Rudolph's Pediatrics, 22nd Ed.

CHAPTER 47. The Small-for-Gestational-Age Infant

William W. Hay Jr.

DEFINITIONS AND INCIDENCE

SMALL FOR GESTATIONAL AGE

Newborn infants are classified according to birth weight as small, average, or large for gestational age (Table 47-1).^1,2 Small-for-gestational-age (SGA) infants are a heterogeneous group of infants who are smaller than normal at birth because of genetic or constitutional conditions, diseases, or nutrient insufficiency. SGA infants have a birth weight less than the 10th percentile of a population-specific birth weight versus gestational age. Broader definitions include infants whose weight percentile is less than that for length and head circumference (eg, weight at 25th percentile but length and head circumference at 75th percentile). In this case, the weight-to-length ratio—or the ponderal index = (weight, g)/(length, cm)³—is less than normal, indicating that growth rates of visceral organs, adipose tissue, and skeletal muscle, the principal determinants of weight, were less than that of length. A low weight-to-length ratio occurs most commonly in fetuses with late gestation nutritional deficiency, usually a result of placental insufficiency.

INTRAUTERINE GROWTH RESTRICTION

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.² IUGR infants therefore can be small for gestational age or simply smaller than they could have been but still with weights and other anthropometric indices within the normal range.⁴ The latter point is important because adverse outcomes of growth restriction are due to the processes that produce slower growth and the fetal adaptations to these, not just whether the infant is less than the 10th percentile. Nearly any aberration of biological activity in the placenta and/or fetus can lead to fetal growth failure.⁵ Moderately and severely IUGR infants tend to have asymmetric growth restriction; that is, body growth restriction is greater than brain growth restriction. The degree of asymmetry varies considerably depending on the duration and severity of the growth inhibition. Constitutionally small infants (from normal but small mothers who have small uteruses) tend to have more symmetrically restricted brain and body growth. Asymmetric and symmetric growth restriction therefore represent the 2 extreme patterns of abnormally slow fetal growth rates.

Table 47-1. Classification of Fetal Growth

LOW BIRTH WEIGHT

Most infants with low birth weights are the result of a shorter than normal gestation (ie, they are preterm). Also, a large fraction of preterm infants are growth restricted; indeed, many causes of growth restriction also lead to preterm delivery. Thus, low birth weight can represent preterm delivery or growth restriction, or both, but does not indicate an infant’s gestational age or whether the infant was growth restricted.^1,2,4

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 fetal genetic growth potential is expressed and modulated.^1,4,6 Maternal genotype is more important than fetal genotype in the overall regulation of fetal growth. However, the paternal genotype is essential for trophoblast development, which secondarily regulates fetal growth by the provision of nutrients. The major maternal factors that regulate fetal growth, which vary among populations and among individuals, include maternal size (height and prepregnancy weight) and maternal weight gain during pregnancy. Maternal size primarily contributes to fetal growth by regulating the size of the uterus, particularly the endometrial surface area, which allows the paternal insulinlike growth factor (IGF)-II gene to express its dominant regulation of placental growth over the maternal IGF-II receptor gene.⁵

Normal variations in maternal nutrition have relatively little impact on fetal growth, 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. The placental trophoblast surface area is the primary regulator of fetal growth via its nutrient transport capacity and its interaction with maternal (uterine) and fetal (umbilical) circulations. The trophoblast regulates nutrient transport through its membrane transporters, with a large variety of energy-dependent or active transporter system proteins for amino acids (which thus are dependent on maternal oxygenation and placental blood flow) and facilitative transporters for glucose and fatty acids (which enhance transport that is dependent on the maternal-fetal concentration gradient). At more advanced stages of placental development, placental production of growth factors and growth-regulating hormones (human placental lactogen or hPL, and placental growth hormone, or PGH) leads to significant autocrine regulation of placental growth and placental regulation of fetal growth processes.

In the fetus, nutrient supply is the primary regulator of fetal growth, dependent most on amino acids for protein synthesis and secondarily on energy from glucose oxidation in fetal tissues.^1,4,5,7 Mineral supply (calcium and phosphorous) is essential to promote bone structure. In addition, nutrient-stimulated secretion of insulin and insulinlike growth factors promote fetal growth via their signal transduction effects on protein synthesis. Insulin acts additively with glucose supply to promote fetal glucose utilization and oxidation as well as storage in glycogen and lipid.

ETIOLOGY OF GROWTH RESTRICTION

Intrinsic abnormalities that limit fetal growth usually begin early in fetal life, whereas the onset of extrinsic adverse factors, such as undernutrition or hypoxia from placental insufficiency, develop at variable times during later gestation.^1,4,5 Abnormalities that limit the growth of both the fetal brain and body include chromosomal anomalies (particularly trisomy conditions), congenital infections (eg, toxoplasmosis, rubella, and cytomegalovirus), dwarf syndromes, some inborn errors of metabolism, and some drugs (eg, maternal smoking and excessive alcohol consumption). Most other cases of fetal growth restriction are the result of a small or poorly functioning placenta. Small placentas can result from natural conditions such as a small mother with a small uterus (the principal form of “maternal constraint” by which maternal size directly contributes to uterine and thus placental size), multiple gestation, or abnormal conditions such as uterine structural abnormalities (fibroids), abnormal placental vasculature (eg, aberrant cord vessel insertions, thrombosis, vasculitis, infarcts, avascular villi), infections, chronic partial abruption with or without placenta previa, or preeclampsia. Table 47-2 lists common maternal conditions associated with intrauterine growth restriction and Table 47-3 lists those conditions in the placenta that lead to it.

EPIDEMIOLOGY AND INTERPRETATION OF GROWTH CURVES

NEONATAL GROWTH CURVES

Cross-sectional growth curves from anthropometric measurements in populations of infants born at different gestational ages demonstrate whether an infant’s birth weight is within the normal range for a given gestational age and thus whether that infant’s in utero growth was greater or less than normal (see Figure 41-3). Each curve is based on local populations with variable composition of maternal age, parity, socioeconomic status, race, ethnic background, body size and body mass index, health, pregnancy-related problems, and nutrition as well as the number of fetuses per mother, the number of infants included in the study, and the methods and accuracy of measurements of body size and gestational age.⁸ Estimating gestational age has considerable error, derived from variability in dating conception, the physical features of maturation in the infant, and interobserver assessments of an infant’s developmental stage.

FETAL GROWTH CURVES

Fetal growth curves were developed from serial ultrasound measurements of fetuses that subsequently were born at term in healthy condition and with normal anthropometric measurements, providing longitudinal indices of fetal growth.⁸ Serial ultrasound measurements of fetal growth more accurately determine how environmental factors, such as severe maternal illness and undernutrition, inhibit fetal growth and how maternal overnutrition and gestational diabetes enhance fetal growth, particularly of adipose tissue. They are much more useful than anthropometric indices at birth as measures of fetal growth rate and deviations from normal growth patterns.

Table 47-2. Maternal Conditions Associated with IUGR

BODY COMPOSITION OF THE SGA FETUS

Nitrogen and protein contents are reduced for body weight in SGA infants, primarily from deficient production of muscle mass. In fact, they often are reduced below that of fat as a fraction of body weight, even when growth restriction is moderate.

Table 47-3. Placental Growth Disorders Associated with IUGR

Glycogen content is highly variable in SGA infants, particularly those who have had intrauterine growth restriction. Glycogen deficiency in IUGR fetuses results from low fetal glucose and insulin concentrations, which normally promote glucose uptake by liver and skeletal muscle cells, the principal storage sites of glycogen. Repeated episodes of hypoxemia that increase epinephrine secretion also deplete glycogen further by activating glycogen phosphorylase and increasing glycogenolysis. In contrast, insulin deficiency or a reduction in insulin signal transduction activation, as occurs in chronically IUGR, nonstressed infants, increases glycogen content by downregulating glycogen synthesis kinase, a normal negative regulator of glycogen synthesis.

Fat content in human fetuses with intrauterine growth restriction may be less than 10% of body weight at term gestation or 30% to 40% less than normal. This usually results from a smaller than normal placenta, which limits fetal fatty acid and triglyceride supply to the fetus and decreases fetal glucose and insulin concentrations. These deficiencies reduce glycerol production, triglyceride synthesis, and fat production. In contrast, IUGR fetuses more recently have been noted to have increased abdominal fat content, for reasons not known, that might portend later life abdominal adiposity associated with intrauterine growth restriction and later life obesity, insulin resistance, and diabetes.

CLINICAL EVALUATION AND TREATMENT OF THE SGA INFANT

ANTENATAL EVALUATION OF THE IUGR FETUS

Serial ultrasound evaluation of growth of fetal body proportions and Doppler velocimetry assessment of uterine, placental, and fetal circulations are the standard diagnostic approaches used to determine the severity of intrauterine growth restriction, detect deteriorating fetal physical condition, and predict impending fetal death. Chronic fetal distress resulting from placental insufficiency, hypoxia, and ischemia, with or without acidosis, is associated with increased Doppler arterial waveform amplitudes in the fetal peripheral vasculature that indicate increased vascular resistance and reduced blood flow to fetal tissues and the placenta. Various ratios of systolic-to-diastolic flow velocity (amplitude) waveforms have been used to detect decreased peripheral blood flow in the fetus, including the systolic-to-diastolic ratio: (systolic – diastolic)/systolic ratio (resistance index) or (systolic – diastolic)/mean ratio (pulsatility index). The most severely affected IUGR fetuses with the greatest risk of death demonstrate absent or reversed diastolic flow in their systemic arteries, with increased umbilical venous pulsation and reversed flow in the abdominal vena cava. Because of associated fetal hypoxemia, which causes vasodilation of certain vital organs such as the brain, some of these fetuses can have increased cerebral or internal carotid artery flow velocities and cerebral blood flow rates. Such conditions have been hypothesized to help maintain brain growth. Doppler waveform abnormalities usually precede less specific signs of fetal distress such as abnormal changes in fetal heart rate that occur spontaneously under basal conditions or in response to increased uterine contractions during oxytocin challenge testing.

GENERAL EVALUATION AND TREATMENT IN THE DELIVERY ROOM

SGA infants lose heat rapidly because of their large surface area relative to body weight and their scant subcutaneous insulation.^1,7,9 To prevent hypothermia, they should be dried quickly and completely, placed under a radiant warmer, and protected from drafts with warmed blankets. Severely undergrown SGA infants often experience marked oxygen and substrate deprivation in utero, which can lead to cardiopulmonary failure at birth. Close to term, they can present with meconium aspiration syndrome and exhibit signs of acute and chronic hypoxia, including hypotension, metabolic and respiratory acidosis, and persistent pulmonary hypertension.

Markedly SGA infants who have severe intrauterine growth restriction usually have disproportionately large heads relative to their undergrown trunks and extremities. Their abdomen can appear shrunken or “scaphoid,” and they must be distinguished from infants with diaphragmatic hernias, who also present with respiratory distress. Their extremities appear scrawny, with thin skin folds and decreased amounts of subcutaneous fat and skeletal muscle. The skin is loose and often rough, dry, and peeling. In term and postterm infants who are markedly small for gestational age, the fingernails can be long, and the hands and feet tend to look large for the size of the body. The face often appears shrunken or “wizened.” Cranial sutures can be widened or overriding. The anterior fontanel often is larger than expected, representing diminished membranous bone formation. The umbilical cord often is thin, and when meconium has been passed in utero, the cord, nails, and skin may have a yellow or green discoloration. SGA infants also have an increased incidence of severe malformations and chromosomal abnormalities accompanied by dysmorphic features and congenital anomalies, “funny-looking facies,” abnormal hands and feet, and the presence of palmar creases. SGA infants with congenital infections can have ocular disorders such as chorioretinitis, cataracts, glaucoma, and cloudy cornea plus hepatosplenomegaly, jaundice, and a “blueberry-muffin” rash, which represents subcutaneous accumulations of extra-medullary hematopoiesis.

Gestational age assessment using physical criteria often is erroneous in infants who are small for gestational age. Vernix caseosa frequently is reduced or absent; thus, the skin more readily desquamates, and sole creases appear more prominent and thus more mature because of increased wrinkling from greater exposure to amniotic fluid. Breast tissue formation also is reduced, and the female external genitalia appear less prominent because of decreased perineal adipose tissue covering the labia. Specific organ maturity often continues at normal developmental rates despite diminished somatic growth; thus, cerebral cortical convolutions, renal glomerular development, and alveolar maturation correlate better with gestational age than with body size.

SGA infants often appear to have advanced neurological maturity, although this observation is derived primarily from comparisons with infants of similar birth weight rather than similar gestational age.³Active and passive tone and posture are usually normal in SGA infants and are reliable guides to gestational age unless there are other factors (eg, serious central nervous system disorders that could alter tone). SGA infants often have a “hyperalert” appearance, generally look “starved and hungry,” and often are described as jittery and hypertonic, even without simultaneous hypoglycemia. They can be hyperexcitable but show mixed aberrations in tone, from hypotonia to hypertonia. When intrauterine growth restriction is severe, SGA infants tend to show abnormal sleep cycles and diminished muscle tone, decreased deep tendon and facial tactile reflexes, and general physical inactivity and apathy. These neurological abnormalities usually reflect brain injury during fetal development.

CLINICAL PROBLEMS OF THE SGA NEONATE

SGA infants frequently have problems of perinatal depression (“asphyxia”), hypothermia, hypoglycemia, polycythemia, long-term growth failure, neurodevelopmental handicaps, and relatively high mortality rates (Table 47-4).

Table 47-4. Clinical Problems of the SGA Neonate

EFFECTS OF IUGR/SGA ON MORTALITY AND MORBIDITY

Constitutionally small infants are not likely to have increased risks of mortality or morbidity. At very early gestational ages, the problems associated with preterm birth have a much greater impact on outcome than does whether they are small for gestational age or appropriate for gestational age (AGA), in contrast to the more mature infants who may suffer more from the impact of growth restriction.^1,4,9 The perinatal mortality rate for SGA infants with relatively severe intrauterine growth restriction is 5 to 20 times that of AGA infants of the same gestational age. This heightened mortality rate is related to intrauterine death from chronic fetal hypoxia, labor- and birth-related hypoxicischemic conditions, multisystem disorders associated with asphyxia (hypoxic-ischemic encephalopathy, persistent pulmonary hypertension, cardiomyopathy, meconium aspiration), and lethal congenital anomalies.

PERINATAL DEPRESSION

Severely IUGR fetuses frequently show signs of distress (fetal bradycardic arrhythmias and decreased movement) and often do not tolerate labor and vaginal delivery.^1,3,4 In such cases, the already stressed, chronically hypoxic fetus is exposed to the acute stress of diminished blood flow during uterine contractions. SGA infants with intrauterine growth restriction tend to have low Apgar scores and frequently need resuscitation.

HYPOGLYCEMIA

Hypoglycemia is extremely common in SGA infants, increasing with the severity of intrauterine growth restriction.⁹ The risk of hypoglycemia is greatest during the first 3 postnatal days, but fasting hypoglycemia (ie, before feedings) can occur repeatedly for several days after birth. Early hypoglycemia usually results from diminished hepatic and skeletal muscle glycogen content and is aggravated by diminished alternative energy substrates, including reduced concentrations of fatty acids from the scant adipose tissue and decreased concentrations of lactate from hypoglycemia. Less commonly, hyperinsulinemia, increased sensitivity to insulin, or both may contribute to the greater incidence of hypoglycemia. Gluconeogenesis usually is decreased, and resolution of persistent hypoglycemia is coincident with improved gluconeogenic capacity and rate. Deficient counterregulatory hormones, particularly catecholamines, also can contribute to the pathogenesis of hypoglycemia. All SGA infants should have early and frequent measurements of blood or plasma glucose concentrations. Blood glucose concentrations should be kept greater than 40 to 45 mg/dL (plasma or serum glucose concentrations greater than 50–55 mg/dL). Early enteral feeding usually can prevent hypoglycemia. In less mature infants or those who have other clinical problems, intravenous glucose should be started at 6 to 8 mg/min per kilogram of body weight as soon after birth as possible. This relatively high rate of glucose infusion is indicated because of the high brain-to-body weight ratio in SGA infants. SGA infants with hypoxicischemic conditions and those who are extremely thin and therefore possess the least amount of alternative substrates for brain metabolism (particularly ketoacids) are at greatest risk of complications of severe hypoglycemia.

HYPERGLYCEMIA

SGA infants who are born very preterm often have low insulin secretion rates and plasma insulin concentrations, leading to the relatively common problem of hyperglycemia that is principally caused by excessive rates of glucose infusion (usually greater than 11 mg/min/kg).⁹ Higher concentrations of stress-induced hormones, such as epinephrine, glucagon, and cortisol, also contribute to hyperglycemia. Insulin treatment of these infants usually decreases glucose concentrations promptly, indicating that they have appropriate or even increased insulin sensitivity.

LIPID METABOLISM

SGA infants have low plasma free fatty acid concentrations.⁹ Fasting glucose concentrations in SGA infants directly correlate with plasma concentrations of free fatty acids and ketoacids. When fed intravenously, however, SGA infants often have deficient cellular uptake and metabolism of intravenous triglycerides, which produces high plasma concentrations of fatty acids and triglycerides but reduced concentrations of ketoacids.

ENERGY METABOLISM

Basal oxygen consumption often decreases immediately after birth in SGA infants but then increases markedly with early feeding. SGA infants have higher oxygen consumption and total energy expenditure rates than normally grown infants at the same gestational age, primarily because their resting energy expenditure rate also is higher. This reflects an increase in cell number relative to body mass and greater heat production in response to increased heat loss due to their larger body surface area relative to tissue mass.^1,9

AMINO ACID AND PROTEIN METABOLISM

Because SGA infants are particularly deficient in muscle mass, providing adequate nutrition for accretion of skeletal muscle, as well as total body protein, is a priority in these infants. Furthermore, SGA infants who are born very preterm often have greater than normal intestinal protein losses, as their intestinal size often is decreased, limiting protein digestion and absorption. Higher protein intakes may partly compensate for these losses, but there is conflicting information about how well SGA infants tolerate high rates of amino acid and protein nutrition, as they may have adapted metabolically to limit their capacity for protein synthesis in response to both amino acid supply and insulin action.^4,10 Also, the pancreas of IUGR infants is smaller with smaller islets and reduced capacity for insulin production, limiting the anabolic effects of this essential growth hormone.

POLYCYTHEMIA-HYPERVISCOSITY SYNDROME

SGA infants have an increased incidence of polycythemia, probably because of chronic intrauterine hypoxia, which induces increased rates of erythropoiesis.^1,4 About one half of all SGA infants have a central hematocrit greater than 60%, and approximately 15% to 20% of term SGA infants have a central hematocrit greater than 65%. In contrast, only about 5% of term AGA infants have a central hematocrit greater than 65% (see Chapter 53).

IMMUNE FUNCTION AND INFECTIOUS DISEASE RISK

Immunologic function of SGA infants can be impaired at birth and even in childhood.^1,4 SGA infants often have deficiencies in lymphocyte number and function, low immunoglobulin levels during infancy, and attenuated antibody response to vaccines.

POSTNATAL NEURODEVELOPMENTAL OUTCOME

Neurologic disorders occur 5 to 10 times more often in SGA than in AGA infants.³ Such disorders include hyperactivity, short attention span, and learning disabilities associated with substandard school performance. Many of these infants, even those with normal intelligence, also have subtle neurological and behavioral problems, including fine motor incoordination, hyperreflexia, speech problems, and diffuse electroencephalographic abnormalities. Relative microcephaly at birth is especially associated with poor developmental outcome in severely SGA infants.⁷

POSTNATAL PHYSICAL GROWTH OF SGA INFANTS

SGA infants who have had severe intrauterine growth restriction continue to have short stature, and males particularly may remain relatively underweight for age as they age. The short stature persists into adulthood, indicating permanence of the growth deficits. SGA infants who have had mild to moderate intrauterine growth restriction tend to have accelerated growth velocity during the first 6 months, and some achieve a growth rate and body size similar to those of AGA infants. Overfeeding such infants can promote obesity, however, indicating that such approaches to nutrition and feeding of SGA infants carry significant risks.

ADULT DISORDERS RESULTING FROM IUGR

Recent epidemiologic evidence indicates that insulin resistance, glucose intolerance, obesity, diabetes, and cardiovascular disease are more common among adults who were small for gestational age secondary to intrauterine growth restriction compared to those who were appropriate for gestational age at birth.⁸ Thus, certain adult pathologies may be unavoidable consequences of environmentally imposed conditions, such as severe and prolonged fetal undernutrition, that allow fetal survival at the expense of normal rates of fetal growth. Adaptive mechanisms that develop in the fetus in response to nutrient deprivation, such as increased glucose and insulin sensitivity, may underlie or contribute to these disorders by enhancing the formation of fat in adipose tissue in response to increased caloric intake, as is common in modern Western diets. Intrauterine growth restriction, therefore, is increasingly seen as a successful adaptive physiological process for short-term survival, even though it increases the risk for certain diseases in later life.