Postnatal Brain Magnetic Resonance Imaging Trajectories and Maternal Intelligence Predict Neurodevelopmental Outcomes in Complex Congenital Heart Disease

Importance Congenital heart disease (CHD), especially the complex forms – such as hypoplastic left heart syndrome (HLHS) and transposition of the great arteries (TGA) – have been linked to neurodevelopmental deficits including impairments in gross cognitive functions, language abilities, and visuo-motor skills. The prognostic value of early infant brain trajectories and cumulative impact of demographic factors in relation to childhood neurodevelopmental outcomes is unknown. Objective To determine whether early structural brain trajectories predict early childhood neurodevelopmental deficits in complex CHD patients and to assess relative cumulative risk profiles of clinical, genetic, and demographic risk factors across early development. Design, Setting, and Participants We studied a prospective cohort study of term neonates with complex CHD (TGA and HLHS) were recruited at Texas Children’s Hospital between 2005-2011. Participants underwent structural MRI scans at three time points (one preoperative scan, one postoperative scan within 7 days of surgery, and one follow-up postoperative scan at 4 months). Participants also received three neurodevelopmental assessments at 1, 3, and 5 years of age. Main Outcomes and Measures Brain region volumes (macrostructure) and white matter tract (microstructure) fractional anisotropy (FA) and radial diffusivity (RD) were measured from the MRI scans acquired in the three neonatal time points. Three imaging trajectories – changes in volume, FA and RD, over time – corresponding to periods of brain changes were determined: perioperative (preoperative to postoperative #1), post-surgical (postoperative #1 to postoperative #2), and overall (preoperative #1 to postoperative #2). Gross cognitive, language, and visuo-motor outcomes were assessed with the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) at 1 and 3 years, and with the Wechsler Preschool and Primary Scale of Intelligence, Third Edition (WPPSI-III Full-Scale IQ and Verbal IQ, and Beery-Buktenica Developmental Test of Visual-Motor Integration (VMI)., 6th Edition at 5 years. The analysis included development of predictive multi-variable models incorporating other known risk factors (i.e., heart lesion type, microdeletion-related genetic abnormality, and maternal IQ) of poor neurodevelopmental outcomes in CHD. Results A total of 95 term (38.5±1.3 weeks gestational age) neonates with complex CHD (49 [51.6%] HLHS, 46 [48.4%] TGA; 42 [44.2%] girls) were analyzed. Reduced overall period trajectories predicted poor language outcomes: brainstem (p=0.0022) and white matter (p=0.0397) predicted poor 5-year verbal IQ; brainstem (p=0.0134), deep grey (p=0.0258), and FA of superior longitudinal fasciculus (SLF) (p=0.0256) predicted poor 3-year language; whole brain volume predicted poor performance on measures of language at 1 year. Maternal IQ was the strongest contributor to language outcome variance that increased from 37% at 1-year, up to 62% at 3-year, and up to 81% at 5-year testing. Genetic abnormality contribution to variance in these same models decreased from 41% in 1-year to about 25% at 3-year, and then to not significant in the 5-year assessments. Heart lesion type was found to be not significant in predicting outcomes in these models. Conclusion and Relevance A dysmaturation pattern of reduced postnatal trajectories of subcortical-cerebral white matter MRI metrics predicted poor early childhood neurodevelopmental outcomes, despite the high relative contribution of maternal IQ. Maternal IQ was cumulative over time, exceeding the influence of known innate cardiac and genetic factors in complex CHD, underscoring the importance of both heritable factors and parent-based environmental factors. Question Do early infant brain trajectories in congenital heart disease (CHD) patients predict early childhood neurodevelopmental (ND) outcomes adjusted for known genetic abnormalities and maternal intelligence (IQ)? Findings Among infants with, reduced brainstem and white matter volumetric trajectories in children with CHD predicted language outcomes at five years, adjusting for maternal IQ and known genetic abnormalities. At the same time, known genetic abnormalities exerted a maximum effect at 1-year relative to 5-year neurodevelopmental testing. Maternal IQ was the most substantial contributor to ND outcome variance, nearly doubling from 1-year relative to 5-year time points. Meaning Postnatal infant brain trajectories may aid in the prognostication of early childhood neurodevelopment outcomes in complex CHD. The influence of maternal IQ is cumulative and can exceed the influence of known innate cardiac and genetic factors in complex CHD, underscoring the importance of not only heritable factors but also parent-based environmental factors. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Funding was provided by the National Heart, Lung, and Blood Institute (R01 HL152740-1, R01 HL128818-05). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study protocol, including all clinical data collection, acquisition of MRI data under sedation, and neurodevelopmental outcomes testing of subjects and maternal IQ testing was approved by the Baylor College of Medicine Institutional Review Board, and written informed parental consent was obtained. Written informed consent was obtained from a parent under Baylor College of Medicine IRB Protocols H-18531 and H-17115. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.