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Tterinelesanprematurity and IUGR are similar and are listed in Table 1.Many of these causes of IUGR have been reviewed in otherartfurtilebirforinfareproIUronolicanearwiaff

genantiodrurelchdeficiency. In these cases, fetal growth is initially normal untilthe rate of growth exceeds substrate provision, generally in

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014doiicles in this issue of the journal and will not be discussedther here. By convention, infants less than the 3rd percen-for weight (10th on the Denver curves because of lowerth weight at higher altitude) are classified as being smallgestational age (SGA). It is important to keep in mind thatants with IUGR may or may not be SGA, and infants whoSGA may not have been affected by growth-restrictingcesses that cause IUGR. The decreased fetal growth rate inGR is an adaptation to an unfavorable intrauterine envi-ment and may result in permanent alterations in metab-sm, growth, and development.1-7 Fetal growth disordershave their origins early or late during gestation. Onset

ly in gestation results in symmetrical growth restrictionth weight, length, and head circumference equivalentlyected. Causes for symmetrical growth restriction include

the third trimester where two-thirds of fetal growth occurs.These fetuses fail to thrive just as infants do with poor weightgain and relative sparing of length and brain growth (headcircumference). With even a slight decrease in energy sub-strate to the fetus, glycogen and fat formation as well as mus-cle growth are limited.8,9 Bone growth and thus length areless affected, whereas sparing of head growth is caused bypreferential substrate delivery to the brain after redistributionof cardiac output.

The acute neonatal consequences of IUGR are perinatalasphyxia and neonatal adaptive problems. The risk of thesecomplications is increased at all gestational ages.10 A list ofpotential neonatal problems that can be anticipated is pre-sented in Table 2. Delivery room management should focuson the anticipation of a depressed infant. Subsequent atten-tion should be concentrated on insuring a normal physio-logic transition. A complete pregnancy and maternal historyshould be obtained focusing on the items listed in Table 1 tobegin to address the etiology of the fetal growth restriction.

artment of Pediatrics, University of Colorado School of Medicine, TheChildrens Hospital, Aurora, CO.ress reprint requests to Adam Rosenberg, MD, University of Coloradohe IUGR Newbornam Rosenberg, MD

Intrauterine growth restriction (IUGR) is charthe population and growth potential of a givweight, length and head circumference indicin pregnancy or asymmetrical with sparingprocesses occurring later in gestation. Theperinatal asphyxia and neonatal adaptive prorespiratory distress due to meconium aspirpulmonary hemorrhage, abnormalities of glupolycythemia are reviewed in this article. Isreviewed as well including an increased incenterocolitis, retinopathy of prematurity andSemin Perinatol 32:219-224 2008 Elsevier

KEYWORDS intrauterine growth restriction, smhypoglycemia, thermoregulation, polycythem

he term low birth weight refers to infants born at a weightless than 2500 g. This group includes infants born pre-

m and those born at term but of reduced weight. Intrauter-growth restriction (IUGR) can be defined as fetal growths than normal for the population and growth potential ofinfant. Risk factors for low birth weight related to bothInfreg

School of Medicine, Box B158, The Childrens Hospital, 13123 E. 16thAve., Aurora, CO 80045. E-mail: Adam.rosenberg@uchsc.edu

6-0005/08/$-see front matter 2008 Elsevier Inc. All rights reserved.:10.1053/j.semperi.2007.11.003zed by fetal growth less than normal fornt. IUGR can be symmetrical with lowsually of a process with its origin earlyead circumference and length due toneonatal consequences of IUGR are

. These adaptive problems that includepersistent pulmonary hypertension orregulation, temperature instability, andpecific to the IUGR preterm infant aree of chronic lung disease, necrotizingatal growth failure.ll rights reserved.

r gestational age, perinatal asphyxia,

etic disorders (trisomies, other chromosomal disorders,d constitutional), dwarf syndromes, congenital viral infec-ns, some inborn errors of metabolism, and intrauterineg exposures. Growth restriction of later onset is usuallyated to impaired uteroplacental function (preeclampsia,ronic hypertension, class D and F diabetes) or nutrientants should be weighed and measured and plotted onion-specific growth curves to confirm symmetric or asym-

219

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220 A. Rosenbergtric growth restriction. The gestational age assessment inse infants can be misleading due to diminished vernixeosa, cracking and peeling of the skin, less well formed eartilage, diminished breast tissue, and less mature-appear-female genitalia. The neurologic portion of the examina-n is less affected by IUGR and can be used to more accu-ely confirm gestational age. Initial physical examinationuld focus on identification of dysmorphic features andnor congenital anomalies (indicative of chromosomal ab-rmality, a syndrome, or intrauterine drug exposure) asll as indicators of congenital viral infection (petechiae, skinhes, hepatosplenomegaly, chorioretinitis, and cataracts) inrticular in the symmetrically growth-restricted infant. Thearacteristic appearance of the infant with asymmetricwth restriction includes a relatively large head with un-rgrown trunk and extremities with a small scaphoid-ap-aring abdomen. There is little subcutaneous tissue or fating the skin a loose, dry, peeling characteristic. Fingernailspear long with hands and feet too large for the rest of thedy. The face gives the appearance of an old man. Theterior fontanel may be large from decreased membranousne formation. With passage of meconium in utero, there islowgreen staining of fingernails, umbilical cord, andn. The umbilical cord is often quite thin. Mild to moder-ly growth-restricted infants often appear somewhat anx-s and hyperalert and are often jittery and hypertonic.

le 1 Risk Factors for Low Birthweight

ican American racew socioeconomic statusw maternal weight for heightw maternal weight at her birthternal short staturevious infant of low birthweightor nutrition in the mother before and during pregnancyternal age (less than 16 or over 35)erine or cervical anomaliesltiple gestationeclampsia or maternal hypertensionronic disease in the motherrauterine infectioncental insufficiency; umbilical cord abnormalitiesavy physical work during pregnancyitudeoking, alcohol or drug usageort interpregnancy interval

le 2 Adaptive Problems in the SGA Infant

rauterine fetal demiserinatal asphyxiaconium aspiration syndromersistent pulmonary hypertension of the newbornlmonary hemorrhagepoglycemiaperglycemia24(fo

lycythemia/hyperviscositymperature instabilityre severely growth-restricted infants can appear hypo-ic, apathetic, and sleepy.

eonatal Problemsthe Term or Latereterm Infant with IUGRe perinatal mortality rate in IUGR infants is 10 to 20es that of AGA infants.10-12 Intrauterine demise fromg-standing hypoxia, birth asphyxia, and congenitalomalies are the usual causes. Perinatal asphyxia is thetial concern in the IUGR fetus. Careful obstetric surveil-ce and timely delivery as outlined in other articles ins issue can prevent perinatal asphyxia and its clinicalnsequences. The sequelae of perinatal asphyxia includeltiorgan dysfunction (Table 3), neonatal encephalopa-, and metabolic acidemia. The clinical features of neo-tal encephalopathy are diminished level of conscious-ss, hypotonia, decreased spontaneous movements,riodic breathing or apnea, and seizures. Brainstem signsluding oculomotor and pupillary disturbances and ab-t gag reflex may also be seen. The severity and durationclinical signs correlate with the severity of the insult.her evaluations helpful in assessing severity includectroencephalogram (EEG), computed tomography (CT)n, and magnetic resonance imaging (MRI). MRI withfusion weighted imaging is useful, especially in thely evaluation of infants.13 Abnormal background pat-ns on the EEG with voltage suppression, CT scans withfuse hypodensity, and loss of gray/white matter differ-tiation as well as injury seen on diffusion weighted MRIominous predictors of outcome.14 Management is sup-rtive with fluids run at 60 to 80 mL/kg to minimizeebral edema while maintaining adequate blood pres-re and blood glucose. In addition, these infants are atk for renal failure and thus prone to fluid overload.ygenation should be maintained with supplemental ox-en and mechanical ventilation if needed. Hypocalcemia,agulation abnormalities, and metabolic acidemia shouldcorrected. Seizures should be treated with IV pheno-rbital (20 mg/kg loading dose, with a total initial first

le 3 Clinical Sequelae of Perinatal Asphyxia

poxicischemic encephalopathy, seizuresspiratory distress due to aspiration, secondaryurfactant deficiency, pulmonary hemorrhagersistent pulmonary hypertensionpotension due to myocardial dysfunctionnsient tricuspid valve insufficiencyuria or oliguria due to acute tubular necrosiseding intolerance, necrotizing enterocolitisvated aminotransferases due to liver injuryrenal insufficiency due to hemorrhageseminated intravascular coagulation-hour dose of up to 40 mg/kg). Other anticonvulsantssphenytoin, topiramate) should be reserved for refrac-

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The IUGR newborn 221y seizures. Hypothermia with selective head coolingth mild systemic hypothermia or whole body coolings been shown to improve outcome at 18 month fol--up of infants with a moderate to severe neurologicdrome and a comparable 1 lead integrated EEG.15-17

cacy has not been proven for severe neonatal enceph-pathy. Finally, it is important to note that careful atten-n needs to be paid to the circumstances surrounding thelivery. Infants that are IUGR may not do well in thelivery room (such as those with a chromosomal abnor-lity or intrauterine infection) in the absence of intrapar-hypoxia. In these cases in which the four essential

teria (Table 4) to make a diagnosis of perinatal asphyxianot met, cord gases can be helpful in confirming thek of intrapartum hypoxia.18,19

The major respiratory complication seen in these infantsmeconium aspiration syndrome with persistent pulmo-ry hypertension. Initial chest x-ray findings will bese of patchy irregular infiltrates with hyperexpansion.the disease process evolves, infants can develop sec-dary surfactant deficiency related to surfactant inhibi-n by meconium or in the case of pulmonary hemorrhageblood. In some cases, administration of exogenous sur-tant is efficacious in improving their respiratory sta-.20 Pulmonary hypertension should be documentedth an echocardiogram showing right to left shunting atlevel(s) of the ductus arteriosus and the foramen ovale.

ecific therapy for persistent pulmonary hypertension ofnewborn (PPHN) is directed at both increasing sys-ic arterial pressure and decreasing pulmonary arterialssure to reverse the right to left shunting through fetalthways. First-line therapy includes oxygen and ventila-n as well as crystalloid infusions for low systemic bloodssure. With compromised cardiac function, systemicssors can be used (dopamine or dobutamine at 5-20/kg/min). Metabolic acidemia should be corrected ass exacerbates pulmonary vasoconstriction. Pulmonaryodilation can be enhanced using inhaled nitric oxide20 ppm), which selectively dilates the pulmonary vas-lar bed.21 High-frequency oscillatory ventilation haso proven effective in many of these infants as well.21 Inants in whom conventional therapy has failed, ECMO is

le 4 Essential Criteria to Define an Acute Intrapartum Hy-xic Event18

Evidence of a metabolic acidosis in fetal umbilical cordarterial blood obtained at delivery (pH < 7 and basedeficit > 12 mmol/L).Early onset severe or moderate neonatal encephalopathyin infants born at 34 or more weeks of gestation.Cerebral palsy of the spastic quadriplegic or dyskinetictype.Exclusion of other identifiable etiologies such astrauma, coagulation disorders, infectious conditions, orgenetic disorders.option, but this needs to be carefully considered in lightthe anticipated neurologic prognosis for the infant.IUGR infants are at increased risk for problems with ther-regulation.22 Ideally, these infants can increase heat pro-ction to compenstate for excessive heat loss because brownipose tissue stores are not usually depleted.23 If heat loss,cerbated by a relatively large body surface area and de-ased subcutaneous tissue, is allowed to continue, hypo-rmia will ensue. In addition, both hypoxia and hypogly-ia can interfere with heat production. Thus, a neutralrmal environment should bemaintained via bundling or ifed be an external heat source.Fasting hypoglycemia is an issue of major concern for theGR infant. The greatest risk for hypoglycemia is during thet several days of life when the newborn must adapt torauterine life without the placental source of nutrients thatuires adequate glycogen stores; intact glycogenolytic, glu-eogenic and lipogenic mechanisms; and appropriatenterregulatory hormone responses. The hypoglycemia inIUGR infant is due primarily to decreased glycogen storese predominant source of glucose in the first hours afterth) with a possible contribution from diminished glucoseduction in the liver from alanine and lactate via glucone-enesis.24-26 The latter, however, has not been a consistentding. In addition, growth-restricted infants also have lim-d fat stores and appear to not oxidize free fatty acids andlycerides effectively,27 thus failing to spare tissue use ofcose. There is also some evidence to support a role for acrease in counterregulatory hormone response.28 Further-re, hyperinsulinism or excessive sensitivity to insulin cancerbate hypoglycemia and in some cases can lead to theed for high glucose infusion rates and prolonged hypogly-ia.29,30 These infants need to be closely observed for clin-

l signs consistent with hypoglycemia as well as with rapidod glucose determinations. In the asymptomatic infant,teral feeds with frequent glucose checks is an adequaten of treatment. Whole blood glucose levels persistentlys than 40 to 45 mg/dL unresponsive to enteral feeding ory asymptomatic infant with very low glucose concentra-ns (less than 20-25 mg/dL) mandate provision of intrave-us glucose.31,32 All symptomatic infants (Table 5) shouldo receive intravenous glucose. An initial bolus of 2 mL/kg0 mg/kg) of D10W can be given followed by an infusion4 to 8 mg/kg/min. The rate of infusion can be slowlyaned once the blood glucose is stable as feedings are ad-ced. Given the risk of some degree of in utero intestinal

le 5 Clinical Signs of Hypoglycemia

Tremors and jitterinessHypotoniaIrritabilityLethargySeizures

Cyanosis; pallorTachypneaApnea

Hypothermia

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222 A. Rosenberghemia in IUGR infants, it is unwise to aggressively use tubeds in the term growth-restricted infant. For the most part,d advancement should use nipple feeds. Tube feeds can bed and advanced cautiously in the growth-restricted lateterm infant. In the case of infants with neonatal encepha-athy, it is important to keep blood glucose in the normalge to avoid exacerbation of brain injury.32,33

Chronic intrauterine hypoxia induces synthesis of eryth-oietin causing an increase in red cell mass.34 In addition,alternatively, placentalfetal transfusions can occur in la-r or during asphyxia, resulting in a shift of placental bloodthe fetus. Both of these mechanisms can account for poly-hema in the IUGR fetus. Depending on sample site, poly-hemia is defined as a capillary hematocrit over 75%, pe-heral venous over 71%, and umbilical vein over 63% interm infant.35 This problem is over-represented in IUGRants with 50% having central hematocrits over 60% and% over 65% compared with 5% in normal term in-ts.36,37 The hematocrit elevation results in hyperviscositysing sludging of red cells in the microcirculation. Clinicalnifestations include plethora, lethargy, irritability, sei-res (rarely), decreased urine output, renal vein thrombosis,ding intolerance or necrotizing enterocolitis (NEC), tachy-ea or congestive heart failure, hyperbilirubinemia, throm-cytopenia, and hypoglycemia. In an asymptomatic polycy-mic infant, monitoring of clinical status and glucoseecks are an adequate approach. Indication for specificatment is symptoms felt to be due to polycythemia.38 Thendard approach includes hemodiluting the infant withrmal saline. The amount to exchange in milliliters is cal-lated with the following formula:

f ml to exchange

(PVH DH) PVH BV (ml kg) wt (kg),

ere PVH is the current peripheral venous hematocrit andis the desired hematocrit and BV is the blood volume.

pecial Issuesr the IUGR Preterm Infantproximately 30% to 50% of extremely preterm neonates areA. Infants with very low birth weight who are SGA haveher mortality rates than their AGA counterparts and are atnificant risk for reduced postnatal growth and developmentwell as acute and chronic morbidities, such as respiratorytress syndrome (RDS), bronchopulmonary dysplasia (BPD),d retinopathy of prematurity (ROP).10,11,39-41 The excess inrtality and morbidity likely has its origins in the unfavor-le in utero environment. Contrary to the common wisdomt the intrauterine stress associated with IUGR enhancesg maturation, McIntire and coworkers reported an in-ased incidence of respiratory distress in infants born at lessn the 26th percentile compared with heavier infants ofilar gestational age.10 Spinillo and coworkers similarly

orted a significantly increased risk of RDS in infants 24 toweeks gestation with IUGR.42 Conversely, other studies

nebeve not demonstrated an increase in RDS in this popula-n.43,44 In accord with an increased incidence of RDS is theparent association between IUGR and BPD.10,44,45 Severalderlying mechanisms can be postulated to explain the in-ased incidence of BPD in these infants, including delayedtabolic adaptation, systemic inflammatory response duechronic hypoxia, more severe early lung disease, and ox-n free radical mediated injury. The risk of NEC in prema-e SGA infants is increased as well compared with AGAants.39,46,47 The postulated mechanism is in utero bowelhemia due to shunting of blood in response to hypoxia toal organs. The incidence of NEC is increased in infantsth fetal absent or reversed end diastolic flow in the umbil-l artery.48 Superior mesenteric artery Doppler studies ony of life 1 show reduced blood flow in SGA infants. Theseanges persist during the first week of life, putting theseants at risk with the onset of enteral nutrition.49 Retinop-y of prematurity also seems to occur with greater fre-ency in these infants.11,46 IUGR can be implicated in theesis of ROP due to intrauterine hypoxia, altered levels ofwth factors, and diminished antioxidant capacity.43 Veryterm SGA infants have developmentally low insulin secre-n rates and plasma insulin concentrations which can leadhyperglycemia, which complicates the administration ofequate parenteral nutrition.

utritional Managementf the IUGR NeonateA infants are particularly deficient in muscle mass, butta about the ability of these infants to tolerate aggressivevision of amino acids and protein are not conclusive.50

terms of lipid metabolism, SGA infants have lowersma free fatty acid concentrations than AGA infants. Indition, use and oxidation of free fatty acids and triglyc-des are diminished in SGA newborns.50 SGA infantsve a relatively elevated energy requirement due to theger body weight percentage of metabolically active or-s. Based on this information, it would seem to followt SGA infants will require high caloric and protein ad-nistration. This is likely not an unreasonable strategyth mild to moderate growth restriction with the antici-tion of catch-up growth a reasonable goal. However, inseverely affected infant, the intrauterine environmenty have altered organ and endocrine development plac-the infant at risk for later complications from hyper-sion, type 2 diabetes, and lipid abnormalities.1-4 In thatting, rapid catch-up growth with high caloric intakesy not be advisable.

utcomee IUGR neonate as described in this review is at risk for aiety of neonatal complications that ultimately can affectinfants long-term outcome. SGA infants are a heteroge-ous group of babies with a variety of outcomes. Some willnormal from a neurodevelopmental standpoint,51 whereas

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The IUGR newborn 223ers will have various diagnoses and neonatal morbidityt will influence outcome.51-53 In terms of growth, somell catch up by 6 months of age,54 whereas others will not.e excellent predictor of neurodevelopmental outcome isether or not catch-up head growth occurs.55,56 PretermGR infants are also at increased risk for neurodevelopmen-handicap when compared with their AGA counter-

rts.57,58

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224 A. Rosenberg

The IUGR NewbornNeonatal Problems in the Term or Late Preterm Infant with IUGRSpecial Issues for the IUGR Preterm InfantNutritional Management of the IUGR NeonateOutcomeReferences