Intrauterine Growth Restriction and the Small for Gestational Age Infant
Paul J. Rozance
Laura D. Brown
Stephanie R. Thorn
Marianne Sollosy Anderson
William W. Hay Jr.
▪ INTRODUCTION
The interest in studying intrauterine growth restriction (IUGR) that produces small for gestational age (SGA) infants began with the observation that newborn infants who were classified according to birth weight as small, average, or large for gestational age (SGA, AGA, and LGA, respectively) showed specific morbidities and rates of death that were unique to each of these birth weight-gestational age classifications (1). IUGR/SGA infants were recognized as having more frequent problems with perinatal depression (“asphyxia”), hypothermia, hypoglycemia, polycythemia, long-term deficits in growth, neurodevelopmental handicaps, and higher rates of fetal and neonatal mortality (Fig. 23.1). In addition, epidemiologic studies have consistently shown strong associations between IUGR/SGA birth and increased risk of developing heart disease, diabetes, and obesity later in life (2). Although there have been tremendous improvements in perinatal diagnosis and treatment, severe IUGR and the birth of markedly SGA infants continue to be frequent problems, and the perinatal morbidity and mortality rates of IUGR fetuses and SGA infants continue to exceed those of normal fetuses and infants.
▪ DEFINITIONS
Small for Gestational Age
SGA infants are defined as having a birth weight that is more than two standard deviations below the mean or less than the 10th percentile of a population-specific birth weight versus gestational age plot. Broader definitions include less than normal anthropometric indices, such as length and head circumference, and marked differences between growth parameters, even when they are within the normal range. For example, an infant can be considered “relatively” SGA when its weight is at the 25th percentile, but its length and head circumference are at the 75th percentile. In this case, the weight/length ratio (or the ponderal index = [weight (g)]/[length (cm)]3) is less than normal, indicating that growth rates of internal organs, adipose tissue, and skeletal muscle, the principal determinants of weight, were less than normal.
Intrauterine Growth Restriction
IUGR is defined as a rate of fetal growth that is less than normal for the population and for the growth potential of a specific infant. IUGR therefore produces infants who are SGA, but also infants who are AGA who experienced reduced fetal growth rates in utero. SGA infants can be the result of normal but slower than average rates of fetal growth, such as those constitutionally small (1). Thus, small size at birth can be either a normal outcome or one that is a result of intrinsic or extrinsic factors that limit fetal growth potential. This distinction is important, because diagnosis by antenatal findings of IUGR such as Doppler velocimetry and fetal heart rate abnormalities are more predictive of need for hospitalization and mortality than is classification of SGA or AGA according to standard neonatal growth curves (1).
Birth Weight Classification of Growth
Many terms are used to describe variations in fetal growth (see Table 23.1 for the standard classification of fetal growth). Classification by weight alone says little about fetal growth rate, however, as most infants with less than normal birth weights are the result of a shorter than normal gestation, that is, they are preterm. Similarly, classifying newborns as preterm or term on the basis of birth weight is erroneous, as infants with IUGR are smaller than normal at any gestational age.
Normal Variations and the Assessment of Fetal Growth
Normal fetal growth varies almost twofold. For example, mean birth weight for neonates born in New Guinea is 2,400 g, whereas normal birth weights in other populations can exceed 4,000 g. Such variations are related to genetic and environmental factors, including local diets. Birth weight does not always represent differences in body composition, either, as intrauterine growth patterns contribute to the relative balance of fat versus lean mass. For example, infants born in India compared to infants born in the United Kingdom are lighter, shorter, and thinner, but have similar subscapular skin fold thicknesses, indicating smaller muscle mass but preserved fat mass (3). These and other normal anthropometric variations must be considered in relation to the diagnosis of IUGR in fetuses and SGA status of newborns.
Symmetric and Asymmetric Growth Restriction
SGA infants have been classified as having symmetric or asymmetric IUGR (Figs. 23.2 and 23.3). Symmetric IUGR implies that both brain and body growth are limited relatively equally. Asymmetric growth indicates that body growth is restricted to a much greater extent than head (and thus, brain) growth (1). In asymmetric cases, brain growth is considered “spared.” Even though brain growth is spared relative to overall fetal growth, head circumference is frequently below the 10th percentile for gestational age (4), and there is reduced brain volume (5). The heart also is larger for body weight and “spared” in these infants, whereas the liver and thymus are smaller for body weight.
Mechanisms that allow brain growth to continue at a faster rate than peripheral tissues are not completely known. Contributing factors may include an increased rate of cerebral blood flow relative to the umbilical and systemic circulations (6). In some experimental models, cerebral glucose transporter concentrations are preserved despite fetal hypoglycemia, supporting cerebral glucose uptake capacity (7).
In general, factors intrinsic to the fetus cause symmetric growth restriction, whereas external factors cause asymmetric growth. Intrinsic factors that limit the growth of both the fetal brain and body include chromosomal anomalies (e.g., particularly trisomy conditions), congenital infections (toxoplasmosis, rubella, cytomegalovirus), dwarf syndromes, some inborn errors of metabolism, and some drugs. Due to their intrinsic nature, patterns of symmetric growth restriction develop early during fetal life.
Asymmetric growth restriction classically develops during the late second and third trimesters. This is due to reductions in energy substrate supply to the fetus, limiting fat and glycogen storage and the growth of skeletal muscle, but allowing for continued bone and brain growth. Indeed, extremely preterm neonates are often SGA and have asymmetric growth, probably reflecting common underlying pathology, like placental insufficiency, that produced growth restriction and preterm birth. More extreme limitations of nutrients for longer periods affect both growth and energy storage, producing reductions in length and head circumference as well as body weight and soft tissue mass. Timing is important; with decreased nutrient supply early in gestation,
growth of all body organs is restricted, whereas decreased fetal nutrient supply later in gestation primarily restricts growth of adipose tissue and skeletal muscle.
growth of all body organs is restricted, whereas decreased fetal nutrient supply later in gestation primarily restricts growth of adipose tissue and skeletal muscle.
 FIGURE 23.1 Morbidities specific to SGA infants. Adapted from Lubchenco LO. The high risk infant. In: Schaffer AJ, Markowitz M, eds. Major problems in clinical pediatrics, Vol. XIV. Philadelphia, PA: WB Saunders, 1976:6. |
▪ INTERPRETATION OF FETAL GROWTH CURVES
Growth Curves Based on Neonatal Measurements
Cross-sectional growth curves have been developed from anthropometric data in populations of infants born at different gestational ages (8,9). Such curves have been used to demonstrate whether an infant’s weight is within the normal range for a given gestational age and thus to estimate whether that infant’s in utero growth was greater or less than normal.
Each curve is based on populations with variable composition of maternal age, parity, socioeconomic status, race, ethnic background, body size, degree of obesity or thinness, health, pregnancy-related problems, and nutrition. Estimating gestational age, in particular, has considerable error. Such error is derived from variability in dating conception because of maternal postimplantation bleeding and irregular menses, wide variability in the development of physical features of maturation in the infant, and interobserver variability in assessing an infant’s developmental stage.
TABLE 23.1 Classification of Fetal Growth | ||||||||
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While the growth curves shown in Figure 23.2 from Lubchenco et al. (10) in Denver, Colorado, published in 1966 are biased to slightly lower birth weights compared with many other growth curves, they are unique in showing the weight/length ratio. This ratio is important for demonstrating failure of weight gain relative to length and head circumference growth as evidence of undernutrition, while an increased ratio would be strong evidence for excessive caloric intake, an increasing problem today in populations with greater frequency of obesity and diabetes among pregnant women. Growth curves similar to those from the original studies by Lubchenco et al. (10) have been produced at sea level among similar socioeconomic and racial groups. Several of these are shown in Figure 23.4, along with the updated Fenton Growth Curve that was derived from six developed countries. Regardless of the population studied or growth curves derived, the key feature that is common in all is the rapid rate of fetal growth from the onset of postnatal viability around 24 weeks of gestation through term.
Growth Curves Based on Fetal Measurements
Fetal growth curves also have been developed from serial ultrasound measurements of fetuses that subsequently were born at term in healthy condition and with normal anthropometric measurements, providing continuous rather than cross-sectional indices of fetal growth. These curves correlate better with the expected rate of normal fetal growth than do cross-sectional, population-based growth curves of infants born at different gestational ages, since the intrauterine growth of those infants was likely affected by the same pathologic factors that led to their preterm birth. Thus, there probably is no ideal fetal growth curve derived from postbirth, cross-sectional measurements. Serial ultrasound measurements of fetal growth also more accurately determine how environmental factors, such as acute, severe maternal illness and undernutrition, can inhibit fetal growth and how improved nutrition can rescue such acute growth restriction. Future growth curves to assess in utero growth of a specific newborn should be based on more thoroughly and accurately determined fetal growth parameters from ultrasound measurements in pregnancies with definitely known dates of conception and birth at term of normally grown and developed infants.
▪ INTRAUTERINE GROWTH RESTRICTION AND PRETERM BIRTH
In cases of severe IUGR, the pathophysiologic processes causing the IUGR also can lead to preterm labor and preterm delivery. Thus, IUGR frequently occurs with a variety of maternal conditions that are associated with preterm delivery (Table 23.2).
Insufficient endometrial surface area for placental invasion and growth, plus abnormal placental perfusion, may combine to restrict nutrient delivery to the fetus, leading to IUGR. Poor placental growth and function limit placental supply of growth-promoting hormones to the fetus, for example, human placental lactogen (hPL), steroid hormones, and insulin-like growth factor-I (IGF-I) (11,12), and limit effective maternal-fetal nutrient exchange. IUGR sometimes occurs in conditions such as fetal infection, anemia, cardiac failure, and neuromuscular disorders. Intrauterine fetal infections can limit fetal growth by damaging the fetal brain and the neuroendocrine axis that support fetal growth via insulin-like growth factors (IGFs) and insulin. Intrauterine infections also can damage the fetal heart, leading to diminished cardiac output, poor placental
perfusion, and inadequate nutrient substrate uptake. Preeclamptic women have poor endometrial vascular support for growth of the placenta, leading to placental growth failure, fetal nutrient deficit, and IUGR (13). Fetal hypoglycemia, hypoxemia, and acidosis usually are present in such cases of poor placental development and perfusion. These factors lead to increased production of prostaglandins and the activation of labor-promoting cytokines, leading to preterm delivery (14). Women at the age limits of childbearing produce IUGR infants who often are born prematurely. Nutritional, uterine, and vascular mechanisms may be common in these situations. Young, still-growing adolescent girls appear less capable of mobilizing fat reserves in late pregnancy, apparently reserving them instead for their own continued development (15). IUGR in cases of maternal smoking and substance abuse may result from reduced placental blood flow, inhibition of uteroplacental vascular development, or direct fetal toxicity.
perfusion, and inadequate nutrient substrate uptake. Preeclamptic women have poor endometrial vascular support for growth of the placenta, leading to placental growth failure, fetal nutrient deficit, and IUGR (13). Fetal hypoglycemia, hypoxemia, and acidosis usually are present in such cases of poor placental development and perfusion. These factors lead to increased production of prostaglandins and the activation of labor-promoting cytokines, leading to preterm delivery (14). Women at the age limits of childbearing produce IUGR infants who often are born prematurely. Nutritional, uterine, and vascular mechanisms may be common in these situations. Young, still-growing adolescent girls appear less capable of mobilizing fat reserves in late pregnancy, apparently reserving them instead for their own continued development (15). IUGR in cases of maternal smoking and substance abuse may result from reduced placental blood flow, inhibition of uteroplacental vascular development, or direct fetal toxicity.
 FIGURE 23.2 Intrauterine growth charts with symbols that define the anthropometric measurements for the three infants shown in Figure 23.3. (○) Preterm infant at 34 weeks of gestation, showing asymmetry of weight (15th percentile) versus length and head circumference (75th percentile), producing a weight-to-length ratio less than 10th percentile; (•) severely but symmetrically SGA infant at 39 weeks, showing weight, length, and head circumference all about equally and markedly less than 10th percentile; and (□) symmetric AGA infant at 40 weeks, showing weight, length, head circumference, and weight-to-length ratio about the 65th to 75th percentile. Growth charts adapted from Lubchenco LO, Hansman C, Boyd E. Intrauterine growth in length and head circumference as estimated from live births at gestational ages from 26 to 42 weeks. Pediatrics 1966;37:403. |
Iatrogenic preterm delivery is performed in the context of suspected fetal acidosis and heart rate abnormalities in severely affected IUGR pregnancies. Many of these cases are delivered preterm to protect the mother from eclampsia. Doppler assessment of the umbilical artery is the recommended method of fetal surveillance once an IUGR pregnancy is suspected (see also Chapter 12). During conditions of placental insufficiency, blood flow in the umbilical artery decreases during diastole, progressing from increased pulsatility of blood flow, to absent blood flow, and then reversed blood flow (see Fig. 12.17). Doppler velocimetry
abnormalities have been shown to develop in a sequential fashion as placental insufficiency progressively worsens, and may predict risk of acidosis and perinatal mortality as well as help to predict optimal timing of delivery (16).
abnormalities have been shown to develop in a sequential fashion as placental insufficiency progressively worsens, and may predict risk of acidosis and perinatal mortality as well as help to predict optimal timing of delivery (16).
 FIGURE 23.3 Preterm, SGA infant at 34 weeks of gestation (left), severely SGA infant at 39 weeks (middle), and AGA infant at 40 weeks (right). |
 FIGURE 23.4 Mean birth weights by gestational age from six early sources. Adapted from Naeye R, Dixon J. Distortions in fetal growth standards. Pediatr Res 1978;12:987 and from the most recent Fenton growth chart for preterm infants for boys and girls in Fenton TR, Kim JH. A systematic review and meta-analysis to revise the Fenton growth chart for preterm infants. BMC Pediatr 2013;13:59. |
TABLE 23.2 Maternal Conditions Associated with Intrauterine Growth Restriction and Preterm Delivery | ||||||||||||||||
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▪ GROWTH OF BODY COMPONENTS IN THE FETUS
Water and Minerals in IUGR, Small for Gestational Age Infants
Fetal body water content, expressed as a fraction of body weight, decreases over gestation as a result of relative increases in protein and mineral accretion and the development of relatively large amounts of adipose tissue in the third trimester (17). Thus, fetuses with marked IUGR and SGA neonates who have decreased body fat content have slightly higher fractional contents of body water. Measurements of extracellular space in SGA infants usually are normal for gestational age, as adipose tissue, skeletal muscle, and mineral accretion all are decreased to about the same extent (18).
Fetal calcium content in SGA and AGA fetuses increases exponentially with a linear increase in length, because bone density, area, and circumference increase exponentially in relation to linear growth. Accretion of other minerals varies more directly with body weight and according to the distribution of the minerals into extracellular (e.g., sodium) or intracellular (e.g., potassium) spaces.
Nitrogen and Protein Accretion in IUGR, Small for Gestational Age Infants
Among SGA infants, nitrogen and protein contents are reduced for body weight, primarily as a result of deficient production of muscle mass. Skeletal muscle growth is particularly vulnerable because blood flow and nutrient supplies are preferentially shunted to vital organs in response to decreasing fetal oxygenation (19). In fact, skeletal muscle mass as well as fat mass are reduced in the IUGR fetus during late gestation when compared to AGA controls (20,21). Findings of reduced muscularity extend into the neonatal period as well as into childhood (22).
Glycogen Content in IUGR, Small for Gestational Age Infants
Many tissues in the fetus, including brain, liver, lung, heart, and skeletal muscle, produce glycogen over the second half of gestation. Liver glycogen content, which increases with gestation, is the most important store of carbohydrate for systemic glucose needs, because only the liver contains sufficient glucose-6-phosphatase for release of glucose into the circulation. Skeletal muscle glycogen content increases during late gestation and forms a ready source of glucose for glycolysis within the myocytes. Lung glycogen content decreases in late gestation with change in cell type, leading to loss of glycogen-containing alveolar epithelium, development of type II pneumocytes, and onset of surfactant production. Cardiac glycogen concentration decreases with gestation, owing to cellular hypertrophy, but cardiac glycogen appears essential for postnatal cardiac energy metabolism and contractile function.
Hepatic glycogen content in IUGR fetal sheep is similar or even increased compared to normal late-gestation fetal sheep (23). Human AGA and SGA infants have similar rates of glycogenolysis, suggesting similar hepatic glycogen stores (24). Previous estimates of lower glycogen content in such infants probably reflected studies done postnatally in preterm infants receiving intravenous nutrition with or without very limited enteral nutrition. In preterm infants, IUGR/SGA or not, gluconeogenesis accounts for nearly 70% of total glucose production rates, indicating a lesser role for glycogenolysis, which may reflect lower available hepatic glycogen stores after birth and in response to insufficient early postnatal nutrition.
Decreased Fat Content in Adipose Tissue in IUGR, Small for Gestational Age Infants
At term, fetal fat content, expressed as a fraction of fetal weight, varies markedly among species. The fat content of the newborn of almost all land mammals at term is 1% to 3%, which is considerably less than the 15% to 20% fat content of human term infants. Between 26 and 30 weeks of gestation, nonfat and fat components contribute equally to the carbon content of the fetal body (25). After that period, fat accumulation exceeds that of the nonfat components. By term, the deposition of fat accounts for more than 90% of the carbon accumulated by the fetus.
Human infants born IUGR have lower total body fat contents than AGA infants, often less than 10% of body weight (26). In these cases, the smaller placenta limits fetal fatty acid and triglyceride supply. Similarly, the smaller placenta decreases fetal glucose supply, which reduces glycerol production and triglyceride synthesis. Decreased production of insulin and lower plasma insulin concentrations in IUGR/SGA infants, a result of decreased glucose and amino acid supply to the fetus, also limit lipid synthesis and peripheral lipoprotein lipase activity, which is necessary to release fatty acids from circulating lipoproteins for adipocyte uptake and triglyceride synthesis. As a result of decreased insulin and decreased adipose tissue mass, IUGR/SGA fetuses and infants also have decreased leptin and other adipocytokine concentrations, which may underlie mechanisms for increased adiposity later in life (27).
Caloric Accretion Deficiency in Small for Gestational Age Infants
Growth of fat and nonfat (protein plus other) tissues is metabolically linked through energy supply that is used for protein synthesis and the production of anabolic hormones. These promote positive protein, fat, and carbohydrate growth. Thus, restriction of nutrient supply produces growth deficits of all tissues, including muscle, glycogen, and fat. For example, chronic selective caloric (glucose) restriction in the experimental fetal sheep model leads to increased protein breakdown and lower rates of fetal growth and lipid content (28). Recent data in a fetal sheep model of IUGR demonstrate that the combined net fetal uptake of glucose, lactate, and amino acids, expressed as nutrient:oxygen quotients, was reduced to nearly 1.0 compared to 1.3 in normally grown fetuses. This demonstrates that net carbon supply to the IUGR fetus is only sufficient to sustain oxidative metabolism, with no additional carbon available for fetal growth (29).
▪ REGULATION OF FETAL GROWTH
Fetal growth is regulated by maternal, placental, and fetal factors, representing a mix of genetic mechanisms and environmental influences through which genetic growth potential is expressed and modulated.
Epidemiologic Considerations
The incidence of IUGR is difficult to ascertain, since actual measurements of fetal growth versus their growth potential are not available. Maternal risk factors for IUGR include maternal nutritional status, maternal BMI, maternal genetics, maternal substance abuse, social determinants, and environmental pollutants.
Genetic Factors
Many genes contribute to fetal growth (Table 23.3). Maternal genotype is more important than is fetal genotype in the overall regulation of fetal growth. However, the paternal genotype is essential for trophoblast development, which secondarily regulates fetal growth by placental provision of nutrients.
Chromosomal abnormalities commonly restrict fetal growth, particularly noted in infants with trisomy 21, 13, and 18, but also among infants with triploidy, various deletion syndromes, and those with multiple or “super” X syndromes (XXY, XXXY, XXXX). As few as 2% to 5% of infants with IUGR have chromosomal abnormalities; the incidence increases when both IUGR and mental retardation are present. Many fetuses with growth restriction have congenital malformations and/or dysmorphic syndromes such as thanatophoric dwarfing; leprechaunism; Potter, Cornelia de Lange, Smith-Lemli-Opitz, Seckel, Silver, or Williams syndromes; or VATER or VACTERL (vertebral, anal, cardiovascular, tracheoesophageal, renal, radial, and limb) associations. Infants with various types of cardiovascular disorders, such as congenital heart disease, particularly hypopolastic left heart syndrome, and those with single umbilical arteries, often have IUGR. Monozygotic twins usually have some degree of IUGR that exceeds that of dizygotic twins; all multiple gestation fetuses are prone to IUGR. Donor fetuses in twin-to-twin transfusion syndrome tend to be growth restricted. These disorders are not common, accounting for less than 2% of infants with IUGR. Certain genetic, metabolic, and endocrine disorders are associated with IUGR. Examples include infants with transient neonatal diabetes mellitus, neonatal thyrotoxicosis, Menkes syndrome, hypophosphatasia, I-cell disease, and iron overload disease.
TABLE 23.3 Factors Determining Variance in Birth Weight | ||||||||||||||||||||||||||||||||||||||||
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Infectious Diseases
A causal relationship for IUGR primarily involves rubella, cytomegaloviral infection, and toxoplasmosis. These infections directly inhibit cell division and/or cell death (including apoptosis), leading to a decreased number of fetal cells. Intrauterine infections with other organisms, including syphilis, varicella-zoster, human immunodeficiency virus (HIV), Trypanosoma, and malaria have also been associated with IUGR, but it is unclear in these cases whether it is the infectious agent itself or the poor maternal health and nutrition that are causal. Congenital infections account for very few cases of IUGR, perhaps as little as 3%.
Nongenetic Maternal Factors
Under usual conditions, fetal growth follows its genetic potential, unless the mother is unusually small and limits fetal growth by a variety of factors considered collectively as “maternal constraint.” Maternal constraint represents a relatively limited uterine size, including placental implantation surface area and uterine circulation, and thus, the capacity to support placental growth and nutrient supply to the fetus. A clear example of maternal constraint is the reduced rate of fetal growth of multiple fetuses in a species—human—that optimally supports only one fetus (1) (Fig. 23.5). Obviously, small fetuses of small parents do not reflect fetal growth restriction; in fact, their rates of growth are normal for their genome and for the size of the mother. Unless maternal constraint is particularly prominent, such fetuses would not grow faster or to a larger size if more nutrients were provided, although they might grow somewhat larger if the maternal uterine endometrial surface area, and thus placental implantation and growth area, were increased.
Maternal stress of many kinds, but particularly noted for hard work, perhaps via increased cortisol secretion, may restrict fetal growth. A study from Thailand, for example, indicated that the risk of delivering an SGA infant was increased for pregnant women working more than 50 hours per week, especially in those women whose work involved protracted squatting and for those having high psychological job demands (30).
Maternal Nutrition
The single most important environmental influence that affects fetal growth is the availability of nutrition for the fetus. Normal variations in maternal nutrition, however, have relatively little
impact on fetal growth and the severity of IUGR. This is because changes in maternal nutrition, unless extreme and prolonged, do not markedly alter maternal plasma concentrations of nutrient substrates or the rate of uterine blood flow, the principal determinants of nutrient substrate delivery and transport to the fetus by the placenta. Human epidemiologic data from conditions of prolonged starvation, and nutritional deprivation in experimental animals, indicate that even severe limitations in maternal nutrition limit fetal growth only by 10% to 20%. Epidemiologic data from the Dutch during the Hunger Winter of 1944 showed an average reduction in fetal weight at term of 300 g (31). In animal models, experimental restriction of calorie and protein intakes to less than 50% of normal for a considerable portion of gestation are needed before marked reductions in fetal growth are observed. Such severe conditions often result in fetal loss before the impact of fetal growth rate in late gestation and fetal size at birth are manifested. Attempts to increase fetal weight gain with maternal nutritional supplements have produced mixed results. Higher caloric feeding increases fetal adiposity, not growth of muscle mass or gain in length or head circumference (32). In contrast, high protein supplements tend to produce delayed fetal growth (32). Mechanisms responsible for these disparate outcomes are not known, though insights resulting from experimental amino acid infusions into pregnant sheep have been proposed, including competitive inhibition among coinfused amino acids for common transporters across the placenta, as well as a possible mismatch between amino acid supply and fetal growth factor availability (i.e., insulin and IGF-1, which also are reduced in IUGR fetuses), limiting anabolic capacity even when amino acid supply might be increased (33).
impact on fetal growth and the severity of IUGR. This is because changes in maternal nutrition, unless extreme and prolonged, do not markedly alter maternal plasma concentrations of nutrient substrates or the rate of uterine blood flow, the principal determinants of nutrient substrate delivery and transport to the fetus by the placenta. Human epidemiologic data from conditions of prolonged starvation, and nutritional deprivation in experimental animals, indicate that even severe limitations in maternal nutrition limit fetal growth only by 10% to 20%. Epidemiologic data from the Dutch during the Hunger Winter of 1944 showed an average reduction in fetal weight at term of 300 g (31). In animal models, experimental restriction of calorie and protein intakes to less than 50% of normal for a considerable portion of gestation are needed before marked reductions in fetal growth are observed. Such severe conditions often result in fetal loss before the impact of fetal growth rate in late gestation and fetal size at birth are manifested. Attempts to increase fetal weight gain with maternal nutritional supplements have produced mixed results. Higher caloric feeding increases fetal adiposity, not growth of muscle mass or gain in length or head circumference (32). In contrast, high protein supplements tend to produce delayed fetal growth (32). Mechanisms responsible for these disparate outcomes are not known, though insights resulting from experimental amino acid infusions into pregnant sheep have been proposed, including competitive inhibition among coinfused amino acids for common transporters across the placenta, as well as a possible mismatch between amino acid supply and fetal growth factor availability (i.e., insulin and IGF-1, which also are reduced in IUGR fetuses), limiting anabolic capacity even when amino acid supply might be increased (33).
 FIGURE 23.5 Mean birth weight of single and multiple human fetuses related to duration of gestation. Adapted from McKeown T, Record RG. Observation on foetal growth in multiple pregnancy in man. J Endocrinol 1952;8:386, with permission. |
Specific micronutrient deficiencies also can restrict fetal growth even in the presence of adequate caloric and protein intakes. Zinc deficiency in pregnant women has been associated with increased rates of preterm delivery and fetal IUGR (34), which can be ameliorated by maternal zinc supplementation. Thiamine deficiency in pregnant women also has been associated with IUGR, though difficult to distinguish from simultaneous inadequate nutritional intake, hyperemesis, alcohol abuse, and various infections, including HIV (35). Severe maternal undernutrition/malnutrition is common in underdeveloped countries and exists in subpopulation areas in developed countries where appropriate nutrition, nutritional supplementation, or nutritional consultation is lacking. It also is seen in pregnant women with severe gastrointestinal disease, such as Crohn disease or ulcerative colitis, and women with chronic, unrelenting hyperemesis. Both animal and human studies have shown that undernutrition in the immediate months prior to pregnancy increases the risk for IUGR (36).
Maternal Chronic Diseases (See also Chapter 13)
Chronic hypertension, pregnancy-induced hypertension, and preeclampsia, as well as other vascular disorders including severe and long-standing diabetes mellitus and serious autoimmune disease associated with the lupus anticoagulant (antiphospholipid antibodies with systemic lupus erythematosus [SLE]), have a common effect of limiting trophoblast invasion, placental growth and development, uteroplacental blood flow, and fetal oxygen and nutrient delivery (1,37). Maternal cyanotic congenital heart disease can limit fetal oxygen supply, which can limit fetal growth (38). Severe sickle cell crises can damage uterine vasculature, leading to decreased placental growth and transport capacities (1). Women with chronic anemias, such as sickle cell disease, sickle-C disease, and thalassemia, more frequently produce IUGR/SGA infants. It also is well recognized that women with a history of poor outcome in pregnancy have an increased risk of IUGR in subsequent pregnancies, doubling after one infant with IUGR and quadrupling after two such outcomes (39). These authors urged that women who have growth-restricted infants should undergo comprehensive testing to search for an underlying maternal disorder if the reason for the IUGR is otherwise not apparent.
Maternal hypoxia that produces fetal hypoxia also significantly reduces fetal growth. The most common example is high-altitude hypoxia, but usually this is only clinically significant for nonindigenous women who move to altitudes above 10,000 ft (40). Infants born to mothers who live at 10,000 ft (3,000 m) or greater above sea level weigh approximately 250 g less at birth than do infants born to mothers who live at sea level (41), increasing to weight reductions of up to 15% at altitudes greater than 15,000 ft (4,500 m). Interestingly, the placentas of these IUGR infants weighed more than those near sea level, indicating compensatory development of mechanisms for nutrient delivery (42). More recent studies have shown that long-term adaptation, involving increased uterine blood flow, to higher altitude increases birth weight, while smaller infants generally come from recent immigrants to high altitude (43). Indigenous high-altitude ancestry also protects against hypoxia-associated fetal growth reduction in a dose-dependent fashion consistent with the involvement of genetic factors. Further, some of the genes involved appear to be influenced by parent-of-origin effects, as maternal transmission restricts and paternal transmission enhances fetal growth via growth effects on the placenta (44).
Maternal Drugs (See also Chapters 14 and 54)
Specific effects of drugs on fetal growth (Table 23.4) are often difficult to sort out clinically, as many women who abuse drugs do so with many drugs taken intermittently, at different doses, and at different periods of fetal vulnerability. These women also frequently suffer from other disorders that could lead to poor fetal growth, such as poor nutrition, recurrent acute illnesses, and chronic diseases. Fetal growth restriction is a major part of the fetal alcohol syndrome. It is not clear when during gestation the specific effects of alcohol on fetal growth rate occur. Alcohol may exert its nonteratogenic effects by limiting placental-to-fetal amino acid transport (45). Cocaine probably exerts its primary effects on producing fetal growth restriction by causing uterine and perhaps umbilical vasoconstriction and reduced placental perfusion (46). There also is evidence that marijuana can reduce fetal growth, though the mechanisms are not clear; this potential problem deserves urgent study as legalization of marijuana is expanding in the United States, and there currently is no legal restriction for its use during pregnancy (47).
TABLE 23.4 Drugs Associated with Intrauterine Growth Restriction | |||||||||||||||||
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The drug most consistently producing fetal growth restriction is nicotine from cigarette smoking (48). Deficits of at least 300 g (about 10% of normal term weight) are not uncommon. A likely mechanism is the constricting effect of nicotine, and of catecholamines released in response, on the uterine and perhaps the umbilical vasculature, reducing placental perfusion. Carbon monoxide, cyanide, and other cellular toxins may limit oxygen transport to fetal tissues and cellular respiration. Caffeine, particularly when consumed in amounts greater than 300 mg/d, has been associated with IUGR, though effects of caffeine are often difficult to separate from those of concurrent smoking (49). Mercury toxicity causing growth restriction was observed during the 1950s to the 1970s in epidemics of mercury poisoning in Japan and Iraq. Methyl mercury has the greatest toxicity, as it crosses the placenta readily, producing both teratogenic and adverse growth effects in the fetus (48). Radiation exposure, common agricultural toxins (e.g., bisphenol A, atrazine), and contaminated food or water, over long periods of time, or at critical stages of fetal development, appear to increase risk for IUGR. The incidence and severity of growth restriction due to these factors are not known at present.
Placenta (See also Chapter 11)
The size of the placenta and its nutrient transport functions are the principal regulators of nutrient supply to the fetus and fetal growth. Nearly all cases of IUGR are associated with a smaller-thannormal placenta. Figure 23.6 shows a direct relationship between fetal weight and placental weight in humans, demonstrating that LGA, AGA, and SGA infants are directly associated with LGA, AGA, and SGA placentas (50). Placental growth normally precedes fetal growth, and failure of placental growth is directly associated with decreased fetal growth, although there is considerable redundancy in placental functional capacity, such that up to 30% loss of placental function can still allow for normal fetal growth. Variable limitations in placental nutrient transfer capacity modulate this primary effect of placental size on fetal growth. In some cases of experimentally reduced placental size, for example, fetal weight is not reduced proportionately (50). This indicates that either the capacity of the smaller placenta to transport nutrients to the fetus increases adaptively or the fetus develops increased capacity to grow. More characteristically, though, fetal growth fails first, or in direct relation to decreased nutrient supply. With primary fetal growth failure, placental growth can increase disproportionately, resulting in a larger-than-normal placental-to-fetal weight ratio for gestational age. This is characteristically seen under chronic hypoxic conditions of high-altitude exposure or maternal anemia and has been seen in certain experimental situations of maternal undernutrition in early gestation (51). A variety of placental pathologic conditions are associated with IUGR (Table 23.5). In most of these cases, the placenta is simply smaller than normal. In many, there also is abnormal trophoblast development, including abnormal vascular growth in the trophoblast villi, frequently associated with limited uterine vascular perfusion of the intervillous spaces.
 FIGURE 23.6 Mean placental weights for LGA (○), AGA (•), and SGA (Δ) human infants at each gestational age. ± SEM given for AGA infants alone. From Molteni RA, Stys SJ, Battaglia FC. Relationship of fetal and placental weight in human beings: fetal/placental weight ratios at various gestational ages and birth weight distributions. J Reprod Med 1978;21:327, with permission. |
TABLE 23.5 Placental Growth Disorders that Lead to or Are Associated with Intrauterine Growth Restriction | |||||||||||||||
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Placental and fetal growth both depend on an adequate supply of maternal blood to the placenta. IUGR is associated with inadequate development of the uteroplacental circulation, and radioisotope studies have demonstrated more than a twofold blood flow reduction in comparison with normal pregnancies (52). IUGR in the second half of gestation is due primarily to a failure of the normal villous vascular tree, mainly in the phase of nonbranching angiogenesis, because terminal villi are critical for oxygen and nutrient transport to the fetus (53). This angiogenesis in turn depends on cytotrophoblast invasion of the uterus and its arterioles. Cytotrophoblast invasion is actually a differentiation process whereby the cells lose the ability to proliferate and modulate their expression of state-specific antigens. These antigens include members of the integrin family of cell-extracellular matrix receptors that are required for migration and invasion of the endometrium and decidua of the uterus (54).
The most common maternal condition with restricted placental growth and function is preeclampsia. Preeclamptic placentas have decreased growth of terminal villi, which limits oxygen, glucose, and amino acid transport to the fetus. Preeclampsia begins with shallow cytotrophoblast invasion (55). Abnormal cytotrophoblast differentiation also occurs, evidenced by the cells’ inability to switch on their integrin repertoire (56). The same observations have been made on cultured normal cytotrophoblast cells in a hypoxic environment (57). These in vitro results indicate that whatever leads to hypoxia of the invading cytotrophoblast cells
increases cytotrophoblast proliferation over differentiation and invasion, thus setting the stage for deficient placental development that can result in deficient nutrient and growth factor supply to the fetus, producing fetal growth restriction.
increases cytotrophoblast proliferation over differentiation and invasion, thus setting the stage for deficient placental development that can result in deficient nutrient and growth factor supply to the fetus, producing fetal growth restriction.
At more advanced stages of placental development, placental production of growth factors and growth-regulating hormones develops, leading to significant autocrine regulation of placental growth and placental regulation of fetal growth processes. Human placental lactogen (hPl) is synthesized and secreted by the syncytiotrophoblast cells of the placenta (58). Fetal growth-promoting actions of placental lactogen are mediated by stimulation of IGF production in the fetus and by increasing the availability of nutrients to fetal tissues (59). Obviously, placental growth failure and/or nutrient deficit to the placenta can result in decreased placental production of growth factors that then would lead to fetal growth failure.
▪ FETAL NUTRIENT UPTAKE AND METABOLISM AND REGULATION OF FETAL GROWTH
IUGR that results from decreased nutrient supply can be interpreted as a successful, if not perfect, adaptation to maintain fetal survival.
Glucose Uptake, Metabolism, and Regulation of Fetal Growth
Nearly all IUGR fetuses, whether studied experimentally in animal models or in women by cordocentesis (direct umbilical blood sampling), have relatively lower plasma glucose concentrations compared with normally grown fetuses (60,61
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