Longitudinal Preterm Cerebellar Volume: Perinatal and Neurodevelopmental Outcome Associations
Impaired cerebellar development is an important determinant of adverse motor and cognitive outcomes in very preterm (VPT) infants. However, longitudinal MRI studies investigating cerebellar maturation from birth through childhood and associated neurodevelopmental outcomes are lacking. We aimed to compare cerebellar volume and growth from term-equivalent age (TEA) to 7 years between VPT (< 30 weeks’ gestation or < 1250 g) and full-term children; and to assess the association between these measures, perinatal factors, and 7-year outcomes in VPT children, and whether these relationships varied by sex. In a prospective cohort study of 224 VPT and 46 full-term infants, cerebellar volumes were measured on MRI at TEA and 7 years. Useable data at either time-point were collected for 207 VPT and 43 full-term children. Cerebellar growth from TEA to 7 years was compared between VPT and full-term children. Associations with perinatal factors and 7-year outcomes were investigated in VPT children. VPT children had smaller TEA and 7-year volumes and reduced growth. Perinatal factors were associated with smaller cerebellar volume and growth between TEA and 7 years, namely, postnatal corticosteroids for TEA volume, and female sex, earlier birth gestation, white and deep nuclear gray matter injury for 7-year volume and growth. Smaller TEA and 7-year volumes, and reduced growth were associated with poorer 7-year IQ, language, and motor function, with differential relationships observed for male and female children. Our findings indicate that cerebellar growth from TEA to 7 years is impaired in VPT children and relates to early perinatal factors and 7-year outcomes.
KeywordsBrain Cerebellum Longitudinal studies Outcome assessment Premature birth Magnetic resonance imaging
The authors gratefully thank Merilyn Bear for recruitment, Michael Kean and the radiographers at Melbourne Children’s MRI Centre, and the VIBeS and Developmental Imaging groups at the Murdoch Children’s Research Institute for their ideas and support, as well as the families and children who participated in this study. We also gratefully acknowledge Sara Cherkerzian for statistical input, and the contributions of Richard Beare, Divyen Shah, and Zohra Ahmadzai who generated the infant and 7-year cerebellar volumes.
This work was supported by Australia’s National Health and Medical Research Council (Centre for Clinical Research Excellence 546519 to LD, PA, and TI; Centre for Research Excellence 1060733 to LD, PA, and DT; Project grants 237117 to TI and LD, 491209 to PA, TI, LD, and DT; Senior Research Fellowship 1081288 to PA; Career Development Fellowship 1085754 to DT; Early Career Fellowship 1012236 to DT; Career Development Fellowship 1127984 to KJL), National Institutes of Health (HD058056), United Cerebral Palsy Foundation (USA), Leila Y. Mathers Charitable Foundation (USA), the Brown Foundation (USA), and the Victorian Government’s Operational Infrastructure Support Program. This work was further conducted with support from Harvard Catalyst | The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, NIH Award UL1 TR001102) and financial contributions from Harvard University and its affiliated academic healthcare centers.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. All phases of the study were approved by the Human Research Ethics Committees at The Royal Women’s Hospital and The Royal Children’s Hospital, Melbourne, Australia.
Parental written informed consent was obtained for all individual participants included in the study.
- 26.Wechsler D. Wechsler Abbreviated Scale of Intelligence. New York, NY: The Psychological Corporation: Harcourt Brace & Company; 1999.Google Scholar
- 27.Semel EM, Wiig EH, Secord WA. Clinical evaluation of language fundamentals (4th-Australian standardised edition). Marrickville, New South Wales, Australia: Harcourt Assessment; 2006.Google Scholar
- 28.Manly T, Robertson I, Anderson V, Nimmo-Smith I. The test of everyday attention for children. Suffolk: Thames Valley Test Co.; 1999.Google Scholar
- 29.Pickering S, Gathercole S. Working memory test battery for children—manual. London: The Psychological Corporation; 2001.Google Scholar
- 30.Henderson SE, Sugden DA, Barnett AL. Movement assessment battery for children—2 second edition (movement ABC-2). London: The Psychological Corporation; 2007.Google Scholar
- 33.Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B Methodol. 1995;57(1):289–300.Google Scholar
- 35.Limperopoulos C. Cerebellar injury in the preterm infant. In: Boltshauser E, Schmahmann J, editors. Cerebellar disorders in children clinics in developmental medicine no 191-192. 1st ed. London: Mac Keith Press; 2012.Google Scholar
- 37.Boltshauser E, Schmahmann J, editors. Cerebellar disorders in children. 1st ed. London: Mac Keith Press; 2012.Google Scholar
- 46.Reeber SL, Otis TS, Sillitoe RV. New roles for the cerebellum in health and disease. Front Syst Neurosci. 2013;7Google Scholar
- 64.Wood NS, Costeloe K, Gibson AT, Hennessy EM, Marlow N, Wilkinson AR. The EPICure study: associations and antecedents of neurological and developmental disability at 30 months of age following extremely preterm birth. Arch Dis Child Fetal Neonatal Ed. 2005;90(2):F134–40.CrossRefPubMedPubMedCentralGoogle Scholar
- 67.Nguon K, Ladd B, Baxter MG, Sajdel-Sulkowska EM. Sexual dimorphism in cerebellar structure, function, and response to environmental perturbations. Prog Brain Res Volume 148: Elsevier; 2005. p. 341–351.Google Scholar