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Current Concepts in Intrauterine Growth Restriction

Article  in  Journal of Intensive Care Medicine · December 2004

DOI: 10.1177/0885066604269663 · Source: PubMed

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Current Concepts in
Intrauterine Growth Restriction
Dara Brodsky, MD
Helen Christou, MD

from obtaining his or her complete growth poten-

Regulation of fetal growth is multifactorial and complex.
Diverse factors, including intrinsic fetal conditions as well
tial. IUGR infants are small for gestational age
as maternal and environmental factors, can lead to (SGA) if their birth weight measures less than 3% to
intrauterine growth restriction (IUGR). The interaction of 10% using standard growth curves [1]. Less com-
these factors governs the partitioning of nutrients and monly, these infants may be characterized as
rate of fetal cellular proliferation and maturation. appropriate for gestational age (AGA) if their
Although IUGR is probably a physiologic adaptive
response to various stimuli, it is associated with distinct
growth restriction is mild. It is important to distin-
short- and long-term morbidities. Immediate morbidities guish between infants who experienced in utero
include those associated with prematurity and inadequate growth restriction from infants with normal in utero
nutrient reserve, while childhood morbidities relate to growth but constitutionally small (ie, no loss in per-
impaired maturation and disrupted organ development. centiles throughout gestation) since IUGR fetuses
Potential long-term effects of IUGR are debated and
explained by the fetal programming hypothesis. In for-
undergo fetal adaptations to a pathologic condi-
mulating a comprehensive approach to the management tion, leading to distinct short- and long-term out-
and follow-up of the growth-restricted fetus and infant, comes.
physicians should take into consideration the etiology, Two main patterns of fetal growth restriction are
timing, and severity of IUGR. In addition, they should be observed (see Table 1). If fetal growth is impaired
cognizant of the immediate perinatal response of the
growth-restricted infant as well as the childhood and long-
during the first or second trimester, the infant will
term associated morbidities. A multidisciplinary approach have symmetric growth restriction. This propor-
is imperative, including early recognition and obstetrical tional lack of growth is caused by reduced fetal cel-
management of IUGR, assessment of the growth-restricted lular proliferation of all organs and occurs in
newborn in the delivery room, possible monitoring in the approximately 20% to 30% of IUGR infants [2]. In
neonatal intensive care unit, and appropriate pediatric
follow-up. Future research is necessary to establish effec-
contrast, asymmetric growth in which an infant has
tive preventive, diagnostic, and therapeutic strategies for a smaller abdominal size compared to head size
IUGR, perhaps affecting the health of future generations. will occur if the decrease in growth velocity hap-
pens in the last trimester. This head-sparing phe-
Key words: intrauterine growth restriction; small for gestational age nomenon is the most common form of IUGR
(~70%-80%) [2] and is attributed to the ability of the
fetus to adapt, redistributing its cardiac output to
the spleen, adrenal, coronary, and cerebral circula-
tions. Although some overlap can occur, the timing
Definition and Classification of the growth delay is more important than the eti-
ology in determining the pattern of growth restric-
Intrauterine growth restriction (IUGR) describes a tion.
decrease in fetal growth rate that prevents an infant
From Children’s Hospital, Harvard Medical School, Department
of Newborn Medicine, Boston, Massachusetts. Epidemiology and Etiology
Received Dec 15, 2003. Received revised Mar 8, 2004. Accepted
for publication Mar 10, 2004. The incidence of IUGR is estimated to be approx-
Address correspondence to Dara Brodsky, MD, Children’s imately 5% to 7%. Some studies identify a greater
Hospital, Harvard Medical School, Department of Newborn percentage (up to 15% of pregnancies), but these
Medicine, Enders 9, 300 Longwood Avenue, Boston, MA 02115,
or e-mail: [email protected].
reports define IUGR and SGA as equivalent.
Brodsky D, Christou H. Current concepts in intrauterine growth
Despite advances in obstetric care, IUGR remains
restriction. J Intensive Care Med. 2004;19:000-000. prevalent in developed countries. However, the
DOI: 10.1177/0885066604269663 causes of IUGR in these areas are different than in

Copyright © 2004 Sage Publications 1

Brodsky, Christou

Table 1. Specific Distinctions Between Symmetric and Asymmetric Intrauterine Growth Restriction (IUGR)
Symmetric IUGR Asymmetric IUGR
Incidence 20%-30% 70%-80%
Period of growth restriction Begins first or second trimester Begins third trimester
Physical characteristics Small head and abdominal size Large head size relative to small abdomen
Pathophysiology Impaired cellular embryonic division Impaired cellular hypertrophy
Impaired cellular hyperplasia ± Decreased cell size
hypertrophy
Decreased cell number ± size
Etiology Mostly intrinsic: chromosomal abnormalities Mostly extrinsic: placental and maternal
and congenital malformations vascular factors (eg, placental
Drugs insufficiency)
Infection
Early-onset severe preeclampsia
Preeclampsia <30 wk superimposed with
chronic hypertension
Outcome Greater morbidity and mortality Lower morbidity and mortality
This table outlines the differences between symmetric and asymmetric IUGR. Although most infants can be categorized into one of
these groups, some infants may have features of both types of IUGR [2,8].

Table 2. Maternal, Placental, and Fetal Etiologies of Intrauterine Growth Restriction (IUGR)
Maternal Placental Fetal
Vascular disorders (~25%-30%) Abnormal trophoblast invasion Genetic (~20%)
Hypertension Placental infarcts Chromosomal abnormalities
Diabetes mellitus Placenta previa Syndromes/congenital malformations
Renal disease Circumvallate placenta Multiple gestation (5%)
Collagen vascular disease Chorioangiomata Intrauterine infection
Hypercoaguable states Velamentous umbilical cord insertion Cytomegalovirus
Thrombophilia Umbilical-placental vascular anomalies Malaria
Antiphosopholipid antibody syndrome Parvovirus
Persistent hypoxia (eg, high altitude, Rubella
pulmonary or cardiac disease, severe Toxoplasmosis
anemia) Herpes virus
Undernutrition Toxins (eg, tobacco, HIV
alcohol, medications, and illicit drugs,
irradiation)
Uterine malformation or masses
Modified from Lee et al [19], Schwart [14], and Lin and Santolaya-Forgas [8].
Overall, IUGR encompasses an extremely heterogeneous group that can be categorized into maternal, placental, and fetal factors. There
is a subgroup of infants with overlapping etiologies. In addition, there are also a significant number of infants with unexplained eti-
ologies.

Third World nations. In most Western societies, pla- 17 to 39 weeks gestation with IUGR, 19% (89) had
cental insufficiency is the major cause of IUGR, chromosomal abnormalities (most commonly tri-
while inadequate maternal nutrition and malaria somy 18) [6]. Among 13,000 infants born with
infections play a greater role in developing coun- major malformations (most commonly anen-
tries [3,4]. cephaly), 22% experienced IUGR [7]. Less frequent-
Overall, IUGR encompasses an extremely hetero- ly, IUGR may be due to first or second trimester
geneous group. While a large number of etiologies fetal infection, including cytomegalovirus, malaria,
are not identified, the known associations involve parvovirus, and rubella. The majority of fetal eti-
fetal, placental, and/or maternal factors (see Table ologies lead to early gestation symmetric IUGR.
2). There is a strong link between IUGR, chromo- Chronic maternal vascular disease due to hyper-
somal abnormalities, and congenital malformations. tension, diabetes mellitus, renal disease, or colla-
Specifically, fetuses with chromosomal disorders gen vascular disease is the most common cause of
such as trisomy 13, 18, and 21 often have impaired IUGR [8] in developed countries. The most pro-
growth. Also, fetuses with other autosomal irregu- found effect is observed if the hypertension is early
larities (eg, deletions, ring chromosomes) typically onset, severe, or due to chronic hypertension with
have inadequate growth [5]. Indeed, of 458 fetuses superimposed preeclampsia [5]. Hypercoaguable

2 Journal of Intensive Care Medicine 18(X); 2004

 Intrauterine Growth Restriction

maternal conditions such as thrombophilia and stress, infarction, cytokine damage, and hyperten-
antiphospholipid antibody syndrome also inhibit sion can further inhibit optimal function of placen-
growth either by placental thrombosis formation or tal villi [22-24]. The response of the placental villi to
by secondary effects of maternal hypertension damage from ischemia and/or hypoxia may involve
[9,10]. Persistent maternal hypoxia due to high alti- erratic angiogenesis, limiting the possibility of com-
tude, severe pulmonary or cardiac disease, and/or plete placental recovery [22].
severe chronic anemia limits oxygen delivery to the Recently, some specific molecular pathways have
fetus and attenuates fetal growth. been associated with the development of IUGR.
Periods of famine in the Netherlands, Germany, Since insulin and its associated insulin-like growth
and the former Soviet Union have shown that factor (IGF)-I and –II are the primary anabolic hor-
severe maternal malnutrition can also impair fetal mones necessary for fetal growth, it is postulated
growth [11,12]. The severity of the available food that they may play a critical role in the develop-
supply [13] and the length of malnutrition [12] cor- ment of IUGR [25,26]. Indeed, low levels of IGF-1
relate with the degree of growth delay. While the and elevated levels of IGF binding protein (BP)-1
fetus is affected by chronic severe maternal malnu- have consistently been observed in growth-restrict-
trition, it seems to be fairly resistant to acute mal- ed infants [27-29]. The involvement of IGF is direct-
nutrition, particularly if it occurs late in gestation ly supported by a report of a patient with a
[14]. homozygous partial deletion of the IGF-I gene who
Maternal toxins can contribute to the develop- had extreme prenatal growth restriction that con-
ment of a growth-restricted fetus. Cigarette smok- tinued postnatally [30]. In addition, IGF-1 receptor
ing reduces uterine blood flow, limiting fetal oxy- mutations have been identified in 2 children with
genation and attenuating growth [15]. The quantity poor intrauterine and postnatal growth [31]. Animal
of cigarettes smoked per day correlates with the studies also support the role of the IGF signaling
degree of IUGR [16-18]. Prolonged maternal alco- pathway in the development of IUGR. Transgenic
hol ingestion and other drugs (eg, steroids, fetal mice overexpressing IGFBP-1 demonstrate
coumadin, hydantoin, cocaine, and heroin) are also impaired fetal growth [32]. In addition, newborn
implicated in the development of IUGR [19]. In mice homozygous null for the IGF-1, IGF-2, and
addition to these factors, physical constraints such IGF-1 receptor genes demonstrate growth deficien-
as large placental abnormalities, uterine masses, or cy with birth weights 45% to 60% of normal size
multiple gestations can lead to growth-restricted [25,33]. Since transgenic mice with excess maternal
fetuses. decidual IGFBP-1 have abnormal trophoblast inva-
sion and differentiation, the IGF-1 pathway may
also regulate placental development [32]. Moreover,
Pathophysiology placental-specific IGF-2 knockout mice develop
IUGR, emphasizing the important role of the pla-
These multifactorial causes of IUGR create 3 pos- centa in fetal growth restriction. In addition to fetal
sible scenarios: (1) abnormal placental function, (2) growth and placental development, it has been
inadequate maternal supply of oxygen and/or suggested that this complex IGF hormonal system
nutrients, and/or (3) decreased ability of the fetus also regulates maternal metabolism [34-37].
to use the supply (Fig 1). The placenta plays an Another potential signaling pathway involved in
integral role in the first 2 categories. Abnormal placental causes of IUGR is the glial cell missing–1
development, inadequate perfusion, and dysfunc- (GCM1) gene, which is necessary for trophoblast
tion of the placental villi are often responsible for morphogenesis and differentiation [38,39]. Targeted
the development of IUGR, especially the early- disruption of this transcription factor in tro-
onset type. Indeed, placentas from mothers with phoblasts leads to inadequate trophoblast differen-
preeclampsia are characterized by shallow cytotro- tiation and similar placental histology as that found
phoblast (CTB) invasion of the uterus and abnor- in early-onset IUGR fetuses [39,40]. Perhaps the
mal CTB differentiation [20]. Inadequate CTB inva- gene itself or signaling pathways leading to GCM1
sion will prevent effective destruction of distal spi- expression are altered, producing maldevelopment
ral decidual arteries leading to inadequate maternal of the placenta villi. Accumulating evidence from
perfusion of placental villi, local placental hypoxia, animal and human studies supports that leptin may
and impaired fetal growth [21]. In addition, also participate in the regulation of fetal growth
increased apoptosis of trophoblasts creates malde- and development [41].
velopment of placental villi, preventing maximal Alterations in the expression or activity of pla-
attainment of placental function [22]. Oxidative cental transporters, particularly those that transfer

Journal of Intensive Care Medicine 18(X); 2004 3

Brodsky, Christou

Fig 1. Pathophysiology of intrauterine growth restriction (IUGR). The potential factors leading to IUGR influence the
maternal supply to the fetus, the ability of the fetus to use the maternal supply, and/or the placental function. If IUGR
develops, there are numerous fetal adaptations that may incur perinatal, childhood, and adult effects. RDS = respirato-
ry distress syndrome; NEC = necrotizing enterocolitis; IVH = intraventricular hemorrhage; SIDS = sudden infant death
syndrome.

amino acids, may also contribute to the develop-

ment of IUGR [42]. Animal models have shown that
Prenatal Management of
pregnant rats with protein malnutrition had Growth-Restricted Fetus
growth-restricted fetuses associated with a decrease
in the Na+-dependent system A amino acid trans- It is crucial that the obstetrician recognizes and
porter [43]. It is possible that the placenta senses its accurately diagnoses a fetus with IUGR. Currently,
own nutrient supply, alters its transport abilities the recommended method is by measuring anthro-
accordingly, and regulates fetal growth; these pometric parameters, which include fetal abdomi-
mechanisms have not yet been well defined. nal circumference, head circumference, biparietal

4 Journal of Intensive Care Medicine 18(X); 2004

 Intrauterine Growth Restriction

diameter, and length. These results are converted The GA of the fetus is a critical component of the
to fetal weight estimates using standard formulas decision-making process. If a growth-restricted
and compared with population-based fetal growth fetus is near term with either poor growth or asso-
curves at specific gestational ages (GA) [5]. Precise ciated severe maternal preeclampsia, delivery is
initial dating by an early ultrasound will ensure that recommended. Similarly, an IUGR fetus between
the accurate GA is used [44]. Sequential assess- 34 and 37 weeks gestation should be delivered if
ments are necessary to determine if there is a there are similar concerns in the setting of mature
decrease in the fetal growth rate. fetal lung indices. The management of premature
Once the diagnosis of IUGR is established, the infants <34 weeks gestation is more challenging.
obstetrician must attempt to determine the specific Indeed, arbitrary delivery of a growth-restricted
cause of the growth delay. An abnormal fetal sur- premature fetus at any GA is not warranted
vey should prompt further investigations, including because fetal mortality is lower than neonatal mor-
fetal karyotyping, specialized genetic tests, and tality prior to 31 weeks gestation [54]. Since ante-
possible consultation with a geneticist. If a viral natal steroids decrease neonatal pulmonary and
infection is suspected, maternal serum studies are central nervous system morbidity in premature
required. Since fetal growth restriction may be the infants, these are still recommended for IUGR pre-
first evidence of preelampsia, maternal blood pres- mature fetuses, although specific effects on fetuses
sures should be monitored closely. The pregnant with growth delay are conflicting [55,56].
woman should be evaluated for vascular and In the group of IUGR fetuses with unclear indi-
hypercoaguable diseases as well as hypoxemic cations for immediate delivery, the obstetrician
conditions. An assessment for malnutrition and must rely on other assessment tools to monitor fetal
medications or toxins, including tobacco, may be well-being and determine the safest time for deliv-
helpful. After delivery, examination of the placenta ery. While some physicians advocate biweekly
by a pathologist may disclose placental vascular nonstress tests, randomized controlled studies have
abnormalities. not shown that outcomes are improved with this
Despite numerous approaches to managing monitoring [57,58]. Similarly, trials assessing effica-
IUGR, there are no effective therapies to improve cy of using biophysical profiles as a modality to
the growth pattern of a fetus [45]. Modalities tested determine the optimal delivery time have not
include maternal nutritional supplementation, plas- shown an association with better outcomes
ma volume expansion, and maternal medications [47,54,57]. Since studies demonstrate that oligohy-
such as low-dose aspirin [5,46,47]. Although mater- dramnios dramatically increases perinatal mortality
nal oxygen supplementation has been shown to in the growth-restricted fetus, this is often used as
increase fetal oxygen tension [48] and transiently an independent indicator for delivery [59].
improve fetal well-being [49,50], long-term benefits Umbilical Doppler flow measurements are the
have not been demonstrated [51]. Some reports most valuable current technique to distinguish the
suggest that any short-term benefit of improved sick IUGR fetus from the well IUGR fetus [60] and,
fetal oxygenation may actually worsen the long- in contrast to other modalities, improve perinatal
term outcome by prolonging the time a fetus outcomes [61-64]. Indeed, using this approach,
spends in an inadequate intrauterine environment fetuses with the worst placental outcome [65,66]
[52]. Although antihypertensive medications can be and the most detrimental perinatal outcome [67-69]
advantageous in the treatment of preeclampsia, can be identified. During this technique, the
they do not prevent or reverse fetal growth restric- impedance to blood flow in fetal arteries and veins
tion [8]. Finally, while bed rest is often encouraged, by Doppler velocimetry is measured; absent or
there is no evidence to support that this approach reversed end-diastolic flow in the umbilical artery
has any effect on fetal growth [53]. indicates an inadequate fetal status [70,71], while
Since there are no effective therapies to reverse normal umbilical Doppler flow is rarely associated
fetal growth restriction, prenatal management is with significant morbidity [72]. If associated abnor-
aimed primarily at determining the ideal timing and malities are observed in the ductus venosus and
mode of delivery. This assessment must be individ- umbilical veins, the IUGR fetus is even more com-
ualized, depending on several variables: GA of the promised with a high chance of imminent death
fetus, maternal health, severity of the IUGR, and [73]. This corresponds with the timing of fetal cir-
fetal well-being. Perhaps optimizing the delivery culatory changes during a compromised state since
time and removing the fetus from a suboptimal venous alterations typically occur after arterial
environment can prevent the risk of hypoxia and changes [74]. The assessment of fetal acid-base bal-
significant morbidities. ance by umbilical blood sampling has been shown

Journal of Intensive Care Medicine 18(X); 2004 5

Brodsky, Christou

to further identify growth-restricted fetuses with At delivery, the presence of a qualified neonatol-
hypoxia and acidosis [75]. ogy team is an important initial step in managing
Some new modalities are currently being investi- IUGR infants. Infants may have perinatal depres-
gated to improve the assessment of a compromised sion with low APGAR scores requiring emergent
fetus. One method records Doppler fetal cerebral resuscitation in the delivery room [5,92,93]. This
circulation and calculates the cerebro-placental may be associated with meconium aspiration
ratio of blood flow [76]. While this ratio has been and/or a severe metabolic acidosis. Because of
shown to be impaired in IUGR fetuses, a correla- decreased liver glycogen and fat stores, IUGR
tion between perinatal complications and neurode- infants must be monitored for hypoglycemia and
velopmental outcome has not been deciphered hypothermia [94]. Polycythemia attributed to a rel-
[77,78]. Qualitative determination of general move- atively hypoxic intrauterine environment may pre-
ments is also proposed as a potential tool to assess dispose the IUGR infant to greater postnatal hemol-
brain function [79-81]. Indeed, preliminary findings ysis and lead to indirect hyperbilirubinemia. In
have found that fidgety movements are predictive addition, since this population of infants is at
of neurological insults [82]. Finally, Doppler imag- increased risk of intrauterine coagulative processes,
ing of the proximal uterine arteries to assess mater- thrombocytopenia can be observed [95].
nal vascular function has been helpful in predicting The high incidence of premature delivery in
the severity of IUGR in mothers with preeclampsia IUGR infants leads to the characteristic postnatal
[83]. risks of prematurity [90,96]. Numerous investiga-
Once the timing of delivery has been established, tions have compared specific complications of pre-
the obstetrician is now responsible for determining maturity among growth-restricted neonates and
the mode of delivery. A trial of labor is often con- gestational age–matched AGA infants. For almost 3
sidered in selected women with growth-restricted decades, it was believed that IUGR infants had
fetuses if antepartum fetal testing by umbilical accelerated lung maturation with decreased rates of
artery Doppler velocimetry is normal [84]. Despite hyaline membrane disease (HMD) due to pro-
this preselection of milder IUGR fetuses, a cesare- longed intrauterine stress inducing fetal corticos-
an delivery may still be required since all growth- teroid production. However, recent studies suggest
restricted fetuses have a greater rate of intolerance that HMD occurs at equal rates in growth-restricted
to labor, evident by abnormal fetal heart rate pat- and AGA premature infants [97-99] and perhaps
terns [85]. may actually be more common in IUGR infants
[44,90]. Most trials have demonstrated an increased
risk of chronic lung disease in IUGR infants
Management and Outcomes [97,98,100]. Perhaps the restricted development of
the fetus enhances the lung’s susceptibility to post-
During the Neonatal Period
natal injury.
Numerous studies have shown that growth- Similar to HMD, the association of necrotizing
restricted fetuses have a greater risk of fetal mor- enterocolitis (NEC) and poor intrauterine growth
tality, correlating directly with the severity of IUGR remains controversial. It has generally been
[5,54,86-90]. Indeed, studies have found that almost believed that the decreased vascular supply to the
half of stillborn fetuses without malformations had gastrointestinal tract in utero predisposes the infant
growth restriction [89]. This increased mortality risk to develop NEC, and studies have demonstrated
extends beyond the fetal period; growth-restricted this increased risk [44,90,99,101,102]. However,
full-term infants weighing 1500 to 2500 g (<10%) other reports have shown no increased risk of NEC
have a 5 to 30 times higher mortality risk compared in IUGR infants [103]. Some reports demonstrate
to term infants born >2500 g (>10%) [5]. that prenatal findings of abnormal flow in the fetal
It is well recognized that growth-restricted infants aorta as well as absent or reversed end-diastolic
are at greater risk of morbidities [86,88,90,91]. umbilical arterial flow predisposes the growth-
Neonates with a greater severity and protracted restricted fetus to develop NEC [104,105]. Further
period of IUGR are at even more risk of perinatal studies are needed to elucidate the correlation of
complications and poor prognoses. It is also impor- NEC and IUGR.
tant to acknowledge that known etiologies of IUGR In addition to HMD and NEC, the association of
will independently influence these morbidities. intraventricular hemorrhage (IVH) in growth-
Specifically, infants with IUGR attributable to fetal restricted and AGA premature infants is still debat-
factors (eg, in utero infection, chromosomal abnor- ed. Some studies have demonstrated a larger risk of
malities) have independent adverse outcomes. IVH [90], while others did not observe any associa-

6 Journal of Intensive Care Medicine 18(X); 2004

 Intrauterine Growth Restriction

tion [99,101]. Another report found that IVH was The literature is inconsistent about the influence
actually decreased in IUGR infants of 28 weeks ges- of IUGR on long-term neurological outcome, rang-
tational age compared to AGA neonates, suggesting ing from minimal decreases in IQ [132,133] or no
a potential protective effect of growth restriction effects [134-138] to cerebral palsy [139-141]. Not
[44]. The heterogeneity of IUGR infants may con- surprisingly, the worst outcomes are observed in
tribute to the discrepancies in potential associations those with severe IUGR [134], early-onset IGUR
with HMD, NEC, and IVH. [142,143], premature birth [144], and prenatal evi-
Although there is a low number of published dence of impaired umbilical arterial flow [145,146].
investigations focused on hypothyroxinemia and The presence of microcephaly at birth with poor
IUGR, all have been consistent; growth-restricted catch-up of head growth is one of the most signif-
infants are at greater risk for early hypothyroxine- icant negative determinants of neurodevelopmental
mia [106-109]. Metabolic reasons for this association outcome [81,147]. The best long-term neurological
have not yet been identified. A higher infection rate prognosis is encountered when the fetus tolerates
has also been consistently observed in IUGR pre- labor, the growth restriction is mild, the delivery
mature infants compared with matched AGA date is carefully determined, immediate neonatal
infants [99,110]. An increased association between care is available, and there is appropriate prenatal
persistent pulmonary hypertension of the newborn and postnatal head growth [2,5,147]. Most reports
(PPHN) and asymmetric growth restriction has also suggest that severe IUGR incurs subtle behavioral
been reported [111]. Our anecdotal experience sug- and learning disabilities during childhood
gests that premature IUGR infants are a subset that [77,135,144,148-151]. Perhaps the disparity of find-
is more likely to develop PPHN. Finally, the kid- ings related to neurological outcome can be
neys appear to be extremely vulnerable to IUGR explained by the heterogeneity of the populations
and are often small in proportion to body weight examined including differences in etiology, defini-
[112,113]. Besides the deficit in nephrons, there is tion of IUGR, age the children are examined, peri-
an impairment of renal function associated with natal and neonatal complications, and distinct
IUGR [114,115]. These renal effects may explain the sociodemographic and postnatal environmental
epidemiological studies connecting the develop- factors [35].
ment of adult hypertension with IUGR [116-118]. Other childhood effects from IUGR have been
identified. There is a slight increased risk of sudden
infant death syndrome reported in growth-restrict-
Management and Outcomes ed infants [152,153], attributed possibly to failure of
breathing or arousal from sleep [154,155]. Fetal
During Childhood
growth restriction also impairs airway function dur-
The effects of IUGR persist beyond the neonatal ing childhood, evident by lower forced expiratory
period and may have profound influences during volumes in 5- to 11-year-old children with a histo-
childhood. The majority of IUGR infants demon- ry of IUGR [156]. The onset duration and severity
strate an increased postnatal growth velocity with of IUGR may influence these childhood effects.
catch-up growth by 2 to 3 years of age [19,119,120].
However, since IUGR infants have low nutritional
stores and often have feeding difficulties, a sub- Long-term Outcomes
group (~10%) remains vulnerable to continued
growth problems [19,121]. Longitudinal studies sup- It is well accepted that an individual’s risk of
port a greater incidence of short stature in IUGR developing adult disease is determined by the
children born prematurely compared with full-term interactions between one’s genetic makeup and
IUGR children [120,122]. If a child with a history of postnatal environmental factors. Epidemiological
IUGR is older than 3 years and has persistent studies since the early 1980s suggest that subopti-
growth delay, he or she should still be evaluated by mal growth during the fetal period also predispos-
a pediatric endocrinologist for other potential caus- es to specific diseases later in life including adult-
es [19]. In addition to growth hormone deficiency, onset hypertension (HTN), type 2 diabetes, and
one should assess for abnormalities of IGF-1, coronary artery disease (CAD) [157]. This epidemi-
IGFBP-3, fasting insulin, glucose, and lipid levels ological association forms the basis of the fetal pro-
[19]. Some studies demonstrate normalization of gramming hypothesis, which proposes that these 3
height after prolonged growth hormone treatment disorders “originate in developmental plasticity, in
despite normal initial hormonal levels [123-131]. response to undernutrition during fetal life and
infancy” [158].

Journal of Intensive Care Medicine 18(X); 2004 7

Brodsky, Christou

Although the association of IUGR and HTN in development of type 2 diabetes and the metabolic
adulthood is still disputed [159], accumulating evi- syndrome [164,165]. Animal data show that this
dence from animal and human studies supports association can be explained partly by permanent
that suboptimal in utero nutrient supply leads to changes in the expression of hormone receptors,
metabolic and hormonal adaptations as well as signaling molecules, and regulatory enzymes in
altered organ structure, which may contribute to liver, pancreatic β cells, muscle, and adipose tissue
HTN, insulin resistance, and CAD. The so-called in response to in utero undernutrition [165-167].
“thrifty phenotype” describes the fetal response to These studies have also questioned whether rapid
inadequate nutrient supply and consists of catch-up growth following early growth retardation
decreased muscle mass, insulin resistance, may add to the risk of developing insulin resistance
decreased capillary network, and an increased [165]. The combination of low birth weight and
stress response. In the setting of this phenotype, it accelerated childhood growth is associated with
has been proposed that subsequent abundance of exaggeration of adiposity and insulin resistance,
nutritional supplements may predispose an individ- particularly for those who were born with IUGR.
ual to the development of the metabolic syndrome The postnatal age of adiposity rebound is a predic-
(syndrome X), which consists of centripetal fat tor of both adult adiposity and insulin resistance. In
accumulation, insulin resistance, glucose intoler- one study, individuals with adiposity rebound
ance, hypertriglyceridemia, low levels of high-den- before age 5 had an 8.6% incidence of diabetes
sity lipids, and HTN. Since this syndrome is com- compared to 2.1% in individuals whose adiposity
plex and multifactorial, the fetal programming rebound occurred after age 7 [168]. Recent studies
hypothesis can be viewed as the result of the inter- in premature human neonates suggest that
action between the genetic makeup of the individ- enhanced nutritional intake postnatally is associat-
ual and nutritional, metabolic, and hormonal cues ed with an increased incidence of insulin resistance
during fetal and neonatal development that ulti- at age 16 [169]. Finally, it has been proposed that
mately determine the risk of adult morbidities. IUGR is an added risk factor in individuals who
Several studies have addressed the possible asso- have another predisposing factor for insulin resist-
ciation of IUGR with HTN in childhood and adult- ance such as PPAR-γ polymorphisms [170].
hood [157,160]. Although the majority of these The association between IUGR and CAD is pre-
studies support an inverse relationship between dominantly indirect, mediated by the effect of low
birth weight and arterial blood pressure, a pub- birth weight on the incidence of HTN, diabetes,
lished meta-analysis suggests that as the statistical and the metabolic syndrome. Studies of in utero
size of the study increases, the magnitude of this anemia in sheep have provided evidence for a
association decreases [159]. In evaluating these direct effect of intrauterine anemia (and the associ-
studies, several methodological considerations ated growth restriction) on coronary artery physiol-
should be taken into account, including the source ogy. Altered coronary conductance and inappropri-
of the birth weight (birth records or memory), the ate cardiac responses to hypoxic stress have been
number of blood pressure measurements, the age observed in adult sheep exposed to in utero ane-
at which blood pressure is reported, and whether mia [171,172]. The importance of these observa-
there is adjustment for current weight and other tions in humans needs to be clarified.
confounding variables. In summary, IUGR has been associated with spe-
Animal and human studies have provided some cific adult diseases. It appears that the nutritional
insight into the possible biological basis for the management of the low-birth-weight infant proba-
association of IUGR and HTN. Because IUGR bly plays a role in the risk of developing some
infants have a significant reduction in nephron long-term morbidities. Regular monitoring of
number [114,161,162], this may predispose them to weight, height, and body mass index during infan-
develop HTN later in life [116-118,163]. cy, childhood, and adolescence should be imple-
Furthermore, since the etiology of HTN is multifac- mented to attempt to avoid excessive weight gain
torial and largely unknown, it is possible that IUGR and possibly HTN, type 2 diabetes, and CAD.
may be a modifying factor in individuals who have
a genetic predisposition to HTN. Clearly, further
elucidation of the underlying molecular mecha- Future Directions
nisms is needed to accomplish early detection and
management of at-risk infants. Innovative intrauterine interventions to prevent,
Many epidemiological studies support a strong detect, and treat growth restriction could reduce
association between IUGR and the subsequent potential neonatal, childhood, and adult effects.

8 Journal of Intensive Care Medicine 18(X); 2004

 Intrauterine Growth Restriction

Presently, there are 3 effective preventive strategies ty to establish effective preventive, diagnostic, and
to optimize fetal growth: (1) discourage smoking therapeutic strategies for IUGR, perhaps affecting
during pregnancy, (2) encourage optimal maternal the health of future generations.
nutrition, and (3) prescribe antimalarial prophylax-
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