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Premature birth: life after surviving the edges of viability


Preterm birth: life after surviving the edges of viability.
Since the introduction of neonatal intensive care in the 1960s, the survival rate of preterm (<32 completed weeks of gestation) and very low birth weight  (VLBW; <1500 grams) infants has improved.

Preterm birth may have long-lasting effects. Although most preterm infants survive without major disabilities, follow-up studies at preschool age have revealed major disabilities such as cerebral palsy, mental retardation, blindness, and deafness (Aylward, 2005). Furthermore, alterations in brain structures such as the grey and white matter are present in preterm children, possibly underlying differences in cognitive and behavioural functioning (Nosarti et al., 2008).

At school age, impairments in cognitive function, learning difficulties and behavioural problems have been frequently reported (please see Box 1). A recent study that examined outcomes at young adulthood documented that 12.6% of preterm and/or VLBW infants experience moderate or severe problems in cognitive or neurosensory functioning at 19 years of age (Hille et al., 2007).

Box 1

A meta-analysis on cognitive function in preterm children demonstrated that preterm birth might result in a loss of 10 IQ-points compared to controls (Bhutta et al., 2002). These lower cognitive scores are likely to have educational and social consequences. Independent of, and in addition to these lower IQs are the higher rates of psychopathology and school problems that are also common in these children. Psychopathology after preterm birth is frequently expressed in an increased risk for Attention Deficit Hyperactivity Disorder (ADHD) and internalizing behavioural problems, such as withdrawn behaviour or anxiety (Aylward, 2005). School problems are defined as academic achievement on the one hand, and school attainment on the other hand. Academic underachievement compared to their peers is common among preterm children. For example, by middle school age, preterm children are three to five times more likely than full-term peers to have a learning problem in reading, spelling, mathematics, or writing, with mathematics being most disrupted (Aarnoudse-Moens et al., 2009).
These cognitive, academic achievement and behavioural difficulties frequently result in school attainment problems such as grade repetition, the need for remedial teaching, or special education.

Why study neurocognitive sequels in preterm children?
In order to develop intervention programs, designed to prevent learning and behavioural problems, research to improve understanding and early identification of these learning and behavioural problems is necessary.

It has been hypothesized that preterm birth and its effects interact with health, neurocognitive and motor functioning to explain the learning and behavioral problems at school age (Aylward, 2005, Taylor et al., 2006)). As a result, the link in developmental pathways between preterm birth and later school and behavioural outcome is presumed to be indirect, and a possible mediating role has been suggested for neurocognitive function (Taylor et al., 2006).

Impairments in neurocognitive functions, such as executive function, perceptual motor skills, verbal list learning, and memory are frequently reported in preterm children (Aylward, 2005). These weaknesses are found even when controlling for IQ or excluding children with cerebral palsy, hearing or vision problems, or global cognitive impairment, and may be associated with poor academic achievement and behavioural problems (Aylward, 2005).

In particular executive function (EF) has been identified to strongly influence academic, social and behavioural functioning. Executive function refers to self-regulatory neurocognitive processes, such as inhibition, working memory, set-shifting, planning and fluency (Pennington & Ozonoff, 1996). Learning problems, such as mathematical difficulties, have been demonstrated to result from deficits in executive function (Bull & Scerif, 2001). Furthermore, a large body of research has pointed out the importance of executive dysfunction in developmental disorders, such as ADHD, conduct disorder and autism (Barkley, 1996; Pennington & Ozonoff, 1996). Recent studies have demonstrated deficits in executive function to underlie both ADHD as well as reading disabilities, which might explain the co-morbidity of these disorders.

Several studies have demonstrated deficits in executive function in preterm children (for a review see Aarnoudse-Moens et al., 2009). Even those preterm children with IQs in the normal range and without overt neurosensory handicaps may have impaired executive function at early school age. As executive dysfunction causes a lack of requisites for functioning in a more complex and demanding environment, these deficits might form the underlying factor explaining the high prevalence of learning and behavioural problems in preterm children. The current project has been set up to disentangle this relationship, as it is remains unknown whether in preterm children executive dysfunction precedes learning and behavioural problems (please see Box 2 for more details concerning this project).

Box 2
The current project studies EF, academic achievement and behavioural functioning in a group of preterm children of 4-12 years and performance will be compared to that of a group of normal full-term peers. EF domains assessed include inhibition, working memory, planning, fluency and cognitive flexibility. Academic achievement is measured using the Dutch national Pupil Monitoring System. Standardized parent and teacher's questionnaires are employed to measure behavioural functioning.


Neurocognitive sequelae and brain functioning
By now, it is still unclear to what extend alterations in brain structures underlie the deficits in neurocognitive functioning of preterm children. Recent findings using DTI scanning techniques showed that fibre tract abnormalities in preterm infants strongly relate to motor skill development at 2 years of age (Drobyshevsky et al., 2007) and for intellectual functioning, visuo-motor abilities and motor functioning at school-age and during adolescence (Constable et al., 2008; Gaddlin et al., 2007; Schmithorst et al., 2005; Skranes et al., 2007; Yung et al., 2007). ). These findings are promising, but await replication using large samples and extension using well defined neurocognitive paradigms. In a second project, the exact relation of white matter integrity and neurocognitive dysfunction of preterm children will be studied, to elucidate the underlying mechanism for the emergence of cognitive and behavioural deficits (please see Box 3 for more details concerning this project).

Box 3
In this study, well-defined neurocognitive paradigms will be employed to give insight in the specific difficulties of neurocognitive functioning of preterm as compared to term born children at 6-8 years of age. White matter integrity using diffusion tensor imaging (DTI) and volumetric parameters of grey and white matter using magnetic resonance imaging (MRI) will be obtained for each child, to disentangle the relation between brain alterations and neurocognitive functioning. Furthermore, standardized parent and teacher's questionnaires are employed to measure behavioural functioning.

Insights from pediatric ophthalmology
Along with growing insights from neuroscience, paediatric neuropsychology and paediatric ophthalmology, there is a rapidly growing interest in the phenomenon of cerebral visual impairments, which is suggested to become the leading cause of visual impairment in children in the western world (Edmond & Foroozan 2006). Cerebral visual impairments can be found in a variety of neurodevelopmental disorders (Dutton, 2001). Even though a comprehensive diagnosis is lacking (Frebel, 2006), preterm children are shown to be at risk for impaired visual and visuocognitive functioning (Atkinson & Braddick, 2007; Edmond & Foroozan, 2006). Until now cerebral visual impairments are mostly described in selected patient groups (e.g. Huo et al., 1999; Ortibus et al., 2009). Therefore, a third project of our department will focus on the potential neurocognitive underpinnings of cerebral visual impairment by studying a large cohort of preterm born children. Effort will be made to shed light on the differences and commonalities of this visually characterised developmental disorder with other known developmental disorders in preterm born children (please see box 4 for more details concerning this project).

Box 4
The aims of this study are to establish visual sensory, visual perceptual and visual attentional performance in a large cohort of 5,5 year old preterm born children using well established neurocognitive paradigms. Subsequently, potential neurocognitive underpinnings of the clinical signs described as cerebral visual impairment can be uncovered. Secondly repercussions on behavioural functioning and academic achievement will be studied, using behavioural questionnaires and ratings from the Dutch National Pupil Monitoring System.
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