Is Association of Preterm Birth with Cognitive-Neurophysiological Impairments and ADHD Symptoms Consistent with a Causal Inference or Due to Familial Confounds?

Abstract

Background: Preterm birth is associated with an increased risk for cognitive-neurophysiological impairments and attention-deficit/hyperactivity disorder (ADHD). Whether the associations are due to the preterm birth insult per se, or due to other risk factors that characterise families with preterm-born children, is largely unknown. We aimed to investigate whether the association of preterm birth with cognitive-neurophysiological impairments and increased ADHD symptoms is consistent with a causal preterm birth inference, or due to familial confounds. Methods: We employed a within-sibling comparison design, using cognitive-performance and event-related potential (ERP) measures from 104 preterm-born adolescents, recruited from South East England schools, and 104 of their term-born siblings. Analyses focused on ADHD symptoms and cognitive and ERP measures from a cued continuous performance test, an arrow flanker task and a reaction time task that we previously found to be impaired in the preterm group when compared to an unrelated control group. Outcomes: Within-sibling analyses showed that preterm birth was significantly associated with increased ADHD symptoms (β=0.18, p=0.01, 95%CI=0.02,0.36) and specific cognitive-ERP impairments, such as IQ (β=- 0.20, p=0.02, 95%CI=-0.40,-0.01), preparation-vigilance measures and measures of error processing (ranging from β=0.71, -0.35). There was no significant within-sibling association between preterm birth with executive control measures of inhibition (NoGo-P3, β=-0.07, p=0.45, 95%CI=-0.33,0.15) or verbal working memory (digit span backward, β=-0.05, p=0.63, 95%CI=-0.30,0.18). Interpretation: The robust within-sibling associations of preterm birth with specific cognitive-neurophysiological impairments (IQ, preparation-vigilance and error processing) and with ADHD symptoms indicate that these associations are independent of family-level risk and consistent with a causal inference. In contrast, the negligible within-sibling association between preterm birth and executive control processes of inhibition and working memory implies that familial risk factors associated with preterm birth underlie these previously observed associations. By distinguishing impairments that are consistent with a causal inference of preterm birth from those that are instead linked to background characteristics of families with a preterm-born child, these results suggest that interventions need to target both preterm-birth specific and family-level risk factors. Funding Statement: Action Medical Research and the Medical Research Council. Declaration of Interests: Prof Asherson has acted in an advisory role for Shire, Janssen-Cilag, Eli Lilly and Flynn Pharma. He has received education or research grants from Shire, Janssen-Cilag and Eli-Lilly. He has given talks at educational events sponsored by the above companies. Prof Kuntsi has given talks at educational events sponsored by Medice; all funds are received by King’s College London and used for studies of ADHD. Dr. Banaschewski served in an advisory or consultancy role for Actelion, Hexal Pharma, Lilly, Lundbeck, Medice, Novartis, Shire. He received conference support or speaker’s fee by Lilly, Medice, Novartis and Shire. He has been involved in clinical trials conducted by Shire & Viforpharma. He received royalities from Hogrefe, Kohlhammer, CIP Medien, Oxford University Press. The present work is unrelated to the above grants and relationships. The other authors report no conflicts of interest. Ethics Approval Statement: Written informed consent was obtained following procedures approved by the National Research Ethics Service Committee London - Bromley (13/LO/0068).