tal brain and coronary arteries.

Rizzo et al. have postulated the theoretical re-

sponse of the fetal cardiovascular system to increas-

ing fetal stress: a decrease in fetal oxygenation or

substrate supply leads to a redistribution of cardiac

output, the so-called brain-sparing effect [14]. Even-

tually the impairment of cardiac function causes an

increase in the atrioventricular gradient and an ab-

normal cardiac filling which causes increased periph-

Fig. 35.5. Cardiomegaly in a 24-week fetus with acute and

chronic abruption

eral venous pressure and fetal decompensation and cardiac failure. Table 35.1 compares the causes of car- diac failure in the adult with known or postulated causes in the fetus.

The Scope of Fetal Cardiac Failure

Changes in obstetrical management, the development of new and more accurate methods of fetal surveil- lance, and a better understanding of the pathogenesis of fetal demise has led to changes in the distribution of the causes of stillbirths. Table 35.2 shows the dis- tribution of stillbirths from a review at the author's institution for the years 1988 through 1992. There were four fetal deaths directly caused by fetal heart failure: one premature closure of the foramen ovale;

one case of non-immune hydrops caused by tachyar- rhythmia; one case of significant increase in cardiac afterload caused by prune-belly syndrome; and one case of myocardial hypertrophy with heart failure in

a fetus of a diabetic mother. Although only 3% of fe- tal deaths were directly caused by fetal heart failure, it most likely played a significant role in many other fetal deaths: heart failure was the most likely terminal event in the cases of intrauterine infection (21%), twin±twin transfusion (6%), cord accidents (7%), and acute maternal problems (3%); and may have play a role in many of the cases of placental failure (17%). It is, therefore, likely that fetal heart failure plays a sig- nificant role in at least 40%±50% of stillbirths.

Duplex Doppler Evaluation

of the Fetal Cardiovascular System

Evaluation of fetal cardiac status includes measure- ments of velocity parameters in both peripheral ves- sels and the heart itself. In peripheral vessels angle- independent indices, such as the pulsatility index, re- sistance index, and systolic/diastolic (S/D) ratio, are most commonly used. The peripheral vessel most commonly evaluated is the umbilical artery. Changes in the velocity indices in this vessel reflect alterations in placental perfusion that may precede evidence of heart failure in situations of uteroplacental insuffi- ciency. Additional peripheral fetal vessels, such as the aorta, renal arteries, and carotid and middle cerebral Table 35.1. Causes of heart failure: comparison of adult

and fetal causes

Cause Adult Fetus

Cardiac arrhythmia Disorders of

arrhythmia Congenital arrhythmias Maternal collagen vascular disease Decreased

contractility Metabolic

disorders Maternal ketoacidosis Anoxia/ischemia Intrauterine

growth restriction Myocarditis Myocarditis Cardiac anomalies Congenital or

acquired Congenital anomalies Increased periph-

eral demand Myocarditis

Systemic infection Myocarditis Chorioamnionitis Systemic infection

Anemia Anemia

AVshunts Fetal tumors Chorioangioma Increased

afterload Hypertension Uteroplacental insufficiency?

Valvular stenosis Congenital heart disease

Increased preload Valvular

regurgitation Recipient twin Indomethacin?

Decreased venous

return Hemorrhage Hemorrhage

(abruption, vasa previa, fetomater- nal, other) Vena cava ob-

struction Venous obstruc- tion (tumor, hydrops, other) Iatrogenic Drug effects Indomethacin,

tocolytics, others

Table 35.2. Causes of fetal death: SJMMC Stillbirths 1988±

1992

Category Number Percentage (%)

Placental

Abruption 13 9

Other 27

17

Infection 32

21

Anomalies 19 13

Twin complications

Mono/Mono 3

2

Twin±twin transfusion 10

6

Unknown 2 1

Cord accident

Nuchal 7 5

True knot 2 1

Vasa previa 1 1

Fetal heart failure 4 3

Maternal

Liver rupture 2 1

Ketoacidosis 1 1

Aortic aneurysm 1 1

Unknown 27 18

Fetal trauma: ± ±

Rh: ± ±

Total 151 100

a

Includes two sets of twins with three stillbirths.

b

Includes one set of twins with two stillbirths.

c

Two sets of twins with one survivor.

d

Includes one set of triplets with a single survivor.

vessels, have also been studied. Alterations in the ve- locity indices of these vessels, especially in the caro- tid and cerebral vessels, have been reported to be a sensitive indication of fetal well-being. Velocity mea- surements at the cardiac level are all absolute values.

Measurements of absolute flow velocities require knowledge of the angle of insonation and vessel di- ameter, each of which maybe difficult to obtain with accuracy. The following formula can be used to calcu- late volume flow per minute:

Volume flow ml=min … †

ˆ p=4  D

 1=cos0  FVI  HR

where D is the diameter (in centimeters) of the vessel studied, 0 is the angle between the ultrasound beam and the vessel, FVI is the flow velocity integral (area under the velocity waveform), and HR is the heart rate in beats per minute [12]. The error in the estimation of the absolute velocity depends on the magnitude of the angle itself and the diameter of the vessel being inter- rogated. For angles <208, the error is low. With larger angles, the cosine term in the Doppler equation changes the small uncertainty in the measurement of the angle to a large error in velocity equations. In ad- dition, small errors in the measurement of the vessel diameter is magnified by the Doppler equation [12].

The parameters most commonly used to describe the cardiac velocity waveforms are: (a) peak velocity, the maximum velocity at a given moment (e.g., systole, diastole); (b) time-to-peak velocity, or acceleration time, expressed by the time interval between the onset of the waveform and its peak; (c) time±velocity inte- gral, calculated by planimetry of the area underneath the Doppler spectrum; and (d) volume flow (see above) [12]. Velocity flow measurements can be obtained from a number of sites in or near the fetal heart.

Umbilical Venous Pulsations

During pathologic situations, increased reverse flow in the inferior vena cava may result in venous pulsa- tions in the umbilical vein [14±21]. Indik et al. postu- lated that it may be possible to distinguish subgroups of fetuses with abnormal umbilical artery S/D ratios by evaluating fetal vena cava flow [21]. They de- scribed five sub-groups of fetuses with abnormal um- bilical venous pulsations:

1. Tachycardia, which shortens ventricular filling and leads to increased end-diastolic pressure. During atrial contraction the increased end-diastolic pres- sure causes increased reverse flow in the inferior vena cava.

2. Sinus bradycardia also increases reverse flow by increased ventricular or atrial filling during pro-

longed diastole, leading to increased pressure dur- ing atrial contraction.

3. Complete heart block may cause increased reverse caval flow during ventricular systole, most likely due to independent atrial contractions against closed atrioventricular valves.

4. Premature atrial contractions were also noted to cause increased reversed caval flow during the pause following a premature atrial contraction.

The mechanism was postulated to be similar to that seen with sinus bradycardia.

5. Abnormal filling of the ventricles is thought to be another etiology for increased reverse flow in the inferior vena cava.

Clinical situations associated with abnormal ventricle filling were congenital heart disease, infants of dia- betic mothers, chorioangioma, nonimmune hydrops, and intrauterine growth restriction (IUGR). Umbilical venous pulsations therefore appear to be a significant pathologic event that requires careful fetal evaluation, especially of the fetal cardiovascular system.

Other Studies

Animal investigations have produced results similar to those seen by Doppler interrogation in the human fetus. Reuss et al. evaluated superior and inferior vena cava and umbilical vein blood flow patterns in fetal sheep using electromagnetic flow transducers [18]. The patterns of velocity flow were similar to those noted above for the human fetus. They were also able to manipulate the circulation of the fetal sheep to study the effects of afterload differences and hypoxia on venous dynamics. Administration of ace- tylcholine caused a reduction in afterload associated with peripheral vasodilatation, which allowed greater ventricular emptying with increased diastolic peak flow. Hypoxia was associated with an increase in su- perior vena caval blood flow through the foramen ovale to the left atrium and ventricle. Rizzo et al.

postulated the pathophysiological steps leading to

changes in biophysical parameters during fetal de-

compensation [14]: (a) increased resistance in the

umbilical artery (S/D ratio); (b) increasing resistance

in fetal peripheral vessels with a concomitant de-

crease in the resistance of vessels in the central ner-

vous system (brain-sparing effect); (c) change in the

ratio of right/left ventricular cardiac output with a

shift to left ventricular dominance; (d) a decrease in

the peak systolic velocities of the outflow tracts with

a decrease in combined cardiac output; (e) increase

in reverse flow in the inferior vena cava during atrial

contractions leading to (f) umbilical venous pulsa-

tions and eventually (g) abnormal fetal heart rate

tracings.

Velocity Measurements Across the Atrioventricular Valves

Blood flow across the atrioventricular valves can easi- ly be seen with Doppler sonography (Fig. 35.6) [14, 22±26]. Blood flow velocity can be studied at the level of the mitral or tricuspid valves by placing the Dop- pler sample volume immediately distal to the valve leaflets in the right or left ventricle. In addition to

obtaining diastolic velocities across the atrioventricu- lar valves, the presence of valvular insufficiency can be ascertained by moving the Doppler gate retrograde through the valve opening. Valvular stenosis has been reported to be associated with increased velocity flow through the affected valve. The waveforms recorded at the level of the mitral and tricuspid valves are characterized by two diastolic peaks: an early ventric- ular filling peak (E wave) and a second filling peak corresponding to the active ventricular filling phase during atrial contraction (A wave; Figs. 35.7, 35.8).

These waveforms can be recorded as early as 12 weeks' gestational age [27].

The ratio between the A and E waves (A/E) is an index of ventricular diastolic function and is related to both cardiac compliance and preload conditions.

The A/E ratio shows a significant decrease with ad- vancing gestational age but remains above unity (Figs. 35.7, 35.8). This picture is the converse of that seen in the adult and suggests that ventricular com- pliance is less in the fetus than the neonate but im- proves with advancing gestational age. Reed [23] and Reed et al. [25] have shown that in most of the fe- tuses studied, tricuspid flow velocities during both early and late diastole were greater than those across the mitral valve. This confirms the impression of right heart dominance in the fetus that is seen when evaluating ventricular outflow.

Fig. 35.6. Gray-scale image of a color Doppler axial scan through the fetal chest at 25 weeks showing flow across the AVvalves

Fig. 35.7. Doppler blood flow across the mitral (left) and tricuspid (right) valves of a 20-week fetus. Note that the A/E ra-

tio is greater than one

There is disagreement in the literature concerning the effects of gestational age on the maximal velocity across the atrioventricular valves. Allan et al. [22]

and Reed [23] thought that there was no significant change in maximum or mean velocity flow across the valves throughout gestation, although van der Mooren et al. [26] showed a small but significant increase in velocity parameters with advancing gestational age.

The decrease in inferior vena cava reverse flow and the A/E ratio with advancing gestational age is con- sistent with the increased ventricular compliance seen during that time.

Ventricular Outflow Velocities

Velocity flow and volume flow measurements have been reported for the right and left ventricular out- flows (pulmonary artery and aorta, respectively; shown in Fig. 35.9) [14, 22±26]. The aortic outflow tract can be visualized as it leaves the left ventricle through a slightly rotated, angled four-chamber view, the ªfive- chamberº view. The pulmonary artery outflow tract as it leaves the right ventricle can be seen from a mod- ified two-chamber view. A number of studies have shown that right cardiac output is greater than left car- diac output throughout gestation, and that beginning at 20 weeks the right/left cardiac output ratio remains constant with a mean value of 1.3, indicating right heart dominance in the human fetus, which has also been reported for the fetal lamb [28, 29].

Ductus Arteriosus

Ductus arteriosus velocity waveforms can be recorded from a parasagittal short-axis view of the fetus that shows the ductal arch. There is continuous forward flow throughout the cardiac cycle. Ductal peak veloc- ity increases with gestation, and its values represent the highest velocity in fetal circulation occurring un- der normal conditions. Premature closure of the duc- tus, which has been reported in patients undergoing indomethacin therapy for premature labor, markedly increases right ventricular afterload and leads to tri- cuspid regurgitation and eventual cardiac failure. Tul- zer et al. confirmed this finding with experimental ductal occlusion in fetal lambs [30].

Errors in Doppler Blood Flow Velocity Measurements

Doppler velocity flow measurements are prone to error [14, 24]. The most critical factor that affects the accu- racy of the measurements is the angle of insonation.

Measurement errors increase rapidly if the angle of in- sonation is greater than 208. Rizzo et al. reported a coef- ficient of variation of less than 10% for Doppler velocity flow indices (except for volume flow) when the angle is kept at less than 208 [14]. In addition, the location of the volume flow gate should be frequently checked with du- plex or color flow Doppler sonography to confirm the accurate placement of the interrogation site.

Fig. 35.8. Doppler blood flow across the mitral (right) and tricuspid (left) valves of a 34-week fetus. Although the A/E ratio

is still greater than one, the ratio is less than that at 20 weeks

Calculation of volume flow introduces an addi- tional error: measurement of vessel or valve diameter.

Because the diameter term is squared in the formula for calculating volume flow, any error in the measure- ment is significantly magnified. Alverson reported a study of 33 pediatric patients who were scheduled for cardiac catheterization where in the Doppler-calcu- lated volume flow and volume flow measured by the Fick principle during catheterization were directly compared [31]. He demonstrated an excellent correla- tion between the two methods, with a correlation coefficient (r) of 0.981. Fillinger and Schwartz studied Doppler flow measurements in an in vivo canine pul- satile flow model and found good correlation between Doppler-calculated and actual flow rates when lami- nar flow was seen [32]. They expressed caution about the accuracy of Doppler calculations, however, when flow was non-laminar, and they stressed the impor- tance of the angle of insonation. In addition to the above measurement techniques, care must be taken to record velocity flow measurements during periods of fetal rest.

Clinical Conditions Associated with Fetal Heart Failure

Experience in obstetrical duplex Doppler examina- tions of the fetus have identified a number of clinical conditions where fetal heart failure is the cause of fe- tal death or a significant contributor to it.

Congenital Heart Disease

Structural fetal heart disease is the most common congenital anomaly seen at birth with an incidence of 7±10 per 1,000 live births. Although congenital heart disease is the most common birth defect seen in the neonatal period, there is strong evidence that it is even more common during the fetal period. Two re- ports have shown that 24% of fetuses with diagnos- able congenital heart disease died in utero, most likely from fetal heart failure [33, 34].

Ultrasound has been used extensively for the diag-

nosis and evaluation of structural congenital heart

disease [35±42]. Many structural anomalies can be vi-

sualized using only conventional ultrasound; however,

the use of color flow Doppler can significantly en-

hance the diagnostic accuracy in suspected congenital

heart disease [33, 34, 38, 43±47]. Color Doppler flow

studies, coupled with velocity flow measurements,

Fig. 35.9. Doppler blood flow across the aortic (left) and pulmonary (right) outflow tracts at 24 weeks of gestation

can (a) confirm the presence or absence of normal flow patterns in cardiac structures, (b) note the pres- ence of abnormal flow patterns such as valvular re- gurgitation, absence of normal chamber filling (which might be seen in valvular atresia), or increased peak velocity (which may be seen in cases of valvular ste- nosis), and (c) identify reversal of normal flow direc- tion (such as in the foramen ovale and aortic arch in the case of mitral atresia or in the ductus arteriosus with pulmonary atresia). In cases of fetal ventricular septal defect (VSD), however, there is little flow across the VSD since the pressure gradient between the two ventricles is minimal during intrauterine life.

Table 35.3, modified from an article by Reed, shows the alterations in velocity flow that are frequently seen in many cases of congenital heart disease [45].

Umbilical and middle cerebral artery flow in fetuses with congenital heart disease was evaluated by Meise et al., who found little change in arterial blood flow velocities compared with normal fetuses [46]. Only in fetuses with severe outflow tract obstructions were there significant changes in arterial flow. They felt that abnormal arterial Doppler waveforms reflected uteroplacental dysfunction rather than alterations caused by the congenital heart disease.

A number of authors have reported hydrops fetalis and fetal heart failure associated with congenital heart disease. Sahn et al. reported a case of trisomy 13 with hypoplastic left heart syndrome that devel- oped hydrops fetalis [44]. Interrogation of the tricus- pid valve revealed high-velocity flow, 1.5 times great-

er than the normal values for their laboratory. Blake et al. reviewed a series of twenty fetuses with hypo- plastic left heart syndrome [33]. Three of the 11 (27%) fetuses that were not terminated died in utero, most likely secondary to fetal cardiac failure. These authors also point out the importance of antenatal di- agnosis of congenital heart disease. It allows (a) timely cytogenetic studies to be done, (b) early diag- nosis and intervention in the neonatal period and planning for definitive therapy, and (c) additional time for parents to plan and discuss various treat- ment options for the fetus and obtain sufficiently in- formed consent.

Additional reports of fetal heart failure in infants with congenital heart disease have also been pub- lished in the literature. Respondek et al. reported a case of heart failure in a fetus with left atrial isomer- ism (common atrium) associated with complete heart block [47]. Color Doppler flow showed abnormal, tur- bulent flow in the regions of both the pulmonary ar- tery and the aortic valve and increased flow velocity across the atrioventricular valves. Pericardial effusion and hepatomegaly were also noted. The infant died shortly after birth and an autopsy also disclosed un- suspected vegetation close to the thickened atrioven- tricular valves. The endocardium also showed evi- dence of endocarditis. Guntheroth et al. [48] and De- Vore et al. [49] have reported abnormal flow studies in cases of pulmonary valve stenosis or atresia. Tri- cuspid regurgitation was felt to be a key sign of im- pending fetal heart failure. Rustico et al. reported a case of endocardial fibroelastosis associated with crit- ical aortic stenosis and abnormal outflow track flow diagnosed at 15 weeks' gestation.

An excellent review of the use of color Doppler flow studies for the diagnosis of congenital heart dis- ease can be found in two articles by DeVore et al.

[49] and DeVore [51]. They describe abnormal Dop- pler flow findings in some of the more common car- diac anomalies:

1. Aortic stenosis: retrograde flow into the left atrium during ventricular systole.

2. Ventricular septal defect (VSD): since the pressure in the left and right ventricle are almost identical in the fetus, there is frequently no flow disturbance across the septum. Flow disturbances may be seen, however, when there is an associated abnormality of the outflow tract with increased resistance to the flow of blood leaving the ventricle.

3. Atrioventricular canal defect (AV canal): the pres- ence of AV valvular regurgitation has been found to be a sign of developing hydrops fetalis and heart failure.

4. Atrial septal defect (ASD): reverse flow (left±right shunt) across the ASD may lead to right ventricu- lar dilatation and heart failure.

Table 35.3. Changes in Doppler flow velocities with cardi- ac anomalies. I increased, D decreased, A absent, U un- changed, R possible regurgitation, V variable. (From [45])

Anomaly Velocity flow Tricuspid valve Mitral

valve Pulmo- nary ar- tery

Aorta

Hypoplastic

right heart D I D I

Hypoplastic

left heart I A I A

Tricuspid atre-

sia A I D

Ebstein's

anomaly I or R I D I

Pulmonary

atresia I or R I A I

Tetralogy of

Fallot U U D I

Transposition U U U U

Double-outlet

right ventricle I D V V

Atrioventricu-

lar canal I or R I or R V V

5. The presence of valvular regurgitation, especially tricuspid regurgitation, has been associated with fetal anemia, right ventricular volume overload, and ductal constriction.

One important consideration that must be empha- sized in the evaluation of fetal congenital heart dis- ease is the high association between structural heart disease in the fetus and chromosomal abnormalities.

Abnormal karyotypes have been reported in 20%±

45% of fetuses with cardiac defects, and Paladini et al. have reported that 48% of fetuses with congenital heart disease had abnormal karyotype: 29% with iso- lated cardiac anomalies and 71% with cardiac and extracardiac anomalies [52]. Amniocentesis or cordo- centesis with cytogenetic evaluation is an integral part of the evaluation of suspected fetal cardiac anomalies.

One very rare but documented congenital condi- tion that leads to fetal heart failure is intrauterine myocardial infarction. Birnbacher et al. reported a case of intrauterine myocardial infarction in a fetus that subsequently developed a large ventricular aneu- rysm [53]. Congenital heart disease, intrauterine as- phyxia, infection, and maternal drug use have been associated with intrauterine myocardial infarction [54±56]. Findings include cardiomegaly, decreased contractility, and hypokinesia of the ventricular wall frequently associated with a ventricular aneurysm.

Fetal Hydrops

Fetal hydrops is defined as a pathological increase in fluid accumulation in serous cavities and/or edema of soft tissues [57]. Prior to 1960, the most common recognizable cause of fetal hydrops leading to fetal or neonatal death was maternal Rh sensitization. Be- cause of the widespread use of Rh prophylaxis, the incidence of fetal hydrops secondary to Rh sensitiza- tion has been drastically reduced. Many of the known causes of non-immune fetal hydrops are listed in Ta- ble 35.4.

Fetal heart failure is a central mechanism in the de- velopment of many cases of non-immune hydrops. In an excellent review of the topic Hutchinson listed six general causes of edema or ascites in the fetus [58]:

1. Heart failure or venous obstruction leading to al- teration in hydrostatic pressure

2. Hypoproteinemia leading to alterations in colloid osmotic pressure

3. Changes in membrane permeability caused by in- flammation or other causes

4. Change in interstitial gel and its affinity for water 5. Alterations in lymphatic drainage

6. Changes in water homeostasis of the fetal±mater- nal±placental unit.

Table 35.4. Causes of non-immune fetal hydrops Hematological

Anemia due to maternal acquired pure red-cell apla- sia Anemia due to blood loss

Fetomaternal bleeding Twin-to-twin transfusion

Hemolysis: glucose-6-phosphate dehydrogenase defi- ciency

Hemoglobinopathy: homozygous alpha-thalassemia Pulmonary

Congenital cystic adenomatoid malformation Pulmonary lymphangiectasia

Pulmonary leiomyosarcoma Alveolar cell adenoma of the lung Diaphragmatic hernia

Extralobar pulmonary sequestration Enlargement of one lung

Chylothorax Neurological

Fetal intracranial hemorrhage Encephalocele

Porencephaly with absent corpus callosum Gastrointestinal

Midgut volvulus Diaphragmatic hernia Atresia

Esophageal with imperforate anus Duodenal

Bowel

Ileal with meconium peritonitis

Meconium peritonitis with gut herniated into perito- neal sac

Meconium peritonitis of unknown etiology Duodenal diverticulum

Imperforate anus Hepatic

Cirrhosis with portal hypertension Giant cell hepatitis

Hepatic necrosis

Hemangioendothelioma of the liver Genitourinary

Congenital nephrotic syndrome (Finnish type) Pelvic kidney

Hypoplastic kidney (with microcephaly) Urethral obstruction with renal dysplasia

Hypoplastic uterus, imperforate hymen, bilateral ac- cessory renal arteries

Polycystic kidneys, vaginal atresia, and hydrocolpos Urogenital sinus, hydronephrosis, bifid uterus, hydro- colpos

Adult polycystic kidney disease Infectious

Coxsackie virus pancarditis Secondary syphilis Toxoplasmosis

Cytomegalovirus hepatitis, myocarditis, encephalitis Parvovirus

Herpes simplex type I

Respiratory syncytial virus

Although primary fetal heart failure can be a cause of non-immune fetal hydrops, heart failure secondary to other causes, such as anemia, hypoproteinemia, or hypoxia, may be a more common etiology of the problem. Many of these postulated causes of non-im- mune fetal hydrops are analogous to some of the causes of heart failure in the adult.

Isoimmunization

Isoimmunization in the fetus (usually as a result of Rh incompatibility) results in a progressive destruc- tion of fetal red cells and fetal anemia [59]. Doppler studies have shown that both left and right cardiac outputs are significantly higher than normal in ane- mic fetuses, with a significant increase in volume flow, peak velocity in the outflow tracts, and an de- Table 35.4 (continued)

Neoplastic Neuroblastoma Teratoma Sacral Mediastinal Malignant

Congenital leukemia with Down syndrome Hemangioendothelioma of the liver Pulmonary leiomyosarcoma Tuberous sclerosis

Cardiovascular Cardiac structure

Atrioventricular canal defect

With abdominal situs inversus and complete heart block

With transposition of great arteries

With transposition of the great vessels and asplenia With transposition of the great vessels and polysple- nia With double-outlet right ventricle and pulmonic ste- nosis

With overriding aorta, tracheoesophageal fistula With complex bradyarrhythmia, atrioventricular (AV) valve insufficiency, interrupted inferior vena cava Complete communication with common AVvalve Tetralogy of Fallot

Absent pulmonary valve or pulmonary atresia Aortic atresia, diminutive left ventricle, and mitral valve

Aortic valve stenosis with mitral insufficiency Aortic arch interruption

Tricuspid dysplasia and Ebstein's anomaly Tricuspid and pulmonary atresia

Myocardial infarction with coronary artery embolus Intrapericardial teratoma

Cardiac rhabdomyoma

Myocardial tumors involving ventricular septum, aor- tic outflow, and left atrium, not requiring surgery Intrauterine closure of foramen ovale

Intrauterine closure of ductus arteriosus Endocardial fibroelastosis

With mitral valve insufficiency With subaortic stenosis Ventricular septal defect

With atrial septal defect (ASD)

With ASD and right atrial conduction system hamar- toma With patent ductus arteriosus with absent right hemidiaphragm

Cardiac rhythm Atrial

Bradycardia and bradyarrhythmia Tachycardia

Paroxysmal

Wolff-Parkinson-White syndrome Flutter with block

Complete heart block

Table 35.4 (continued) Vascular

Vena cava thrombosis Hemangioendothelioma Arterial calcification Arteriovenous malformation Cerebral angioma

Metabolic

Gaucher's disease Sialidosis

Gangliosidosis GM1 Mucopolysaccharidosis Skeletal dysplasias

Achondroplasia Achondrogenesis

Parenti-Fraccaro (or type I) Langer-Saldino (or type II) Osteogenesis imperfecta Thanatophoric dwarfism Short rib-polydactyly syndrome Saldino-Noonan type

Majewski type

Asphyxiating thoracic dysplasia Chromosomal

Triploidy Trisomies

13 21 (Down's syndrome) 18 (Edward's syndrome) 47XY+der, t(11:21)(q23:q11) mat Abnormal chromosome 11 Mosaic 46XX/XY

Mosaic 46XY/92XXYY 45XO (Turner's syndrome) dup (11p)

Hereditary

Pena-Shokeir type I

Lethal multiple pterygium syndrome

Noonan syndrome with congenital heart defect Placental

Chorioangioma

crease in the A/E ratio at both atrioventricular valves [60]. The increased cardiac output seen in these ane- mic fetuses my be due to a decrease in blood viscosi- ty which, in turn, leads to increased venous return and cardiac preload; and/or to peripheral vasodilata- tion caused by a fall in blood oxygen content and therefore reduced cardiac afterload. There is no evi- dence for a redistribution of cardiac output similar to that described in hypoxic IUGR fetuses [60].

The traditional method of evaluating fetal anemia in sensitized patients is the serial determination of amniotic fluid changes in optical density at 450 nm [61, 62]. The use of Doppler ultrasound to measure peak velocity in the fetal middle cerebral artery has been shown to be an accurate, non-invasive method of evaluating fetal anemia [63±65]. Figure 35.10 shows the correlation between fetal/neonatal hematocrit and peak velocity in the fetal middle cerebral artery in 36 patients with suspected fetal anemia (primarily due to isoimmunization) followed at the author's institu- tion. Doppler ultrasound appears to be as accurate as serial amniocentesis in evaluating suspected fetal ane- mia, and has the important advantage of being a non-invasive test [66].

Non-Immune Hydrops

As has been mentioned previously non-immune fetal hydrops may be secondary to a multitude of different causes. The first step, therefore, in the evaluation and management of fetuses with suspected non-immune hydrops is to attempt to determine its etiology. Some of the more common causes of non-immune fetal hydrops include chromosomal abnormalities, mass lesions that affect fetal blood flow, lymphatic abnor- malities, metabolic diseases of the fetus, and infection

[67±72]. Table 35.5, modified from a review by Holz- greve et al., lists many of the tests necessary to appro- priately evaluate cases of non-immune hydrops [57].

A study by Saltzman et al. reviewed the ultrasonic differences seen in anemic and non-anemic fetuses with hydrops [60]. The lack of a thickened placenta, and the presence of pleural effusions and/or marked edema, was more frequently associated with non-ane- mic causes of fetal hydrops. Doppler echocardiography may be useful in the additional differentiation between cardiac and non-cardiac causes of non-immune hy- drops [45, 71]. Increased velocity in the middle cere- Fig. 35.10. Regression of the peak velocity of the middle

cerebral artery [converted to multiples of the mean (MOM) for gestational age] against the fetal/neonatal hematocrit (converted to MOM for gestational age) at cordocentesis or

delivery. The right side of the figure shows the peak velo- city in the middle cerebral artery in anemic vs non-anemic fetuses or neonates

Table 35.5. Evaluation of non-immune fetal hydrops.

TORCH toxoplasmosis, other, rubella, cytomegalovirus, herpes. (From [57])

Evaluation Test Etiology?

Maternal Antibody screen Rule out isoimmuni- zation

Complete blood

count and indices Hematological disor- Electrophoresis ders Thalassemia Kleihauer-Betke stain Fetal±maternal

hemorrhage VDRL and TORCH

titers Fetal infection

Glucose tolerance

test Maternal diabetes

Fetus Level II ultrasound

and color Doppler Anatomical or physi- ological abnormali- ties of the fetus Cordocentesis Karyotype (chromo-

somal anomalies) Amniocentesis

Paracentesis Cultures/immunology (infection)

Thoracenteses

bral artery correlates with fetal anemia. Low-peak velo- city in the outflow tracts, exaggerated pulsations in the inferior vena cava, or an increase in the percentage of reverse flow in the inferior vena cava during atrial con- tractions, pulsations in the umbilical vein, and tricus- pid regurgitation are all developing signs of fetal heart failure. Pulsations in the umbilical vein appear to be a sign of significant fetal compromise.

The outcome for fetal non-immune hydrops de- pends on the cause of the condition and the gestational age at diagnosis. Diagnosis before 20 weeks carries a worse prognosis, but even with aggressive therapy the mortality rate for non-immune hydrops is 40%±60%

[73±75]. As has been mentioned previously, there are multiple causes of non-immune hydrops and a discus- sion of even some of its major causes is beyond the scope of this chapter; however, two specific causes of non-immune hydrops should be mentioned since they are directly related to fetal heart failure: fetal cardiac arrhythmia and fetal anemia.

Fetal Cardiac Arrhythmia

Persistent alterations in the rate or rhythm of the fetal heart can lead to heart failure, non-immune hydrops, and significant neurological morbidity after delivery [76±84]. A number of excellent review articles on the diagnosis and treatment of fetal cardiac arrhythmia have been published [77]. Arrhythmia tachycardia is the most common pathological anomaly noted and the one that most frequently leads to hydrops.

Doppler echocardiographic evaluation of the fetal heart can be an important adjunct in the proper classi- fication of fetal cardiac arrhythmia and in the evalua- tion of fetal therapy. Chan et al. reported the use of si- multaneous recordings of the Doppler waveforms from the inferior vena cava and aorta for the precise diagno- sis of the type of arrhythmia seen [82]. Intermittent or non-persistent tachycardia can be managed by careful observation [85±88]. In many situations, spontaneous resolution of fetal tachycardia has been noted, leading some investigators to recommend a conservative approach to fetal tachycardia if there is no evidence of fetal cardiac compromise (no evidence of chamber dilatation, valvular regurgitation, hydrops, or de- creased ventricular systolic function) [89].

If there are any signs of fetal cardiac compromise or if the tachyarrhythmia is persistent, intrauterine therapy may be necessary. Table 35.6, modified from the work of a number of investigators, lists the dos- age of maternally administered oral drugs frequently used in the treatment of in utero fetal arrhythmias [77±80]. Careful monitoring of both fetus and mother is necessary in the pharmacological treatment of fetal arrhythmia, and consultation with a cardiologist is essential.

Persistent fetal bradycardia is a much less frequent problem. Congenital heart block, which may be asso- ciated with maternal systemic lupus or with some congenital heart defects (transposition of the great vessels or AV canal defects), can usually be managed conservatively [84]. The use of M-mode for diagnosis and evaluation of fetal arrhythmias has also been re- ported [86].

Fetal Anemia

Fetal anemia can develop from a number of causes, with isoimmunization leading to fetal hemolysis being a classical case. Alpha-thalassemia-1 (Bart's dis- ease), caused by an inherent deficiency in the alpha- globin hemoglobin chain, leads to severe fetal ane- mia, hydrops and fetal death [90]. Cardiomegaly, in- creasing velocities in the middle cerebral artery, and eventual fetal hydrops are ultrasonic hallmarks of the disease [90, 91].

Significant fetal±maternal hemorrhage can be a cause of stillbirth or neonatal anemia [92]. The diag- nosis is usually made after delivery by finding signifi- cant fetal blood in the maternal circulation using the Kleihauer-Betke test. The use of Doppler ultrasound to measure the peak velocity in the middle cerebral artery has provided an accurate, non-invasive method of evaluating suspected fetal anemia. Figure 35.11 shows the graph of the peak velocity in the middle cerebral artery of a fetus that was evaluated for de- creased movement at 32 weeks of gestation. The marked increase in peak velocity together with a non-reactive NST led to an emergency Cesarean de- livery. The neonate was anemic with a hemoglobin/

hematocrit of 10.2/29. A Kleihauer-Betke test on the mother's blood showed evidence of greater than 120 cc of fetal blood, confirming the diagnosis of fe- tal±maternal bleeding.

A number of other causes of fetal bleeding and subsequent anemia have been reported. Cases of in- tracranial hemorrhage secondary to trauma, throm- bocytopenia, or preeclampsia has been published [93±95]. Fetal hemorrhage into cystic tumors or fetal bleeding secondary to abruption or ruptured vasa previa can also cause severe fetal anemia.

Table 35.6. In utero therapy of fetal arrhythmia

Arrhythmia Drug Dosage (maternal)

Supraventricular ta-

chycardia Digoxin 0.25±0.75 mg q 8 h (may be added if no

response) (Verapamil) 80±120 mg q 6±8 h (Flecainide) 100 mg three to

four times a day

Twin±Twin Transfusion Syndrome

A complication peculiar to monochorionic twin gesta- tion is the ªtwin±twin transfusion syndromeº [96±

101]. The clinical features of this syndrome are listed in Table 35.7.

The diagnostic criteria for the syndrome include the above clinical findings, and, in addition (a) a he- moglobin difference of greater that five grams of he- moglobin per decaliter, (b) weight discordance, and (c) pathological confirmation of monochorionic pla- centation with significant vascular communications between the placentas.

This last criterion is the suggested cause for the de- velopment of twin±twin transfusion, namely vascular anastomosis between the two twin placentae of the ar- terial±venous type, from the donor to the recipient, deep within the placenta that is uncompensated [101].

This in turn leads to anemia and IUGR in the donor twin, and polycythemia and high-output failure in the recipient twin [102±106]. The ultrasonic diagnosis of twin±twin transfusion requires the features listed in Table 35.8. Monochorionic twins have a 5%±20%

risk developing some degree of twin±twin transfusion [107±109]. Twin±twin transfusion is exceedingly rare in monoamniotic twin gestation because of the large number of vascular anastomoses found in this type of twin gestation leading to an overall balanced flow be- tween the two placentas. Reports of twin±twin transfu- sion syndrome cases list a mortality rate of 30%±60%

for at least one of the twins and a high incidence of congenital abnormalities (10%) [107±109].

Doppler velocity studies of the umbilical artery and vascular communications between the twin pla-

centas have added additional information concerning the management of twin±twin transfusion [102, 103].

Although there is some disagreement between investi- gators, most authors feel that abnormal umbilical S/D ratios (or other abnormal ratios) are of prognostic value in determining the severity of the twin±twin transfusion [104±106]. Achiron et al. described a spontaneous remission of hydrops fetalis in a case of twin±twin transfusion syndrome that was followed using two-dimensional echocardiography, Doppler ul- trasound, and color flow mapping [105]. The recipi- ent twin, who developed hydrops, showed cardiome-

Fig. 35.11. The significantly elevated peak velocity (cm/s) in the middle ce- rebral artery of a 32-week fetus who was shown to have significant fetal±

maternal hemorrhage

Table 35.7. Twin±twin transfusion syndrome

Recipient twin Donor twin

Polyhydramnios Oligohydramnios

Plethoric Anemic

Edema Non-edematous

Large for gestational age Small for gestational age

Hypertensive Hypotensive

Hyperbilirubinemia Normal bilirubin

Table 35.8. Ultrasonic diagnosis of twin±twin transfusion Single placenta

Same sex Monochorionic

Significant weight discordance

Discordant amniotic fluid volume (oligohydramnios/

polyhydramnios)

Hydrops or cardiac failure (may not be apparent until

late)

galy and venous distention. It also showed a signifi- cant increase in cardiac output and evidence of mi- tral and tricuspid regurgitation. Velocity flow studies remained stable throughout the pregnancy and a gradual improvement in the hydrops in the recipient twin was seen. After birth, a neonatal echocardiogram showed cardiomegaly, poor contractility, and mitral and tricuspid regurgitation in the recipient twin. The donor twin had normal cardiac output and velocity measurements. These authors recommended serial cardiac velocity flow studies in all cases of suspected twin±twin transfusions [104]. Cardiomegaly and tri- cuspid valve regurgitation are consistent findings seen in the recipient twin as it deteriorates [108].

Some investigators have attempted to identify pregnancies at risk for twin±twin transfusion by eval- uating blood flow in the first trimester. Matias et al.

evaluated 20 monochorionic twin pairs in the first trimester and felt that the presence of an increased nuchal fold and abnormal ductus venosus blood flow (reversed A wave) was highly predictive of the devel- opment of twin±twin transfusion syndrome later in pregnancy [109].

Intrauterine Growth Restriction

True IUGR is a pathological process that affects normal fetal growth and results in an infant whose growth is less than its inherent potential [109±114]. A number of chronic maternal medical conditions, such as the he- moglobinopathies or significant heart disease, result in decreased oxygen delivery to the fetus and lead to IUGR. Other maternal diseases, especially those in which hypertension is a component, or abnormalities of the placenta can also cause IUGR. Problems such as congenital anomalies or intrauterine infection dam- age the developing fetus and decrease its growth. These pathological processes can diminish the normal inher- ent growth potential of the fetus. This, in turn, can re- sult in chronic fetal hypoxia and eventual fetal heart failure and death. The combined use of ultrasonic fetal weight estimation, fetal anthropometric ratios, and Doppler ultrasound has been shown to be a reasonably accurate method of diagnosing and following fetuses with IUGR. This topic is discussed more fully in the chapter on IUGR and Doppler.

True IUGR caused by abnormalities in uteropla- cental perfusion is characterized by selective changes in peripheral vascular resistance that can be evaluated using any of the angle-independent indices of Dop- pler velocity flow studies in the fetal peripheral ves- sels [112]. The author's experience has shown that umbilical artery Doppler velocity studies have been a significant help in the diagnosis and management of IUGR [13, 111].

The role of Doppler velocity flow studies in the heart and great vessels is not fully known. Increased placental resistance and increased systemic resistance due to hypoxia that may be seen in IUGR may lead to increased right heart work and decreased right ventricular flow. A redistribution of cardiac output in IUGR results in a decreased left ventricle afterload due to the cerebral vasodilatation, and an increased right ventricle afterload due to the systemic vasocon- striction [114±116]. Furthermore, hypoxemia may im- pair myocardial contractility, while the polycythemia that is usually present might alter blood viscosity and therefore preload. A number of investigators have shown alterations in velocity flow in the heart with impaired ventricular filling causing an increased A/E ratio at the level of the atrioventricular valves, lower peak velocity in the aorta and pulmonary arteries, in- creased aortic and decreased pulmonary time-to-peak velocities, and a relative increase of left cardiac out- put associated with decreased right cardiac output [110±114]. These changes are compatible with a pre- ferential shift of cardiac output in favor of the left ventricle, leading to improved perfusion to the brain, the ªbrain-sparingº effect.

As the fetus deteriorates, peak velocity and cardiac output gradually decline and cardiac filling is im- paired. An increase in reverse flow in the inferior vena cava during atrial contraction may occur and the fetus continues to deteriorate which, in turn, will lead to pulsations in the umbilical vein. Rizzo et al.

have speculated that the fetal heart adapts to placen- tal insufficiency in order to maximize brain sub- strates and oxygen supply [14]. With progressive de- terioration of the fetal condition, this protective mechanism is overwhelmed by the fall in cardiac out- put and fetal distress occurs. These findings suggest that the study of cardiac and great vessel blood flow patterns will be a useful tool for longitudinal moni- toring of the fetal condition in pregnancies compli- cated by uteroplacental insufficiency. Makikallio et al.

have shown that the development of retrograde flow in the aortic isthmus of IUGR fetuses indicated high right ventricular afterload [116].

Diabetes Mellitus

Infants of diabetic mothers have long been recognized as being at risk for cardiac enlargement, heart failure, and stillbirth. Cardiac hypertrophy and a transient type of hypertrophic subaortic stenosis have been de- scribed in these infants. Although many investigators feel that fetal cardiac hypertrophy in infants of dia- betic mothers is due to poor maternal glucose control with resultant fetal hyperinsulinemia, Rizzo et al.

have described a progressive thickening of the inter-

ventricular septum and right and left ventricular

walls in fetuses of diabetic mothers even in infants of mothers who were under good glucose control [117].

The hemodynamic effects of these morphological changes may lead to impairment of cardiac diastolic function and eventual heart failure. Infants of dia- betic mothers, even in those situations where tight glucose control has been obtained, have a signifi- cantly higher incidence of sudden fetal death [117±

122]. An increased thickness in the ventricular walls, particularly in the interventricular septum, has been noted in these infants. Hypertrophy and disorganiza- tion of the myofibrils of the fetal heart have also been found at time of autopsy.

Doppler studies have shown evidence that the dis- proportional thickening of the intraventricular sep- tum results in functional left ventricular outflow tract obstruction which may lead to cardiac failure. In- creased A/E ratios at the level of both atrioventricular valves and higher peak velocity values at the outflow tracts were found in such fetuses. Weiner et al. felt that this was due to an increasing A wave during the later part of gestation suggesting increased cardiac contractility and output in fetuses of diabetic women [121]. Polycythemia, which is frequently present at birth in infants of diabetic mothers, results in in- creased blood viscosity which may alter preload and affect ventricular filling. The high peak velocity val- ues in the aorta and pulmonary artery may be due to increased contractility, or secondary to an increased intra-cardiac flow volume, due to the fetal macroso- mia frequently seen in infants of diabetic mothers.

Other Causes of Fetal Heart Failure

A wide variety of other known, and probably un- known, conditions can lead to fetal heart failure [122±129]. Primary myocarditis of viral etiology has been reported in the fetus. Blood-borne transplacen- tal infection or ascending chorioamnionitis may cause significant systemic fetal infection which, in turn, may cause fetal cardiac failure. High output fail- ure in the fetus has been reported in association with rare fetal tumors, such as fetal teratoma, goitrous hy- pothyroidism, hemangiomas, or rhabdomyosarcomas [122±129]. In most of these cases the high output failure is due to arterial±venous shunts within the tu- mor itself or secondary to vascular compression by an expanding mass.

Morine et al. described a case of high-output fail- ure in a fetus (cardiomegaly, pleural effusion, and in- creased velocity in the carotid artery) diagnosed with goitrous hypothyroidism [127]. The symptoms re- versed after intrauterine treatment with levothyrox- ine. Arterial±venous malformations in the fetus, such as an aneurysm of the vein of Galen, have also been reported to cause fetal hydrops [128]. Chorioangio-

mas of the placenta are benign hemangiomas that can be seen in 1% of all placentas. Usually they cause no problems, but when large (>5 cm), they can cause polyhydramnios and, occasionally, high-output failure in the fetus secondary to arterial±venous shunts [129]. Cardiomegaly and abnormal venous flow in the fetus are typical signs of developing heart failure [130].

Iatrogenic causes of fetal heart failure may be as- sociated with maternal drug use, especially indo- methacin, which has been reported to cause prema- ture closure of the fetal ductus arteriosus resulting in fetal heart failure. Indomethacin has been shown to cause transient constriction of the ductus arteriosus, resulting in an increase in both systolic and diastolic velocity in the ductus. As a consequence, tricuspid regurgitation and heart failure may occur. Beta-ago- nists have an inotropic effect on the fetal heart which may lead to an increase of both peak velocity in the aorta and pulmonary artery and an increase of the stroke volume. Levy et al. have reported that the com- bined use of indomethacin and corticosteroids may have additive effects on ductal constriction [131]. The long-term effects of these drugs is still unknown.

Fisher has reviewed many of the causes of cardio- myopathies that may affect the fetus [132]. Hypoxia and acidemia, metabolic abnormalities, such as hypo- calcemia, or congenital metabolic diseases, such as Pompe's disease or endocardial fibroelastosis, have all been reported to cause fetal cardiac failure.

Summary and Conclusion

A large number of clinical conditions have been found that may lead to intrauterine cardiac failure.

Pulsed and color Doppler techniques have improved our knowledge of fetal cardiovascular response to structural and functional heart diseases. Key features of developing fetal heart failure that may be seen in- clude:

1. Valvular regurgitation 2. Altered velocities 3. Chamber dilatation

4. Fluid collections: ascites, edema, pericardial 5. Reverse flow: vena cava, umbilical pulsations.

Doppler blood flow studies have enabled investigators and clinicians to better understand the pathological processes involved in developing fetal heart failure and to plan appropriate treatments or interventions.

We can expect that further study and experience with

the use of Doppler blood flow studies will lead to

increased improvement in perinatal morbidity and

mortality.

References

1. Braunwald E, Grossman W (1992) Clinical aspects of heart failure. In: Braunwald E (ed) Heart disease: a textbook of cardiovascular medicine. Saunders, Phila- delphia, pp 444±449

2. Friedman R (1987) Congestive heart failure. In: Kravis T, Warner C (eds) Emergency medicine: a comprehen- sive review. Aspen, Rockville, Maryland, pp 1005±1011 3. Kiserud T, Eik-New H, Blaas H et al. (1992) Foramen

ovale: an ultrasonography study of its relation to the inferior vena cava, ductus venosus and hepatic veins.

Ultrasound Obstet Gynecol 2:389±396

4. Dawes GS (1982) Physiological changes in the circula- tion after birth. In: Fishman AP, Richards DW (eds) Circulation of the blood. Men and ideas. American Physiological Society, Bethesda, pp 743±816

5. Barclay AE, Franklin KJ, Prichard MM (1942) Further data about the circulation and about cardiovascular system before and just after birth. Br J Radiol 15:249±

6. Barcroft J (1946) Researches on pre-natal life, vol 1. 256 Blackwell, Oxford, pp 211±225

7. Lind J, Wegelius C (1949) Angiographic studies on the human fetal circulation. Pediatrics 4:391±400

8. Peltonen T, Hirvonen L (1965) Experimental studies on fetal and neonatal circulation. Acta Pediatr 44 (Suppl 161):1±55

9. Hofstaetter C, Plath H, Hansmann M (2000) Prenatal diagnosis of abnormalities of the fetal venous system.

Ultrasound Obstet Gynecol 15:231±241

10. Filkins KA, Brown TI, Levine OR (1981) Real time ul- trasonic evaluation of the fetal heart. Int J Gynaecol Obstet 19:35±39

11. Deng J, Cheng P, Gao S et al. (1992) Echocardiographic evaluation of the valves and roots of the pulmonary ar- tery and aorta in the developing fetus. J Clin Ultra- sound 20:3±9

12. Shiraishi H, Silverman N, Rudolph A (1993) Accuracy of right ventricular output estimated by Doppler echo- cardiography in the sheep fetus. Am J Obstet Gynecol 168:947±953

13. Ott WJ (1988) The diagnosis of altered fetal growth.

Obstet Gynecol Clin North Am 15:237±264

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

Ultrasound Obstet Gynecol 2:434±445

15. Wladimiroff J, Huisman T, Stewart P (1991) Normal fe- tal arterial and venous flow-velocity waveforms in early and late gestation. In: Jaffe R, Warsof S (eds) Color Doppler imaging in obstetrics and gynecology.

McGraw-Hill, New York, pp 155±173

16. Reed K (1991) Venous flow velocities in the fetus. In:

Jaffe R, Warsof S (eds) Color Doppler imaging in obstetrics and gynecology. McGraw-Hill, New York, pp 175±181

17. Appleton C, Hatle L, Popp R (1987) Superior vena cava and hepatic vein Doppler echocardiography in healthy adults. J Am Coll Cardiol 10:1032±1039

18. Reuss M, Rudolph A, Dae M (1993) Phasic blood flow patterns in the superior and inferior venae cavae and umbilical vein of fetal sheep. Am J Obstet Gynecol 145:70±78

19. Huisman T, van den Eijnde S, Tweart P (1993) Changes in inferior vena cava blood flow velocity and diameter during breathing movements in the human fetus. Ultra- sound Obstet Gynecol 3:26±30

20. Reed K, Appleton C, Anderson C (1990) Doppler stud- ies of vena cava flows in human fetuses. Circulation 81:498±505

21. Indik J, Chen V, Reed K (1991) Association of umbilical venous with inferior vena cava blood flow velocities.

Obstet Gynecol 77:551±557

22. Allan L, Chita S, Al-Ghazali W et al. (1987) Doppler echocardiographic evaluation of the normal human fetal heart. Br Heart J 57:528±533

23. Reed K (1987) Fetal and neonatal cardiac assessment with Doppler. Semin Perinatol 11:347±356

24. Kurjak A, Alfirevic Z, Miljan M (1988) Conventional and color Doppler in the assessment of fetal and mater- nal circulation. Ultrasound Med Biol 14:337±354 25. Reed K, Shan D, Scagnelli S et al. (1986) Doppler echo-

cardiographic studies of diastolic function in the hu- man fetal heart: changes during gestation. J Am Coll Cardiol 8:391±395

26. Van der Mooren K, Barendregt L, Waldimiroff J (1991) Fetal atrioventricular and outflow tract flow velocity waveforms during normal second half of pregnancy.

Am J Obstet Gynecol 165:668±674

27. Leiva MC, Tolosa JE, Binotto CN, Weiner S, Huppert L, Denis AL, Huhta JC (1999) Fetal cardiac development and hemodynamics in the first trimester. Ultrasound Obstet Gynecol 14:169±174

28. Anderson DF, Bissonnette JM, Faber JJ et al. (1981) Central shunt flows and pressures in the mature fetal lamb. Am J Physiol 241:H60

29. Daws GS, Mott JC, Widdicombe JG (1954) The fetal cir- culation in the lamb. J Physiol (Lond) 126:563±566 30. Tulzer G, Gudmundsson S, Rotondo K et al. (1991)

Acute fetal ductal occlusion in the fetal lamb. Am J Ob- stet Gynecol 165:775±778

31. Alverson D (1985) Neonatal cardiac output measure- ments using pulsed Doppler ultrasound. Clin Perinatol 12:101±127

32. Fillinger M, Schwartz R (1993) Volumetric blood flow measurement with color Doppler ultrasonography: the importance of visual clues. J Ultrasound Med 3:123±

33. Blake D, Copel J, Kleinman C (1991) Hypoplastic left 130 heart syndrome: prenatal diagnosis, clinical profile and management. Am J Obstet Gynecol 165:529±534 34. Chiba Y, Kanzaki T, Kobayashi H et al. (1990) Evalua-

tion of fetal structural heart disease using color flow mapping. Ultrasound Med Biol 16:221±229

35. DeVore G (1985) The prenatal diagnosis of congenital heart disease: a practical approach for the fetal sono- grapher. J Clin Ultrasound 13:229±245

36. DeVore G, Saissi B, Platt L (1988) Fetal echocardiogra- phy: VIII. Aortic root dilatation: a market for Tetralogy of Fallot. Am J Obstet Gynecol 159:129±136

37. DeVore G, Saissi B, Platt L (1985) Fetal echocardiogra- phy. V. M-mode measurements of the aortic root and aortic valve in second- and third-trimester normal hu- man fetuses. Am J Obstet Gynecol 152:543±550 38. Huhta J, Rotondo K (1991) Fetal Echocardiography.

Semin Roentgenol 26:5±11