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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;288:728-737.

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 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.

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