Prediction of neurodevelopmental outcome in children born extremely preterm
Keywords: Extermely preterm birt
Longitudinal follow up
Neurodevelopmental outcome
Prediction

Background: The survival rate of preterm children has risen steadily due to advances in obstetric and neonatal intensive care. Children born extremely preterm (≤28 weeks of gestation) are at high risk of long term developmental problems, including cerebral palsy, motor and cognitive impairment, visual and auditory deficits and behavioural problems. This can have serious implications for their quality of life and that of their family and carers. These children take up a disproportionate amount of neonatal intensive care unit resources and overall costs, and as they grow up are more likely to require additional health and social care services beyond routine care to compensate for their functional limitations. The early identification and management of factors that mediate long term outcome is necessary to assist healthcare professionals in selecting appropriate treatment pathways, and to develop, target and evaluate interventions. Many risk factor analyses for neurodevelopmental impairment have been published in preterm populations, but this vast literature has not been formally summarised. Furthermore, there is a dearth of studies reporting longitudinal analysis of neurodevelopmental trajectories from early childhood to adulthood.
Objectives: The first aim of this thesis was to perform a comprehensive systematic review of the world literature over the last two decades, to consolidate the evidence about the prognosis of neurodevelopmental outcome in children born very preterm or with very low birth weight. The second aim was to conduct a longitudinal analysis of a cohort of extremely preterm participants followed up into early adulthood to investigate the trajectories of long term sequelae over time, and to examine the association of neurodevelopmental course in relation to the predictive factors identified in the systematic review.
Methods: A systematic review was conducted using MEDLINE, EMBASE and PyscINFO databases to identify studies published between January 1 1990 and June 1 2014 reporting multivariable prediction models for the neurodevelopment of children born ≤32 weeks of gestation or with a birth weight ≤1250 grams (protocol registration number CRD42014006943). Seventy-eight studies reporting 222 risk factor models for neurodevelopmental outcome were identified. Two independent reviewers extracted key information about study design, outcome definition, risk factor selection, model development, reporting, and conducted a risk of bias assessment. To address the second objective of the study, a longitudinal analysis of cognitive and behavioural trajectories was conducted using a prospective, population-based cohort study in the United Kingdom and the Republic of Ireland. Three hundred and fifteen surviving infants born less than 26 completed weeks of gestation recruited at birth in 1995 and 160 term-born classroom peers recruited at age six were followed-up to 19 years. Participants were invited for up to four standardized, blinded cognitive assessments and the parent-completed Strengths and Difficulties Questionnaire was used to assess behavioural problems.
Results: The systematic review of risk factors for motor impairment in children born very preterm or with very low birth weight provided strong evidence that neonatal brain injury is a robust prognostic factor for cerebral palsy, and some evidence that the use of postnatal steroids increases the risk and the use of antenatal steroids reduces the risk of cerebral palsy. There was moderate evidence that male sex was prognostic for motor impairment at school age in children free of major disability. The systematic review of risk factors for cognitive impairment identified male sex, non-white ethnicity, lower levels of parental education and lower birth weight as significant predictors of global cognitive dysfunction in early infancy, with parental education having a sustained impact after five years of age. There was also evidence that male sex was predictive of delayed language development in early infancy. Gestational age was found to be of limited use as prognostic factor for cerebral palsy, motor and cognitive impairment in cohorts restricted to ≤32 weeks of gestation. There was a dearth of good quality studies investigating risk factors for behavioural problems and psychiatric disorders and the findings of this review were inconclusive. The only factors that appeared to be consistent predictors of general behavioural problems were markers of socio-economic deprivation, neurodevelopmental or cognitive delay, and an abnormal behavioural screen in early infancy.
In the longitudinal analysis of the prospective, population-based cohort of extremely preterm children, cognitive trajectories were stable in both the extremely preterm and term-born groups over time with persistent deficit in the extremely preterm group of 25.2 IQ points (95% CI: -27.8 to -22.6, p&LT;0.001) and only minimal catch-up over time. Participants with neonatal brain injury and of male sex had the largest deficits, but a lower level of maternal education and earlier gestational age at birth were also associated with reduced IQ scores. Behavioural problems were also more prevalent among the extremely preterm participants who had a mean Total Difficulties Score of 4.81 points above their term-born peers (95% CI: 3.76 to 5.87, p&LT;0.001) and which persisted over the time period. Behavioural difficulties were mainly due to hyperactivity, inattention and peer problems and were strongly associated with a positive behavioural screen in early infancy.
Conclusions: The most robust predictors of poor neurodevelopmental outcome identified by the systematic review were neonatal brain injury, male sex, and markers of social disadvantage. The unclear findings for many risk factors may reflect differences in study design, study population, methodological quality and lack of standardization of measures. Or it may simply reflect the fact that prognostic modelling in such a heterogeneous population is challenging and complex, with multiple risk factors acting sequentially over time, and often with the existence of multiple impairments within the same individual. The main conclusions from the longitudinal analysis of children born extremely preterm is that being born too soon appears to place limits on brain plasticity and function which is not recovered over time; with the most vulnerable being males and those with evidence of brain injury early in life. These structural abnormalities may disturb neurodevelopmental processes and impede the brain from maintaining a normal developmental trajectory. If extremely preterm children fail to achieve optimum levels of cognitive function and are still experiencing behavioural problems once they have reached maturity, then this has implications for health and well-being in later adulthood and old age. Cognitive test scores in infancy and early childhood reflect early adult outcomes and a positive behavioural screen in infancy is strongly associated with early adult behavioural outcomes.
Recommendations: The systematic review revealed some shortcomings in methodology and reporting that could be improved in future studies, and confirmed that that there is a dearth of properly designed and well-conducted prognostic modelling studies in this field. The findings and recommendations of this critical review should be used as a basis for the design, analysis and reporting of future studies seeking to develop multivariate risk factor or prognostic models in this population. There is an urgent need for larger population cohorts followed up routinely beyond two years as subtle outcomes such as impairment of executive function and fine motor skills cannot be reliably assessed at this age, and the natural course of some disorders may have their onset later in childhood. Studies with larger sample sizes and greater power are needed for studying less common conditions in preterm populations and there should be more standardisation of outcome and risk factor measurements, particularly with the use of standard diagnostic evaluations to assess psychiatric disorders. Future studies should include a term-born comparison group and adopt appropriate statistical analysis techniques to analyse longitudinal outcome data and the impact of risk factors on these trajectories. Additional research is required to improve the prediction of individual differences, and to identify the neuropathological differences underlying different developmental trajectories and their interaction with environmental influences over time.