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Original Investigation
April 2018

Cognitive Outcomes of Children Born Extremely or Very Preterm Since the 1990s and Associated Risk FactorsA Meta-analysis and Meta-regression

Author Affiliations
  • 1Clinical Neuropsychology Section, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
  • 2Department of Pediatrics, Emma Children’s Hospital, Academic Medical Center, Amsterdam, the Netherlands
  • 3Department of Pediatrics, Vrije Universiteit Medical Center, Amsterdam, the Netherlands
  • 4Nutricia Research, Utrecht, the Netherlands
JAMA Pediatr. 2018;172(4):361-367. doi:10.1001/jamapediatrics.2017.5323
Key Points

Question  What are the cognitive outcomes of children born extremely or very preterm since 1990, and what perinatal and demographic factors predict outcome?

Findings  This meta-analysis of 71 studies (7752 extremely or very preterm and 5155 full-term children) showed a large (0.86 standard deviation) difference in intelligence between extremely or very preterm children and controls, which was stable in children born between 1990 and 2008. Bronchopulmonary dysplasia explained 65% of the variance in intelligence across studies.

Meaning  Despite advancing perinatal care, cognitive outcomes of children born extremely or very preterm did not improve between 1990 and 2008; preventive strategies to reduce the incidence of bronchopulmonary dysplasia may be crucial to improve outcomes after extremely or very preterm birth.


Importance  Despite apparent progress in perinatal care, children born extremely or very preterm (EP/VP) remain at high risk for cognitive deficits. Insight into factors contributing to cognitive outcome is key to improve outcomes after EP/VP birth.

Objective  To examine the cognitive abilities of children of EP/VP birth (EP/VP children) and the role of perinatal and demographic risk factors.

Data Sources  PubMed, Web of Science, and PsycINFO were searched without language restriction (last search March 2, 2017). Key search terms included preterm, low birth weight, and intelligence.

Study Selection  Peer-reviewed studies reporting intelligence scores of EP/VP children (<32 weeks of gestation) and full-term controls at age 5 years or older, born in the antenatal corticosteroids and surfactant era, were included. A total of 268 studies met selection criteria, of which 71 covered unique cohorts.

Data Extraction and Synthesis  MOOSE guidelines were followed. Data were independently extracted by 2 researchers. Standardized mean differences in intelligence per study were pooled using random-effects meta-analysis. Heterogeneity in effect size across studies was studied using multivariate, random-effects meta-regression analysis.

Main Outcomes and Measures  Primary outcome was intelligence. Covariates included gestational age, birth weight, birth year, age at assessment, sex, race/ethnicity, socioeconomic status, small for gestational age, intraventricular hemorrhage, periventricular leukomalacia, bronchopulmonary dysplasia (BPD), necrotizing enterocolitis, sepsis, and postnatal corticosteroid use.

Results  The 71 included studies comprised 7752 EP/VP children and 5155 controls. Median gestational age was 28.5 weeks (interquartile range [IQR], 2.4 weeks) and the mean age at assessment ranged from 5.0 to 20.1 years. The median proportion of males was 50.0% (IQR, 8.7%). Preterm children had a 0.86-SD lower IQ compared with controls (95% CI, −0.94 to −0.78, P < .001). Results were heterogeneous across studies (I2 = 74.13; P < .001). This heterogeneity could not be explained by birth year of the cohort. Multivariate meta-regression analysis with backward elimination revealed that BPD explained 65% of the variance in intelligence across studies, with each percent increase in BPD rate across studies associated with a 0.01-SD decrease in IQ (0.15 IQ points) (P < .001).

Conclusions and Relevance  Extremely or very preterm children born in the antenatal corticosteroids and surfactant era show large deficits in intelligence. No improvement in cognitive outcome was observed between 1990 and 2008. These findings emphasize that improving outcomes after EP/VP birth remains a major challenge. Bronchopulmonary dysplasia was found to be a crucial factor for cognitive outcome. Lowering the high incidence of BPD may be key to improving long-term outcomes after EP/VP birth.