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Preterm Birth: Causes, Consequences, and Prevention 11 Neurodevelopmental, Health, and Family Outcomes for Infants Born Preterm ABSTRACT Although advances in high-risk obstetric and neonatal care have resulted in improved survival of infants born preterm, many studies have documented the prevalence of a broad range of neurodevelopmental impairments in preterm survivors. The spectrum of neurodevelopmental disabilities includes cerebral palsy, mental retardation, visual and hearing impairments, and more subtle disorders of central nervous system function. These dysfunctions include language disorders, learning disabilities, attention deficit-hyperactivity disorder, minor neuromotor dysfunction or developmental coordination disorders, behavioral problems, and social-emotional difficulties. Preterm infants are more likely to have lower intelligence quotients and academic achievement scores, experience greater difficulties at school, and require significantly more educational assistance than children who were born at term. Preterm infants have an increased risk of rehospitalization during the first few years of life and increased use of outpatient care. Among the conditions leading to poorer health are reactive airway disease or asthma, recurrent infections, and poor growth. The smallest and most immature infants have the highest risk of health problems and neurodevelopmental disabilities. Limited evidence of the impact of prematurity on families suggests that caring for a child born preterm has negative and positive effects that change over time, that these effects extend to adolescence and are
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Preterm Birth: Causes, Consequences, and Prevention influenced by different environmental factors over time, and that many areas of family well-being are affected. The prevalence of neurodevelopmental disabilities and health impairments varies. This is not surprising, in light of the multiple etiologies and complications of preterm birth and the variability of both the intrauterine and the extrauterine environments to which fetuses and children born preterm are exposed. In recognition of the increased developmental and emotional risks of children born preterm, several interventions have focused on the provision of services in the early years of life to prevent subsequent developmental and health problems. Although early interventions have a short-term impact, it has been more difficult to demonstrate more long-term benefits. At first glance, a wealth of data seems to be available for characterization of the outcomes of infants born preterm; however, as with many other areas addressed in this report, much of this literature uses birth weight as the measure of prematurity (see Chapter 2). The use of birth weight as a selection criterion for studies of the outcomes for infants born preterm introduces a well-recognized bias by including various proportions of more mature infants who experienced intrauterine growth retardation (IUGR). Many infants with IUGR are small for gestational age when they are born full term (i.e., at 37 to 41 weeks of gestation). Most infants with birth weights of less than 1,500 grams are preterm, but those who also have IUGR are vulnerable to the complications of both IUGR and prematurity (Garite et al., 2004). A number of the more recent studies have reported on the outcomes for preterm infants by gestational age category, but as in other parts of this report, this chapter uses birth weight-specific data when information by gestational age is not available. Finding 11-1: Most studies of the outcomes of preterm birth use birth weight criteria for the selection of study participants. Few studies report on the outcomes for preterm infants by gestational age. In addition to infants born preterm, studies with samples of infants with birth weights less than 2,500 grams include full-term infants who are small for gestational age. When this literature is examined, it is also well to keep in mind that preterm delivery is not a disease with a fixed set of outcomes. Rather, preterm delivery increases the risk of adverse outcomes that are also seen in term infants. Nevertheless, the more preterm an infant is, the greater the risk of adverse outcomes. Thus, these outcomes are a probability for a group
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Preterm Birth: Causes, Consequences, and Prevention and not a certainty for any given infant. Although the adverse outcomes associated with preterm delivery are discussed individually, readers should be aware that individual children may experience more than one outcome. Thus, it would not be unusual for a child to have some coordination difficulty and a specific health problem like asthma. Indeed, multiple milder problems may create more functional difficulties than a single, more severe one. Relatively few studies of the outcomes for infants born preterm provide comparison groups, and those that do have almost uniformly selected healthy full-term infants or infants with birth weights above 2,500 grams. Some have used siblings or classmates as comparisons. The study question determines the criteria used to select the comparison group. Some have proposed the use of infants or children who experienced other life-threatening conditions to provide a better sense of the disabilities and outcomes from serious neonatal health problems. Finally, a number of biological and environmental factors may affect the risk of adverse outcomes independent of gestational age or birth weight. To the extent that such independent risk factors have been identified, including some of those that may ameliorate the risks due to prematurity, they are discussed. Nevertheless, researchers are far from understanding all these factors, and prediction of the outcome for an individual child born preterm with any degree of certainty remains impossible. This chapter describes the outcomes of preterm birth from a life-span perspective, including the prevalence of neurodevelopmental disabilities, health-related quality of life, and functional outcomes to adolescence and early adulthood. The chapter concludes with a discussion of intervention strategies that can be used for the developmental support of children who were born preterm after discharge from the neonatal intensive care unit (NICU). NEURODEVELOPMENTAL DISABILITIES Among the earliest concerns about the health of premature infants was the association between preterm delivery and neurodevelopmental disabilities. Neurodevelopmental disabilities are a group of chronic interrelated disorders of central nervous system function due to malformation of or injury to the developing brain. The spectrum of neurodevelopmental disabilities includes the major disabilities: cerebral palsy (CP) and mental retardation. Sensory impairments include visual impairment and hearing impairment. The more subtle disorders of central nervous system function include language disorders, learning disabilities, attention deficit-hyperactivity disorder (ADHD), minor neuromotor dysfunction or developmental
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Preterm Birth: Causes, Consequences, and Prevention coordination disorders, behavioral problems, and social-emotional difficulties. Early studies focused primarily on cognitive impairment, as measured by intelligence quotient (IQ) and by the detection of motor abnormalities on standardized neurological examinations. A landmark study, the Collaborative Perinatal Project of the National Institute of Neurological and Communicative Disorders and Stroke, monitored 35,000 children born before neonatal intensive care (i.e., in the late 1950s and early 1960s) for 7 years. Although only 177 children born at less than 34 weeks gestation survived, the study documented the increased risk of cognitive and motor impairment as a function of decreasing gestational age. It highlighted the need for neurodevelopmental follow-up of populations born preterm, especially as the emergence of neonatal intensive care and high-risk obstetric care dramatically reduced gestational age-specific mortality rates but not preterm birth rates (see Chapters 1, 2, and 10). The history of neonatal intensive care is not only one of miracles achieved, but also of therapeutic misadventures (Allen, 2002; Baker, 2000; Silverman, 1980; Silverman, 1998). Iatrogenic complications have contributed to adverse health and neurodevelopmental outcomes in the past, but a shift from a trial and error approach toward evidence-based medicine is establishing a more empiric basis for treating mothers and preterm infants. Although new therapies are generally evaluated in randomized clinical trials, the safety and efficacy of many currently used treatments and medications have not been adequately studied (see Chapter 10). The resulting literature demonstrates wide variations in the prevalence of neurodevelopmental disabilities (Allen, 2002; Aylward, 2002b; Aylward, 2002a; Aylward, 2005). Much of this variation is due to methodological issues, for example, a lack of uniformity in sample selection criteria, the method and the length of follow-up, follow-up rates, and the outcome measures and the diagnostic criteria used. Variations in outcome frequencies reported also reflect differences in the population base and in clinical practice. Whenever possible, outcomes data are provided by gestational age categories for preterm infants born in the 1990s to the present. However, because the age of evaluation determines which outcomes can be assessed, recent studies of the outcomes for adolescents who were born preterm report on preterm births that occurred in the 1980s. The time lag required for follow-up makes caution necessary in generalizing reported adolescent and adult outcomes to preterm infants who survive with the technology available today. Perinatal and neonatal risk factors do not reliably predict these long-term outcomes. Therefore, research is needed to identify better neonatal predictors of neurodevelopmental disabilities, functional abilities, health and other long-term outcomes.
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Preterm Birth: Causes, Consequences, and Prevention Motor Impairment Cerebral Palsy Cerebral palsy (CP) is a general term to describe a group of chronic conditions that impair control of movement and posture. CP is due to malformation of or damage to motor areas in the brain, which disrupts the brain’s ability to control movement and posture. Symptoms of CP may range from mild to severe, change over time and differ from person to person, and include difficulty with balance, walking, and fine motor tasks (such as writing or using scissors) and involuntary movements. Many people with CP also have associated cognitive, sensory, social, and emotional disabilities (NIDS, 2005). The diagnosis of CP may not become certain until the second year of life. As many as 17 to 48 percent of preterm infants demonstrate neuromotor abnormalities during infancy (e.g., abnormal muscle tone or asymmetries) (Allen and Capute, 1989; Khadilkar et al., 1993; Pallas Alonso et al., 2000; Vohr et al., 2005). Some of these infants go on to develop significant neuromotor abnormalities and motor delays that signify CP, but most do not. Although neuromotor abnormalities tend to resolve or do not interfere with function, transient neuromotor abnormalities are associated with an increased risk of later school and behavioral problems (Drillien et al., 1980; Khadilkar et al., 1993; Sommerfelt et al., 1996; Vohr et al., 2005). The severity of CP is determined by the type of CP, which limbs are affected, and the degree of functional limitation. Increasingly, investigators are distinguishing between mild CP and moderate to severe (i.e., disabling) CP (Doyle and Anderson, 2005; Grether et al. 2000; Vohr et al., 2005; Wood et al., 2000). Many longitudinal studies of the outcomes for preterm infants show good stability between motor assessments at 18 to 30 months of age and at school age (Hack et al., 2002; Marlow et al., 2005; Wood et al., 2000). The smallest and most immature infants have the highest risk of CP. In their seventh report of CP in Sweden, Hagberg and associates (1996) reported an almost stepwise increase in the prevalence of CP with gestational age: 1.4 per 1,000 live births for children born at more than 36 weeks gestation, 8 per 1,000 live births for children born between 32 and 36 weeks gestation, 54 per 1,000 live births for children born between 28 and 31 weeks gestation, and 80 per 1,000 live births for children born at less than 28 weeks of gestation. Because they report prevalence as the number who have CP per 1,000 live births, infants who die are included in the denominator. For the most immature infants, another meaningful statistic is the rate of CP among survivors. On the basis of data for preterm survivors born in the late 1980s through the 1990s, the rate of CP increases with decreasing
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Preterm Birth: Causes, Consequences, and Prevention gestational age or birth weight category (Table 11-1) (Colver et al., 2000; Cooke, 1999; Doyle et al., 1995; Doyle and Anderson, 2005; Elbourne et al., 2001; Emsley et al., 1998; Finnstrom et al., 1998; Grether et al., 2000; Hack et al., 2000, 2005; Hansen and Greisen, 2004; Hintz et al., 2005; Lefebvre et al., 1996; Mikkola et al., 2005; O’Shea et al., 1997; Piecuch et al., 1997a,b; Salokorpi et al., 2001; Sauve et al., 1998; Stanley et al., 2000; Tommiska et al., 2003; Vohr et al., 2000, 2005; Wilson-Costello et al., 2005; Wood et al., 2000). Only 0.1 to 0.2 percent of full-term children develop CP, whereas 11 to 12 percent born at 27 to 32 weeks of gestation and 7 to 17 percent born at less than 27 or 28 weeks of gestation develop CP (Doyle, 2001; Elbourne et al., 2001; Finnstrom et al., 1998; Lefebvre et al., 1996; Vohr et al., 2005). A comprehensive British study of preterm infants born in 1995 with gestational ages of less than 26 weeks diagnosed CP in 20 percent of the survivors at 6 years of age (Marlow et al., 2005). In the few reported survivors with birth weights of less than 500 grams, a quarter to a half developed CP (Sauve et al., 1998; Vohr et al., 2000). Many more studies have reported on the outcomes of CP in terms of birth weight categories. In a review of 17 studies published from 1988 to 2000, Bracewell and Marlow (2002) estimated that approximately 10 percent of preterm infants with birth weights of less than 1,000 grams developed CP. An older meta-analysis of 85 studies of infants with birth weights of less than 1,500 grams estimated that 7.7 percent of survivors developed CP (Escobar et al., 1991). Studies of 18- to 20-year-olds reported that from 5 to 7 percent of those who were born with birth weights of less than 1,500 grams and up to 13 percent of those born with birth weights of less than 1,000 grams had CP (Ericson and Kallen, 1998; Hack et al., 2002; Lefebvre et al., 2005; Saigal et al., 2006a). A Swedish study of young men born as singletons from 1973 to 1975 with birth weights of less than 1,500 grams estimated an odds ratio for CP of 55 (95 percent confidence interval = 41 to 75) (Ericson and Kallen, 1998). With continuing improvements in high-risk obstetric and neonatal intensive care over the last several decades, several studies have demonstrated small increases or decreases in the overall prevalence of CP (Colver et al., 2000; Hagberg et al., 1996; Stanley and Watson, 1992; Stanley et al., 2000). However, any improvements in gestational age- or birth weight-specific rates of CP are offset by dramatic decreases in the rates of infant mortality. The net result is that more preterm children survive, but more children have CP as well. Many regional studies of children with CP find an overrepresentation of preterm children with CP than the number expected for their birth rates (Table 11-1) (Amiel-Tison et al., 2002; Colver et al., 2000; Cummins et al., 1993; Dolk et al., 2001; Hagberg et al., 1996; MacGillivray and Campbell, 1995; Petterson et al., 1993; Stanley and Watson, 1992). Although only 1.4
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Preterm Birth: Causes, Consequences, and Prevention TABLE 11-1 Rates of Cerebral Palsy in Preterm Children by Gestational Age Category Study Year(s) of Birth Age (yr) Follow-up Rate (%) Number of Subjects Gestational Age (wk) Rate of Cerebral Palsy (%) Hintz et al., 2005a 1996–1999 1.8 87 467 <25 21 1993–1996 77 360 <25 23 Vohr et al., 2005a 1997–1998 1.8 84 910 <27 18 82 512 27–32 11 1995–1996 1.8 84 716 <27 19 81 538 27–32 11 1993–1994 1.8 74 665 <27 20 70 444 27–32 12 Mikkola et al., 2005 1996–1997 5 95 103 <27 19 Tommiska et al., 2003 1996–1997 1.5–2 100 5 22–23 20 18 24 11 34 25 12 47 26 11 Wood et al., 2000 1995 2.5 92 283 <26 18 Emsley et al., 1998 1990–1994 2.2–6.1 100 40 23–25 18 Piecuch et al., 1997b 1990–1994 >1 95 18 24 11 30 25 20 38 26 11 94 24–26 13 Jacobs et al., 2000 1990–1994 1.5–2 90 274 23–26 15 Doyle, 2001 1991–1992 5 98 221 23–27 11 Finnstrom et al., 1998a 1990–1992 3 98 362 23–24 14 25–26 10 >26 3 Lefebvre et al., 1996 1991–1992 1.5 85 9 24 11 24 25 25 40 26 27 72 27 10 72 28 17 217 24–28 17 aBirth weight less than 1,000 grams.
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Preterm Birth: Causes, Consequences, and Prevention percent of infants are born at less than 32 weeks of gestation, they comprise 26 percent of children with CP. Four percent of all live births are born at 32 to 36 weeks of gestation, and they constitute 16 to 37 percent of children with CP. Although less than 10 percent of births are preterm, approximately 40 to 50 percent of children with CP are born preterm. Although children born preterm are vulnerable to all types of CP, the most common type is spastic diplegia (Hack et al., 2000; Hagberg et al., 1996; Wood et al., 2000). Spasticity is characterized by tight muscle tone, increased reflexes, and limited movement around one or more joints. Spasticity of both lower extremities but no or very little involvement of the arms constitutes spastic diplegia. Although most children with spastic diplegia require physical therapy and medical interventions (e.g., orthopedic surgery, orthoses, or Botulinum Toxicum injections), many children with spastic diplegia are quite functional by school age. In a study of children born at less than 26 weeks gestation, 43 percent with spastic diplegia were unable to walk and 43 percent had an abnormal gait at 6 years of age (Marlow et al., 2005). A large regional study of Swedish preterm children with CP reported that 66 percent had spastic diplegia, 22 percent had spastic hemiplegia, and 7 percent had spastic quadriplegia (Hagberg et al., 1996). Associated deficits were common: 39 percent had mental retardation, 26 percent had epilepsy, 18 percent had severe visual impairment, and 23 percent had hydrocephalus. The proportion of children with CP who had spastic diplegia decreased with increasing gestational age category: 80 percent for children born at less than 28 weeks of gestation, 66 percent for children born at between 28 and 31 weeks of gestation, 58 percent for children born at between 32 and 36 weeks of gestation, and 29 percent for children born at greater than 36 weeks of gestation. The proportion of children with hemiplegia increased with gestational age: 10 percent for children born at less than 28 weeks gestation, 16 percent for children born at between 28 and 31 weeks gestation, 34 percent for children born at between 32 and 36 weeks gestation, and 44 percent for children born at less than 36 weeks gestation. Coordination and Motor Planning Children with incoordination and motor planning problems are less likely to enjoy and participate in many preschool and playground activities. Minor neuromotor dysfunction is a diagnosis used to describe infants and children who have persistent neuromotor abnormalities but minimally to mildly impaired motor function. Children with minor neuromotor dysfunction may have mild motor delay but are able to walk by age 2 years and have good mobility. They have a higher risk of coordination difficulties,
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Preterm Birth: Causes, Consequences, and Prevention motor planning problems, fine motor incoordination, or sensorimotor integration problems (which at preschool and school age may be diagnosed as developmental coordination disorder) (Botting et al., 1998; Hadders-Algra, 2002; Hall et al., 1995; Khadilkar et al., 1993; Mikkola et al., 2005; Pharoah et al., 1994; Vohr and Coll, 1985). In a study of 5-year-olds born between 1996 and 1997 with birth weights of less than 1,000 grams, 51 percent had coordination problems, 18 to 20 percent had abnormal reflexes or abnormal posture, and 17 percent had exceptional involuntary movements (Mikkola et al., 2005). Sensorimotor integration problems can range from inability to tolerate certain textures of food or clothing (e.g., an inability to tolerate lumpy food or the tag on the back of a T-shirt) to difficulty following demonstrated directions (e.g., how to put on a shirt or tie shoelaces) or an inability to tolerate motion (e.g., swinging). Preterm children, even those with normal intelligence and no CP, have more difficulties than full-term children with fine motor, visual motor, visual perceptual, and visual spatial tasks. These tasks include drawing, cutting with scissors, dressing, writing, copying figures, perceptual mapping, spatial processing, finger tapping, and pegboard performance. In a study of 5-year-old children with birth weights of less than 1,500 grams, 23 percent had impaired fine motor skills and 71 percent scored 1 standard deviation or more below average on tests of fine motor function (Goyen et al., 1998). Below-average performances in visual motor skills and visual perceptual tasks were noted for 17 and 11 percent of the children, respectively. These problems were most common in children born at less than 28 weeks of gestation. Even the more mature preterm children are at risk for these problems; a third of school-age children born at 32 to 36 weeks of gestation had poor fine motor and writing skills (Huddy et al., 2001). Failures at gross motor, fine motor, sensorimotor, and visual perceptual activities are mild in comparison with the difficulties with mobility and adaptive skills that many children with CP face. Nonetheless, these subtle abnormalities of central nervous system function can, over time, adversely influence the child’s self-esteem and peer relationships, which in turn contribute to a cycle of frustration and despair that interferes with academic progress and social relationships. Early recognition of these subtle deficits allows modification of expectations, teaching methods, and the environment to support the development of these children and prevent adverse secondary consequences. Cognitive Impairment Cognitive Test Scores and Mental Retardation Intelligence is not one skill but a composite of multiple cognitive processes, including visual and auditory memory, abstract reasoning, complex
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Preterm Birth: Causes, Consequences, and Prevention language processing, understanding of syntax, visual perception, visual motor integration, and visual spatial processing. A variety of standardized intelligence tests are available for use with children at each age level. Scores across a variety of cognitive tasks are summed to form an IQ or, for younger children, a developmental quotient (DQ) (Lichtenberger, 2005). Cognitive assessments of very young infants are limited in their predictive ability because of their reliance on assessment of visual-motor and perceptual abilities. As children mature, more verbal and abstract cognitive processes can be evaluated, and scores more accurately reflect their abilities. Cognitive tests are standardized for diverse large populations, with an IQ score of 100 considered the population mean. The IQ score is a global score that does not include information about subtle dysfunctions. The full range of cognitive deficits seen in preterm children is not well described by the IQ score, and further cognitive analyses are necessary. Many preterm children have a wide scatter in their cognitive abilities, with excellent performance in some areas but relative weakness in other areas, and these contribute to difficulties in the classroom and at home. Calculation of a DQ for preterm infants is complicated by whether their age should be calculated from their birth date (i.e., the chronological age) or from their due date (i.e., age corrected for the degree of prematurity). This issue is more important arithmetically the younger the infant is and the lower the gestational age at birth was. For example, a 6-month-old preterm infant born 3 months early who has skills at the normal level for a 3-month-old would have a normal DQ of 100 if it was corrected for the degree of prematurity but would be considered delayed in skill attainment, with a DQ of 50, if the chronological age was used. For the most part, neuromaturation of the preterm infant in the NICU proceeds along the same timeline as intrauterine development (Allen, 2005a; Saint-Anne Dargassies, 1977). From biological and maturational perspectives, few environmental influences significantly accelerate neuromaturation, and most agree that one should fully correct for the degree of prematurity when preterm infants are evaluated and that this correction should be incorporated for at least the first 2 years of life (Allen, 2002; Aylward, 2002a). Whether or not one corrects for the degree of prematurity may influence IQ scores for up to 8 years (Rickards et al., 1989). Mental retardation is a disability that originates in childhood and is characterized by significant limitations both in intellectual functioning and in adaptive behavior, as expressed in conceptual, social, and practical adaptive skills (AAMR, 2005). Intellectual functioning is considered subaverage or significantly limited when an individual’s IQ score is 2 or more standard deviations below the mean on a standardized intelligence test (generally an IQ less than 70 or 75, depending on the test). Borderline intelligence is
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Preterm Birth: Causes, Consequences, and Prevention when an individual’s IQ score is between 1 and 2 standard deviations below the mean (generally, IQs of 70 to 80 or 85). In a study of children with mental retardation in Norway, children born at 32 to 36 weeks of gestation had a 1.4 times increased risk of mental retardation than full-term children, and this risk increased to 6.9-fold for children born at less than 32 weeks of gestation (Stromme and Hagberg, 2000). The risks of mental retardation in children born preterm compared with those in children born with normal birth weights increase from 2.3-fold for children with birth weights of 1,500 to 2,499 grams to 12-fold for children with birth weights of less than 1,500 grams, 15-fold for children with birth weights of less than 1,000 grams, and 22-fold for children with birth weights of less than 750 grams (Resnick et al., 1999; Stromme and Hagberg, 2000). Nonetheless, children born at less than 32 weeks of gestation or with birth weights of less than 1,500 grams comprised only 4 percent of children with mental retardation. On the basis of data for preterm children born in the late 1980s and 1990s, survivors born preterm with the lowest gestational ages and birth weights have the highest risk of mental retardation and borderline intelligence (Tables 11-2 and 11-3). A recent large study of infants born at less than 26 weeks gestation in 1995 in the British Isles and evaluated at age 6 years reported that 21 percent had an IQ 2 or more standard deviations below the test mean and 25 percent had borderline intelligence (i.e., IQs 1 to 2 standard deviations below the test mean), whereas for the controls born full term the rates were 0 and 2 percent, respectively (Marlow et al., 2005). Studies that compare preterm children’s performance on intelligence tests against published test norms may underestimate their cognitive disadvantage. Although cognitive tests are standardized on the basis of a mean IQ of 100 for normal populations, there is a tendency for the mean IQ score in normal or control populations to drift upward over time. Marlow et al. (2005) noted a mean cognitive score of 106 in their full-term classmate controls. With restandardization, the percentage of children born before 26 weeks of gestation who had cognitive scores 2 standard deviations or more below the full-term comparison group’s mean score rose from 21 to 41 percent. Children born full term with normal birth weights and raised in similar environments have generally served as comparison groups in studies of the outcomes of preterm birth. In a 1989 meta-analysis, 4,000 children born with birth weights of less than 2,500 grams had a mean IQ that was 5 to 7 points lower than the mean for 1,568 controls who were born full term (Aylward et al., 1989). In more recent studies of children with birth weights of less than 1,500 or 1,000 grams, the preterm children have mean IQ scores that were 10 to 17 points, or 1 standard deviation, below those for
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Preterm Birth: Causes, Consequences, and Prevention out data on the presence or the absence of interim growth decelerations or subsequent catch-up growth. Furthermore, social class (paternal occupation) was based on recall by adult subjects 50 to 70 years later and the studies did not control for postnatal modifiers, such as socioeconomic, environmental or behavioral factors, or social deprivation in the early critical period of life (Joseph and Kramer, 1996; Paneth, 1994; Paneth and Susser, 1995; Paneth et al., 1996). In addition, retention rates in most study cohorts were extremely poor with only between 19 and 60 percent of the subjects available for further follow-up (Bhargava et al., 2004; Cooke, 2004; Strauss, 2000). Only a paucity of studies have been designed to investigate specifically whether the fetal origins hypothesis is also applicable to preterm infants and not just to those who are small for gestational age. Fewtrell and colleagues (2000) examined the relationship between gestational age and size for gestational age on glucose and insulin concentrations at ages 9 to12 years in 385 children who had been born preterm with birth weights less than 1,850 grams. Low birth weight, whether it was due to being born preterm or intrauterine growth restriction, was associated with higher plasma glucose levels 30 minutes after administration of a glucose load. Recently, Hofman and colleagues (2004a) have demonstrated that 4- to 10-year- olds born preterm have metabolic abnormalities similar to those observed in infants born fullterm but small for gestational age and that these occur irrespective of whether the preterm infants are small or appropriate for gestational age. In fact, there did not seem to be an additive effect on reduced sensitivity from being born both preterm and small for gestational age. A subsequent study by the same investigators confirms the reduction in insulin sensitivity, which may be a risk factor for Type II diabetes mellitus (Hofman et al., 2004b). This reduction was similar in infants born between 24 and 32 weeks gestation, suggesting that a critical window exists in the third trimester in which insulin activity is altered. In another study by Hovi et al. (2005), young adults born with birth weights less than 1,500 grams had fasting insulin levels that were 34 percent higher than those for controls, and their mean fasting serum glucose level was also higher (but an oral glucose tolerance test was not done). Unfortunately, these studies examined only 50 percent of the cohort. Childhood weight gain has also been shown to be an important predictor of measures of insulin secretion and resistance in some studies (Fewtrell et al., 2000). Singhal and colleagues (2003a) have shown that preterm infants with birth weight less than 1,850 grams who received nutrientenriched formula had higher fasting 32–33 split pro-insulin levels (a marker of insulin resistance) at adolescence. This effect of postnatal diet was a proxy for greater weight gain in infants in the first 2 weeks of life, independently of birth weight, gestational age, and other sociodemographic factors.
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Preterm Birth: Causes, Consequences, and Prevention The authors propose that relative undernutrition in preterm infants early in life may actually have beneficial long-term effects on insulin resistance. Similar beneficial effects on vascular structure and endothelial function were also observed (Singhal et al., 2004). These studies have raised further controversy regarding the nutritional management of very preterm infants and what should be considered “optimal” catch-up growth. Other studies have also shown high rates of type II diabetes in individuals who were small for gestational age at birth and who later became overweight as adults (Bavdekar et al., 1999; Eriksson et al., 1999; Newsome et al., 2003). In a recent prospective longitudinal study of 1,492 Indian subjects 26 to 32 years of age, the growth of children in whom impaired glucose tolerance or diabetes later developed was characterized by a low body mass index between birth and 2 years of age, followed by an early adiposity rebound and a sustained and accelerated increase in body mass index until adulthood (Bhargava et al., 2004). In two other studies with young adults, individuals who experienced the largest increase in body mass index and those who remained overweight over time had evidence of vascular change manifest by increased common carotid intima-media thickness (CIMT) (to estimate cardiovascular risk) (Eriksson et al., 2001; Oren et al., 2003). Thus the association of low birth weight and later CVD and metabolic factors is very likely modified by postnatal factors, although this has not been adequately studied. Body composition, specifically the distribution of the fat and lean bone mass compartments, may also be important predictors of risk of CVD, hypertension and diabetes in adult life. Fat mass and fat-free mass were lower in 8- to 12-year-old children born with birth weights less than 1,850 grams than in children born with normal birth weights (Fewtrell et al., 2004). Such findings may reflect programming of body composition by early growth and nutrition. Indeed, a higher birth weight was associated with a greater fat free mass in adolescents (Singhal et al., 2003b). The authors suggest that an association of low birth weight and lower lean mass may be the underpinnings of programming for suboptimal insulin sensitivity, lower metabolic activity, and a subsequent propensity to greater adiposity and risk of CVD (Singhal et al., 2003b). Using whole-body magnetic resonance, Uthaya and colleagues (2005) have recently shown that by the time that infants born preterm reached their term age, they had a highly significant decrease in subcutaneous adipose tissue and significantly increased levels of intra-abdominal adipose tissue. They caution that preterm infants may be at risk of metabolic complications later in life through this increased and aberrant adiposity. In a cohort of 132 20-year-old individuals who had been born small for gestational age and average for gestational age and who were born fullterm (Levitt et al., 2005), the association between low birth weight and expres-
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Preterm Birth: Causes, Consequences, and Prevention sion of adult chronic cardiometabolic disease was not dependent on birth weight alone, but was also dependent on its interaction with subsequent fat accumulation (either generally or abdominally) (Levitt et al., 2005). Fewer studies have explored the association of preterm birth and CVD in adulthood. Irving and colleagues (2000) investigated 61 young adults who had been born with low birth weights less than 2,000 grams at a mean age of 24 years and showed that those who were small because of prematurity were also at risk of hypertension, an adverse metabolic profile (higher plasma insulin triglyceride and total cholesterol levels and lower high-density lipoprotein cholesterol levels) and hyperglycemia as adults. Among the preterm cohort, those who were small for gestational age were not measurably more disadvantaged than those who were average for gestational age. CIMT studies, however, were not performed. A study conducted in the Netherlands attempted to elucidate the effects of prenatal and infancy growth on the lipid and CIMT measures in a very preterm cohort at age 19 years (Martin et al., 2006). Their findings support an effect of current body composition rather than early growth on CVD risk. Two recent studies (Doyle et al., 2003; Hack et al., 2005a) have shown higher systolic blood pressure among very low birth weight infants in late adolescence and young adulthood. However, no relationship was found between intrauterine growth and blood pressure. Not all studies have found higher blood pressure in preterm subjects in childhood (Morley et al., 1994) or at young adulthood (Saigal et al., 2005). Further prospective, long-term studies of preterm infants monitored to adulthood are warranted to confirm whether preterm infants are at increased risk for CVD and metabolic problems as adults. IMPACT OF PRETERM BIRTH ON FAMILIES Families caring for a child born preterm face long-term and multilayered challenges. The limited research on this topic suggests that this impact is largely negative (Beckman and Pokorni, 1988; Cronin et al., 1995; Davis et al., 2003; Eisengart et al., 2003; Lee et al., 1991; Macey et al., 1987; McCain, 1990; McCormick et al., 1986; Singer et al., 1999; Stjernqvist and Svenningsen, 1995; Taylor et al., 2001; Veddovi et al., 2001), although some studies found positive outcomes (Macey et al., 1987; Saigal et al., 2000a; Singer et al., 1999). Furthermore, the impact varies according to sociodemographic risk factors as well as the severity of the child’s health condition (Beckman and Pokorni, 1988; Cronin et al., 1995; Davis et al., 2003; Eisengart et al., 2003; Lee et al., 1991; McCormick et al., 1986; Rivers et al., 1987; Saigal et al., 2000a; Singer et al., 1999; Taylor et al., 2001; Veddovi et al., 2001). Most studies on the impact of caring for a preterm infant have focused
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Preterm Birth: Causes, Consequences, and Prevention on those born at less than 32 weeks gestation (Davis et al., 2003) and less than 35 weeks of gestation (Veddovi et al., 2001), although others studied infants with birth weights less than 1,500 grams or less than 1,750 grams (Eisengart et al., 2003; Macey et al., 1987; Singer et al., 1999). Others have used prematurity and low birth weight as a continuous variable (Beckman and Pokorni, 1988). The assessment of outcomes has centered on the mother’s psychological well-being in the postpartum period and suggests that the mothers of infants born preterm are at risk of experiencing depressive symptoms (Davis et al., 2003; Singer et al., 1999; Veddovi et al., 2001). Longitudinal studies of children born preterm and with low birth weights in the first 2 to 3 years of life suggest that the levels of maternal depression and psychological distress (Singer et al., 1999), as well as problems related to the child, decreased over time (Beckman and Pokorni, 1988) except among high-risk (defined as having bronchopulmonary dysplasia) infants (Singer et al., 1999). Furthermore, specific factors that may contribute to depressive symptoms include a higher medical risk for the infants, the less frequent use of informal networks to obtain information about their infants, increased use of escape-avoidance coping strategies, and less knowledge of infant development (Eisengart et al., 2003; Veddovi et al., 2001). On the other hand, factors that might buffer these mothers from depressive symptoms include a higher level of educational attainment and support from nurses (Davis et al., 2003). Families caring for a child who was born preterm continue to manage the effects of prematurity when the children are toddlers (Lee et al., 1991; McCormick et al., 1986; Singer et al., 1999), school age (Cronin et al., 1995; Lee et al., 1991; McCain, 1990; Rivers et al., 1987; Taylor et al., 2001), and adolescents (Saigal et al., 2000a). Studies focusing on these children have mainly included children who were born weighing less than 2,500 grams (Cronin et al., 1995; Lee et al., 1991; McCormick et al., 1986; Rivers et al., 1987; Singer et al., 1999; Taylor et al., 2001); and only one focused on children born weighing less than 1,000 grams (Saigal et al., 2000a). Their findings suggest that the impact on families is long term and that the parents, siblings, finances, and family functioning are all affected (Cronin et al., 1995; Saigal et al., 2000a; Singer et al., 1999; Taylor et al., 2001). Furthermore, the families of children with more severe levels of impairment are the most affected (Cronin et al., 1995; Rivers et al., 1987; Saigal et al., 2000a; Singer et al., 1999; Taylor, 2001). At the individual level of the impact of a preterm birth on the family, the parents of children born preterm report higher levels of emotional distress (Saigal et al., 2000a; Singer et al., 1999; Taylor et al., 2001) and strain and a compromised sense of mastery (Cronin et al., 1995). One study suggests that some of the factors that parents associate with higher stress levels might include supervision of the child, the child’s peer relationships and
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Preterm Birth: Causes, Consequences, and Prevention self-esteem, the impact of the child’s difficulties on family routines, and worrying about the child’s future (Taylor et al., 2001). The length of time that the newborn preterm infant must stay in the hospital also affects the ability of the mother to fulfill her role in the family (McCain, 1990). Other studies suggest that there might be gender role differences in parents’ perception of problems. Mothers perceived that the preterm birth of a child had a greater impact on their sense of mastery, finances, and employment (Cronin et al., 1995). They also perceived greater satisfaction in caring for their child (Cronin et al., 1995). The mothers also perceived a greater impact when the child was born at a younger gestational age (Lee et al., 1991), experienced more physical symptoms during the pregnancy, and were more likely than the fathers to experience crisis reactions (Stjernqvist, 1992). On the other hand, fathers perceived greater uncertainty, less individual strain (Cronin et al., 1995), and greater effects at lower levels of progression of the infant’s development (Lee et al., 1991). Beyond the impact on each of the parents individually, caring for children born preterm affects other units within the family, including the couple, the siblings, and the family as a whole (Beckman and Pokorni, 1988; Cronin et al., 1995; Macey et al., 1987; McCormick et al., 1986; Saigal et al., 2000a; Singer et al., 1999; Stjernqvist, 1992; Taylor et al., 2001). Specifically, the parent’s marital relationship is stressed (Macey et al., 1987; Stjernqvist, 1992), at times leading to divorce (Saigal et al., 2000a), and parenting difficulties emerge (Taylor et al., 2001). Siblings are affected because of the decreased attention that they receive from their parents (Saigal et al., 2000a). The family as a unit is affected by the greater likelihood of not having additional children (Cronin et al., 1995; Saigal et al., 2000a), the financial burden (Cronin et al., 1995; Macey et al., 1987; McCormick et al., 1986; Rivers et al., 1987), limits on family social life (Cronin et al., 1995; McCormick et al., 1986), high levels of adverse family outcomes (family stress and dysfunction) (Beckman and Pokorni, 1988; Singer et al., 1999; Taylor et al., 2001), and parents’ difficulty maintaining employment (Macey et al., 1987; Saigal et al., 2000a). Lower income and education place an additional burden on families caring for children born preterm (Cronin et al., 1995; McCormick et al., 1986; Taylor et al., 2001), although one study found that the higher medical risks faced by neonates had more significant impacts on socioeconomically advantaged families (Taylor et al., 2001). Furthermore, different factors predict family stress at different ages (Beckman and Pokorni, 1988). When the neonate born preterm was 3 months of age, it was found that informal support, the number of siblings, and the family’s socioeconomic condition were the most important factors; at 6 months of age, gestational age at birth, home environment, caregiving demands, and the number of parents in the home were the most important;
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Preterm Birth: Causes, Consequences, and Prevention at 12 months of age, race, home environment, and scores on the Bayley scales of infant development were the most important; and at 24 months of age, birth weight at birth, informal social support, temperament, caregiving demands, and race were the most important (Beckman and Pokorni, 1988). Families and parents also have positive experiences and demonstrate resilience in caring for a child with impairments related to preterm birth. A study by Saigal and colleagues (2000a) found that parents perceived positive interactions with friends and within the family stemming from their efforts to care for their child born with birth weight less than 1,000 grams. The parents also reported enhanced personal feelings and improved marital closeness (Saigal et al., 2000a). Macey and colleagues (1987) found that at 12 months (corrected for prematurity), 50 percent of the infants’ mothers perceived their marriage to be more cohesive. Other studies suggest that these parents perceive their children to be acceptable, attached, and reinforcing (Singer et al., 1999) and to have a greater appreciation for their child than was the case when the child was an infant (Rivers et al., 1987). Thus, the impact of caring for a child born preterm may also contribute to the growth of the family as well as its members. In summary, the limited evidence presented here suggests that caring for a child born preterm has negative and positive impacts on the family that change over time, that these impacts extend to adolescence and are influenced by different environmental factors across time, and that many areas of family well-being are affected. However, because of the limitations of these studies, further research is needed. First, these findings are limited in their generalizability because of a lack of ethnic and socioeconomic diversity in the samples and because a higher proportion of mothers than fathers were surveyed. Research should strive to balance these sociodemographic factors in the samples used. Second, the measures used to determine the effects of a child born preterm on the family and the child’s functional health were not uniform across studies. For example, the effects on the family were measured as the economic burden, parental symptomatology, and parenting stress, among others. Similarly, the child’s health and functional health status were assessed on the basis of the presence of serious health conditions in one study, whereas other studies formally assessed functional health status by the use of validated measures. Future studies could advance knowledge in this area by developing a measure that would capture the particular health and functional health challenges that these families and the children born preterm face. In a recent review of functional health outcomes of preterm children, Donohue (2002) suggested that measures that are sensitive to the child’s developmental stage should be developed for children and that the measures for parents should focus on the peculiarities of their role as caregivers for these children. Third, the few longitudinal studies reviewed in this section suggest that
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Preterm Birth: Causes, Consequences, and Prevention future research is needed to study changes in the impact of a child born preterm on the family over time. The fourth limitation noted in the studies reviewed were the variations in the gestational ages and the birth weights of the infants. Researchers should be encouraged to focus on prematurity by gestational age in addition to birth weight, so that the variations in the impacts on families can be ascertained by gestational age. Finally, studies of the impacts of an infant born preterm on families during the child’s infancy should assess outcomes beyond maternal depressive symptoms in the post-partum period. POST-NICU DISCHARGE INTERVENTIONS In recognition of the increased developmental and emotional risks for children born preterm, several interventions have focused on the provision of services in the early years of life to prevent subsequent developmental and health problems. Coordinated, community-based, multidisciplinary programs for early intervention, based on the findings of some seminal studies, have been established for children and their families. The types and severities of the conditions affecting children with disabilities are varied, and so are the intensity and the extent of the services provided. Research suggests that these programs may be effective in improving some cognitive outcomes in individual children and can also lead to important improvements in family function (Berlin et al., 1998; Majnemer, 1998; McCormick et al., 1998; Ramey et al., 1992; Ramey and Ramey, 1999). However, longterm follow-up of the children in some of these studies has shown mixed results, with some evidence that differences apparent within 3 years of an intervention all but disappear after time. Early Infant and Childhood Interventions Several longitudinal studies have attempted to ascertain the effects of early intervention on the emotional, physical, and developmental outcomes in children born preterm or with disabilities. The Infant Health and Development Program (IHDP) is a multicentered, randomized, controlled, U.S. nationwide study of preterm infants born in 1985 at gestational ages of less than 37 weeks and with birth weights of less than 2,500 grams and their families. Infants and their families were randomly assigned to either the intervention group (n = 377) or the follow-up-only (FUO) group (n = 608) within two birth weight strata: less than 2,000 grams and 2,000 to 2,499 grams. For their first 3 years, both groups received medical, developmental, and social assessments, as well as referrals for services such as health care. An educational intervention for infants and families in the intervention group consisted of home visits (weekly during the first year and every other
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Preterm Birth: Causes, Consequences, and Prevention week thereafter), enrollment in a child development center at 12 months from the due date, and parent group meetings (Ramey et al., 1992). The educational sessions at home and the center encouraged parents to use games and activities to promote their child’s cognitive, language, and social skills development; and parents were provided with information on health, safety, and child-rearing topics. At the outcome evaluation at 36 months from the due date, the children in the intervention group had higher cognitive scores (14 points higher for those with birth weights of 2,000 to 2,499 grams and 7 points higher for those with birth weights of less than 2,000 grams) and fewer behavioral problems than the children in the FUO group (Brooks-Gunn et al., 1992b; McCormick et al., 1993). Receptive language, visual motor, and spatial skills were also improved for those in the intervention group. Even among the smallest infants; that is, those with birth weights of less than 1,500 grams and less than 1,000 grams, IQ scores were higher and behavior was better with the early intervention. The effects were the greatest for the highest-risk children, whose parents had no more than a high school education or were of an ethnic-racial minority status (Brooks-Gunn, 1992a,b). The effects were long lasting for children with birth weights of 2,000 to 2,499 grams. The children of well-educated mothers did not benefit from the intervention (McCormick et al., 1998). Mothers who had less than a high school education reported less emotional distress as a result of the intervention (Klebanov et al., 2001). These findings suggest that early intervention programs should especially target children and families at risk for poor outcomes. The cohort in the IHDP study was again evaluated at 5, 8, and 18 years of age (Brooks-Gunn, 1992a,b; McCarton et al., 1997; McCormick et al., 2006). Among children with birth weights of 2,000 to 2,499 grams, the differences in IQ scores, behavior, and math and reading achievement persisted, although for the IQ scores the difference decreased to 4 points. In adolescence, the intervention group reported lower rates of engagement in risky behavior (e.g., substance use or delinquency). These findings are consistent with those of other long-term studies of single-site educational interventions for poor healthy children (Campbell et al., 2002; Reynolds et al., 2001; Belfield et al., 2006). The lack of a persistent difference in those with birth weights of less than 2,000 grams raises questions about their subsequent experiences and the need for more sustained support for neurologically vulnerable children. Avon Premature Infant Project The United Kingdom Avon Premature Infant Project was a randomized controlled trial in which the parents of 284 infants born at less than 33 weeks gestation received a home-based developmental education program,
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Preterm Birth: Causes, Consequences, and Prevention a social support intervention, or standard care (Johnson et al., 2005). A fullterm reference population served as a control group. Although there were some differences in cognitive, motor, and behavioral outcomes at 2 years of age, there were no differences at 5 years of age (mean age, 58 months and 15 days) among the intervention groups. The children born preterm had poorer cognitive performance than their peers born fullterm. Further analyses, in which the outcomes data were adjusted for social factors, did not reveal any differences between the intervention groups or between subgroups classified by a range of perinatal variables. The authors concluded that the small advantage shown at 2 years of age is no longer detectable at 5 years of age and questioned the effectiveness of early intervention in sustained cognitive, behavioral, and motor functions. National Early Intervention Longitudinal Study The National Early Intervention Longitudinal Study (NEILS), sponsored by the Office of Special Education Programs of the U.S. Department of Education, is monitoring more than 3,338 children who have disabilities or who are at risk for disabilities and their families through their experiences in early intervention and into early elementary school. Information about the characteristics of the children and their families, the services that they receive, and the outcomes that they experience is being collected. A nationally representative sample of children between birth and 31 months of age and their families who began early intervention services for the first time between September 1997 and November 1998 has been recruited for the study. NEILS is focusing on, among other issues, the early intervention services that participating children and families receive and the outcomes that participating children and families experience. Because this study will also assess how outcomes relate to variations in child and family characteristics and the services that they received, it has particular relevance for infants born preterm and their families. A three-stage stratified sampling procedure was used to identify the original sample for the study. Twenty states were selected on the basis of the number of children served in early intervention and the region of the country. These states represented considerable variation with regard to the lead agency and whether or not the agencies served children at risk. The second stage involved the selection of counties on the basis of the estimated number of children served in Part C programs.1 Three to seven counties 1 Part C of the Individuals with Disabilities Education Act elevated the family component of early intervention to a new level. This legislation replaced the Individualized Education Program for children ages 3 to 21 years with the Individualized Family Service Plan for infants and toddlers with disabilities.
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Preterm Birth: Causes, Consequences, and Prevention were selected within each state, for a total of 93 counties. The children ranged in age from birth to 30 months when they began receiving early intervention services (between 1997 and 1998). The initial results from this study have been favorable. In a 2004 report by Bailey et al., it was found that most parents considered early intervention to have had a significant impact on their families, reporting that their families were much better off (59 percent) or somewhat better off (23 percent) as a result of the help and information that the early intervention program provided. Most parents (96 percent) also believed that they were able to help their children learn and develop, although in comparison, when they were asked about their perceived competence in caring for their child’s basic needs, fewer (64 percent) reported strong agreement and more (32 percent) reported simple agreement. A separate assessment of functional status over the time of the intervention showed that the proportion of children with vision, hearing, or motor skills problems stayed constant over the period of the intervention. However, some children who had problems with communication when the services began showed improvement over time (Markowitz, 2004). The assessment also found that 96 percent of the families reported that the intervention helped them become more proficient in working with professionals and advocating for their child’s needs. Summary Although the short-term impact of early interventions has been well demonstrated, the findings of evaluations of the long-term impact of early interventions for preterm infants have been ambiguous. Long-term prenatal and perinatal cohort studies conducted before the introduction of neonatal intensive care concluded that social factors and the quality of the home environment can compensate for the disadvantages encountered perinatally and neonatally (Wolke, 1998). Recent evidence shows that intervention providing social and environmental enhancement through home visits and child development programs, is associated with catch-up in cognitive and behavioral development in large preterm infants, especially those from socieconomically disadvantaged backgrounds (Brooks-Gunn et al., 1994; Olds and Kitzman, 1993; Ramey and Ramey, 1999). This suggests that these larger preterm infants may not have persistent central nervous system insults. In contrast, although early interventions may have an impact on the outcomes for smaller preterm infants, biological factors may be the best predictors of cognitive and behavioral outcomes at school age. However, McCormick (1997) and others have argued that the lack of comparability across studies that use such a broad categorization of morbidity is but one methodological flaw recurring in the follow-up literature. Other methodological problems include the failure to characterize the study
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Preterm Birth: Causes, Consequences, and Prevention samples by the eligibility for the study and the number of losses in the cohort, the failure to provide sufficient information with which the representativeness of the sample can be assessed, and the failure to use appropriate controls (McCormick, 1997). In addition, the outcomes being assessed may be too limited. Finally, even for the outcomes selected, many studies fail to incorporate a specific underlying pathogenic or conceptual model to identify potential factors influencing the relationship between the initial state (i.e., prematurity or low birth weight) and the outcomes observed (McCormick, 1997). Finding 11-4: Early childhood educational and other therapeutic research interventions have been demonstrated to improve outcomes for some infants born preterm; however, it is critical to determine the appropriate intensity, type of service, personnel, and curricula to achieve improvement in interventions. CONCLUSION There is a wide range of health and neurodevelopmental outcomes for infants born preterm, and many resources are required to provide the necessary medical, neurodevelopmental and educational support for the children and support for their families. More outcomes data are reported by birth weight categories than by gestational age categories, but until better measures of organ maturation are available, information regarding gestational age is necessary for medical decision making and parent counseling when a preterm delivery is anticipated. Because of their long-term impact, health care providers should focus not on preterm birth but on degree of organ maturity at birth and on short and long-term neurodevelopmental, functional, and health outcomes. Just as the etiologies of preterm birth are multifactorial, the neurodevelopmental, functional, and health outcomes of infants born preterm are determined by interactions among the genome, intrauterine environment, high-risk obstetric and neonatal intensive care provided, the home environment, and available community resources. Future research to develop better predictors of outcomes should focus on the relationships between brain structural and functional development, areas of the brain typically affected by brain insult and corresponding neurodevelopmental and behavioral deficits, and how organ recovery and plasticity occur. Better predictors of outcomes will allow for improved parent counseling, enhance safety of trials of maternal and infant interventions by providing more immediate feedback, and facilitate planning for use of comprehensive follow-up and early intervention resources. Until preterm birth can be prevented, much work also needs to be done to develop treatment strategies that prevent injury to the brain and other organs and support the infant’s ongoing development.
Representative terms from entire chapter: