Behavioural adjustment sequelae in children born very preterm: measurement issues and neonatal neurological correlates.

Abstract

Background: Children born very preterm are at an elevated risk of behavioural adjustment problems, particularly Attention-Deficit/Hyperactivity Disorder (ADHD) or inattention/hyperactivity difficulties. Importantly, these risks remain even after controlling for the effects of social risk factors correlated with very preterm birth. Behavioural outcomes in follow-up studies of children born very preterm are typically assessed using parent reports only. However, the extent to which behavioural problems are evident across multiple contexts (i.e., parent or teacher report) is not well known. Furthermore, the neonatal neuropathology underlying these behavioural difficulties in this population remains poorly understood.

Aims: Three research studies are undertaken primarily to examine: (1) the degree of agreement between parent and teacher reports of child behaviour adjustment, and the extent of situational (parent- or teacher-identified) and pervasive (parent- and teacher-identified) inattention/hyperactivity problems at ages 4, 6, and 9 years among children born very preterm and full-term; (2) to cross-validate the classification of children with situational and pervasive inattention/hyperactivity problems across the ages of 4 to 9, for a clinical diagnosis of ADHD at age 9 years; (3) to document risk of persistent ADHD symptoms between ages 4 and 9 years in children born very preterm, and to examine associations between qualitative measures of neonatal cerebral white matter injury/abnormality and quantitative volumetric measures of cerebral structural development, identified using magnetic resonance imaging (MRI) at term equivalent age, and children’s later risks of persistent symptoms. Persistent ADHD symptoms were defined as behavioural inattention/hyperactivity problems shown at ages 4, 6, and 9, along with meeting the criteria for an ADHD clinical diagnosis at age 9 years.

Methods: As part of a prospective longitudinal study, a regional cohort of 110 very preterm (≤ 33 weeks of gestation) and 113 full-term children born between 1998 and 2000 were studied from birth to age 9 years. At term equivalent age, all children born very preterm and 10 children born full-term underwent an MRI scan that was analysed using qualitative measures for cerebral white matter injury/abnormality, and quantitative volumetric techniques with tissue segmentation and regional parcellation for cortical and subcortical grey matter, myelinated and unmyelinated white matter, and cerebrospinal fluid. At ages 4, 6 (corrected for the extent of prematurity), and 9 years (uncorrected), children were screened for behavioural adjustment problems including inattention/hyperactivity symptoms using the parent and teacher rated Strengths and Difficulties Questionnaire (SDQ). At age 9, the Development and Well-Being Assessment (DAWBA) structured psychiatric interview was also completed with primary caregiver and an independent clinical diagnosis of ADHD determined by a child psychiatrist blinded to child’s perinatal history and group status.

Results: Agreement between parent and teacher reports regarding child behaviour adjustment was lower for children born very preterm than full-term (mean alternative chance-correlated coefficient, AC₁ = 0.63 vs. 0.80). Across all assessment time-points, very preterm birth was associated with on average a 2-fold increased risk of behavioural inattention/hyperactivity problems. These elevated risks largely reflected high rates of situational symptoms (very preterm = 22.3% − 31.7%; full-term = 10.9% − 16.7%). In contrast, rates of pervasive symptoms were relatively modest (very preterm = 6.8% − 11.5%; full-term = 4.7% − 7.3%). Examination of the predictive validity of inattention/hyperactivity problems identified using parent and teacher reports showed that children exhibiting situational symptoms at ages 4 and 6 were much less likely than those exhibiting pervasive symptoms, for a subsequent clinical diagnosis of ADHD at age 9 years (very preterm = 29% − 47.8% vs. 66.7% − 75%; full-term = 13.3% − 22.2% vs. 33.3% − 40%). Furthermore, receiver operating characteristic curves fitted to the data showed that children born very preterm exhibiting inattention/hyperactivity problems at two or three time-points (area under curve, AUC = .909) have better predictive validity for later ADHD diagnosis, compared to those exhibiting symptoms at age 4 (AUC = .794) or 6 years (AUC = .813) only. Children born very preterm were also at an elevated risk of persistent ADHD symptoms across the ages of 4 to 9 years, with the risk being 5-fold higher than their full-term peers (13.1% vs. 2.8%). Results also revealed possible associations between neonatal neuropathology and later risk of persistent ADHD symptoms. There were no significant linear associations between increasing severity of qualitative neonatal MRI measures of white matter injury/abnormality and very preterm children’s later risk of persistent ADHD symptoms. However, reduction in total cerebral tissue volumes and corresponding increase of cerebrospinal fluid (adjusted for intracranial volume) were significantly associated with increased risk of persistent symptoms in children born very preterm (p = .001). In terms of regional tissue volumes, total cerebral tissues in the dorsal prefrontal region showed the largest volumetric reductions among all the subregions in children born very preterm exhibiting persistent ADHD symptoms, with 3.2 ml (7%) and 8.2 ml (16%) lower tissue volumes than children born very preterm and full-term without persistent symptoms, respectively.

Conclusions: Reliance on a single informant to examine child behaviour outcomes at a single time-point may lead to an under- or over-estimation of later ADHD risks. Combining reports from multiple informants and repeated assessments over time may provide better clinical prognostic validity. Children born very preterm are at an increased risk of behavioural inattention/hyperactivity problems during their early school years; although risks of more severe, pervasive problems are relatively modest compared with situational problems. Behavioural adjustment difficulties recognised as early as during preschool age using standardised behaviour screening tools can be a reliable indicator for identifying children born very preterm at risk of subsequent ADHD diagnosis. Finally, study findings suggest that increased risk of ADHD symptoms in children born very preterm can at least in part be accounted for by disturbances to neonatal cerebral growth and maturation.