Fetal Growth Restriction due to Placental

Disease
Ahmet A. Baschat* and Kurt Hecher

Normal fetal growth depends on the genetically predetermined growth potential and its modulation
by the health of the fetus, placenta and the mother. Fetuses that are small because of intrauterine
growth restriction (IUGR) are at higher risk for poor perinatal and long-term outcome than those who
are appropriately grown. Of the many potential underlying processes that may result in IUGR,
placental disease is clinically the most relevant. Fetal cardiovascular and behavioral responses to
placental insufficiency and the metabolic status are interrelated. The concurrent evaluation of fetal
biometry, amniotic fluid volume, heart rate patterns, arterial and venous Doppler, and biophysical
variables therefore allow the most comprehensive fetal evaluation in IUGR. In the absence of
successful intrauterine therapy, the timing of delivery is perhaps the most critical aspect of the
antenatal management. A discussion of the fetal responses to placental insufficiency and a manage-
ment protocol that accounts for multiple Doppler and biophysical parameters as well as gestational
age is provided in this review.
2004 Elsevier Inc. All rights reserved.

ince the landmark observations of Lub-
S chenco et al in 1963, it is becoming increas-
ingly apparent that neonates who fail to fulfill
their growth potential in fetal life are at in-
creased risk for adverse health events through-
out life.1-5 It is the aim of modern perinatology
to identify fetuses with intrauterine growth re-
striction (IUGR) early enough to institute ap-
propriate intervention and hopefully prevent
further damage. This process requires knowl-
edge about the etiology, pathophysiology, natu-
ral history, prognostic factors, and effects of in-
tervention. Because our knowledge is expanding
in all aspects of this disease, ongoing reappraisal
is necessary to incorporate new information into
the clinical management.
Neonatal weight, size and condition at birth
are dependent on 4 principle variables. The ge-
netically predetermined growth potential mod-
ulated by the health of the fetus, placenta, and
the mother. Successful implantation of a genet-
ically normal fetus and placenta in a healthy
mother is most likely to produce a healthy baby.
On the other hand, if any of these factors is
deficient, adverse pregnancy outcome and/or
fetal growth restriction may be the consequence.
Therefore, IUGR is a not a specific disease per
se, because it may be the manifestation of a
variety of conditions. Because outcome is often
dependent on the etiology an attempt at identi-
fication of the underlying disease is an essential
first step to direct appropriate management in a
patient in whom fetal growth failure is sus-
pected.
The many causes of IUGR have traditionally
been subdivided into fetal, placental and mater-
nal. From a clinicians standpoint fetal abnormal-
ities (both chromosomal and/or anatomic) and
abnormal placental vascular development in the
fetal and/or maternal compartments are re-
sponsible for the vast majority of IUGR in sin-
gleton pregnancies.6-10 Maternal causes such as
chronic renal disease, hypertension, collagen
vascular disease, thrombophilia, and aggravating
circumstances such as smoking, malnutrition,
and drug use are either readily apparent
through the maternal history or can be deter-
mined with relatively minor effort. Prenatal ul-
trasound evaluation and invasive fetal testing
offer the opportunity to investigate fetal causes.
This review focuses on the pathophysiology, di-
From the *Department of Obstetrics, Gynecology & Reproductive
Sciences, Center for Advanced Fetal Care, University of Maryland,
Baltimore, MD; and Department of Fetal Diagnosis and Therapy,
Allgemeines Krankenhaus Barmbek, Hamburg, Germany.
Address reprint requests to Ahmet A. Baschat, MD, Department of
Obstetrics, Gynecology & Reproductive Sciences, Center for Ad-
vanced Fetal Care, 405 W. Redwood St, 4th Floor, University of
Maryland, Baltimore, MD 21201.
2004 Elsevier Inc. All rights reserved.
0146-0005/04/2801-0008$30.00/0
doi:10.1053/j.semperi.2003.10.014

Seminars in Perinatology, Vol 28, No 1 (February), 2004: pp 67-80 67

68 Baschat and Hecher
agnosis, and management of IUGR caused by
placental vascular disturbance.
Fetal Consequences of Placental Vascular
Insufficiency
Adequate fetal growth depends on the efficient
delivery of nutrients from the mother to the
fetus and therefore requires normal uterine per-
fusion, normal transplacental exchange of nutri-
ents and waste and normal umbilical perfusion.
Glucose and essential aminoacids are actively
transported across the placenta and metabolized
aerobically by the fetus.11,12 The glucose/insu-
lin/insulin-like growth factor (ILF) axis plays a
central role in tissue-specific growth regulation
during critical periods of development and over-
all regulation of fetal growth.13 Because approx-
imately 70% of glucose and 45% of oxygen are
used by the placenta itself, adequate fetal deliv-
ery of nutrients and oxygen is dependent on
uterine perfusion, fetoplacental exchange area
and high oxygen affinity of fetal hemoglo-
bin.14,15 Drastic changes in maternal and fetal
placental blood flow dynamics are necessary to
accommodate accelerating fetal growth with ad-
vancing gestation. With successful trophoblast
invasion and increased compliance of the spiral
arteries a low impedance high capacitance pla-
cental vascular bed is established. As a result, an
increasing proportion of maternal cardiac out-
put is distributed to placental cotyledons as ges-
tation advances and blood flow volumes reach
500 to 600 mL/minute at term.16-18 In the fetal
vascular compartment of the placenta, this pro-
cess is paralleled by increases in villous and cap-
illary surface areas resulting in marked decrease
in umbilical vascular resistance and an increase
in the exchange area.19 Concurrently fetal car-
diac function increases exponentially permitting
an almost 5- to 10-fold rise in umbilical artery
and venous volume flow with advancing gesta-
tion.20-23 This increase is necessary to maintain a
relatively constant blood flow volume/Kg fetal
body weight throughout gestation.21,22
Once nutrients have entered the fetal circu-
lation through the umbilical vein their distribu-
tion to vital organs such as the liver, heart, brain,
and kidney is insured by the unique dynamics of
the fetal circulation. Venous shunting at the
level of the ductus venosus modifies the propor-
tion of nutrient rich blood that is distributed to
the liver and heart.24 At the level of the right
atrium differential directionality of the incom-
ing bloodstreams ensures that nutrient rich
blood is distributed to the heart and brain while
venous return is distributed to the placenta for
re-oxygenation and nutrient and waste ex-
change.25,26 In addition to this overall distribu-
tion of left- and right-sided cardiac output, sev-
eral organs are able to modify local blood flow to
meet oxygen and nutrient demands by the pro-
cess of autoregulation.23 The consequences of
uteroplacental insufficiency are complex since
fetoplacental respiratory function is affected at
multiple levels. Nutrient delivery, placental up-
take, and distribution within the fetus as well as
delivery of waste to the placenta are deficient.
The combination of these factors is responsible
for the multisystem disorder that constitutes
IUGR.
In IUGR fetuses, transplacental transfer of
oxygen, glucose, and aminoacids is impaired
and pancreatic insulin responses to glucose are
blunted.28-31 The relative hypoinsulinemia may
decrease placental glucose transfer even fur-
ther.32,33 This places the fetus into a situation
where supply of oxygen and substrate and there-
fore the ability for aerobic metabolism and tissue
growth become limited. Enhanced erythropoie-
sis may improve oxygen carrying and buffering
capacity through increases in red cell mass and
hemoglobin concentration.34 Other nutrient de-
mands are harder to accommodate. Hepatic gly-
cogen stores may initially provide a limited
supply of glucose. Eventually gluconeogenic
aminoacids from endogenous tissue catabolism
may serve as an alternative nutrient sources.35-39
With these limitations, lactate production
through anaerobic metabolism increases. Al-
though glucose is the primary fuel for the brain
and heart, lactate and ketones become substi-
tutes during prolonged hypoglycemia.40 Under
such circumstances cardiac metabolism may re-
move up to 80% of the circulating lactate.41,42
Concurrently increases in vessel caliber in vari-
ous oxygen sensitive vascular beds optimize per-
fusion in vital organs while perfusion to less vital
parts of the body may be compromised. Sequen-
tial decline in fetal dynamic variables such as
heart rate variation, movement, and tone help to
conserve energy.43
Fetal adaptations are therefore made at many
levels and if compensatory mechanisms are suc-
 Fetal Growth Restriction in Placental Disease 69

cessful fetal survival and even growth are possi-

ble. Fetal decompensation sets in when adapta-
tion cannot maintain organ function and is
characterized by concurrent failure of forward
cardiac function, metabolic acidemia and loss of
normal fetal behavior and finally stillbirth.44-46
Impairment of placental transport mechanism
cannot be directly measured but may be inferred
by the degree of vascular insufficiency. A num-
ber of cardiovascular and central nervous system
(CNS) responses in IUGR fetuses have been de-
scribed.

Circulatory Findings in Uteroplacental

Insufficiency
Elevation of the uterine artery Doppler index
and/or persistence of an early diastolic notch
beyond the mid-trimester is evidence of abnor-
mal trophoblast invasion, placental bed infarcts
and enhanced apoptosis47,48 (Fig 1). Decrease,
absence, or reversal of umbilical artery end-dia-
stolic velocity indicate progressive increases in
blood flow resistance due to loss of tertiary vil-
lous vessels49 (Fig 2). Disturbed feto-placental
perfusion also effects venous return and a de-
crease in umbilical venous volume flow is ob-
served and precedes the onset of overt growth
delay.50 Abnormal flow patterns in the uterine
arteries identify patients at risk for pre eclamp-
sia, placental abruption, and IUGR,51 while ab-
normal umbilical flow patterns indicate in-
creased risk for hypoxemia and acidemia
proportional to the severity of Doppler abnor-
mality.49
Several fetal arterial blood flow characteristics
may accompany elevated placental blood flow
resistance. There may be elevation of thoracic
and descending aortic blood flow imped-
ance,52-54 reflecting the elevated blood flow re-
sistance in the placenta and/or the lower limb
(hind limb reflex).55 Through the parallel ar-
rangement of the fetal circulation elevated feto-
placental blood flow resistance favors redistribu-
tion of cardiac output towards the left ventricle
and therefore cardiac and cerebral circulations.
This redistribution can be verified by direct mea-
surement of cardiac output or by demonstrating
end-diastolic flow reversal in the aortic isth-
mus.56-58 Enhanced cerebral perfusion can be
documented in two principal ways. Doppler ex-
amination of the middle cerebral artery wave-
Figure 1. Flow velocity waveforms obtained from the
uterine artery beyond 24 weeks gestation. In the first
patient (A) high volume diastolic flow is established
indicating successful trophoblast invasion. (B) Ele-
vated placental vascular resistance is associated with a
decline in diastolic velocities and a subsequent rise in
the Doppler index. Persistence of an early diastolic
notch in the uterine artery flow velocity waveform is
evidence of increased spiral artery blood flow resis-
tance. (C) Frequently notching is more subtle be-
yond 32 weeks (C) than in the (D) late second or early
third trimesters.
form may indicate decreased blood flow imped-
ance (brain sparing)59 (Fig 3). Alternatively,
the ratio between cerebral and descending tho-
racic aorta or placental Doppler indices (cere-
broplacental ratio) enhances the detection of
centralization of cardiac output toward the cere-
bral circulation particularly in fetuses with more
subtle Doppler findings.60-64 Enhanced perfu-
sion of the myocardium on the other hand is
evident through examination of the coronary
circulation.65 Examination of multiple arterial
beds suggests that blood flow in the adrenal
glands,66 spleen,67 and liver68 is enhanced while
perfusion of the lungs,69 bowel,70 and kidneys71
is decreased with further compromise. Although
arterial Doppler can provide information on
downstream distribution of cardiac output this
information is incomplete without the evalua-
70 Baschat and Hecher

Figure 2. (A) The normal umbilical artery flow velocity waveform has marked positive end-diastolic velocity that
increases in proportion to systole toward term. (B) Moderate abnormalities in the villous vascular structure raise
the blood flow resistance and are associated with a decline in end-diastolic velocities. When a significant
proportion of the villous vascular tree is abnormal (50%-70%), end-diastolic velocities may be (C) absent or even
(D) reversed. Depending on the magnitude of placental blood flow resistance and the fetal cardiac function
reversal of end-diastolic velocities may be (D) minimal, (E) moderate, or (F) severe. In the latter case, precordial
venous flows were universally abnormal.

tion of cardiac function. Failure of forward car-
diac function is the hallmark of cardiovascular
deterioration in IUGR72 and can be associated
with deregulation of cardiovascular homeostasis
(normalization of cerebral Doppler indices,73,74
which in turn could affect reliability of arterial
Doppler analysis. Under such circumstances ex-
amination of the venous system provides docu-
mentation of cardiac status and therefore im-
proves detection of further compromise.
Forward blood flow in the venous system is
determined by cardiac compliance, contractility
and afterload. A decline in forward velocities
during atrial systole (a-wave) results in increased
venous Doppler indices and suggests impaired
preload handling75-77 (Fig 4 and 5). Evidence of
impaired cardiac forward function has been doc-
umented in the precordial veins (ductus veno-
sus,77 inferior vena cava,78 superior vena cava79),
the hepatic veins (right, middle and left he-
patic80,81) and head and neck veins (jugular
veins82 and cerebral transverse sinus83). If failure
to accommodate preload is progressive umbili-
cal venous pulsations may be observed as the
ultimate reflection of increased central venous
pressure84 (Fig 6). In the final stages of compro-
mise cardiac dilatation with holosystolic tricus-
pid insufficiency may be observed preceding in-
trauterine demise.85
Fetal Biophysical Responses in
Uteroplacental Insufficiency
Normal development of fetal behavior involves
incorporation of isolated movements into pat-
terns and finally behavioral states. Once orga-
nized behavioral states are established diurnal
and responsive cyclicity (eg, fetal movement cou-
pling with heart rate variables) are generally
achieved by 28 weeks of gestation.86 In IUGR
fetuses with chronic hypoxemia all aspects of
this process may be delayed. This includes the
establishment of organized behavior and transi-
tion between behavioral states as well as de-
creases in overall unstimulated and stimulated
(ie, vibroacoustic stimulation) behavior. These
behavioral alterations are particularly evident
between 28 to 32 weeks gestation.87-91 The de-
crease in all behavioral variables and probably
also delayed maturation in the central integra-
tion of fetal heart rate control results in higher
basal heart rates and lower short- and long-term
variation on computerized analysis.92,93 Progres-
sive hypoxemia is associated with gradual de-
 Fetal Growth Restriction in Placental Disease
Figure 3. (A) The normal middle cerebral artery
flow pattern has relatively little diastolic flow. With
elevation of placental blood flow resistance the
changes in the middle cerebral artery waveform may
be subtle, although the cerebroplacental ratio may
become abnormal as in fetus B. With progressive pla-
cental dysfunction there may be increase in the dia-
stolic velocity resulting in a decrease in the Doppler
index (Brain sparing, C). With marked brain sparing
the systolic down slope of the waveform becomes
smoother so that the waveform almost resembles that
of the umbilical artery (D). The associated rise in the
mean velocity results in a marked decline in the
Doppler index.
cline in amniotic fluid volume, fetal breathing,
gross body movements, tone and computerized
heart rate variables.94-96 While this development
may be associated with abnormal Doppler find-
ings in the placental, arterial, and venous circu-
lations, the decline of biophysical variables is
determined by effects of hypoxemia/acidemia
on the central regulation of fetal behavior rather
than vascular status.43,46,97,98-100 With the devel-
opment of acidemia fetal movement and tone
are lost and overtly abnormal heart rate pat-
terns may be observed.97,101 These may include
overt late decelerations and/or a decrease of the
short term variation on computerized analy-
sis.46,74,83,102,103,104 (Fig 7).
71
The biophysical profile score is a composite
score that applies categorical cut-offs for dy-
namic variables such as fetal tone, breathing
movement, gross body movement, and the am-
niotic fluid volume as well as traditional fetal
heart rate analysis. Although a gradual decline
in all of these parameters precedes an overtly
abnormal BPS analysis of percentage changes in
these variables offers no advantage in the pre-
diction of acidemia.95 The BPS shows a reliable
and reproducible relationship with the fetal pH
irrespective of the underlying pathology and ges-
tational age.105,106
Identification of the Small Fetus at Risk
for Adverse Outcome
The first step in the management of IUGR fe-
tuses is to identify those fetuses that are truly at
risk for adverse outcome. This requires exclu-
sion of small fetuses that are normally grown and
Figure 4. The venous flow velocity waveform reflects
atrial pressure changes during the cardiac cycle and
therefore has a triphasic flow pattern. In the inferior
vena cava blood flow may be antegrade toward the
heart throughout the whole cardiac cycle (A) or brief
reversal of blood flow during atrial systole (B) is nor-
mal. However a relative decrease of diastolic forward
velocity (*) and marked reversal of the a-wave () is
abnormal and in this fetus (C) was associated with
cardiac dilatation, tricuspid insufficiency and subse-
quent stillbirth.
72 Baschat and Hecher

Figure 5. In the ductus venosus, blood flow is always antegrade throughout the cardiac cycle under normal
circumstances. Pulsatility is less pronounced in waveform patterns obtained at the inlet (A) versus the outlet (B).
With impaired cardiac forward function there is a decline in forward flow during atrial systole (C). If progressive
atrial forward flow may be lost (D) or reversed (E). In the last fetus with this severely abnormal waveform pattern
at 28 weeks (F), the neonatal course was complicated by circulatory insufficiency, necrotising enterocolitis, grade
IV intraventricular hemorrhage and finally neonatal death.

those in whom IUGR is due to an underlying

Figure 6. In the umbilical vein the normally constant
waveform pattern may show subtle pulsations with
elevated placental blood flow resistance (A). With
progressive increase in precordial venous indices
monophasic, biphasic and even triphasic pulsations
may be observed (B,C,D).
condition where management will not alter
outcome (eg, aneuploidy, nonaneuploid syn-
dromes, viral infection). The initial focus there-
fore lies on a complete maternal history and
physical examination and a thorough ultra-
sound evaluation of fetal anatomy, size, symme-
try, and amniotic fluid volume.
Identification of small fetal size is initially
based on combined measurements of head size
[biparietal diameter and head circumference
(HC)], abdominal circumference (AC) and
bone length [femur (FL) and humerus length].
IUGR may be defined as an estimated fetal
weight (calculated through algorisms using the
HC, AC and FL) below the 10th percentile or an
AC below the 5th, 3rd, or 2nd percentiles. The
AC offers superior sensitivity that may be further
enhanced by serial measurements at least 14
days apart.107,108 Fetal asymmetry of the HC/AC
ratio suggests altered growth dynamics, while
symmetrically small growth may simply indicate
reduced genetic potential.109-111 However, al-
though biometry provides important clues to the
presence of IUGR the liability of preterm deliv-
ery and iatrogenic complications is great if the
diagnosis is based solely on biometry.112 The
combination of biometry with umbilical and
middle cerebral artery Doppler provides the best
tool to identify small fetuses at risk for adverse
outcome. This applies both to small fetuses with
 Fetal Growth Restriction in Placental Disease 73

Figure 7. A progressive deterioration in fetal cardiovascular and behavioral variables that is observed with
decline of metabolic status. In the majority of IUGR fetuses, Doppler abnormalities progress from the arterial to
the venous side of the circulation. While cardiac adaptations and alterations in coronary blood flow dynamics
may be operational for a variable period, overt abnormalities of cardiac function and evidence of markedly
enhanced coronary blood flow is generally not observed until the late stages of disease. The decline in
biophysical variables shows a reproducible relationship with acid base status. If adaptation mechanisms fail,
stillbirth ensues. UA, umbilical artery; EDV, end-diastolic velocity; UV, umbilical vein; AV, atrioventricular valves;
FH, fetal heart rate; BPS, biophysical profile score.

elevated umbilical artery, and those with evi-
dence of brain sparing and normal umbilical
artery Doppler.63,107,111,113,114 Randomized trials
and meta-analyses confirm that the use of um-
bilical artery Doppler in this setting results in a
significant reduction in perinatal mortality.114-116
Once the suspicion of IUGR is confirmed
fetal karyotyping should be offered and further
specialized tests such as maternal serology
(TORCH), thrombophilia studies, or amniotic
fluid viral DNA testing, may be indicated. Once
nontreatable underlying fetal conditions and
chromosome abnormalities have been ruled out
further antenatal surveillance should be insti-
tuted based on the severity of the maternal
and/or fetal condition.
Antenatal Surveillance of the High-risk
Fetus
Antenatal surveillance should provide longitudi-
nal assessment that is tailored to the severity of
the fetal condition and directs appropriate in-
tervention to improve outcomes of critical im-
portance. Although assessment should be de-
tailed, antenatal tests also need be practicable to
facilitate application on a large scale as is neces-
sary for a global problem such as IUGR.
Fetal heart rate analysis (both traditional and
computerized), Doppler ultrasound, measure-
ment of amniotic fluid volume, assessment of
fetal breathing, movement, and tone are pri-
mary fetal assessment tools. Traditional heart
rate analysis has the advantage of widespread
familiarity but carries the disadvantage of poor
inter- and intraobserver agreement even in the
interpretation of key factors such as accelera-
tions, reactivity and decelerations.117 While a re-
active CTG even by criteria graded for gesta-
tional age virtually excludes hypoxemia, a
nonreactive CTG has a poor correlation with
fetal status unless overtly abnormal patterns are
observed.46,74,118 The computerized analysis cir-
cumvents some of these problems as it provides
an objective and reproducible means of longitu-
dinal analysis of fetal heart rate characteristics.
74 Baschat and Hecher
Doppler analysis is an invaluable tool to grade
the severity of the fetal disease. Although multi-
ple vessels have been investigated in IUGR a
combination of arterial and venous vessels is the
most practicable to demonstrate 1) degree of
placental disease, 2) level of redistribution, and
3) degree of cardiac compromise. The umbilical
artery, middle cerebral artery, descending tho-
racic aorta, ductus venosus, inferior vena cava
and free umbilical vein provide comprehensive
evaluation of these aspects. Since the longitudi-
nal progression of Doppler abnormalities ad-
vances from arterial to the venous side in the
majority of cases46,73,74,102,104 multivessel Doppler
is indispensable in planning the frequency of
fetal testing.119
Although the combination of nonstress test-
ing and amniotic fluid index (modified biophys-
ical profile score)120 works well in a low-risk
context assessment of many aspects of IUGR
remains incomplete. The biophysical profile us-
ing the full five component score evaluates fetal
responses to metabolic disturbance and provides
accurate reflection of current metabolic status
and can provide reasonable assurance of fetal
well being.121 As a single assessment tool in
IUGR, it has several disadvantages. Fetal heart
rate scoring is based on visual assessment of
reactivity and therefore has the same drawbacks
as the traditional nonstress test. In the absence
of oligohydramnios the biophysical profile score
provides insufficient information on the severity
of the fetal cardiovascular compromise to plan
longitudinal assessment.46,118,119
Even more comprehensive fetal assessment
can be provided through concurrent evaluation
of arterial and venous Doppler waveforms and
biophysical parameters (integrated fetal test-
ing).118 In general, the most comprehensive pre-
diction of critical perinatal variables is achieved
when multiple testing modalities are com-
bined.122 This can take the form of arterial and
venous Doppler, the combination of Doppler
and computerized CTG,104 5 component bio-
physical profile scoring or a combination of
Doppler and biophysical profile scoring.123 The
accurate guidance of intervention is of particu-
lar importance in the preterm IUGR fetus in
whom risks of adverse outcome due to prematu-
rity are disproportionally high.3,112
Timing of Intervention
Intervention may be preventative or therapeutic.
A recent Finnish prospective randomized study
on first trimester low-dose aspirin administration
in patients with abnormal uterine artery blood
flow showed encouraging prevention of pre-
eclampsia.124 Although the rate of IUGR was not
significantly affected there are several argu-
ments that support the use of low-dose Aspirin
in high-risk pregnancies that are identified
through abnormal uterine artery Doppler. The
safety of Aspirin in pregnancy has been docu-
mented in a large number of patients.125,126 The
severity of IUGR may be decreased127 and a de-
cline of maternal delivery indications for pre-
eclampsia is likely to decrease the preterm deliv-
ery rate. Placental disease with severe IUGR may
be the first manifestation of previously undiag-
nosed underlying thrombophilia.128
Numerous studies have evaluated other ther-
apeutic interventions such as maternal oxygen
therapy,129 intravascular volume expansion,130
and administration of aminoacids131 to alleviate
the fetal condition. The detailed appraisal of
these approaches goes beyond the scope of this
review. The universally available therapeutic op-
tions that currently show any promise in affect-
ing outcome are the antenatal administration of
steroids in preterm pregnancies and delivery at
an institution with a neonatal care unit that is
able to address the management complexities of
the IUGR neonate. Antenatal steroids should be
administered to any IUGR fetus in whom deliv-
ery is anticipated before 34 weeks gestation.
The longheld belief that the stress of the in-
trauterine condition enhances maturation and is
protective against the effects of prematurity is a
myth that is not supported by large population
studies of IUGR neonates.3,132
The timing of delivery is of greatest relevance
to the managing physician. Unfortunately there
are no randomized management trials that con-
clusively adress the issue of delivery timing
across the whole clinical spectrum of IUGR.
There are several difficulties in conducting such
a trial. The background morbidity and mortality
that is not affected through intervention is un-
known. The critical perinatal variables that im-
pact on short and in particular long-term quality
of life are incompletely defined. Conclusive in-
vestigation of these issues requires large sample
 Fetal Growth Restriction in Placental Disease 75

Figure 8. The management algorithm for pregnancies complicated by fetal growth restriction is based on the
ability to perform arterial and venous Doppler as well as a full five component biophysical profile score. AC,
abdominal circumference; AFV, amniotic fluid volume; A/REDV, absent/reversed end-diastolic velocity; BPS,
biophysical profile score; CPR, cerebroplacental ratio; DV, ductus venosus; HC, head circumference; MCA,
middle cerebral artery; NST, nonstress test; NICU, neonatal intensive care unit; tid, 3 times daily; UA, umbilical
artery.

sizes that con only be accumulated through
multi-center collaboration. The efficiency of
these collaborations is hampered by regional
differences in primary fetal assessment tools, cri-
teria for definition of fetal status and standards
of care that govern intervention. In principle
delivery timing is straightforward in the term
fetus, when fetal lung maturity has been docu-
mented, if there is fetal distress, or if the mater-
nal condition dictates delivery. Management is
more complicated for pregnancies between 25
to 32 weeks gestation, where each day gained in
utero may improve survival by up to 1% to
2%.118 In recent years, several concepts have
emerged that are likely to alter the standard of
management in these pre-term IUGR pregnan-
cies. Early delivery of IUGR fetuses with abnor-
mal umbilical artery waveform (after completion
of antenatal steroid course) offers the benefit of
a higher lifeborn rate and disadvantage of a high
neonatal mortality. Delaying delivery until fetal
distress evident may be associated with a higher
stillbirth rate but a lower neonatal mortality.
While overall mortality is not affected, signifi-
cant intrauterine time and weight gain can be
expected.133 Timing the delivery between these
two points would be desirable. When a tempo-
rizing approach is elected assessment of fetal
status needs to be accurate to avoid preventable
adverse outcomes. The ultimate impact of ante-
natal management protocols on outcomes is
likely to be greatest if critical outcomes are ac-
curately predicted prenatally. Such outcomes in-
clude the risk for stillbirth and moderate to
76 Baschat and Hecher
severe peripartum acidemia, which has been re-
lated to poor neuro-development.134
We use a monitoring approach that combines
fetal heart rate analysis with Doppler and bio-
physical assessment of the fetus that is initiated
at 24 weeks gestation. The management algo-
rithm that is depicted in figure 8 requires the
ability to perform arterial and venous Doppler
studies and is aimed at defining three key as-
pects: 1) correct diagnosis of IUGR, 2) docu-
mentation of a fetal compensatory response 3)
Evidence of fetal decompensation. The interven-
tions are guided by severity of the fetal condition
and gestational age at presentation.
Our knowledge about the pathophysiology
and clinical management impacts in IUGR are
still evolving. The potential for improved clinical
application of different fetal testing modalities is
currently being investigated in 2 multicenter
studies. An IUGR registry has been created to
obtain observational data in order to define the
combination of Doppler and biophysical vari-
ables that offer the most accurate prediction of
adverse outcomes. The TRUFFLE study group is
leading an interventional trial randomizing
IUGR pregnancies before 32 weeks to delivery
based on computer CTG versus ductus venosus
Doppler.
References
1. Lubchenco LO, Hansman C, Boyd E: Intrauterine
growth as estimated from live born birth-weight data at
24-42 weeks of gestation. Pediatrics 32:793, 1963
2. Battaglia FC, Lubchenco LO: A practical classification
of newborn infants by weight and gestational age. J Pe-
diatr 71:159-163, 1967
3. Bernstein IM, Horbar JD, Badger GJ, et al: Morbidity
and mortality among very-low-birth-weight neonates
with intrauterine growth restriction. The Vermont
Oxford Network. Am J Obstet Gynecol 182:198-206,
2000
4. Schreuder AM, McDonnell M, Gaffney G, et al: Out-
come at school age following antenatal detection of
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