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Original Investigation |

Examination of the Pattern of Growth of Cerebral Tissue Volumes From Hospital Discharge to Early Childhood in Very Preterm Infants

Brian B. Monson, PhD1,2; Peter J. Anderson, PhD3,4; Lillian G. Matthews, PhD1,3,4; Jeffrey J. Neil, MD, PhD5; Kush Kapur, PhD5; Jeanie L. Y. Cheong, MD3,6,7; Lex W. Doyle, MD, MSc3,4,7; Deanne K. Thompson, PhD3,4,8; Terrie E. Inder, MD1
[+] Author Affiliations
1Department of Pediatric Newborn Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
2Department of Radiology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts
3Clinical Sciences, Murdoch Childrens Research Institute, Melbourne, Australia
4Department of Paediatrics, The University of Melbourne, Melbourne, Australia
5Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts
6Neonatal Services, The Royal Women’s Hospital, Melbourne, Australia
7Department of Obstetrics and Gynaecology, The Royal Women’s Hospital, University of Melbourne, Melbourne, Australia
8Florey Institute of Neuroscience and Mental Health, Melbourne, Australia
JAMA Pediatr. 2016;170(8):772-779. doi:10.1001/jamapediatrics.2016.0781.
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Importance  Smaller cerebral volumes at hospital discharge in very preterm (VPT) infants are associated with poor neurobehavioral outcomes. Brain growth from the newborn period to middle childhood has not been explored because longitudinal data have been lacking.

Objectives  To examine the pattern of growth of cerebral tissue volumes from hospital discharge to childhood in VPT infants and to determine perinatal risk factors for impaired brain growth and associations with neurobehavioral outcomes at 7 years.

Design, Setting, and Participants  Prospective cohort study of VPT infants (<30 weeks’ gestation or <1250 g) born between April 11, 2001, and April 26, 2004, and followed up at 7 years’ corrected age. The setting was The Royal Women’s Hospital and The Royal Children’s Hospital, Melbourne, Australia. Of 224 VPT infants and 46 full-term (FT) infants, usable magnetic resonance imaging data at either infancy or 7 years were collected for 214 VPT children (95.5%) and 46 FT children (100%), while 126 VPT children (56.3%) and 31 FT children (67.4%) had usable magnetic resonance imaging data at both time points. Follow-up was conducted from April 28, 2008, to August 9, 2011. Our final analysis was on March 3, 2016.

Exposure  Prematurity.

Main Outcomes and Measures  Absolute tissue growth, defined as change in absolute tissue volume, between infancy and 7 years was calculated for cortical gray matter volume (GMV), white matter volume (WMV), and subcortical GMV. IQ, language, and motor function were measured at 7 years.

Results  The study cohort comprised 260 participants. Their mean (SD) age was 7.5 (0.2) years, and 49.2% (128 of 260) were female. Early GMV deficits in VPT infants were magnified by 7 years, with less growth than FT controls. Growth differences were 31.4 (95% CI, 14.8-48.1) cm3 for cortical GMV and 1.7 (95% CI, 0.5-2.8) cm3 for subcortical GMV. Within the VPT group, greater growth was observed in boys for cortical GMV (31.9; 95% CI, 16.8-46.9 cm3), WMV (31.7; 95% CI, 19.7-43.7 cm3), and subcortical GMV (1.8; 95% CI, 0.8-2.8 cm3). After controlling for sex and maternal education, all tissue volumes in infancy correlated with IQ (r ≥ 0.35, P < .05) and language (r ≥ 0.29, P < .05). Seven-year volumes correlated with IQ (r = 0.28, P = .04 for cortical GMV), language (r = 0.29, P = .04 for cortical GMV), and motor functioning (r ≥ 0.29, P < .05 for all tissues). There was no evidence of any association between brain growth during childhood and outcomes in VPT infants.

Conclusions and Relevance  Low brain volumes observed in VPT infants are exaggerated at 7 years. Low brain volume in infancy is associated with long-term functional outcomes, emphasizing the persisting influence of early brain development on subsequent growth and outcomes.

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Figure 1.
Flowchart of Participants in the Study

Magnetic resonance imaging (MRI) numbers reflect usable images suitable for this analysis. FT indicates full term; PMA, postmenstrual age; TEA, term-equivalent age; and VPT, very preterm. FreeSurfer is version 4.4.0 (http://surfer.nmr.mgh.harvard.edu).

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Figure 2.
Effect Size Calculations for Differences in Volume at Both Time Points for the Longitudinal Cohort

cGMV indicates cortical gray matter volume; scGMV, subcortical gray matter volume; TEA, term-equivalent age; and WMV, white matter volume.

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