Cognitive and Behavioral Outcomes of
School-Aged Children Who Were Born Preterm

JAMA v.288, n.6, 14aug02

A Meta-analysis

Adnan T. Bhutta, MBBS; Mario A. Cleves, PhD; Patrick H. Casey, MD; Mary M. Cradock, PhD; K. J. S. Anand, MBBS, DPhil

Context
The cognitive and behavioral outcomes of school-aged children who were born preterm have been reported extensively. Many of these studies have methodological flaws that preclude an accurate estimate of the long-term outcomes of prematurity.

Objective
To estimate the effect of preterm birth on cognition and behavior in school-aged children.

Data Sources
MEDLINE search (1980 to November 2001) for English-language articles, supplemented by a manual search of personal files maintained by 2 of the authors.

Study Selection
We included case-control studies reporting cognitive and/or behavioral data of children who were born preterm and who were evaluated after their fifth birthday if the attrition rate was less than 30%. From the 227 reviewed studies, cognitive data from 15 studies and behavioral data from 16 studies were selected.

Data Extraction
Data on population demographics, study characteristics, and cognitive and behavioral outcomes were extracted from each study, entered in a customized database, and reviewed twice to minimize error. Differences between the mean cognitive scores of cases and controls were pooled. Homogeneity across studies was formally tested using a general variance-based method and graphically using Galbraith plots. Linear meta-analysis regression models were fitted to explore the impact of birth weight and gestational age on cognitive outcomes. Study-specific relative risks (RRs) were calculated for the incidence of attention-deficit/hyperactivity disorder (ADHD) and pooled. Quality assessment of the studies was performed based on a 10-point scale. Publication bias was examined using Begg modified funnel plots and formally tested using the Egger weighted-linear regression method.

Data Synthesis
Among 1556 cases and 1720 controls, controls had significantly higher cognitive scores compared with children who were born preterm (weighted mean difference, 10.9; 95% confidence interval [CI], 9.2-12.5). The mean cognitive scores of preterm-born cases and term-born controls were directly proportional to their birth weight (R2 = 0.51; P<.001) and gestational age (R2 = 0.49; P<.001). Age at evaluation had no significant correlation with mean difference in cognitive scores (R2 = 0.12; P = .20). Preterm-born children showed increases in externalizing and internalizing behaviors in 81% of studies and had more than twice the RR for developing ADHD (pooled RR, 2.64; 95% CI, 1.85-3.78). No differences were noted in cognition and behaviors based on the quality of the study.

Conclusions
Children who were born preterm are at risk for reduced cognitive test scores and their immaturity at birth is directly proportional to the mean cognitive scores at school age. Preterm-born children also show an increased incidence of ADHD and other behaviors.

Author/Article Information

Author Affiliations: Departments of Pediatrics (Drs Bhutta, Cleves, Casey, Cradock, and Anand), Biostatistics (Dr Cleves), Anesthesiology (Dr Anand), Pharmacology (Dr Anand), and Neurobiology (Dr Anand) and Arkansas Center for Birth Defects Research and Prevention (Dr Cleves), University of Arkansas for Medical Sciences, Little Rock.

Corresponding Author and Reprints: K. J. S. Anand, MBBS, DPhil, Arkansas Children's Hospital, 800 Marshall St, S-431, Little Rock, AR 72202 (e-mail: anandsunny@exchange.uams.ed ). Author Contributions: Study concept and design: Bhutta, Anand.

Acquisition of data: Bhutta, Anand.

Analysis and interpretation of data: Bhutta, Cleves, Casey, Cradock, Anand.

Drafting of the manuscript: Bhutta, Cleves, Casey, Anand.

Critical revision of the manuscript for important intellectual content: Bhutta, Cleves, Casey, Cradock, Anand.

Statistical expertise: Cleves.

Obtained funding: Anand.

Administrative, technical, or material support: Bhutta, Anand.

Study supervision: Anand.

Funding/Support: Dr Anand received grant HD36484-02 from the National Institute for Child Health and Human Development and grant 01-199 from the Blowitz-Ridgeway Foundation.

Acknowledgment: We gratefully acknowledge the help of Tracy L. Thurman, BS, for constructing the database used for our study

COMMENT

Our meta-analysis shows that preterm birth is associated with lower cognitive scores and increased risks for ADHD and other behaviors at school age compared with term-born controls. Lower cognitive scores for the cases were noted in all the studies selected for this metaanalysis, and a WMD of greater than 10 between the cognitive scores of cases and controls is likely to have significant educational and social consequences.44 Lower birth weight and gestational age were significantly correlated with decreases in cognitive test scores, highlighting the developmental vulnerability of the immature brain. Superimposed on this vulnerability are the factors associated with severity of illness in preterm neonates, their physiological instability and exposure to early adverse experiences, which may have a persistent impact on brain development leading to these cognitive and behavioral outcomes.

The results of this meta-analysis must be viewed in the light of its limitations. Multiple studies conducted over the decades have also demonstrated the significant impact of demographic and environmental factors (such as age, sex, race, and socioeconomic status) on the trajectory of cognitive and behavioral development in both preterm39,45-48 and full-term12,49 infants. In a recent study of 118 children at age 10 years who were born preterm, family factors were stronger predictors of school performance than were perinatal complications." All the studies included in our meta-analysis featured cases and controls matched for 1 or more demographic variables. Thus, we were unable to determine the specific impact of demographic variables on the measured cognitive and behavioral outcomes.

We limited our search to Englishlanguage literature because of practical difficulties in abstracting data from articles published in other languages. Gregoire et a15' showed that in only 1 of 36 consecutive meta-analyses of randomized clinical trials, the inclusion of nonEnglish-language articles produced results different from the published metaanalysis (with a change in pooled odds ratio from 0.70 to 0.67). Such comparisons have not been published for metaanalyses of observational studies similar to ours. Despite the exclusion of nonEnglish-language articles, our metaanalysis contains data from many countries and no significant differences occurred in the cognitive outcomes of children born preterm in the United States vs non-US cohorts. For the sake of completeness, a repeat MEDLINE search found only 4 non-Englishlanguage articles (with online abstracts in English) that were designed as casecontrol studies with cognitive and/or behavioral data for preterm or term-born school-aged children. 52-55 Because of the limited information contained in each abstract, we cannot say whether these studies fulfilled all the inclusion and exclusion criteria for this meta-analysis. All 4 of these studies reached conclusions that are consistent with the results of our meta-analysis. Based on these considerations, we propose that including the results from non-English-language studies would not have altered our results or conclusions.

Furthermore, the included studies were published in an era when rapid advances were occurring in the field of fetal medicine and perinatology. Therefore, the care provided to these infants was not uniform and must have evolved over the period studied. The selected studies differed from one another in their baseline characteristics, such as mean birth weight and gestational age. All neonates with a gestational age of less than 37 weeks were defined as cases, and the data obtained from those who were born full-term but were small for their gestational age were excluded. It is possible, however, that some studies may have included those who were born full term but were small for their gestational age and were not identified in the description of their cohorts.

Data on birth weight and gestational age were not always reported as mean (SD) or range (Table 1). For these control groups, we assumed a mean term gestation of 40 weeks56 and a mean birth weight of 3200 g (50th percentile for age). Cases with severe neurological and cognitive disability were excluded in all but 3 of the studies included in the meta-analysis, although the exact definition of severe disability varied between these studies. The studies that included cases with severe neurological and cognitive disability had the highest WMD between the cases and controls (Figure 1).2',32,35 For the purposes of our analysis, we assumed that the cognitive scores from the various tests were comparable because of similar normative data for all the cognitive tests used (mean [SDI, 100 [15]). Similarly, we assumed that the different standardized assessments used for the diagnosis of ADHD had comparable sensitivity and specificity (DSMIII, DSM-III-R, and DSM-IV). These assumptions overlook the subtle differences between the cognitive and behavioral tests used, as well as the variability in administering these tests.

The stringent application of our selection criteria resulted in the exclusion of studies with poor methodologic quality (eg, attrition rate >30%) and poor generalizability (eg, reports of subgroup analyses 57). Assessment of study quality for meta-analyses of randomized clinical trials has been questioned and may give misleading results in meta-analyses " Specific criteria are widely accepted for assessing the quality of randomized controlled trials (eg, randomization, double-blinding, dropouts, or allocation concealment); however, similar criteria have not been developed for observational studies. We devised a quality assessment tool specifically for this meta-analysis, using the objective criteria listed in Table l. The quality of the studies included in this meta-analysis was assessed independently by 2 of the authors, but showed no differences in cognitive or behavioral outcomes between high-quality and low-quality studies.

This meta-analysis provides evidence from a large number of subjects that children who were born preterm are at significant risk for reduced cognitive performance at school age and that gestational age and birth weight are directly proportional to their mean cognitive test scores. These robust differences should eliminate controversies generated from the variable cognitive outcomes reported by individual follow-up studies. Is a mean difference of 10.9 points between the cognitive scores of school-aged cases and controls clinically significant? McCarton et a144 argued that a 4-point difference between cognitive scores may not produce functionally detectable differences between children, but on a group basis these differences will significantly alter the proportion of children classified as "intellectually deficient and of borderline intelligence." Children who were born preterm or at LBW are 50% more likely to be enrolled in special education classes compared with term-born children, which was conservatively estimated in 1988 to result in an incremental cost of $370.8 million.59 Based on such projections, we propose that the cognitive differences reported in this meta-analysis will have a significant impact on the educational requirements for children who were born preterm and may determine their future socioeconomic potential.

The perinatal course of these children may shed some light on the mechanisms underlying these differences. Preterm neonates are at higher risk for postnatal complications, such as intraventricular hemorrhage, sepsis, metabolic complications (eg, hypoglycemia), and chronic lung disease. They are subjected to multiple painful procedures and maternal separation for prolonged periods. Experimental evidence from animal models shows that all these factors can promote or precipitate neuronal cell death in the immature brain.60 Increased rates of neuronal cell death could lead to volumetric losses in specific brain regions and may at least partially explain the cognitive and behavioral abnormalities noted in these children. Volumetric measurements of brain regions in 8-year-old children born preterm showed disproportionately smaller volumes of the sensorimotor cortex, other cortical areas, the corpus callosum, amygdala, hippocampus, and basal ganglia, which were associated with significantly lower cognitive scores (mean difference= 23.5) and an increased incidence of ADHD and other behavioral disorders57 Similarly, an increased incidence of neurocognitive and behavioral abnormalities were correlated with magnetic resonance imaging abnormalities in the brains of 14-yearold children who were born preterm.61 Since developing neurons are more vulnerable to cell death during the perinatal period , 62,63 we propose that the biological and environmental insults associated with preterm birth may promote some of these anatomical differences.

This meta-analysis further shows that children born preterm have a 2.64fold risk for developing ADHD and frequently manifest externalizing or internalizing behaviors during school age. Multiple studies report an increased prevalence of psychiatric disorders in preterm-born children '40,64 which may contribute to increased parenting stress and maternal depression during early childhood .65,66

Could the impairment of preattentional mechanisms (such as the sensory gating of paired stimuli67) lead to ADHD, which ultimately manifests as poor cognition at school age? Pretermborn infants show differences in their threshold for arousal, which supports sustained attention and information encoding.68,69 Children who were born preterm have been shown to be less capable of the selective attention states required for learning.70 Thus, we propose a series of testable hypotheses to examine the pathogenesis of poor cognition in children born preterm.

Proposals to test such hypotheses will require the concerted efforts of clinicians and neuroscientists to develop a complete understanding of the biological, environmental, and psychosocial mechanisms responsible for these cognitive and behavioral differences. Previous research has demonstrated that psychosocial interventions with preterm infants and their parents may improve cognitive and behavioral outcomes 44,71 whereas others report that socioeconomic factors have minimal effects on neurodevelopmental outcomes 4 With an improved understanding of the underlying biological mechanisms, more focused therapeutic interventions can be developed to decrease or prevent these long-term impairments following survival after preterm birth.