Integrated Testing and Management in Fetal Growth Restriction

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Integrated Testing and Management in Fetal Growth Restriction
Integrated Testing and
Management in Fetal Growth Restriction
Sifa Turan, MD, RDMS, Jena Miller, MD, and Ahmet A. Baschat, MD
Growth-restricted fetuses are at higher risk for poor perinatal and long-term outcome than
those who are appropriately grown. Multiple antenatal testing modalities can help document the sequence of fetal deterioration. The full extent of this compromise is best
identified by a combination of fetal biometry, biophysical profile scoring, and arterial and
venous Doppler. In the preterm growth-restricted fetus, timing of delivery is critically
determined by the balance of fetal versus neonatal risks. In the near-term fetus, accurate
diagnosis continues to be a challenge as unrecognized growth restriction contributes to a
significant proportion of unexplained stillbirths. In this review, we present an integrated
diagnostic and surveillance approach that accounts for these factors.
Semin Perinatol 32:194-200 © 2008 Elsevier Inc. All rights reserved.
KEYWORDS fetal growth restriction, non stress testing, computerized cardiotocography, biophysical profile scoring, Doppler ultrasound, integrated testing
E
valuation of fetal growth is common obstetric practice.
Fetal growth restriction (FGR) affects 15% of pregnancies and is associated with significant morbidity and mortality in perinatal and adult life.1 Clinical suspicion of FGR
requires further investigation as growth delay may be the
physical manifestation of many possible conditions. When
FGR is established early in pregnancy, the diagnosis is readily
made. In these patients, safe prolongation of pregnancy and
timing of delivery are critical issues. As gestational age at
delivery has an independent effect on outcomes, early delivery can result in neonatal complications, whereas delayed
delivery can increase stillbirth risk.2 When FGR presents in
the third trimester, clinical manifestations and signs of deterioration may be more subtle. In these patients, accurate
identification of FGR provides a challenge. Failure to recognize clinically significant FGR may contribute to over 50% of
unexplained stillbirths near term.3
Antenatal surveillance modalities can provide insight into
many aspects of fetal well-being. Available tests are the nonstress test (NST), computerized cardiotocography (cCTG),
biophysical profile score (BPS), and multi-vessel arterial and
venous Doppler. Each modality independently evaluates be-
Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland, Baltimore, MD.
Address reprint requests to Ahmet A. Baschat, MD, Department of Obstetrics, Gynecology & Reproductive Sciences, University of Maryland, Baltimore, 405 Redwood Street, Baltimore, MD 21201. E-mail: [email protected]
hotmail.com
194
0146-0005/08/$-see front matter © 2008 Elsevier Inc. All rights reserved.
doi:10.1053/j.semperi.2008.02.008
havioral or cardiovascular responses to hypoxemia, but when
used in isolation may have limitations in the management of
FGR. Integration of antenatal assessment modalities concurrently evaluates physical, behavioral, and cardiovascular
manifestations of FGR. This approach can bypass the limitations of individual tests and therefore provide the most comprehensive insight into the fetal condition to guide management.
Antenatal Surveillance Tests
Progression of fetal hypoxemia to acidemia is an important
antecendent to adverse short- and long-term outcome.
Therefore, antenatal surveillance aims to detect fetal responses that accompany such deterioration. These responses
include changes in fetal heart rate pattern, dynamic variables
(tone, movement, breathing activity), amniotic fluid volume,
placental Doppler studies, and fetal arterial and venous
Doppler parameters.
Fetal Heart Rate Analysis
Fetal heart rate analysis in the form of the NST is one of the
first surveillance tests introduced into obstetric practice. The
NST can be used to assess central and autonomic control of
intrinsic cardiac activity by applying visual analysis according to criteria that have recently been updated by the American College of Obstetricians and Gynecologists.4 However,
heart rate variables such as the baseline, magnitude, and du-
Integrated testing and management in FGR
ration of accelerations as well as decelerations are influenced
by many factors, including the maturational state of the fetal
central nervous system, gestational age, behavioral state, amniotic fluid volume, maternal status, and medications. In addition, there is significant intraobserver and interobserver
variability in the interpretation of key heart rate variables,
even when strict interpretative guidelines are applied.5 Accordingly, a “normal” reactive NST provides strong evidence
of fetal well-being and absence of hypoxemia. However, a
“nonreactive” NST is a nonspecific finding, particularly in the
setting of FGR where delayed maturation of central fetal heart
rate control contributes to a higher incidence of nonreactive
NSTs.1
The cCTG was developed to compensate for the limitations of visual fetal heart rate analysis. It is not widely used in
the United States, but decreases inconsistencies of visual NST
analysis by providing an objective interpretation of the fetal
heart rate. In addition, computer-generated variables, such as
the short-term variation (SVT), are derived.6 The STV expresses the variance in beat-to-beat intervals during a fixed
time period in milliseconds. A decrease in the short-term
variation below 3.5 milliseconds has been suggested as an
optimal cutoff to identify prelabor acidemia in FGR, providing superior prediction compared with the traditional NST.7
An additional advantage of the cCTG is the ability to evaluate
longitudinal trends of multiple fetal heart rate variables that
cannot be assessed with the traditional NST.8
Amniotic Fluid
Volume Assessment
Ultrasound assessment of amniotic fluid volume was added
to antenatal testing to improve the prediction of poor perinatal outcome.9 Regulation of amniotic fluid volume is complex, but by the second trimester primarily reflects fetal urine
production. Placental dysfunction and fetal hypoxemia may
both cause redistribution of renal blood flow leading to fetal
oliguria and consequently oligohydramnios. However, the
correlation between both the four-quadrant amniotic fluid
index (⬍5 cm) or a single vertical pocket (⬍2 cm) with the
actual decline in amniotic fluid volume is limited. Although
multiple studies have related oligohydramnios with increased risk for FGR, congenital abnormalities, postdates
pregnancy, meconium passage, abnormal FHR patterns, and
lower Apgar scores, a reliable concordance with more objective outcome measures such as fetal acidosis has not been
demonstrated.10
Dynamic Fetal Variables
Dynamic fetal variables including tone, movement, and
breathing activity are centrally regulated components of fetal
behavior. Although these individual variables can be observed as early as the first trimester, their frequency and
persistence is determined by central nervous system development, maternal factors, and oxygenation of the regulatory
centers. When these factors are accounted for, central effects
195
of progressive hypoxemia and acidemia produce a predictable effect on fetal behaviors.8 Fetal breathing movement
ceases first, but this may be observed over a wide pH range.
Gross body movements and tone decrease further until they
are no longer observed over extended periods of time. Loss of
fetal tone and movement are typically observed at a median
pH of 7.10, and therefore provide the most consistent prediction of prelabor acidemia.11 However, when dynamic fetal
variables are considered in isolation, their predictive accuracy for acidemia is limited by the physiologic variation that
is observed in normal pregnancies.9
Placental Doppler
Doppler ultrasound of the uterine and umbilical arteries assesses the integrity of the maternal and fetal vascular compartments of the placenta. In the uterine arteries, increased
blood flow resistance and/or prolonged gestational persistence of a diastolic notch indicates abnormal trophoblast invasion. Such suboptimal maternal placental vascularization
predisposes to maternal hypertensive disorders, FGR, and
fetal demise. In the umbilical arteries, a decline in end-diastolic blood flow velocities correlates with the degree of abnormalities in the villous vascular tree and the risk for fetal
hypoxemia, acidemia, and stillbirth.1 However, as placental
Doppler studies do not directly reflect the degree of fetal
compromise, they have a limited predictive accuracy for acidemia and stillbirth in FGR.12
Fetal Doppler
Fetal cardiovascular responses to abnormal placentation can
be observed in multiple vascular beds. From a practical
standpoint, the cerebral and precordial venous circulations
have been most widely studied in the human fetus. Increases
in placental blood flow resistance and perceived fetal hypoxemia are associated with a decrease in the cerebroplacental
Doppler ratio and/or increased end-diastolic velocity in the
cerebral circulation.1 These responses contribute to the preferential distribution of well-oxygenated blood from the ductus venosus to the brain, upper body, and the heart. With
progressive placental dysfunction, abnormalities may be observed in the venous flow velocity waveforms. An associated
decline in forward velocities during atrial systole indicates
abnormalities in forward cardiac function that may be related
to worsening placental disease and/or cardiac impacts of metabolic compromise. The most severe venous Doppler abnormalities include absence/reversal of the ductus venosus atrial
systolic forward velocity and bi-triphasic pulsations in the
umbilical venous flow velocity profile. However, as vascular parameters are influenced by several variables, including gestational age, blood viscosity, and blood pressure,
there is a wide range in the distribution of blood gas values
associated with abnormal arterial and venous Doppler
findings (Fig. 1).
196
S. Turan, J. Miller, and A.A. Baschat
tal acidemia with 70% to 90% sensitivity and specificity.16,17 Similarly, absence or reversal of the ductus venosus a wave and multiphasic umbilical venous pulsation
predict subsequent stillbirth with 65% sensitivity and
95% specificity.18,19
Clinical Features of FGR
Figure 1 This figure displays a diagramatic representation of pH
deviation from the gestational age mean (⌬pH) with abnormal test
results in various antenatal tests. These include fetal heart rate
(FHR) analysis using traditional nonstress testing (NST; –react, nonreactive) and the computerized cardiotocogram (cCTG; ⫹acc, accelerations present; ⫹dec, obvious decelerations present; STV,
short-term variation). Biophysical variables (AFV, amniotic fluid
volume; FBM, fetal body movement; FGM, fetal gross movement).
The same relationships are expressed for umbilical artery absent
end-diastolic velocity (AEDV) and deviation of the arterial or venous
Doppler index ⬎2 SD from the gestational age mean for the thoracic
aorta (TAO), descending aorta (DAO), the middle cerebral artery
(MCA), cerebroplacental ratio (CPR), and the ductus venosus (DV).
The median pH values for abnormal BPS and Doppler findings are
indicated by bars.
Integrated Approaches
to Fetal Surveillance
The rationale to combine surveillance modalities is based on
the recognition that, in the absence of overt abnormalities,
individual tests have a limited ability to distinguish between
physiologic and pathologic variation in fetal status. The fivecomponent BPS demonstrates best how integration of shortterm parameters of fetal well-being (tone, movement, breathing, fetal heart rate reactivity) and amniotic fluid volume
status as a marker of chronic changes in fetal status results in
the most reliable and reproducible relationship with the fetal
pH irrespective of the underlying pathology and gestational
age.13 The modified biophysical profile score introduced by
Nageotte and coworkers14 combines the NST and the amniotic fluid index and provides an economical first-line triage in
low-risk populations.
Analogous to the development of biophysical testing,
Doppler surveillance has evolved, integrating several vascular beds. Specific to FGR, assessment of the placental and fetal
circulations is necessary to accurately stratify the risk for
adverse outcome. Elevated umbilical artery Doppler index
and brain sparing in the presence of normal venous Doppler
parameters is typically associated with a normal pH.15 However, elevation of venous Doppler indices, either alone or in
combination with umbilical artery pulsations, predicts fe-
There are several clinical features that are unique to placentabased fetal growth restriction that require consideration in
the diagnosis and management. As one of the earliest manifestations of placental dysfunction, a reduction in umbilical
venous volume flow leads to decreased nutrient delivery to
the fetal liver.20 Accordingly, a decrease in liver size and
abdominal circumference is the first fetal physical manifestation of placental dysfunction. More widespread placental disease leads to either a decrease in umbilical artery end-diastolic velocity when the villous vascular tree is abnormal or
isolated brain-sparing if placental gas exchange is affected.
Chronic nutrient deprivation has multiple organ effects that
are proportional to the degree of placental dysfunction. Of
particular relevance to fetal surveillance are central nervous
system and cardiovascular effects. Growth-restricted fetuses
exhibit delayed maturation of behavioral milestones, including a delay in the development of fetal heart rate reactivity.
Despite this delay in behavioral development, the responses
to deteriorating acid-base status are preserved.1 In the cardiovascular system, development of brain sparing typically follows blood flow abnormalities in the placental vascular bed.
When placental blood flow resistance is significantly increased, umbilical artery end-diastolic velocity ceases, or may
reverse (UA-REDV). In this setting, a progressive rise in venous Doppler indices may be observed which will eventually
escalate over a wide range.12,18,19
The behavioral and cardiovascular responses to placental
dysfunction can be subdivided into early and late. Early responses include delayed behavioral maturation (including a
nonreactive NST), elevated umbilical artery Doppler index,
and brain sparing. These findings may be observed early in
the clinical course in preterm FGR, or as isolated findings in
late onset disease beyond 34 weeks, where behavioral and
vascular manifestations are typically more subtle.1 Their
value is therefore primarily to aid in the diagnosis of placental
dysfunction. In contrast, late responses include UA-REDV
and progressive venous Doppler abnormalities. These typically accompany the sequential loss of biophysical variables
but precede the rapid deterioration of the five-component
BPS (Fig. 2). When these late responses are observed, FGR is
typically clinically apparent. In this setting, late Doppler findings and declining amniotic fluid volume indicate accelerating disease and, therefore, are useful to modify monitoring intervals. Given the differential diagnosis of FGR, the
range of manifestations, and time courses of clinical progression, integration of antenatal testing modalities offers
the most comprehensive approach to diagnosis and management.
Integrated testing and management in FGR
197
Figure 2 This figure summarizes the early and late responses to placental insufficiency. Doppler variables in the
placental circulation precede abnormalities in the cerebral circulation. Fetal heart rate (FHR), amniotic fluid volume
(AFV), and biophysical parameters (BPS) are still normal at this time, and computerized analysis of fetal behavioral
patterns is necessary to document a developmental delay. With progression to late responses, venous Doppler abnormality in the fetal circulation is characteristic, often preceding the sequential loss of fetal dynamic variables and
frequently accompanying the decline in amniotic fluid volume. The * in the ductus venosus flow velocity waveform
marks reversal of blood flow during atrial systole (a-wave). The decline in biophysical variables shows a reproducible
relationship with acid base status. Because the BPS is a composite score of five variables, an abnormal BPS less than 6
often develops late and may be sudden. Absence or reversal of the ductus venous a-wave, decrease of the short-term
variation (STV) of the computerized fetal heart rate analysis, spontaneous late decelerations, and an abnormal biophysical profile score are the most advanced testing abnormalities. If adaptation mechanisms fail and the fetus remains
undelivered, stillbirth ensues. (Reproduced with permission: Baschat A: Intrauterine growth restriction, in Gabbe SG
(ed): Obstetrics: Normal and Problem Pregnancies (ed 5). Philadelphia, PA, Churchill Livingstone, 2007, pp 771-814.)
An Integrated Approach
to the Diagnosis of FGR
FGR may be a manifestation of placental insufficiency, aneuploidy, genetic syndromes, or viral infection. With this differential diagnosis in mind, a detailed anatomic survey, fetal
biometry, assessment of amniotic fluid volume, and placental
Doppler studies are necessary in any patient with suspected
FGR. The formula for the sonographically estimated fetal
weight (SEFW) typically incorporates measurements of the
fetal head, abdomen, and femur length. As growth restriction
affects the abdominal circumference (AC) first, this measurement is frequently abnormal, whereas the SEFW may still be
in the normal range. The abdominal circumference, head to
abdomen symmetry, and long bone length should therefore
be reviewed individually as they may give additional pointers
toward aneuploidy or skeletal dysplasia. The finding of oligohydramnios is another important marker of FGR and may
be the first ultrasound sign. Although, oligohydramnios is a
poor primary screening tool for FGR or fetal acidemia, its
value in clinical practice is as an additional diagnostic sign of
placental dysfunction.9 In contrast, an increased amniotic
fluid volume in the setting of small fetal size may suggest
aneuploidy or fetal infection.1
The diagnostic criteria that best identifies the growth-restricted fetus with placental disease at risk for adverse outcome include a combination of biometry and Doppler parameters. An AC below the 5th percentile predicts FGR with
a sensitivity of 98% but only has a positive predictive value of
37%, whereas a SEFW below the 10th percentile has a sensitivity of 86% but a positive predictive value of 51%. But
when these biometric parameters are combined with an abnormal umbilical artery Doppler index, sensitivity ranges
from 63% to 100%, and positive predictive values between
60% and 80% can be achieved.21 One notable exception is
the near-term fetus, where umbilical artery Doppler studies
may be normal but brain sparing is the only evidence of
placental dysfunction.22 An integrated diagnostic approach to FGR that incorporates these concepts is described in Figure 3.
198
Figure 3 This figure displays a decision tree following the evaluation
of fetal anatomy, amniotic fluid volume, umbilical and middle cerebral artery Doppler. The most likely clinical diagnosis based on
the test results is presented on the right hand side. A high index of
suspicion for aneuploidy, viral, and nonaneuploid syndrome needs
to be maintained at all times. (Reproduced with permission: Baschat
A: Intrauterine growth restriction, in Gabbe SG (ed): Obstetrics:
Normal and Problem Pregnancies (ed 5). Philadelphia, PA,
Churchill Livingstone, 2007, pp 771-814.)
Choosing Monitoring Intervals
The choice of monitoring intervals depends on the anticipated speed of clinical deterioration and risk for impending
acidemia and/or stillbirth. With the exception of trend-analysis of the cCTG short-term variation, amniotic fluid volume
and short-term biophysical parameters provide limited information on the rate of fetal deterioration since they are dependent on the metabolic state at the time of testing. The need to
consider Doppler parameters was recognized almost two
decades ago when Divon and coworkers published their outcome of FGR pregnancies with absent umbilical artery enddiastolic velocity that underwent daily biophysical profile
scoring with strict criteria for delivery. Their management
approach resulted in excellent outcome without any stillbirths or acidemia.23
Today, with a better understanding of the sequence of
deterioration in FGR, the value of integrating biophysical and
Doppler parameters for FGR monitoring is even more apparent. For the fetus with mildly abnormal umbilical artery
Doppler studies, new onset of brain sparing or evidence of
decreasing amniotic fluid volume indicate accelerating disease.18,19,22 If absence/reversal of umbilical artery end-diastolic velocity is observed, attention to venous Doppler studies is critical to assess the degree of disease acceleration.
When ductus venosus Doppler indices increase over the
course of a week or absence or reversal of the ductus venosus
a-wave is observed, deterioration of the biophysical profile
score may be imminent.18,24,25 In a longitudinal monitoring
study of growth-restricted fetuses, we observed a stillbirth
rate of 11/1330 within 1 week of a normal BPS. These were
predicted by an abnormal DV Doppler before 34 weeks or
S. Turan, J. Miller, and A.A. Baschat
brain sparing thereafter.26 There are important differences in
the cardiovascular manifestations in FGR that are determined
by the severity of placental disease and gestational age. In
mild, nonprogressive placental dysfunction, the umbilical artery Doppler index does not increase above 3 standard deviations and vascular deterioration beyond brain sparing is not
observed. In progressive placental dysfunction, disease onset
is earlier in gestation and umbilical artery Doppler indices
progressively rise. The most severe early-onset disease is associated with severe umbilical artery Doppler abnormalities.
It is only in these two more severe patterns where progression
to venous Doppler abnormalities is observed. Accordingly,
once FGR has been diagnosed, weekly umbilical artery
Doppler is suggested to determine the pattern of progression.
After the initial 14 days, rapidly progressive severe disease
will be revealed by definitive deterioration of umbilical artery
Doppler and emergence of additional vessel abnormalities.
For the remainder, a less fulminant course is expected. If
there is still no change over the next 2 weeks, then venous
Doppler monitoring is unlikely to yield abnormal results.27
Intervention Triggers
There is only limited intrauterine therapy available once FGR
is established, and delivery is frequently the only option. The
decision on delivery timing is in principle determined by the
balance of fetal and postdelivery risks. These have mostly
been studied for the preterm growth-restricted fetus as fetal
and neonatal risks are prominent in this subset of FGR.2,28
There are no randomized controlled studies that clarify when
the preterm growth-restricted fetus should ideally be delivered. Growth-restricted fetuses have a less than 50% chance
of survival before 26 weeks and below a birth weight of 600 g.
Until 28 weeks gestation, a growth-restricted fetus may gain
2% increase in survival for each day he remains in utero.28
The growth restriction intervention trial suggests that early
delivery carries the risk of higher neonatal mortality and adverse neurodevelopment at age 2, which is predominantly
related to prematurity-related complications.2,29 Based on
these observations, the prevailing opinion is that safe prolongation of pregnancy in FGR presenting before 34 weeks is
desirable.28 However, delivery triggers have not been identified and are based on expert opinion.
Several observations in preterm FGR strongly support the
integration of biophysical and Doppler parameters. The sequence of arterial and venous Doppler abnormalities that
presage the deterioration of biophysical parameters has been
reasonably well established.1,15,18,19,24,25,27,30 Biophysical variables including the cCTG and arterial and venous Doppler
parameters appear to synergistically predict fetal risks.31-34 At
early gestational ages where safe prolongation of pregnancy is
important, close surveillance of biophysical and multivessel
Doppler parameters may gain up to 1 week in utero.24,25,30 As
gestational age remains the main determinant of neonatal
outcomes, late Doppler findings such as an abnormal BPP
and/or ductus venosus a-wave reversal may need to be
present before delivery is considered. The integrated man-
Integrated testing and management in FGR
199
Figure 4 The management algorithm for pregnancies complicated by FGR is based on the ability to perform arterial and
venous Doppler as well as a full five-component biophysical profile score. This is the typical management approach we
practice at the University of Maryland, Baltimore for preterm growth restricted fetuses (unless otherwise indicated).
Max, maximum; A/REDV, absent/reversed end-diastolic velocity; BPS, biophysical profile score; DV, ductus venosus;
MCA, middle cerebral artery; NICU, neonatal intensive care unit; UA, umbilical artery.
agement protocol that is practiced at our institution is displayed in Figure 4.
In pregnancies presenting after 34 weeks gestation, the
neonatal risks are low. When these are related to the stillbirth
risk for undelivered fetuses (prospective stillbirth risk), the
balance is in favor of delivery from 38 weeks onwards. Although this has not been studied in a randomized fashion,
these data support a low delivery threshold in growth-restricted fetuses identified near term.3,35
Conclusion
As our understanding of the multi-system impacts of placental dysfunction is evolving, there is little advance in the management approach to these pregnancies. Randomized evaluation of preventive strategies, delivery triggers, and neonatal
management are of high priority. In this context, an integrated approach to diagnosis and monitoring provides the
most comprehensive framework to evaluate FGR.
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