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Cognitive and Behavioral Outcomes of School-Aged Children Who Were Born Preterm 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
JAMA. 2002;288(6):728-737. doi:10.1001/jama.288.6.728.
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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.

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Figure 1. Random-Effects Meta-analysis Comparing Cognitive Test Scores Between Cases and Controls
Graphic Jump Location
The test for heterogeneity was significant (χ216 = 33.65; P = .006). The weighted mean difference significantly favors controls (z = 13.14; P<.001). The size of the data marker corresponds to the weight of that study. Error bars represent 95% confidence intervals.
Figure 2. Correlations Between Mean Cognitive Scores, Birth Weight, and Gestational Age
Graphic Jump Location
Correlations between each variable (birth weight and gestational age) and mean cognitive test scores were significant (birth weight: R2 = 0.51; P<.001; and gestational age: R2 = 0.49; P<.001). The preterm-born children scored lower on tests of cognition for both variables.
Figure 3. Random-Effects Meta-analysis for Studies Assessing Attention-Deficit/Hyperactivity Disorder
Graphic Jump Location
Diagnostic criteria used were based on the Diagnostic and Statistical Manual of Mental Disorders, Third Edition; Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition; or Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. An increased relative risk existed among cases for attention-deficit/hyperactivity disorder (z = 5.32; P<.001). The test for heterogeneity was not significant (χ26 = 2.60; P = .86). CI indicates confidence interval, illustrated by the error bars. The size of the data marker corresponds to the weight of that study.

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