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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- first step to direct appropriate management in a
S chenco et al in 1963, it is becoming increas-
ingly apparent that neonates who fail to fulfill
patient in whom fetal growth failure is sus-
pected.
their growth potential in fetal life are at in- The many causes of IUGR have traditionally
creased risk for adverse health events through- been subdivided into fetal, placental and mater-
out life.1-5 It is the aim of modern perinatology nal. From a clinicians standpoint fetal abnormal-
to identify fetuses with intrauterine growth re- ities (both chromosomal and/or anatomic) and
striction (IUGR) early enough to institute ap- abnormal placental vascular development in the
propriate intervention and hopefully prevent fetal and/or maternal compartments are re-
further damage. This process requires knowl- sponsible for the vast majority of IUGR in sin-
edge about the etiology, pathophysiology, natu- gleton pregnancies.6-10 Maternal causes such as
ral history, prognostic factors, and effects of in- chronic renal disease, hypertension, collagen
tervention. Because our knowledge is expanding vascular disease, thrombophilia, and aggravating
in all aspects of this disease, ongoing reappraisal circumstances such as smoking, malnutrition,
is necessary to incorporate new information into and drug use are either readily apparent
the clinical management. through the maternal history or can be deter-
Neonatal weight, size and condition at birth mined with relatively minor effort. Prenatal ul-
are dependent on 4 principle variables. The ge-
trasound evaluation and invasive fetal testing
netically predetermined growth potential mod-
offer the opportunity to investigate fetal causes.
ulated by the health of the fetus, placenta, and
This review focuses on the pathophysiology, di-
the mother. Successful implantation of a genet-
ically normal fetus and placenta in a healthy
mother is most likely to produce a healthy baby. From the *Department of Obstetrics, Gynecology & Reproductive
Sciences, Center for Advanced Fetal Care, University of Maryland,
On the other hand, if any of these factors is
Baltimore, MD; and Department of Fetal Diagnosis and Therapy,
deficient, adverse pregnancy outcome and/or Allgemeines Krankenhaus Barmbek, Hamburg, Germany.
fetal growth restriction may be the consequence. Address reprint requests to Ahmet A. Baschat, MD, Department of
Therefore, IUGR is a not a specific disease per Obstetrics, Gynecology & Reproductive Sciences, Center for Ad-
se, because it may be the manifestation of a vanced Fetal Care, 405 W. Redwood St, 4th Floor, University of
Maryland, Baltimore, MD 21201.
variety of conditions. Because outcome is often 2004 Elsevier Inc. All rights reserved.
dependent on the etiology an attempt at identi- 0146-0005/04/2801-0008$30.00/0
fication of the underlying disease is an essential doi:10.1053/j.semperi.2003.10.014
agnosis, and management of IUGR caused by the liver and heart.24 At the level of the right
placental vascular disturbance. atrium differential directionality of the incom-
ing bloodstreams ensures that nutrient rich
blood is distributed to the heart and brain while
Fetal Consequences of Placental Vascular
venous return is distributed to the placenta for
Insufficiency
re-oxygenation and nutrient and waste ex-
Adequate fetal growth depends on the efficient change.25,26 In addition to this overall distribu-
delivery of nutrients from the mother to the tion of left- and right-sided cardiac output, sev-
fetus and therefore requires normal uterine per- eral organs are able to modify local blood flow to
fusion, normal transplacental exchange of nutri- meet oxygen and nutrient demands by the pro-
ents and waste and normal umbilical perfusion. cess of autoregulation.23 The consequences of
Glucose and essential aminoacids are actively uteroplacental insufficiency are complex since
transported across the placenta and metabolized fetoplacental respiratory function is affected at
aerobically by the fetus.11,12 The glucose/insu- multiple levels. Nutrient delivery, placental up-
lin/insulin-like growth factor (ILF) axis plays a take, and distribution within the fetus as well as
central role in tissue-specific growth regulation delivery of waste to the placenta are deficient.
during critical periods of development and over- The combination of these factors is responsible
all regulation of fetal growth.13 Because approx- for the multisystem disorder that constitutes
imately 70% of glucose and 45% of oxygen are IUGR.
used by the placenta itself, adequate fetal deliv- In IUGR fetuses, transplacental transfer of
ery of nutrients and oxygen is dependent on oxygen, glucose, and aminoacids is impaired
uterine perfusion, fetoplacental exchange area and pancreatic insulin responses to glucose are
and high oxygen affinity of fetal hemoglo- blunted.28-31 The relative hypoinsulinemia may
bin.14,15 Drastic changes in maternal and fetal decrease placental glucose transfer even fur-
placental blood flow dynamics are necessary to ther.32,33 This places the fetus into a situation
accommodate accelerating fetal growth with ad- where supply of oxygen and substrate and there-
vancing gestation. With successful trophoblast fore the ability for aerobic metabolism and tissue
invasion and increased compliance of the spiral growth become limited. Enhanced erythropoie-
arteries a low impedance high capacitance pla- sis may improve oxygen carrying and buffering
cental vascular bed is established. As a result, an capacity through increases in red cell mass and
increasing proportion of maternal cardiac out- hemoglobin concentration.34 Other nutrient de-
put is distributed to placental cotyledons as ges- mands are harder to accommodate. Hepatic gly-
tation advances and blood flow volumes reach cogen stores may initially provide a limited
500 to 600 mL/minute at term.16-18 In the fetal supply of glucose. Eventually gluconeogenic
vascular compartment of the placenta, this pro- aminoacids from endogenous tissue catabolism
cess is paralleled by increases in villous and cap- may serve as an alternative nutrient sources.35-39
illary surface areas resulting in marked decrease With these limitations, lactate production
in umbilical vascular resistance and an increase through anaerobic metabolism increases. Al-
in the exchange area.19 Concurrently fetal car- though glucose is the primary fuel for the brain
diac function increases exponentially permitting and heart, lactate and ketones become substi-
an almost 5- to 10-fold rise in umbilical artery tutes during prolonged hypoglycemia.40 Under
and venous volume flow with advancing gesta- such circumstances cardiac metabolism may re-
tion.20-23 This increase is necessary to maintain a move up to 80% of the circulating lactate.41,42
relatively constant blood flow volume/Kg fetal Concurrently increases in vessel caliber in vari-
body weight throughout gestation.21,22 ous oxygen sensitive vascular beds optimize per-
Once nutrients have entered the fetal circu- fusion in vital organs while perfusion to less vital
lation through the umbilical vein their distribu- parts of the body may be compromised. Sequen-
tion to vital organs such as the liver, heart, brain, tial decline in fetal dynamic variables such as
and kidney is insured by the unique dynamics of heart rate variation, movement, and tone help to
the fetal circulation. Venous shunting at the conserve energy.43
level of the ductus venosus modifies the propor- Fetal adaptations are therefore made at many
tion of nutrient rich blood that is distributed to levels and if compensatory mechanisms are suc-
Fetal Growth Restriction in Placental Disease 69
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- pid insufficiency may be observed preceding in-
diac function is the hallmark of cardiovascular trauterine demise.85
deterioration in IUGR72 and can be associated
with deregulation of cardiovascular homeostasis
(normalization of cerebral Doppler indices,73,74 Fetal Biophysical Responses in
which in turn could affect reliability of arterial Uteroplacental Insufficiency
Doppler analysis. Under such circumstances ex-
Normal development of fetal behavior involves
amination of the venous system provides docu-
incorporation of isolated movements into pat-
mentation of cardiac status and therefore im-
terns and finally behavioral states. Once orga-
proves detection of further compromise. nized behavioral states are established diurnal
Forward blood flow in the venous system is and responsive cyclicity (eg, fetal movement cou-
determined by cardiac compliance, contractility pling with heart rate variables) are generally
and afterload. A decline in forward velocities achieved by 28 weeks of gestation.86 In IUGR
during atrial systole (a-wave) results in increased fetuses with chronic hypoxemia all aspects of
venous Doppler indices and suggests impaired this process may be delayed. This includes the
preload handling75-77 (Fig 4 and 5). Evidence of establishment of organized behavior and transi-
impaired cardiac forward function has been doc- tion between behavioral states as well as de-
umented in the precordial veins (ductus veno- creases in overall unstimulated and stimulated
sus,77 inferior vena cava,78 superior vena cava79), (ie, vibroacoustic stimulation) behavior. These
the hepatic veins (right, middle and left he- behavioral alterations are particularly evident
patic80,81) and head and neck veins (jugular between 28 to 32 weeks gestation.87-91 The de-
veins82 and cerebral transverse sinus83). If failure crease in all behavioral variables and probably
to accommodate preload is progressive umbili- also delayed maturation in the central integra-
cal venous pulsations may be observed as the tion of fetal heart rate control results in higher
ultimate reflection of increased central venous basal heart rates and lower short- and long-term
pressure84 (Fig 6). In the final stages of compro- variation on computerized analysis.92,93 Progres-
mise cardiac dilatation with holosystolic tricus- sive hypoxemia is associated with gradual de-
Fetal Growth Restriction in Placental Disease 71
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.
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- tervention to improve outcomes of critical im-
dence of brain sparing and normal umbilical portance. Although assessment should be de-
artery Doppler.63,107,111,113,114 Randomized trials tailed, antenatal tests also need be practicable to
and meta-analyses confirm that the use of um- facilitate application on a large scale as is neces-
bilical artery Doppler in this setting results in a sary for a global problem such as IUGR.
significant reduction in perinatal mortality.114-116 Fetal heart rate analysis (both traditional and
Once the suspicion of IUGR is confirmed computerized), Doppler ultrasound, measure-
fetal karyotyping should be offered and further ment of amniotic fluid volume, assessment of
specialized tests such as maternal serology fetal breathing, movement, and tone are pri-
(TORCH), thrombophilia studies, or amniotic mary fetal assessment tools. Traditional heart
fluid viral DNA testing, may be indicated. Once rate analysis has the advantage of widespread
nontreatable underlying fetal conditions and familiarity but carries the disadvantage of poor
chromosome abnormalities have been ruled out inter- and intraobserver agreement even in the
further antenatal surveillance should be insti- interpretation of key factors such as accelera-
tuted based on the severity of the maternal tions, reactivity and decelerations.117 While a re-
and/or fetal condition. active CTG even by criteria graded for gesta-
tional age virtually excludes hypoxemia, a
nonreactive CTG has a poor correlation with
Antenatal Surveillance of the High-risk
fetal status unless overtly abnormal patterns are
Fetus
observed.46,74,118 The computerized analysis cir-
Antenatal surveillance should provide longitudi- cumvents some of these problems as it provides
nal assessment that is tailored to the severity of an objective and reproducible means of longitu-
the fetal condition and directs appropriate in- dinal analysis of fetal heart rate characteristics.
74 Baschat and Hecher
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 mal umbilical artery waveform (after completion
multi-center collaboration. The efficiency of of antenatal steroid course) offers the benefit of
these collaborations is hampered by regional a higher lifeborn rate and disadvantage of a high
differences in primary fetal assessment tools, cri- neonatal mortality. Delaying delivery until fetal
teria for definition of fetal status and standards distress evident may be associated with a higher
of care that govern intervention. In principle stillbirth rate but a lower neonatal mortality.
delivery timing is straightforward in the term While overall mortality is not affected, signifi-
fetus, when fetal lung maturity has been docu- cant intrauterine time and weight gain can be
mented, if there is fetal distress, or if the mater- expected.133 Timing the delivery between these
nal condition dictates delivery. Management is two points would be desirable. When a tempo-
more complicated for pregnancies between 25 rizing approach is elected assessment of fetal
to 32 weeks gestation, where each day gained in status needs to be accurate to avoid preventable
utero may improve survival by up to 1% to adverse outcomes. The ultimate impact of ante-
2%.118 In recent years, several concepts have natal management protocols on outcomes is
emerged that are likely to alter the standard of likely to be greatest if critical outcomes are ac-
management in these pre-term IUGR pregnan- curately predicted prenatally. Such outcomes in-
cies. Early delivery of IUGR fetuses with abnor- clude the risk for stillbirth and moderate to
76 Baschat and Hecher
severe peripartum acidemia, which has been re- 8. Sickler GK, Nyberg DA, Sohaey R, et al: Polyhydram-
lated to poor neuro-development.134 nios and fetal intrauterine growth restriction: Ominous
combination. J Ultrasound Med 16:609-614, 1997
We use a monitoring approach that combines 9. Odegard RA, Vatten LJ, Nilsen ST, et al: Preeclampsia
fetal heart rate analysis with Doppler and bio- and fetal growth. Obstet Gynecol 96:950-955, 2000
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at 24 weeks gestation. The management algo- lence of the prothrombin gene mutation in women
rithm that is depicted in figure 8 requires the with intrauterine growth retardation, abruptio placen-
tae and second trimester loss. Acta Obstet Gynecol
ability to perform arterial and venous Doppler
Scand 79:963-967, 2000
studies and is aimed at defining three key as- 11. Nicolini U, Hubinont C, Santolaya J, et al: Maternal-
pects: 1) correct diagnosis of IUGR, 2) docu- fetal glucose gradient in normal pregnancies and in
mentation of a fetal compensatory response 3) pregnancies complicated by alloimmunization and fe-
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tions are guided by severity of the fetal condition
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