Current Concepts in Intrauterine Growth Restriction

Current Concepts in Intrauterine Growth Restriction Dara Brodsky, MD Helen Christou, MD Regulation of fetal growth is multifactorial and complex. Diverse factors, including intrinsic fetal conditions as well as maternal and environmental factors, can lead to intrauterine growth restriction (IUGR). The interaction of these factors governs the partitioning of nutrients and rate of fetal cellular proliferation and maturation. Although IUGR is probably a physiologic adaptive response to various stimuli, it is associated with distinct short- and long-term morbidities. Immediate morbidities include those associated with prematurity and inadequate nutrient reserve, while childhood morbidities relate to impaired maturation and disrupted organ development. Potential long-term effects of IUGR are debated and explained by the fetal programming hypothesis. In formulating a comprehensive approach to the management and follow-up of the growth-restricted fetus and infant, physicians should take into consideration the etiology, timing, and severity of IUGR. In addition, they should be cognizant of the immediate perinatal response of the growth-restricted infant as well as the childhood and longterm associated morbidities. A multidisciplinary approach is imperative, including early recognition and obstetrical management of IUGR, assessment of the growth-restricted newborn in the delivery room, possible monitoring in the neonatal intensive care unit, and appropriate pediatric follow-up. Future research is necessary to establish effective preventive, diagnostic, and therapeutic strategies for IUGR, perhaps affecting the health of future generations. Key words: intrauterine growth restriction; small for gestational age Definition and Classification Intrauterine growth restriction (IUGR) describes a decrease in fetal growth rate that prevents an infant From Children’s Hospital, Harvard Medical School, Department of Newborn Medicine, Boston, Massachusetts. Received Dec 15, 2003. Received revised Mar 8, 2004. Accepted for publication Mar 10, 2004. Address correspondence to Dara Brodsky, MD, Children’s Hospital, Harvard Medical School, Department of Newborn Medicine, Enders 9, 300 Longwood Avenue, Boston, MA 02115, or e-mail: dara.brodsky@tch.harvard.edu. Brodsky D, Christou H. Current concepts in intrauterine growth restriction. J Intensive Care Med. 2004;19:000-000. DOI: 10.1177/0885066604269663 Copyright © 2004 Sage Publications from obtaining his or her complete growth potential. IUGR infants are small for gestational age (SGA) if their birth weight measures less than 3% to 10% using standard growth curves [1]. Less commonly, these infants may be characterized as appropriate for gestational age (AGA) if their growth restriction is mild. It is important to distinguish between infants who experienced in utero growth restriction from infants with normal in utero growth but constitutionally small (ie, no loss in percentiles throughout gestation) since IUGR fetuses undergo fetal adaptations to a pathologic condition, leading to distinct short- and long-term outcomes. Two main patterns of fetal growth restriction are observed (see Table 1). If fetal growth is impaired during the first or second trimester, the infant will have symmetric growth restriction. This proportional lack of growth is caused by reduced fetal cellular proliferation of all organs and occurs in approximately 20% to 30% of IUGR infants [2]. In contrast, asymmetric growth in which an infant has a smaller abdominal size compared to head size will occur if the decrease in growth velocity happens in the last trimester. This head-sparing phenomenon is the most common form of IUGR (~70%-80%) [2] and is attributed to the ability of the fetus to adapt, redistributing its cardiac output to the spleen, adrenal, coronary, and cerebral circulations. Although some overlap can occur, the timing of the growth delay is more important than the etiology in determining the pattern of growth restriction. Epidemiology and Etiology The incidence of IUGR is estimated to be approximately 5% to 7%. Some studies identify a greater percentage (up to 15% of pregnancies), but these reports define IUGR and SGA as equivalent. Despite advances in obstetric care, IUGR remains prevalent in developed countries. However, the causes of IUGR in these areas are different than in 1 Brodsky, Christou Table 1. Specific Distinctions Between Symmetric and Asymmetric Intrauterine Growth Restriction (IUGR) Symmetric IUGR Incidence Period of growth restriction Physical characteristics Pathophysiology Etiology Outcome Asymmetric IUGR 20%-30% Begins first or second trimester Small head and abdominal size Impaired cellular embryonic division Impaired cellular hyperplasia ± hypertrophy Decreased cell number ± size Mostly intrinsic: chromosomal abnormalities and congenital malformations Drugs Infection Early-onset severe preeclampsia Preeclampsia <30 wk superimposed with chronic hypertension Greater morbidity and mortality 70%-80% Begins third trimester Large head size relative to small abdomen Impaired cellular hypertrophy Decreased cell size Mostly extrinsic: placental and maternal vascular factors (eg, placental insufficiency) Lower morbidity and mortality This table outlines the differences between symmetric and asymmetric IUGR. Although most infants can be categorized into one of these groups, some infants may have features of both types of IUGR [2,8]. Table 2. Maternal, Placental, and Fetal Etiologies of Intrauterine Growth Restriction (IUGR) Maternal Vascular disorders (~25%-30%) Hypertension Diabetes mellitus Renal disease Collagen vascular disease Hypercoaguable states Thrombophilia Antiphosopholipid antibody syndrome Persistent hypoxia (eg, high altitude, pulmonary or cardiac disease, severe anemia) Undernutrition Toxins (eg, tobacco, alcohol, medications, and illicit drugs, irradiation) Uterine malformation or masses Placental Fetal Abnormal trophoblast invasion Genetic (~20%) Placental infarcts Chromosomal abnormalities Placenta previa Syndromes/congenital malformations Circumvallate placenta Multiple gestation (5%) Chorioangiomata Intrauterine infection Velamentous umbilical cord insertion Cytomegalovirus Umbilical-placental vascular anomalies Malaria Parvovirus Rubella Toxoplasmosis Herpes virus HIV Modified from Lee et al [19], Schwart [14], and Lin and Santolaya-Forgas [8]. Overall, IUGR encompasses an extremely heterogeneous group that can be categorized into maternal, placental, and fetal factors. There is a subgroup of infants with overlapping etiologies. In addition, there are also a significant number of infants with unexplained etiologies. Third World nations. In most Western societies, placental insufficiency is the major cause of IUGR, while inadequate maternal nutrition and malaria infections play a greater role in developing countries [3,4]. Overall, IUGR encompasses an extremely heterogeneous group. While a large number of etiologies are not identified, the known associations involve fetal, placental, and/or maternal factors (see Table 2). There is a strong link between IUGR, chromosomal abnormalities, and congenital malformations. Specifically, fetuses with chromosomal disorders such as trisomy 13, 18, and 21 often have impaired growth. Also, fetuses with other autosomal irregularities (eg, deletions, ring chromosomes) typically have inadequate growth [5]. Indeed, of 458 fetuses 2 17 to 39 weeks gestation with IUGR, 19% (89) had chromosomal abnormalities (most commonly trisomy 18) [6]. Among 13,000 infants born with major malformations (most commonly anencephaly), 22% experienced IUGR [7]. Less frequently, IUGR may be due to first or second trimester fetal infection, including cytomegalovirus, malaria, parvovirus, and rubella. The majority of fetal etiologies lead to early gestation symmetric IUGR. Chronic maternal vascular disease due to hypertension, diabetes mellitus, renal disease, or collagen vascular disease is the most common cause of IUGR [8] in developed countries. The most profound effect is observed if the hypertension is early onset, severe, or due to chronic hypertension with superimposed preeclampsia [5]. Hypercoaguable Journal of Intensive Care Medicine 18(X); 2004 Intrauterine Growth Restriction maternal conditions such as thrombophilia and antiphospholipid antibody syndrome also inhibit growth either by placental thrombosis formation or by secondary effects of maternal hypertension [9,10]. Persistent maternal hypoxia due to high altitude, severe pulmonary or cardiac disease, and/or severe chronic anemia limits oxygen delivery to the fetus and attenuates fetal growth. Periods of famine in the Netherlands, Germany, and the former Soviet Union have shown that severe maternal malnutrition can also impair fetal growth [11,12]. The severity of the available food supply [13] and the length of malnutrition [12] correlate with the degree of growth delay. While the fetus is affected by chronic severe maternal malnutrition, it seems to be fairly resistant to acute malnutrition, particularly if it occurs late in gestation [14]. Maternal toxins can contribute to the development of a growth-restricted fetus. Cigarette smoking reduces uterine blood flow, limiting fetal oxygenation and attenuating growth [15]. The quantity of cigarettes smoked per day correlates with the degree of IUGR [16-18]. Prolonged maternal alcohol ingestion and other drugs (eg, steroids, coumadin, hydantoin, cocaine, and heroin) are also implicated in the development of IUGR [19]. In addition to these factors, physical constraints such as large placental abnormalities, uterine masses, or multiple gestations can lead to growth-restricted fetuses. Pathophysiology These multifactorial causes of IUGR create 3 possible scenarios: (1) abnormal placental function, (2) inadequate maternal supply of oxygen and/or nutrients, and/or (3) decreased ability of the fetus to use the supply (Fig 1). The placenta plays an integral role in the first 2 categories. Abnormal development, inadequate perfusion, and dysfunction of the placental villi are often responsible for the development of IUGR, especially the earlyonset type. Indeed, placentas from mothers with preeclampsia are characterized by shallow cytotrophoblast (CTB) invasion of the uterus and abnormal CTB differentiation [20]. Inadequate CTB invasion will prevent effective destruction of distal spiral decidual arteries leading to inadequate maternal perfusion of placental villi, local placental hypoxia, and impaired fetal growth [21]. In addition, increased apoptosis of trophoblasts creates maldevelopment of placental villi, preventing maximal attainment of placental function [22]. Oxidative Journal of Intensive Care Medicine 18(X); 2004 stress, infarction, cytokine damage, and hypertension can further inhibit optimal function of placental villi [22-24]. The response of the placental villi to damage from ischemia and/or hypoxia may involve erratic angiogenesis, limiting the possibility of complete placental recovery [22]. Recently, some specific molecular pathways have been associated with the development of IUGR. Since insulin and its associated insulin-like growth factor (IGF)-I and –II are the primary anabolic hormones necessary for fetal growth, it is postulated that they may play a critical role in the development of IUGR [25,26]. Indeed, low levels of IGF-1 and elevated levels of IGF binding protein (BP)-1 have consistently been observed in growth-restricted infants [27-29]. The involvement of IGF is directly supported by a report of a patient with a homozygous partial deletion of the IGF-I gene who had extreme prenatal growth restriction that continued postnatally [30]. In addition, IGF-1 receptor mutations have been identified in 2 children with poor intrauterine and postnatal growth [31]. Animal studies also support the role of the IGF signaling pathway in the development of IUGR. Transgenic fetal mice overexpressing IGFBP-1 demonstrate impaired fetal growth [32]. In addition, newborn mice homozygous null for the IGF-1, IGF-2, and IGF-1 receptor genes demonstrate growth deficiency with birth weights 45% to 60% of normal size [25,33]. Since transgenic mice with excess maternal decidual IGFBP-1 have abnormal trophoblast invasion and differentiation, the IGF-1 pathway may also regulate placental development [32]. Moreover, placental-specific IGF-2 knockout mice develop IUGR, emphasizing the important role of the placenta in fetal growth restriction. In addition to fetal growth and placental development, it has been suggested that this complex IGF hormonal system also regulates maternal metabolism [34-37]. Another potential signaling pathway involved in placental causes of IUGR is the glial cell missing–1 (GCM1) gene, which is necessary for trophoblast morphogenesis and differentiation [38,39]. Targeted disruption of this transcription factor in trophoblasts leads to inadequate trophoblast differentiation and similar placental histology as that found in early-onset IUGR fetuses [39,40]. Perhaps the gene itself or signaling pathways leading to GCM1 expression are altered, producing maldevelopment of the placenta villi. Accumulating evidence from animal and human studies supports that leptin may also participate in the regulation of fetal growth and development [41]. Alterations in the expression or activity of placental transporters, particularly those that transfer 3 Brodsky, Christou Fig 1. Pathophysiology of intrauterine growth restriction (IUGR). The potential factors leading to IUGR influence the maternal supply to the fetus, the ability of the fetus to use the maternal supply, and/or the placental function. If IUGR develops, there are numerous fetal adaptations that may incur perinatal, childhood, and adult effects. RDS = respiratory distress syndrome; NEC = necrotizing enterocolitis; IVH = intraventricular hemorrhage; SIDS = sudden infant death syndrome. amino acids, may also contribute to the development of IUGR [42]. Animal models have shown that pregnant rats with protein malnutrition had growth-restricted fetuses associated with a decrease in the Na+-dependent system A amino acid transporter [43]. It is possible that the placenta senses its own nutrient supply, alters its transport abilities accordingly, and regulates fetal growth; these mechanisms have not yet been well defined. 4 Prenatal Management of Growth-Restricted Fetus It is crucial that the obstetrician recognizes and accurately diagnoses a fetus with IUGR. Currently, the recommended method is by measuring anthropometric parameters, which include fetal abdominal circumference, head circumference, biparietal Journal of Intensive Care Medicine 18(X); 2004 Intrauterine Growth Restriction diameter, and length. These results are converted to fetal weight estimates using standard formulas and compared with population-based fetal growth curves at specific gestational ages (GA) [5]. Precise initial dating by an early ultrasound will ensure that the accurate GA is used [44]. Sequential assessments are necessary to determine if there is a decrease in the fetal growth rate. Once the diagnosis of IUGR is established, the obstetrician must attempt to determine the specific cause of the growth delay. An abnormal fetal survey should prompt further investigations, including fetal karyotyping, specialized genetic tests, and possible consultation with a geneticist. If a viral infection is suspected, maternal serum studies are required. Since fetal growth restriction may be the first evidence of preelampsia, maternal blood pressures should be monitored closely. The pregnant woman should be evaluated for vascular and hypercoaguable diseases as well as hypoxemic conditions. An assessment for malnutrition and medications or toxins, including tobacco, may be helpful. After delivery, examination of the placenta by a pathologist may disclose placental vascular abnormalities. Despite numerous approaches to managing IUGR, there are no effective therapies to improve the growth pattern of a fetus [45]. Modalities tested include maternal nutritional supplementation, plasma volume expansion, and maternal medications such as low-dose aspirin [5,46,47]. Although maternal oxygen supplementation has been shown to increase fetal oxygen tension [48] and transiently improve fetal well-being [49,50], long-term benefits have not been demonstrated [51]. Some reports suggest that any short-term benefit of improved fetal oxygenation may actually worsen the longterm outcome by prolonging the time a fetus spends in an inadequate intrauterine environment [52]. Although antihypertensive medications can be advantageous in the treatment of preeclampsia, they do not prevent or reverse fetal growth restriction [8]. Finally, while bed rest is often encouraged, there is no evidence to support that this approach has any effect on fetal growth [53]. Since there are no effective therapies to reverse fetal growth restriction, prenatal management is aimed primarily at determining the ideal timing and mode of delivery. This assessment must be individualized, depending on several variables: GA of the fetus, maternal health, severity of the IUGR, and fetal well-being. Perhaps optimizing the delivery time and removing the fetus from a suboptimal environment can prevent the risk of hypoxia and significant morbidities. Journal of Intensive Care Medicine 18(X); 2004 The GA of the fetus is a critical component of the decision-making process. If a growth-restricted fetus is near term with either poor growth or associated severe maternal preeclampsia, delivery is recommended. Similarly, an IUGR fetus between 34 and 37 weeks gestation should be delivered if there are similar concerns in the setting of mature fetal lung indices. The management of premature infants <34 weeks gestation is more challenging. Indeed, arbitrary delivery of a growth-restricted premature fetus at any GA is not warranted because fetal mortality is lower than neonatal mortality prior to 31 weeks gestation [54]. Since antenatal steroids decrease neonatal pulmonary and central nervous system morbidity in premature infants, these are still recommended for IUGR premature fetuses, although specific effects on fetuses with growth delay are conflicting [55,56]. In the group of IUGR fetuses with unclear indications for immediate delivery, the obstetrician must rely on other assessment tools to monitor fetal well-being and determine the safest time for delivery. While some physicians advocate biweekly nonstress tests, randomized controlled studies have not shown that outcomes are improved with this monitoring [57,58]. Similarly, trials assessing efficacy of using biophysical profiles as a modality to determine the optimal delivery time have not shown an association with better outcomes [47,54,57]. Since studies demonstrate that oligohydramnios dramatically increases perinatal mortality in the growth-restricted fetus, this is often used as an independent indicator for delivery [59]. Umbilical Doppler flow measurements are the most valuable current technique to distinguish the sick IUGR fetus from the well IUGR fetus [60] and, in contrast to other modalities, improve perinatal outcomes [61-64]. Indeed, using this approach, fetuses with the worst placental outcome [65,66] and the most detrimental perinatal outcome [67-69] can be identified. During this technique, the impedance to blood flow in fetal arteries and veins by Doppler velocimetry is measured; absent or reversed end-diastolic flow in the umbilical artery indicates an inadequate fetal status [70,71], while normal umbilical Doppler flow is rarely associated with significant morbidity [72]. If associated abnormalities are observed in the ductus venosus and umbilical veins, the IUGR fetus is even more compromised with a high chance of imminent death [73]. This corresponds with the timing of fetal circulatory changes during a compromised state since venous alterations typically occur after arterial changes [74]. The assessment of fetal acid-base balance by umbilical blood sampling has been shown 5 Brodsky, Christou to further identify growth-restricted fetuses with hypoxia and acidosis [75]. Some new modalities are currently being investigated to improve the assessment of a compromised fetus. One method records Doppler fetal cerebral circulation and calculates the cerebro-placental ratio of blood flow [76]. While this ratio has been shown to be impaired in IUGR fetuses, a correlation between perinatal complications and neurodevelopmental outcome has not been deciphered [77,78]. Qualitative determination of general movements is also proposed as a potential tool to assess brain function [79-81]. Indeed, preliminary findings have found that fidgety movements are predictive of neurological insults [82]. Finally, Doppler imaging of the proximal uterine arteries to assess maternal vascular function has been helpful in predicting the severity of IUGR in mothers with preeclampsia [83]. Once the timing of delivery has been established, the obstetrician is now responsible for determining the mode of delivery. A trial of labor is often considered in selected women with growth-restricted fetuses if antepartum fetal testing by umbilical artery Doppler velocimetry is normal [84]. Despite this preselection of milder IUGR fetuses, a cesarean delivery may still be required since all growthrestricted fetuses have a greater rate of intolerance to labor, evident by abnormal fetal heart rate patterns [85]. Management and Outcomes During the Neonatal Period Numerous studies have shown that growthrestricted fetuses have a greater risk of fetal mortality, correlating directly with the severity of IUGR [5,54,86-90]. Indeed, studies have found that almost half of stillborn fetuses without malformations had growth restriction [89]. This increased mortality risk extends beyond the fetal period; growth-restricted full-term infants weighing 1500 to 2500 g (<10%) have a 5 to 30 times higher mortality risk compared to term infants born >2500 g (>10%) [5]. It is well recognized that growth-restricted infants are at greater risk of morbidities [86,88,90,91]. Neonates with a greater severity and protracted period of IUGR are at even more risk of perinatal complications and poor prognoses. It is also important to acknowledge that known etiologies of IUGR will independently influence these morbidities. Specifically, infants with IUGR attributable to fetal factors (eg, in utero infection, chromosomal abnormalities) have independent adverse outcomes. 6 At delivery, the presence of a qualified neonatology team is an important initial step in managing IUGR infants. Infants may have perinatal depression with low APGAR scores requiring emergent resuscitation in the delivery room [5,92,93]. This may be associated with meconium aspiration and/or a severe metabolic acidosis. Because of decreased liver glycogen and fat stores, IUGR infants must be monitored for hypoglycemia and hypothermia [94]. Polycythemia attributed to a relatively hypoxic intrauterine environment may predispose the IUGR infant to greater postnatal hemolysis and lead to indirect hyperbilirubinemia. In addition, since this population of infants is at increased risk of intrauterine coagulative processes, thrombocytopenia can be observed [95]. The high incidence of premature delivery in IUGR infants leads to the characteristic postnatal risks of prematurity [90,96]. Numerous investigations have compared specific complications of prematurity among growth-restricted neonates and gestational age–matched AGA infants. For almost 3 decades, it was believed that IUGR infants had accelerated lung maturation with decreased rates of hyaline membrane disease (HMD) due to prolonged intrauterine stress inducing fetal corticosteroid production. However, recent studies suggest that HMD occurs at equal rates in growth-restricted and AGA premature infants [97-99] and perhaps may actually be more common in IUGR infants [44,90]. Most trials have demonstrated an increased risk of chronic lung disease in IUGR infants [97,98,100]. Perhaps the restricted development of the fetus enhances the lung’s susceptibility to postnatal injury. Similar to HMD, the association of necrotizing enterocolitis (NEC) and poor intrauterine growth remains controversial. It has generally been believed that the decreased vascular supply to the gastrointestinal tract in utero predisposes the infant to develop NEC, and studies have demonstrated this increased risk [44,90,99,101,102]. However, other reports have shown no increased risk of NEC in IUGR infants [103]. Some reports demonstrate that prenatal findings of abnormal flow in the fetal aorta as well as absent or reversed end-diastolic umbilical arterial flow predisposes the growthrestricted fetus to develop NEC [104,105]. Further studies are needed to elucidate the correlation of NEC and IUGR. In addition to HMD and NEC, the association of intraventricular hemorrhage (IVH) in growthrestricted and AGA premature infants is still debated. Some studies have demonstrated a larger risk of IVH [90], while others did not observe any associaJournal of Intensive Care Medicine 18(X); 2004 Intrauterine Growth Restriction tion [99,101]. Another report found that IVH was actually decreased in IUGR infants of 28 weeks gestational age compared to AGA neonates, suggesting a potential protective effect of growth restriction [44]. The heterogeneity of IUGR infants may contribute to the discrepancies in potential associations with HMD, NEC, and IVH. Although there is a low number of published investigations focused on hypothyroxinemia and IUGR, all have been consistent; growth-restricted infants are at greater risk for early hypothyroxinemia [106-109]. Metabolic reasons for this association have not yet been identified. A higher infection rate has also been consistently observed in IUGR premature infants compared with matched AGA infants [99,110]. An increased association between persistent pulmonary hypertension of the newborn (PPHN) and asymmetric growth restriction has also been reported [111]. Our anecdotal experience suggests that premature IUGR infants are a subset that is more likely to develop PPHN. Finally, the kidneys appear to be extremely vulnerable to IUGR and are often small in proportion to body weight [112,113]. Besides the deficit in nephrons, there is an impairment of renal function associated with IUGR [114,115]. These renal effects may explain the epidemiological studies connecting the development of adult hypertension with IUGR [116-118]. Management and Outcomes During Childhood The effects of IUGR persist beyond the neonatal period and may have profound influences during childhood. The majority of IUGR infants demonstrate an increased postnatal growth velocity with catch-up growth by 2 to 3 years of age [19,119,120]. However, since IUGR infants have low nutritional stores and often have feeding difficulties, a subgroup (~10%) remains vulnerable to continued growth problems [19,121]. Longitudinal studies support a greater incidence of short stature in IUGR children born prematurely compared with full-term IUGR children [120,122]. If a child with a history of IUGR is older than 3 years and has persistent growth delay, he or she should still be evaluated by a pediatric endocrinologist for other potential causes [19]. In addition to growth hormone deficiency, one should assess for abnormalities of IGF-1, IGFBP-3, fasting insulin, glucose, and lipid levels [19]. Some studies demonstrate normalization of height after prolonged growth hormone treatment despite normal initial hormonal levels [123-131]. Journal of Intensive Care Medicine 18(X); 2004 The literature is inconsistent about the influence of IUGR on long-term neurological outcome, ranging from minimal decreases in IQ [132,133] or no effects [134-138] to cerebral palsy [139-141]. Not surprisingly, the worst outcomes are observed in those with severe IUGR [134], early-onset IGUR [142,143], premature birth [144], and prenatal evidence of impaired umbilical arterial flow [145,146]. The presence of microcephaly at birth with poor catch-up of head growth is one of the most significant negative determinants of neurodevelopmental outcome [81,147]. The best long-term neurological prognosis is encountered when the fetus tolerates labor, the growth restriction is mild, the delivery date is carefully determined, immediate neonatal care is available, and there is appropriate prenatal and postnatal head growth [2,5,147]. Most reports suggest that severe IUGR incurs subtle behavioral and learning disabilities during childhood [77,135,144,148-151]. Perhaps the disparity of findings related to neurological outcome can be explained by the heterogeneity of the populations examined including differences in etiology, definition of IUGR, age the children are examined, perinatal and neonatal complications, and distinct sociodemographic and postnatal environmental factors [35]. Other childhood effects from IUGR have been identified. There is a slight increased risk of sudden infant death syndrome reported in growth-restricted infants [152,153], attributed possibly to failure of breathing or arousal from sleep [154,155]. Fetal growth restriction also impairs airway function during childhood, evident by lower forced expiratory volumes in 5- to 11-year-old children with a history of IUGR [156]. The onset duration and severity of IUGR may influence these childhood effects. Long-term Outcomes It is well accepted that an individual’s risk of developing adult disease is determined by the interactions between one’s genetic makeup and postnatal environmental factors. Epidemiological studies since the early 1980s suggest that suboptimal growth during the fetal period also predisposes to specific diseases later in life including adultonset hypertension (HTN), type 2 diabetes, and coronary artery disease (CAD) [157]. This epidemiological association forms the basis of the fetal programming hypothesis, which proposes that these 3 disorders “originate in developmental plasticity, in response to undernutrition during fetal life and infancy” [158]. 7 Brodsky, Christou Although the association of IUGR and HTN in adulthood is still disputed [159], accumulating evidence from animal and human studies supports that suboptimal in utero nutrient supply leads to metabolic and hormonal adaptations as well as altered organ structure, which may contribute to HTN, insulin resistance, and CAD. The so-called “thrifty phenotype” describes the fetal response to inadequate nutrient supply and consists of decreased muscle mass, insulin resistance, decreased capillary network, and an increased stress response. In the setting of this phenotype, it has been proposed that subsequent abundance of nutritional supplements may predispose an individual to the development of the metabolic syndrome (syndrome X), which consists of centripetal fat accumulation, insulin resistance, glucose intolerance, hypertriglyceridemia, low levels of high-density lipids, and HTN. Since this syndrome is complex and multifactorial, the fetal programming hypothesis can be viewed as the result of the interaction between the genetic makeup of the individual and nutritional, metabolic, and hormonal cues during fetal and neonatal development that ultimately determine the risk of adult morbidities. Several studies have addressed the possible association of IUGR with HTN in childhood and adulthood [157,160]. Although the majority of these studies support an inverse relationship between birth weight and arterial blood pressure, a published meta-analysis suggests that as the statistical size of the study increases, the magnitude of this association decreases [159]. In evaluating these studies, several methodological considerations should be taken into account, including the source of the birth weight (birth records or memory), the number of blood pressure measurements, the age at which blood pressure is reported, and whether there is adjustment for current weight and other confounding variables. Animal and human studies have provided some insight into the possible biological basis for the association of IUGR and HTN. Because IUGR infants have a significant reduction in nephron number [114,161,162], this may predispose them to develop HTN later in life [116-118,163]. Furthermore, since the etiology of HTN is multifactorial and largely unknown, it is possible that IUGR may be a modifying factor in individuals who have a genetic predisposition to HTN. Clearly, further elucidation of the underlying molecular mechanisms is needed to accomplish early detection and management of at-risk infants. Many epidemiological studies support a strong association between IUGR and the subsequent 8 development of type 2 diabetes and the metabolic syndrome [164,165]. Animal data show that this association can be explained partly by permanent changes in the expression of hormone receptors, signaling molecules, and regulatory enzymes in liver, pancreatic β cells, muscle, and adipose tissue in response to in utero undernutrition [165-167]. These studies have also questioned whether rapid catch-up growth following early growth retardation may add to the risk of developing insulin resistance [165]. The combination of low birth weight and accelerated childhood growth is associated with exaggeration of adiposity and insulin resistance, particularly for those who were born with IUGR. The postnatal age of adiposity rebound is a predictor of both adult adiposity and insulin resistance. In one study, individuals with adiposity rebound before age 5 had an 8.6% incidence of diabetes compared to 2.1% in individuals whose adiposity rebound occurred after age 7 [168]. Recent studies in premature human neonates suggest that enhanced nutritional intake postnatally is associated with an increased incidence of insulin resistance at age 16 [169]. Finally, it has been proposed that IUGR is an added risk factor in individuals who have another predisposing factor for insulin resistance such as PPAR-γ polymorphisms [170]. The association between IUGR and CAD is predominantly indirect, mediated by the effect of low birth weight on the incidence of HTN, diabetes, and the metabolic syndrome. Studies of in utero anemia in sheep have provided evidence for a direct effect of intrauterine anemia (and the associated growth restriction) on coronary artery physiology. Altered coronary conductance and inappropriate cardiac responses to hypoxic stress have been observed in adult sheep exposed to in utero anemia [171,172]. The importance of these observations in humans needs to be clarified. In summary, IUGR has been associated with specific adult diseases. It appears that the nutritional management of the low-birth-weight infant probably plays a role in the risk of developing some long-term morbidities. Regular monitoring of weight, height, and body mass index during infancy, childhood, and adolescence should be implemented to attempt to avoid excessive weight gain and possibly HTN, type 2 diabetes, and CAD. Future Directions Innovative intrauterine interventions to prevent, detect, and treat growth restriction could reduce potential neonatal, childhood, and adult effects. Journal of Intensive Care Medicine 18(X); 2004 Intrauterine Growth Restriction Presently, there are 3 effective preventive strategies to optimize fetal growth: (1) discourage smoking during pregnancy, (2) encourage optimal maternal nutrition, and (3) prescribe antimalarial prophylaxis for primigravida in developing countries [45]. Future research necessitates the development of other approaches to prevent IUGR. Since the delay in fetal growth is often insidious, we need to develop new, accurate diagnostic tools to identify fetuses at the early stages of IUGR. Doppler ultrasounds may become more sensitive to subtle vascular changes. It is also possible that ultrasound imaging could measure fat concentrations during late gestation to decipher small, wellproportioned fetuses with appropriate growth velocities from IUGR fetuses [173]. Currently, research trials are investigating the ability to quantify placental transfer by administering a cocktail of stable isotopes (eg, glucose, specific amino acids) to pregnant mothers. Since these substrates are expected to cross the placenta at a standard rate, measurement of fetal concentrations by cordocentesis would correlate with placental function [35,174]. New fetal diagnostic techniques to assess fetal well-being are critical to guide obstetricians about the optimal timing and mode of delivery. Ideally, these approaches would correlate with short- and long-term outcomes. Future studies will need to identify effective therapeutic strategies that could reverse fetal growth restriction. Targeting the anabolic hormone IGF-1 may be one possible approach. Infusion of IGF-1 into fetal sheep increased growth of the heart, liver, kidneys, spleen, and pituitary gland [175]. Since this may not be feasible in humans, maternal administration of IGF-1 may improve fetal growth. Unfortunately, one study demonstrated that pregnant rats who received IGF-1 had accelerated growth of maternal tissues without any changes in fetal growth [37]. Further research focused on IGF1 as a therapy for IUGR is required. A second approach could focus on enhancing placental growth and/or function to potentially induce fetal growth. To accomplish these therapeutic goals, the distinct pathophysiology of IUGR must be elucidated using additional molecular techniques, animal models, epidemiological studies, and clinical investigations. These tools must unravel the intricate interactions between the health of the pregnant woman, the function of the placenta, and the growth of the fetus. This integrative approach requires tremendous consistency in the definition, classification, etiology, and severity of IUGR. 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