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Durie DE, Sciscione AC, Hoffman MK, Mackley AB, Paul DA. Mode of delivery and outcomes in
very low-birth weight infants in the vertex presentation. Am J Perinatol. 2011;28:195–200.
Ecury-Goossen GM, Dudink J, Lequin M, Feijen-Roon M, Horsch S, Govaert P. The clini-
cal presentation of preterm cerebellar haemorrhage. Eur J Pediatr. 2010;169:1249–1253.
Kaukola T, Herva R, Perhomaa M, et al. Population cohort associating chorioamnionitis, cord,
inflammatory cytokines and neurologic outcome in very preterm, extremely low birth
weight infants. Pediatr Res. 2006;59:478–483.
Laughon M, Bose C, Allred E, et al. Factors associated with treatment for hypotension in
extremely low gestational age newborns during the first postnatal week. Pediatrics.
2007;119:273–280.
Levene MI, de Vries LS.  Hypoxia-ischemic encephalopathy: pathophysiology, assessment
tools, and management. In: Martin RJ, Fanaroff AA, Walsh MC, eds. Fanaroff &
Martin’s Neonatal-Perinatal Medicine: Diseases of the Fetus and Infant. 9th ed. St. Louis,
MO: Elsevier Mosby; 2011:952–976.
Maitre NL, Marshall DD, Price WA, et al. Neurodevelopmental outcome of infants with unilateral
or bilateral periventricular hemorrhagic infarction. Pediatrics. 2009;124:e1153–e1160.
Ment LR, Peterson BS, Meltzer JA, et al. A functional magnetic resonance imaging study of
the long term influences of early indomethacin exposure on language processing in the
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Mohamed AM, Aly H. Transport of premature infants is associated with increased risk for
intraventricular hemorrhage. Arch Dis Child Fetal Neonatal Ed. 2010;95:F403–F407.
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NICHD neonatal research network. Pediatrics. 2010;126:443–456.
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oxygenation in preterm infants with germinal matrix-intraventricular hemorrhages.
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evidence for a diagnostic plan and treatment strategy. Pediatrics. 2010;126:e693–e700.

105 Intrauterine Growth Restriction

(Small for Gestational Age)
I. Definition. The terms intrauterine growth restriction (IUGR) and small for gesta-
tional age (SGA) are sometimes used interchangeably. Although related, they are not
synonymous. SGA describes an infant whose weight is lower than population norms or
lower than a predetermined cutoff weight. Most commonly, SGA infants are defined
as having a birthweight below the 10th percentile for gestational age or >2 standard
deviations below the mean for gestational age. In contrast, IUGR infants have not
attained optimal intrauterine growth.
105: INTRAUTERINE GROWTH RESTRICTION (SMALL FOR GESTATIONAL AGE) 733

The ponderal index, arrived at by the following formula, can be used to identi-
fy infants whose soft tissue mass is below normal for the stage of skeletal develop-
ment. A ponderal index <10th percentile may be used to identify IUGR infants. Thus,
all IUGR infants may not be SGA, and all SGA infants may not be small as a result of
a growth-restrictive process.

Birthweight  × 100
Ponderal index =
Crown − heel length 3

A. Symmetric IUGR. (HC = Ht = Wt, all <10%) The head circumference (HC),

length (Ht), and weight (Wt) are all proportionately reduced for gestational age.
Symmetric IUGR is due to either decreased growth potential of the fetus (con-
genital infection or genetic disorder) or extrinsic conditions that are active early
in pregnancy.
B. Asymmetric IUGR. (HC = Ht < Wt, all <10%) Fetal weight is reduced out of
proportion to length and head circumference. The head circumference and length
are closer to the expected percentiles for gestational age than is the weight. In
these infants, brain growth is usually spared. The usual causes are uteroplacental
insufficiency, maternal malnutrition, or extrinsic conditions appearing late in
pregnancy.
C. More recently, fetal growth restriction (FGR) is being used to denote impaired
fetal growth based on healthy fetal growth standards. An individual baby’s growth
potential is determined by both maternal and fetal factors. Recent attempts have
been made to develop individualized growth charts taking into account maternal
physiological characteristics such as race, ethnicity, parity, height, and so on, as
well as fetal characteristics like gender.
Term optimal weight (TOW) is defined as the optimal weight based on fetal
weight curves of healthy infants born at term. For an individual pregnancy, fe-
tal growth can be combined with TOW to show the gestation-related optimal
growth (GROW) curve. GROW charts adjusted for maternal height, weight, par-
ity, and ethnicity are available at www.gestation.net.
Estimation of fetal growth velocity with serial measurements may be useful to
identify FGR. For example, a fetus with weight >10th percentile may be growth
restricted if fetal growth velocity declines. FGR may be early or late, comparable
to symmetric and asymmetric IUGR.
Early FGR is difficult to identify (by measuring crown-rump length), as often
the timing of conception is not known. However, slow growth velocity between
the first and second trimesters can identify infants at risk for perinatal death be-
fore 34 weeks’ gestation. The onset of FGR before 34 weeks is associated with
sequential changes on Doppler studies that parallel worsening placental function.
Typically, umbilical artery Doppler changes precede biophysical profile param-
eters. Late FGR after 34 weeks’ gestational age is more difficult to identify and has
less characteristic Doppler changes.
II. Incidence. About 3–10% (up to 15%) of all pregnancies are associated with IUGR, and
20% of stillborn infants are growth retarded. The perinatal mortality rate is 5–20 times
higher for growth-retarded fetuses, and serious short- or long-term morbidity is noted
in half of the affected surviving infants. IUGR is estimated to be the predominant cause
for low birthweight in developing countries. It is estimated that a third of infants with
birthweights <2500 g are in fact growth retarded and not premature. Term infants with
birthweights <3rd percentile have a higher morbidity and a 10 times higher mortal-
ity than appropriate for gestational age infants. In the United States, uteroplacental
insufficiency is the leading cause of IUGR. An estimated 10% of cases are secondary
to congenital infection. Chromosomal and other genetic disorders are reported in
5–15% of IUGR infants.
734 NEONATOLOGY

III. Pathophysiology. Fetal growth is influenced by fetal, maternal, and placental factors.

A. Fetal factors
1. Genetic. Approximately 20% of birthweight variability in a given population is
determined by fetal genotype. Genetic determinants of fetal growth have their
greatest impact in early gestation during the period of rapid cell development.
Racial and ethnic backgrounds influence size at birth irrespective of socioeco-
nomic status. Males weigh an average of 150–200 g more than females at birth.
This weight increase occurs late in gestation. Birth order affects fetal size; infants
born to primiparous women weigh less than subsequent siblings.
2. Chromosome anomalies.  Chromosomal deletions or imbalances result in
diminished fetal growth. Nearly 20% of fetal growth restriction is due to chro-
mosomal aberration.
3. Congenital malformations. Anencephaly, gastrointestinal atresia, Potter syn-
drome, and pancreatic agenesis are examples of congenital anomalies associated
with IUGR. Frequency of IUGR increases as the number of congenital defects
increases.
4. Cardiovascular anomalies. (With the possible exception of transposition of the
great vessels and tetralogy of Fallot.) Abnormal hemodynamics are thought to
be the basis of IUGR.
5. Congenital infection. TORCH infections (toxoplasmosis, other, rubella, cyto-
megalovirus, and herpes simplex virus) are often associated with IUGR and
account for ~5% of IUGR fetuses. The incidence of IUGR is highest when
infection occurs in the first trimester. The clinical findings in different con-
genital infections are nonspecific and overlap considerably. Cytomegalovirus
and rubella are associated with severe IUGR. Rubella causes damage during
organogenesis and results in a decreased number of cells, whereas cytomega-
lovirus infection results in cytolysis and localized necrosis within the fetus.
6. Inborn errors of metabolism.  Transient neonatal diabetes, galactosemia,
and phenylketonuria are other disorders associated with IUGR. Single-gene
defects associated with impaired insulin secretion or action are associated with
impaired fetal growth (see Chapter 101).
B. Maternal factors (Table 105–1)
1. Reduced uteroplacental blood flow. Maternal disorders such as preeclampsia-
eclampsia, chronic renal vascular disease, and chronic hypertensive vascular
disease often result in decreased uteroplacental blood flow and associated
IUGR. Impaired delivery of oxygen and other essential nutrients is thought to
limit organ growth and musculoskeletal maturation. Risk of placental thrombi
is increased in conditions of inherited thrombophilias.
2. Maternal malnutrition. The major risk factors for IUGR include small mater-
nal size (height and prepregnancy weight) and minimal maternal weight gain.
Low body mass index, defined as (weight [kg]/height [m2])/100, is a major pre-
dictor of IUGR. Maternal malnutrition leads to deficient substrate supply to the
fetus. Total caloric consumption rather than protein or fat consumption appears
to be the principal nutritional influence on birthweight. A balanced protein
energy supplementation during pregnancy decreases the risk of IUGR birth.
3. Multiple pregnancies. Impaired growth results from failure to provide opti-
mal nutrition for more than 1 fetus in utero. There is a progressive decrease in
weight of singletons, twins, and triplets. In parabiotic twins, the smaller twin
has decreased nutrient delivery secondary to abnormal placental blood flow
resulting from arteriovenous communication in the chorionic plate.
4. Maternal substance use. See also Chapter 103.
a. Cigarettes and alcohol. Chronic abuse of cigarettes or alcohol is demon-
strably associated with IUGR. The effects of alcohol and tobacco seem to be
dose dependent, with IUGR becoming more serious and predictable with
heavy abuse.
105: INTRAUTERINE GROWTH RESTRICTION (SMALL FOR GESTATIONAL AGE) 735

Table 105–1. MATERNAL FACTORS IN INTRAUTERINE GROWTH RESTRICTION

Pregnancy-induced hypertension (>140/90 mm Hg)
Weight gain (<0.9 kg every 4 weeks)
Uterus fundus growth lag (<4 cm for gestational age)
Cyanotic heart disease
Heavy smoking
Residing at high altitude
Substance abuse and drugs
Short stature
Low socioeconomic class
Anemia (hematocrit <30%)
Asthma
Prepregnancy weight (<50 kg)
Prior history of IUGR
Chronic hypertension, diabetes mellitus
Collagen vascular disorders such as lupus
Renal disease
Severe maternal malnutrition
Multiple pregnancy
Low maternal age
Preeclampsia
Inherited thrombophilias
Previous growth restricted baby

b. Heroin. Maternal heroin addiction is also often associated with IUGR.

c. Cocaine. Cocaine use in pregnancy is associated with increased rates of
IUGR. The IUGR may be mediated by placental insufficiency or direct toxic
effect on the fetus.
d. Others. Other drugs and chemical agents causing IUGR include known
teratogens, antimetabolites, and therapeutic agents such as trimethadione,
warfarin, and phenytoin. Each of these agents causes characteristic malfor-
mation syndromes. Repeated use of antenatal steroids and lithium use are
also associated with low birthweight.
5. Maternal hypoxemia. Hypoxemia is seen in mothers with hemoglobinopa-
thies, especially sickle cell disease, and they often have IUGR infants. Infants
born at high altitudes tend to have lower mean birthweights for gestational
age.
6. Other maternal factors. Maternal short stature, young maternal age, short
interpregnancy interval, uterine anomalies, low socioeconomic class, primipa-
rous, grand multiparous, and low prepregnancy weight are associated with sub-
normal birthweight. Maternal hyperhomocysteinemia is also associated with
low birthweight.
7. DNA damage. Measured by micronucleus (MN) formation, may play a role.
MNs are formed by the lagging chromosomal fragments during anaphase in
both mitosis and meiosis. Increased MN count in maternal lymphocytes at
20 weeks’ gestation is associated with increased risk of IUGR and preeclampsia.
C. Placental factors
1. Placental insufficiency. In the first and second trimesters, fetal growth is deter-
mined mostly by inherent fetal growth potential. By the third trimester, placen-
tal factors (ie, an adequate supply of nutrients) assume major importance for
fetal growth. When the duration of pregnancy exceeds the nurturing capacity
736 NEONATOLOGY

of the placenta, placental insufficiency results with subsequent impaired fetal

growth. This phenomenon occurs mostly in post-term gestations but may occur
at any time during gestation.
2. Uteroplacental insufficiency (UPI). Seen in almost 70% of infants with IUGR.
Impaired oxygen extraction and nutrient delivery (glucose and amino acids)
lead to fetal hypoglycemia and hypoxia. The latter is associated with decrease
in cell size and number, lighter brain weight, and lower DNA content. Small
placental volume and a reduction in terminal villi are seen in IUGR placentas.
3. Placenta structural abnormalities. Various anatomic factors, such as mul-
tiple infarcts, aberrant cord insertions, umbilical vascular thrombosis, and
hemangiomas, are described in IUGR placentas. IUGR is twice as common
with a 2-vessel-cord pregnancy as compared with 3-vessel-cord pregnancies.
Premature placental separation may reduce the surface area exchange, resulting
in impaired fetal growth. An adverse intrauterine environment is apt to affect
both placental and fetal development, hence IUGR infants usually have small
placentas.
4. IUGR fetuses. These fetuses have downregulation of placental amino acid and
lipoprotein lipase transporters Na+/K+ ATPase and Na+/H+ exchanger, lead-
ing to lower plasma amino acid levels and decreased fatty acid transfer. Genetic
imprinting may also play a role (eg, alterations of the placenta-specific gene
IGF-2 in knockout mice has produced IUGR fetuses).
5. Fetal endocrine responses. Include alterations in the hypothalamic-pituitary
axis, resulting in elevated corticotropin-releasing hormone, adrenocortico-
tropic hormone, and cortisol with a decrease in insulin-like growth factor-1
(IGF-1). Thyroid-stimulating hormone is high, but thyroxine and triiodothy-
ronine are low, as are serum vitamin D and osteocalcin. High cortisol levels are
associated with decreased postnatal catch-up growth and delayed neurodevel-
opmental outcomes.
6. Fetal response to placental dysfunction. Different for early FGR and late FGR.
In early FGR, decrease in umbilical venous flow and decreased fetal cardiac
return to the placenta (due to increased resistance) precede clinical FGR. Fetal
events include increased ductal shunting to the heart, decreased hepatic flow,
downregulation of glucose-insulin-IGF, and decreased hepatic glycogen stores.
With increasing villous obliteration, middle cerebral artery Doppler changes
precede changes in the biophysical profile (BPP) with the loss of fetal heart rate
reactivity, breathing, and loss of body movements. BPP changes also correlate
with fetal acidosis. A decrease in amniotic fluid occurs in 20–30% of FGR that is
independent of Doppler changes and correlates with fetal cardiac decompensa-
tion. Doppler changes usually progress over 4–6 weeks.
7. Others. Placental mosaicism, wherein the placental cytogenetics are different
from the fetal cytogenetics, may account for ~15% of IUGR. Fibrin deposition
in the decidua basalis, the intervillous space, and mesenchymal dysplasia are
associated with an increased risk for placental thrombosis and IUGR.
IV. Risk factors. Related to fetal, maternal, or placental pathophysiologic factors (see pre-
vious text) (Table 105–2).
V. Clinical presentation. The maternal history will raise the index of suspicion regarding
suboptimal fetal growth. The infant will have a reduced birthweight for gestational
age. Using growth charts and the Ballard score can help assess gestational age, and
intrauterine and postnatal growth. See Figures 5–1, 5–3 through 5–5.
VI. Diagnosis
A. Establishing gestational age. Determining the correct gestational age is impera-
tive. The last menstrual period, size of the uterus, time of quickening (fluttering
movements in the abdomen caused by fetal activity, appreciated by the mother for
the first time), and early ultrasound measurements are used to determine gesta-
tional age. (See Chapter 5.)
105: INTRAUTERINE GROWTH RESTRICTION (SMALL FOR GESTATIONAL AGE) 737

Table 105–2. PLACENTAL FACTORS IN INTRAUTERINE GROWTH RESTRICTION

Two-vessel cord
Abruptio placentae, placental hematoma, placenta previa, chronic abruption
Hemangioma
Single umbilical artery
Infarction
Aberrant cord insertion
Umbilical vessel thrombosis
Circumvallate placentation
Confined placental mosaicism
Massive perivillous fibrin deposition (immune mediated)
Chronic villitis of unknown etiology (VUE)
Placental mesenchymal dysplasia

B. Fetal assessment
1. Clinical diagnosis. Manual estimations of weight, serial measurements for fun-
dus height, and maternal estimates of fetal activity are simple clinical measures.
2. Ultrasonography. Because of its reliability to date pregnancy and to detect
impaired fetal growth by anthropomorphic measurements and fetal anomalies,
ultrasonography currently offers the greatest promise for diagnosis. The follow-
ing anthropomorphic measurements are used in combination to predict growth
impairment with a high degree of accuracy.
a. Biparietal diameter (BPD). When serial measurements of BPD are less than
optimal, 50–80% of infants have subnormal birthweights.
b. Abdominal circumference. The liver is the first organ to suffer the effects of
growth retardation due to redistribution of ductus venosus blood flow to the
heart and a decrease in glycogen deposition in the liver. Reduced growth of
the abdominal circumference (<5 mm/wk) is the earliest sign of asymmetric
growth retardation and diminished glycogen storage. Abdominal circumfer-
ence <10th percentile for age is suggestive of growth retardation.
c. Ratio of head circumference to abdominal circumference. This ratio nor-
mally changes as pregnancy progresses. In the second trimester, the head
circumference is greater than the abdominal circumference. At about 32–36
weeks’ gestation, the ratio is 1:1, and after 36 weeks the abdominal mea-
surements become larger. Persistence of a head-to-abdomen ratio <1 late in
gestation is predictive of asymmetric IUGR.
d. Femur length.  Femur length appears to correlate well with crown-heel
length and provides an early and reproducible measurement of length. Serial
measurements of femur length are as effective as head measurements for
detecting symmetric IUGR.
e. Placental morphology and amniotic fluid assessment. May help in dis-
tinguishing a constitutionally small fetus from a growth-retarded fetus. For
example, placental aging with oligohydramnios suggests IUGR and fetal
jeopardy, whereas normal placental morphology with a normal amount of
amniotic fluid suggests a constitutionally small fetus.
f. Placental volume measurements. May be helpful in predicting subsequent
fetal growth. Placental weight and/or volume is decreased before fetal growth
decreases. IUGR with decreased placental size is more likely to be associated
with fetal acidosis. Placental volume correlates with placental flow indices.
3. Doppler measurements. In both maternal and various fetal vascular beds are
increasingly used to detect, monitor, and optimize time of delivery in IUGR
infants. Doppler studies are more helpful in diagnosing moderate to severe
IUGR than mild IUGR. The various groups of vessels used are as follows:
738 NEONATOLOGY

a. Uterine artery (UtA) flow abnormalities. Used to predict IUGR as early as

12–14 weeks. A persistent abnormality at 23–24 weeks has a ~75% sensitivity
in predicting early FGR.
b. Umbilical artery (UA) flow abnormalities.  Used to evaluate placental
insufficiency, particularly in high-risk pregnancies. Normally, the UA resis-
tance declines with pregnancy. Increased pulsatility index (PI), decreased
end-diastolic velocity (EDV), and absent or reversed EDV (AREDV) occur
with worsening fetal compromise. AREDV is associated with 20–68% mor-
tality. Decreased EDV is seen when 30% placental flow is attenuated, and
ARDEV is noted when 60–70% placental flow is affected. Absent EDV and
AREDV are associated with a 4.0- and 10.6-fold increased risk of mortality,
respectively, compared to those with normal Doppler.
c. Fetal cerebral arterial flow. Usually studied in the middle cerebral artery as
a pulsatility index (MCA PI) and middle cerebral artery peak systolic velocity
(MCA PSV). With worsening IUGR, MCA PSV increases. Abnormal MCA
PI precedes MCA PSV changes. Changes in MCA PI are not as consistent in
predicting mortality, although decreased MCA resistance is associated with
worse perinatal outcomes.
d. Doppler venous flow studies of the vena cava, umbilical vein (UV), and
ductus venosus (DV) provide information about fetal cardiovascular and
respiratory responses. Decreased venous blood flow in the UV and an
abnormal deep or retrograde “a” wave in DV are suggestive of ventricu-
lar decompensation. Changes in venous flow are usually late and represent
more severe decompensation. Absent or reversed DV flow correlates with
acidosis and is associated with 63–100% mortality.
e. Aortic isthmus (AoI). Absolute flow velocities are decreased in growth-
restricted fetuses. Retrograde flow in the AoI correlates strongly with adverse
perinatal outcome.
4. Biophysical profile (BPP). Used for noninvasive fetal monitoring.
5. Cardiotocography (CTG). Used more commonly in Europe to assess timing of
delivery for situations wherein significant fetal acidosis is suspected.
6. Placental magnetic resonance imaging (MRI). This can assess severity of FGR
on the basis of decreased placental volume and changes in placental thickness-
to-volume ratio. Fetal demise can also be predicted by abnormal signal intensity.
7. Compensated versus decompensated fetus. Persistence of UPI results in fetal
adaptation to maintain adequate cerebral oxygenation and growth.
a. UPI results in increased placental vascular resistance and fetal hypoxemia
by reducing umbilical blood flow. The fetus responds by redistribution of
blood to the brain (brain sparing) by cerebral vasodilatation, mesenteric
vasoconstriction, preferential shunting through the foramen ovale, increased
fractional extraction of oxygen (O2), polycythemia, and a relative decrease in
fetal O2 consumption. Fetal growth velocity and weight gain are decreased.
Nonstress test (NST), BPP, and CTG are normal. Decreased or absent dia-
stolic flow in the umbilical artery and increased diastolic component in the
MCA are seen. The fetus is hypoxemic but does not have cerebral hypoxemia
at this stage.
b. With worsening fetal compromise. There is cerebral hypoxemia and acide-
mia associated with no fetal weight gain, oligohydramnios, decreased fetal
heart rate variability, and abnormal NST, CTG, and BPP. Umbilical arteries
show absence or reversal of end-diastolic flow (AREDV). Deep “a” wave
is seen in the ductus venosus, suggestive of ventricular dysfunction. With
severe acidosis, MCA PI and MCA PSV decrease, suggesting imminent col-
lapse of the fetus.
c. Acute fetal decompensation. AREDV in umbilical arteries (UAs) in early-onset
FGR babies can be present up to 1 week before acute decompensation.
105: INTRAUTERINE GROWTH RESTRICTION (SMALL FOR GESTATIONAL AGE) 739

Table 105–3. SEQUENTIAL CHANGES OF DOPPLER STUDIES IN DECOMPENSATING FETAL

GROWTH RESTRICTION
Initial changes Decreased amniotic fluid index
Increased uterine artery resistance with EDV
Early changes Decreased MCA resistance (brain sparing)
(in 50% 2–3 weeks before nonreactive FHR) Absent uterine artery EDV
Late changes Increased resistance in DV-reversed EDV in uterine artery
(~6 days before nonreactive FHR)
Very late changes Reversed flow in DV and pulsatile flow in umbilical vein
(in 70%, 24 hours before changes in BPP)
BPP, biophysical profile; DV, ductus venosus; EDV, end-diastolic flow; FHR, fetal heart rate; MCA, middle
cerebral artery.

Approximately 40% of fetus with acidosis have AREDV pattern. MCA vasodi-
lation with abnormal PI may be present for up to 2 weeks before acute deteriora-
tion in 50–80% of infants. MCA vasodilation may be independently associated
with abnormal outcomes in late-onset FGR. Oligohydramnios develops in
20–30% of IUGR infants about 1 week before acute deterioration (Table 105–3).
C. Neonatal assessment
1. Reduced birthweight for gestational age.  This is the simplest method of
diagnosing IUGR. However, this method tends to misdiagnose constitution-
ally small infants.
2. Physical appearance. When infants with congenital malformation syndromes
and infections are excluded, the remaining groups of IUGR infants have a char-
acteristic physical appearance. These infants in general are thin with loose, peel-
ing skin because of loss of subcutaneous tissue, a scaphoid abdomen, and a
disproportionately large head.
3. Appropriate growth charts should be used.  Several standardized growth
charts are available to assess intrauterine and postnatal growth. See Lubchenco
and Olsen charts (Chapter 5). Additional growth charts for infants based on
Centers for Disease Control and Prevention (CDC) and World Health Organi-
zation (WHO) data from birth to 36 months can be found at the CDC website:
http://www.cdc.gov/growthcharts/.
4. Ponderal index <10th percentile helps identify neonates with IUGR, especially
those with birthweight <2500 g.
5. Ballard score. Gestational age can also be assessed by means of the Ballard
scoring system. This examination is accurate within 2 weeks of gestation in
infants weighing <999 g at birth and is most accurate at 30–42 hours of age.
(See Chapter 5.)
D. Observe for the following complications:
1. Hypoxia
a. Perinatal asphyxia. IUGR infants frequently have birth asphyxia because
they tolerate the stress of labor poorly. IUGR accounts for a large proportion
of stillborn infants with hypoxia in utero.
b. Persistent pulmonary hypertension.  Many IUGR infants are subjected to
chronic intrauterine hypoxia, which results in abnormal thickening of the
smooth muscles of the small pulmonary arterioles. This in turn reduces pulmo-
nary blood flow and results in varying degrees of pulmonary artery hyperten-
sion. IUGR infants are particularly at risk for persistent pulmonary hypertension.
c. Respiratory distress syndrome. Several reports suggest accelerated fetal
pulmonary maturation in association with IUGR secondary to chronic
740 NEONATOLOGY

intrauterine stress. Hyaline membrane disease is less frequently seen in

IUGR because these infants tend to manifest advanced pulmonary maturity
secondary to chronic intrauterine stress.
d. Meconium aspiration. Post-term IUGR infants are particularly at risk for
meconium aspiration.
e. Patent ductus arteriosus (PDA). Conflicting data suggest that hemody-
namically significant PDA may be bigger and occur earlier in IUGR infants
than in appropriate for gestational age (AGA) infants, but spontaneous clo-
sure of PDA is more frequent in IUGR infants <1000 g birthweight. IUGR
infants with PDA are at greater risk for pulmonary hemorrhage, intraventric-
ular hemorrhage (IVH), necrotizing enterocolitis (NEC), and renal failure.
2. Hypothermia. Thermoregulation is compromised in IUGR infants because of
diminished subcutaneous fat insulation. Infants with IUGR secondary to fetal
malnutrition late in gestation tend to be thin as a result of loss of subcutaneous fat.
3. Metabolic
a. Hypoglycemia. Carbohydrate metabolism is seriously disturbed, and IUGR
infants are highly susceptible to hypoglycemia as a consequence of diminished
glycogen reserves and decreased capacity for gluconeogenesis. Oxidation of
free fatty acids and triglycerides is reduced in IUGR infants, which limits alter-
nate fuel sources. Hyperinsulinism, excess sensitivity to insulin, and deficient
catecholamine release during hypoglycemia suggest abnormality of counter-
regulatory hormone mechanisms during periods of hypoglycemia in IUGR
infants. Hypothermia may potentiate the problem of hypoglycemia.
b. Hyperglycemia. Very low birthweight infants have low insulin secretion,
resulting in hyperglycemia.
c. Hypocalcemia. Hypocalcemia may occur in asphyxiated IUGR infants.
d. Liver disease. IUGR infants are at greater risk for developing cholestasis
associated with parenteral nutrition. There is also an increased risk of non–
fatty liver disease in children born SGA.
e. Other.  Hypertriglyceridemia, increased sympathetic tone, and reduced
concentrations of IGF-1 have been associated with increased aortic intimal
thickness in IUGR infants.
4. Hematologic disorders. Hyperviscosity and polycythemia may result from
increased erythropoietin levels secondary to fetal hypoxia associated with
IUGR. Thrombocytopenia, neutropenia, and altered coagulation profile are
also seen in IUGR infants. Polycythemia may also contribute to hypoglycemia
and lead to cerebral injury. There is an increased number of nucleated red cells
secondary to extramedullary hematopoiesis. Persistent elevated nucleated red
cell counts are associated with worse prognosis.
5. Altered immunity. IUGR infants have decreased immunoglobulin G (IgG)
levels. In addition, the thymus is reduced in size by 50%, and peripheral blood
lymphocytes are decreased. Reduction in total white cell count, neutrophils,
monocyte and lymphocyte subpopulations, and thrombocytopenia may occur,
and selective suppression of helper and cytotoxic T cells can be seen.
6. Others. IUGR infants are at increased risk of developing NEC, particularly
when associated with an absent or reversed end-diastolic flow on an umbilical
artery Doppler. Preterm IUGR infants are also at increased risk of pulmonary
hemorrhage, chronic lung disease, more severe IVH, and renal failure.
VII. Management. Antenatal diagnosis is the key to proper management of IUGR.
A. History of risk factors. The presence of maternal risk factors should alert the
obstetrician to the likelihood of fetal growth retardation. Ultrasonography con-
firms the diagnosis. Correctable causes of impaired fetal growth warrant immedi-
ate attention.
B. Delivery and resuscitation. The optimal timing for delivery of IUGR infants is
still debated, but Doppler measurements provide an important tool for monitoring
fetal well-being. IUGR infants have a 2- to 3-fold increased risk of preterm delivery
105: INTRAUTERINE GROWTH RESTRICTION (SMALL FOR GESTATIONAL AGE) 741

when fetal growth standards are used for diagnosis. IUGR infants delivered before
28–30 weeks have worse outcomes. Outcomes are more favorable with cesarean
delivery. Delivery is usually undertaken when the lungs are mature or when bio-
physical data obtained by monitoring reveal fetal distress. Labor is particularly
stressful to IUGR fetuses. Skilled resuscitation should be available because peri-
natal depression is common.
C. Prevention of heat loss. Meticulous care should be taken to conserve body heat
(see Chapter 7).
D. Hypoglycemia. Close monitoring of blood glucose levels is essential for all IUGR
infants. Hypoglycemia should be treated promptly with parenteral dextrose and
early feeding (see Chapter 62).
E. Hematologic disorders. A central hematocrit reading should be obtained to detect
polycythemia.
F. Congenital infection. IUGR infants should be examined for congenital malforma-
tions or signs of congenital infections. Many intrauterine infections are clinically
silent, and screening for these should be done routinely in IUGR infants.
G. Genetic anomalies. Screening for genetic anomalies should be done as indicated
by the physical examination.
VIII. Prognosis. Mortality increases with decreasing gestational age when IUGR is also
present. Mortality decreases by 48% for each week that the fetus remains in utero before
30 weeks’ gestation. Neurodevelopmental morbidities are seen 5–10 times more
often in IUGR infants compared with AGA infants. Neurodevelopmental outcome
depends not only on the cause of IUGR but also on the adverse events in the neonatal
course (eg, perinatal depression or hypoglycemia). Many studies reveal evidence of
minimal brain dysfunction, including hyperactivity, short attention span, and learning
problems. Preterm IUGR infants also show alterations in early neurobehavioral func-
tions like attention-interaction capacity and cognitive and memory dysfunction that
persist. Increased risk of cerebral palsy, a wide spectrum of learning disabilities, mental
retardation, pervasive developmental disorders, and neuropsychiatric disorders are seen
in later years. The risk of morbidities is higher in term IUGR infants. IUGR infants who
have normal Doppler studies have better outcomes than those with abnormal antenatal
Doppler studies. Even mild FGR increases the risk of mortality and long-term development.
A. Symmetric versus asymmetric IUGR. Infants with symmetric IUGR caused by
decreased growth potential generally have a poor outcome, whereas those with
asymmetric IUGR in which brain growth is spared usually have a better outcome.
Smaller head circumference is associated with cognitive, psychomotor, and behav-
ioral delays that persist into adolescence. Neuroimaging studies using MRI and
ultrasound show that preterm IUGR infants have a high incidence of white matter
loss and reduced myelination in the internal capsule associated with decreased
cortical gray matter volume by as much as 28%. The total brain volume is also
reduced by 10% when compared with AGA infants, particularly in the hippocam-
pal, parietal, and parieto-occipital areas.
B. Preterm IUGR. These infants have a higher incidence of abnormalities than the gen-
eral population because they are subjected to the risks of prematurity in addition to
the risks of IUGR. Outcomes are significantly poorer for children whose brain growth
failure occurred before 26 weeks’ gestation. Gestational age may be a more important
predictor of developmental outcomes than FGR, particularly before 32–34 weeks.
C. Chromosomal disorders. IUGR infants with major chromosomal disorders have
a 100% incidence of disability.
D. Congenital infections. Infants with congenital rubella or cytomegalovirus infec-
tion with microcephaly have a poor outcome, with a disability rate >50%.
E. Learning ability. The school performance of IUGR infants is significantly influenced
by social class; children from higher social classes score better on achievement tests.
F. Adult disorders. Epidemiologic evidence indicates that obesity, insulin-resistant
diabetes, hypertension, and cardiovascular diseases are more common among
adults who were IUGR at birth.
742 NEONATOLOGY

G. Risk for recurrence of IUGR in subsequent pregnancies. Depends on the under-

lying condition. The presence of previous fetal growth retardation, preeclampsia,
abruption, infarction, and acquired or inherited thrombophilias increase the risk
of fetal growth retardation in the subsequent pregnancies. Placental pathologic
examination should be attempted in all IUGR infants as the risk of FGR in subse-
quent pregnancy is very high (eg, risk of recurrence is 50–100% with fibrin deposi-
tion). In selected cases, folic acid, aspirin, and supplementation with L-arginine to
improve placental blood flow may improve outcomes.
H. FGR and stillbirth.  FGR is an important predictor of unexplained stillbirths.
Greater than 50% of fetuses without congenital anomalies are IUGR. Maternal
obesity increases the risk of concomitant FGR and stillbirth.

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