105: Intrauterine Growth Restriction (Small for Gestational Age)

The terms intrauterine growth restriction (IUGR) and small for gestational age (SGA) are sometimes used interchangeably. Although related, they are not synonymous. SGA describes an infant whose weight is lower than population norms or lower than a predetermined cutoff weight. Most commonly, SGA infants are defined as having a birthweight below the 10th percentile for gestational age or >2 standard deviations below the mean for gestational age. In contrast, IUGR infants have not attained optimal intrauterine growth.

The ponderal index, arrived at by the following formula, can be used to identify infants whose soft tissue mass is below normal for the stage of skeletal development. A ponderal index <10th percentile may be used to identify IUGR infants. Thus, all IUGR infants may not be SGA, and all SGA infants may not be small as a result of a growth-restrictive process.

1. Symmetric IUGR. (HC = Ht = Wt, all <10%) The head circumference (HC), length (Ht), and weight (Wt) are all proportionately reduced for gestational age. Symmetric IUGR is due to either decreased growth potential of the fetus (congenital infection or genetic disorder) or extrinsic conditions that are active early in pregnancy.

2. Asymmetric IUGR. (HC = Ht < Wt, all <10%) Fetal weight is reduced out of proportion to length and head circumference. The head circumference and length are closer to the expected percentiles for gestational age than is the weight. In these infants, brain growth is usually spared. The usual causes are uteroplacental insufficiency, maternal malnutrition, or extrinsic conditions appearing late in pregnancy.

3. More recently, fetal growth restriction (FGR) is being used to denote impaired fetal growth based on healthy fetal growth standards. An individual baby's growth potential is determined by both maternal and fetal factors. Recent attempts have been made to develop individualized growth charts taking into account maternal physiological characteristics such as race, ethnicity, parity, height, and so on, as well as fetal characteristics like gender.

   Term optimal weight (TOW) is defined as the optimal weight based on fetal weight curves of healthy infants born at term. For an individual pregnancy, fetal growth can be combined with TOW to show the gestation-related optimal growth (GROW) curve. GROW charts adjusted for maternal height, weight, parity, and ethnicity are available at www.gestation.net.

   Estimation of fetal growth velocity with serial measurements may be useful to identify FGR. For example, a fetus with weight >10th percentile may be growth restricted if fetal growth velocity declines. FGR may be early or late, comparable to symmetric and asymmetric IUGR.

   Early FGR is difficult to identify (by measuring crown-rump length), as often the timing of conception is not known. However, slow growth velocity between the first and second trimesters can identify infants at risk for perinatal death before 34 weeks' gestation. The onset of FGR before 34 weeks is associated with sequential changes on Doppler studies that parallel worsening placental function. Typically, umbilical artery Doppler changes precede biophysical profile parameters. Late FGR after 34 weeks' gestational age is more difficult to identify and has less characteristic Doppler changes.

About 3–10% (up to 15%) of all pregnancies are associated with IUGR, and 20% of stillborn infants are growth retarded. The perinatal mortality rate is 5–20 times higher for growth-retarded fetuses, and serious short- or long-term morbidity is noted in half of the affected surviving infants. IUGR is estimated to be the predominant cause for low birthweight in developing countries. It is estimated that a third of infants with birthweights <2500 g are in fact growth retarded and not premature. Term infants with birthweights <3rd percentile have a higher morbidity and a 10 times higher mortality than appropriate for gestational age infants. In the United States, uteroplacental insufficiency is the leading cause of IUGR. An estimated 10% of cases are secondary to congenital infection. Chromosomal and other genetic disorders are reported in 5–15% of IUGR infants.

Fetal growth is influenced by fetal, maternal, and placental factors.

1. Fetal factors

   1. Genetic. Approximately 20% of birthweight variability in a given population is determined by fetal genotype. Genetic determinants of fetal growth have their greatest impact in early gestation during the period of rapid cell development. Racial and ethnic backgrounds influence size at birth irrespective of socioeconomic status. Males weigh an average of 150–200 g more than females at birth. This weight increase occurs late in gestation. Birth order affects fetal size; infants born to primiparous women weigh less than subsequent siblings.

   2. Chromosome anomalies. Chromosomal deletions or imbalances result in diminished fetal growth. Nearly 20% of fetal growth restriction is due to chromosomal aberration.

   3. Congenital malformations. Anencephaly, gastrointestinal atresia, Potter syndrome, and pancreatic agenesis are examples of congenital anomalies associated with IUGR. Frequency of IUGR increases as the number of congenital defects increases.

   4. Cardiovascular anomalies. (With the possible exception of transposition of the great vessels and tetralogy of Fallot.) Abnormal hemodynamics are thought to be the basis of IUGR.

   5. Congenital infection. TORCH infections (toxoplasmosis, other, rubella, cytomegalovirus, and herpes simplex virus) are often associated with IUGR and account for ∼5% of IUGR fetuses. The incidence of IUGR is highest when infection occurs in the first trimester. The clinical findings in different congenital infections are nonspecific and overlap considerably. Cytomegalovirus and rubella are associated with severe IUGR. Rubella causes damage during organogenesis and results in a decreased number of cells, whereas cytomegalovirus infection results in cytolysis and localized necrosis within the fetus.

   6. Inborn errors of metabolism. Transient neonatal diabetes, galactosemia, and phenylketonuria are other disorders associated with IUGR. Single-gene defects associated with impaired insulin secretion or action are associated with impaired fetal growth (see Chapter 101).

2. Maternal factors (Table 105–1)

   1. Reduced uteroplacental blood flow. Maternal disorders such as preeclampsia-eclampsia, chronic renal vascular disease, and chronic hypertensive vascular disease often result in decreased uteroplacental blood flow and associated IUGR. Impaired delivery of oxygen and other essential nutrients is thought to limit organ growth and musculoskeletal maturation. Risk of placental thrombi is increased in conditions of inherited thrombophilias.

   2. Maternal malnutrition. The major risk factors for IUGR include small maternal size (height and prepregnancy weight) and minimal maternal weight gain. Low body mass index, defined as (weight [kg]/height [m²])/100, is a major predictor of IUGR. Maternal malnutrition leads to deficient substrate supply to the fetus. Total caloric consumption rather than protein or fat consumption appears to be the principal nutritional influence on birthweight. A balanced protein energy supplementation during pregnancy decreases the risk of IUGR birth.

   3. Multiple pregnancies. Impaired growth results from failure to provide optimal nutrition for more than 1 fetus in utero. There is a progressive decrease in weight of singletons, twins, and triplets. In parabiotic twins, the smaller twin has decreased nutrient delivery secondary to abnormal placental blood flow resulting from arteriovenous communication in the chorionic plate.

   4. Maternal substance use. See also Chapter 103.

      1. Cigarettes and alcohol. Chronic abuse of cigarettes or alcohol is demonstrably associated with IUGR. The effects of alcohol and tobacco seem to be dose dependent, with IUGR becoming more serious and predictable with heavy abuse.

      2. Heroin. Maternal heroin addiction is also often associated with IUGR.

      3. Cocaine. Cocaine use in pregnancy is associated with increased rates of IUGR. The IUGR may be mediated by placental insufficiency or direct toxic effect on the fetus.

      4. Others. Other drugs and chemical agents causing IUGR include known teratogens, antimetabolites, and therapeutic agents such as trimethadione, warfarin, and phenytoin. Each of these agents causes characteristic malformation syndromes. Repeated use of antenatal steroids and lithium use are also associated with low birthweight.

   5. Maternal hypoxemia. Hypoxemia is seen in mothers with hemoglobinopathies, especially sickle cell disease, and they often have IUGR infants. Infants born at high altitudes tend to have lower mean birthweights for gestational age.

   6. Other maternal factors. Maternal short stature, young maternal age, short interpregnancy interval, uterine anomalies, low socioeconomic class, primiparous, grand multiparous, and low prepregnancy weight are associated with subnormal birthweight. Maternal hyperhomocysteinemia is also associated with low birthweight.

   7. DNA damage. Measured by micronucleus (MN) formation, may play a role. MNs are formed by the lagging chromosomal fragments during anaphase in both mitosis and meiosis. Increased MN count in maternal lymphocytes at 20 weeks' gestation is associated with increased risk of IUGR and preeclampsia.

3. Placental factors

   1. Placental insufficiency. In the first and second trimesters, fetal growth is determined mostly by inherent fetal growth potential. By the third trimester, placental factors (ie, an adequate supply of nutrients) assume major importance for fetal growth. When the duration of pregnancy exceeds the nurturing capacity of the placenta, placental insufficiency results with subsequent impaired fetal growth. This phenomenon occurs mostly in post-term gestations but may occur at any time during gestation.

   2. Uteroplacental insufficiency (UPI). Seen in almost 70% of infants with IUGR. Impaired oxygen extraction and nutrient delivery (glucose and amino acids) lead to fetal hypoglycemia and hypoxia. The latter is associated with decrease in cell size and number, lighter brain weight, and lower DNA content. Small placental volume and a reduction in terminal villi are seen in IUGR placentas.

   3. Placenta structural abnormalities. Various anatomic factors, such as multiple infarcts, aberrant cord insertions, umbilical vascular thrombosis, and hemangiomas, are described in IUGR placentas. IUGR is twice as common with a 2-vessel-cord pregnancy as compared with 3-vessel-cord pregnancies. Premature placental separation may reduce the surface area exchange, resulting in impaired fetal growth. An adverse intrauterine environment is apt to affect both placental and fetal development, hence IUGR infants usually have small placentas.

   4. IUGR fetuses. These fetuses have downregulation of placental amino acid and lipoprotein lipase transporters Na⁺/K⁺ ATPase and Na⁺/H⁺ exchanger, leading to lower plasma amino acid levels and decreased fatty acid transfer. Genetic imprinting may also play a role (eg, alterations of the placenta-specific gene IGF-2 in knockout mice has produced IUGR fetuses).

   5. Fetal endocrine responses. Include alterations in the hypothalamic-pituitary axis, resulting in elevated corticotropin-releasing hormone, adrenocorticotropic hormone, and cortisol with a decrease in insulin-like growth factor-1 (IGF-1). Thyroid-stimulating hormone is high, but thyroxine and triiodothyronine are low, as are serum vitamin D and osteocalcin. High cortisol levels are associated with decreased postnatal catch-up growth and delayed neurodevelopmental outcomes.

   6. Fetal response to placental dysfunction. Different for early FGR and late FGR. In early FGR, decrease in umbilical venous flow and decreased fetal cardiac return to the placenta (due to increased resistance) precede clinical FGR. Fetal events include increased ductal shunting to the heart, decreased hepatic flow, downregulation of glucose-insulin-IGF, and decreased hepatic glycogen stores. With increasing villous obliteration, middle cerebral artery Doppler changes precede changes in the biophysical profile (BPP) with the loss of fetal heart rate reactivity, breathing, and loss of body movements. BPP changes also correlate with fetal acidosis. A decrease in amniotic fluid occurs in 20–30% of FGR that is independent of Doppler changes and correlates with fetal cardiac decompensation. Doppler changes usually progress over 4–6 weeks.

   7. Others. Placental mosaicism, wherein the placental cytogenetics are different from the fetal cytogenetics, may account for ∼15% of IUGR. Fibrin deposition in the decidua basalis, the intervillous space, and mesenchymal dysplasia are associated with an increased risk for placental thrombosis and IUGR.

Related to fetal, maternal, or placental pathophysiologic factors (see previous text) (Table 105–2).

The maternal history will raise the index of suspicion regarding suboptimal fetal growth. The infant will have a reduced birthweight for gestational age. Using growth charts and the Ballard score can help assess gestational age, and intrauterine and postnatal growth. See Figures 5–1, 5–3,5–4 and 5–5,.

1. Establishing gestational age. Determining the correct gestational age is imperative. The last menstrual period, size of the uterus, time of quickening (fluttering movements in the abdomen caused by fetal activity, appreciated by the mother for the first time), and early ultrasound measurements are used to determine gestational age. (See Chapter 5.)

2. Fetal assessment

   1. Clinical diagnosis. Manual estimations of weight, serial measurements for fundus height, and maternal estimates of fetal activity are simple clinical measures.

   2. Ultrasonography. Because of its reliability to date pregnancy and to detect impaired fetal growth by anthropomorphic measurements and fetal anomalies, ultrasonography currently offers the greatest promise for diagnosis. The following anthropomorphic measurements are used in combination to predict growth impairment with a high degree of accuracy.

      1. Biparietal diameter (BPD). When serial measurements of BPD are less than optimal, 50–80% of infants have subnormal birthweights.

      2. Abdominal circumference. The liver is the first organ to suffer the effects of growth retardation due to redistribution of ductus venosus blood flow to the heart and a decrease in glycogen deposition in the liver. Reduced growth of the abdominal circumference (<5 mm/wk) is the earliest sign of asymmetric growth retardation and diminished glycogen storage. Abdominal circumference <10th percentile for age is suggestive of growth retardation.

      3. Ratio of head circumference to abdominal circumference. This ratio normally changes as pregnancy progresses. In the second trimester, the head circumference is greater than the abdominal circumference. At about 32–36 weeks' gestation, the ratio is 1:1, and after 36 weeks the abdominal measurements become larger. Persistence of a head-to-abdomen ratio <1 late in gestation is predictive of asymmetric IUGR.

      4. Femur length. Femur length appears to correlate well with crown-heel length and provides an early and reproducible measurement of length. Serial measurements of femur length are as effective as head measurements for detecting symmetric IUGR.

      5. Placental morphology and amniotic fluid assessment. May help in distinguishing a constitutionally small fetus from a growth-retarded fetus. For example, placental aging with oligohydramnios suggests IUGR and fetal jeopardy, whereas normal placental morphology with a normal amount of amniotic fluid suggests a constitutionally small fetus.

      6. Placental volume measurements. May be helpful in predicting subsequent fetal growth. Placental weight and/or volume is decreased before fetal growth decreases. IUGR with decreased placental size is more likely to be associated with fetal acidosis. Placental volume correlates with placental flow indices.

   3. Doppler measurements. In both maternal and various fetal vascular beds are increasingly used to detect, monitor, and optimize time of delivery in IUGR infants. Doppler studies are more helpful in diagnosing moderate to severe IUGR than mild IUGR. The various groups of vessels used are as follows:

      1. Uterine artery (UtA) flow abnormalities. Used to predict IUGR as early as 12–14 weeks. A persistent abnormality at 23–24 weeks has a ∼75% sensitivity in predicting early FGR.

      2. Umbilical artery (UA) flow abnormalities. Used to evaluate placental insufficiency, particularly in high-risk pregnancies. Normally, the UA resistance declines with pregnancy. Increased pulsatility index (PI), decreased end-diastolic velocity (EDV), and absent or reversed EDV (AREDV) occur with worsening fetal compromise. AREDV is associated with 20–68% mortality. Decreased EDV is seen when 30% placental flow is attenuated, and ARDEV is noted when 60–70% placental flow is affected. Absent EDV and AREDV are associated with a 4.0- and 10.6-fold increased risk of mortality, respectively, compared to those with normal Doppler.

      3. Fetal cerebral arterial flow. Usually studied in the middle cerebral artery as a pulsatility index (MCA PI) and middle cerebral artery peak systolic velocity (MCA PSV). With worsening IUGR, MCA PSV increases. Abnormal MCA PI precedes MCA PSV changes. Changes in MCA PI are not as consistent in predicting mortality, although decreased MCA resistance is associated with worse perinatal outcomes.

      4. Doppler venous flow studies of the vena cava, umbilical vein (UV), and ductus venosus (DV) provide information about fetal cardiovascular and respiratory responses. Decreased venous blood flow in the UV and an abnormal deep or retrograde “a” wave in DV are suggestive of ventricular decompensation. Changes in venous flow are usually late and represent more severe decompensation. Absent or reversed DV flow correlates with acidosis and is associated with 63–100% mortality.

      5. Aortic isthmus (AoI). Absolute flow velocities are decreased in growth-restricted fetuses. Retrograde flow in the AoI correlates strongly with adverse perinatal outcome.

   4. Biophysical profile (BPP). Used for noninvasive fetal monitoring.

   5. Cardiotocography (CTG). Used more commonly in Europe to assess timing of delivery for situations wherein significant fetal acidosis is suspected.

   6. Placental magnetic resonance imaging (MRI). This can assess severity of FGR on the basis of decreased placental volume and changes in placental thickness-to-volume ratio. Fetal demise can also be predicted by abnormal signal intensity.

   7. Compensated versus decompensated fetus. Persistence of UPI results in fetal adaptation to maintain adequate cerebral oxygenation and growth.

      1. UPI results in increased placental vascular resistance and fetal hypoxemia by reducing umbilical blood flow. The fetus responds by redistribution of blood to the brain (brain sparing) by cerebral vasodilatation, mesenteric vasoconstriction, preferential shunting through the foramen ovale, increased fractional extraction of oxygen (O₂), polycythemia, and a relative decrease in fetal O₂ consumption. Fetal growth velocity and weight gain are decreased. Nonstress test (NST), BPP, and CTG are normal. Decreased or absent diastolic flow in the umbilical artery and increased diastolic component in the MCA are seen. The fetus is hypoxemic but does not have cerebral hypoxemia at this stage.

      2. With worsening fetal compromise. There is cerebral hypoxemia and acidemia associated with no fetal weight gain, oligohydramnios, decreased fetal heart rate variability, and abnormal NST, CTG, and BPP. Umbilical arteries show absence or reversal of end-diastolic flow (AREDV). Deep “a” wave is seen in the ductus venosus, suggestive of ventricular dysfunction. With severe acidosis, MCA PI and MCA PSV decrease, suggesting imminent collapse of the fetus.

      3. Acute fetal decompensation. AREDV in umbilical arteries (UAs) in early-onset FGR babies can be present up to 1 week before acute decompensation. Approximately 40% of fetus with acidosis have AREDV pattern. MCA vasodilation with abnormal PI may be present for up to 2 weeks before acute deterioration in 50–80% of infants. MCA vasodilation may be independently associated with abnormal outcomes in late-onset FGR. Oligohydramnios develops in 20–30% of IUGR infants about 1 week before acute deterioration (Table 105–3).

3. Neonatal assessment

   1. Reduced birthweight for gestational age. This is the simplest method of diagnosing IUGR. However, this method tends to misdiagnose constitutionally small infants.

   2. Physical appearance. When infants with congenital malformation syndromes and infections are excluded, the remaining groups of IUGR infants have a characteristic physical appearance. These infants in general are thin with loose, peeling skin because of loss of subcutaneous tissue, a scaphoid abdomen, and a disproportionately large head.

   3. Appropriate growth charts should be used. Several standardized growth charts are available to assess intrauterine and postnatal growth. See Lubchenco and Olsen charts (Chapter 5). Additional growth charts for infants based on Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO) data from birth to 36 months can be found at the CDC website: http://www.cdc.gov/growthcharts/.

   4. Ponderal index <10th percentile helps identify neonates with IUGR, especially those with birthweight <2500 g.

   5. Ballard score. Gestational age can also be assessed by means of the Ballard scoring system. This examination is accurate within 2 weeks of gestation in infants weighing <999 g at birth and is most accurate at 30–42 hours of age. (See Chapter 5.)

4. Observe for the following complications:

   1. Hypoxia

      1. Perinatal asphyxia. IUGR infants frequently have birth asphyxia because they tolerate the stress of labor poorly. IUGR accounts for a large proportion of stillborn infants with hypoxia in utero.

      2. Persistent pulmonary hypertension. Many IUGR infants are subjected to chronic intrauterine hypoxia, which results in abnormal thickening of the smooth muscles of the small pulmonary arterioles. This in turn reduces pulmonary blood flow and results in varying degrees of pulmonary artery hypertension. IUGR infants are particularly at risk for persistent pulmonary hypertension.

      3. Respiratory distress syndrome. Several reports suggest accelerated fetal pulmonary maturation in association with IUGR secondary to chronic intrauterine stress. Hyaline membrane disease is less frequently seen in IUGR because these infants tend to manifest advanced pulmonary maturity secondary to chronic intrauterine stress.

      4. Meconium aspiration. Post-term IUGR infants are particularly at risk for meconium aspiration.

      5. Patent ductus arteriosus (PDA). Conflicting data suggest that hemodynamically significant PDA may be bigger and occur earlier in IUGR infants than in appropriate for gestational age (AGA) infants, but spontaneous closure of PDA is more frequent in IUGR infants <1000 g birthweight. IUGR infants with PDA are at greater risk for pulmonary hemorrhage, intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), and renal failure.

   2. Hypothermia. Thermoregulation is compromised in IUGR infants because of diminished subcutaneous fat insulation. Infants with IUGR secondary to fetal malnutrition late in gestation tend to be thin as a result of loss of subcutaneous fat.

   3. Metabolic

      1. Hypoglycemia. Carbohydrate metabolism is seriously disturbed, and IUGR infants are highly susceptible to hypoglycemia as a consequence of diminished glycogen reserves and decreased capacity for gluconeogenesis. Oxidation of free fatty acids and triglycerides is reduced in IUGR infants, which limits alternate fuel sources. Hyperinsulinism, excess sensitivity to insulin, and deficient catecholamine release during hypoglycemia suggest abnormality of counter-regulatory hormone mechanisms during periods of hypoglycemia in IUGR infants. Hypothermia may potentiate the problem of hypoglycemia.

      2. Hyperglycemia. Very low birthweight infants have low insulin secretion, resulting in hyperglycemia.

      3. Hypocalcemia. Hypocalcemia may occur in asphyxiated IUGR infants.

      4. Liver disease. IUGR infants are at greater risk for developing cholestasis associated with parenteral nutrition. There is also an increased risk of non–fatty liver disease in children born SGA.

      5. Other. Hypertriglyceridemia, increased sympathetic tone, and reduced concentrations of IGF-1 have been associated with increased aortic intimal thickness in IUGR infants.

   4. Hematologic disorders. Hyperviscosity and polycythemia may result from increased erythropoietin levels secondary to fetal hypoxia associated with IUGR. Thrombocytopenia, neutropenia, and altered coagulation profile are also seen in IUGR infants. Polycythemia may also contribute to hypoglycemia and lead to cerebral injury. There is an increased number of nucleated red cells secondary to extramedullary hematopoiesis. Persistent elevated nucleated red cell counts are associated with worse prognosis.

   5. Altered immunity. IUGR infants have decreased immunoglobulin G (IgG) levels. In addition, the thymus is reduced in size by 50%, and peripheral blood lymphocytes are decreased. Reduction in total white cell count, neutrophils, monocyte and lymphocyte subpopulations, and thrombocytopenia may occur, and selective suppression of helper and cytotoxic T cells can be seen.

   6. Others. IUGR infants are at increased risk of developing NEC, particularly when associated with an absent or reversed end-diastolic flow on an umbilical artery Doppler. Preterm IUGR infants are also at increased risk of pulmonary hemorrhage, chronic lung disease, more severe IVH, and renal failure.

Antenatal diagnosis is the key to proper management of IUGR.

1. History of risk factors. The presence of maternal risk factors should alert the obstetrician to the likelihood of fetal growth retardation. Ultrasonography confirms the diagnosis. Correctable causes of impaired fetal growth warrant immediate attention.

2. Delivery and resuscitation. The optimal timing for delivery of IUGR infants is still debated, but Doppler measurements provide an important tool for monitoring fetal well-being. IUGR infants have a 2- to 3-fold increased risk of preterm delivery when fetal growth standards are used for diagnosis. IUGR infants delivered before 28–30 weeks have worse outcomes. Outcomes are more favorable with cesarean delivery. Delivery is usually undertaken when the lungs are mature or when biophysical data obtained by monitoring reveal fetal distress. Labor is particularly stressful to IUGR fetuses. Skilled resuscitation should be available because perinatal depression is common.

3. Prevention of heat loss. Meticulous care should be taken to conserve body heat (see Chapter 7).

4. Hypoglycemia. Close monitoring of blood glucose levels is essential for all IUGR infants. Hypoglycemia should be treated promptly with parenteral dextrose and early feeding (see Chapter 62).

5. Hematologic disorders. A central hematocrit reading should be obtained to detect polycythemia.

6. Congenital infection. IUGR infants should be examined for congenital malformations or signs of congenital infections. Many intrauterine infections are clinically silent, and screening for these should be done routinely in IUGR infants.

7. Genetic anomalies. Screening for genetic anomalies should be done as indicated by the physical examination.

Mortality increases with decreasing gestational age when IUGR is also present. Mortality decreases by 48% for each week that the fetus remains in utero before 30 weeks' gestation. Neurodevelopmental morbidities are seen 5–10 times more often in IUGR infants compared with AGA infants. Neurodevelopmental outcome depends not only on the cause of IUGR but also on the adverse events in the neonatal course (eg, perinatal depression or hypoglycemia). Many studies reveal evidence of minimal brain dysfunction, including hyperactivity, short attention span, and learning problems. Preterm IUGR infants also show alterations in early neurobehavioral functions like attention-interaction capacity and cognitive and memory dysfunction that persist. Increased risk of cerebral palsy, a wide spectrum of learning disabilities, mental retardation, pervasive developmental disorders, and neuropsychiatric disorders are seen in later years. The risk of morbidities is higher in term IUGR infants. IUGR infants who have normal Doppler studies have better outcomes than those with abnormal antenatal Doppler studies. Even mild FGR increases the risk of mortality and long-term development.

1. Symmetric versus asymmetric IUGR. Infants with symmetric IUGR caused by decreased growth potential generally have a poor outcome, whereas those with asymmetric IUGR in which brain growth is spared usually have a better outcome. Smaller head circumference is associated with cognitive, psychomotor, and behavioral delays that persist into adolescence. Neuroimaging studies using MRI and ultrasound show that preterm IUGR infants have a high incidence of white matter loss and reduced myelination in the internal capsule associated with decreased cortical gray matter volume by as much as 28%. The total brain volume is also reduced by 10% when compared with AGA infants, particularly in the hippocampal, parietal, and parieto-occipital areas.

2. Preterm IUGR. These infants have a higher incidence of abnormalities than the general population because they are subjected to the risks of prematurity in addition to the risks of IUGR. Outcomes are significantly poorer for children whose brain growth failure occurred before 26 weeks' gestation. Gestational age may be a more important predictor of developmental outcomes than FGR, particularly before 32–34 weeks.

3. Chromosomal disorders. IUGR infants with major chromosomal disorders have a 100% incidence of disability.

4. Congenital infections. Infants with congenital rubella or cytomegalovirus infection with microcephaly have a poor outcome, with a disability rate >50%.

5. Learning ability. The school performance of IUGR infants is significantly influenced by social class; children from higher social classes score better on achievement tests.

6. Adult disorders. Epidemiologic evidence indicates that obesity, insulin-resistant diabetes, hypertension, and cardiovascular diseases are more common among adults who were IUGR at birth.

7. Risk for recurrence of IUGR in subsequent pregnancies. Depends on the underlying condition. The presence of previous fetal growth retardation, preeclampsia, abruption, infarction, and acquired or inherited thrombophilias increase the risk of fetal growth retardation in the subsequent pregnancies. Placental pathologic examination should be attempted in all IUGR infants as the risk of FGR in subsequent pregnancy is very high (eg, risk of recurrence is 50–100% with fibrin deposition). In selected cases, folic acid, aspirin, and supplementation with L-arginine to improve placental blood flow may improve outcomes.

8. FGR and stillbirth. FGR is an important predictor of unexplained stillbirths. Greater than 50% of fetuses without congenital anomalies are IUGR. Maternal obesity increases the risk of concomitant FGR and stillbirth.