111i ifferential sparing is particularly promin I1t wh 1

p .ivation occurs in the latter half of pr gl1311Cy. D privation

earl), in pregnancy is associated with less cer br I sparing
and diffu ely lowed brain growtll.
Alth ugh this classification is helpful ill establishing a
differential diagnosis and framework for discussion, it is 110t
suffi iently precise tOI serve as a basis for decisions regarding
intervention or viability.
A number of etiologies have been shown to have all a O>
ciation with IUGR, either symmetric or asymmetric.

A. etop acental Causes

1. Congenital abnormalities-Genetic disorders account
for approximately one-third of IUGR infants. The frequency
of IUGR in chromosomally abnormal infants ranges from
20 to 60%) and the risk of an IUGR infant having a major
.~Ollg 111(.1,1lllomaly b 10%. All infant with an autosomal tri-
'tlI11 b 1111..1c1
likely 10 be IVCR. The most common trisomy
is tdsomy 21 (Down syndrome), with an incidence of 1.6
pc?r WOO Jive births. At term, such infants weigh an average
ot 350 g less than comparable normal infants and are 4 times
more likely to be IUGR. This decrease is most apparent in
the last 6 weeks of pregnancy. A similar decrease in birth-
weight occurs in translocation Down syndrome, whereas
mosaic Down syndrome is associated with an intermediate
decrease in birthweight.
The second most common autosomal trisomy is trisomy
18 (Edwards' syndrome), which occurs in ] in 6000-S000
live births. Eighty-four percent of these infants are IUGR.
Ultrasound evaluation may reveal associated anomalies.
The condition is associated with an increased likelihood
of breech presentation, polyhydramnios, fetal neural lube
defects, and visceral anomalies. The average birthwcight of
infants with trisomy IS is almost 1000 g less than that of
controls. In contrast to the placental weight in infants with
trisomies 13 and 21, the placental weight in infants with
trisomy IS also is markedly reduced.
Trisomy 13 occurs in 1 in 5000-10,000 live births. More
than 50% of affected infants have IUGR. Birthweights aver-
age 700-S00 g less than those of controls.
Other more rare autosomal chromosome abnormali-
ties, such as ring chromosomes, deletions, and partial
trisomies, are associated with an increased likelihood of
IUGR. Sex chromosome abnormalities may be associated
with lower birthweight. Extra X chromosomes (>2) are
associated with a 200-g to 300-g decrease in birth weight
for each extra X. Turner's syndrome is associated with an
average birthweight of approximately 400 g below average.
Fetuses with mosaic Turner's syndrome are intermediately
affected.
Growth impairment as a result of fetal chromosome
abnormalities usually occurs earlier than impairment caused
by placental abnormalities. However, there is considerable
clinical overlap, so gestational age at the time of diagnosis is
not always of clinical value.
Fetuses with neural tube defects frequently are
IUGR, weighing approximately 250 g less than controls.
Anencephalic fetuses are IUGR, even considering the
absent brain and skull, with average third-trimester birth-
weights of approximately 1000 g less than matched con-
trols. Certain dysmorphic syndromes are associated with
an increased incidence of IUGR fetuses. Achondroplasia
may be associated with low birthweight if either parent is
affected but usually is associated with normal birthweight if
a spontaneous mutation is the ca.use. Osteogenes~s imper-
fecta consists of a spectrum of diseases, all of which result
in IUGR fetuses.
Infants born with abdominal walJ defects are characteris
ucally IUGR, particularly th~se with gastroachisi . .
Other autosomal receSSive syndromes associated WIth
IUGR include Smith-Lemli-Opitz syacirome, Meckel',
drome, Robert's syndrome, DollObue 5 syndrome, and
al'l'l"I)xilllllll'iy 2()() g, with the amount of y,rowlh restriction
proport ionul 10 the number of cigart'lks smoked per day.
WOI)Il'1) who quit smoking u l 7 months' geslalion have new-
horns with higher mean birthwcights than do women who
smoke tlnoughout the entire prcgnancy. WOnll'11 who slop
smoking before 16 weeks' gesLllioll arc nut ut lucrcuscd risk
f~lI' having an lUCR lctus.
Heroin and cocaine art' also associated with an increased
risk ofIUGR, bUI conloundiug variables make determination
01'.1 direct cuusc-und-ettcct rclut iouship difficult. Methadone
Lise has 1101 been shown to be associated with all increased
incidence of I U<..3R.
Phal'l1l.,(()logic agents have been associated with all
increased incidence or IUGR. primarily as a result of terato-
genic effects. Warfarin has been associated with an increased
incidence of IUGR. primarily as a result of the sequelae of
intrauterine hemorrhage. Folic acid antagonists are associ-
ated with an increased risk of spontaneous abortion still-
birth. severe malformations, and IUGR.
IUGR fetuses are more common with maternally admin-
istered immunosuppressive drugs (eg, cyclosporine, azathio-
prine, corticosteroids), but when controlled for the underlying
maternal disease, the medications per se probably have little
effect on fetal growth. Furthermore, ~-blockers are also asso-
ciated with an increased risk of IUGR.

3. Malnutrition and malabsorption-Maternal weight at

birth, prepregnancy weight, and weight gain during preg-
nancy account for 10% of the variance in fetal weight and
increase the risk of delivering an infant <2500 g. Studies
of infants borne by women who were pregnant during the
Siege of Leningrad during World War II showed that daily
intake must be reduced to <1500 kcal/d before a measur-
able effect on birthweight becomes evident. Maternal
malabsorption may predispose to IUGR pregnancy. The
most common clinical situations are inflammatory bowel
disease (ulcerative colitis or regional enteritis), pancreatitis,
and intestinal parasites. Maternal eating disorders such as
bulimia and anorexia are also associated with IUGR.

4. Vascular disease and hypoxemia-Diseases that affect

maternal microvascular perfusion can be associated with
IUGR. These include collagen vascular disease, insulin-
dependent diabetes mellitus associated with rnicrovasculop-
athy, and preeclampsia. Also, chronic maternal hypoxemia
due to pulmonary disease or cyanotic heart disease is associ-
ated with growth restriction.

S. Maternal features-A small woman may have a smaller-

than-normal infant because of reduced growth potential.
These mothers and infants are completely normal and healthy,
but they are constitutionally small because of genetic variation.
The ponderal index (PI) can be used to evaluate whether an
infant is simply constitutionally small Of. is affected by lUGR.
The PI is calculated using the following formula:

PI = [Weight (in g) x lOO!/llength (in cm)p

 , l nlant , afkcted by asymmetric IUCR will have a low PI
(If. they will he long,lightweight infants with a PI below the
1 (lth pcrc(.'l1tik), whereas small normal infants will have a
i1nrmal PI.
Women who were SGA at birth have a 2-fold increase in
risk of lUGR in their offspring.
" Maternal parity exerts a modest effect on birthweight.
hrst-born infants tend to be smaller and more often catego-
rized as IVGR. This effect decreases with successive deliver-
ies and is not seen beyond the third birth.
6. Sex of fetus-At term, female fetuses are an average 5%
(150 g) smaller and 2% (l em) shorter than male fetuses.
Referring to separate norms for male and female fetuses may
increase the power of biometry in assessing IUGR.

Prevention
Because many causes of IVGR are not preventable,
few interventions have proved effective for prevention.
Interventions that have shown benefit include smoking
cessation, antimalarial chemoprophylaxis, and balanced
protein and energy supplementation. Smoking is the single
most common preventable cause of IUGR in infants born
in the United States. As discussed in Maternal Factors,
women who quit smoking at 7 months' gestation have
newborns with higher mean birth weights than do women
who smoke throughout the pregnancy. Women who quit
smoking before 16 weeks' gestation are not at any increased
risk for an IUGR infant. Limited data suggest that balanced
nutritional supplementation improves mean birthweight.
As expected, such supplementation more likely will ben-
efit those with poor nutrition or adolescent pregnancies.
Pregnant women should avoid close contact with individu-
als known to be infected or colonized with rubella virus or
CMV. Nonpregnant women of reproductive age should
be tested for immunity to rubella virus and, if susceptible,
should be immunized prior to conception. Currently no
vaccine exists for CMV.
Women of childbearing age should be tested for immu-
nity to T gondii if this protozoan infection is clinically
suspected. If the woman is immune, her risk of having an
affected infant is remote. However, if she is susceptible, she
should be cautioned to avoid cat feces and uncooked meat.
If the screening immunoglobulin M (lgM) for Toxoplasma
is positive, no action should .be taken based on this res~lt
without confirmation by a regIOnal reference laboratory with
expertise in Toxoplasma testing. .
Therapeutic medications are not a major cause of IUGR
pregnan cy , but benefits and risks should be weig.hed wh.enever
me dirca ti10 ns are prescribed. Any woman
...
of childbearing age
estioned about the possibility of pregnancy before
shou.'Id b ethqurapeutic or . di th lvi
diagnostIC ra tanon to e pe VIS.
recelvmg e GR . .
ental factors IU pregnanCies are not
.
causing
Plac reventable. It has been postulated that low-
generally. ~ d dipyridamole may increase prostacyclin
dose aspIflI1 an
 production in certain patients and thus prevent idiopathic
uteroplacental insufficiency. The role of these agents in
preventing IUGR resulting from placental insufficiency in
at-risk populations is unclear at this time.
Preventive measures for the maternal diseases listed in
Table 16-3 are beyond the scope of this chapter. Treatment
of Inany of these conditions may decrease the likelihood of
IUGR pregnancy. Treatment of hypertension has a positive
effect 011 birthweight, at least in the third trimester. However,
strict bed rest and hospitalization do not seem to have any ~
beneficial effects for patients with a history of hypertension.
Although a complex issue, protein supplements for patients
with significant proteinuria may increase the amount of pro-
tein available for placental transfer. Correction of maternal
anemia (of whatever cause) improves oxygen delivery to the
fetus, thus improving fetal growth. However, routine supple-
ments, such as with iron, have not been shown to be associ- .t
ated with any altered clinical outcomes. ,
Treatment of malabsorption syndrome (of whatever
cause) can be expected to improve nutrient absorption and
subsequent nutrient transfer to the fetus. Inflammatory
bowel disease should be treated if required, but if possible,
pregnancy should be deferred until the disease has been
quiescent for approximately 6 months. Intestinal parasites
should be appropriately treated and negative cultures con-
firmed prior to pregnancy.
 Trisomy 13 occurs in 1 in 5000-10,000 live births. More
than 50% of affected infants have IUGR. Birthweights aver-
age 700-800 g less than those of controls.
Other more rare autosomal chromosome abnormali-
ties, such as ring chromosomes, deletions, and partial
trisomies, are associated with an increased likelihood of
IUGR. Sex chromosome abnormalities may be associated
with lower birthweight. Extra X chromosomes (>2) are
associated with a 200-g to 300-g decrease in birthweight
for each extra X. Turner's syndrome is associated with an
average birthweight of approximately 400 g below average.
Fetuses with mosaic Turner's syndrome are intermediately
affected.
Growth impairment as a result of fetal chromosome
abnormalities usually occurs earlier than impairment caused
by placental abnormalities. However, there is considerable
clinical overlap, so gestational age at the time of diagnosis is
not always of clinical value.
Fetuses with neural tube defects frequently are
IUGR, weighing approximately 250 g less than controls.
Anencephalic fetuses are IUGR, even considering the
absent brain and skull, with average third-trimester birth-
weights of approximately 1000 g less than matched con-
trols. Certain dysmorphic syndromes are associated with
an increased incidence of IUG,R fetuses. Achondroplasia
maybe associated with low birth weight if either parent is
affected but usually is associated with normal birthweight if
a spontaneous mutation is the cause. Osteogenesis imper-
fecta consists of a spectrum of diseases, all of which result
in JUGR fetuses.
Infants born with abdominal wall defects are characteris-
tically lUG R, particularly th?se with gastroschisi~. .
Other autosomal recessive syndromes associated WIth
JUGR include Smith-Lemll-Opitz syndrome, Meckel's
syadro~ Robert's syndrome. Donohue's syndrome, and
2. Congenital infections-(See also Chapter 15, Congenital
Fetal Infectious, for more discussion.) Chronic intrauterine
infection is responsible for 5-100/0 of I UGR pregnancies
(Table 16-3). The 1l10St commonly identified pathoge 1 is
C\1,,)}H galovirus (CMV). Although CMV can be isolated
from 0.5 to _<)6 of all newborns in the United States, clinically
obvious infection at the time of birth affects only 0.2-2 in
1000 live births. Active fetoplacental infection is character.
ized by cytolysis, followed by secondary inflammation, fibre-
sis, and calcification. Only infants with clinically apparent
infection at birth are likely to be IUGR. Signs of congenital
infection are nonspecific but include central nervous system
involvement (eg, microcephaly) chorioretinitis, intracranial
(peri' entricular) calcifications) pneumonitis, hepatospleno-
megaly, and thrombocytopenia.
Congenital rubella infection increases the risk of IUGR.
Infection in the first trimester results in the most severely
ail ted fetuses, primarily as a result of microvascular endo-
thelial damage. Such infants are likely to have structural
cardiovascular and central nervous system defects such as
microcephaly, deafness) glaucoma, and cataracts.
Other viruses implicated in causing IUGR are herpesvi-
ru . v ricella-zo ter virus, influenza virus, and poliovirus,
but the number of such cases is small. As expected by vir-
t ~ of their chronic. indolent nature) protozoan infections
~ . i ted ~ ith I VGR. The most common protozoan,
To rpwm" gOtldi;. usually is acquired by ingestion of
_t.~w me t. Only women with a primary infection are at
ri~ for h ving an affected infant. The average incidence
is 1 in 1000 live births in the United States, but the inci-
«0. - \wies wtdely among locations and social population$.
. A~~atdy 20% of newborns with congenital tOX(:f~ ~~
1.lle will have I GR. Malaria is another protozoan 111tt.'
Don. iated with IUGR.
th ugh ba terial infe tion occur ommonlv in r~·
l\U"cy. and fl'tqUt"ntly art implicated in premature ddt' ~.~
 . . not omm nly ociated . ("hrvfla~
with I R. J •

i.n L......~ L' . ~t·'rllvn.

. '; ':'_' nvm I. lena mono ytogene, is an ~c . and
ijIh~'

. lilfan! ,"",an, aft Uy ill at the time of d~Ia¥('f") 41f)

t

_" ~, en, ,haliu pneumonni nlyocarc.lill her

. '~"~ ,*Ul'ldl and petechiae.
t
B.' aternal Factors
1 umerous maternal disease are associated with suboptimal
eta} growth. Ally woman who ha borne 1 IUGR fetus is t
increased risk for re urrence, with a 2-fold and 4-fold
increased risk for IUGR birth after 1 or 2 IUGR births,
respectively .

1. Hypertension-Hypertension is the most common

maternal complication causing IUGR. Systemic hyperten-
sion results in decreased blood flow through the spiral
arterioles and decreased delivery of oxygen and nutrients to
the placenta and fetus. Hypertension may be associated with
placental infarction.
2. Drugs-Both social drugs and prescribed medications
can affect fetal growth. Alcohol use has long been known to
be associated with impaired fetal growth. Virtually all infants
with fetal alcohol syndrome exhibit signs of growth restriction.
Cigarette smoking is much more common among
women of childbearing age in the United States than is
alcoholism. Smoking causes one-third of IUGR cases and is
the single most preventable cause of IUGR pregnancy in the
. 'United States today. Women who smoke have a 3-fold to
4-fold increase in IUGR infants. Birthweight is reduced by