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Human pregnancy, similar to pregnancy in other polytocous animal species, can be affected by conditions that restrict the normal growth of the fetus. The growth-restricted fetus is at higher risk for perinatal morbidity and mortality, the risk rising with the severity of the restric-tion. This chapter reviews the various causes of fetal growth restriction and considers the methods of antepartum recognition and diagnosis along with clinical management. The term intrauterine growth restric-tion (IUGR), which we fi rst introduced in the third edition of this text, is preferred over intrauterine growth retardation, which frequently connotes mental retardation to the patient.

Defi nitionsAt the beginning of the 20th century all small newborns were thought to be premature, but by the middle of the century the concept of the undernourished neonate arose, and newborns weighing less than 2500 g were then classifi ed by the World Health Organization as low-birth-weight infants. In the 1960s, Lubchenco, Battaglia and colleagues, in a series of classic papers, published detailed graphs of birth weight as a function of gestational age and associated adverse outcomes.1,2 It was then suggested to classify low-birth-weight neonates into three groups2,3:

1. Preterm neonates—newborns delivered before 37 completed weeks of gestation who are of appropriate size for gestational age (AGA)

2. Preterm and growth-restricted neonates—newborns delivered before 37 completed weeks of gestation who are small for gestational age (SGA)

3. Term growth-restricted neonates—newborns delivered after 37 com-pleted weeks of gestation who are SGA. (Not all SGA term neonates are growth restricted; some cases result from the normal distribu-tion of neonatal weight among a normal base population.)

The classifi cation of newborns by birth weight percentile is of prog-nostic signifi cance in that those of lower percentiles are at increased risk for immediate perinatal morbidity and mortality, as well as sub-sequent adult disease.

There is continuing debate as to whether the 10th, 5th, or 3rd birth weight percentile should be used as a cutoff for designation of SGA. The lower the percentile, the higher the risk of poor outcome, but also the greater the chance that a neonate with IUGR and poor outcome will not be detected. The population-based growth curves that tradi-

tionally have been used in the United States defi ne SGA as a birth weight below the 10th percentile for gestational age. However, it has been shown4 that mortality for infants with birth weights between the 10th and 15th percentile are still increased, with an odds ratio approach-ing 2. Conversely, many newborns whose weights are below the 10th percentile are perfectly normal and simply constitutionally small. An alternative approach, which has sound physiologic and epidemiologic rationale, is that of using customized rather than population-based fetal growth curves.5 This concept uses optimal birth weight as the end 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 optimal fetal weight at delivery. A recent large Spanish study6 showed that customized birth weight percentiles more accurately refl ect the potential for adverse outcome. Indeed, newborns considered to be of low birth weight by the general standards, but not by the customized percentiles, did very well. These fi ndings were confi rmed by studies from New Zealand and France.7-9 Customized growth charts can be downloaded at Gestation Network (http://www.gestation.net [accessed February 5, 2008]).

The reliance on only gestational age and birth weight also neglects the issue of body size and length and the clinical observations that 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 below normal (asymmetrically small), and (2) the neonate whose length and weight are both below normal (symmetrically small). Many SGA newborns are merely constitutionally smaller than others and are not at increased risk for either early or remote morbidity and mortality.

One method to evaluate this issue is the ponderal index,10,11 which is calculated from the birth weight (in grams) and the crown-heel length (in centimeters):

Ponderal index = (birth weight)/(crown-heel length)3 × 100

Neonates with a ponderal index of less than the 10th percentile for gestational age are defi ned as growth restricted. In term infants, this index is not signifi cantly affected by differences in race or sex. The disadvantage of this index is the potential error introduced by cubing the crown-heel length. It is not clear whether asymmetric IUGR and symmetric IUGR are two distinct entities or are merely refl ections of the severity of the growth restriction process (excluding chromosomal aberrations and infectious disease).

Chapter 34

Intrauterine Growth RestrictionRobert Resnik, MD, and Robert K. Creasy, MD

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636 CHAPTER 34 Intrauterine Growth Restriction

There is currently no acceptable means, except perhaps by the pon-deral index, to classify a newborn whose weight is more than 2500 g as having IUGR. The newborn who weighs 2800 g at birth may be growth restricted if the mother has had three previous infants weighing more than 3700 g, but the classifi cation systems would place such an infant in the normal growth category.12

Rate of Fetal GrowthDifferent 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 to 97.5th percentile) or between the 10th and 90th percentiles for fi xed gestational ages. The standards most widely used in the United States in the 1960s and 1970s were those developed in Denver, Colorado.1,2 The Denver standards, however, do not refl ect the increase in median birth weight that has occurred over the last 4 decades or the birth weight standards for babies born at sea level. More contemporary standards are available from large geographic regions, such as the state of California, based on data from more than 2 million singleton births between 1970 and 1976.13 Brenner and colleagues14 used data on black and white infants from Cleveland and aborted fetuses from North Carolina. Ott15 studied newborns from St. Louis. Arbuckle and associ-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. national data with that of previous reports (Fig. 34-1) reveals that most of the latter underestimated fetal growth beginning at about 32 weeks. For example, the use of the Colorado1 or California13 databases would have resulted in only 2.8% and 7.1% of births, respectively, being clas-sifi ed as below the 10th percentile compared with the 1991 data. The gender-specifi c 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

at 14 to 15 weeks of gestation to 10 g/day at 20 weeks, and to 30 to 35 g/day at 32 to 34 weeks. The total substrate needs of the fetus are thus relatively small in the fi rst half of pregnancy, after which the rate of weight gain rises precipitously. The mean weight gain peaks at approximately 230 to 285 g/wk at 32 to 34 weeks of gestation, after 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 fi rst trimester and decreases steadily thereafter.

Incidence of Intrauterine Growth RestrictionThe incidence of IUGR varies according to the population under examination, the geographic location, the standard growth curves used as reference, and the percentile chosen to indicate abnormal growth (i.e., the 3rd, 5th, 10th, or 15th).

Approximately one fourth to one third of all infants weighing less than 2500 g at birth have sustained IUGR, and approximately 4% to 8% of all infants born in developed countries and 6% to 30% of those born in developing countries have been classifi ed as growth restricted.18

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22 24 26

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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 College of Obstetricians and Gynecologists.)

TABLE 34-1 10TH PERCENTILE OF BIRTH WEIGHT (g) FOR GESTATIONAL AGE BY GENDER: UNITED STATES, 1991, SINGLE LIVE BIRTHS TO RESIDENT MOTHERS

From Alexander GR, Himes JH, Kaufman RB, et al: A United States

national reference for fetal growth. Obstet Gynecol 87:167, 1996.

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637CHAPTER 34 Intrauterine Growth Restriction

Perinatal Mortality and MorbidityIUGR 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 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 percentile, the fetal and neonatal mortality rates rise as gestation advances if birth weights do not increase.

As depicted in Figure 34-3, Manning showed that perinatal morbid-ity and mortality increase if birth weights are below the 10th percentile, 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 higher mortality rate than female fetuses. The 10% to 30% increase in incidence of minor and major congenital anomalies associated with IUGR accounts for 30% to 60% of the IUGR perinatal deaths (50% of stillbirths and 20% of neonatal deaths).20 Infants with symmetric IUGR are more likely to die in association with anomalous develop-ment or infection. If, however, in the absence of congenital abnormali-ties, chromosomal defects, and infection, neonates with symmetric IUGR are probably not at increased risk of neonatal morbidity.21 The incidence of mortality in the preterm newborn is higher if IUGR is also present.22 The incidence of intrapartum fetal distress with IUGR approximates 25% to 50%.23,24

In addition, IUGR may contribute to perinatal morbidity and mor-tality by leading to both induced and spontaneous preterm births and

the neonatal problems associated with preterm delivery.25 Specifi c 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, are discussed in greater detail in Chapter 59. Lower intelligence quo-tients, increased mental retardation, and cerebral palsy have also been reported.26-28

Etiology of Intrauterine Growth RestrictionIUGR encompasses many different maternal and fetal entities. Some can be detected before birth, whereas others can be found only at autopsy. It is important to discern the cause of IUGR, because in many cases subsequent pregnancies may also be affected.

Genetic FactorsThere has been much interest in determining the relative contributions of factors that produce birth weight variation, namely the maternal and fetal genetic factors and the environment of the fetus. Approxi-mately 40% of total birth weight variation is due to the genetic con-tributions from mother and fetus (approximately half from each), and the other 60% is due to contributions from the fetal environment.29

Although both parents’ genes affect childhood growth and fi nal adult size, the maternal genes have the main infl uence on birth weight. The classic horse-pony cross-breeding experiments by Walton and Hammond demonstrated the important role of the mother.30 Foals of the maternal horse and paternal pony are signifi cantly larger than foals of the maternal pony and paternal horse, and foals of each cross are comparable in size to foals of the pure maternal breed. These results

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Weeks of gestation completed

Multiples

Singletons

150

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0

24 28 32 36 40 44 48

�50

�100

�150

�200

FIGURE 34-2 Median growth rate curves for single and multiple births in California, 1970-1976. (From Williams RL, Creasy RK, Cunningham GC, et al: Fetal growth and perinatal viability in California. Obstet Gynecol 59:624, 1982. Reprinted with permission from the American College of Obstetricians and Gynecologists.)

FIGURE 34-3 Morbidity and mortality in 1560 small-for-gestational-age fetuses. (From Manning FA: Intrauterine growth retardation. In Manning FA: Fetal Medicine: Principles and Practice. Norwalk, CT, Appleton & Lange, 1995, p. 312.)

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clearly demonstrated the widely held thesis of a maternally related constraint on fetal growth.

Similar conclusions of maternal constraint to growth are reached from family studies in humans. Low and high birth weights recur in families with seemingly otherwise normal pregnancies. Sisters of women with IUGR babies tend to have IUGR babies, a trend that is not seen in their brothers’ babies.31 There is also a greater similarity in birth weight between maternal half siblings and full siblings than between paternal half siblings and full siblings. Mothers of IUGR infants were frequently growth restricted at birth themselves.32,33 Although the maternal phenotypic expression—particularly maternal height—may affect fetal growth, the evidence for such an infl uence is not convincing. Social deprivation has also been associated with IUGR, a fi nding not explained by known physiologic or pathologic factors.34

The one defi nite paternal infl uence on fetal growth and size at birth 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 also a suggestion that paternal size at birth can infl uence fetal growth, with birth weights potentially increased by 100 to 175 g.36 Also, the greater the antigenic dissimilarity between the parents, the larger the fetus.

Whether it is genetically determined or not, women who were SGA at birth have double the risk of reduced intrauterine growth in their fetuses.37 In similar fashion, fetuses destined to deliver preterm have a higher incidence of reduced fetal growth.25,38 The role of the genetic constitution of mother or fetus in these observations is not clear.

Specifi c maternal genotypic disorders can cause IUGR, one example being phenylketonuria.39 Infants born to homozygously affected mothers almost always have IUGR, but whether the reason is an abnor-mal amount of metabolite crossing from mother to fetus or an inher-ent problem in the fetus is unknown.

There is a signifi cant association between IUGR and congenital malformations (see later discussion) Such abnormalities can be caused by established chromosomal disorders or by dysmorphic syndromes, such as various forms of dwarfi sm. Some of these malformations are the expression of a specifi c gene abnormality with a known inheritance pattern, whereas others are only presumed to be the result of a gene mutation or an adverse environmental infl uence.

Although in some reports only 2% to 5% of IUGR infants have a chromosomal abnormality, the incidence rises to 20% if IUGR and mental retardation are both present.40 Birth weights in infants with trisomy 13, 18, and 21 are lower than normal,41,42 with the decrease in birth weight being less pronounced in trisomy 21. The frequency dis-tribution of birth weights in infants with trisomy 21 is shifted to the left of the normal curve after 34 weeks of gestation, resulting in gesta-tional ages 1 to 1.5 weeks less than normal, and birth weights and lengths are less than in control infants from 34 weeks until term. This effect is more marked after 37 weeks of gestation, but birth weights are still only approximately 1 standard deviation from mean weight. Birth weights in translocation trisomy 21 are comparable to those in primary trisomy 21. Birth weights of newborns who are mosaic for normal and 21-trisomic cells are lower than normal but higher than those of 21-trisomic infants.29 Newborns with other autosomal abnormalities, such as deletions (chromosomes 4, 5, 13, and 18) and ring chromosome structure alterations, also have had impaired fetal growth.

Although abnormalities of the female (X) and male (Y) sex chro-mosomes are frequently lethal (80% to 95% result in fi rst-trimester spontaneous abortions), they could be a cause of IUGR in a newborn.18,28 Infants with XO sex chromosomes have a lower mean birth weight than control infants (approximately 85% of normal for gestational age)

and are approximately 1.5 cm shorter at birth. Mosaics of 45,X and 46,XX cells are affected to a lesser degree. Although a paucity of reports prevents defi nite conclusions, it appears that the repressive effect on fetal growth is increased with the addition of X chromosomes, each of which results in a 200- to 300-g reduction in birth weight.43

IUGR is associated with numerous other dysmorphic syndromes, particularly those causing abnormal brain development (see Chapters 1 and 17).

The overall contribution that chromosomal and other genetic dis-orders make to human IUGR is estimated to be 5% to 20%. Approxi-mately 25% of fetuses with early-onset fetal growth restriction could have chromosomal abnormalities, and karyotyping via cordocentesis can be considered (see Chapter 17). A genetic basis should be consid-ered strongly if IUGR is encountered in association with neurologic impairment or early polyhydramnios.

Congenital AnomaliesIn a study of more than 13,000 anomalous infants, 22% had IUGR.44 Newborns with cardiac malformations are frequently of low birth weight and length for gestation, with the possible exception of those with tetralogy of Fallot and transposition of the great vessels. The subnormal size of many infants with cardiac anomalies (as low as 50% to 80% of normal weight with septal defects) is associated with a sub-normal number of parenchymal cells in organs such as the spleen, liver, kidneys, adrenals, and pancreas.45 The anencephalic fetus is also usually growth restricted.

Approximately 25% of newborns with a single umbilical artery weigh less than 2500 g at birth, and some of these are born preterm.46 Abnormal umbilical cord insertions into the placenta are also occa-sionally associated with poor fetal growth.47 The presence of cord encirclements around the fetal body is also associated with IUGR.48

Structural malformations, single umbilical artery, and monozygotic twins are relatively rare and probably account for no more than 1% to 2% of all human instances of IUGR.

InfectionInfectious disease is known to cause IUGR, but the number of organ-isms having this effect is poorly defi ned, and the extent of the growth restriction can be variable There is suffi cient evidence for a causal relationship between infectious disease and IUGR for two viruses—rubella and cytomegalovirus,49 and there is evidence for a possible relationship with varicella,50 severe herpes zoster, and human immu-nodefi ciency virus (HIV) infection, although the latter may be com-plicated by other problems associated with HIV (see Chapter 38).

With rubella infection, the incidence of IUGR may be as high as 60%, with infected cells remaining viable for many months.51 There is capillary endothelial damage, hypoplasia, and necrotizing angiopathy in many fetal organs.52 With cytomegalovirus infection, there is cytoly-sis, localized necrosis within various fetal organs, and a decrease in cell number.53

Although there are no bacterial infections known to cause IUGR, histologic chorioamnionitis is strongly associated with symmetric IUGR between 28 and 36 weeks, and with asymmetric IUGR after 36 weeks of gestation.54

Protozoan infections resulting from Toxoplasma gondii, Plasmo-dium sp., or Trypanosoma cruzi (Chagas disease) reportedly can cause IUGR.49

Although the incidence of maternal infections with various organ-isms may be as high as 15%, the incidence of congenital infections is

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estimated to be no more than 5%. It is believed that infectious disease can account for no more than 5% to 10% of human IUGR.

Multiple GestationIt has long been recognized that multiple pregnancies are associated with a high progressive decrease in fetal and placental weight as the number of offspring increases in humans and in various animal species (see Chapter 25).55,56 In both singleton and twin gestations, there is a relationship between total fetal mass and maternal mass. The increase in fetal weight in singleton gestations is linear from approximately 22 to 24 weeks until approximately 32 to 36 weeks of gestation.13,17 During the last weeks of pregnancy, the increase in fetal weight declines, actu-ally becoming negative after 42 weeks in some pregnancies.

If nutrition is adequate in the neonatal period, the slope of the increase in neonatal weight parallels the increase in fetal weight seen before 34 to 38 weeks. The decline in fetal weight increase occurs when the total fetal mass approximates 3000 to 3500 g for either singleton or twin gestations. When growth rate is expressed incrementally, the weekly gain in singletons peaks at approximately 230 to 285 g/wk between 32 and 34 weeks of gestation (see Fig 34-2). In individual twin fetuses, the incremental weekly gain peaks at 160 to 170 g/wk between 28 and 32 weeks of gestation.13 However, recent studies in triplets have indicated that the growth of individual triplets may continue in a linear fashion well beyond a total combined weight of 3500 g.57 Others have reported that before 35 weeks of gestation, triplets grow at about the 30th percentile for singletons, and by 38 weeks the average weight of each triplet is at the 10th percentile.58 Signifi cant birth weight discor-dance also occurs if there is unequal sharing of the placental mass.59 If multifetal reduction is performed, there is an increase in IUGR in the surviving fetuses.60

The decrease in weight of twin fetuses, frequently with mild IUGR, is usually due to decreased cell size; the exception is severe IUGR asso-ciated with monozygosity and vascular anastomoses, wherein cell number also may be decreased.61 These changes in twins are similar to those seen in IUGR secondary to poor uterine perfusion or maternal malnutrition. Twins with mild IUGR have an acceleration of growth after birth, so that their weight equals the median weight of singletons by 1 year of age. This observation supports the thesis that the etiology of poor fetal growth in twin gestations is an inability of the environ-ment to meet fetal needs, rather than an inherent diminished growth capacity of the twin fetus. The example of twin fetuses supports the thesis derived from normal singleton pregnancies that the human fetus is seldom able to express its full potential for growth.

Many components of the environment can limit fetal growth (see later discussions). Twin-to-twin transfusion secondary to vascular anastomoses in monochorionic-monozygotic twins frequently results in IUGR of one twin, usually the donor (see Chapter 25). Maternal complications associated with IUGR occur more frequently with twins, and the incidence of congenital anomalies is almost twice that of sin-gletons, primarily among monozygotic twin gestations. The incidence of IUGR in twins is 15% to 25%16,62; because the incidence of sponta-neous multiple gestations approximates 1%, these pregnancies proba-bly account for less than 3% of all cases of human IUGR. The actual incidence could be closer to 5% because of the increase in multiple gestations secondary to assisted reproductive techniques.

Inadequate Maternal NutritionNumerous animal studies have demonstrated that undernutrition of the mother caused by protein or caloric restriction can affect fetal

growth adversely. However, information from experiments using 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, such animal studies have engendered important concepts.

Winick63 reported that there are three phases of fetal growth: cel-lular hyperplasia, followed by both hyperplasia and hypertrophy, and then predominantly hypertrophy. If there is a decrease in available substrate, the timing of the decrease is refl ected in the type of IUGR observed. If the insult occurs early in pregnancy, the fetus is likely to be born with a decrease in cell number and cell size (such as might be observed with severe chronic maternal undernutrition or an inability to increase uteroplacental blood fl ow during gestation) and to have symmetric IUGR. If the insult occurs late in gestation, such as with twin gestation, the fetus is likely to have a normal cell number but a restriction of cell size (which can be returned to normal with adequate postnatal nutrition) and to have asymmetric IUGR.

The importance of maternal nutrition in fetal growth and birth weight was demonstrated by studies in Russia and Holland, where women suffered inadequate nutrition during World War II. The popu-lation in Leningrad underwent a prolonged period of poor nutrition, during which both preconception nutritional status and gestational nutrition were poor and birth weights were reduced by 400 to 600 g.64 In Holland, a 6-month famine created conditions that permitted evalu-ation of the effect of malnutrition during each of the trimesters of pregnancy in a group of women previously well nourished.65 Birth weights declined by approximately 10%, and placental weights by 15%, only when undernutrition occurred in the third trimester with daily caloric intake of less than 1500 kcal. The difference in severity of the IUGR in these two populations suggests the importance of prepreg-nancy nutritional status, an idea that has been substantiated.18,66 In addition, animal studies indicate that fetal growth, metabolic and endocrine function, as well as placental status and function in late pregnancy, are signifi cantly altered by the periconception maternal nutritional status, an effect independent of fetal size.67 More recent studies have shown that inadequate weight gain in pregnancy (defi ned as <0.27 kg/wk, or <10 kg at 40 weeks, or based on suggested weight gain for body mass indices; see Chapter 10) is associated with an increased risk of IUGR. Weight gain in the second trimester appears to be particularly important.67 Adequate maternal weight gain by 24 to 28 weeks in multiple pregnancies correlates positively with good fetal growth.68

It is still unclear whether it is generalized calorie intake reduction or specifi c substrate limitation (e.g., protein or key mineral restric-tion), or both, that is important in producing IUGR (see Chapter 10). Glucose uptake by the fetus is critical, because there is the suggestion that little glucogenesis occurs in the normal fetus. In the IUGR fetus, the maternal-fetal glucose concentration difference is increased as a function of the severity of the IUGR,69 facilitating glucose transfer across the small placenta. Decreases in zinc content of peripheral blood leukocytes also correlate positively with IUGR,70 and serum zinc con-centrations of less than 60 μg/dL in the third trimester are associated with a fi vefold increase in the incidence of low birth weight.71 Similarly, an association between low serum folate levels and IUGR has been reported.72 Although there have been numerous studies on supplemen-tation, there is no convincing evidence that high protein intake or caloric supplementation has a benefi cial effect on fetal weight. In addi-tion, if a fetus is receiving decreased oxygen delivery as a result of decreased uteroplacental perfusion and has adapted by slowing metab-olism and growth, it may not be advisable to increase substrate deliv-ery. This important issue remains unresolved.

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Another maternal nutrient that is important to fetal growth is oxygen. It is probably a primary determinant of fetal growth. IUGR infants have a decrease in the partial pressure of oxygen and decreased oxygen saturation values in the umbilical vein and artery.73 The median birth weight of infants of women living more than 10,000 feet above sea level is approximately 250 g less than that of infants of women living at sea level.74 Pregnancies complicated by maternal cyanotic heart disease usually result in IUGR, but it is unclear whether abnor-mal maternal hemodynamics or the reduction in oxygen saturation (by approximately 40% in the umbilical vein) accounts for the poor fetal growth.75 The association between hemoglobinopathies and IUGR could be due to decreased blood viscosity or decreased fetal oxygen-ation. Patients with chronic pulmonary disease (e.g., poorly controlled asthma, cystic fi brosis, bronchiectasis) and those with severe kypho-scoliosis may be at increased risk of IUGR.

Environmental ToxinsMaternal cigarette smoking decreases birth weight by approximately 135 to 300 g; the fetus is symmetrically smaller.76,77 If smoking is stopped before the third trimester, its adverse effect on birth weight is reduced.77 More disturbing is the reported dose-response relationship between maternal smoking and a smaller infant head size, specifi cally a circumference of less than 32 cm, as well as a head circumference more than 2 standard deviations below that expected for gestational age.78 The reason why not all women who smoke have IUGR infants could be a function of maternal genetic susceptibility.79

Reduction in birth weight also occurs with maternal alcohol inges-tion of as little as one to two drinks per day.80 Cocaine use in pregnancy similarly decreases birth weight, but there is also a reduction of head circumference that is more pronounced than the reduction in birth weight.81 Use of other drugs, such as the anticonvulsants phenytoin and trimethadione, warfarin, and heroin, has been implicated in IUGR (see Chapter 20).

Placental FactorsAlthough placental size does not necessarily equate with function, our 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 placental weight in both animals and humans. IUGR without other anomalies is usually associated with a small placenta. Chromosomally normal IUGR newborns have a 24% smaller placenta for gestational age.82 A small placenta is not always associated with an IUGR newborn, but a large infant from an otherwise normal pregnancy does not have a small placenta. Placental weight increases throughout normal gesta-tion; with IUGR, the placental weight plateaus after 36 weeks or earlier, and the placenta (after being trimmed of the membranes and cord) weighs less than 350 g.83 As normal gestation advances, there is a greater increase in fetal weight than in placental weight, so there is an increase in the fetal-placental weight ratio in large-for-gestational-age (LGA), AGA, and SGA infants in the last half of gestation. In all three categories, when the fetal-placental weight ratio is greater than 10, there is an increased incidence of depressed newborns; this suggests that it is not only the IUGR fetus that can outgrow the capacity of the placenta to bring about adequate transfer of necessary nutrients.83

Adequate trophoblastic invasion of the uterine decidual bed, and the resultant alteration in uterine blood fl ow, is a vital necessity, not only for the initial establishment and adherence of the pregnancy, but for also the adequate supply of nutrients to the fetus. The trophoblasts

invade the decidua and myometrium to anchor the placenta, and a subpopulation of cytotrophoblasts invades the uterine blood vessels at the implantation site, resulting in extensive remodeling of the vessels.84-87 There is a replacement of endothelium and uterine smooth muscle cells, which leads to a reduction in uterine arterial resistance and an increase in uteroplacental perfusion. Apoptosis plays an integral role in these vascular changes. It has also been suggested that the cytotro-phoblast initiates lymphangiogenesis in the pregnant uterus; this is normally lacking in the nonpregnant state.

A number of reports have revealed that, in many cases of IUGR, particularly in early IUGR, the depth of invasion by the cytotropho-blasts is shallow and the endovascular invasion rudimentary; they have thus confi rmed the early classic work of Brosens and colleagues,88 who described reduced trophoblastic invasion and decreased pregnancy-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 surface area were reduced in the placentas of IUGR newborns. Apop-tosis at the implantation site is increased with IUGR, and this has been suggested to be the mechanism limiting endovascular invasion.86,90,91 The placental vascular endothelial growth factor (VEGF) and placenta growth factor (PIGF) were reduced, and antagonists were increased, in studies of early IUGR confi rmed by Doppler imaging.92 In summary, early abnormal implantation plays a key role in IUGR, but the exact controlling mechanisms behind the impaired placentation remain to be delineated.

The terminal villi are maldeveloped in IUGR pregnancies when absent end-diastolic fl ow is demonstrated, indicating that these mor-phologic changes are associated with increased vascular impedance.93 When end-diastolic fl ow, is absent, there are more occlusive lesions of the intraplacental vasculature than when end-diastolic fl ow is present.94

Information from cordocentesis studies has revealed fetal hypox-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

Abnormal insertions of the cord, placental hemangiomas, abruptio placentae, and placenta previa are also associated with IUGR.98-100

Maternal Vascular DiseaseSubstantial evidence from experimental animal studies suggests that alterations in uteroplacental perfusion affect the growth and status of the placenta as well as the fetus. Ligation of the uterine artery of one horn of the pregnant rat results in IUGR of those fetuses nearest the constriction, and fetal and placental weights in guinea pigs, mice, and rabbits are lowest in the middle of each uterine horn, where arterial perfusion is lowest. Repetitive embolization of the uterine vascular bed during the last quarter of gestation in sheep gives rise to localized hyalinization and fi brinoid changes in the placenta101 and results in a 40% reduction in placental weight and alterations in organ growth patterns similar to those observed in IUGR fetuses from preg-nancies complicated by maternal hypertensive disease. In addition, umbilical blood fl ow is reduced and fetal oxidative metabolism is decreased.101,102

It has been strongly suggested in various studies that uteroplacental blood fl ow is decreased in pregnancies complicated by maternal hyper-tensive disease. Defective trophoblastic invasion of the uterine vascular bed results in relatively intact musculoelastic vessels that resist the normal decrease in uterine vascular resistance.103 Clearance of radioac-tive tracers from the intervillous space is reduced in preeclamptic

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patients.104,105 Because maternal body mass and plasma volume are correlated, reduced plasma volume or prevention of plasma volume expansion could lead to decreased cardiac output and uterine perfu-sion and a resultant decrease in fetal growth.106,107 Alternatively, it may be that abnormal placentation comes fi rst.

The importance of normal trophoblastic invasion leading to normal maternal cardiovascular changes has been indicated by central mater-nal cardiovascular studies. IUGR below the 3rd percentile at 25 to 37 weeks of gestation is associated with reduced maternal systolic func-tion, increased vascular resistance, and probable lack of volume expan-sion in otherwise normotensive patients.108

Uteroplacental fl ow-velocity waveform studies, using Doppler methods in pregnancies complicated by hypertension, have shown a higher incidence of IUGR in pregnancies in which abnormal wave-forms were recorded. These abnormal waveforms are thought to refl ect abnormally increased resistance to blood fl ow.109,110 High-resistance hypertension is associated with a marked decrease in fetal weight com-pared with low-resistance hypertension.111 Increasing uteroplacental resistance, recorded with this methodology, has been positively corre-lated with fetal hypoxemia as determined by cordocentesis in IUGR fetuses.95

As discussed in Chapter 40, there is confl icting evidence as to whether the congenital thrombophilias contribute to the clinical devel-opment of IUGR, with most recent studies suggesting the lack of an association.112-115

There are only fragmentary suggestions relating abnormal ana-tomic uterine vascular anatomy and IUGR. IUGR may occur at a higher frequency if the pregnancy is in a unicornuate uterus; vascular abnormalities are likely but unproven in such cases.116 Patients with two (rather than the usual one) ascending uterine arteries on each side of the uterus also have a higher rate of IUGR.117 However, pregnancy after bilateral ligation of the internal iliac and ovarian arteries, or after 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 levels of exercise (>50% of prepregnancy levels) in middle and late pregnancy result mainly in a symmetric reduction in fetal growth and neonatal fat mass.121 In assessing levels of aerobic activity, neonates born to women in the highest quartile weighed 600 g less than those in the lowest quartile, an effect mainly seen in taller women.122

Clinical maternal vascular disease and the presumed decrease in uteroplacental perfusion can account for at least 25% to 30% of IUGR infants. Undiagnosed decreased perfusion could also be the cause of IUGR in an otherwise normal pregnancy, such as with recurrent idio-pathic fetal growth restriction. A history of a previous low-birth-weight infant is signifi cantly associated with the subsequent birth of an infant with decreased weight, decreased ponderal index, and decreased head circumference.123 This fi nding of symmetric growth restriction is in contrast to the asymmetric IUGR usually seen with maternal vascular disease.

Vascular disease becomes more prevalent with advancing age. In one recent large study, after controlling for confounding variables, the incidence of SGA births was increased more in nulliparous patients than in multiparous patients older than 30 years of age.124

Maternal and Fetal HormonesIn general, there is limited transfer of the various circulating maternal hormones into the fetal compartments (see Chapters 46 through 48).

Although the effects of hypothyroidism or hyperthyroidism on fetal size are not striking, studies in subhuman primates indicate that, when the mother and fetus are athyroid, there is retarded osseous develop-ment and reduced protein synthesis in the fetal brain.125

Maternal diabetes without vascular disease is frequently associated with excessive fetal size (see Chapter 46). Although insulin does not cross the placenta, fetal hyperinsulinemia as well as hyperplasia of the pancreatic islet cells is seen frequently with maternal diabetes. These changes are thought to occur as a result of maternal hyperglycemia, which leads to fetal hyperglycemia and an increased response of the fetal pancreas. Fetal hypoinsulinemia produced experimentally in the rhesus monkey results in IUGR; rarely, infants have been born with severe IUGR and requiring insulin treatment at birth, suggesting hypo-insulinemia in utero.126,127 If nutrient transfer becomes limited owing to placental disease secondary to maternal vascular disease, the fetus of the diabetic mother can sustain IUGR.

Even though human growth hormone is present early in gestation, there is minimal evidence that it regulates fetal weight, although a defi -ciency could retard skeletal growth.128 Convincing evidence is also lacking that adrenal hormones have a role in producing IUGR in humans.

Several small polypeptides with in vitro growth-promoting activity have been purifi ed (e.g., insulin-like growth factor 1 [IGF-1], IGF-2), but the exact role of these peptides and their binding proteins as fetal growth factors and their potential relationship to IUGR are currently not well understood.

Leptin (from Greek leptos, “thin”) is a polypeptide hormone dis-covered in 1994. It has been shown to moderate feeding behavior and adipose stores. It is produced predominantly by adipocytes but can also be produced by the placenta, because neonatal levels fall dramatically after birth.128 Reported concentrations in IUGR have varied, and the exact role that this hormone plays in fetal growth remains to be clarifi ed.

Diagnosis of Intrauterine Growth RestrictionDetermination of CauseAn attempt should be made to determine the cause of fetal aberrant growth before delivery in order to provide appropriate counseling; perform ultrasonographic evaluation for fetal growth velocity, delin-eate anatomy and function; and obtain neonatal consultation.

The various disorders associated with suboptimal fetal growth were addressed earlier in this chapter and are summarized in Table 34-2. Often, the cause is readily apparent. Among patients with signifi cant chronic hypertensive disease, those who take prescribed medications known to be associated with prenatal growth defi ciency, and those whose fetuses have congenital or chromosomal abnormalities, the diagnosis is easily established and management plans can be made. At times, however, the causal factors can be more elusive. For example, growth restriction associated with preeclampsia may antedate the appearance of hypertension or proteinuria by several weeks. In many instances, a careful history, maternal examination, and ultrasound evaluation reveal the etiology.

History and Physical ExaminationClinical diagnosis of IUGR by physical examination alone is inaccu-rate; often, the diagnosis is not made until after delivery. Most clinical

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studies demonstrate that, with the use of physical examination alone, the diagnosis of IUGR is missed or incorrectly made almost half the time. Techniques such as measurement of the symphysis-fundal height are helpful in screening for abnormal fetal growth and documenting continued growth if they are performed repeatedly by the same observer, but they are not sensitive enough for accurate detection of most infants with IUGR.129,130

Despite the inaccuracy of such indicators, fetal assessment and specifi c aspects of the patient’s risk factors increase the clinician’s index of suspicion about suboptimal fetal growth, without which more defi nitive laboratory investigation might not be considered. As discussed earlier, maternal disease entities such as hypertension, in particular severe preeclampsia and chronic hypertension with superimposed preeclampsia, carry a high incidence of IUGR. The diagnosis of a multiple gestation suggests the likelihood of diminished fetal growth relative to gestational age, as well as preterm birth. Addi-tional maternal risk factors include documented rubella or cytomega-lovirus infection, heavy smoking, heroin or cocaine addiction, alcoholism, and poor nutritional status both before conception and during pregnancy combined with inadequate weight gain during pregnancy.

UltrasonographyCurrently, ultrasonographic evaluation of the fetus is the preferred and accepted modality for the diagnosis of inadequate fetal growth. It offers the advantages of reasonably precise estimations of fetal weight, deter-mination of interval fetal growth velocity, and measurement of several fetal dimensions to describe the pattern of growth abnormality. Use of these ultrasound measurements requires accurate knowledge of gesta-tional age. Accordingly, if a patient is known to be at risk for a fetal growth abnormality, the crown-to-rump length should be determined during the fi rst trimester.

Measurements of biparietal diameter, head circumference, abdomi-nal circumferences, and femur length allow the clinician to use accepted formulas to estimate fetal weight and to determine whether a fetal growth aberration represents an asymmetric, symmetric, or mixed

pattern131 (Fig. 34-4). As discussed previously, intrinsic fetal insults occurring early in pregnancy (e.g., infection, exposure to certain drugs or other chemical agents, chromosomal abnormalities, other congeni-tal malformations) are likely to affect fetal growth at a time of develop-ment when cell division is the predominant mechanism of growth. Consequently, musculoskeletal dimensions and organ size may be adversely affected, and a symmetric pattern of aberrant growth is observed. Given this set of circumstances, one might expect to fi nd that the femur length and head circumference are small for a given gesta-tional age, as are the abdominal circumference and overall fetal weight, all of which are characterized as symmetric IUGR. Symmetric IUGR accounts for approximately 20% to 30% of all growth-restricted fetuses.

At the other end of the spectrum, an extrinsic insult occurring later in pregnancy, usually characterized by inadequate fetal nutrition due to placental insuffi ciency, is more likely to result in asymmetric growth restriction. In this type, femur length and head circumference are spared, but abdominal circumference is decreased because of subnor-mal hepatic growth, and there is a paucity of subcutaneous fat. The most common disorders that limit the availability of fetal substrates for metabolism are the hypertensive complications of pregnancy, 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 abdominal circumference is one of the earliest fi ndings in extrinsic or asymmetric IUGR132,133; conversely, the fi nding of an abdominal cir-cumference in the normal range for gestational age markedly decreases the likelihood of IUGR. Frequently, these patterns of growth abnor-mality merge, particularly after long-standing fetal nutritional deprivation.

Distinguishing between symmetric and asymmetric IUGR is also of considerable clinical signifi cance and may provide useful informa-tion for both diagnostic and counseling purposes. For example, a diag-nosis of symmetric IUGR in early pregnancy suggests a poor prognosis when the diagnostic possibilities are considered (e.g., fetal infection, aneuploidy); conversely, asymmetric IUGR observed in the third tri-mester, particularly if it is associated with maternal hypertension or placental dysfunction, usually imparts a more favorable prognosis with careful fetal evaluation, appropriate delivery timing, and skillful neo-natal management.

Considerable attention has been directed at early ultrasound fi nd-ings that may provide for the early prediction of IUGR. In a study of 976 women whose pregnancies were the product of assisted reproduc-tive technologies, the risk of delivering an SGA fetus decreased as a function of increasing crown-rump length in the fi rst trimester.134 This confi rmed previous fi ndings suggesting that suboptimal growth in the fi rst trimester is associated with IUGR.135

Efforts have also been made to correlate Doppler fi ndings in the uterine artery with subsequent pregnancy complications, including IUGR. Utilizing transvaginal color Doppler at 23 weeks’ gestation, Papageorghiou and colleagues observed that increases in the uterine artery pulsatility index and “notching” were associated with subse-quent development of IUGR, although the predictive value was low.136 In a more recent study of uterine artery pulsatility index at 11 to 14 weeks’ gestation, a value greater than the 95th percentile predicted SGA with accuracy in 23% of the cases, and with increased sensitivity if the maternal serum concentration of plasma-associated pregnancy protein A (PAPP-A) was low. However, this parameter did not reach statistical signifi cance.137 The eventual practical role that uterine artery Doppler ultrasound may play in the prediction of IUGR, if any, awaits more extensive evaluation.

TABLE 34-2 DISORDERS AND OTHER FACTORS ASSOCIATED WITH INTRAUTERINE GROWTH RESTRICTION*

Maternal Factors

Hypertensive disease, chronic or preeclampsiaRenal diseaseSevere nutritional defi ciencies (e.g., infl ammatory bowel disease,

markedly inadequate pregnancy weight gain in the underweight woman, malnutrition)

Pregnancy at high altitudeSpecifi c prescribed medications (e.g., antiepileptics)Smoking, alcohol use, illicit drug use

Fetal Factors

Multiple gestationsPlacental abnormalitiesInfectionsAneuploidy or structural abnormalities

*Growth is also strongly infl uenced by maternal prepregnancy weight

and by ethnicity, which must be considered when evaluating overall

growth (by use of customized versus population-based growth

curves).

Ch034-X4224.indd 642 8/26/2008 4:05:17 PM


Fetal Head Circumferencevs.

Gestational Age (Mean � 2 S.D.)

Fetal Head Circumference/AbdominalCircumference Ratio

vs.Gestational Age (Mean � 2 S.D.)

Gestational age (weeks)


12

810121416

Fet

al c

ircum

fere

nce

(cm

)

Abd

omin

al c

ircum

fere

nce

(cm

)

1820222426283032343638

86

40

101214161820222426283032343638

14 16 18 20 22 24 26 28 30 32 34 36 38 40 42


Gestational age (weeks)24

0.4

Wei

ght (

kilo

gram

s)

0.60.81.01.21.41.61.82.02.22.42.62.83.03.23.43.63.84.04.24.44.6

26 28 30 32 34 36 38 40 42

120.6

0.8

1.0

1.2

1.4

H/A

rat

io

1.6

14 16 18 20 22 24 26 28 30 32 34 36 38 40

Gestational age (weeks)14

10

20

30

Fem

ur le

ngth

(m

m)

40

50

60

70

80

90

16 18 20 22 24 26 28 30 32 34 36 38 40

12 14 16 18 20 22 24 26 28 30 32 34 36 38 40

Femur Lengthvs.


Fetal Weightvs.


Fetal Abdominal Circumferencevs.


FIGURE 34-4 Composite of fetal body measurements used for serial evaluations of fetal growth.

Ch034-X4224.indd 643 8/26/2008 4:05:18 PM


Management of PregnancyThe cornerstones of management for the pregnancy complicated by IUGR are surveillance of fetal growth velocity and function (well-being) and determination of appropriate delivery timing. Delivery at or near term is usually indicated if fetal growth has continued to be adequate and antenatal testing results have been normal. Management is far more challenging remote from term and requires use of the bio-physical profi le (BPP), measurement of amniotic fl uid volume (AFV), and Doppler assessment of the fetal circulation, combined with good clinical judgment. The comments in the following sections pertain primarily to the use of antenatal testing in the preterm fetus with IUGR.

Antenatal Fetal TestingThe various diagnostic modalities used for fetal assessment are discussed in detail in Chapter 21, but specifi c points are reemphasized here.

Biophysical Profi le and Amniotic Fluid VolumeThe BPP is appealing, inasmuch as it provides a multidimensional survey of fetal physiologic parameters. In particular, AFV assessment is an important aspect of the BPP, because oligohydramnios is a fre-quent fi nding in the IUGR pregnancy caused by placental insuffi ciency. This is presumably a result of diminished fetal blood volume, renal blood fl ow, and urinary output. Human fetal urinary production rates can be measured with considerable accuracy,138 and three separate studies have shown decreased rates in the presence of fetal growth restriction.139-141

The signifi cance of AFV with respect to fetal outcome has been well documented. Manning and coworkers reported the diagnostic value of AFV measurement in discriminating normal from aberrant fetal growth. Among 91 patients with normal AFV, 86 delivered infants whose birth weights were appropriate for gestational age. In contrast, 26 of 29 patients with decreased AFV delivered growth-restricted infants.142 Severe oligo-hydramnios is associated with a high risk of fetal compromise.143,144

It is likely that the chronic hypoxic state frequently observed in the fetus with IUGR is responsible for diverting blood fl ow from the kidney to other organs that are more critical during fetal life (see Chapters 12 and 14). Nicolaides and associates141 observed reduced fetal urinary fl ow rates in IUGR, and the degree of reduction was well correlated with the degree of fetal hypoxemia as refl ected by fetal blood PO2 measured after cordocentesis.

The most appropriate technique for assessment of AFV, as well as the arguments for and against each technique, are addressed in Chap-ters 21 and 32. It is reasonable to conclude at this time that a single vertical pocket smaller than 2 cm, or an amniotic fl uid index of less than 5 cm, or both, suggests that there is a clinically signifi cant decrease in AFV; conversely, a normal AFV is very reassuring with respect to fetal well-being and also suggests the possibility of a normal but con-stitutionally small fetus.

There is a paucity of evidence from randomized trials to validate the use of the BPP.145 However, its usefulness was suggested by several large observational reports. In a study of 19,221 high-risk pregnancies, Manning and colleagues146 observed that the fetal death rate after a normal BPP score (≥8) was 0.726 in 1000 births; only 14 such fetuses died. Of the total patient population, approximately 4380 pregnancies were complicated by IUGR, and only 4 of those infants died after a normal test, yielding a false-negative test rate of less than 1 in 1000. In

a subsequent analysis of perinatal morbidity and mortality among patients monitored with the BPP, a highly signifi cant inverse correla-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 IUGR. Conversely, if the last test score was 4 or 2, the incidence of IUGR increased to 29% and 41%, respectively.147

Doppler Ultrasound Assessment of the

Fetal VasculatureARTERIAL CIRCULATIONThere has been great interest in the role of Doppler assessment of

the fetal arterial and venous circulation in predicting and evaluating fetal growth restriction as well as other fetal complications (see Chapter 21). It is now clear that umbilical arterial velocimetry is of considerable 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-tance in IUGR. Specifi cally, fetuses demonstrating an absence of end-diastolic fl ow exhibited maldevelopment of the placental terminal villous tree. The correlations among placental pathology, abnormal umbilical artery velocimetry, and IUGR were reviewed by Kingdom and coworkers.148

Several randomized trials have been reported which, taken together, demonstrated a decrease in perinatal deaths when umbilical arterial Doppler assessment was used in conjunction with other types of ante-natal testing.149-151 A meta-analysis of 12 randomized, controlled trials showed that clinical action guided by umbilical Doppler velocimetry reduced the odds of perinatal death by 38% and decreased the risk of inappropriate intervention in pregnancies thought to be at risk of IUGR.152 Although the authors hypothesized that this benefi cial effect depended on the incidence of absent end-diastolic velocity rather than simply decreased fl ow, the number of studies with suffi cient data was inadequate to draw this conclusion. A recent retrospective cohort study of 151 IUGR fetuses comparing abnormal umbilical artery Doppler, a “nonreactive” nonstress test, and a BPP value of 6 or less confi rmed that abnormal Doppler fl ow was the best predictor of adverse outcome.153

Therefore, umbilical artery velocimetry plays a signifi cant role in the management of IUGR. A normal velocimetry result in the suspect small fetus is usually indicative of a constitutionally small but other-wise normal baby,154 although a normal fi nding is also observed in the chromosomally or structurally abnormal fetus.155 Diminished end-diastolic fl ow is rarely associated with signifi cant neonatal morbidity, but the absence or reversal of end-diastolic fl ow predicts signifi cantly increased perinatal morbidity and mortality and long-term poor neu-rologic outcome, compared with continuing diastolic fl ow.156,157 Fur-thermore, markedly diminished end-diastolic fl ow can be observed at very premature gestational ages, well before the BPP demonstrates abnormalities. Consequently, abnormal umbilical velocimetry fi ndings should be interpreted in conjunction with other tests of fetal well-being and in the context of the gestational age.

There also has been interest in the evaluation of middle cerebral artery fl ow, inasmuch as the normal adaptive response to hypoxia within the fetus is to increase cerebral blood fl ow (“brain-sparing”). However, the results from several studies have been contradictory, and the focus of attention has been on umbilical artery fl ow and the venous circulation.

VENOUS CIRCULATIONIn contrast to abnormalities in arterial circulation, abnormalities

observed in the venous circulation presumably refl ect central cardiac

Ch034-X4224.indd 644 8/26/2008 4:05:18 PM


failure, and multiple current studies suggest that specifi c aberrations of fl ow through the ductus venous and umbilical vein are indicative of imminent fetal demise, as well as substantial morbidity among survi-vors. The temporal sequence of Doppler-measured fl ow abnormalities in the arterial and venous circulations of the IUGR fetus has been delineated.158,159 The fetus with severe IUGR fi rst demonstrates changes in the umbilical and middle cerebral arteries. This is followed by altera-tions in the venous circulation, including the ductus venosus (abnor-malities in the atrial portion of the fl ow) and the umbilical vein (pulsatile fl ow). These changes and their pathophysiology have been summarized in detail by Baschat and Harman.160 What has become clear is that abnormal venous Doppler waveforms in the preterm IUGR fetus are indicative of poor acid-base status and outcome.161,162 There-fore, the challenge for the clinician is to try to optimize delivery timing in the very preterm fetus, before signifi cant abnormalities in the venous circulation occur.

Antepartum TherapyMaternal hyperoxia has been shown to increase umbilical PO2 and pH in the hypoxemic, acidotic, growth-restricted fetus.163 Among surviv-ing fetuses, there was also an improvement in mean velocity of blood fl ow through the thoracic aorta. In support of these fi ndings, Battaglia and coworkers treated 17 of 36 women whose pregnancies were com-plicated by IUGR with maternal hyperoxia and confi rmed improve-ment in both blood gases and Doppler fl ow. They also observed a signifi cant improvement in perinatal mortality in the oxygen-treated patients.164 However, the evidence is inconclusive regarding whether chronic maternal oxygen therapy is of value, and any differences reported in outcome could be due to more advanced gestational age in oxygen-treated groups.165

Nutritional supplements, including antioxidants such as vitamins C and E, have not been shown to be effective in reducing the risk of IUGR.166 There has also been considerable interest in the role of fi sh oil supplements, but a Cochrane Database Review of six trials revealed no signifi cant difference in the proportion of SGA infants in treated versus untreated groups.167

The role of low-dose aspirin remains controversial, and most studies have examined subsets of women treated for the prevention of preeclampsia. A meticulous analysis of the current data revealed a 10% reduction in SGA infants, but this strong trend did not achieve statisti-cal signifi cance.168 This subject was recently reviewed by Berghella.169

Timing of DeliveryThe prohibitive perinatal morbidity and mortality rates among IUGR infants were discussed previously. Controversy continues with regard to the timing of delivery for such infants to ensure that neurologic damage or fetal intrauterine death does not occur because of chronic oxygen deprivation. This problem is underscored by the fact that, if deaths among congenitally infected and anomalous infants are excluded, the perinatal risk is still higher for growth-restricted infants 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 continues and antenatal tests are reassuring. Tests of fetal lung matura-tion may be of value if the course of action is not entirely clear. In the case of the preterm fetus, delivery is indicated in the presence of wors-ening maternal hypertensive disease, failure of continuing growth, or reversal of umbilical artery fl ow as assessed by Doppler ultrasound. The preterm fetus (<34 weeks’ gestation) should receive the benefi t of corticosteroids for lung maturation.

The Growth Restriction Intervention Trial (GRIT) study under-scored the diffi culty in selecting the most appropriate delivery time to prevent morbidity.170 In a randomized trial of 548 preterm IUGR preg-nancies (24 to 36 weeks’ gestation) in which fetal compromise was identifi ed but uncertainty regarding delivery persisted, approximately half of the pregnancies were delivered and the other half continued until the clinical course was clear. There was no difference in mortality between the two groups. However, among infants with less than 31 weeks’ gestation, severe disabilities were observed in 13% of the imme-diate deliveries, compared with 5% of those that were delayed.

The overall fi ndings and guidelines for evaluation and management 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.

Ch034-X4224.indd 645 8/26/2008 4:05:18 PM


Intrapartum ManagementIt has long been recognized that lower Apgar scores and meconium aspiration, as well as other manifestations of poor oxygenation during labor, occur with greater frequency among IUGR infants. The problem of intrapartum asphyxia has been further elucidated by studies dem-onstrating the acid-base status of growth-restricted infants at the time of delivery. If moderate-to-severe metabolic acidosis is defi ned as an umbilical artery buffer base value of less than 37 mEq/L (normal, >40 mEq/L), almost 50% of IUGR neonates show signs of acidosis at the time of delivery.171 These fi ndings document the problems of oxy-genation during labor in such fetuses and emphasize that meticulous fetal surveillance is required during this critical period.

Consequently, the clinician should proceed to cesarean delivery if there is evidence of deteriorating fetal status or an unripe cervix or if there is any indication of additional fetal compromise during labor.

Neonatal Complications and Long-term SequelaeThe growth-restricted fetus can experience numerous complications in the neonatal period related to the etiology of the growth insult as well as antepartum and intrapartum factors. These include neonatal asphyxia, meconium aspiration, hypoglycemia and other metabolic abnormalities, and polycythemia (see Chapter 58). After correction for gestational age, a large population-based outcomes analysis showed that the premature IUGR infant is at increased risk of mortality, nec-rotizing enterocolitis, and need for respiratory support at 28 days of age.172 This observation takes on more signifi cance inasmuch as pre-maturity and IUGR frequently coexist.

Beyond the neonatal period, data by Low and colleagues173 showed that fetal growth restriction has a deleterious effect on cognitive func-tion, independent of other variables. With the use of numerous stan-dardized tests to evaluate learning ability, and excluding those children with genetic or major organ system malformations, they found that almost 50% (37/77) of SGA children had learning defi cits at ages 9 to 11 years. Blair and Stanley174 also reported a strong association between IUGR and spastic cerebral palsy in newborns born after 33 weeks of gestation. This association was highest in IUGR infants who were short, thin, and of small head size. Newborns who were at or above the 10th percentile for weight but had abnormal ponderal indices were also at risk for spastic cerebral palsy.175 In a recent Danish autopsy study, investigators observed a signifi cantly lower cell number in the cortex of IUGR fetuses and infants compared with normal controls, a fi nding that may, in part, explain the clinical observations.176 Other investiga-tors have reported more favorable neurologic outcomes in IUGR infants.177,178

There is currently substantial research effort to explore the role of IUGR and adult disease: the so-called “fetal origins of disease” hypoth-esis. This subject is addressed in Chapter 11. The epidemiologic studies of Barker’s group have indicated that IUGR is a signifi cant risk factor for the subsequent development of chronic hypertension, ischemic heart disease, type 2 diabetes, and obstructive lung disease.179 Maternal and fetal malnutrition seem to have both short- and long-term effects. The concept of programming during intrauterine life, however, needs to include a host of other factors, such as the genotype of both mother and fetus, maternal size and obstetric history, and postnatal and life-style factors.

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