1. Chapter 34
Intrauterine Growth Restriction
Robert Resnik, MD, and Robert K. Creasy, MD
Human pregnancy, similar to pregnancy in other polytocous animal tionally have been used in the United States define SGA as a birth
species, can be affected by conditions that restrict the normal growth weight below the 10th percentile for gestational age. However, it has
of the fetus. The growth-restricted fetus is at higher risk for perinatal been shown4 that mortality for infants with birth weights between the
morbidity and mortality, the risk rising with the severity of the restric- 10th and 15th percentile are still increased, with an odds ratio approach-
tion. This chapter reviews the various causes of fetal growth restriction ing 2. Conversely, many newborns whose weights are below the 10th
and considers the methods of antepartum recognition and diagnosis percentile are perfectly normal and simply constitutionally small. An
along with clinical management. The term intrauterine growth restric- alternative approach, which has sound physiologic and epidemiologic
tion (IUGR), which we first introduced in the third edition of this text, rationale, is that of using customized rather than population-based fetal
is preferred over intrauterine growth retardation, which frequently growth curves.5 This concept uses optimal birth weight as the end
connotes mental retardation to the patient. point of a growth curve; it is based on the ability of a fetus to achieve
its growth potential, determined prospectively and independently of
maternal pathology. This approach uses the known variables affecting
fetal weight, such as maternal height, weight, ethnicity, and parity at
the beginning of pregnancy, to calculate fetal weight trajectories and
Definitions optimal fetal weight at delivery. A recent large Spanish study6 showed
that customized birth weight percentiles more accurately reflect the
At the beginning of the 20th century all small newborns were thought potential for adverse outcome. Indeed, newborns considered to be of
to be premature, but by the middle of the century the concept of low birth weight by the general standards, but not by the customized
the undernourished neonate arose, and newborns weighing less than percentiles, did very well. These findings were confirmed by studies
2500 g were then classified by the World Health Organization as low- from New Zealand and France.7-9 Customized growth charts can be
birth-weight infants. In the 1960s, Lubchenco, Battaglia and colleagues, downloaded at Gestation Network (http://www.gestation.net [accessed
in a series of classic papers, published detailed graphs of birth weight February 5, 2008]).
as a function of gestational age and associated adverse outcomes.1,2 It The reliance on only gestational age and birth weight also neglects
was then suggested to classify low-birth-weight neonates into three the issue of body size and length and the clinical observations that
groups2,3: there are two main clinical types of IUGR newborns: (1) the infant
who is of normal length for gestational age but whose birth weight is
1. Preterm neonates—newborns delivered before 37 completed weeks below normal (asymmetrically small), and (2) the neonate whose
of gestation who are of appropriate size for gestational age (AGA) length and weight are both below normal (symmetrically small). Many
2. Preterm and growth-restricted neonates—newborns delivered before SGA newborns are merely constitutionally smaller than others and
37 completed weeks of gestation who are small for gestational age are not at increased risk for either early or remote morbidity and
(SGA) mortality.
3. Term growth-restricted neonates—newborns delivered after 37 com- One method to evaluate this issue is the ponderal index,10,11 which
pleted weeks of gestation who are SGA. (Not all SGA term neonates is calculated from the birth weight (in grams) and the crown-heel
are growth restricted; some cases result from the normal distribu- length (in centimeters):
tion of neonatal weight among a normal base population.)
Ponderal index = (birth weight)/(crown-heel length)3 × 100
The classification of newborns by birth weight percentile is of prog-
nostic significance in that those of lower percentiles are at increased Neonates with a ponderal index of less than the 10th percentile for
risk for immediate perinatal morbidity and mortality, as well as sub- gestational age are defined as growth restricted. In term infants, this
sequent adult disease. index is not significantly affected by differences in race or sex. The
There is continuing debate as to whether the 10th, 5th, or 3rd birth disadvantage of this index is the potential error introduced by cubing
weight percentile should be used as a cutoff for designation of SGA. the crown-heel length. It is not clear whether asymmetric IUGR and
The lower the percentile, the higher the risk of poor outcome, but also symmetric IUGR are two distinct entities or are merely reflections of
the greater the chance that a neonate with IUGR and poor outcome the severity of the growth restriction process (excluding chromosomal
will not be detected. The population-based growth curves that tradi- aberrations and infectious disease).

2. 636 CHAPTER 34 Intrauterine Growth Restriction
There is currently no acceptable means, except perhaps by the pon- at 14 to 15 weeks of gestation to 10 g/day at 20 weeks, and to 30 to
deral index, to classify a newborn whose weight is more than 2500 g 35 g/day at 32 to 34 weeks. The total substrate needs of the fetus are
as having IUGR. The newborn who weighs 2800 g at birth may be thus relatively small in the first half of pregnancy, after which the rate
growth restricted if the mother has had three previous infants weighing of weight gain rises precipitously. The mean weight gain peaks at
more than 3700 g, but the classification systems would place such an approximately 230 to 285 g/wk at 32 to 34 weeks of gestation, after
infant in the normal growth category.12 which it decreases, possibly even reaching zero weight gain, or even
weight loss, at 41 to 42 weeks of gestation (Fig. 34-2).13,17 If growth rate
is expressed as the percentage of increase in weight over the previous
week, however, the percentage of increase reaches a maximum in the
Rate of Fetal Growth first trimester and decreases steadily thereafter.
Different standards for fetal growth throughout gestation have been
reported. These standards set the normal range, on the basis of statisti-
cal considerations, between 2 standard deviations of the mean (2.5th Incidence of Intrauterine
to 97.5th percentile) or between the 10th and 90th percentiles for fixed
gestational ages. The standards most widely used in the United States
Growth Restriction
in the 1960s and 1970s were those developed in Denver, Colorado.1,2 The incidence of IUGR varies according to the population under
The Denver standards, however, do not reflect the increase in median examination, the geographic location, the standard growth curves used
birth weight that has occurred over the last 4 decades or the birth as reference, and the percentile chosen to indicate abnormal growth
weight standards for babies born at sea level. More contemporary (i.e., the 3rd, 5th, 10th, or 15th).
standards are available from large geographic regions, such as the state Approximately one fourth to one third of all infants weighing less
of California, based on data from more than 2 million singleton births than 2500 g at birth have sustained IUGR, and approximately 4% to
between 1970 and 1976.13 Brenner and colleagues14 used data on black 8% of all infants born in developed countries and 6% to 30% of
and white infants from Cleveland and aborted fetuses from North those born in developing countries have been classified as growth
Carolina. Ott15 studied newborns from St. Louis. Arbuckle and associ- restricted.18
ates16 based their study on more than 1 million singleton births and
more than 10,000 twin gestations in Canada between 1986 and 1988,
and Alexander and colleagues17 used information from 3.8 million
births in the United States in 1991. A comparison of their 1991 U.S. TABLE 34-1 10TH PERCENTILE OF BIRTH
national data with that of previous reports (Fig. 34-1) reveals that most WEIGHT (g) FOR GESTATIONAL
of the latter underestimated fetal growth beginning at about 32 weeks.
AGE BY GENDER: UNITED
For example, the use of the Colorado1 or California13 databases would
STATES, 1991, SINGLE LIVE
have resulted in only 2.8% and 7.1% of births, respectively, being clas-
sified as below the 10th percentile compared with the 1991 data. The BIRTHS TO RESIDENT MOTHERS
gender-specific 10th percentile values from 20 to 44 weeks are listed in
Table 34-1.
Data obtained from study of induced abortions and spontaneous
deliveries indicate that the rate of fetal growth increases from 5 g/day
4000
3500
Lubchenco
3000
Birth weight in grams
Brenner
Williams
2500
Ott
2000 U.S. Reference
1500
1000
500
0
20 22 24 26 28 30 32 34 36 38 40 42 44
Gestational age in complete weeks
FIGURE 34-1 Fetal weight as a function of gestational age by
selected references. (From Alexander GR, Himes JH, Kaufman RB,
et al: A United States national reference for fetal growth. Obstet
Gynecol 87:167, 1996. Reprinted with permission from the American From Alexander GR, Himes JH, Kaufman RB, et al: A United States
College of Obstetricians and Gynecologists.) national reference for fetal growth. Obstet Gynecol 87:167, 1996.

3. CHAPTER 34 Intrauterine Growth Restriction 637
300
250
200
Singletons
Birth weight gain per week (g)
150
100
Multiples
50
0
50
100
150
200
24 28 32 36 40 44 48
Weeks of gestation completed
FIGURE 34-3 Morbidity and mortality in 1560 small-for-
FIGURE 34-2 Median growth rate curves for single and multiple gestational-age fetuses. (From Manning FA: Intrauterine growth
births in California, 1970-1976. (From Williams RL, Creasy RK, retardation. In Manning FA: Fetal Medicine: Principles and Practice.
Cunningham GC, et al: Fetal growth and perinatal viability in Norwalk, CT, Appleton & Lange, 1995, p. 312.)
California. Obstet Gynecol 59:624, 1982. Reprinted with permission
from the American College of Obstetricians and Gynecologists.)
the neonatal problems associated with preterm delivery.25 Specific
morbidities are discussed later in this chapter and in Chapter 58.
Long-term sequelae of IUGR , such as various adult diseases includ-
ing chronic hypertension, heart and lung disease, and type 2 diabetes,
Perinatal Mortality are discussed in greater detail in Chapter 59. Lower intelligence quo-
and Morbidity tients, increased mental retardation, and cerebral palsy have also been
reported.26-28
IUGR is associated with an increase in fetal and neonatal mortality
and morbidity rates. Perinatal mortality rates for fetuses and neonates
weighing less than the 10th percentile, but between 1500 and 2500 g,
were 5 to 30 times greater than those of newborns between the 10th Etiology of Intrauterine
and 90th percentiles; for those weighing less than 1500 g, the rates were
70 to 100 times greater.13 In addition, for birth weights below the 10th
Growth Restriction
percentile, the fetal and neonatal mortality rates rise as gestation IUGR encompasses many different maternal and fetal entities. Some
advances if birth weights do not increase. can be detected before birth, whereas others can be found only at
As depicted in Figure 34-3, Manning showed that perinatal morbid- autopsy. It is important to discern the cause of IUGR, because in many
ity and mortality increase if birth weights are below the 10th percentile, cases subsequent pregnancies may also be affected.
and markedly so if below the 6th percentile.19
In general, fetal mortality rates for IUGR fetuses are 50% higher
than neonatal mortality rates, and male fetuses with IUGR have a Genetic Factors
higher mortality rate than female fetuses. The 10% to 30% increase in There has been much interest in determining the relative contributions
incidence of minor and major congenital anomalies associated with of factors that produce birth weight variation, namely the maternal
IUGR accounts for 30% to 60% of the IUGR perinatal deaths (50% of and fetal genetic factors and the environment of the fetus. Approxi-
stillbirths and 20% of neonatal deaths).20 Infants with symmetric mately 40% of total birth weight variation is due to the genetic con-
IUGR are more likely to die in association with anomalous develop- tributions from mother and fetus (approximately half from each), and
ment or infection. If, however, in the absence of congenital abnormali- the other 60% is due to contributions from the fetal environment.29
ties, chromosomal defects, and infection, neonates with symmetric Although both parents’ genes affect childhood growth and final
IUGR are probably not at increased risk of neonatal morbidity.21 The adult size, the maternal genes have the main influence on birth weight.
incidence of mortality in the preterm newborn is higher if IUGR is The classic horse-pony cross-breeding experiments by Walton and
also present.22 The incidence of intrapartum fetal distress with IUGR Hammond demonstrated the important role of the mother.30 Foals of
approximates 25% to 50%.23,24 the maternal horse and paternal pony are significantly larger than foals
In addition, IUGR may contribute to perinatal morbidity and mor- of the maternal pony and paternal horse, and foals of each cross are
tality by leading to both induced and spontaneous preterm births and comparable in size to foals of the pure maternal breed. These results

4. 638 CHAPTER 34 Intrauterine Growth Restriction
clearly demonstrated the widely held thesis of a maternally related and are approximately 1.5 cm shorter at birth. Mosaics of 45,X and
constraint on fetal growth. 46,XX cells are affected to a lesser degree. Although a paucity of reports
Similar conclusions of maternal constraint to growth are reached prevents definite conclusions, it appears that the repressive effect on
from family studies in humans. Low and high birth weights recur in fetal growth is increased with the addition of X chromosomes, each of
families with seemingly otherwise normal pregnancies. Sisters of which results in a 200- to 300-g reduction in birth weight.43
women with IUGR babies tend to have IUGR babies, a trend that is IUGR is associated with numerous other dysmorphic syndromes,
not seen in their brothers’ babies.31 There is also a greater similarity in particularly those causing abnormal brain development (see Chapters
birth weight between maternal half siblings and full siblings than 1 and 17).
between paternal half siblings and full siblings. Mothers of IUGR The overall contribution that chromosomal and other genetic dis-
infants were frequently growth restricted at birth themselves.32,33 orders make to human IUGR is estimated to be 5% to 20%. Approxi-
Although the maternal phenotypic expression—particularly maternal mately 25% of fetuses with early-onset fetal growth restriction could
height—may affect fetal growth, the evidence for such an influence is have chromosomal abnormalities, and karyotyping via cordocentesis
not convincing. Social deprivation has also been associated with IUGR, can be considered (see Chapter 17). A genetic basis should be consid-
a finding not explained by known physiologic or pathologic factors.34 ered strongly if IUGR is encountered in association with neurologic
The one definite paternal influence on fetal growth and size at birth impairment or early polyhydramnios.
is the contribution of a Y chromosome rather than an X chromosome.
The male fetus grows more quickly than the female fetus and weighs
approximately 150 to 200 g more than the female at birth.35 There is Congenital Anomalies
also a suggestion that paternal size at birth can influence fetal growth, In a study of more than 13,000 anomalous infants, 22% had IUGR.44
with birth weights potentially increased by 100 to 175 g.36 Also, the Newborns with cardiac malformations are frequently of low birth
greater the antigenic dissimilarity between the parents, the larger the weight and length for gestation, with the possible exception of those
fetus. with tetralogy of Fallot and transposition of the great vessels. The
Whether it is genetically determined or not, women who were SGA subnormal size of many infants with cardiac anomalies (as low as 50%
at birth have double the risk of reduced intrauterine growth in their to 80% of normal weight with septal defects) is associated with a sub-
fetuses.37 In similar fashion, fetuses destined to deliver preterm have a normal number of parenchymal cells in organs such as the spleen, liver,
higher incidence of reduced fetal growth.25,38 The role of the genetic kidneys, adrenals, and pancreas.45 The anencephalic fetus is also usually
constitution of mother or fetus in these observations is not clear. growth restricted.
Specific maternal genotypic disorders can cause IUGR, one example Approximately 25% of newborns with a single umbilical artery
being phenylketonuria.39 Infants born to homozygously affected weigh less than 2500 g at birth, and some of these are born preterm.46
mothers almost always have IUGR, but whether the reason is an abnor- Abnormal umbilical cord insertions into the placenta are also occa-
mal amount of metabolite crossing from mother to fetus or an inher- sionally associated with poor fetal growth.47 The presence of cord
ent problem in the fetus is unknown. encirclements around the fetal body is also associated with IUGR.48
There is a significant association between IUGR and congenital Structural malformations, single umbilical artery, and monozygotic
malformations (see later discussion) Such abnormalities can be caused twins are relatively rare and probably account for no more than 1% to
by established chromosomal disorders or by dysmorphic syndromes, 2% of all human instances of IUGR.
such as various forms of dwarfism. Some of these malformations are
the expression of a specific gene abnormality with a known inheritance
pattern, whereas others are only presumed to be the result of a gene Infection
mutation or an adverse environmental influence. Infectious disease is known to cause IUGR, but the number of organ-
Although in some reports only 2% to 5% of IUGR infants have a isms having this effect is poorly defined, and the extent of the growth
chromosomal abnormality, the incidence rises to 20% if IUGR and restriction can be variable There is sufficient evidence for a causal
mental retardation are both present.40 Birth weights in infants with relationship between infectious disease and IUGR for two viruses—
trisomy 13, 18, and 21 are lower than normal,41,42 with the decrease in rubella and cytomegalovirus,49 and there is evidence for a possible
birth weight being less pronounced in trisomy 21. The frequency dis- relationship with varicella,50 severe herpes zoster, and human immu-
tribution of birth weights in infants with trisomy 21 is shifted to the nodeficiency virus (HIV) infection, although the latter may be com-
left of the normal curve after 34 weeks of gestation, resulting in gesta- plicated by other problems associated with HIV (see Chapter 38).
tional ages 1 to 1.5 weeks less than normal, and birth weights and With rubella infection, the incidence of IUGR may be as high as
lengths are less than in control infants from 34 weeks until term. This 60%, with infected cells remaining viable for many months.51 There is
effect is more marked after 37 weeks of gestation, but birth weights are capillary endothelial damage, hypoplasia, and necrotizing angiopathy
still only approximately 1 standard deviation from mean weight. Birth in many fetal organs.52 With cytomegalovirus infection, there is cytoly-
weights in translocation trisomy 21 are comparable to those in primary sis, localized necrosis within various fetal organs, and a decrease in cell
trisomy 21. Birth weights of newborns who are mosaic for normal and number.53
21-trisomic cells are lower than normal but higher than those of 21- Although there are no bacterial infections known to cause IUGR,
trisomic infants.29 Newborns with other autosomal abnormalities, such histologic chorioamnionitis is strongly associated with symmetric
as deletions (chromosomes 4, 5, 13, and 18) and ring chromosome IUGR between 28 and 36 weeks, and with asymmetric IUGR after 36
structure alterations, also have had impaired fetal growth. weeks of gestation.54
Although abnormalities of the female (X) and male (Y) sex chro- Protozoan infections resulting from Toxoplasma gondii, Plasmo-
mosomes are frequently lethal (80% to 95% result in first-trimester dium sp., or Trypanosoma cruzi (Chagas disease) reportedly can cause
spontaneous abortions), they could be a cause of IUGR in a newborn.18,28 IUGR.49
Infants with XO sex chromosomes have a lower mean birth weight Although the incidence of maternal infections with various organ-
than control infants (approximately 85% of normal for gestational age) isms may be as high as 15%, the incidence of congenital infections is

5. CHAPTER 34 Intrauterine Growth Restriction 639
estimated to be no more than 5%. It is believed that infectious disease growth adversely. However, information from experiments using
can account for no more than 5% to 10% of human IUGR. small animals, in which the fetomaternal mass is much greater than in
human pregnancy and the fetal and neonatal growth rate reaches its
maximum after birth, must be extrapolated with caution. Nevertheless,
Multiple Gestation such animal studies have engendered important concepts.
It has long been recognized that multiple pregnancies are associated Winick63 reported that there are three phases of fetal growth: cel-
with a high progressive decrease in fetal and placental weight as the lular hyperplasia, followed by both hyperplasia and hypertrophy, and
number of offspring increases in humans and in various animal species then predominantly hypertrophy. If there is a decrease in available
(see Chapter 25).55,56 In both singleton and twin gestations, there is a substrate, the timing of the decrease is reflected in the type of IUGR
relationship between total fetal mass and maternal mass. The increase observed. If the insult occurs early in pregnancy, the fetus is likely to
in fetal weight in singleton gestations is linear from approximately 22 be born with a decrease in cell number and cell size (such as might be
to 24 weeks until approximately 32 to 36 weeks of gestation.13,17 During observed with severe chronic maternal undernutrition or an inability
the last weeks of pregnancy, the increase in fetal weight declines, actu- to increase uteroplacental blood flow during gestation) and to have
ally becoming negative after 42 weeks in some pregnancies. symmetric IUGR. If the insult occurs late in gestation, such as with
If nutrition is adequate in the neonatal period, the slope of the twin gestation, the fetus is likely to have a normal cell number but a
increase in neonatal weight parallels the increase in fetal weight seen restriction of cell size (which can be returned to normal with adequate
before 34 to 38 weeks. The decline in fetal weight increase occurs when postnatal nutrition) and to have asymmetric IUGR.
the total fetal mass approximates 3000 to 3500 g for either singleton The importance of maternal nutrition in fetal growth and birth
or twin gestations. When growth rate is expressed incrementally, the weight was demonstrated by studies in Russia and Holland, where
weekly gain in singletons peaks at approximately 230 to 285 g/wk women suffered inadequate nutrition during World War II. The popu-
between 32 and 34 weeks of gestation (see Fig 34-2). In individual twin lation in Leningrad underwent a prolonged period of poor nutrition,
fetuses, the incremental weekly gain peaks at 160 to 170 g/wk between during which both preconception nutritional status and gestational
28 and 32 weeks of gestation.13 However, recent studies in triplets have nutrition were poor and birth weights were reduced by 400 to 600 g.64
indicated that the growth of individual triplets may continue in a linear In Holland, a 6-month famine created conditions that permitted evalu-
fashion well beyond a total combined weight of 3500 g.57 Others have ation of the effect of malnutrition during each of the trimesters of
reported that before 35 weeks of gestation, triplets grow at about the pregnancy in a group of women previously well nourished.65 Birth
30th percentile for singletons, and by 38 weeks the average weight of weights declined by approximately 10%, and placental weights by 15%,
each triplet is at the 10th percentile.58 Significant birth weight discor- only when undernutrition occurred in the third trimester with daily
dance also occurs if there is unequal sharing of the placental mass.59 If caloric intake of less than 1500 kcal. The difference in severity of the
multifetal reduction is performed, there is an increase in IUGR in the IUGR in these two populations suggests the importance of prepreg-
surviving fetuses.60 nancy nutritional status, an idea that has been substantiated.18,66 In
The decrease in weight of twin fetuses, frequently with mild IUGR, addition, animal studies indicate that fetal growth, metabolic and
is usually due to decreased cell size; the exception is severe IUGR asso- endocrine function, as well as placental status and function in late
ciated with monozygosity and vascular anastomoses, wherein cell pregnancy, are significantly altered by the periconception maternal
number also may be decreased.61 These changes in twins are similar to nutritional status, an effect independent of fetal size.67 More recent
those seen in IUGR secondary to poor uterine perfusion or maternal studies have shown that inadequate weight gain in pregnancy (defined
malnutrition. Twins with mild IUGR have an acceleration of growth as <0.27 kg/wk, or <10 kg at 40 weeks, or based on suggested weight
after birth, so that their weight equals the median weight of singletons gain for body mass indices; see Chapter 10) is associated with an
by 1 year of age. This observation supports the thesis that the etiology increased risk of IUGR. Weight gain in the second trimester appears
of poor fetal growth in twin gestations is an inability of the environ- to be particularly important.67 Adequate maternal weight gain by 24 to
ment to meet fetal needs, rather than an inherent diminished growth 28 weeks in multiple pregnancies correlates positively with good fetal
capacity of the twin fetus. The example of twin fetuses supports the growth.68
thesis derived from normal singleton pregnancies that the human fetus It is still unclear whether it is generalized calorie intake reduction
is seldom able to express its full potential for growth. or specific substrate limitation (e.g., protein or key mineral restric-
Many components of the environment can limit fetal growth (see tion), or both, that is important in producing IUGR (see Chapter 10).
later discussions). Twin-to-twin transfusion secondary to vascular Glucose uptake by the fetus is critical, because there is the suggestion
anastomoses in monochorionic-monozygotic twins frequently results that little glucogenesis occurs in the normal fetus. In the IUGR fetus,
in IUGR of one twin, usually the donor (see Chapter 25). Maternal the maternal-fetal glucose concentration difference is increased as
complications associated with IUGR occur more frequently with twins, a function of the severity of the IUGR,69 facilitating glucose transfer
and the incidence of congenital anomalies is almost twice that of sin- across the small placenta. Decreases in zinc content of peripheral blood
gletons, primarily among monozygotic twin gestations. The incidence leukocytes also correlate positively with IUGR,70 and serum zinc con-
of IUGR in twins is 15% to 25%16,62; because the incidence of sponta- centrations of less than 60 μg/dL in the third trimester are associated
neous multiple gestations approximates 1%, these pregnancies proba- with a fivefold increase in the incidence of low birth weight.71 Similarly,
bly account for less than 3% of all cases of human IUGR. The actual an association between low serum folate levels and IUGR has been
incidence could be closer to 5% because of the increase in multiple reported.72 Although there have been numerous studies on supplemen-
gestations secondary to assisted reproductive techniques. tation, there is no convincing evidence that high protein intake or
caloric supplementation has a beneficial effect on fetal weight. In addi-
tion, if a fetus is receiving decreased oxygen delivery as a result of
Inadequate Maternal Nutrition decreased uteroplacental perfusion and has adapted by slowing metab-
Numerous animal studies have demonstrated that undernutrition of olism and growth, it may not be advisable to increase substrate deliv-
the mother caused by protein or caloric restriction can affect fetal ery. This important issue remains unresolved.

6. 640 CHAPTER 34 Intrauterine Growth Restriction
Another maternal nutrient that is important to fetal growth is invade the decidua and myometrium to anchor the placenta, and a
oxygen. It is probably a primary determinant of fetal growth. IUGR subpopulation of cytotrophoblasts invades the uterine blood vessels at
infants have a decrease in the partial pressure of oxygen and decreased the implantation site, resulting in extensive remodeling of the vessels.84-87
oxygen saturation values in the umbilical vein and artery.73 The median There is a replacement of endothelium and uterine smooth muscle
birth weight of infants of women living more than 10,000 feet above cells, which leads to a reduction in uterine arterial resistance and an
sea level is approximately 250 g less than that of infants of women increase in uteroplacental perfusion. Apoptosis plays an integral role
living at sea level.74 Pregnancies complicated by maternal cyanotic in these vascular changes. It has also been suggested that the cytotro-
heart disease usually result in IUGR, but it is unclear whether abnor- phoblast initiates lymphangiogenesis in the pregnant uterus; this is
mal maternal hemodynamics or the reduction in oxygen saturation (by normally lacking in the nonpregnant state.
approximately 40% in the umbilical vein) accounts for the poor fetal A number of reports have revealed that, in many cases of IUGR,
growth.75 The association between hemoglobinopathies and IUGR particularly in early IUGR, the depth of invasion by the cytotropho-
could be due to decreased blood viscosity or decreased fetal oxygen- blasts is shallow and the endovascular invasion rudimentary; they have
ation. Patients with chronic pulmonary disease (e.g., poorly controlled thus confirmed the early classic work of Brosens and colleagues,88 who
asthma, cystic fibrosis, bronchiectasis) and those with severe kypho- described reduced trophoblastic invasion and decreased pregnancy-
scoliosis may be at increased risk of IUGR. associated alterations in the placental bed of IUGR pregnancies. The
detailed morphologic studies of Aherne and Dunnill89 also demon-
strated that the mean surface area and, more importantly, the capillary
Environmental Toxins surface area were reduced in the placentas of IUGR newborns. Apop-
Maternal cigarette smoking decreases birth weight by approximately tosis at the implantation site is increased with IUGR, and this has been
135 to 300 g; the fetus is symmetrically smaller.76,77 If smoking is suggested to be the mechanism limiting endovascular invasion.86,90,91
stopped before the third trimester, its adverse effect on birth weight is The placental vascular endothelial growth factor (VEGF) and placenta
reduced.77 More disturbing is the reported dose-response relationship growth factor (PIGF) were reduced, and antagonists were increased, in
between maternal smoking and a smaller infant head size, specifically studies of early IUGR confirmed by Doppler imaging.92 In summary,
a circumference of less than 32 cm, as well as a head circumference early abnormal implantation plays a key role in IUGR, but the exact
more than 2 standard deviations below that expected for gestational controlling mechanisms behind the impaired placentation remain to
age.78 The reason why not all women who smoke have IUGR infants be delineated.
could be a function of maternal genetic susceptibility.79 The terminal villi are maldeveloped in IUGR pregnancies when
Reduction in birth weight also occurs with maternal alcohol inges- absent end-diastolic flow is demonstrated, indicating that these mor-
tion of as little as one to two drinks per day.80 Cocaine use in pregnancy phologic changes are associated with increased vascular impedance.93
similarly decreases birth weight, but there is also a reduction of head When end-diastolic flow, is absent, there are more occlusive lesions
circumference that is more pronounced than the reduction in birth of the intraplacental vasculature than when end-diastolic flow is
weight.81 Use of other drugs, such as the anticonvulsants phenytoin present.94
and trimethadione, warfarin, and heroin, has been implicated in IUGR Information from cordocentesis studies has revealed fetal hypox-
(see Chapter 20). emia, hypercapnia, acidosis, and hypoglycemia in severe IUGR.95,96
There is also a decrease in α-aminonitrogen, particularly branched-
chain amino acids, in the plasma of the IUGR fetus.97
Placental Factors Abnormal insertions of the cord, placental hemangiomas, abruptio
Although placental size does not necessarily equate with function, our placentae, and placenta previa are also associated with IUGR.98-100
inability to clinically properly evaluate human placental function has
resulted in studies of the interrelationships of size, morphometry, and
clinical outcome. In general, birth weight increases with increasing Maternal Vascular Disease
placental weight in both animals and humans. IUGR without other Substantial evidence from experimental animal studies suggests that
anomalies is usually associated with a small placenta. Chromosomally alterations in uteroplacental perfusion affect the growth and status of
normal IUGR newborns have a 24% smaller placenta for gestational the placenta as well as the fetus. Ligation of the uterine artery of one
age.82 A small placenta is not always associated with an IUGR newborn, horn of the pregnant rat results in IUGR of those fetuses nearest the
but a large infant from an otherwise normal pregnancy does not have constriction, and fetal and placental weights in guinea pigs, mice, and
a small placenta. Placental weight increases throughout normal gesta- rabbits are lowest in the middle of each uterine horn, where arterial
tion; with IUGR, the placental weight plateaus after 36 weeks or earlier, perfusion is lowest. Repetitive embolization of the uterine vascular bed
and the placenta (after being trimmed of the membranes and cord) during the last quarter of gestation in sheep gives rise to localized
weighs less than 350 g.83 As normal gestation advances, there is a hyalinization and fibrinoid changes in the placenta101 and results
greater increase in fetal weight than in placental weight, so there is an in a 40% reduction in placental weight and alterations in organ
increase in the fetal-placental weight ratio in large-for-gestational-age growth patterns similar to those observed in IUGR fetuses from preg-
(LGA), AGA, and SGA infants in the last half of gestation. In all three nancies complicated by maternal hypertensive disease. In addition,
categories, when the fetal-placental weight ratio is greater than 10, umbilical blood flow is reduced and fetal oxidative metabolism is
there is an increased incidence of depressed newborns; this suggests decreased.101,102
that it is not only the IUGR fetus that can outgrow the capacity of the It has been strongly suggested in various studies that uteroplacental
placenta to bring about adequate transfer of necessary nutrients.83 blood flow is decreased in pregnancies complicated by maternal hyper-
Adequate trophoblastic invasion of the uterine decidual bed, and tensive disease. Defective trophoblastic invasion of the uterine vascular
the resultant alteration in uterine blood flow, is a vital necessity, not bed results in relatively intact musculoelastic vessels that resist the
only for the initial establishment and adherence of the pregnancy, but normal decrease in uterine vascular resistance.103 Clearance of radioac-
for also the adequate supply of nutrients to the fetus. The trophoblasts tive tracers from the intervillous space is reduced in preeclamptic

7. CHAPTER 34 Intrauterine Growth Restriction 641
patients.104,105 Because maternal body mass and plasma volume are Although the effects of hypothyroidism or hyperthyroidism on fetal
correlated, reduced plasma volume or prevention of plasma volume size are not striking, studies in subhuman primates indicate that, when
expansion could lead to decreased cardiac output and uterine perfu- the mother and fetus are athyroid, there is retarded osseous develop-
sion and a resultant decrease in fetal growth.106,107 Alternatively, it may ment and reduced protein synthesis in the fetal brain.125
be that abnormal placentation comes first. Maternal diabetes without vascular disease is frequently associated
The importance of normal trophoblastic invasion leading to normal with excessive fetal size (see Chapter 46). Although insulin does not
maternal cardiovascular changes has been indicated by central mater- cross the placenta, fetal hyperinsulinemia as well as hyperplasia of the
nal cardiovascular studies. IUGR below the 3rd percentile at 25 to 37 pancreatic islet cells is seen frequently with maternal diabetes. These
weeks of gestation is associated with reduced maternal systolic func- changes are thought to occur as a result of maternal hyperglycemia,
tion, increased vascular resistance, and probable lack of volume expan- which leads to fetal hyperglycemia and an increased response of the
sion in otherwise normotensive patients.108 fetal pancreas. Fetal hypoinsulinemia produced experimentally in the
Uteroplacental flow-velocity waveform studies, using Doppler rhesus monkey results in IUGR; rarely, infants have been born with
methods in pregnancies complicated by hypertension, have shown a severe IUGR and requiring insulin treatment at birth, suggesting hypo-
higher incidence of IUGR in pregnancies in which abnormal wave- insulinemia in utero.126,127 If nutrient transfer becomes limited owing
forms were recorded. These abnormal waveforms are thought to reflect to placental disease secondary to maternal vascular disease, the fetus
abnormally increased resistance to blood flow.109,110 High-resistance of the diabetic mother can sustain IUGR.
hypertension is associated with a marked decrease in fetal weight com- Even though human growth hormone is present early in gestation,
pared with low-resistance hypertension.111 Increasing uteroplacental there is minimal evidence that it regulates fetal weight, although a defi-
resistance, recorded with this methodology, has been positively corre- ciency could retard skeletal growth.128 Convincing evidence is also lacking
lated with fetal hypoxemia as determined by cordocentesis in IUGR that adrenal hormones have a role in producing IUGR in humans.
fetuses.95 Several small polypeptides with in vitro growth-promoting activity
As discussed in Chapter 40, there is conflicting evidence as to have been purified (e.g., insulin-like growth factor 1 [IGF-1], IGF-2),
whether the congenital thrombophilias contribute to the clinical devel- but the exact role of these peptides and their binding proteins as fetal
opment of IUGR, with most recent studies suggesting the lack of an growth factors and their potential relationship to IUGR are currently
association.112-115 not well understood.
There are only fragmentary suggestions relating abnormal ana- Leptin (from Greek leptos, “thin”) is a polypeptide hormone dis-
tomic uterine vascular anatomy and IUGR. IUGR may occur at a covered in 1994. It has been shown to moderate feeding behavior and
higher frequency if the pregnancy is in a unicornuate uterus; vascular adipose stores. It is produced predominantly by adipocytes but can also
abnormalities are likely but unproven in such cases.116 Patients with be produced by the placenta, because neonatal levels fall dramatically
two (rather than the usual one) ascending uterine arteries on each side after birth.128 Reported concentrations in IUGR have varied, and the
of the uterus also have a higher rate of IUGR.117 However, pregnancy exact role that this hormone plays in fetal growth remains to be
after bilateral ligation of the internal iliac and ovarian arteries, or after clarified.
embolization of leiomyomata, is not associated with IUGR.118,119
Because exercise can affect uterine perfusion, this subject has been
studied extensively. A moderate regimen of weight-bearing exercise in
early pregnancy probably enhances fetal growth.120 However, high Diagnosis of Intrauterine
levels of exercise (>50% of prepregnancy levels) in middle and late
pregnancy result mainly in a symmetric reduction in fetal growth and Growth Restriction
neonatal fat mass.121 In assessing levels of aerobic activity, neonates
born to women in the highest quartile weighed 600 g less than those Determination of Cause
in the lowest quartile, an effect mainly seen in taller women.122 An attempt should be made to determine the cause of fetal aberrant
Clinical maternal vascular disease and the presumed decrease in growth before delivery in order to provide appropriate counseling;
uteroplacental perfusion can account for at least 25% to 30% of IUGR perform ultrasonographic evaluation for fetal growth velocity, delin-
infants. Undiagnosed decreased perfusion could also be the cause of eate anatomy and function; and obtain neonatal consultation.
IUGR in an otherwise normal pregnancy, such as with recurrent idio- The various disorders associated with suboptimal fetal growth were
pathic fetal growth restriction. A history of a previous low-birth-weight addressed earlier in this chapter and are summarized in Table 34-2.
infant is significantly associated with the subsequent birth of an infant Often, the cause is readily apparent. Among patients with significant
with decreased weight, decreased ponderal index, and decreased head chronic hypertensive disease, those who take prescribed medications
circumference.123 This finding of symmetric growth restriction is in known to be associated with prenatal growth deficiency, and those
contrast to the asymmetric IUGR usually seen with maternal vascular whose fetuses have congenital or chromosomal abnormalities, the
disease. diagnosis is easily established and management plans can be made. At
Vascular disease becomes more prevalent with advancing age. In times, however, the causal factors can be more elusive. For example,
one recent large study, after controlling for confounding variables, the growth restriction associated with preeclampsia may antedate the
incidence of SGA births was increased more in nulliparous patients appearance of hypertension or proteinuria by several weeks. In many
than in multiparous patients older than 30 years of age.124 instances, a careful history, maternal examination, and ultrasound
evaluation reveal the etiology.
Maternal and Fetal Hormones
In general, there is limited transfer of the various circulating History and Physical Examination
maternal hormones into the fetal compartments (see Chapters 46 Clinical diagnosis of IUGR by physical examination alone is inaccu-
through 48). rate; often, the diagnosis is not made until after delivery. Most clinical

8. 642 CHAPTER 34 Intrauterine Growth Restriction
TABLE 34-2 DISORDERS AND OTHER FACTORS pattern131 (Fig. 34-4). As discussed previously, intrinsic fetal insults
ASSOCIATED WITH INTRAUTERINE occurring early in pregnancy (e.g., infection, exposure to certain drugs
or other chemical agents, chromosomal abnormalities, other congeni-
GROWTH RESTRICTION*
tal malformations) are likely to affect fetal growth at a time of develop-
Maternal Factors ment when cell division is the predominant mechanism of growth.
Hypertensive disease, chronic or preeclampsia Consequently, musculoskeletal dimensions and organ size may be
Renal disease adversely affected, and a symmetric pattern of aberrant growth is
Severe nutritional deficiencies (e.g., inflammatory bowel disease, observed. Given this set of circumstances, one might expect to find that
markedly inadequate pregnancy weight gain in the underweight the femur length and head circumference are small for a given gesta-
woman, malnutrition)
tional age, as are the abdominal circumference and overall fetal weight,
Pregnancy at high altitude
Specific prescribed medications (e.g., antiepileptics)
all of which are characterized as symmetric IUGR. Symmetric IUGR
Smoking, alcohol use, illicit drug use accounts for approximately 20% to 30% of all growth-restricted
fetuses.
Fetal Factors At the other end of the spectrum, an extrinsic insult occurring later
Multiple gestations in pregnancy, usually characterized by inadequate fetal nutrition due
Placental abnormalities to placental insufficiency, is more likely to result in asymmetric growth
Infections restriction. In this type, femur length and head circumference are
Aneuploidy or structural abnormalities spared, but abdominal circumference is decreased because of subnor-
*Growth is also strongly influenced by maternal prepregnancy weight
mal hepatic growth, and there is a paucity of subcutaneous fat. The
and by ethnicity, which must be considered when evaluating overall most common disorders that limit the availability of fetal substrates
growth (by use of customized versus population-based growth for metabolism are the hypertensive complications of pregnancy,
curves). which are associated with decreased uteroplacental perfusion, and
placental infarcts, which limit the trophoblastic surface area available
for substrate transfer. In fact, a falloff in the interval growth of the
studies demonstrate that, with the use of physical examination alone, abdominal circumference is one of the earliest findings in extrinsic or
the diagnosis of IUGR is missed or incorrectly made almost half the asymmetric IUGR132,133; conversely, the finding of an abdominal cir-
time. Techniques such as measurement of the symphysis-fundal height cumference in the normal range for gestational age markedly decreases
are helpful in screening for abnormal fetal growth and documenting the likelihood of IUGR. Frequently, these patterns of growth abnor-
continued growth if they are performed repeatedly by the same mality merge, particularly after long-standing fetal nutritional
observer, but they are not sensitive enough for accurate detection of deprivation.
most infants with IUGR.129,130 Distinguishing between symmetric and asymmetric IUGR is also
Despite the inaccuracy of such indicators, fetal assessment and of considerable clinical significance and may provide useful informa-
specific aspects of the patient’s risk factors increase the clinician’s tion for both diagnostic and counseling purposes. For example, a diag-
index of suspicion about suboptimal fetal growth, without which nosis of symmetric IUGR in early pregnancy suggests a poor prognosis
more definitive laboratory investigation might not be considered. when the diagnostic possibilities are considered (e.g., fetal infection,
As discussed earlier, maternal disease entities such as hypertension, aneuploidy); conversely, asymmetric IUGR observed in the third tri-
in particular severe preeclampsia and chronic hypertension with mester, particularly if it is associated with maternal hypertension or
superimposed preeclampsia, carry a high incidence of IUGR. The placental dysfunction, usually imparts a more favorable prognosis with
diagnosis of a multiple gestation suggests the likelihood of diminished careful fetal evaluation, appropriate delivery timing, and skillful neo-
fetal growth relative to gestational age, as well as preterm birth. Addi- natal management.
tional maternal risk factors include documented rubella or cytomega- Considerable attention has been directed at early ultrasound find-
lovirus infection, heavy smoking, heroin or cocaine addiction, ings that may provide for the early prediction of IUGR. In a study of
alcoholism, and poor nutritional status both before conception and 976 women whose pregnancies were the product of assisted reproduc-
during pregnancy combined with inadequate weight gain during tive technologies, the risk of delivering an SGA fetus decreased as a
pregnancy. function of increasing crown-rump length in the first trimester.134 This
confirmed previous findings suggesting that suboptimal growth in the
first trimester is associated with IUGR.135
Ultrasonography Efforts have also been made to correlate Doppler findings in the
Currently, ultrasonographic evaluation of the fetus is the preferred and uterine artery with subsequent pregnancy complications, including
accepted modality for the diagnosis of inadequate fetal growth. It offers IUGR. Utilizing transvaginal color Doppler at 23 weeks’ gestation,
the advantages of reasonably precise estimations of fetal weight, deter- Papageorghiou and colleagues observed that increases in the uterine
mination of interval fetal growth velocity, and measurement of several artery pulsatility index and “notching” were associated with subse-
fetal dimensions to describe the pattern of growth abnormality. Use of quent development of IUGR, although the predictive value was low.136
these ultrasound measurements requires accurate knowledge of gesta- In a more recent study of uterine artery pulsatility index at 11 to 14
tional age. Accordingly, if a patient is known to be at risk for a fetal weeks’ gestation, a value greater than the 95th percentile predicted SGA
growth abnormality, the crown-to-rump length should be determined with accuracy in 23% of the cases, and with increased sensitivity if the
during the first trimester. maternal serum concentration of plasma-associated pregnancy protein
Measurements of biparietal diameter, head circumference, abdomi- A (PAPP-A) was low. However, this parameter did not reach statistical
nal circumferences, and femur length allow the clinician to use accepted significance.137 The eventual practical role that uterine artery Doppler
formulas to estimate fetal weight and to determine whether a fetal ultrasound may play in the prediction of IUGR, if any, awaits more
growth aberration represents an asymmetric, symmetric, or mixed extensive evaluation.

9. CHAPTER 34 Intrauterine Growth Restriction 643
Fetal Head Circumference Fetal Abdominal Circumference
vs. vs.
Gestational Age (Mean 2 S.D.) Gestational Age (Mean 2 S.D.)
38
36
34 40
32 38
30 36
Fetal circumference (cm)
28 34
Abdominal circumference (cm)
26 32
24 30
22 28
20 26
18 24
16 22
14 20
12 18
10 16
8 14
12
12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42
10
Gestational age (weeks) 8
6
Fetal Head Circumference/Abdominal
12 14 16 18 20 22 24 26 28 30 32 34 36 38 40
Circumference Ratio
vs. Gestational age (weeks)
Gestational Age (Mean 2 S.D.)
1.6
Fetal Weight
1.4 vs.
Gestational Age (Mean 2 S.D.)
4.6
H/A ratio
1.2
4.4
4.2
1.0
4.0
3.8
0.8
3.6
3.4
0.6
12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 3.2
Weight (kilograms)
Gestational age (weeks) 3.0
2.8
2.6
Femur Length 2.4
vs. 2.2
Gestational Age (Mean 2 S.D.) 2.0
90
1.8
1.6
80
1.4
1.2
70 1.0
Femur length (mm)
0.8
60 0.6
0.4
50 24 26 28 30 32 34 36 38 40 42
Gestational age (weeks)
40
30
20
10
14 16 18 20 22 24 26 28 30 32 34 36 38 40
Gestational age (weeks)
FIGURE 34-4 Composite of fetal body measurements used for serial evaluations of fetal growth.

10. 644 CHAPTER 34 Intrauterine Growth Restriction
a subsequent analysis of perinatal morbidity and mortality among
patients monitored with the BPP, a highly significant inverse correla-
Management of Pregnancy tion was observed for IUGR and last test score. If the last test score was
8 or higher, only 3.4% of 6500 high-risk patients had infants with
The cornerstones of management for the pregnancy complicated by IUGR. Conversely, if the last test score was 4 or 2, the incidence of
IUGR are surveillance of fetal growth velocity and function (well- IUGR increased to 29% and 41%, respectively.147
being) and determination of appropriate delivery timing. Delivery at
or near term is usually indicated if fetal growth has continued to be Doppler Ultrasound Assessment of the
adequate and antenatal testing results have been normal. Management Fetal Vasculature
is far more challenging remote from term and requires use of the bio- ARTERIAL CIRCULATION
physical profile (BPP), measurement of amniotic fluid volume (AFV), There has been great interest in the role of Doppler assessment of
and Doppler assessment of the fetal circulation, combined with good the fetal arterial and venous circulation in predicting and evaluating
clinical judgment. The comments in the following sections pertain fetal growth restriction as well as other fetal complications (see Chapter
primarily to the use of antenatal testing in the preterm fetus with 21). It is now clear that umbilical arterial velocimetry is of considerable
IUGR. value in predicting perinatal outcome in the fetus with IUGR, and it
is the only modality validated by randomized trials. A substantial
pathologic correlation helps to explain the increased vascular resis-
Antenatal Fetal Testing tance in IUGR. Specifically, fetuses demonstrating an absence of end-
The various diagnostic modalities used for fetal assessment are discussed diastolic flow exhibited maldevelopment of the placental terminal
in detail in Chapter 21, but specific points are reemphasized here. villous tree. The correlations among placental pathology, abnormal
umbilical artery velocimetry, and IUGR were reviewed by Kingdom
Biophysical Profile and Amniotic Fluid Volume and coworkers.148
The BPP is appealing, inasmuch as it provides a multidimensional Several randomized trials have been reported which, taken together,
survey of fetal physiologic parameters. In particular, AFV assessment demonstrated a decrease in perinatal deaths when umbilical arterial
is an important aspect of the BPP, because oligohydramnios is a fre- Doppler assessment was used in conjunction with other types of ante-
quent finding in the IUGR pregnancy caused by placental insufficiency. natal testing.149-151 A meta-analysis of 12 randomized, controlled trials
This is presumably a result of diminished fetal blood volume, renal showed that clinical action guided by umbilical Doppler velocimetry
blood flow, and urinary output. Human fetal urinary production rates reduced the odds of perinatal death by 38% and decreased the risk of
can be measured with considerable accuracy,138 and three separate inappropriate intervention in pregnancies thought to be at risk of
studies have shown decreased rates in the presence of fetal growth IUGR.152 Although the authors hypothesized that this beneficial effect
restriction.139-141 depended on the incidence of absent end-diastolic velocity rather than
The significance of AFV with respect to fetal outcome has been well simply decreased flow, the number of studies with sufficient data was
documented. Manning and coworkers reported the diagnostic value of inadequate to draw this conclusion. A recent retrospective cohort study
AFV measurement in discriminating normal from aberrant fetal growth. of 151 IUGR fetuses comparing abnormal umbilical artery Doppler, a
Among 91 patients with normal AFV, 86 delivered infants whose birth “nonreactive” nonstress test, and a BPP value of 6 or less confirmed
weights were appropriate for gestational age. In contrast, 26 of 29 patients that abnormal Doppler flow was the best predictor of adverse
with decreased AFV delivered growth-restricted infants.142 Severe oligo- outcome.153
hydramnios is associated with a high risk of fetal compromise.143,144 Therefore, umbilical artery velocimetry plays a significant role in
It is likely that the chronic hypoxic state frequently observed in the management of IUGR. A normal velocimetry result in the suspect
the fetus with IUGR is responsible for diverting blood flow from the small fetus is usually indicative of a constitutionally small but other-
kidney to other organs that are more critical during fetal life (see wise normal baby,154 although a normal finding is also observed in the
Chapters 12 and 14). Nicolaides and associates141 observed reduced chromosomally or structurally abnormal fetus.155 Diminished end-
fetal urinary flow rates in IUGR, and the degree of reduction was well diastolic flow is rarely associated with significant neonatal morbidity,
correlated with the degree of fetal hypoxemia as reflected by fetal blood but the absence or reversal of end-diastolic flow predicts significantly
PO2 measured after cordocentesis. increased perinatal morbidity and mortality and long-term poor neu-
The most appropriate technique for assessment of AFV, as well as rologic outcome, compared with continuing diastolic flow.156,157 Fur-
the arguments for and against each technique, are addressed in Chap- thermore, markedly diminished end-diastolic flow can be observed at
ters 21 and 32. It is reasonable to conclude at this time that a single very premature gestational ages, well before the BPP demonstrates
vertical pocket smaller than 2 cm, or an amniotic fluid index of less abnormalities. Consequently, abnormal umbilical velocimetry findings
than 5 cm, or both, suggests that there is a clinically significant decrease should be interpreted in conjunction with other tests of fetal well-
in AFV; conversely, a normal AFV is very reassuring with respect to being and in the context of the gestational age.
fetal well-being and also suggests the possibility of a normal but con- There also has been interest in the evaluation of middle cerebral
stitutionally small fetus. artery flow, inasmuch as the normal adaptive response to hypoxia
There is a paucity of evidence from randomized trials to validate within the fetus is to increase cerebral blood flow (“brain-sparing”).
the use of the BPP.145 However, its usefulness was suggested by several However, the results from several studies have been contradictory, and
large observational reports. In a study of 19,221 high-risk pregnancies, the focus of attention has been on umbilical artery flow and the venous
Manning and colleagues146 observed that the fetal death rate after a circulation.
normal BPP score (≥8) was 0.726 in 1000 births; only 14 such fetuses
died. Of the total patient population, approximately 4380 pregnancies VENOUS CIRCULATION
were complicated by IUGR, and only 4 of those infants died after a In contrast to abnormalities in arterial circulation, abnormalities
normal test, yielding a false-negative test rate of less than 1 in 1000. In observed in the venous circulation presumably reflect central cardiac

11. CHAPTER 34 Intrauterine Growth Restriction 645
failure, and multiple current studies suggest that specific aberrations The role of low-dose aspirin remains controversial, and most
of flow through the ductus venous and umbilical vein are indicative of studies have examined subsets of women treated for the prevention of
imminent fetal demise, as well as substantial morbidity among survi- preeclampsia. A meticulous analysis of the current data revealed a 10%
vors. The temporal sequence of Doppler-measured flow abnormalities reduction in SGA infants, but this strong trend did not achieve statisti-
in the arterial and venous circulations of the IUGR fetus has been cal significance.168 This subject was recently reviewed by Berghella.169
delineated.158,159 The fetus with severe IUGR first demonstrates changes
in the umbilical and middle cerebral arteries. This is followed by altera-
tions in the venous circulation, including the ductus venosus (abnor- Timing of Delivery
malities in the atrial portion of the flow) and the umbilical vein The prohibitive perinatal morbidity and mortality rates among IUGR
(pulsatile flow). These changes and their pathophysiology have been infants were discussed previously. Controversy continues with regard
summarized in detail by Baschat and Harman.160 What has become to the timing of delivery for such infants to ensure that neurologic
clear is that abnormal venous Doppler waveforms in the preterm IUGR damage or fetal intrauterine death does not occur because of chronic
fetus are indicative of poor acid-base status and outcome.161,162 There- oxygen deprivation. This problem is underscored by the fact that,
fore, the challenge for the clinician is to try to optimize delivery timing if deaths among congenitally infected and anomalous infants are
in the very preterm fetus, before significant abnormalities in the venous excluded, the perinatal risk is still higher for growth-restricted infants
circulation occur. than for AGA newborns. Although opinions vary as to the role of
preterm versus term delivery of the IUGR fetus, it is usually prudent
to deliver the growth-restricted infant close to term, as long as growth
Antepartum Therapy continues and antenatal tests are reassuring. Tests of fetal lung matura-
Maternal hyperoxia has been shown to increase umbilical PO2 and pH tion may be of value if the course of action is not entirely clear. In the
in the hypoxemic, acidotic, growth-restricted fetus.163 Among surviv- case of the preterm fetus, delivery is indicated in the presence of wors-
ing fetuses, there was also an improvement in mean velocity of blood ening maternal hypertensive disease, failure of continuing growth, or
flow through the thoracic aorta. In support of these findings, Battaglia reversal of umbilical artery flow as assessed by Doppler ultrasound.
and coworkers treated 17 of 36 women whose pregnancies were com- The preterm fetus (<34 weeks’ gestation) should receive the benefit of
plicated by IUGR with maternal hyperoxia and confirmed improve- corticosteroids for lung maturation.
ment in both blood gases and Doppler flow. They also observed a The Growth Restriction Intervention Trial (GRIT) study under-
significant improvement in perinatal mortality in the oxygen-treated scored the difficulty in selecting the most appropriate delivery time to
patients.164 However, the evidence is inconclusive regarding whether prevent morbidity.170 In a randomized trial of 548 preterm IUGR preg-
chronic maternal oxygen therapy is of value, and any differences nancies (24 to 36 weeks’ gestation) in which fetal compromise was
reported in outcome could be due to more advanced gestational age identified but uncertainty regarding delivery persisted, approximately
in oxygen-treated groups.165 half of the pregnancies were delivered and the other half continued
Nutritional supplements, including antioxidants such as vitamins until the clinical course was clear. There was no difference in mortality
C and E, have not been shown to be effective in reducing the risk of between the two groups. However, among infants with less than 31
IUGR.166 There has also been considerable interest in the role of fish weeks’ gestation, severe disabilities were observed in 13% of the imme-
oil supplements, but a Cochrane Database Review of six trials revealed diate deliveries, compared with 5% of those that were delayed.
no significant difference in the proportion of SGA infants in treated The overall findings and guidelines for evaluation and management
versus untreated groups.167 of the fetus with IUGR are summarized in Table 34-3.
TABLE 34-3 EVALUATION AND MANAGEMENT OF THE FETUS WITH INTRAUTERINE GROWTH
RESTRICTION
From Resnik R: Intrauterine growth restriction. Obstet Gynecol 99:490, 2002.

12. 646 CHAPTER 34 Intrauterine Growth Restriction
Intrapartum Management References
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