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Neonatal Intensive Care: Is It Worth It?: Developmental Sequelae of Very Low Birthweight
F Development and Behavior: The Very Young Child
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Neonatal Intensive Care: Is It Worth It? Developmental Sequelae of Very Low Birthweight
James A. Blackman, MD, MPH*
From miniaturized ventilators, parenteral nutrition, and warming devices that launched the modern intensive care era in the late 1960s and early 1970s to extracorporeal membrane oxygenators (ECMO) and artificial surfactant in the 1990s, we have come a long way. Progress in neonatal intensive care has brought with it a substantial social and emotional as well as monetary burden. Although the much improved chances for survival among very small infants made possible by the new technology are admirable and appreciated, it is appropriate to question the long-term benefits of these advances: What are the chances for good developmental outcomes for low-birthweight graduates of neonatal intensive care? Do these chances justify the cost?
THE COST OF NEONATAL INTENSIVE CARE Between 150,000 and 200,000 infants (4% to 6% of all newborns) are treated annually in neonatal intensive care units (NICU), and at least half of them are low-birthweight infants. Neonatal intensive care is among the most expensive services that many hospitals provide. Average hospital costs for low-birthweight babies in 1985 ranged from $10,000 to $65,000, depending on birthweight category.61 Using the medical care component of the consumer price index, it is estimated that average hospital costs for the smallest surviving preterm infants exceeded $100,000 in 1990. Costs for an infant with a birthweight of less than 1000 g is three to four times higher than those for an infant more than 1500 g at birth. Infants less than 750 g have the longest hospital stays (average, 98 days) and the highest costs. 53 *Associate Professor of Pediatrics, and Director of Research, Kluge Children's Rehabilitation Center and Research Institute, Department of Pediatrics, University of Virginia, Charlottesville, Virginia
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In addition to in-hospital costs, NICU graduates continue to have high medical costs after discharge. According to a study by Shankaran et al 63 in 1988, whereas the US Department of Agriculture estimates of medical costs of raising a child at home ranged from $22 to $26.80 per month, average outpatient costs for former NICU babies were as follows: unhandicapped, $31 per month; mildly handicapped, $86 per month; and moderately to severely handicapped, $109 per month.
OTHER CONSIDERATIONS IN EVALUATING NEWBORN INTENSIVE CARE The time-honored Hippocratic dictum "Primum non nocere" (above all, do no harm) applies here. No one who has ever worked in or visited a neonatal intensive care unit forgets the many invasive and usually painful procedures that are required to sustain life. The technology itself, designed to save lives, often inflicts harm or suffering on recipients of intensive care. Physicians are caught between the moral principles of nonmaleficence (not doing harm) and justice (which compels the physician to allocate finite resources equitably) on the one hand, and patient-centered beneficence (which requires the physician to make every possible effort to benefit the patient) on the other hand. 79 Heroic medical measures can be justified only if there is a reasonable hope for short- and long-term benefit. There are state-to-state and international differences in the way limited resources have been allocated to newborn intensive care. Sweden and Britain provide special care (everything short of assisted ventilation) but not intensive care for infants weighing less than 750 g unless there is strong reason to do otherwise. 79 Stanford University's practice is to resuscitate initially all critically ill newborns, but with participation of parents, they are prepared to curtail aggressive therapy and redirect care to measures that provide comfort for the infant. 79 An early end to gestation not only interrupts fetal growth and development but also the psychologic process through which the pregnant woman and her husband evolve with their fetus in preparation for beginning their relationship to their newborn.23 The often long intensive care experience, with its uncertainties about life or death, drains parents' physical and emotional stamina. Parents take home a normal, although medically fragile, infant, an infant who will be a slow starter, or an infant who will have an atypical or abnormal developmental course. Confirmation of either global abnormality or specific sensory abnormality is a devastating event. For every family and every type of low-birthweight infant who survives the experience of neonatal intensive care, there is the lingering aftermath. 47
SECULAR TRENDS IN MORTALITY AND MORBIDITY The marked decline in birthweight-specific mortality over the past 25 years is undoubtedly one of the major success stories in modern medicine. Improved obstetric care, the new sophistication in neonatal intensive care,
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and the regionalization of perinatal care are largely responsible. During this period the neonatal death rate (i.e., within the first 28 days of life) for infants with birthweights of 1000 to 1500 g has fallen from more than 50% to 10%. In 1960 more than 90% of all infants weighing less than 1000 g died, whereas more than 70% of those between 750 and 1000 g now survive. Mortality among those newborns weighing less than 750 g remains high, with two thirds dying. 9 An early attempt to draw on the totality of worldwide published reports in interpreting the outcomes of low birthweight was made by Stewart et al in 1981. 69 The purpose was to allow rational health care planning and to provide guidance to parents about the chances of very low-birthweight infants surviving as healthy children. They found that very low-birthweight infants born between 1946 and 1960 had high mortality and morbidity rates. From 1960 to 1977 the chances of healthy survival trebled, whereas the prevalence of major handicap remained stable at 6% to 8% of very lowbirthweight live births. Figure 1 shows the relative changes in mortality and morbidity over the 30-year period. These data were derived from areas in the forefront of the development and introduction of modern methods of perinatal care. Thus their mortality rates for very low-birthweight infants were usually below the national figures for the countries concerned. Ehrenhaft et aF2 reviewed pooled data from unpublished as well as published United States perinatal center reports to derive mortality and morbidity trends for subgroups of very low-birthweight infants between 1960 and 1985. Figures 2 and 3, reprinted from their report, illustrate the effects of declining mortality on the relative proportions of normal and
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Figure 1. Pooled data from 16 international studies arranged by quinquennium to show percentage of very low-birthweigbt infants (:5 1500 grams) who died, survived and were handicapped, or survived and were healthy. (From Stewart AL, Reynolds EOR, Lipscomb AP: Outcome for infants of very low birthweight: Survey of world literature. Lancet 1:10381040, 1981: with permission.)
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Figure 2. Outcomes for very low-birthweight infants (:51500 grams) born in Level III hospitals, 1960-1985. Health Technology Case Study 38. (Neonatal Intensive Care for Low Birthweight Infants: Costs and Effectiveness. Washington, DC, Office of Technology Assessment, Congress of the United States, 1987.)
abnormal survivors. Because many very sick newborns who previously would have died are now surviving, an increasing rate of handicap might be expected. Whereas there are now larger absolute numbers of both seriously handicapped and normal survivors among all subgroups of very low-birthweight infants, the proportion of NICU survivors who have serious handicaps has not changed significantly since the introduction of neonatal intensive care. It should be noted, however, that the rate of serious longterm disability increases with decreasing birthweight. Among survivors during the 1980 to 1985 period, there was a 22% rate of handicap for babies less than 1500 g, and a 34% rate for babies less than 1000 g. Meta-analyses of these sorts, although useful for looking at overall trends, are limited by sociodemographic differences in the study populations, variability in the definitions and measurements of developmental outcomes, and the length and completeness of follow-up. Next we review selected individual studies of developmental outcomes of low-birthweight infants from the perspective of historical and current trends, lessons to be learned, and recommendations regarding the practical aspects of optimal care for these children.
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Figure 3. Outcomes for extremely low-birthweight infants (:0;1000 grams) born in Level III hospitals, 1960-1985. Health Technology Case Study 38. (Neonatal Intensive Care for Low Birthweight Infants: Costs and Effectiveness. Washington, DC, Office of Technology Assessment, Congress of the United States, 1987.)
Grogaard et al,27 in a study of nearly 2000 Tennessee infants weighing less than 1500 g at birth, found no increase in the incidence of handicaps among infants born weighing less than 1500 g between 1976 and 1985, although the survival rate increased. Not only did the number of very low-birthweight survivors increase between 1975 and 1984 in Alberta, Canada, but the incidence rate of neurologic impairment fell significantly from 19% to 13% so that there was no significant increase in the rate of disabled children. 57 Survival rates for very low-birthweight infants in Tiibingen, Germany, increased from 70% in 1977 to 1979 to 77% in 1982 to 1983. During the same period, severe neurologic sequelae decreased from 9% to 4%. The incidence of minor neurodevelopmental problems remained unchanged. 30 In a statewide infant tracking program in Iowa, 31% of surviving very low-birthweight infants born between 1979 and 1983 failed developmental screening through 30 months of age and 90% of them proved to have significant disability on further comprehensive evaluation. 9 The prevalence of moderate to severe motor or cognitive disability for infants whose birthweights were between 1000 and 1500 g was 23%, whereas that for
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infants with birthweight less than 1000 g was just over 45%. Three fourths of these babies were flagged in the first year of life. With increasing survivability of extremely low-birthweight infants, attention is now focused on their outcomes. In a comparison of survival and morbidity between the late 1970s and early 1980s for babies weighing 501 to 1000 g born to residents in central-west Ontario, Canada, Saigal et al 60 found a significant improvement in the proportion of infants considered to have disabilities at age 3, but only for those weighing more than 800 g. The disability rate in the first period was 50% versus 27% in the latter period. University of Washington researchers compared two cohorts of neonates with birthweights less than 800 g born between 1977 and 1980 and 1983 and 1985. 36 There were more survivors in the second period compared to the first. Whereas the prevalence of major central nervous system handicaps did not change, the severity of handicap was greater for the second cohort. Thus, these smallest of survivors remain at particularly high risk despite improved medical interventions.
OUTCOMES RELATED TO SPECIFIC PERINATAL RISK FACTORS Neurodevelopmental outcome cannot be predicted solely on the basis of birthweight, but is related to a number of specific medical complications common among very low-birthweight infants: intraperiventricular hemorrhage (IPVH), bronchopulmonary dysplasia (BPD), and nutritional deficits. Intraperiventricular Hemorrhage The introduction of computerized tomography and especially ultrasonography permitted serial examinations of very low-birthweight infants' brains. This led to the recognition and classification of hemorrhages in the regions adjacent to the lateral ventricles: grade I, subependymal hemorrhage; grade II, intraventricular hemorrhage without ventricular dilatation; grade III, intraventricular hemorrhage with ventricular dilatation; and grade IV, intraventricular hemorrhage with parenchymal hemorrhage. 55 IPVH occurs in as many as 40% of infants less than 1500 g.62 Subsequently, a number of papers have appeared that generally suggest the benign nature of grades I and II but increased risks for grades III and IV.!' 24. 25 Grade II IPVH, even when accompanied by posthemorrhagic hydrocephalus, often has a favorable outcome. 42 Adverse sequelae are related more to persistent ventriculomegaly (hydrocephalus ex vacuo) and loss of brain tissue than to the hemorrhage itself. Volpe 72 points out that careful assessment of the ultrasonographic appearance of the periventricular parenchyma, looking for signs of infarction (the relationship between such lesions and IPVH is uncertain), is of major value in estimating outcome. He and his associates found a correlation between the severity of these signs, which they termed periventricular intraparenchymal echodensities, and outcomes. 29 Referred to in some literature as periventricular leukomalacia and including the intraparenchy-
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mal lesions of grade IV IPVH, these echodensities, especially when extensive, were likely to have motor impairment, Bozynski et al l3 found the early cranial sonograms to be a useful predictor of the neurologic examination when premature infants reached term. One must always keep in mind the potential of an individual child despite adverse odds. Blackman et al 8 reported the surprisingly favorable outcomes for infants with large porencephalic cysts associated with the intraparenchymal lesions of grade IV IPVH. Although spastic cerebral palsy, usually the hemiplegic type with involvement contralateral to the cyst, was almost always present, cognitive abilities were relatively spared, perhaps because the lesions were in the subcortical white matter. Of 16 affected children, 5 (31%) showed normal cognitive function and 9 (56%) had borderline to mild cognitive deficits. Caution is in order even when the head ultrasound looks bad. In this same study and one reported by Boynton et al,l1 seizures at the time of the hemorrhage are a bad prognostic indicator. Recognizing the wide range of outcomes after detection of periventricular echodensities, Bennett et aF caution against communicating overly pessimistic prognoses based on ultrasonographic findings alone. Studies of children who had IPVH as neonates show that they perform more poorly at age 5 than children without hemorrhages on indices of cognitive, motor, and neuromotor functioning. 77 Even when those with hemorrhages who subsequently manifest moderate to severe disability (i.e., cerebral palsy or mental retardation) are excluded, researchers have found affected children to perform significantly lower than comparison groups on measures of perceptual-motor and memory skills (Selzer et aI, unpublished data). Furthermore, those with mild hemorrhages (grades I and II) have been shown to be at risk for low severity developmental dysfunction at ages 5 to 6. 46 Bronchopulmonary Dysplasia Bronchopulmonary dysplasia (BPD) is a chronic lung condition of premature infants characterized by the need for mechanical ventilation, persistent dependence on supplemental oxygen therapy, and a characteristic chest radiograph. Bozynski l2 has thoroughly reviewed the pathophysiology and literature on developmental outcomes of infants with BPD. Because children with BPD frequently have many recurrent and prolonged medical complications due to extreme prematurity, it is difficult to assess the specific contribution of BPD to development. Studies indicate that BPD with its attendant postnatal complications places children at increased risk for neurodevelopmental abnormalities, however. 26. 49. 71 In one study, the best predictor of handicap was the duration of assisted ventilation. 18 Growth and Development of Very Low-Birthweight Infants Physical growth, including increasing head size, is an excellent marker of the well-being of low-birthweight infants. In a multicenter, longitudinal study of 608 low-birthweight preterm babies, Casey et aP5 found them to demonstrate growth patterns lower than published standards for term infants of the same age and sex. No catch-up growth was noted by the 12month examination (gestation-corrected age) for any birthweight group. This finding, supported by earlier studies,34, 38, 39 runs counter to the
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prevailing impression that low-birthweight infants do indeed approach the growth patterns of their chronologically equivalent full-term peers during infancy. Even if these babies stay smaller in infancy, however, Ross et al 58 have shown that by 7 to 8 years of age, very low-birthweight infants who had been smaller than full-term peers at the first and third years of life have caught up to the normal population. There is general agreement that small-for-gestational-age low preterm infants are less likely to catch up in growth than those of appropriate size for gestational age. 76 Symmetrically small for gestational age (SGA) preterm infants (i. e., head circumference as well as length and weight are below the tenth percentile) are at increased risk of developmental delay and this delay seems related to the head growth restriction. 73 Data by Vohr75 indicate that there is a gradual developmental catch-up pattern between 9 months and 5 years for both SGA and appropriate for gestational age (AGA) infants, and that even SGA children with significantly more early delay have potential to catch up by 4 to 5 years. Failure to catch up in weight for both AGA and SGA preterm infants seems to be associated with a poorer developmental outcome, however. 33 Intrauterine or postnatal growth failure before term is not of sinister prognostic significance if catch-up occurs thereafter. Catch-up head growth has been particularly emphasized. In fact, rapid head growth in the first year of life, crossing percentiles on the growth charts, often raises concerns about hydrocephalus. 56 On the other hand, failure of catch-up growth is viewed as an unfavorable sign. Hack et al demonstrated that subnormal « third percentile) head size at 8 months (corrected) age among very low-birthweight AGA infants was associated with significantly lower mean Stanford-Binet IQ scores at 3 years compared with normal head size (79 vs. 95).31 Early postnatal head growth may summarize the adverse effects of many perinatal risk factors, thus making it a strong predictor of early developmental outcome in very low-birthweight infants. 28
LONG-TERM FOLLOW-UP OF LOW-BIRTHWEIGHT INFANTS It is clear that there are short-term risks for serious developmental disability from early birth. The shorter the gestation, the greater the risk. How stable are the findings of questionable neurologic abnormalities observed in the first few years of life, however? Nelson and Ellenberg52 found in the National Perinatal Collaborative Study of over 37,000 infants that some babies appear to "outgrow" abnormalities of muscle tone. AmielTison and Grenier further suggest that when a infant has a clearly normal neurologic examination, a normal outcome can be anticipated. Similarly, when the examination is clearly abnormal, an abnormal outcome is likely. When the examination is equivocal, however (i. e., mild hypotonia or hypertonia is observed), the outcome cannot be predicted confidently. 2 Many short-term follow-up studies of cognitive function in low-birthweight babies have shown reduced mean scores on the Bayley Scales of Infant Development4 or other tests in contrast to various comparison groups, but psychologists and others have stressed the limitations of predictability for the widely used measures of intellectual abilities in infants. 65, 66 Furthermore, among babies who show no abnormalities in the early years, is
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there a remaining risk for learning and behavior problems? To address the total impact of very low birthweight on developmental outcomes, children must be tracked into school age. The findings of long-term studies of very low-birthweight infants have been quite consistent. Whereas group means on tests of general cognitive abilities fall within the normal range,3 specific areas of developmental weakness have been noted, particularly in visual-perceptual-motor skills. 60, 67 Even when children with obvious mental and motor disabilities are excluded, these difficulties persist. 55, 56 Thus underachievement, grade retention, and a need for special education resources are more likely to occur for very lowbirthweight children than for the general population. 10, 20, 62
INFLUENCES ON OUTCOME: BIOLOGIC VERSUS ENVIRONMENTAL VARIABLES The conventional wisdom is that biologic risk factors have relatively greater impact on measures of cognitive and neuromotor performance in infancy,45 whereas environmental factors seem more influential on cognitive function from toddlerhood onward. 59 Although prematurity and the attendant complications that infants sustain place them at risk, recovery occurs in most infants. Therefore, social factors playa major role in determining outcome regardless of neonatal complications. I6 Numerous investigators have found family status, parental education levels, mother-infant interaction, and general environmental quality far better indicators of long-term outcome than measures of perinatal or physical status. 6, 69 The effects of perinatal stress on children are mediated by and influence the environment in which they are reared. 21, 37, 68 A child with neurologic injury has an improved outcome when in a nurturing environment. Conversely, a child with biologic risk factors but no overt disability may not achieve potential in a suboptimal setting. Leonard et al 44 found that although increasing grades of intracranial hemorrhage had increasing rates of neurologic and cognitive abnormalities, the factors associated with the highest incidence of later abnormality were parenting risk factors. Although a broad array of sociodemographic factors correlates with poor outcomes, such as school difficulties, biologic risk contributes independently to these results. 48 Moreover, the early environment and the interaction an infant has with its mother explains only a small portion of the variation in mental test performance, concurrently and later. All studies of risk children have noted wide variations in outcome. Some children appear to be invulnerable to early sickness, unresponsive caregiving, and poor family circumstances. 5
THE HEALTH CARE ROLE IN FOLLOW-UP OF LOWBIRTHWEIGHT INFANTS Because low-birthweight infants are at risk for developmental problems and have increased chronic health problems, there is a need for systematic follow-up to be certain that their needs are identified and addressed as
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early as possible. 32 Several states have developed statewide screening and tracking programs for infants with perinatal risk factors. 9.41 With the advent of Public Law 99-457, the 1986 Amendment to the Education for All Handicapped Act, states have a mandate to develop systems of early identification of children with or at risk for developmental disabilities. 19 Children with very low birthweight are almost universally considered at sufficient risk that they receive services under this law, including screening, tracking, and, if needed, special educational, therapeutic, and social support services. Many existing neonatal follow-up clinics have joined with early intervention programs to facilitate community-based, comprehensive, coordinated, family-centered care. Bennett describes the potential benefits of early intervention for high-risk infants elsewhere in this issue. Lasky et al43 have pointed out the higher rates of attrition and developmental delay for indigent populations. Despite considerable effort to prevent attrition in their program in Texas, 43% of high-risk babies were unavailable for follow-up at the I-year visit. Furthermore, the incidence of developmental delay exceeds that of most other studies of developmental outcomes. 43 Researchers in Chicago reported that only 26% of infants discharged from urban NICU s versus 57% from suburban hospitals were followed developmentally.14 They also found a 20% rate of developmental delay among presumably normal inner city infants. Thus, children who may be most in need of early intervention services are often the ones most likely to be outside a system of coordinated, comprehensive care.
PREVENTION OF LOW BIRTHWEIGHT The previous discussion would be moot and mute were the knowledge and recommendations regarding prevention of low birthweight successfully implemented. The Institute of Medicine's Committee to Study the Prevention of Low Birthweight concluded that enough is known at present to reduce the incidence of premature birth. It estimated that if expanded use of prenatal care reduced the low birthweight rate only 0.7%, the increased expenditures for prenatal services would be approximately equal to a single year of cost savings in direct medical care expenditures for the lowbirthweight infants born to the target population.17 Increasing the birthweight of just one low-birthweight infant from 2 pounds to 2.5 pounds would result in cost savings of nearly $17,000 in acute inpatient hospital costs alone. Small improvements in the average birthweight of all lowbirthweight infants would result in an immediate savings of $70 to $95 million in short-term acute care costs; long-term cost savings would be much greater. 61 The National Commission to Prevent Infant Mortality has noted that progress in lowering the percentage oflow-birthweight infants is stagnating, placing more than 250,000 infants per year at risk for chronic handicapping conditions. To reverse this trend, there must be increasing commitment to (1) providing universal access to early maternity and pediatric care for all mothers and infants, and (2) making the health and well-being of mothers and infants a national priority. 51 The United States Office of Technology
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Assessment found that 15 of 25 studies that scrutinized the effectiveness of augmented prenatal care services had a positive impact on birth outcomes. 54
SUMMARY A significant portion of the health care dollar has been spent on neonatal intensive care since the early 1970s when technologic developments permitted salvage of very small premature infants. The wisdom of allocating so much for so few has been challenged, especially if the result is an increase in the number of severely mentally and motorically disabled children. Studies from around the world of the secular trends in mortality and morbidity for very and extremely low-birthweight babies uniformly indicate that there have been dramatic decreases in mortality and morbidity in the past 20 years. The relative proportion of moderate to severe disability has remained stable during this period of increasing survival potential. Thus, although the absolute numbers of children with disabilities caused by complications of very low birthweight may have increased slightly, they constitute a small minority of the overall number of children with disabilities requiring special educational and other services. Most surviving children with birthweights less than 1500 g remain free of significant functional impairments. It is often difficult for the clinician to identify early or even midway through the neonatal course which infants will have severe, life-long disabilities. By the time identification is feasible, heroic decisions about life supports are no longer called for. Thus, the ethical issues discussed earlier regarding decision-making based on anticipated quality of life become less relevant as the child's condition stabilizes. Given the generally favorable prognosis for even the smallest premature infant, the clinician is probably best advised to give the individual patient the benefit of the doubt. Undoubtedly, there will be exceptions. The more subtle effects of very low birthweight on learning and behavior are just becoming clear as long-term follow-up studies appear in the literature. Very low-birthweight infants who do not manifest severe disability do seem to be at risk for learning problems, although overall cognitive function is in the normal range. There are other effects of pre term birth. On average, stature appears to remain lower, although there may be catch-up growth later in childhood. Having a very low-birthweight infant places considerable stress on the family, but it is unclear whether this has a long-term impact. Studies have failed to show a consistent influence of preterm birth on long-term behavior. Behavior is likely affected more by the social-emotional milieu in which the child is reared than prematurity itself. The environment seems to take over in importance in affecting cognitive functioning after the first several years of life. There appears to be an interaction between biologic and environmental risks. Those responsible for health, educational, and social services should be cognizant of this interaction. Allocation and prioritization oflimited resources for health care continues to challenge our society. Oregon is pursuing a health care rationing
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plan in which medical services reimbursed by Medicaid are ranked according to their net benefits. When the dollars run out, items low on the list will not be funded. 35 Those who would limit neonatal intensive care cannot use poor return on the dollar as an argument, however. Clearly and dramatically, neonatal intensive care is a wonder of twentieth century medicine. For most very low-birthweight infants and their parents, it is worth it. There are those who say we must find a way to protect highquality health care, whatever the cost, for everyone who needs it, including the smallest premature infant.79 The next wave of advances must be in the prevention of preterm birth.
REFERENCES 1. Amato M, von Muralt HG: Neurological prognosis of high-risk preterm infants with periventricular hemorrhage and ventricular dilatation. Eur Neurol 25:241-247, 1986 2. Amiel-Tison C, Grenier A: Neurological Assessment During the First Year of Life. New York, Oxford University Press, 1986 3. Aylward GP, Pfeiffer SI, Wright A, Verhulst SJ: Outcome studies of low birth weight infants published in the last decade: A metaanalysis. J Pediatr 115:515-520, 1989 4. Bayley N: Bayley Scales ofInfant Development. New York, The Psychological Corporation, 1969 5. Beckwith L: Parent interaction with their preterm infants and later mental development. In Honig AS (ed): Risk Factors in Infancy. Special Aspects of Education: 7. New York, Gordon and Breach Science Publishers, 1986, pp 27-39 6. Bee HL, Barnard KE, Eyres SJ, et al: Prediction of IQ and language skill from perinatal stature, child performance, family characteristics, and mother-infant interaction. Child Dev 53:1134-1156, 1982 7. Bennett FC, Silver G, Leung EJ et al: Periventricular echodensities detected by cranial ultrasonography: Usefulness in predicting neurodevelopmental outcome in low-birthweight, preterm infants. Pediatrics 85:400-410, 1990 8. Blackman JA, McGuinness GA, Bale JF Jr, et al: Large postnatally acquired porencephalic cysts: Unexpected developmental outcomes. J Child Neurol 6:58-64, 1991 9. Blackman JA, Hein HA: Iowa's system for screening and tracking high-risk infants. Am J Dis Child 139:826-831, 1985 10. Blackman JA, Lindgren SD, Hein HA, et al: Long-term surveillance of high-risk children. Am J Dis Child 141:1293-1299, 1987 11. Boynton BR, Boynton CA, Merritt TA, et al: Ventriculoperitoneal shunts in low birth weight infants with intracranial hemorrhage: Neurodevelopmental outcome. Neurosurgery 18:141-145, 1986 12. Bozynski MEA: Comprehensive management of the infant with bronchopulmonary dysplasia: A growing challenge. Infants and Young Children 2:14-24, 1989 13. Bozynski MEA, DiPietro MA, Meisels SJ, et al: Cranial sonography and neurological examination of extremely preterm infants. Dev Med Child Neurol 32:575-581, 1990 14. Brinker RP, Frazier W, Lancelot B, et al: Identifying infants from the inner city for early intervention. Infants and Young Child 2:49-58, 1989 15. Casey PH, Kraemer HC, Bernbaum J, et al: Growth patterns oflow birth weight preterm infants: A longitudinal analysis of a large, varied sample. J Pediatr 117:298-307, 1990 16. Cohen SE, Parmelee AH, Beckwith L, et al: Cognitive development in preterm infants: Birth to 8 years. J Dev Behav Pediatr 7:102-110, 1986 17. Committee to Study the Prevention of Low Birthweight, Institute of Medicine: Preventing Low Birthweight. Washington, DC, National Academy Press, 1985 18. Davidson S, Schrayer A, Wielunsky E, et al: Energy intake, growth, and development in ventilated very low birth-weight infants with and without bronchopulmonary dysplasia. Am J Dis Child 144:553-559, 1990 19. Education of the Handicapped Amendments, 1986. Federal Register 54(119):2630626348, 1989
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20. Eilers BL, Desai NS, Wilson MA, et al: Classroom performance and social factors of children with birthweights of 1,250 grams or less: Follow-up at 5 to 8 years. Pediatrics 77:203-208, 1986 21. Escalona SK: Babies at double hazard: Early development of infants at biologic and social risk. Pediatrics 70:670-676, 1982 22. Ehrenhaft PM, Wagner JL, Herdman RC: Changing prognosis for very low birth weight infants. Obstet Gynecol 74:528-535, 1989 23. Fleischman AR: The immediate impact of the birth of a low birth weight infant on the family. Zero to Three 6:1-5, 1986 24. Ford LM, Steichen J, Steichen Asch PA, et al: Neurologic status and intracranial hemorrhage in very low birth weight preterm infants. Am J Dis Child 143:1186-1190, 1989 25. Garfinkel E, Tejani N, Boxer HS, et al: Infancy and early childhood follow-up of neonates with periventricular or intraventricular hemorrhage or isolated ventricular dilatation: A case controlled study. Am J Perinatol 5:214-219, 1988 26. Goldson E: Severe bronchopulmonary dysplasia in the very low birth weight infant: Its relationship to developmental outcome. J Dev Behav Pediatr 5:165-168, 1984 27. Griigaard JB, Lindstrom DP, Parker RA, et al: Increased survival rate in very low birth weight infants (1500 grams or less): No association with increased incidence of handicaps. J Pediatr 117:139-146, 1990 28. Gross SJ, Oehler JM, Eckerman CO: Head growth and developmental outcome in very low birth weight infants. Pediatrics 71:70-75, 1983 29. Guzzetta F, Shackelford GD, Volpe S, et al: Periventricular intraparenchymal echodensities in the premature newborn: Critical determinant of neurologic outcome. Pediatrics 78:995-1006, 1986 30. Haas G, Buchwald-Saal M, Leidig E, et al: Improved outcome in very low birth weight infants from 1977 to 1983. Eur J Pediatr 145:337-340, 1986 31. Hack M, Breslau N: Very low birth weight infants: Effects of brain growth during infancy on intelligence quotient at 3 years of age. Pediatrics 77:196-202, 1986 32. Hack M, Caron B, Rivers A, et al: The very low birth weight infant: The broader spectrum of morbidity during infancy and early childhood. J Dev Behav Pediatr 4:243-249, 1983 33. Hack M, Merkatz IR, Gordon D, et al: The prognostic significance of postnatal growth in very low birth weight infants. Am J Obstet GynecoI143:693-699, 1982 34. Hack M, Merkatz IR, Gordon D, et al: Catch-up growth and developmental outcome in very low birthweight infants. Am J Dis Child 138:370-375, 1984 35. Hamilton DP: Oregon's plan comes to the capital. Science 249:469, 1990 36. Hoffman EL, Bennett FC: Birth weight less than 800 grams: Changing outcomes and influences of gender and gestation number. Pediatrics 86:27-34, 1990 37. Hunt JV, Cooper BAB, Tooley WHo Very low birth weight infants at 8 and 11 years of age: Role of neonatal illness and family status. Pediatrics 82:596-603, 1988 38. Kimble KJ, Ariagno RL, Stevenson DK, et al: Growth to 3 years among very low birth weight sequelae-free survivors of modern neonatal intensive care. J Pediatr 100:622624, 1982 39. Kitchen WH, Ford GW, Doyle LW: Growth and very low birthweight. Arch Dis Child 64:379-382, 1989 40. Klein N, Hack M, Gallagher J, et al: Preschool performance of children with normal intelligence who were very low birth weight infants. Pediatrics 75:531-537, 1985 41. Knutson ML, Biro pJ, Padgett D: Tracking infants at risk: Washington State's High Priority Infant Tracking System. Journal of Pediatric Health Care 1:180-188, 1987 42. Krishnamoorthy KS, Kuehnle KJ, Todres ID, et al: Neurodevelopmental outcome of survivors with posthemorrhagic hydrocephalus following Grade II neonatal intraventricular hemorrhage. Ann Neurol 15:201-204, 1984 43. Lasky RE, Tyson JE, Rosenfeld CR, et al: Disappointing follow-up findings for indigent high-risk newborns. Am J Dis Child 141:100-105, 1987 44. Leonard CH, Clyman RI, Piecuch RE, et al: Effect of medical and social risk factors on outcome of prematurity and very low birth weight. J Pediatr 116:620-626, 1990 45. Low JA, Galbraith RS, Muir DW, et al: The predictive significance of biologic risk factors for deficits in children of a high-risk population. Am J Obstet Gynecol 145:1059-1068, 1983
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46. Lowe J, Papile L: Neurodevelopmental performance of very low birth weight infants with mild periventricular, intraventricular hemorrhage. Am J Dis Child 144:1242-1245, 1990 47. McCarton CM: The long-term impact of a low birth weight infant on the family. Zero to Three 6:6-10, 1986 48. McCormick MC, Gortmaker SL, Sobol AM: Very low birth weight children: Behavior problems and school difficulty in a national sample. J Pediatr 117:687-693, 1990 49. Meisels SJ, Plunkett JW, Roloff DW, et al: Growth and development of preterm infants with respiratory distress syndrome and bronchopulmonary dysplasia. Pediatrics 77:345352, 1986 50. Ment LR, Duncan CC, Ehrenkranz RA: Intraventricular hemorrhage of the preterm neonate. Semin Perinatol 11:132-141, 1987 51. National Commission to Prevent Infant Mortality: Troubling Trends: The Health of America's Next Generation. Washington, DC, The National Commission to Prevent Infant Mortality, 1990 52. Nelson KB, Ellenberg JH: Children who "outgrew" cerebral palsy. Pediatrics 69:529536, 1982 53. Neonatal care for low birthweight infants: Costs and effectiveness. Washington, DC, Office of Technology Assessment, 1987 54. Office of Technology Assessment (OTA), Congress of the United States: Healthy Children: Investing in Our Future. Washington, DC, U.S. Government Printing Office (GPO), 1988 55. Papile L, Burstein J, Burstein R, et al: Incidence and evolution of subependymal and intraventricular hemorrhage: A study of infants with birth weights less than 1,500 grams. J Pediatr 92:529-534, 1978 56. Perlman JM, Lynch B, Volpe JJ: Late hydrocephalus after arrest and resolution of neonatal post-hemorrhagic hydrocephalus. Dev Med Child NeuroI32:725-729, 1990 57. Robertson CMT, Etches PC: Decreased incidence of neurologic disability among neonates at high risk born between 1975 and 1984 in Alberta. Can Med Assoc J 139:225-229, 1988 58. Ross G, Lipper EG, Auld PAM: Growth achievement of very low birth weight premature children at school age. J Pediatr 117:307-309, 1990 59. Rutter M: Continuities and discontinuities from infancy. In Osofsky JD (ed): Handbook of Infant Development, ed 2. New York, John Wiley & Sons, 1987, p 1269 60. Saigal S, Szatmari P, Rosenbaum P, et al: Intellectual and functional status at school entry of children who weighed 1000 grams or less at birth: A regional perspective of births in the 1980s. J Pediatr 116:409-416, 1990 61. Schwartz RM: What price prematurity? Fam Plann Perspect 21:170-174, 1989 62. Sell EJ, Gaines JA, Gluckman C, et al: Early identification of learning problems in neonatal intensive care graduates. Am J Dis Child 139:460-463, 1985 63. Shankaran S, Cohen SN, Linver M, Zonia S: Medical care costs of high-risk infants after neonatal intensive care: A controlled study. Pediatrics 81:372-378, 1988 64. Shelton TL: The assessment of cognition/intelligence in infancy. Infants and Young Children 1:10-25, 1989 65. Shonkoff J: The limitations of normative assessments of high-risk infants. Topics in Early Childhood Special Education 3:29-43, 1983 66. Siegel LS: Reproductive, perinatal, and environmental variables as predictors of development of preterm «1500 grams) and full-term children at 5 years. Semin Perinatol 6:274-279, 1982 67. Siegel LS: Home environmental influences on cognitive development in preterm and fullterm children during the first 5 years. In Gottfried AW (ed): Home Environment and Early Cognitive Development: Longitudinal Research. Orlando, Academic Press, 1984 68. Smith AC, Flick GL, Ferriss GS, et al: Prediction of developmental outcome from prenatal, perinatal and postnatal event. Child Dev 43:495-507, 1972 69. Stewart AL, Reynolds EOR, Lipscomb AP: Outcome for infants of very low birthweight: Survey of world literature. Lancet 1038-1040, 1981 70. Storch TG: The unkindest cut. Am J Dis Child 144:533, 1990 71. Vohr BR, Bell EF, Oh W: Infants with bronchopulmonary dysplasia. Am J Dis Child 136:443-447, 1982 72. Volpe JJ: Intraventricular hemorrhage in the premature infant: Current concepts. Ann Neurol 25:109-116, 1989 73. Vohr BR, Garcia Coli C, Oh W: Increased morbidity in very low birth weight (VLBW)
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small for gestational age (SGA) infants with reduced head circumference (HC) at birth: A two year follow-up study [abstract]. Pediatr Res 27:lOA, 1990 Vohr BR, Garcia Coll CT: Neurodevelopmental and school performance of very low birth weight infants: A seven year longitudinal study. Pediatrics 76:345-350, 1985 Vohr BR, Oh W: Growth and development in preterm infants small for gestational age. J Pediatr 103:941-945, 1983 Vohr BR, Oh W, Rosenfeld AG, et al: The preterm small for gestational age infant: A two year follow-up study. Am J Obstet Gynecol 133:425-431, 1979 Williams ML, Lewandowski LJ, Coplan J, et al: Neurodevelopmental outcome of preschool children born preterm with and without intracranial hemorrhage. Dev Med Child Neurol 29:243-249, 1987 Willis WO: Parental perspectives on the system of care for low birth weight infants. Infants and Young Children 3:v-x, 1991 Young EWD, Stevenson DK: Limiting treatment for extremely premature, low-birthweight infants (500 to 750 g). Am J Dis Child 144:549-552, 1990
Address reprint requests to James A. Blackman, MD, MPH Kluge Children's Rehabilitation Center University of Virginia 2270 Ivy Road Charlottesville, VA 22901
0031-3955/91 $0.00
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Neonatal Intensive Care: Is It Worth It? Developmental Sequelae of Very Low Birthweight
James A. Blackman, MD, MPH*
From miniaturized ventilators, parenteral nutrition, and warming devices that launched the modern intensive care era in the late 1960s and early 1970s to extracorporeal membrane oxygenators (ECMO) and artificial surfactant in the 1990s, we have come a long way. Progress in neonatal intensive care has brought with it a substantial social and emotional as well as monetary burden. Although the much improved chances for survival among very small infants made possible by the new technology are admirable and appreciated, it is appropriate to question the long-term benefits of these advances: What are the chances for good developmental outcomes for low-birthweight graduates of neonatal intensive care? Do these chances justify the cost?
THE COST OF NEONATAL INTENSIVE CARE Between 150,000 and 200,000 infants (4% to 6% of all newborns) are treated annually in neonatal intensive care units (NICU), and at least half of them are low-birthweight infants. Neonatal intensive care is among the most expensive services that many hospitals provide. Average hospital costs for low-birthweight babies in 1985 ranged from $10,000 to $65,000, depending on birthweight category.61 Using the medical care component of the consumer price index, it is estimated that average hospital costs for the smallest surviving preterm infants exceeded $100,000 in 1990. Costs for an infant with a birthweight of less than 1000 g is three to four times higher than those for an infant more than 1500 g at birth. Infants less than 750 g have the longest hospital stays (average, 98 days) and the highest costs. 53 *Associate Professor of Pediatrics, and Director of Research, Kluge Children's Rehabilitation Center and Research Institute, Department of Pediatrics, University of Virginia, Charlottesville, Virginia
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In addition to in-hospital costs, NICU graduates continue to have high medical costs after discharge. According to a study by Shankaran et al 63 in 1988, whereas the US Department of Agriculture estimates of medical costs of raising a child at home ranged from $22 to $26.80 per month, average outpatient costs for former NICU babies were as follows: unhandicapped, $31 per month; mildly handicapped, $86 per month; and moderately to severely handicapped, $109 per month.
OTHER CONSIDERATIONS IN EVALUATING NEWBORN INTENSIVE CARE The time-honored Hippocratic dictum "Primum non nocere" (above all, do no harm) applies here. No one who has ever worked in or visited a neonatal intensive care unit forgets the many invasive and usually painful procedures that are required to sustain life. The technology itself, designed to save lives, often inflicts harm or suffering on recipients of intensive care. Physicians are caught between the moral principles of nonmaleficence (not doing harm) and justice (which compels the physician to allocate finite resources equitably) on the one hand, and patient-centered beneficence (which requires the physician to make every possible effort to benefit the patient) on the other hand. 79 Heroic medical measures can be justified only if there is a reasonable hope for short- and long-term benefit. There are state-to-state and international differences in the way limited resources have been allocated to newborn intensive care. Sweden and Britain provide special care (everything short of assisted ventilation) but not intensive care for infants weighing less than 750 g unless there is strong reason to do otherwise. 79 Stanford University's practice is to resuscitate initially all critically ill newborns, but with participation of parents, they are prepared to curtail aggressive therapy and redirect care to measures that provide comfort for the infant. 79 An early end to gestation not only interrupts fetal growth and development but also the psychologic process through which the pregnant woman and her husband evolve with their fetus in preparation for beginning their relationship to their newborn.23 The often long intensive care experience, with its uncertainties about life or death, drains parents' physical and emotional stamina. Parents take home a normal, although medically fragile, infant, an infant who will be a slow starter, or an infant who will have an atypical or abnormal developmental course. Confirmation of either global abnormality or specific sensory abnormality is a devastating event. For every family and every type of low-birthweight infant who survives the experience of neonatal intensive care, there is the lingering aftermath. 47
SECULAR TRENDS IN MORTALITY AND MORBIDITY The marked decline in birthweight-specific mortality over the past 25 years is undoubtedly one of the major success stories in modern medicine. Improved obstetric care, the new sophistication in neonatal intensive care,
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and the regionalization of perinatal care are largely responsible. During this period the neonatal death rate (i.e., within the first 28 days of life) for infants with birthweights of 1000 to 1500 g has fallen from more than 50% to 10%. In 1960 more than 90% of all infants weighing less than 1000 g died, whereas more than 70% of those between 750 and 1000 g now survive. Mortality among those newborns weighing less than 750 g remains high, with two thirds dying. 9 An early attempt to draw on the totality of worldwide published reports in interpreting the outcomes of low birthweight was made by Stewart et al in 1981. 69 The purpose was to allow rational health care planning and to provide guidance to parents about the chances of very low-birthweight infants surviving as healthy children. They found that very low-birthweight infants born between 1946 and 1960 had high mortality and morbidity rates. From 1960 to 1977 the chances of healthy survival trebled, whereas the prevalence of major handicap remained stable at 6% to 8% of very lowbirthweight live births. Figure 1 shows the relative changes in mortality and morbidity over the 30-year period. These data were derived from areas in the forefront of the development and introduction of modern methods of perinatal care. Thus their mortality rates for very low-birthweight infants were usually below the national figures for the countries concerned. Ehrenhaft et aF2 reviewed pooled data from unpublished as well as published United States perinatal center reports to derive mortality and morbidity trends for subgroups of very low-birthweight infants between 1960 and 1985. Figures 2 and 3, reprinted from their report, illustrate the effects of declining mortality on the relative proportions of normal and
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Figure 1. Pooled data from 16 international studies arranged by quinquennium to show percentage of very low-birthweigbt infants (:5 1500 grams) who died, survived and were handicapped, or survived and were healthy. (From Stewart AL, Reynolds EOR, Lipscomb AP: Outcome for infants of very low birthweight: Survey of world literature. Lancet 1:10381040, 1981: with permission.)
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Figure 2. Outcomes for very low-birthweight infants (:51500 grams) born in Level III hospitals, 1960-1985. Health Technology Case Study 38. (Neonatal Intensive Care for Low Birthweight Infants: Costs and Effectiveness. Washington, DC, Office of Technology Assessment, Congress of the United States, 1987.)
abnormal survivors. Because many very sick newborns who previously would have died are now surviving, an increasing rate of handicap might be expected. Whereas there are now larger absolute numbers of both seriously handicapped and normal survivors among all subgroups of very low-birthweight infants, the proportion of NICU survivors who have serious handicaps has not changed significantly since the introduction of neonatal intensive care. It should be noted, however, that the rate of serious longterm disability increases with decreasing birthweight. Among survivors during the 1980 to 1985 period, there was a 22% rate of handicap for babies less than 1500 g, and a 34% rate for babies less than 1000 g. Meta-analyses of these sorts, although useful for looking at overall trends, are limited by sociodemographic differences in the study populations, variability in the definitions and measurements of developmental outcomes, and the length and completeness of follow-up. Next we review selected individual studies of developmental outcomes of low-birthweight infants from the perspective of historical and current trends, lessons to be learned, and recommendations regarding the practical aspects of optimal care for these children.
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Figure 3. Outcomes for extremely low-birthweight infants (:0;1000 grams) born in Level III hospitals, 1960-1985. Health Technology Case Study 38. (Neonatal Intensive Care for Low Birthweight Infants: Costs and Effectiveness. Washington, DC, Office of Technology Assessment, Congress of the United States, 1987.)
Grogaard et al,27 in a study of nearly 2000 Tennessee infants weighing less than 1500 g at birth, found no increase in the incidence of handicaps among infants born weighing less than 1500 g between 1976 and 1985, although the survival rate increased. Not only did the number of very low-birthweight survivors increase between 1975 and 1984 in Alberta, Canada, but the incidence rate of neurologic impairment fell significantly from 19% to 13% so that there was no significant increase in the rate of disabled children. 57 Survival rates for very low-birthweight infants in Tiibingen, Germany, increased from 70% in 1977 to 1979 to 77% in 1982 to 1983. During the same period, severe neurologic sequelae decreased from 9% to 4%. The incidence of minor neurodevelopmental problems remained unchanged. 30 In a statewide infant tracking program in Iowa, 31% of surviving very low-birthweight infants born between 1979 and 1983 failed developmental screening through 30 months of age and 90% of them proved to have significant disability on further comprehensive evaluation. 9 The prevalence of moderate to severe motor or cognitive disability for infants whose birthweights were between 1000 and 1500 g was 23%, whereas that for
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infants with birthweight less than 1000 g was just over 45%. Three fourths of these babies were flagged in the first year of life. With increasing survivability of extremely low-birthweight infants, attention is now focused on their outcomes. In a comparison of survival and morbidity between the late 1970s and early 1980s for babies weighing 501 to 1000 g born to residents in central-west Ontario, Canada, Saigal et al 60 found a significant improvement in the proportion of infants considered to have disabilities at age 3, but only for those weighing more than 800 g. The disability rate in the first period was 50% versus 27% in the latter period. University of Washington researchers compared two cohorts of neonates with birthweights less than 800 g born between 1977 and 1980 and 1983 and 1985. 36 There were more survivors in the second period compared to the first. Whereas the prevalence of major central nervous system handicaps did not change, the severity of handicap was greater for the second cohort. Thus, these smallest of survivors remain at particularly high risk despite improved medical interventions.
OUTCOMES RELATED TO SPECIFIC PERINATAL RISK FACTORS Neurodevelopmental outcome cannot be predicted solely on the basis of birthweight, but is related to a number of specific medical complications common among very low-birthweight infants: intraperiventricular hemorrhage (IPVH), bronchopulmonary dysplasia (BPD), and nutritional deficits. Intraperiventricular Hemorrhage The introduction of computerized tomography and especially ultrasonography permitted serial examinations of very low-birthweight infants' brains. This led to the recognition and classification of hemorrhages in the regions adjacent to the lateral ventricles: grade I, subependymal hemorrhage; grade II, intraventricular hemorrhage without ventricular dilatation; grade III, intraventricular hemorrhage with ventricular dilatation; and grade IV, intraventricular hemorrhage with parenchymal hemorrhage. 55 IPVH occurs in as many as 40% of infants less than 1500 g.62 Subsequently, a number of papers have appeared that generally suggest the benign nature of grades I and II but increased risks for grades III and IV.!' 24. 25 Grade II IPVH, even when accompanied by posthemorrhagic hydrocephalus, often has a favorable outcome. 42 Adverse sequelae are related more to persistent ventriculomegaly (hydrocephalus ex vacuo) and loss of brain tissue than to the hemorrhage itself. Volpe 72 points out that careful assessment of the ultrasonographic appearance of the periventricular parenchyma, looking for signs of infarction (the relationship between such lesions and IPVH is uncertain), is of major value in estimating outcome. He and his associates found a correlation between the severity of these signs, which they termed periventricular intraparenchymal echodensities, and outcomes. 29 Referred to in some literature as periventricular leukomalacia and including the intraparenchy-
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mal lesions of grade IV IPVH, these echodensities, especially when extensive, were likely to have motor impairment, Bozynski et al l3 found the early cranial sonograms to be a useful predictor of the neurologic examination when premature infants reached term. One must always keep in mind the potential of an individual child despite adverse odds. Blackman et al 8 reported the surprisingly favorable outcomes for infants with large porencephalic cysts associated with the intraparenchymal lesions of grade IV IPVH. Although spastic cerebral palsy, usually the hemiplegic type with involvement contralateral to the cyst, was almost always present, cognitive abilities were relatively spared, perhaps because the lesions were in the subcortical white matter. Of 16 affected children, 5 (31%) showed normal cognitive function and 9 (56%) had borderline to mild cognitive deficits. Caution is in order even when the head ultrasound looks bad. In this same study and one reported by Boynton et al,l1 seizures at the time of the hemorrhage are a bad prognostic indicator. Recognizing the wide range of outcomes after detection of periventricular echodensities, Bennett et aF caution against communicating overly pessimistic prognoses based on ultrasonographic findings alone. Studies of children who had IPVH as neonates show that they perform more poorly at age 5 than children without hemorrhages on indices of cognitive, motor, and neuromotor functioning. 77 Even when those with hemorrhages who subsequently manifest moderate to severe disability (i.e., cerebral palsy or mental retardation) are excluded, researchers have found affected children to perform significantly lower than comparison groups on measures of perceptual-motor and memory skills (Selzer et aI, unpublished data). Furthermore, those with mild hemorrhages (grades I and II) have been shown to be at risk for low severity developmental dysfunction at ages 5 to 6. 46 Bronchopulmonary Dysplasia Bronchopulmonary dysplasia (BPD) is a chronic lung condition of premature infants characterized by the need for mechanical ventilation, persistent dependence on supplemental oxygen therapy, and a characteristic chest radiograph. Bozynski l2 has thoroughly reviewed the pathophysiology and literature on developmental outcomes of infants with BPD. Because children with BPD frequently have many recurrent and prolonged medical complications due to extreme prematurity, it is difficult to assess the specific contribution of BPD to development. Studies indicate that BPD with its attendant postnatal complications places children at increased risk for neurodevelopmental abnormalities, however. 26. 49. 71 In one study, the best predictor of handicap was the duration of assisted ventilation. 18 Growth and Development of Very Low-Birthweight Infants Physical growth, including increasing head size, is an excellent marker of the well-being of low-birthweight infants. In a multicenter, longitudinal study of 608 low-birthweight preterm babies, Casey et aP5 found them to demonstrate growth patterns lower than published standards for term infants of the same age and sex. No catch-up growth was noted by the 12month examination (gestation-corrected age) for any birthweight group. This finding, supported by earlier studies,34, 38, 39 runs counter to the
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prevailing impression that low-birthweight infants do indeed approach the growth patterns of their chronologically equivalent full-term peers during infancy. Even if these babies stay smaller in infancy, however, Ross et al 58 have shown that by 7 to 8 years of age, very low-birthweight infants who had been smaller than full-term peers at the first and third years of life have caught up to the normal population. There is general agreement that small-for-gestational-age low preterm infants are less likely to catch up in growth than those of appropriate size for gestational age. 76 Symmetrically small for gestational age (SGA) preterm infants (i. e., head circumference as well as length and weight are below the tenth percentile) are at increased risk of developmental delay and this delay seems related to the head growth restriction. 73 Data by Vohr75 indicate that there is a gradual developmental catch-up pattern between 9 months and 5 years for both SGA and appropriate for gestational age (AGA) infants, and that even SGA children with significantly more early delay have potential to catch up by 4 to 5 years. Failure to catch up in weight for both AGA and SGA preterm infants seems to be associated with a poorer developmental outcome, however. 33 Intrauterine or postnatal growth failure before term is not of sinister prognostic significance if catch-up occurs thereafter. Catch-up head growth has been particularly emphasized. In fact, rapid head growth in the first year of life, crossing percentiles on the growth charts, often raises concerns about hydrocephalus. 56 On the other hand, failure of catch-up growth is viewed as an unfavorable sign. Hack et al demonstrated that subnormal « third percentile) head size at 8 months (corrected) age among very low-birthweight AGA infants was associated with significantly lower mean Stanford-Binet IQ scores at 3 years compared with normal head size (79 vs. 95).31 Early postnatal head growth may summarize the adverse effects of many perinatal risk factors, thus making it a strong predictor of early developmental outcome in very low-birthweight infants. 28
LONG-TERM FOLLOW-UP OF LOW-BIRTHWEIGHT INFANTS It is clear that there are short-term risks for serious developmental disability from early birth. The shorter the gestation, the greater the risk. How stable are the findings of questionable neurologic abnormalities observed in the first few years of life, however? Nelson and Ellenberg52 found in the National Perinatal Collaborative Study of over 37,000 infants that some babies appear to "outgrow" abnormalities of muscle tone. AmielTison and Grenier further suggest that when a infant has a clearly normal neurologic examination, a normal outcome can be anticipated. Similarly, when the examination is clearly abnormal, an abnormal outcome is likely. When the examination is equivocal, however (i. e., mild hypotonia or hypertonia is observed), the outcome cannot be predicted confidently. 2 Many short-term follow-up studies of cognitive function in low-birthweight babies have shown reduced mean scores on the Bayley Scales of Infant Development4 or other tests in contrast to various comparison groups, but psychologists and others have stressed the limitations of predictability for the widely used measures of intellectual abilities in infants. 65, 66 Furthermore, among babies who show no abnormalities in the early years, is
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there a remaining risk for learning and behavior problems? To address the total impact of very low birthweight on developmental outcomes, children must be tracked into school age. The findings of long-term studies of very low-birthweight infants have been quite consistent. Whereas group means on tests of general cognitive abilities fall within the normal range,3 specific areas of developmental weakness have been noted, particularly in visual-perceptual-motor skills. 60, 67 Even when children with obvious mental and motor disabilities are excluded, these difficulties persist. 55, 56 Thus underachievement, grade retention, and a need for special education resources are more likely to occur for very lowbirthweight children than for the general population. 10, 20, 62
INFLUENCES ON OUTCOME: BIOLOGIC VERSUS ENVIRONMENTAL VARIABLES The conventional wisdom is that biologic risk factors have relatively greater impact on measures of cognitive and neuromotor performance in infancy,45 whereas environmental factors seem more influential on cognitive function from toddlerhood onward. 59 Although prematurity and the attendant complications that infants sustain place them at risk, recovery occurs in most infants. Therefore, social factors playa major role in determining outcome regardless of neonatal complications. I6 Numerous investigators have found family status, parental education levels, mother-infant interaction, and general environmental quality far better indicators of long-term outcome than measures of perinatal or physical status. 6, 69 The effects of perinatal stress on children are mediated by and influence the environment in which they are reared. 21, 37, 68 A child with neurologic injury has an improved outcome when in a nurturing environment. Conversely, a child with biologic risk factors but no overt disability may not achieve potential in a suboptimal setting. Leonard et al 44 found that although increasing grades of intracranial hemorrhage had increasing rates of neurologic and cognitive abnormalities, the factors associated with the highest incidence of later abnormality were parenting risk factors. Although a broad array of sociodemographic factors correlates with poor outcomes, such as school difficulties, biologic risk contributes independently to these results. 48 Moreover, the early environment and the interaction an infant has with its mother explains only a small portion of the variation in mental test performance, concurrently and later. All studies of risk children have noted wide variations in outcome. Some children appear to be invulnerable to early sickness, unresponsive caregiving, and poor family circumstances. 5
THE HEALTH CARE ROLE IN FOLLOW-UP OF LOWBIRTHWEIGHT INFANTS Because low-birthweight infants are at risk for developmental problems and have increased chronic health problems, there is a need for systematic follow-up to be certain that their needs are identified and addressed as
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early as possible. 32 Several states have developed statewide screening and tracking programs for infants with perinatal risk factors. 9.41 With the advent of Public Law 99-457, the 1986 Amendment to the Education for All Handicapped Act, states have a mandate to develop systems of early identification of children with or at risk for developmental disabilities. 19 Children with very low birthweight are almost universally considered at sufficient risk that they receive services under this law, including screening, tracking, and, if needed, special educational, therapeutic, and social support services. Many existing neonatal follow-up clinics have joined with early intervention programs to facilitate community-based, comprehensive, coordinated, family-centered care. Bennett describes the potential benefits of early intervention for high-risk infants elsewhere in this issue. Lasky et al43 have pointed out the higher rates of attrition and developmental delay for indigent populations. Despite considerable effort to prevent attrition in their program in Texas, 43% of high-risk babies were unavailable for follow-up at the I-year visit. Furthermore, the incidence of developmental delay exceeds that of most other studies of developmental outcomes. 43 Researchers in Chicago reported that only 26% of infants discharged from urban NICU s versus 57% from suburban hospitals were followed developmentally.14 They also found a 20% rate of developmental delay among presumably normal inner city infants. Thus, children who may be most in need of early intervention services are often the ones most likely to be outside a system of coordinated, comprehensive care.
PREVENTION OF LOW BIRTHWEIGHT The previous discussion would be moot and mute were the knowledge and recommendations regarding prevention of low birthweight successfully implemented. The Institute of Medicine's Committee to Study the Prevention of Low Birthweight concluded that enough is known at present to reduce the incidence of premature birth. It estimated that if expanded use of prenatal care reduced the low birthweight rate only 0.7%, the increased expenditures for prenatal services would be approximately equal to a single year of cost savings in direct medical care expenditures for the lowbirthweight infants born to the target population.17 Increasing the birthweight of just one low-birthweight infant from 2 pounds to 2.5 pounds would result in cost savings of nearly $17,000 in acute inpatient hospital costs alone. Small improvements in the average birthweight of all lowbirthweight infants would result in an immediate savings of $70 to $95 million in short-term acute care costs; long-term cost savings would be much greater. 61 The National Commission to Prevent Infant Mortality has noted that progress in lowering the percentage oflow-birthweight infants is stagnating, placing more than 250,000 infants per year at risk for chronic handicapping conditions. To reverse this trend, there must be increasing commitment to (1) providing universal access to early maternity and pediatric care for all mothers and infants, and (2) making the health and well-being of mothers and infants a national priority. 51 The United States Office of Technology
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Assessment found that 15 of 25 studies that scrutinized the effectiveness of augmented prenatal care services had a positive impact on birth outcomes. 54
SUMMARY A significant portion of the health care dollar has been spent on neonatal intensive care since the early 1970s when technologic developments permitted salvage of very small premature infants. The wisdom of allocating so much for so few has been challenged, especially if the result is an increase in the number of severely mentally and motorically disabled children. Studies from around the world of the secular trends in mortality and morbidity for very and extremely low-birthweight babies uniformly indicate that there have been dramatic decreases in mortality and morbidity in the past 20 years. The relative proportion of moderate to severe disability has remained stable during this period of increasing survival potential. Thus, although the absolute numbers of children with disabilities caused by complications of very low birthweight may have increased slightly, they constitute a small minority of the overall number of children with disabilities requiring special educational and other services. Most surviving children with birthweights less than 1500 g remain free of significant functional impairments. It is often difficult for the clinician to identify early or even midway through the neonatal course which infants will have severe, life-long disabilities. By the time identification is feasible, heroic decisions about life supports are no longer called for. Thus, the ethical issues discussed earlier regarding decision-making based on anticipated quality of life become less relevant as the child's condition stabilizes. Given the generally favorable prognosis for even the smallest premature infant, the clinician is probably best advised to give the individual patient the benefit of the doubt. Undoubtedly, there will be exceptions. The more subtle effects of very low birthweight on learning and behavior are just becoming clear as long-term follow-up studies appear in the literature. Very low-birthweight infants who do not manifest severe disability do seem to be at risk for learning problems, although overall cognitive function is in the normal range. There are other effects of pre term birth. On average, stature appears to remain lower, although there may be catch-up growth later in childhood. Having a very low-birthweight infant places considerable stress on the family, but it is unclear whether this has a long-term impact. Studies have failed to show a consistent influence of preterm birth on long-term behavior. Behavior is likely affected more by the social-emotional milieu in which the child is reared than prematurity itself. The environment seems to take over in importance in affecting cognitive functioning after the first several years of life. There appears to be an interaction between biologic and environmental risks. Those responsible for health, educational, and social services should be cognizant of this interaction. Allocation and prioritization oflimited resources for health care continues to challenge our society. Oregon is pursuing a health care rationing
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plan in which medical services reimbursed by Medicaid are ranked according to their net benefits. When the dollars run out, items low on the list will not be funded. 35 Those who would limit neonatal intensive care cannot use poor return on the dollar as an argument, however. Clearly and dramatically, neonatal intensive care is a wonder of twentieth century medicine. For most very low-birthweight infants and their parents, it is worth it. There are those who say we must find a way to protect highquality health care, whatever the cost, for everyone who needs it, including the smallest premature infant.79 The next wave of advances must be in the prevention of preterm birth.
REFERENCES 1. Amato M, von Muralt HG: Neurological prognosis of high-risk preterm infants with periventricular hemorrhage and ventricular dilatation. Eur Neurol 25:241-247, 1986 2. Amiel-Tison C, Grenier A: Neurological Assessment During the First Year of Life. New York, Oxford University Press, 1986 3. Aylward GP, Pfeiffer SI, Wright A, Verhulst SJ: Outcome studies of low birth weight infants published in the last decade: A metaanalysis. J Pediatr 115:515-520, 1989 4. Bayley N: Bayley Scales ofInfant Development. New York, The Psychological Corporation, 1969 5. Beckwith L: Parent interaction with their preterm infants and later mental development. In Honig AS (ed): Risk Factors in Infancy. Special Aspects of Education: 7. New York, Gordon and Breach Science Publishers, 1986, pp 27-39 6. Bee HL, Barnard KE, Eyres SJ, et al: Prediction of IQ and language skill from perinatal stature, child performance, family characteristics, and mother-infant interaction. Child Dev 53:1134-1156, 1982 7. Bennett FC, Silver G, Leung EJ et al: Periventricular echodensities detected by cranial ultrasonography: Usefulness in predicting neurodevelopmental outcome in low-birthweight, preterm infants. Pediatrics 85:400-410, 1990 8. Blackman JA, McGuinness GA, Bale JF Jr, et al: Large postnatally acquired porencephalic cysts: Unexpected developmental outcomes. J Child Neurol 6:58-64, 1991 9. Blackman JA, Hein HA: Iowa's system for screening and tracking high-risk infants. Am J Dis Child 139:826-831, 1985 10. Blackman JA, Lindgren SD, Hein HA, et al: Long-term surveillance of high-risk children. Am J Dis Child 141:1293-1299, 1987 11. Boynton BR, Boynton CA, Merritt TA, et al: Ventriculoperitoneal shunts in low birth weight infants with intracranial hemorrhage: Neurodevelopmental outcome. Neurosurgery 18:141-145, 1986 12. Bozynski MEA: Comprehensive management of the infant with bronchopulmonary dysplasia: A growing challenge. Infants and Young Children 2:14-24, 1989 13. Bozynski MEA, DiPietro MA, Meisels SJ, et al: Cranial sonography and neurological examination of extremely preterm infants. Dev Med Child Neurol 32:575-581, 1990 14. Brinker RP, Frazier W, Lancelot B, et al: Identifying infants from the inner city for early intervention. Infants and Young Child 2:49-58, 1989 15. Casey PH, Kraemer HC, Bernbaum J, et al: Growth patterns oflow birth weight preterm infants: A longitudinal analysis of a large, varied sample. J Pediatr 117:298-307, 1990 16. Cohen SE, Parmelee AH, Beckwith L, et al: Cognitive development in preterm infants: Birth to 8 years. J Dev Behav Pediatr 7:102-110, 1986 17. Committee to Study the Prevention of Low Birthweight, Institute of Medicine: Preventing Low Birthweight. Washington, DC, National Academy Press, 1985 18. Davidson S, Schrayer A, Wielunsky E, et al: Energy intake, growth, and development in ventilated very low birth-weight infants with and without bronchopulmonary dysplasia. Am J Dis Child 144:553-559, 1990 19. Education of the Handicapped Amendments, 1986. Federal Register 54(119):2630626348, 1989
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20. Eilers BL, Desai NS, Wilson MA, et al: Classroom performance and social factors of children with birthweights of 1,250 grams or less: Follow-up at 5 to 8 years. Pediatrics 77:203-208, 1986 21. Escalona SK: Babies at double hazard: Early development of infants at biologic and social risk. Pediatrics 70:670-676, 1982 22. Ehrenhaft PM, Wagner JL, Herdman RC: Changing prognosis for very low birth weight infants. Obstet Gynecol 74:528-535, 1989 23. Fleischman AR: The immediate impact of the birth of a low birth weight infant on the family. Zero to Three 6:1-5, 1986 24. Ford LM, Steichen J, Steichen Asch PA, et al: Neurologic status and intracranial hemorrhage in very low birth weight preterm infants. Am J Dis Child 143:1186-1190, 1989 25. Garfinkel E, Tejani N, Boxer HS, et al: Infancy and early childhood follow-up of neonates with periventricular or intraventricular hemorrhage or isolated ventricular dilatation: A case controlled study. Am J Perinatol 5:214-219, 1988 26. Goldson E: Severe bronchopulmonary dysplasia in the very low birth weight infant: Its relationship to developmental outcome. J Dev Behav Pediatr 5:165-168, 1984 27. Griigaard JB, Lindstrom DP, Parker RA, et al: Increased survival rate in very low birth weight infants (1500 grams or less): No association with increased incidence of handicaps. J Pediatr 117:139-146, 1990 28. Gross SJ, Oehler JM, Eckerman CO: Head growth and developmental outcome in very low birth weight infants. Pediatrics 71:70-75, 1983 29. Guzzetta F, Shackelford GD, Volpe S, et al: Periventricular intraparenchymal echodensities in the premature newborn: Critical determinant of neurologic outcome. Pediatrics 78:995-1006, 1986 30. Haas G, Buchwald-Saal M, Leidig E, et al: Improved outcome in very low birth weight infants from 1977 to 1983. Eur J Pediatr 145:337-340, 1986 31. Hack M, Breslau N: Very low birth weight infants: Effects of brain growth during infancy on intelligence quotient at 3 years of age. Pediatrics 77:196-202, 1986 32. Hack M, Caron B, Rivers A, et al: The very low birth weight infant: The broader spectrum of morbidity during infancy and early childhood. J Dev Behav Pediatr 4:243-249, 1983 33. Hack M, Merkatz IR, Gordon D, et al: The prognostic significance of postnatal growth in very low birth weight infants. Am J Obstet GynecoI143:693-699, 1982 34. Hack M, Merkatz IR, Gordon D, et al: Catch-up growth and developmental outcome in very low birthweight infants. Am J Dis Child 138:370-375, 1984 35. Hamilton DP: Oregon's plan comes to the capital. Science 249:469, 1990 36. Hoffman EL, Bennett FC: Birth weight less than 800 grams: Changing outcomes and influences of gender and gestation number. Pediatrics 86:27-34, 1990 37. Hunt JV, Cooper BAB, Tooley WHo Very low birth weight infants at 8 and 11 years of age: Role of neonatal illness and family status. Pediatrics 82:596-603, 1988 38. Kimble KJ, Ariagno RL, Stevenson DK, et al: Growth to 3 years among very low birth weight sequelae-free survivors of modern neonatal intensive care. J Pediatr 100:622624, 1982 39. Kitchen WH, Ford GW, Doyle LW: Growth and very low birthweight. Arch Dis Child 64:379-382, 1989 40. Klein N, Hack M, Gallagher J, et al: Preschool performance of children with normal intelligence who were very low birth weight infants. Pediatrics 75:531-537, 1985 41. Knutson ML, Biro pJ, Padgett D: Tracking infants at risk: Washington State's High Priority Infant Tracking System. Journal of Pediatric Health Care 1:180-188, 1987 42. Krishnamoorthy KS, Kuehnle KJ, Todres ID, et al: Neurodevelopmental outcome of survivors with posthemorrhagic hydrocephalus following Grade II neonatal intraventricular hemorrhage. Ann Neurol 15:201-204, 1984 43. Lasky RE, Tyson JE, Rosenfeld CR, et al: Disappointing follow-up findings for indigent high-risk newborns. Am J Dis Child 141:100-105, 1987 44. Leonard CH, Clyman RI, Piecuch RE, et al: Effect of medical and social risk factors on outcome of prematurity and very low birth weight. J Pediatr 116:620-626, 1990 45. Low JA, Galbraith RS, Muir DW, et al: The predictive significance of biologic risk factors for deficits in children of a high-risk population. Am J Obstet Gynecol 145:1059-1068, 1983
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46. Lowe J, Papile L: Neurodevelopmental performance of very low birth weight infants with mild periventricular, intraventricular hemorrhage. Am J Dis Child 144:1242-1245, 1990 47. McCarton CM: The long-term impact of a low birth weight infant on the family. Zero to Three 6:6-10, 1986 48. McCormick MC, Gortmaker SL, Sobol AM: Very low birth weight children: Behavior problems and school difficulty in a national sample. J Pediatr 117:687-693, 1990 49. Meisels SJ, Plunkett JW, Roloff DW, et al: Growth and development of preterm infants with respiratory distress syndrome and bronchopulmonary dysplasia. Pediatrics 77:345352, 1986 50. Ment LR, Duncan CC, Ehrenkranz RA: Intraventricular hemorrhage of the preterm neonate. Semin Perinatol 11:132-141, 1987 51. National Commission to Prevent Infant Mortality: Troubling Trends: The Health of America's Next Generation. Washington, DC, The National Commission to Prevent Infant Mortality, 1990 52. Nelson KB, Ellenberg JH: Children who "outgrew" cerebral palsy. Pediatrics 69:529536, 1982 53. Neonatal care for low birthweight infants: Costs and effectiveness. Washington, DC, Office of Technology Assessment, 1987 54. Office of Technology Assessment (OTA), Congress of the United States: Healthy Children: Investing in Our Future. Washington, DC, U.S. Government Printing Office (GPO), 1988 55. Papile L, Burstein J, Burstein R, et al: Incidence and evolution of subependymal and intraventricular hemorrhage: A study of infants with birth weights less than 1,500 grams. J Pediatr 92:529-534, 1978 56. Perlman JM, Lynch B, Volpe JJ: Late hydrocephalus after arrest and resolution of neonatal post-hemorrhagic hydrocephalus. Dev Med Child NeuroI32:725-729, 1990 57. Robertson CMT, Etches PC: Decreased incidence of neurologic disability among neonates at high risk born between 1975 and 1984 in Alberta. Can Med Assoc J 139:225-229, 1988 58. Ross G, Lipper EG, Auld PAM: Growth achievement of very low birth weight premature children at school age. J Pediatr 117:307-309, 1990 59. Rutter M: Continuities and discontinuities from infancy. In Osofsky JD (ed): Handbook of Infant Development, ed 2. New York, John Wiley & Sons, 1987, p 1269 60. Saigal S, Szatmari P, Rosenbaum P, et al: Intellectual and functional status at school entry of children who weighed 1000 grams or less at birth: A regional perspective of births in the 1980s. J Pediatr 116:409-416, 1990 61. Schwartz RM: What price prematurity? Fam Plann Perspect 21:170-174, 1989 62. Sell EJ, Gaines JA, Gluckman C, et al: Early identification of learning problems in neonatal intensive care graduates. Am J Dis Child 139:460-463, 1985 63. Shankaran S, Cohen SN, Linver M, Zonia S: Medical care costs of high-risk infants after neonatal intensive care: A controlled study. Pediatrics 81:372-378, 1988 64. Shelton TL: The assessment of cognition/intelligence in infancy. Infants and Young Children 1:10-25, 1989 65. Shonkoff J: The limitations of normative assessments of high-risk infants. Topics in Early Childhood Special Education 3:29-43, 1983 66. Siegel LS: Reproductive, perinatal, and environmental variables as predictors of development of preterm «1500 grams) and full-term children at 5 years. Semin Perinatol 6:274-279, 1982 67. Siegel LS: Home environmental influences on cognitive development in preterm and fullterm children during the first 5 years. In Gottfried AW (ed): Home Environment and Early Cognitive Development: Longitudinal Research. Orlando, Academic Press, 1984 68. Smith AC, Flick GL, Ferriss GS, et al: Prediction of developmental outcome from prenatal, perinatal and postnatal event. Child Dev 43:495-507, 1972 69. Stewart AL, Reynolds EOR, Lipscomb AP: Outcome for infants of very low birthweight: Survey of world literature. Lancet 1038-1040, 1981 70. Storch TG: The unkindest cut. Am J Dis Child 144:533, 1990 71. Vohr BR, Bell EF, Oh W: Infants with bronchopulmonary dysplasia. Am J Dis Child 136:443-447, 1982 72. Volpe JJ: Intraventricular hemorrhage in the premature infant: Current concepts. Ann Neurol 25:109-116, 1989 73. Vohr BR, Garcia Coli C, Oh W: Increased morbidity in very low birth weight (VLBW)
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small for gestational age (SGA) infants with reduced head circumference (HC) at birth: A two year follow-up study [abstract]. Pediatr Res 27:lOA, 1990 Vohr BR, Garcia Coll CT: Neurodevelopmental and school performance of very low birth weight infants: A seven year longitudinal study. Pediatrics 76:345-350, 1985 Vohr BR, Oh W: Growth and development in preterm infants small for gestational age. J Pediatr 103:941-945, 1983 Vohr BR, Oh W, Rosenfeld AG, et al: The preterm small for gestational age infant: A two year follow-up study. Am J Obstet Gynecol 133:425-431, 1979 Williams ML, Lewandowski LJ, Coplan J, et al: Neurodevelopmental outcome of preschool children born preterm with and without intracranial hemorrhage. Dev Med Child Neurol 29:243-249, 1987 Willis WO: Parental perspectives on the system of care for low birth weight infants. Infants and Young Children 3:v-x, 1991 Young EWD, Stevenson DK: Limiting treatment for extremely premature, low-birthweight infants (500 to 750 g). Am J Dis Child 144:549-552, 1990
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