Abnormal brain development in newborns with congenital heart disease
Open accessAbstract
BACKGROUND: Congenital heart disease in newborns is associated with global impairment in development. We characterized brain metabolism and microstructure, as measures of brain maturation, in newborns with congenital heart disease before they underwent heart surgery. METHODS: We studied 41 term newborns with congenital heart disease--29 who had transposition of the great arteries and 12 who had single-ventricle physiology--with the use of magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and diffusion tensor imaging (DTI) before cardiac surgery. We calculated the ratio of N-acetylaspartate to choline (which increases with brain maturation), the ratio of lactate to choline (which decreases with maturation), average diffusivity (which decreases with maturation), and fractional anisotropy of white-matter tracts (which increases with maturation). We compared these findings with those in 16 control newborns of a similar gestational age. RESULTS: As compared with control newborns, those with congenital heart disease had a decrease of 10% in the ratio of N-acetylaspartate to choline (P=0.003), an increase of 28% in the ratio of lactate to choline (P=0.08), an increase of 4% in average diffusivity (P<0.001), and a decrease of 12% in white-matter fractional anisotropy (P<0.001). Preoperative brain injury, as seen on MRI, was not significantly associated with findings on MRS or DTI. White-matter injury was observed in 13 newborns with congenital heart disease (32%) and in no control newborns. CONCLUSIONS: Term newborns with congenital heart disease have widespread brain abnormalities before they undergo cardiac surgery. The imaging findings in such newborns are similar to those in premature newborns and may reflect abnormal brain development in utero.
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Reductions in brain volumetric growth, cortical folding, and microstructural white matter maturation are well recognized in this high-risk population.
“Additionally, reductions in brain volumetric growth, cortical folding, and microstructural white matter maturation are well recognized in this high-risk population.7,8”
From Perioperative neonatal brain injury is associated with worse school-age neurodevelopment in children with critical congenital heart disease (2018) · cites this paper as [7]
The Results passage in our copy (indexed under Abstract; page not supplied) reports lower white-matter fractional anisotropy in newborns with congenital heart disease, supporting reduced microstructural white-matter maturation. The paper does not report reductions in brain volumetric growth or cortical folding in this population; a reference to cortical gyration concerns a separate study of premature newborns. (LLM, conf=0.87)
Experimental — accuracy not yet measuredFetuses with CHDs benefit from intra-uterine growth, including a possible beneficial effect of growth on brain maturation.
“This association is likely due to the fact that fetuses with CHDs benefit from intra-uterine growth, including a possible beneficial effect of growth on brain maturation [28–30].”
From Early Evaluation and the Effect of Socioeconomic Factors on Neurodevelopment in Infants with Tetralogy of Fallot. (2021) · cites this paper as [30]
The paper describes brain maturation with advancing maturity (Introduction, page not available) and discusses brain development in utero in fetuses with congenital heart disease (Discussion, page not available). It does not show that intrauterine growth benefits these fetuses or improves their brain maturation; the Discussion instead reports evidence of impaired prenatal brain development. (LLM, conf=0.74)
Experimental — accuracy not yet measuredA high prevalence of anatomic and functional neurologic abnormalities has been documented before surgery in newborns with congenital heart disease, and such abnormalities are associated with childhood developmental status.
“Reports from a number of investigators have documented a high prevalence of anatomic and functional neurologic abnormalities prior to surgery in newborns with CHD [9-17], and an association of such abnormalities with childhood developmental status [11,13,18,19].”
From Brain Volume and Metabolism in Fetuses With Congenital Heart Disease: Evaluation With Quantitative Magnetic Resonance Imaging and Spectroscopy (2010) · cites this paper as [15]
Adverse neurodevelopmental outcomes in children with complex congenital heart disease are due not only to perioperative insult but also to inborn factors.
“However, there is increasing evidence that adverse neurodevelopmental outcomes in children with complex CHD are due not only perioperative insult, but to inborn factors as well.”
From Brain Volume and Metabolism in Fetuses With Congenital Heart Disease: Evaluation With Quantitative Magnetic Resonance Imaging and Spectroscopy (2010) · cites this paper as [15]
Cerebral lactate is a marker of anaerobic metabolism in the newborn and fetus, has been found in up to 50% of preoperative infants with congenital heart disease, and is associated with adverse outcome in other high-risk infants.
“Cerebral lactate, a marker of anaerobic metabolism in the newborn and fetus [38,39], has been found in up to 50% of preoperative infants with CHD [14,15] and is associated with adverse outcome in other high-risk infants [40].”
From Brain Volume and Metabolism in Fetuses With Congenital Heart Disease: Evaluation With Quantitative Magnetic Resonance Imaging and Spectroscopy (2010) · cites this paper as [15]
Prior work has documented that peri-operative brain injury and delayed brain development are common in newborns with CHD.
“Studies have documented a high prevalence of peri-operative brain injury and delayed brain development in neonates with CHD (7–10).”
From Neonatal Brain Injury and Timing of Neurodevelopmental Assessment in Patients With Congenital Heart Disease (2018) · cites this paper as [7]
Impaired fetal brain growth in congenital heart disease results in delayed white matter development whose severity is associated with the extent of perinatal white matter injury, and white matter injury affects subsequent brain maturation.
“Impaired fetal brain growth in the setting of CHD results in delayed white matter development, the severity of which is associated with the extent of perinatal WMI, whereas WMI affects subsequent brain maturation.28,42”
From Associations Between Age at Arterial Switch Operation, Brain Growth, and Development in Infants With Transposition of the Great Arteries (2019) · cites this paper as [28]
Similar results appear in human newborns with congenital heart disease, both at autopsy and on brain imaging.
“Similar findings have been observed in human newborns with congenital heart disease (CHD) at autopsy and on brain-imaging studies.[27][28][29][30]”
From Associations Between Age at Arterial Switch Operation, Brain Growth, and Development in Infants With Transposition of the Great Arteries (2019) · cites this paper as [28]
The first diffusion MRI study of disrupted postnatal brain development in congenital heart disease found lower fractional anisotropy throughout the brain before neonatal surgery in both single ventricle pathology and transposition of the great arteries compared with healthy controls.
“The first study using dMRI to examine disrupted postnatal brain development in CHD observed that fractional anisotropy values were lower throughout the brain before neonatal surgery in both SVP and TGA when compared with healthy controls. 52”
From Neuroimaging, cardiovascular physiology, and functional outcomes in infants with congenital heart disease (2017) · cites this paper as [52]
White matter injury is described in full-term neonates with congenital heart disease with remarkably high incidence.
“White matter injury (WMI) is described in full-term neonates with CHD with remarkably high incidence.52,59,[74][75][76][77]”
From Neuroimaging, cardiovascular physiology, and functional outcomes in infants with congenital heart disease (2017) · cites this paper as [52]
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Delayed cortical gray matter development in neonates with severe congenital heart disease
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White Matter Volume Predicts Language Development in Congenital Heart Disease
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Self-citationAltered Gray Matter in Adolescents with d-Transposition of the Great Arteries
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Self-citationScoring system for periventricular leukomalacia in infants with congenital heart disease
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Late surgical treatment of tetralogy of Fallot
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“Of these time periods, the prenatal and postpartum preoperative periods are considered to carry the highest risk of brain injury (23, 24); additionally, they overlap with a critical period of cerebral development (25, 26).”
BackgroundCerebral blood flow dynamics during cardiac surgery in infants
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- Authors
- Miller, S. P., McQuillen, P. S., Hamrick, S., Xu, D., Glidden, D. V., Charlton, N., Karl, T., Azakie, A., Ferriero, D. M., Barkovich, A. J., & Vigneron, D. B.
- Affiliations
- University of British Columbia (CA)
- University of California, San Francisco (US)
- Emory University (US)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2007-11-08
- Volume
- 357
- Issue
- 19
- Pages
- 1928-1938
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2042862484
- Cited by
- 860
- References
- 48
- Citations by year
- 2026: 42 · 2025: 44 · 2024: 33 · 2023: 48 · 2022: 60 · 2021: 53 · 2020: 48 · 2019: 55 · 2018: 47 · 2017: 57 · 2016: 53 · 2015: 45 · 2014: 44 · 2013: 52 · 2012: 38
- FWCI
- 21.14
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association
- Michael Smith Health Research BC
- National Institutes of Health
- Canadian Institutes of Health Research
- National Institute of Neurological Disorders and Stroke (R01NS040117, P50NS035902)
- National Center for Research Resources (M01RR001271)
- Topics
- Health Sciences › Medicine › Epidemiology › Congenital Heart Disease Studies
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Fetal and Pediatric Neurological Disorders
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced MRI Techniques and Applications
- Keywords
- congenital heart disease, neonates, brain development, brain maturation, transposition of the great arteries, single ventricle physiology, white matter injury, fractional anisotropy, brain metabolism, cardiac surgery
- MeSH terms
- Brain, Brain Diseases, Female, Gestational Age, Heart Defects, Congenital, Heart Ventricles, Humans, Infant, Newborn, Magnetic Resonance Imaging, Male, Magnetic Resonance Spectroscopy, Prospective Studies, Transposition of Great Vessels, Case-Control Studies, Imaging, Three-Dimensional, Diffusion Magnetic Resonance Imaging
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