The High-Risk Infant

THE CHILD WITH DEVELOPMENTAL DISABILITIES

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THE HIGH-RISK INFANT Marilee C. Allen, MD

A large number of children are born each year with biologic or environmental factors that carry an increased risk of developmental disability. Although most of these children do well, the chance that they will have a developmental disability is increased. Some factors carry a much higher risk for developmental disability than others. For example, preterm infants with birthweights below 750 g, severe chronic lung disease, and severe intraventricular hemorrhage have a much higher incidence of cerebral palsy and mental retardation than preterm infants without any of those factors. 3, 20, 29, 35, 44-46, 48 Infants with multiple risk factors generally have a much greater risk of disability than infants with single risk factors. Yet risk for developmental disability by no means implies a causal relationship, Many conditions that in the past were believed to be the cause of a disability, such as difficult or preterm deliveries, perinatal asphyxia, and intrauterine growth retardation, have been shown to be markers of, or even caused by, prior central nervous system (eNS) damage, I, 4, 12, 17,32

IDENTIFICATION OF INFANTS WITH DEVELOPMENTAL DISABILITY

Early identification of infants who are at risk for developmental disability allows for appropriate parent counseling and for planning for the child's future. This counseling and planning should take into account the uncertainty of the child's developmental outcome. If the infant has severe or multiple risk factors or resources are plentiful, he or she may be immediately enrolled in an early intervention program. In most cases, however, early intervention resources are limited and may be reserved for children with identified developmental delay or conditions that carry a high probability of delay. In that case, a system that would track the child and monitor his or her development would be a fairly From the Department of Pediatrics, The Johns Hopkins University School of Medicine; The Johns Hopkins Hospital; and Kennedy Krieger Institute, Baltimore, Maryland

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efficient method of identifying developmental delay early and allowing for timely referral for evaluations or early intervention programs. Not all children with developmental disability have risk factors at birth. Most children with cerebral palsy, for example, are full term and have normal birthweighU2 Many causes of developmental disability are unknown." A system of tracking and monitoring high-risk infants thus fails to identify a large number of infants who would benefit from early intervention services. Pediatricians are in a unique position to promote a system of early intervention services and help provide access to this system for most infants at risk for developmental delay. In caring for these high-risk neonates, they can identify important risk factors and counsel parents appropriately. In the course of their routine office or clinic visits, they can track and monitor the development of at-risk infants (and even of infants at no increased risk of developmental disability) . When they identify developmental delay or other developmental concerns, prompt referral for multidisciplinary evaluation and early intervention services help promote the welfare of the child and the family. Equally important, pediatricians have the opportunity to support the family during the initial period of uncertainty and anxiety and can help to explain questions about risks, diagnoses, and prognosis. RISK FACTORS FOR DEVELOPMENTAL DISABILITY

Risk factors can be viewed as either biologic or environmental in origin, although several risk factors overlap these groupings. For example, cocaine and heroin abuse during pregnancy can cause damage to the developing brain of the fetus. In addition, the mother's ongoing drug use can be related to and contribute to chaos within the household. A disorganized mother who is focused on coping with her "habit" has little energy to devote to mothering her infant. This may lead to neglect or even to physical abuse of that infant. Inattention to the child's nutrition or health needs may further compromise the child. All of these factors may contribute to later cognitive or neuromotor deficits. Recognizing this overlap, it is still traditional to categorize risk factors into the biologiC and environmental categories. This section outlines some of the risk factors and discusses what is known about their degree of risk for developmental disability. Most research on risk factors has focused on two major developmental disabilities: cerebral palsy and mental retardation. Biologic Risk Factors

Table 1 lists a number of identifiable biologic risk factors. Some carry a much higher risk of developmental disability than others or may exert their effect through other risk factors. For example, a number of obstetric variablesfor example, abruptio placenta, maternal antepartum hemorrhage, and fetal distress during labor-are associated with neonatal mortality and morbidity, but are only weakly correlated with infant developmental outcome. Neonates with a history of one or more obstetric complications who were also symptomatic in the neonatal period (e.g., with hypoxic-ischemic encephalopathy) have a much greater likelihood of developmental disability than neonates with a history of obstetric complications who were asymptomatic. In this case, the

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Table 1_ BIOLOGIC RISK FACTORS

Prematurity Intracranial hemorrhage Intrauterine growth retardation Hypoxic ischemic encephalopathy Brain abnormalities on imaging studies Biochemical abnormalities (hypoglycemia, polycythemia, hyperbilirubinemia) Microcephaly Congenital malformations Congenital infections Sepsis/meningitis Lung disease (chronic lung disease, severe persistent pulmonary hypertension/meconium aspiration syndrome, ECMO) Neonatal seizures Maternal substance abuse

neonatal variables are much better predictors of developmental outcome than the obstetric variables. Prematurity

Developmental outcome of prl"term infants has been reported primarily in terms of birthweight criteria. The incidence of major developmental disability varies from 5% to 10% for infants with birthweights below 1500 g and up to 20% for infants with birthweights below 1000 g.3, 5, 13, 27, 33, 34, 40, 41, 47 Saigal et a14D ,41 found that although survival improved dramatically with increasing birthweight, the incidence of neurologic handicap was not significantly different. This means that a child born at 850 g had less chance of survival than a child born at 1400 g, but if they both survived, they had the same chance of developing a major disability. 5, 4D, 41 Children born at the limit of viability «750-800 g) do seem to have a much higher morbidity rate (10%-40%) as well as a higher mortality rate than larger, more mature preterm infants,2D In addition, they are more likely to develop severe chronic lung disease, severe intraventricular hemorrhage, retinopathy of prematurity, hearing impairment, and failure to thrive, and they are more likely to be technology dependent during infancy, Although prematurity is a risk factor for developmental disability, 80% to 95% of preterm infants are free of major disability. 3, 5, 13, 27, 33, 34, 40, 41, 47 Visual impairment occurs in 5% to 12% of preterm infants with birthweight below 1000 g, and hearing impairment occurs in 6% to 12%.33, 42, 47 Myopia and strabismus are common. The more subtle abnormalities of CNS dysfunction also appear to be common: from 20% to 65% of school-aged children with birthweights less than 1000 g have diagnosed learning disability, require special education or resource help, or demonstrate poor school performance. 33.42 Prematurity alone is a relatively weak risk factor. A number of perinatal risk factors for preterm infants (e,g., intraventricular hemorrhage, ventricular dilation, periventricular leukomalacia, chronic lung disease, neonatal seizures, abnormal neonatal neurodevelopmental examination) have been identified that are more predictive of developmental outcome than prematurity alone, A study by Drillien et ai'2 showed that preterm children with birthweight below 1500 g who had no evidence of intrauterine insult and were normal neurologically during the first year were indistinguishable from full-term control children at school age, This finding suggests that it is not the preterm delivery, per se,

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but rather the causes or complications of prematurity that cause developmental disability. Intracranial Hemorrhage

Preterm infants are vulnerable to intraventricular or intraparenchymal hemorrhage as well as to infarction. Extreme immaturity, asphyxia, and wide swings in systemic blood pressure or cerebral circulation all contribute. Whether germinal matrix (subependymal) or small intraventricular hemorrhages increase a preterm infant's risk for developmental disability is still not clear. Approximately 30% to 60% of preterm infants with severe (grade 3) intraventricular hemorrhage and ventriculomegaly develop major developmental disabilities, especially cerebral palsy. 35,44-46 Ventricular dilation even without hemorrhage is associated with an increased risk of disability. 45 Intraparenchymal hemorrhage or cysts are even more worrisome, Preterm infants with intra parenchymal (grade 4) hemorrhage have a 70% to 90% incidence of major, and often multiple, disability.35, 45 Large, bilateral periventricular cysts carry an 80% to 100% risk of major disability .19,30,46 If the cysts are unilateral, focal, or small, however, the risk of disability appears to be less (18%-75% ).19,30

Full-term newborns also can demonstrate abnormalities on neuroimaging studies, including intraventricular, intraparenchymal and subarachnoid hemorrhages, infarctions, diffuse encephalomalacia, hydrocephalus, and porencephaly. These generally carry an increased risk of developmental disability, depending on their severity, and in the case of infarctions and hemorrhages, their location. Fitzhardinge et aP6 found that diffuse encephalomalacia, intraventricular hemorrhage, and intraparenchymal hemorrhage all carried a high risk (70% to 90%) of major handicap in asphyxiated full-term infants. Intrauterine Growth Retardation or Small for Gestational Age

Fetuses with intrauterine growth retardation (IUGR) and infants who are small for gestational age (SGA) are identified by comparing their size or growth pattern with norms. There are multiple reasons for small size at birth, and some are quite benign. Some causes indicate not only poor growth but abnormalities of, or damage to, the eNS. I, 4 The infant with IUGR may be compromised in such a way as to make him or her vulnerable to a number of perinatal complications. 1,4 The developmental outcome of these infants, then, depends highly on both the etiology of the small size and any resulting perinatal complications. I, 4 Severe chromosomal disorders and congenital infections frequently present with early IUGR and are generally associated with severe CNS malformation or injury. Even infants who demonstrate early IUGR from unknown cause have a higher incidence of developmental abnormalities than infants who develop IUGR later in pregnancy.36 Maternal medications (e.g., phenytoin), drugs of abuse, or environmental toxins may impair fetal growth, cause congenital malformations or dysmorphic features, and damage the fetus's CNS.26 Some fetuses develop IUCR in response to maternal or unknown conditions that interfere with uteroplacental circulation, oxygenation, or nutrition, such as pregnancy induced hypertension, maternal cyanotic congenital heart disease, and maternal chronic renal disease. Poor growth may well be an adaptive response of the fetus in order to maintain itself as efficiently as possible in such limited circumstances. 49 In this case, weight is affected first, then length, and

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finally, head growth. Most outcome studies support this. " 4 Although retrospective studies of children with cerebral palsy or severe mental retardation have found that a disproportionate number had IUGR/SGA, they do not distinguish cause of the growth retardation. Full-term SGA infants with no major congenital anomalies or infection do not appear to have a significantly higher risk of cerebral palsy or mental retardation than full-term appropriate for gestational age (AGA) infants, but they do demonstrate more subtle problems, such as speech deficits, hyperactivity, minor neuromotor dysfunction, and learning disability when followed to preschool and school age. 15, 50 Preterm SGA infants have a higher incidence of both cerebral palsy and mental retardation than either full-term SGA infants or preterm AGA infants, When Pena et al37 compared a group of preterm SGA infants with two groups of preterm AGA infants (one matched for birthweight and one for gestational age), the preterm SGA infants had lower cognitive abilities than both groups of AGA preterm infants and a similar rate of neurologic disability than the preterm AGA infants matched for birthweight. Both preterm SGA and their birthweight matched controls had a higher incidence of neurologic abnormalities than AGA infants matched for gestational age. Infants with IVGR demonstrate greater vulnerability to a number of perinatal complications including asphyxia, polycythemia, hypoglycemia, and pulmonary hemorrhage. Each of these complications can further impair the infant's ability to achieve homeostasis and may affect further growth and development. Perinatal Asphyxia and Hypoxic Ischemic Encephalopathy

The greatest difficulty in describing the developmental outcome of fullterm asphyxiated infants is in defining the degree of the asphyxiating insult, We are left, then, with describing the effects of the asphyxia on the infant. One approach to quantifying the results of asphyxia is the Apgar score. It correlates somewhat better with mortality than with neurodevelopmental outcome, but its usefulness is limited because prediction is best only for low Apgar scores for an extended period of time. 31 Severely asphyxiated infants generally are markedly symptomatic, with seizures, coma, lethargy or irritability, severe abnormalities of tone, or difficulty feeding in the newborn period. This constitutes hypoxic-ischemic encephalopathy. In studies of severely asphyxiated full-term newborns (i.e., apparent stillbirth, prolonged asphyxia, severe neonatal symptoms), 30% to 75% die,25.31 Of those who survive, up to 30% develop cerebral palsy or mental retardation!' 25 Of those who develop major disability, most have multiple disabilities (i.e., spastic quadriplegia or mixed cerebral palsy, severe mental retardation, microcephaly, seizure disorder, cortical blindness, or hearing impairment). The number and type of neonatal symptoms correlate with developmental outcome. Infants with multiple symptoms or infants with initial hypotonia who then develop extensor hypertonia have a high incidence of major disability! Neonatal seizures are also correlated with neurodevelopmental outcome, 25, 39 Abnormalities on electroencephalograms (EEG) and brain imaging studies are rarely encountered, but when they are present, they correlate highly with adverse neurodevelopmental outcome, 16, 39 Sarnat and Sarnat'3 developed a scoring system for severity of hypoxicischemic encephalopathy (HIE) that incorporates the infant's state of arousal, neurologic examination, signs of autonomic system dysfunction, and EEG abnormalities. It was found to be highly predictive of long-term developmental

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outcome: all infants with severe HIE (stage 3) died or had severe disabilities, only 20% to 50% with moderate HIE (stage 2) developed disability, and all with mild HIE (stage 1) were normal. 39 Biochemical or Hematologic Complications

Symptomatic hypoglycemia appears to carry an increased risk of developmental abnormalities, especially if it is severe and prolonged. Polycythemia is often a sign of hyperviscosity and may lead to sludging of the blood in small vessels and thus to infarction or injury of major organs. Even asymptomatic polycythemia appears to be associated with minor neurologic abnormalities, but it also may be a sign of prenatal hypoxia and not a cause." Whether and when to perform a double volume exchange transfusion for jaundice is also controversial because it is still not clear what influences the development of kernicterus in either the full-term or preterm infant. Although the risk still appears to be low, infants whose bilirubin rises above 20 to 25 or who receive an exchange transfusion should have their development during infancy monitored and their hearing tested. Microcephaly

Microcephaly at birth carries an increased risk of major disability, especially if it is associated with poor postnatal head growth. IS Severity of neonatal illness, nutrition, and brain growth all contribute to decreased head growth. Head size at 8 months and at 6 to 8 years, even when excluding children with neurologic impairments, is highly correlated with IQ in preterm children. 21 , 27,47 Congenital Abnormalities

Infants with congenital abnormalities should be carefully evaluated for the presence of other abnormalities, If indicated, a chromosomal analysis should be performed. The diagnosis of a chromosomal disorder or dysmorphic syndrome implies a known risk of developmental disability,26 Even if there is no associated chromosomal disorder or dysmorphic syndrome, infants with major congenital anomalies have an increased incidence of developmental problems, 11 Congenital and Central Nervous System Infections

Sepsis, and especially meningitis, increases an infant's risk of developmental disability, including hearing impairment. All infants with meningitis should have their hearing carefully evaluated as they are recovering. Congenital infection, especially rubella, toxoplasmosis, and cytomegalovirus (CMV), can cause intrauterine death, major congenital malformations, severe growth retardation, CNS injury, neonatal illness or death, and longterm developmental sequelae. 38 Infants who are symptomatic with congenital infection at birth have a high incidence of developmental disability, Infants with congenital infection who are asymptomatic at birth are still at risk for hearing and visual impairment and for later learning disabilities, 23 Congenital syphilis, if unrecognized and untreated, can lead to developmental disability. Neonatal herpes infections are generally acquired during vaginal delivery from an infected mother. Even if treated, they are associated with a high incidence of developmental abnormalities if the neonate had CNS symptoms. Infants whose mothers are HIV positive will be HIV positive

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themselves because of passively acquired maternal IgC antibody. Approximately 30% to 50% remain HIV positive, and in addition to their susceptibility to infections, they may demonstrate developmental delay or even CNS degenerative disorder. 14 Chronic Lung Disease

Chronic lung disease (bronchopulmonary dysplasia) occurs in preterm or full-term infants who were acutely ill, generally with respiratory distress syndrome, persistent pulmonary hypertension, meconium aspiration syndrome, or pneumothoraces and are cared for in a neonatal intensive care unit immediately after birth. These same conditions may well have insulted their brain. In addition, many of these children are fluid sensitive and have difficulty maintaining good nutrition and growth. Many are labile and may have unrecognized periods of hypoxia. It is not surprising, then, that up to 80% of infants with chronic lung disease also develop neuromotor and cognitive abnormalities. 2.,48 Some demonstrate mild hypotonia and delayed motor development, but as their pulmonary and nutritional status improves, they improve, and by 1 to 2 years have no or only mild functional impairment. Others, however, develop cerebral palsy, minor neuromotor dysfunction, language abnormalities, cognitive impairment, or school problems. 29, 48 Abnormal Neurodevelopmental Examination

An abnormal neonatal neurodevelopmental examination is associated with abnormal developmental outcome in full-term infants, full-term asphyxiated infants, and in high-risk preterm infants. 2, 9, 25, 3' Although a normal neonatal examination is reassuring, an abnormal examination is not diagnostic of later disability, although it can be used to select a high-risk group for careful followup and intervention. During infancy, infants with persistent, consistent abnormalities of tone and reflexes may develop cerebral palsy or minor neuromotor dysfunction, often manifested later in childhood as clumsiness. Infants with abnormal neurologic examinations are at risk for later learning and behavior problems, even if their neuromotor status improves by 1 to 2 years. '2 Maternal Drug Abuse

It is extremely difficult to sort out the effects of maternal drug abuse from other environmental and biologic risk factors. Maternal use of heroin or methadone during pregnancy has been associated with IUCR, neonatal withdrawal syndrome and subtle neurologic abnormalities, attention deficits, and behavioral problems. 2s Maternal cocaine use during pregnancy has been associated with lower birthweights, microcephaly, lUCR, abruptio placenta, fetal distress, behavioral and EEC abnormalities in the newborn, and cerebral infarction in the fetus or newborn,6, 10 although long-term effects of cocaine are as yet unknown. In all of these studies, maternal polydrug use during pregnancy must be considered, making it even more difficult to assess the effect of anyone drug. Even legitimate drugs can cause congenital anomalies, dysmorphic features, and developmental sequelae, and frequently the number of anomalies correlates with the severity of intellectual impairment.>6

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Environmental Risk Factors

Table 2 lists a number of identified environmental risk factors. For the most part, these factors all represent conditions in which family resources are limited (e.g., poverty, homelessness) or parenting ability is impaired (e.g., maternal mental retardation or mental illness, illicit drug use in the child's caregiver, child abuse or neglect). These conditions may affect a child's developmental outcome in a variety of ways: a detrimental effect on the child's health, nutritional status or safety, lack of sufficient positive environmental stimulation for normal cognitive development, inconsistent or harmful childrearing practices that hinder his or her social and emotional development, and exposure to environmental toxins. In some environments, severe neurologic injuries may result from child abuse or from inadequate supervision with resulting accidental injury. Nevertheless, most environmental risk factors primarily affect the child's cognitive or social and emotional development, as measured by IQ, behavior problems, conduct disorders, or signs of mental illness. When there are both environmental and biologic risk factors, the effect is at least additive. Although it shows little influence before age 2, socioeconomic status strongly correlates with later cognitive performance in preterm children. 5 It makes sense, then, that infant stimulation programs target infants with multiple risk factors, especially those with a combination of biologic and environmental factors.

IMPLICATIONS FOR EARLY INTERVENTION

What is early intervention? Who should receive it? What are its anticipated benefits? In the field of developmental disabilities, early intervention implies a system of programs that work with an infant or young child and his or her family to prevent or minimize adverse developmental outcomes for that child. Early intervention includes a number of services, including educational programs for cognitive and sensory stimulation, physical and occupational therapy for positioning, handling and feeding, and speech therapy for language stimulation. If we take the broader view encouraged by Public Law 99-457, it also includes services that assist families in functioning, such as drug counseling Table 2. ENVIRONMENTAL RISK FACTORS

Low socioeconomic status (poverty/parental unemployment) Absence of medical insurance Teenage mother Diagnosis of mental retardation in parent or caregiver Diagnosis of serious emotional disturbance or mental illness in parent or caregiver (e.g., severe depression, schizophrenia or psychosis) Substance abuse by caregiver History of child abuse or neglect in the family High level of family disruption or dysfunction (e.g., homelessness or inadequate shelter, history of family violence) Inadequate parenting skills (e.g., the caregiver'S inability to respond to the infant's or toddler's needs), disordered attachment Lack of prenatal care Parent child separation (e.g., divorce, maternal incarceration)

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programs for parents and home health aide; evaluation services, such as psychological testing and audiologic evaluation; transportation to evaluations and services; medical evaluations to assess special needs or ability to participate in a program; and parent support services such as parenting classes and parent support groups. Although a number of studies have demonstrated beneficial effects of early intervention programs, there are no convincing data to suggest that early intervention prevents developmental disability.' Nevertheless, many feel that early intervention strategies do help to minimize secondary complications and to support parents through a generally difficult time of uncertainty and coming to grips with their child's disability. While early intervention programs are generally accepted, it is not clear who should be targeted, what type of intervention should be provided, and what the optimal timing for this intervention is. Generally, early intervention services are targeted for infants with developmental delay, and the timing and type of intervention are determined individually. For example, the infant with motor delay and persistent neuromotor abnormalities is at risk for cerebral palsy. Rather than just referring the child for physical therapy, this child should undergo a multidisciplinary evaluation. There also may be cognitive delays, sensory impairments, feeding problems, or orthopedic abnormalities that may require other interventions beyond physical therapy. Early intervention services are expensive and require much time and effort on the part of a variety of professionals and the families themselves. As we have seen, only a small proportion of infants with risk factors go on to have developmental delay. Most infants demonstrate only mild abnormalities or are unaffected. The costs of providing a wide range of early intervention services to all at-risk infants and their families may well be prohibitive. There may be emotional costs as well. Because early intervention services are traditionally provided to children with developmental delay and disability, parents of at-risk infants may interpret their child's eligibility for such services as a sign that his or her outcome is more certain to be adverse than it truly is. Early intervention workers themselves often have a difficult time distinguishing between "risk for" and "diagnOSis of" developmental disability and so may contribute to this misconception. Nevertheless, in many cases, early intervention services are warranted. Social services and supports may help to decrease family stresses and bolster their strengths. Attention to growth and health needs may minimize or even prevent some effects on cognitive performance. Attention to how high-risk infants with abnormalities of tone and posture are handled and positioned may improve later motor function. In some high-risk populations, infant stimulation programs may not only help support parents but improve cognitive performance. 24 Thus, some compromise between providing the whole array of early intervention services and providing no services at all to the at-risk population is in order. Identification of infants at risk for developmental disability and providing a system of tracking and monitoring their development is a middle ground. As the infant with risk factor(s) is identified, a decision can then be made as to whether any infant stimulation, health, or social support services are indicated. Perhaps children with multiple risk factors would be identified for immediate early intervention services, whereas infants with less risk would be tracked and monitored. The infant and his or her family would then be followed as the situation changes. Infants who demonstrate developmental delays can then be targeted for specific evaluation and therapeutic services. As the family changes, specific social supports can be added or withdrawn.

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This system requires considerable flexibility and a willingness to provide services in a thoughtful and judicious manner in anticipation of a beneficial effect. Most of all, it requires the cooperation of many professionals from widely disparate backgrounds with the common goal of serving the infant and his or her family.

SUMMARY A large number of infants are born each year with biologic or environmental risk factors that put them at increased risk for developmental disability, although most do not go on to have major disabilities. Some risk factors, for example, intraparenchymal hemorrhage, periventricular cysts, encephalomalacia, and abnormal neurodevelopmental examination, carry a much higher risk of developmental disability than others. There is much overlap among risk factors, and infants with multiple risk factors generally have a greater risk of disability than infants with just a single risk factor. All high-risk infants should receive careful pediatric follow-up that includes developmental screening, but efficient use of so far guite limited resources argues for selection of the highest risk infants for comprehensive developmental follow-up or early intervention programs. A system of tracking and monitoring high-risk infants during infancy and childhood would allow for early identification of developmental delay and appropriate referral for community resources.

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Address reprint requests to Marilee C. Allen, MD The Johns Hopkins Hospital, CMSC 210 600 North Wolfe Street Baltimore, MD 21205