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Cited by 663Congenital Heart Disease StudiesFetal and Pediatric Neurological DisordersCongenital heart defects research

Brain Volume and Metabolism in Fetuses With Congenital Heart Disease: Evaluation With Quantitative Magnetic Resonance Imaging and Spectroscopy

Open access
Limperopoulos, Catherine, Tworetzky, Wayne, McElhinney, Doff B., Newburger, Jane W., Brown, David W., Robertson, Richard L., Guizard, Nicolas, McGrath, Ellen +6 more·2010·Circulation
DOI 10.1161/circulationaha.109.865568PMC PMC2819908
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Abstract

BACKGROUND: Adverse neurodevelopmental outcome is an important source of morbidity in children with congenital heart disease (CHD). A significant proportion of newborns with complex CHD have abnormalities of brain size, structure, or function, which suggests that antenatal factors may contribute to childhood neurodevelopmental morbidity. METHODS AND RESULTS: Brain volume and metabolism were compared prospectively between 55 fetuses with CHD and 50 normal fetuses with the use of 3-dimensinal volumetric magnetic resonance imaging and proton magnetic resonance spectroscopy. Fetal intracranial cavity volume, cerebrospinal fluid volume, and total brain volume were measured by manual segmentation. Proton magnetic resonance spectroscopy was used to measure the cerebral N-acetyl aspartate: choline ratio (NAA:choline) and identify cerebral lactate. Complete fetal echocardiograms were performed. Gestational age at magnetic resonance imaging ranged from 25 1/7 to 37 1/7 weeks (median, 30 weeks). During the third trimester, there were progressive and significant declines in gestational age-adjusted total brain volume and intracranial cavity volume in CHD fetuses relative to controls. NAA:choline increased progressively over the third trimester in normal fetuses, but the rate of rise was significantly slower (P<0.001) in CHD fetuses. On multivariable analysis adjusted for gestational age and weight percentile, cardiac diagnosis and percentage of combined ventricular output through the aortic valve were independently associated with total brain volume. Independent predictors of lower NAA:choline included diagnosis, absence of antegrade aortic arch flow, and evidence of cerebral lactate (P<0.001). CONCLUSIONS: Third-trimester fetuses with some forms of CHD have smaller gestational age- and weight-adjusted total brain volumes than normal fetuses and evidence of impaired neuroaxonal development and metabolism. Hemodynamic factors may play an important role in this abnormal development.

Integrity signals

Registry

Crossref · 10.1161/circulationaha.109.865568

Cites

41 of 41 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 30 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    No control fetus had detectable cerebral lactate.

    “No control fetuses had detectable cerebral lactate.”
    Quote in the paperSubstantial claim
  • Findingown data

    Cerebral lactate was detected in 7 of 36 (20%) fetuses with congenital heart disease (5 with hypoplastic left heart syndrome and 2 with transposition of the great arteries) between 29 3/7 and 35 5/7 weeks of gestation.

    “Cerebral lactate was detected in 7 of 36 (20%) fetuses with CHD (5 with HLHS, 2 with TGA) between 29 3/7 and 35 5/7 weeks GA.”
    Quote in the paperSubstantial claim
  • Findingown data

    In a multivariable model adjusted for gestational age and total brain volume, the presence of cerebral lactate was an independent predictor of lower cerebral N-acetyl aspartate:choline ratio (p<0.001; model R2=0.90).

    “On multivariable analysis adjusting for both GA and TBV (a stronger correlate of NAA:Cho than GA), independent predictors of lower NAA:Cho included diagnostic category (HLHS, TGA or pulmonary atresia, other CHD or control; p<0.001), absence of antegrade flow in the aortic arch (p=0.01), and the presence of lactate (p<0.001) (model R2=0.90).”
    • Also stated in: § Methods and Results · plain
      “Independent predictors of lower NAA:Cho included diagnosis, absence of antegrade aortic arch flow, and evidence of cerebral lactate (p<0.001).”
    Quote in the paperSubstantial claim
  • Findingown data

    There was no clear difference in total brain volume between the six fetuses with congenital heart disease and mild abnormalities on conventional MRI and those without such abnormalities.

    “There was no clear difference in TBV between the 6 CHD fetuses with mild abnormalities on conventional MRI and those without.”
    Quote in the paperNot a substantial claim
  • Findingown data

    In a multivariable model adjusted for gestational age and weight percentile, cardiac diagnostic category was independently associated with smaller total brain volume (p<0.001; model R2=0.94).

    “In a multivariable model adjusted for GA and weight percentile, a lower percentage of combined ventricular output from the aorta (p<0.001) and diagnostic category (p<0.001) were independently associated with smaller TBV (model R2=0.94).”
    • Also stated in: § Methods and Results · plain
      “On multivariable analysis adjusting for GA and weight percentile, cardiac diagnosis and percentage of combined ventricular output through the aortic valve were independently associated with TBV.”
    Quote in the paperSubstantial claim
  • May combine two claims. 17
  • Borderline: one of the tests for a substantial claim is unclear. 1
  • Classified as probably not a substantial claim. 8

  • May combine two claims.

    Findingown data

    At 25 weeks of gestation, total brain volume and intracranial cavity volume did not differ between fetuses with congenital heart disease and controls.

    “At 25 weeks gestation, TBV and ICV were similar in CHD fetuses and controls (i.e., the 25-week Y-intercept of the control and CHD regression equations did not differ).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The choline:creatine ratio generally declined over gestation in both control and congenital heart disease fetuses, with relatively weak correlation with gestational age in both groups (quadratic R2=0.47 and R2=0.23 respectively).

    “Cho:Cr generally declined over gestation in control (quadratic R2=0.47) and CHD (R2=0.23) fetuses, with relatively weak correlation with GA in both groups.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In control fetuses, cerebrospinal fluid volume and the proportion of intracranial cavity volume occupied by cerebrospinal fluid decreased with increasing gestational age (R2=0.80 and 0.93 respectively, p<0.001).

    “CSF (R2=0.80, p<0.001) and the proportion of ICV occupied by CSF (CSF:ICV, R2=0.93, p<0.001) decreased with increasing GA (Figure 4).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    There was no difference in the choline:creatine ratio between fetuses with congenital heart disease and controls, and no predictors of choline:creatine were identified.

    “There was no difference in Cho:Cr between cases and controls, and no predictors of Cho:Cr were identified.”
    Quote in the paperNot a substantial claim

  • Borderline on S1 (asserted), S3 (load-bearing), S4 (based): unclear from the text.

    Study design and conductnone given

    Complete volumetric MRI analysis was possible in all 105 fetuses.

    “Complete volumetric MRI analysis was possible in all 105 fetuses.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Brain volume and metabolism are abnormal in third-trimester fetuses with some forms of complex congenital heart disease, with smaller gestational-age- and weight-adjusted total brain volume and evidence of impaired neuroaxonal development and metabolism.

    “Third-trimester fetuses with some forms of CHD have smaller GA- and weight-adjusted TBV than normal fetuses, and evidence of impaired neuroaxonal development and metabolism.”
    • Also stated in: § Conclusions · plain
      “Brain volume and metabolism are abnormal in third-trimester fetuses with some forms of complex CHD, particularly those with HLHS or TGA, and reduced flow through the systemic ventricle or antegrade around the aortic arch.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    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.”
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    Premisecitation

    A 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].”
    Quote in the paperSubstantial claim0 of 10 sources checked
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  • May combine two claims.

    Premisecitation

    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].”
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  • May combine two claims.

    Premisecitation

    N-acetyl aspartate increases with gestational age and decreases with brain injury, and reflects the development of dendrites and synapses as well as oligodendrocyte proliferation and differentiation.

    “NAA increases with GA and decreases with brain injury [24], and reflects not only the development of dendrites and synapses but also oligodendrocyte proliferation and differentiation [36].”
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  • May combine two claims.

    Study design and conductown data

    Serial fetal brain volumes were not measured, so growth could not truly be assessed.

    “Finally, we did not measure serial fetal brain volumes and therefore could not truly assess growth.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    Intra-observer correlation coefficients for volumetric measurements were at least 0.997 on individual slices and 0.95-0.98 for summed volumes.

    “Intra-observer correlation coefficients were determined for measurements of ICV (n=481), TBV (n=458), and CSF (n=481) on all individual slices from 10 MRI studies, and were ≥0.997 in all cases.”
    • Also stated in: § Fetal Brain MRI · plain
      “Intra-observer correlation coefficients were also determined for the summed volumes ICV, TBV, and CSF from 15 MRI scans, and were 0.98 for ICV, 0.96 for TBV, and 0.95 for CSF.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Study design and conductreasoning

    Undiagnosed or unknown genetic conditions may have been missed and may be more common in subjects with congenital heart disease than in controls, potentially introducing bias.

    “Although we attempted to exclude fetuses with genetic and/or cerebral dysgenetic conditions, undiagnosed or as yet unknown genetic conditions may have been missed. Such anomalies may be more common in subjects with CHD than in controls, potentially introducing bias.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductreasoning

    Because MRI in control fetuses was typically performed later in gestation than echocardiography, echocardiographic data were not used as predictor variables in analyses including controls, though adjustment used weight percentiles from ultrasound estimates.

    “Because MRI studies in control fetuses were typically obtained later in gestation than echocardiograms, echocardiographic data were not included as predictor variables in analyses that included control fetuses, although adjustment was performed using weight percentiles derived from ultrasound estimates of fetal weight.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    All volumetric measurements were made by a single operator who was blinded to clinical data.

    “All measurements were made by a single operator (CL) who was blinded to clinical data.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    Choline:creatine and N-acetyl aspartate:choline ratios were calculated only when MR spectra met a reliable fit criterion of standard deviation below 20% for each metabolite.

    “Cho:Cr and NAA:Cho ratios were calculated when MR spectra satisfied a reliable fit with a standard deviation <20% for each metabolite [27].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Of 116 enrolled fetuses, 11 were excluded (8 for inadequate MRI data from excessive fetal motion, 2 for brain dysgenesis, 1 for maternal claustrophobia), leaving 105 fetuses in the analysis.

    “A total of 116 fetuses were enrolled, but 11 were excluded due to excessive fetal motion resulting in inadequate MRI data (n=8), brain dysgenesis (inferior vermian hypoplasia) detected by fetal MRI (n=2, both with CHD), and maternal claustrophobia preventing completion of the MRI (n=1).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Written informed consent was obtained from mothers according to a protocol approved by the institutional committee for clinical investigation.

    “Written informed consent from mothers was obtained according to a protocol approved by the Children's Hospital Committee for Clinical Investigation.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Fetal MRI studies were analyzed by an attending neuroradiologist who was blinded to all clinical data.

    “Fetal MRI studies were analyzed by an attending neuroradiologist (RLR) who was blinded to all clinical data.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductreasoning

    The interval between fetal MRI and echocardiography differed between control and congenital heart disease groups, so cardiovascular parameters could not be compared between the groups.

    “The temporal relationship between fetal MRI and echocardiograms differed between control and CHD groups; therefore, comparison of cardiovascular parameters was not possible between these groups.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    1H-MRS spectra were successfully obtained in 75 fetuses, 36 with congenital heart disease (72%) and 39 controls (71%).

    “1H-MRS spectra were successfully obtained in 75 fetuses, 36 with CHD (72%) and 39 controls (71%).”
    Quote in the paperSubstantial claim
21 of 21

  • The authors state this as an assumption.

    Circulatory abnormalities in fetuses with complex congenital heart disease such as hypoplastic left heart syndrome, transposition of the great arteries and pulmonary atresia place them at risk of inadequate delivery of oxygen and metabolic substrate to the developing brain, slowing brain growth and impairing cortical organization and myelination.

    “The basis for this hypothesis was the assumption that circulatory abnormalities in fetuses with these anomalies would place them at risk for inadequate delivery of oxygen and metabolic substrate to the developing brain, slowing normal brain growth and impairing cortical organization and myelination.”

  • The paper relies on this without support.

    The content of oxygen and glucose in cerebral arterial blood is abnormal in fetuses with some forms of complex congenital heart disease.

    “Thus, in theory, the content of oxygen and glucose in cerebral arterial blood is likely to be abnormal in fetuses with some forms of complex CHD, although there are no data of which we are aware to support this speculation.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • In fetuses and neonates with critical CHD, chronically decreased oxygen and nutrient delivery disturbs optimal cerebral development, resulting in slower brain growth with delayed maturation when compared with healthy controls.

    “In fetuses and neonates with critical CHD, chronically decreased oxygen and nutrient delivery disturbs optimal cerebral development, resulting in slower brain growth with delayed maturation when compared with healthy controls.9,10”

    From Perioperative neonatal brain injury is associated with worse school-age neurodevelopment in children with critical congenital heart disease (2018) · cites this paper as [9]

    The Discussion reports smaller brain volumes and lower NAA:Cho, a marker of maturation, in third-trimester fetuses with CHD compared with normal controls. It describes reduced oxygen or glucose delivery as a hypothesis that could not be tested, not an established cause. The paper also discusses neonatal abnormalities, but its reported comparison with controls is in fetuses. (LLM, conf=0.89)

    Experimental — accuracy not yet measured

  • Metabolic alterations in the in utero fetal brain precede morphologic brain changes.

    “Metabolic alterations in the in utero fetal brain have been shown to precede morphologic brain changes [104]”

    From Brain structural and functional outcomes in the offspring of women experiencing psychological distress during pregnancy (2024) · cites this paper as [104]

    The Results and Discussion report altered cerebral metabolism and smaller brain volumes in fetuses with congenital heart disease during the third trimester. But the Discussion explicitly describes the MRI and spectroscopy measurements as cross-sectional; it does not establish that metabolic changes preceded morphologic changes. No page numbers were provided in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Studies have reported that PDMS detects deficits in motor functioning in 42% of young children with repaired CHD.

    “Studies have reported that the PDMS detects deficits in motor functioning in 42% of young children with repaired CHD; however, the utility of early administration of the PDMS during infancy has not been reported [24].”

    From Early Evaluation and the Effect of Socioeconomic Factors on Neurodevelopment in Infants with Tetralogy of Fallot. (2021) · cites this paper as [24]

    The Methods and Results describe fetal MRI and spectroscopy, not PDMS testing in young children after CHD repair. Searches for PDMS, the Peabody Developmental Motor Scales, and the 42% figure found no passage addressing the claimed motor-deficit rate. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

  • The utility of early administration of the PDMS during infancy has not been reported.

    “Studies have reported that the PDMS detects deficits in motor functioning in 42% of young children with repaired CHD; however, the utility of early administration of the PDMS during infancy has not been reported [24].”

    From Early Evaluation and the Effect of Socioeconomic Factors on Neurodevelopment in Infants with Tetralogy of Fallot. (2021) · cites this paper as [24]

    The Methods and Results describe fetal MRI and spectroscopy, not administration of the PDMS to infants. The Introduction discusses developmental difficulties in children with CHD, but does not address whether early PDMS administration has been reported. Searches for PDMS, infancy, and the cited 42% motor-deficit figure found no passage establishing the claim; page numbers were not provided. (LLM, conf=0.77)

    Experimental — accuracy not yet measured

  • In the fetal phase, reduced flow through the systemic ventricle is associated with smaller total brain volume.

    “In the fetal phase, reduced flow through the systemic ventricle (measured with echocardiography) is associated with smaller total volume of the brain.37”

    From Neuroimaging, cardiovascular physiology, and functional outcomes in infants with congenital heart disease (2017) · cites this paper as [37]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • CHD and control group sizes are reversed in the abstract

    Major

    The abstract reports 55 fetuses with CHD and 50 controls, whereas the Results section reports 50 with CHD and 55 controls. The spectroscopy counts and percentages also align with the Results section's group sizes.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Guizard N Lepag C Fonov V Hakyemez H Evans A Limperopoulos C. Development of a fetal brain atlas from multi-axial MR acquisitions. In: Proceedings of the 16th Scientific Meeting International Society for Magnetic Resonance in Medicine; May 3–9 2008; Toronto Ontario Canada. Abstract 672.

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Authors
Limperopoulos, C., Tworetzky, W., McElhinney, D. B., Newburger, J. W., Brown, D. W., Robertson, R. L., Guizard, N., McGrath, E., Geva, J., Annese, D., Dunbar-Masterson, C., Trainor, B., Laussen, P. C., & du Plessis, A. J.
Affiliations
  • McGill University (CA)
  • From the Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada (C.L., N.G.); and Fetal-Neonatal Neurology Research Group, Department of Neurology (C.L., A.J.d.P.), and Departments of Cardiology and Pediatrics (W.T., D.B.M., J.W.N., D.W.B., E.M., J.G., D.A., C.D.-M., B.T.), Radiology (R.L.R.), and Cardiology and Anaesthesia (P.C.L.), Children’s Hospital Boston and Harvard Medical School, Boston, Mass.
ORCID
Venue
Circulation
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2010-01-05
Volume
121
Issue
1
Pages
26-33
ISSN
  • 0009-7322 (ISSN-L)
  • 1524-4539
DOI
10.1161/circulationaha.109.865568
PMC
PMC2819908
OpenAlex
W2068174282
Cited by
663
References
41
Citations by year
2026: 37 · 2025: 50 · 2024: 38 · 2023: 37 · 2022: 49 · 2021: 55 · 2020: 48 · 2019: 49 · 2018: 43 · 2017: 42 · 2016: 49 · 2015: 35 · 2014: 26 · 2013: 31 · 2012: 22
FWCI
16.34
Type
journal article
Language
en
Open access
Locations
  • Circulation (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • American Heart Association
  • Canadian Institutes of Health Research (81116_1)
  • National Institute of Neurological Disorders and Stroke (K24NS057568)
Topics
  • Health Sciences › Medicine › Epidemiology › Congenital Heart Disease Studies
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Fetal and Pediatric Neurological Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
Keywords
congenital heart disease, fetal brain volume, fetal brain metabolism, cerebral lactate, cerebrospinal fluid volume, neurodevelopmental outcomes, fetal hemodynamics, third trimester
MeSH terms
Aspartic Acid, Brain, Choline, Female, Gestational Age, Heart Defects, Congenital, Humans, Magnetic Resonance Imaging, Magnetic Resonance Spectroscopy, Pregnancy, Prenatal Diagnosis, Prospective Studies, Protons, Lactic Acid, Imaging, Three-Dimensional

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