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Ultrasound Obstet Gynecol 2003; 21: 18

Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/uog.21

Editorial

Integrated fetal testing in growth


restriction: combining multivessel Doppler
and biophysical parameters

A. A. BASCHAT
Center for Advanced Fetal Care, Department of Obstetrics,
Gynecology and Reproductive Sciences, University of Maryland,
405 West Redwood Street, 4th Floor, Baltimore, MD 21201-1703,
USA (e-mail: aabaschat@hotmail.com)

ANTENATAL SURVEILLANCE IN FETAL


GROWTH RESTRICTION: A SCREENING
TOOL FOR COMPROMISE

The assessment of fetal growth, development and


health are considered standard care in most societies.
Surveillance has been applied to pregnancies complicated
by intrauterine growth restriction (IUGR) to improve
fetal outcome. But antenatal fetal surveillance is evolving.
It is no longer adequate to act only at the last
moment to prevent fetal mortality. Rather, we aim to
identify critical risk factors and improve outcome by
directing appropriately timed intervention. And it is
the timing of intervention that is perhaps the greatest
challenge. This process is complicated by incomplete
knowledge of what actually damages the fetus prior Cardiotocography (CTG), Doppler and biophysical
to causing death chronic hypoxemia, acidemia, or a profile score (BPS) are the principal antenatal testing
combination of both and the impact of gestational modalities. These have predominantly been compared in
age on fetal responses to hypoxic stress. Based on our their ability to predict fetal compromise and optimize the
current understanding of fetal deterioration our focus timing of intervention1,2 . However, the prognostic and
lies on screening for fetal responses to compromised diagnostic information gained in each testing modality is
oxygenation. in great part independent of each other. The question that
The criteria for a successful screening test are well I will address here is: might it be better to combine, or
defined. The targeted condition must be an important integrate these modalities3 ?
health problem at least 80% of the population should
be at risk. The epidemiology, natural history and disease
T H E N A T U R A L H I S T O R Y OF F E T A L
spectrum must be well delineated. There must be an
GROWTH RESTRICTION DUE TO
identifiable early stage with a sufficiently long latent phase
PLACENTAL INSUFFICIENCY
to allow intervention, which will change outcome. The
employed tests should be simple, precise and applicable to We have no accurate estimate of the impact of IUGR since
the target population. The tests should be well validated the effects of this condition extend from fetal life all the
with a known distribution of results and a suitable cut-off way into adulthood4 . The interactions between maternal,
level to identify pre-disease. If a screening policy is to placental and fetal factors in the regulation of growth
be finalized, there should be evidence from high-quality and development are complex. While the impact of these
randomized controlled trials that the screening program factors on long- and short-term outcome is still under
is clinically, financially, socially and ethically acceptable investigation, considerable insight into natural disease
and is effective in reducing morbidity or mortality. And history in fetal life has been gathered.
there should be a plan for managing and monitoring the Abnormal villous development and/or trophoblast
screening program and an agreed set of quality assurance invasion compromises fetal nutrient and waste exchange
standards. These criteria have yet to be fulfilled for any and causes disturbed placental blood flow dynamics.
test of fetal well-being. This condition may manifest as overt abnormalities of

Copyright 2003 ISUOG. Published by John Wiley & Sons, Ltd. EDITORIAL
2 Baschat

blood flow in fetoplacental and uterine vessels, fetal effects on the regulatory centers, decreased overall global
growth restriction, abnormal fetal behavior, abnormal fetal activity or delayed development of reactivity16 20 .
fetal heart rate patterns, a decline in amniotic fluid When the physiological responses to hypoxia become
production, or a variable combination of the above. exhausted the fetus cannot adapt any further. Fetal decom-
Once a discrepancy between placental supply and fetal pensation may be associated with several findings. There
demand is established, there are several possibilities. If is a decline in forward cardiac function21 , associated with
placental disease precludes fetal growth and development, an increase in venous Doppler indices22 24 . Deregulation
stillbirth occurs. If placental disease is less severe and of cardiovascular homeostasis may be seen (normaliza-
survival is made possible through a series of adaptations, tion of cerebral Doppler indices25,26 ) and assessment of
the price may be long-term dysfunction. If placental the arterial circulation becomes a less reliable index of
disease is very mild, growth and development may still compromise. Following a decline in global fetal activity,
be perceived to be normal but fall short of the genetically fetal breathing movement, body movements and tone may
determined potential. Decompensation may occur at any be lost18,27 . The development of overtly abnormal fetal
time, triggered by aggravation of the maternal, placental heart rate patterns appears to be related to a significant
or fetal condition, or by the stress of labor. Irrespective worsening of cardiac dysfunction as a result of worsening
of intervention the fetus remains at risk for additional hypoxemia28 30 .
damage and stillbirth. A variety of cardiovascular and It is apparent that the clinical presentation and disease
central nervous system (CNS) responses to placental spectrum of IUGR is variable reflecting the diverse patho-
insufficiency have been described. physiology. Several authors have suggested a sequence of
deterioration that is evident on various antenatal surveil-
lance tests. Abnormal umbilical artery flow, CPR and
FETAL VASCULAR AND BIOPHYSICAL brain sparing are early circulatory abnormalities10,31,32 .
RESPONSES IN PLACENTAL Oligohydramnios, loss of fetal tone and or movement,
INSUFFICIENCY abnormal venous flow and overt heart rate decelera-
tions are typically late changes10,26,27,33 . Yet such a
Evidence of abnormal placentation may be found in rigid classification does not take into account individ-
the uterine circulation as elevation of the Doppler ual variations in responses, the impact of gestational
resistance index or persistence of an early diastolic age, inconsistent relationships between circulatory and
notch5 . In the umbilical circulation, end-diastolic velocity biophysical deterioration and the differential effects that
may be normal, decreased, absent or reversed (A/REDV) sudden alterations in maternal status may have on fetal
proportional to the degree of villous vascular damage6 . testing variables3,27,34 36 . There is no uniform agreement
Elevated placental blood flow resistance favors redis- on the relationship between computerized fetal heart rate
tribution of cardiac output towards vital organs7 . This changes and venous Doppler abnormalities33,37 . Stud-
may be apparent through increased aortic blood flow ies by Hecher and Ferrazzi suggest that only 50% of
impedance8 , a decrease in the ratio of cerebral to placen- fetuses with abnormal computerized CTG (cCTG) may
tal Doppler indices (cerebroplacental ratio = CPR)9 or a develop abnormal venous indices10,33 . It is apparent,
decline in amniotic fluid volume10 as a sign of decreased however, that arterial Doppler abnormalities identify a
renal perfusion. With fetal perception of hypoxemia addi- prodrome of fetal disease when the decline in biophys-
tional vascular responses such as brain sparing may be ical variables is subtle and predominantly evident on
invoked to enhance local perfusion11,12 . Although often computerized analysis. In the preterm fetus, deterioration
used interchangeably, redistribution (umbilical artery of circulatory and biophysical status occurs in a close
A/REDV), centralization (low CPR) and brain sparing temporal relationship27 . Because subtle Doppler findings
appear to be different vascular responses. While the CPR are more common this relationship may not hold near
is almost always abnormal in fetuses with overtly abnor- term10,38 40 . In contrast, the loss in biophysical variables
mal umbilical artery flow, brain sparing may develop with metabolic deterioration is largely independent of the
independently of the umbilical artery waveform13 15 . gestational age41 .
A number of changes in fetal biophysical variables
are observed with chronic placental dysfunction. These
may reflect abnormal maturation of brainstem reflexes, R E L A T I O N S H I P B E T W E E N N O N-I N V A S I V E
chronic hypoxemia, redistribution of cardiac output or a ANTENATAL TESTS AND FETAL ACID
combination of these. Autonomic reflexes superimposed BASE BALANCE
on the intrinsic cardiac activity determine fetal heart rate.
These reflexes originate from the brainstem and may be Absence of umbilical artery end-diastolic velocities
modulated through incorporation of signals from higher indicates a significant villous abnormality. However,
centers, the reticular activating system and peripheral the relationship between placental pathology and fetal
sensory inputs. Variations of the heart rate and episodic acidemia is inconsistent both at cordocentesis and
accelerations coupled to fetal movement are indicative birth28,42 45 . Brain sparing, elevation in thoracic and
of normal functioning of these connections. Conversely, abdominal aortic pulsatility index (PI) and an abnormal
lack of normal heart rate may represent hypoxia-mediated CPR are all associated with a decrease in fetal pO2 and

Copyright 2003 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2003; 21: 18.
Editorial 3

a median decrease of the pH of two standard deviations is the clinical relevance of a pH < 7.20 at delivery.
(2 SD)46 48 . Loss of fetal breathing movements is associated with a
An elevation in precordial venous indices (inferior moderate decrease in pO2 and a wide range of pH in
vena cava and ductus venosus) has to date provided both cordocentesis samples and at birth. In contrast, the
the most consistent relationship with a significant decline absence of fetal tone and gross body movement is almost
in umbilical venous pH ( 4 SD) in IUGR fetuses48 50 . always associated with acidemia41,51,52 .
Based on receiveroperating curve (ROC) statistics with a
background acidemia rate of 41.5% and 52.8%, use of the
T H E EF F E C T S O F G E S T A T I O N A L A G E
inferior vena cava percentage reverse flow or the preload
index provides sensitivities for the prediction of fetal Gestational age has a profound impact on all aspects
acidemia ranging from 73.5% to 95% and specificities of of IUGR. The degree of placental pathology determines
72.3% to 75%49,50 . And while the Doppler findings in uteroplacental blood flow patterns, gestational age and
each of the vascular beds correlate with fetal acidbase spectrum of manifestation as well as the overall risk for
status, there is a wide variation of fetal pH with abnormal adverse outcome.
results (Figure 1). Mild placental dysfunction with minimal or no
Similar observations have been made for fetal heart umbilical artery blood flow abnormality is more common
rate analysis, breathing, tone, gross body movement among fetuses presenting with IUGR in the third
and amniotic fluid volume. While a reactive CTG even trimester, and an abnormal CPR or brain sparing may
by criteria graded for gestational age virtually excludes be the only Doppler evidence of placental dysfunction.
hypoxemia, a non-reactive CTG is associated with a wide In contrast, umbilical artery A/REDV is rarely seen
range of pH values41,51,52 . The accuracy for the prediction beyond 3234 weeks since it is associated with early
of acidemia can be enhanced by computerized fetal heart growth failure (second and early third trimester)
rate analysis. All computerized variables such as short- marked fetal vascular and behavioral responses and
term, long-term mean minute variation and episodic or early decompensation6,10,15,40,56 . Abnormal venous flows
periodic changes are related to a range of normal and are therefore almost exclusively reported in fetuses
abnormal fetal pH values29,53,54 . In IUGR fetuses, a with markedly abnormal umbilical artery blood flow
short-term variation of 3.5 ms due to prolonged episodes and early-onset IUGR. In the third trimester subtle
of low variation appears to be the best predictor of a Doppler findings in the arterial circulation are more
cord artery pH < 7.20 at birth by ROC analysis with characteristic10,34,39,40,57 .
a background acidemia rate of 21%55 . Though clearly There is a physiological change in the reference range
abnormal in the non-laboring patient, lost in this analysis for almost all Doppler indices with gestational age. To
account for this, measurements need to be transformed
FHR analysis Biophysical Doppler to Z-scores for statistical analysis. An index deviation
variables velocimetry > 2 SD from the gestational age mean provides a widely
0 + acc accepted statistical cut-off for an abnormal result. The
react + dec
three arterial Doppler indices (S/D ratio, resistance index
2 and PI) appear to vary little clinically58 . It has not been
resolved whether there are relevant differences between
4 the numerous venous indices currently in use49 .
pH

The establishment of fetal behavioral states and


maturation of fetal heart rate control with coupling
6
to fetal behavior is achieved at various gestational
epochs. Delayed maturation of biophysical milestones
8
is a feature of IUGR. The physiologic decline of
the baseline heart rate and maturation of reactivity
10 are delayed while short- and long-term variability is
cCTG

AEDV
FGM

decreased59,60 . Similarly, development of behavioral


MCA
FBM

Tone

DAO
AFV
NST

TAO

CPR

DV

states and integration of behavior patterns may be


Figure 1 A diagrammatic representation of pH deviation from the delayed61 . These developmental abnormalities could
gestational age mean ( pH) with abnormal test results in various influence the reliability of computerized, as well as
antenatal tests. These include fetal heart rate (FHR) analysis using traditional, fetal heart rate analysis.
traditional non-stress testing (NST; react, non-reactive)52 and the
computerized cardiotocogram (cCTG; + acc, accelerations present; In addition to fetal manifestations, gestational age has
+ dec, obvious decelerations present)29 . Biophysical variables a significant impact on short- and long-term outcomes.
(AFV, amniotic fluid volume; FBM, fetal body movement; FGM, A/REDV is associated with an increased risk for stillbirth
fetal gross movement)52 . The same relationships are expressed for and premature delivery due to fetal decompensation36,62 .
umbilical artery absent end-diastolic velocity (AEDV) and deviation Fetal acidemia, poor transition to extrauterine life,
of the arterial or venous Doppler index > 2 SD from the gestational
age mean for the thoracic aorta (TAO), descending aorta (DAO), condition of the neonate after delivery and degree of
the middle cerebral artery (MCA), cerebroplacental ratio (CPR) prematurity pose additional risks. IUGR fetuses are
and the ductus venosus (DV)28,45 48 . at higher risk for neonatal complications than their

Copyright 2003 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2003; 21: 18.
4 Baschat

appropriately grown counterparts63 65 . This risk is As our understanding of fetal cardiovascular adaptation
even higher for the preterm IUGR fetus and appears to IUGR has grown, Doppler surveillance has evolved to
independent of Doppler status38,66,67 . The summation of incorporate multiple vessels to enhance prediction of fetal
these factors is responsible for high morbidity, mortality acidbase status. A clinically validated risk stratification
and adverse neurodevelopmental outcome of the preterm and management protocol comparable to the BPS has
IUGR fetus, particularly if delivered before 28 weeks66 69 . not yet been presented using multivessel Doppler. Given
These associations determine the relative balance of the variable manifestations of IUGR it is intuitive to
management decisions. Near-term delivery outweighs the incorporate an even broader range of practicable antenatal
risks of temporizing intervention and delivery is generally testing variables into the development of a surveillance
indicated. The risk for adverse neonatal outcomes is protocol that will accurately assess fetal status.
low and benefits of modified perinatal interventions are
more likely to be reflected in long-term outcomes. In the
WHY COMBINE DOPPLER AND BPS?
preterm IUGR fetus intervention is triggered by balancing
fetal and neonatal risks and its success is measured Fetal deterioration may be manifested by through abnor-
by impacts on short-term variables such as perinatal mal behavior, central deregulation of cardiorespiratory
mortality and morbidity. function, alterations in vascular tone in oxygen-sensitive
vessels and cardiovascular dysfunction. Each of the afore-
WHY COMBINE ANTENATAL TESTING mentioned fetal testing variables has an independent
MODALITIES? relationship with metabolic status. But only their com-
bination evaluates the whole spectrum of cardiovascular
The clinical spectrum of IUGR is wide, both in and CNS manifestations found in IUGR fetuses.
presentation and progression. Gestational age, differential Doppler ultrasound has been instrumental to our
fetal maturation, maternal condition, and therapeutic understanding of the relationship between cardiovascular
interventions (possibly) modulate the presentation and and metabolic deterioration. The initial alterations in
manifestation of fetal disease in various testing modalities. Doppler velocities occur long before there are detectable
There is normal variation in biological parameters and abnormalities of growth and acidbase balance. As such,
their relationship with fetal acidbase status. As a result Doppler is a powerful diagnostic tool that allows the
the prevalence of abnormal test results in a single testing identification of a pre-disease period during which an
modality and their relationship between acidbase status intervention could be applied. Neither the BPS nor the
are inconsistent. Therefore, no single test provides well- CTG alone provide this kind of information in the
validated cut-offs to accurately depict fetal status in IUGR. absence of overt signs of compromise. Conceptually, the
Two principal approaches may be taken to solve the application of Doppler and BPS information in tandem
problem of accurate fetal assessment. allows an assessment of the immediate fetal condition and
One approach to the diversity of the clinical spec- the institution of appropriate longitudinal management.
trum is to increase the level of sophistication for testing The same cannot be said if one confines assessment to one
modalities. Measurement of venous volume flow, incor- modality. For example, venous Doppler alone allows for
poration of multiple oxygen-sensitive vascular beds and the detection of compromise in only 5060% of fetuses
validation of venous flow abnormalities through mea- with early onset IUGR, and an even lower proportion
surements of the vessel diameter may be incorporated near term10,27,33,34,38 .
to enhance the sensitivity of Doppler surveillance23,70 72 . Fetal deterioration of Doppler and biophysical variables
Similarly, computerized analysis of percentage of fetal progresses in different time frames. Arterial Doppler
activity, fractal fetal behavior, percentage of rapid eye changes precede compromise by weeks, while changes
movements and fetal movements during F2 activity states in amniotic fluid volume, abnormal venous Doppler,
can be incorporated into the biophysical assessment17,19 . and decline in fetal breathing, tone and movement
These techniques have yet to be validated and would occur over progressively shorter periods. The integration
substantially increase the technical complexity of routine of multivessel Doppler and BPS allows for detection
fetal evaluation thus prohibiting large-scale application. of multiple patterns of placental insufficiency and
An alternative approach is to combine antenatal testing fetal compromise76 . Doppler and BPS will both detect
modalities currently in use to improve diagnostic and deterioration in severe early-onset IUGR27 . In milder or
predictive accuracy73 . late-onset IUGR with equivocal Doppler findings the BPS
The logic and potential value of combining antenatal will detect fetal compromise. In addition, hypoxemia
testing modalities that are independent is illustrated well or acidemia is also likely to be detected in apparently
by biophysical profile scoring. Each of the parameters of normally grown fetuses with mild placental dysfunction.
the BPS is independently altered by hypoxemia. Yet, the If acute intervention is not mandated, the timeframe for
combination of the five components into a composite score ongoing surveillance can be tailored based on the severity
performs better than each single parameter to predict fetal of the condition and the constellation of early vs. late
well-being. The BPS has a reproducible relationship with Doppler changes. This may include transfer to a referral
the fetal pH, perinatal morbidity and mortality from the center with highest level of perinatal care, admission
mid-trimester onwards in IUGR fetuses41,74,75 . for daily inpatient monitoring and administration of

Copyright 2003 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2003; 21: 18.
Editorial 5

steroids in anticipation of preterm delivery3 . The goal of the Fisher score84 . The fetal Apgar score was compa-
comprehensive fetal assessment tailored to the condition rable to the BPS in the prediction of fetal distress and
can be achieved using widely available technology. poor transition to extrauterine life, but was superior in
identifying IUGR fetuses with acidemia at birth84 . Most
I S T H E R E EV I D E N C E T H A T S U P P O R T S recently we were able to show that the combination of
INTEGRATION OF DOPPLER AND the BPS with multivessel arterial and venous Doppler is
BIOPHYSICAL PARAMETERS? better in the prediction of critical outcomes than either
modality alone. In this study we evaluated prediction of
The concept of combining assessment of fetal growth with perinatal mortality, acidemia at birth and major neonatal
examination of Doppler and biophysical parameters in the morbidity76 .
management of high-risk patients is not new. Doppler and While the study of associations provides insight into
biometry are essential to distinguish between the small the relationships between fetal status and outcome,
but normally grown vs. the growth restricted fetus at risk the most compelling evidence is provided by clinical
for adverse outcome36,77,78 . Combining umbilical artery management studies. James and coworkers suggested that
Doppler with biometry preselects patients who will need once placental-based IUGR is diagnosed by biometry
antenatal surveillance. In low-risk patients, the frequency and umbilical artery Doppler analysis, institution of
of antenatal testing, labor induction and iatrogenic serial BPS can direct appropriate management by
preterm delivery can be reduced without jeopardizing accurately identifying the risk for acidemia and stillbirth
outcome79,80 . irrespective of gestational age and Doppler pattern31 .
Perinatal morbidity and mortality are outcomes that Similarly, Divon and coworkers demonstrated that the
are currently used to measure impacts of perinatal combination of umbilical artery Doppler and biophysical
interventions. Since effective fetal therapy is currently profile scoring produced excellent outcomes85 . In a
unavailable and gestational age is a critical determinant randomized management protocol, fetuses with AEDV
of the therapeutic margin of interventions, timing of were followed with daily BPS and delivered for worsening
delivery is our current focus. A recent analysis by the maternal status, oligohydramnios, BPS < 6 or verified
GRIT study group suggests that delaying delivery by lung maturity. Compared to fetuses with positive end-
up to 2 weeks can achieve an average weight gain of diastolic velocities, there were no differences in pH and
200 g in the fetus without affecting overall perinatal low Apgar scores at birth. Moreover, there were no
mortality56 . Therefore, temporizing intervention appears perinatal deaths in any of the treatment arms! Combined
justified between 25 and 29 weeks, where each day in longitudinal fetal surveillance using combined multivessel
utero may reduce neonatal mortality by 12%. However, Doppler and BPS is likely to enhance surveillance further
the increased stillbirth rate when delivery is triggered by early anticipation of deterioration and individualized
by overt abnormalities of fetal testing such as recurrent care in the preterm IUGR fetus27 .
spontaneous late decelerations stresses the importance of Prediction of long-term outcomes is vastly understudied
defining better tools to understand fetal compromise. and associations are predominantly based on observa-
Several authors have prospectively documented the tional data. Population-wide institution of BPS-directed
superiority of combined assessment. Arabin and cowork- management has resulted in a 50% reduction of cerebral
ers used ROC analysis and showed that the combination palsy in the tested population86 . In addition, relation-
of umbilical/carotid artery Doppler and traditional CTG ships between the score and attention deficit disorder,
improved prediction of fetal distress and low Apgar scores mental retardation and emotional disorder have been
and obviated the use of vibroacoustic stimulation or demonstrated87 89 . Doppler findings such brain sparing,
contraction stress testing81 . Ott and coworkers reported absent aortic- and reversed umbilical artery end-diastolic
improved assessment of fetal well-being among small- velocity have equally been associated with a variety of
for-gestational-age fetuses using the modified biophysical neurodevelopmental impacts69,90,91 . It stands to reason
score in combination with umbilical and middle cerebral that application of integrated fetal testing to a high-risk
artery Doppler velocimetry. Doppler abnormalities were population of IUGR fetuses is likely to clarify perinatal
used to determine the frequency of fetal testing and con- determinants of long-term outcome.
tributed to the earlier detection of fetal compromise82 .
It has been suggested that replacing standard CTG with WHAT TO CONCLUDE?
computerized analysis further improves the prediction of
fetal distress and mortality in IUGR fetuses83 . A decade Doppler, CTG and BPS are widely available examination
ago, Arabin and coworkers constructed a fetal Apgar, techniques that have evolved over the past 20 years. It
substituting components traditionally used in the eval- is clear that these monitoring systems combined provide
uation of the neonate with a combination of Doppler a wealth of information on fetal health, perinatal- and
and biophysical parameters. Respiration and color were long-term risks. It is also clear that their combination
expressed through the uterine artery resistance index and enables a better understanding of fetal pathophysiology
the carotid/umbilical artery Doppler ratio, respectively. in IUGR. Furthermore, impediments of the past such as
Tone was assessed by BPS criteria, reflexes by vibroa- equipment and personnel limitations and local standards
coustic stimulation and the heart rate was analyzed with of care are less relevant. What is unclear is how they

Copyright 2003 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2003; 21: 18.
6 Baschat

should be combined and whether an intervention will 16. Henson G, Dawes GS, Redman CW. Characterization of the
improve long-term outcome. In addition we need more reduced heart rate variation in growth-retarded fetuses. Br J
Obstet Gynaecol 1984; 91: 751755.
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