Developmental-Behavioral Aspects of Chronic Conditions

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CHAPTER 10 Developmental-Behavioral Aspects of Chronic Conditions

10A. Effects of Adverse Natal Factors and Prematurity

EDWARD. GOLDSON, SANDRA L. GARDNER

At the beginning of the 21st century, many infants with very low birth weight (VLBW) (weight, <1500 g) are surviving the neonatal intensive care experience and are being discharged home to their families. Their posthospital care has become increasingly important for the primary care pediatrician as well as for the developmental pediatrician and clinical researcher.^1,² The pediatrician’s skills must meet these infants’ complex medical needs, as well as meet the associated developmental and psychological challenges that many of these children and their families present.

In 2002, there were 4,019,280 children born in the United States, a birth rate of 13.9 per 1000. Of these infants, 12% were born prematurely: that is, before 37 weeks’ gestation. This is an increase from 9.4% of such births in 1981 to 10.6% in 1990. These preterm births occurred primarily among non-Hispanic white women. Similarly, there has been an increase in the percentage of children born with birth weights lower than 2500 g. Such infants represented 6.7% of the births in 1984 and 7.8% of the births in 2002. Also, there was steady increase in the number of infants with VLBW from the 1980s through the 1990s (1.15% in 1980 to 1.45% in 1999 and 2002). Moreover, 95% of children with birth weights between 1250 and 1499 g currently survive.³ Thus, as noted by the March of Dimes, approximately one per eight infants is born prematurely and is at risk for later problems. Such children present a significant public health issue that must be addressed.

In the past, pediatricians were concerned primarily with the survival of infants with VLBW and with the medical and developmental sequelae of their prenatal, perinatal, and postnatal experiences. Although these remain critical issues for the neonatologist and primary care physician, the affective and cognitive consequences of VLBW are now emerging as significant public health issues, as children who were born with VLBW confront the challenges of education and school performance. In this chapter, we provide a brief historical overview of the advances in neonatal intensive care, examine the short-term and long-term developmental and behavioral outcomes of premature infants, and provide recommendations for the follow-up care and assessment of this high-risk population of children.⁴

HISTORICAL OVERVIEW

Although the development of centers for the care of premature infants began in the 1950s, these centers had very little effect on the outcome of infants with VLBW; the reported mortality rate continued to be about 75% for the next 10 years.⁵ Of the infants who did survive, some did relatively well.^6,⁷ However, it was not until the major advances in basic scientific knowledge and technology of the 1960s led to more rigorous neonatal intensive care that survival increased. In 1960, Alexander Schaffer coined the term neonatology to identify the newly emerging pediatric subspecialty that was to devote itself to the care of the sick and premature infants and those with low birth weight.

Two major factors proved critical for the later advances made in the care of these infants. The first was an increase in the understanding of fetal and neonatal physiology, which led to advances in technology. Recognition of the significance of maintaining normal body temperature, providing adequate nutrition, and preventing infection led to the development of the early neonatal intensive care nursery.⁸ The understanding of the effect of oxygen and its use in the treatment of respiratory distress was also a significant achievement.⁹ Although an incomplete understanding of the properties of oxygen and its toxicity resulted in retrolental fibroplasia (now called retinopathy of prematurity), the introduction of oxygen resulted in the survival of many small infants who, in the past, would have died. Another example was the appreciation of the role of bilirubin in the etiology of kernicterus and athetoid cerebral palsy. Recognition of the association between blood group incompatibilities and hemolytic anemia of the newborn led to the development of Rh_O(D) immune globulin (RhoGAM) and a marked diminution in the incidence of severe hyperbilirubinemia and kernicterus. A further example was recognition of the need for prompt feeding of the newborn.^10,¹¹ Consequently, nurseries stopped waiting the customary 24 hours before feeding the infant, thus avoiding hypoglycemia and other metabolic disturbances of delayed feeding.

The technology that developed as a result of this expanded knowledge of physiology played a major role in the survival of the small infant. Although small babies had been ventilated in the 1950s and 1960s, the development of continuous positive airway pressure, which evolved in response to an understanding of lung and chest wall mechanics, had a great impact on the survival of the small infant.¹² Continuous positive airway pressure stabilizes the alveoli, prevents atelectasis, and facilitates respiration. This technique also led to the development of more efficient and effective ventilators. The design of sophisticated monitoring systems, including the capability for monitoring blood gases noninvasively,¹³^–¹⁶ allowed for better control of oxygenation with the aim of decreasing the incidence of the complications of oxygen therapy. The discovery of phototherapy for the treatment of hyperbilirubinemia led to a decrease in the incidence of kernicterus. The development of hyperalimentation¹⁷ and its application to premature infants facilitated care for infants with significant bowel disturbances and those too small or too sick to feed on their own. Natural and synthetic surfactant are now being administered to infants with VLBW at birth to prevent the major pulmonary complications of surfactant deficiency.¹⁸^–²² Most recently, with the discovery of the vasodilator properties of nitric oxide, there is more hope for the survival of infants with VLBW with such problems as persistent pulmonary hypertension.²³

In summary, the care of very small infants since the early 1980s has progressed from minimal support to intensive intervention, as a consequence of the expansion of knowledge of neonatal physiology and significant technological advances. Infants surviving today are smaller and sicker than those who survived 30 years ago. Their survival has stimulated a wide range of investigations in which researchers monitor mortality and morbidity,^24,²⁵ evaluate long-term outcome, determine the quality of their lives,²⁶ and debate the ethics of applying technological advances to prolong survival of severely premature infants.²⁷ Such debate is crucial as resources become increasingly limited. At the same time, survival of these infants has stimulated a wide range of questions about such issues as mother-infant attachment,^28,²⁹ the temperament of premature infants,^30,³¹ and the effect of the premature and potentially disabled or chronically ill infant on the family.

FOLLOW-UP STUDIES OF INFANTS WITH VERY LOW BIRTH WEIGHT

Over the years, researchers have gathered considerable information on the outcome of infants with VLBW and those with extremely low birth weight (ELBW) (i.e., birth weight <1000 g). Data from perinatal programs document the effectiveness of neonatal intensive care.³² In early studies, all premature infants were grouped together, and an increase in survival was demonstrated after the introduction of intensive care. However, it soon became apparent that this group of babies was not homogeneous; for example, there are significant differences between an infant weighing 2000 g at birth and one weighing 1250 g and between an infant who is of appropriate size for gestational age and one who is small for gestational age.³³ Moreover, investigators performed many of these studies over relatively short time periods and tended to focus on gross abnormalities and to ignore more subtle, long-term issues. As a result, the understanding of the outcome of these babies was limited and superficial. Furthermore, the failure to consider more subtle but important adverse outcomes contributed to an unrealistically positive impression of the effectiveness of intensive interventions.

To better understand findings from longitudinal studies, clinicians should consider factors that confound the interpretation of data from a variety of settings. Follow-up studies on the outcomes of prematurity vary in several ways: (1) reporting and defining of handicapping conditions (e.g. mild, moderate, severe)³⁴; (2) inclusion of appropriate controls (e.g., full-term neonates and classmates)³⁵; (3) use of retrospective versus prospective study designs; (4) addressing sources of bias (e.g., evaluators’ unawareness of experimental condition; parental compliance with follow-up; selection of study subjects)^36,³⁷; (5) use of birth weight or gestational age to measure morbidity; (6) use of a single center, multicenter, and population-based paradigm^35,³⁸; (7) definition of outcome measures (e.g., what/how/when to measure^34,³⁵ and the “disability paradox” in quality of life studies)³⁹; and (8) and study length (e.g., subject attrition; ages at follow-up).⁴⁰^–⁴³

Place of birth (i.e., type of facility), characteristics of the neonatal intensive care unit (NICU) (e.g., approaches to management, the general environment, and use of technology), and parental factors influence both short- and long-term outcomes. Research findings from as long ago as the 1970s have documented better outcomes for infants with ELBW or VLBW born in Level III perinatal centers than for those born in Levels I and II centers.^44,⁴⁵ Use of developmental care in the NICU has been shown to alter brain function and structure,⁴⁶ to have physiological benefits (e.g., less intraventricular hemorrhage, chronic lung disease/bronchopulmonary dysplasia, retinopathy of prematurity, ventilator and oxygen use), and to have developmental benefits (e.g., improvements in behavior organization, self-regulation, interactive capability and quality with parents, ability of mother to read and respond to infant’s cues, and cognitive function/IQ; fewer behavior problems and attention difficulties).^46,⁴⁷ Advances in neonatal intensive care with the development of new technologies (e.g., high-frequency ventilation, inhaled nitric oxide) and use of drugs influence outcomes of premature infants.⁴⁸^–⁵⁰ For example, use of one course of antenatal steroids and surfactant replacement lowers rates of morbidity and mortality, whereas multiple courses of antenatal steroids and use of postnatal steroids results in long-term central nervous system deficits. Indeed, the short-term benefits (e.g., earlier weaning from the ventilator) of postnatal steroid use are offset by their long-term consequences (e.g., effect on the developing brain).⁵¹ Well-documented variations in outcome morbidity (e.g., chronic lung disease/bronchopulmonary dysplasia, retinopathy of prematurity, infection, intraventricular hemorrhage) among NICUs have a myriad of causes, including different centers’ approaches to infants at the “limits of viability” and the use of and expertise with technologies, nutritional management, pain relief, and infection control.^49,^50,⁵²^–⁵⁴ International comparisons are made difficult by the greater sociodemographic diversity of the United States population in comparison with those of many European countries (e.g., socioeconomic, educational, and marital status; ethnic or cultural differences; access to community resources or supports).^52,⁵⁵

Finally, parental factors have an important effect on the outcomes of the preterm infant. Parent-infant interaction is influenced by preterm birth and, in turn, influences the outcome of the preterm infant. Characteristics such as maternal responsiveness, the physical appearance of the infant, parental expectations for the child, and child-rearing abilities have been shown to influence both caretaking ability and children’s subsequent cognitive and academic achievement.⁵⁵^–⁶⁰ These confounders and variations make comparisons between different studies often difficult, if not impossible.

In the late 1970s and early 1980s, investigators began to examine different populations of infants more closely and to consider the effect of factors other than birth weight and gestational age more rigorously, including perinatal and postnatal complications (e.g., intracranial hemorrhage, bronchopulmonary dysplasia), socioeconomic status, access to care, and place of birth.

Early Studies

Douglas ⁶ reported on 163 infants with birth weights of 2000 g or less born in the United Kingdom during a single week in 1946. Some of the babies were born at home and some in the hospital. Of those cared for in a hospital, 18 received oxygen, and 11 were in incubators. None of the infants weighing less than 1000 g, whether born at home or in the hospital, survived; only 32% of the infants weighing 1001 to 1500 g lived. Of the infants weighing 1500 to 2000 g who did survive, none had handicaps. Of the infants weighing less than 1500 who survived, 17% had significant physical, neurological, mental, or behavioral problems. In 1958, Dann and associates⁷ described the outcomes for 73 of 116 infants born in the New York City area between 1940 and 1952 with birth weights of 1000 g or less or whose weight dropped below 1000 g during their hospitalization. The infants were kept in incubators, and most received oxygen and meticulous but nonintrusive medical support. The children were evaluated between 1950 and 1957. All 73 studied, who were among the 116 survivors, were found to have generally good physical health with few neurological defects. Most had achieved normal height, but often not until after 4 years of age. However, the IQs of 84%, while in the average range, were below those of their full-term siblings. Sixteen percent had IQs below 80. After considering variables such as birth weight, gender, race, and socioeconomic status, Dann and associates found that the infants with the highest IQs were from families with higher socioeconomic status.

Both of these studies are unique in that they preceded, by approximately two decades, the establishment of modern neonatal intensive care. As a result, they provide a historical perspective and also demonstrate that even without neonatal intensive care, some infants with low birth weight did survive and did well. With the introduction of new methods of care, survival increased and outcomes improved, although other issues have emerged.⁶¹^–⁶³ In the next section of this chapter, we review later follow-up studies on the infants with VLBW and those with ELBW.

Studies from 1979 to the Early 1980s

Studies published after 1979 ^1,⁶⁴^–⁷⁰ documented the results of the emergence of the modern age of neonatology and the progress in the evolution of care for the infant with VLBW. With technological advances and recognition of the importance of continuous and comprehensive assessment of outcomes, findings extend beyond morbidity, mortality, and medical issues to include such issues as the psychosocial, neurodevelopmental, educational, and behavioral sequelae of premature birth for children and their families.

INFANTS WITH BIRTH WEIGHTS OF 1000 TO 1500 GRAMS

In 1982, Orgill et al.⁷¹ published 6- and 12-month follow-up findings on 123 survivors of a cohort of 148 infants born between January 1979 and July 1980, with birth weights of 1500 g or less. Twenty-one infants had birth weights of 1000 g or lower. At 18 months, 84 (57%) were alive. Of this group of infants, 16 (19%) were handicapped (i.e., had a developmental level 2 standard deviations below the norm, cerebral palsy, visual deficits, or sensorineural deafness.) There were no reports of bronchopulmonary dysplasia, but one child had retinopathy of prematurity. The authors acknowledged their very short-term follow-up, the small number of subjects, and the inability to generalize to other populations.

In 1981, Rothberg and colleagues ⁶⁵ reported on the 2-year outcome of 28 infants with birth weights lower than 1250 g who were born between May 1, 1973, and July 31, 1976 and had been mechanically ventilated. It is noteworthy that these authors addressed not only survival and early morbidity but also the effect of various complications of prematurity, aspects that had not been examined in earlier studies. These 28 infants were the survivors of a population of 144 infants, of whom 22% were inborn and 78% were outborn then transported to the authors’ neonatal intensive care unit. Thus, it can be seen from this small sample, despite the numerous advances in neonatal intensive care in the 1970s, the mortality and morbidity for these small infants remained high. It was suggested that if the best results were to be obtained, these infants should be delivered in perinatal centers; if they are not, such infants with VLBW should be expeditiously transferred to a tertiary care nursery.

INFANTS WITH BIRTH WEIGHTS OF 800 TO 1000 GRAMS

In 1979, Yu and Hollingsworth ⁷² reported on 55 infants with birth weights of 1000 g or less who were born in 1977 and 1978. The overall survival rate was 60%; 44% of infants weighing 501 to 750 g and 67% of infants weighing 751 to 1000 g survived. The authors reported no major abnormalities and suggested that the prognosis for these very small infants was good. However, these investigators based this suggestion on only a 1-year follow-up period, during which time no formal neurodevelopmental assessments were performed. The investigators also did not identify whether there were complications of prematurity, and they did not compare their results with those of earlier studies. Nevertheless, this work set the stage for researchers in the 1980s, who maintained that the chances of the very small infant surviving were improving, as were the developmental outcomes.

Saigal and associates,⁶⁹ in a study of children born between 1973 and 1978, found that among the 294 infants weighing between 501 and 1000 g, there was a 31.9% survival rate. The investigators monitored 37 discharged infants in this weight group for a minimum of 2 years and found that 9 (24.3%) had some functional handicap. Of the 35 patients they evaluated, 21 (60%) had some dysfunction, whereas they determined 14 (40%) to be normal. Among the 21 with some dysfunction, 9 had neurological impairments, including hydrocephalus and cerebral palsy. Factors associated with poor outcome included ventilatory support and intracranial hemorrhage. As with the previous study, these authors suggested improvement in the outcome for this population, although they acknowledged the underestimation of minor disabilities in younger infants.

Ruiz and colleagues ⁶⁶ reported the 1-year outcome for 38 infants born between 1976 and 1978 with birth weights lower than 1000 g. These infants were selected from a cohort of 134 infants, 47 (35%) of whom survived. The investigators concluded the ventilated infants seemed to fare worse than the nonventilated infants. Multiple disabilities were common, with overlap between neuromuscular and developmental problems. Of the 38 infants studied, 20 (53%) had no problems, 17 (45%) had multiple disabilities, and 3 (8%) had severe neurological or developmental impairment.

Driscoll and associates ⁶⁷ reported on a prospective study of 54 infants born in 1977 and 1978 who survived with birth weights lower than 1000 g, half of whom were born in a center with a NICU. None of the infants with birth weights lower than 700 g survived. On the basis of their results, the authors concluded that there had been improvement in the survival of these small infants but that there was a high complication rate, including intellectual impairment in 30% of the group. Unfortunately, they did not separate the outcome of children with bronchopulmonary dysplasia and/or intracranial hemorrhage from that of children without these complications, and thus the characterization of the population studied is incomplete.

Kitchen and associates ⁷³ reported on 351 infants born in one region in Australia with birth weights of 500 to 999 g who were monitored for 2 years. Eighty-nine (25.4%) survived, and investigators evaluated 83. Overall, 22.5% had severe functional handicaps, 29.2% had moderate-to-mild handicaps, and 48.3% had no handicap; 13.5% had cerebral palsy, 3.4% had bilateral blindness, and 3.4% had severe sensorineural hearing loss. Those born in tertiary care centers did better than those who were born elsewhere, as reflected in a significantly lower incidence of functional handicaps and higher scores on the Mental Developmental Index of the Bayley Scales of Infant Development. The authors concluded that to optimize outcome, infants with VLBW should be delivered in the setting most capable of responding to their unique needs. This view is similar to that of Rothberg and colleagues⁶⁵ and Lubchenco and coworkers.⁷⁴

Kitchen and associates ⁷⁵ also reported on 54 children with birth weights of 500 to 999 g born during 1977 to 1980 and seen at 2 years of corrected age. Fifty of these children were also seen at age 5½ years. There was a 39.6% survival rate with a mean birth weight of 864 g. At age 2 years, on the Bayley Scales of Infant Development, the study children had a mean Mental Developmental Index score of 91.1 (standard deviation, 16.5) and a mean Psychomotor Developmental Index score of 87.7 (standard deviation, 17.0), both of which are below the population mean. Of the 50 children evaluated at 5½ years of corrected age, 30 (60%) had no impairment, 5 (10%) had severe sensorineural hearing loss or intellectual deficits, 5 (10%) had mild-to-moderate impairment, and 10 (20%) had minor neurological abnormalities. Three children had spastic diplegia. The authors also noted a small number of patients with sensorineural deficits and blindness. The mean score on the full Wechsler Preschool and Primary Scales of Intelligence was 101.8. This study suggested that outcome may improve from ages 2 to 5½ years among VLBW survivors. Nevertheless, even at the later time, 40% of survivors had some difficulty.

In another population, Kitchen and associates ⁷⁶ reported on the 5-year outcome for the same weight group (500 to 999 g) born during 1979 and 1980. The survival rate in this group was 25.4%; investigators evaluated 83 of 89. Of the 83, 60 (72%) had no functional impairment, 16 (19%) had severe impairment, 4 (5%) had moderate impairment, and 3 (4%) had mild involvement. In this regional study, the patients who were not born at the tertiary care center did worse than those born at the center. Eight children had cerebral palsy, six were blind, and four had sensorineural or mixed deafness. Once again, the authors found that the outcome at 5 years was better than at 2 years. However, they did not comment on whether these children had been in any kind of therapy or early intervention program.

INFANTS WITH BIRTH WEIGHTS LOWER THAN 800 GRAMS

Britton and colleagues ²⁶ questioned whether intensive care was justified for infants weighing less than 801 g at birth. They examined a population of 158 infants weighing less than 801 g born between 1974 and 1977 who were transported to the intensive care unit. The infants with birth weights higher than 750 g did somewhat better than those with lower birth weights.

Hirata and associates ⁷⁷ obtained similar findings in 22 infants with birth weights 501 to 750 g, 36.7%. Of these 22 infants, 18 were monitored from ages 20 months to 7 years. The investigators found that 11% had neurological sequelae, 22% were functional and of borderline or below-average intelligence, and 67% were normal. Thus, the results of these studies suggested that the outcome for children with birth weights higher than 750 g was better than previously expected and that aggressive therapy improved the outcome, although many survivors had significant neurodevelopmental problems.

The reports on the survival and follow-up study of children born in the 1970s were largely optimistic. There was a definite increase in the survival of small infants receiving intensive care, including those with birth weights lower than 800 g. Moreover, the infants who did survive, including those of extremely low birth weight, seemed to do fairly well, at least over the short term. Thus, clinicians believed that they should provide every possible support for these infants. However, a nagging concern began to emerge: that although many of these infants survived and did fairly well, they would have problems as they grew up. Furthermore, the appreciation that premature infants were not a homogeneous group and that multiple factors affected outcomes influenced the follow-up study of premature infants in the 1980s and 1990s.

Studies in the Late 1980s

In 1989, Hack and Fanaroff ¹ reported on the outcome of infants with birth weights lower than 750 g born between 1982 and 1988. Ninety-eight infants were born between July 1982 and June 1985 (period 1), and 120 infants were born between July 1985 and June 1988 (period 2). There was some increase in survival from period 1 to period 2 among infants with gestational ages between 25 and 27 weeks (52% vs. 71%), but the overall rates of neonatal morbidity in the two groups were similar. The neurodevelopmental outcomes were also similar. Period 1 children had Bayley motor and mental scores of 90 ± 17 and 88 ± 14, respectively, at 20 months of corrected age. The period 2 children were seen at 8 months of corrected age and had motor and mental scores of 77 ± 25 and 81 ± 30. There was more aggressive intervention with the period 2 children who had many complications, including bronchopulmonary dysplasia, septicemia, retinopathy of prematurity, intraventricular hemorrhage, and deficits in neurodevelopmental function.

O’Callaghan and coworkers ⁷⁸ reported on the 2-year outcome of 63 children with ELBW born between 1988 and 1990 and cared for in a neonatal intensive care unit. Findings provide some insight into how more recent cohorts of children with ELBW may be functioning at 2 years of age. Investigators compared the children to full-term matched controls by using a cognitive function measure, a neurosensory motor developmental assessment, and a medical assessment. Furthermore, they studied these children as a whole group and as a subset, a low-risk group, which included children with no intracranial hemorrhage, periventricular leukomalacia, or chronic lung disease (i.e., bronchopulmonary dysplasia). The interesting findings very much mirrored those of earlier studies. The total ELBW group differed significantly from the control group (children born at term) with regard to cognitive and personal-social functioning, although they scored in the average range. The low-risk ELBW group did not differ from the control group. There were more striking differences with review of the neurosensory motor findings. Both the total ELBW group and the low-risk ELBW group had poorer total scores than did the control group, as well as poorer gross and fine motor subscale scores.

In the past, there was interest primarily in the IQs of children born very early. Most investigators assessed early neurodevelopmental functioning and found that, as a group, the infants with VLBW did not do as well as the older and heavier premature infants or a matched control group of infants born at term. However, investigators are now able to assess more subtle aspects of central nervous system function that have an effect on cognitive functioning.

Herrgaard and colleagues ⁷⁹ undertook a 5-year neurodevelopmental assessment of 60 children born before 32 weeks of gestation. These children were matched with 60 full-term controls. Assessment tools used included a standardized neurological examination, a neuropsychological assessment, an audiological examination, and an ophthalmological examination. Included in the preterm group were children thought to be handicapped (children with cerebral palsy, mental retardation [IQ < 70], bilateral hearing loss, visual impairment, and epilepsy) and those not disabled. With regard to IQ, there were significant differences between the entire preterm group and the control group, as well as significant differences between the handicapped and nonhandicapped preterm groups. The control group had the highest IQs, the nonhandicapped preterm group had lower IQs, and the handicapped group had the lowest IQs. The neurodevelopmental profile was composed of eight functional entities: gross motor, fine motor, visual-motor, attention, language, visual-spatial, sensorimotor, and memory skills. The investigators noted several interesting findings. First, all of the children born preterm had difficulty with gross, fine, and visual-motor skills. They also had difficulty with language, sensorimotor, visual-spatial, and memory skills. Second, the nonhandicapped children with minor neurodevelopmental difficulties had a similar spectrum of problems, although their IQs were in the average range, with some even in the exceptional range.

These findings are similar to those of Sostek ⁸⁰ in her study of children born before 33 weeks of gestational age and with a mean birth weight of 1358 g, in comparison with children born at term. None of the premature children had lung disease, intracranial hemorrhage, or other medical problems. Although these children had normal IQs, they were compromised with regard to perceptual-motor integration and recognition, perceptual performance tasks, quantitative tasks, memory, and visual-motor skill and were found to be more distractible and to have poorer attention and less readiness for kindergarten than were full-term controls. These findings emphasize the importance of assessing neurodevelopmental profiles, rather than relying on global measures of intelligence.

Teplin and associates ⁸¹ assessed the neurodevelopmental, health, and growth status at 6 years of age in 28 children with birth weights lower than 1001 g. In comparison with 26 control children born at term, the children with ELBW had significantly more mild or moderate-to-severe neurological problems (61% vs. 23%) including cerebral palsy; abnormalities of muscle tone; and immaturities of balance, speech, and articulation. In cognitive function, the controls scored significantly higher than the children with ELBW. However, more than half of the children with ELBW with normal IQs had mildly abnormal neurological findings, whereas the controls with normal IQs had normal neurological findings. When they determined the overall functional status, the investigators found that 46% of children with ELBW were normal, 36% were mildly disabled, and 18% were moderately to severely disabled; in comparison, 75% of the controls were normal, only 4% were significantly disabled, and the remainder had some mild degree of abnormality. In contrast to other reports, attentional disturbances were not a problem for the preterm groups described in these two studies.^82,⁸³

Halsey and colleagues ⁸⁴ conducted another provocative and important study on children with VLBW when they were in preschool. They studied 60 white, middle-class children with VLBW and compared them with a matched peer group. They used a general developmental scale and a scale of visual-motor integration. They found that the VLBW group’s mean scores were significantly lower than those of the controls, although they were still within one standard deviation of the mean. Of the children with VLBW, 23% were clearly disabled, 51% obtained borderline scores, and 26% were average. The control group had cognitive scores 15 to 18 points higher than those of the VLBW group and were 2.5 times more likely to have normal development. The authors were reluctant to make any predictions on the basis of these data but expressed concern that this pattern of performance placed the children with VLBW at higher risk for later difficulties. A subsequent study, to be discussed later,⁹⁰ confirmed that these data are indeed predictive of later difficulties. Thus, follow-up studies suggest that premature infants with VLBW, despite relatively intact cognitive skills as evidenced by normal IQs, appear to have neuropsychological and neuromotor disturbances that can adversely affect their school performance, self-esteem, and behavior.

The studies of the 1980s, in which children were monitored to only the preschool years, reinforced the concerns of the 1970s. Although investigators did note an increase in survival and found that many children did well, they also noted that these children were functioning at lower levels than their peers and with a variety of neurodevelopmental problems that earlier studies had not identified. These problems included deficiencies in their perceptual skills, social skills, and level of maturity.

We have thus far reviewed reports on infants with VLBW evaluated after only 2 to 6 years. However, among the most important indicators of successful outcome are the child’s social-emotional adaptation and how well the child does in school. Studies have acknowledged that many infants with VLBW have significant difficulties that persist throughout their lives. Although such children may have IQs in the average range, they do not perform as well as controls on measures of fine and gross motor and visual-motor tasks and display so-called “minor disabilities” that become more apparent in school. An important question, then, is what effect these difficulties have on school performance and peer relationships. Eilers and associates ⁸⁵ studied a group of children with birth weights of 1250 g or lower who were born between July 1974 and July 1978. There were 43 survivors, 33 of whom were studied at 5 to 8 years of age. Of the 33 children, 16 were functioning at an age-appropriate level, 3 had major handicaps, and 14 were in regular classes but needed remedial help. The authors noted that 51.5% of this group required special education support, in comparison with 21.4% of the general school population.

Vohr and Garcia Coll ⁸⁶ reported on a 7-year longitudinal study of children with birth weights lower than 1500 g who were born in 1975. Of their original population, 62 (51.2%) survived, and 42 (67%) were monitored. The investigators evaluated patterns of neurological and developmental functioning at 1 year of age and compared them with normal functioning children at age 7. Using a classification of “normal,” “suspect,” and “abnormal,” they found that the patterns at 1 year were significantly related to those at 7 years and that 54% of the total sample required special education or resource help at 7 years. Furthermore, those who had abnormal findings at 1 year were most likely to have difficulties at 7 years. This was less clear for the groups with suspect and normal functioning. Based on their identification at age 1 year, 27% of the children with normal patterns, 50% of the children with suspect patterns, and 87% of the children with abnormal patterns required special educational services by age 7. The investigators also noted that 45% of the children with normal patterns, 75% of those with suspect patterns, and 100% of those with abnormal patterns had visual-motor disturbances.

Another study ⁸⁷ revealed that even among a relatively normal group of children with birth weights of 1500 g or lower, there was an increased incidence of visual-motor problems. Klein and coworkers⁸³ found that a group of children with VLBW scored lower at 9 years of age on tests measuring general intelligence, visual or spatial skills, and academic achievement than did full-term controls. Klein and coworkers found that a subset of children with VLBW but normal IQs showed significant deficits in mathematics skills. Crowe and associates⁸⁸ reported on 90 children born between 24 and 36 weeks of gestation who participated in a longitudinal follow-up program; children with such major neurological impairments as cerebral palsy were excluded from study. Crowe and associates found that motor development at 4½ years of corrected age was relatively intact, but children with birth weights of about 1000 g displayed significantly poorer motor skills. Moreover, such children with symptomatic intracranial hemorrhage also had significantly poorer motor performance.

Saigal and associates ⁸² conducted a longitudinal, regionally based study over many years and reported on the cognitive and school abilities at 8 years of a cohort of relatively socioeconomically advantaged infants with birth weights of 501 to 1000 g who were born between 1977 and 1981. The investigators compared the children’s intellectual, motor, visual-motor, and adaptive capabilities and their teachers’ perceptions to those of a matched group of children born at term. They found that the majority of children with ELBW had IQs in the normal range but significantly lower than those of the controls. This was true even when handicapped children were excluded from the analysis. Moreover, the ELBW group was significantly disadvantaged on every measure. Furthermore, the teachers rated the ELBW group as performing below grade level. Interestingly, neurologically normal children also performed below the normal range on tests of visual-motor and motor abilities.

Hack and coworkers ⁸⁹ reported on the 8-year neurocognitive abilities of a group of 249 infants with VLBW born between 1977 and 1979, in comparison with 363 randomly selected normal children born at the same time. The investigators administered a neurological examination and tests of intelligence, language, speech, reading, mathematics, spelling, visual and fine motor abilities, and behavior. Twenty-four (10%) of the children with VLBW had a major neurological abnormality. None of the controls had such a finding. With the exception of speech and total behavior scores, the VLBW group scored significantly more poorly than did the controls on all tests. Even neurologically intact children with VLBW but normal IQs had significantly poorer scores than did the controls in expressive language, memory, visual-motor function, fine motor function, and measures of hyperactivity. When the investigators controlled for social risk as a significant determinant of poor outcome, VLBW still had an adverse affect on functioning, with the exception of verbal IQ. The investigators concluded that prematurity may contribute only minimally to the negative effect of a poor psychosocial environment in this area. In contrast, biological factors may have a greater effect on the deficits of more advantaged children, in comparison with their peers.

In a more recent study, Hille and associates ⁹⁰ assessed the school performance at 9 years of age of children with VLBW born in the Netherlands. They were able to gather data on 84% (N = 813) of the survivors from an almost complete birth cohort at 9 years of age. Nineteen percent were in special education programs, half of whom had been placed since 5 years of age for identified problems. Of the children with VLBW in mainstream classes, 32% were in a grade below their age level, and another 38% required special assistance. Of the children who were retained, 60% required special assistance, in comparison with 28% of children in an age-appropriate grade. The authors identified a number of factors at 5 years of age that were predictive of school difficulties at 9 years. These included developmental delays, speech and language delay, behavioral problems, and low socioeconomic status, which confirmed the findings of Hack and coworkers⁸⁹ and Halsey and colleagues.⁸⁴

A final issue to consider with this group of children is the possible effect of VLBW on behavior. We noted previously that many of these children have significant problems with hyperactivity and attention. Weisglas-Kuperus and colleagues ⁹¹ addressed the issue of behavior problems in this group of children. In a study of 73 children with VLBW who were compared with 192 full-term children at 3½ years of age, the authors found a significant degree of behavioral disturbance in the VLBW group. Problems included depression and internalizing difficulties.

Studies in the 1990s

Follow-up studies proliferated throughout the 1990s. These studies focused not only on the improved survival of the infant with VLBW as a result of further technological advances but also, of even more importance, on developmental, cognitive, academic, and social outcomes. Investigators noted the improved survival rates among infants with VLBW, as well as among infants with ELBW, during this period, in comparison with the 1970s and 1980s. As a group, the studies addressed cognition (IQ), academic performance, behavioral issues and social competence, health, language development, and visual and fine motor capacities. These follow-up studies were of longer term than previous studies, extending up to 11 to 13 years of age. As in the 1980s, the investigators divided the infants into groups of those with birth weight lower than 750 g, 750 to 1000 g, 1001 to 1499 g, and 1500 to 2500 g and used as controls children with birth weights higher than 2500 g, who were also matched for gender and socioeconomic status.

The prenatal and perinatal factors with the greatest effect on outcome included birth weight, gestational age, whether the infant was born in or outside of a special care center, and the nature and degree of the complications of premature birth. These complications included chronic lung disease and the need for oxygen, the presence of intraventricular hemorrhage and its complications, and the presence of seizures. Of note, many of these children had significant infections and gastroenterological problems, including necrotizing enterocolitis and undernutrition. In addition, many of these children had recurrent ear infections, which often necessitated myringotomy and tubes retinopathy of prematurity. The lighter and more immature the infant, the more prevalent were complications and so the higher was the risk for a more adverse outcome. Thus, the smallest infants who survived, those with birth weight lower than 750 g, had the worst outcomes. As a group, they had an increased incidence of cerebral palsy, mental retardation, autism, attention-deficit/hyperactivity disorder, and learning disability and had lower IQs than their peers. In addition, these children were less socially adept than their heavier or full-term peers. This same pattern appeared with other premature infants of greater birth weights.

Ross and associates ⁹² measured the academic and social competence at 7 to 8 years of age of boys and girls with birth weights lower than 1501 g. They found that, as group, these children had lower scores than their full-term peers on measures of social competence and cognitive functioning and had a greater incidence of conduct disorders. Differences were greatest for children from the lower socioeconomic groups and for boys.

Investigators in Canada have been effective in capturing regional cohorts. Saigal and associates ⁸² examined the 8-year outcome of somewhat socioeconomically advantaged children with birth weights of 501 to 1000 g and compared them with a matched group of children born at term. They found that the majority of children with ELBW had IQs in the normal range but lower than those of the full-term controls. Moreover, 8% to 12% of the children with ELBW scored in the “abnormal range,” in comparison with only 1% to 2% of the controls. Even the children with ELBW who were neurologically “normal” were performing below grade level, according to their teachers’ ratings, and had difficulties with visual-motor tasks. In a later study, Saigal and associates⁹³ evaluated children with birth weights lower than 1500 g and compared them to full-term children at ages 8 to 9 years. Very few of the children with ELBW had no functional limitations, and significant numbers of these children had cognitive problems and difficulties with mobility and the processing of sensory information.

In the United States, the studies of Hack and coworkers are of particular interest because their follow-up program has continued for many years, entails evaluation of infants admitted to a single tertiary care unit, and has had excellent subject retention. Hack and coworkers ⁸⁹ compared children with birth weights lower than 1500 g to full-term children at ages 8 to 9 years. They found that 10% of the infants with VLBW had major neurological deficits and an additional 21% had IQ scores lower than 85. Although the neurologically intact infants with VLBW had IQs similar to those of full-term controls, they had significantly poorer scores on tests of expressive language, memory, and visual—fine motor skills and had a higher incidence of hyperactivity. These differences persisted even after the investigators controlled for social risks.

In another study, Hack and coworkers ⁹⁴ evaluated a small group of children with birth weights lower than 1000 g and found that those with birth weights lower than 750 g did much worse in school than did premature children with higher birth weights. In turn, the latter performed more poorly than did matched full-term controls. Interestingly, abnormal head ultrasonograms and prolonged oxygen dependence were associated with mental retardation and cerebral palsy. In a similar study, Halsey and colleagues⁹⁵ monitored 210 children with birth weights lower than 800 g into the school years and found that although many of these children scored in the cognitively normal range, their scores were significantly lower than those of matched full-term children. In addition, 20% of this group had disabilities, including cerebral palsy, mental retardation, autism, and learning problems, and half of the children with ELBW required special educational services. Similar patterns were reported by Taylor and associates⁹⁶ and LaPine and coworkers.⁹⁷

Kilbride and Daily ⁹⁸ performed an 8-year follow-up study on 114 children with birth weights of 500 to 750 g. Of this group, 30% were considered normal at 3 years and 89% were in regular classes without educational assistance. Fifty percent had suspect IQ scores (69 to 83) and motor quotients at age 3 years. Of importance, 20% of these children were in special education classes and 33% were held back a grade and were receiving learning support. Forty-six percent were functioning in an age-appropriate class, although only 15% were not receiving additional services. (Twenty percent were abnormal at 3 years.) Seventy-five percent of there children with combined cognitive-motor concerns were in special remedial classes. This study revealed that performance at 3 years of adjusted age was predictive of functioning at 8 years. This pattern of outcome is described by a number of other reports from different centers.^82,^90,⁹²^–¹²⁶

These studies from the 1990s documented an increase in survival of children with VLBW and ELBW in comparison with earlier decades, but they also documented significant morbidity. Even among children who seem “normal,” there are ongoing major academic and behavioral challenges necessitating educational interventions and supports.

More recent studies, published between 1999 and 2005, focused primarily on infants with VLBW or ELBW.¹²⁷^–¹⁶⁷ Although most earlier studies were conducted in the United States, Canada, and Australia, later studies documented outcomes from Germany, as well as other European countries. In the Bavarian Longitudinal Study,¹²⁷ investigators reviewed the outcomes from multiple centers in Germany, assessing at 6 years of age children born with gestational ages of less than 32 weeks and comparing them with matched, full-term controls. The investigators found that the children born before term scored significantly lower on cognitive, language, and prereading skills than did the controls and were more likely to have deficits in simultaneous processing. Preterm birth had a greater effect on outcome than did socioeconomic status.

Investigators in the Epidemiological Project for ICU Research and Evaluation (EPICure) study ^129,¹³⁰ evaluated children with gestational ages of less than 25 weeks when they were 30 months old and then at 6 years of age. The investigators found that severe disability at 30 months was predictive of outcome at 6 years. At the 6-year pediatric visit, 46% of the 78% of surviving children who had participated at 30 months had cognitive and neurological impairments. Twenty-one percent had moderate to severe cognitive impairments in comparison to test norms, 41% had moderate to severe impairments in comparison with their classmates, 22% had severe developmental disability, 24% had moderate disability, 34% had mild disability, and 12% had disabling cerebral palsy and cognitive deficits. Thirty-eight percent whose impairments were classified as “other disability” at 30 months of age had severe disability at 6 years. Twenty-four percent who had been classified as having no disability at 30 months had significant disability at 6 years of age. Vohr¹³² reported the same pattern of outcome for a large multicenter cohort of children with birth weights of 501 to 1000 g. Significant numbers of these children had neurodevelopmental disorders, cerebral palsy, and Bayley scores lower than 70, in addition to hearing and vision impairments.

Follow-up studies from this period in which investigators evaluated very premature children and children with VLBW at 7 to 12 years of age reveal significant, previously undetected deficits in social functioning, academic performance, and attention.^133,¹³⁴ The increasing survival of more immature and lighter babies is evident in comparisons of outcomes with earlier time periods. However, the consequences of this survival are increasing numbers of children with significant neurodevelopmental problems and the emergence during the school-age years of previously undetected social, academic, and behavioral difficulties.

IMPLICATIONS FOR CLINICAL ASSESSMENT, MONITORING, AND CHILD HEALTH SUPERVISION

Findings from longitudinal follow-up studies raise the question of whether a more aggressive and proactive approach to detection of potential learning problems during the preschool years would be worthwhile in preventing or ameliorating later difficulties. The earlier identification of such problems may improve the overall outcome for the child and family. Helpful implications from follow-up studies include the observations that any child requiring neonatal intensive care is at risk for later difficulties (medical, developmental, behavioral, and psychological) and that the smaller and more immature (in weight and gestational age) the infant, the greater is the risk for complications and adverse outcomes.

Study findings suggest that all children born prematurely should be evaluated and monitored by a multidisciplinary team of clinicians to identify strengths and weaknesses, suggest intervention strategies, assess the efficacy of the interventions, and monitor the child’s progress into the early school years. These evaluations and early interventions should inform educational and psychological strategies whose objectives are to optimize outcome in this high-risk population of children.¹⁶⁸

With regard to child health supervision services, children “born too soon and too small” require care and monitoring beyond that indicated for most children born at term. At the time of discharge from the nursery, the clinician should clearly identify the infant’s needs and establish a plan for medical and developmental follow-up. Infants with conditions such as bronchopulmonary dysplasia, intracranial hemorrhage and possible hydrocephalus, or other serious complications of prematurity require close follow-up by a primary care provider and appropriate subspecialists and may benefit from referral for occupational, physical, and speech therapy. Assessment should include tests of hearing and vision. Children with previously identified problems should be assessed at least every 6 months through the first 2 years and then yearly until school entry. Evaluation before school entry is crucial for facilitating appropriate school placement. Assessments should include intelligence testing, as well as evaluations of language, social maturity, and behavioral status and functioning.

Premature infants in apparently good health also require careful monitoring. We suggest that such children be evaluated between the ages of 3 and 4 months, 6 and 8 months, and 12 and 14 months and at 18 months and 2 years of age. Measurements of height, weight, and head circumference should be obtained at every health supervision visit, as should an assessment of general health and well-being.¹⁶⁹ Evaluation during the first 2 years of life should include developmental and language assessments, as well as evaluations by an occupational and physical therapist. We also recommend evaluation between the ages of 3 and 5 years to help determine school readiness and during the school-age years to monitor educational progress.

CONCLUSIONS

The introduction of neonatal intensive care has had a dramatic effect on the prognosis of premature infants. Ongoing research will undoubtedly contribute to new approaches to management and further changes in outcome. We draw the following conclusions from our review of longitudinal studies to date:

Important clinical advances since the early 1970s have resulted in increasing numbers of infants with VLBW who survive the neonatal period. Whether the absolute number of children surviving with some disability is also increasing is controversial. Stewart ⁶² maintained that the number of surviving children with disabilities is not increasing, whereas Paneth and colleagues,²⁵ Pharoah and coworkers,¹⁷⁰ and Bhushan and associates¹⁷¹ reported the opposite. We believe that the current data suggest that the incidence of cerebral palsy and major disability has not increased since the first reports of the 1960s but that the absolute numbers of children with some disabilities has increased.