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Cited by 167Congenital Heart Disease StudiesFetal and Pediatric Neurological DisordersCongenital heart defects research

Association of Prenatal Diagnosis of Critical Congenital Heart Disease With Postnatal Brain Development and the Risk of Brain Injury

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Peyvandi, Shabnam, De Santiago, Veronica, Chakkarapani, Elavazhagan, Chau, Vann, Campbell, Andrew, Poskitt, Kenneth J., Xu, Duan, Barkovich, A. James +2 more·2016·JAMA Pediatrics
DOI 10.1001/jamapediatrics.2015.4450PMC PMC5083633
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Abstract

IMPORTANCE: The relationship of prenatal diagnosis of critical congenital heart disease (CHD) with brain injury and brain development is unknown. Given limited improvement of CHD outcomes with prenatal diagnosis, the effect of prenatal diagnosis on brain health may reveal additional benefits. OBJECTIVE: To compare the prevalence of preoperative and postoperative brain injury and the trajectory of brain development in neonates with prenatal vs postnatal diagnosis of CHD. DESIGN, SETTING, AND PARTICIPANTS: Cohort study of term newborns with critical CHD recruited consecutively from 2001 to 2013 at the University of California, San Francisco and the University of British Columbia. Term newborns with critical CHD were studied with brain magnetic resonance imaging preoperatively and postoperatively to determine brain injury severity and microstructural brain development with diffusion tensor imaging by measuring fractional anisotropy and the apparent diffusion coefficient. Comparisons of magnetic resonance imaging findings and clinical variables were made between prenatal and postnatal diagnosis of critical CHD. A total of 153 patients with transposition of the great arteries and single ventricle physiology were included in this analysis. MAIN OUTCOMES AND MEASURES: The presence of brain injury on the preoperative brain magnetic resonance imaging and the trajectory of postnatal brain microstructural development. RESULTS: Among 153 patients (67% male), 96 had transposition of the great arteries and 57 had single ventricle physiology. The presence of brain injury was significantly higher in patients with postnatal diagnosis of critical CHD (41 of 86 [48%]) than in those with prenatal diagnosis (16 of 67 [24%]) (P = .003). Patients with prenatal diagnosis demonstrated faster brain development in white matter fractional anisotropy (rate of increase, 2.2%; 95% CI, 0.1%-4.2%; P = .04) and gray matter apparent diffusion coefficient (rate of decrease, 0.6%; 95% CI, 0.1%-1.2%; P = .02). Patients with prenatal diagnosis had lower birth weight (mean, 3184.5 g; 95% CI, 3050.3-3318.6) than those with postnatal diagnosis (mean, 3397.6 g; 95% CI, 3277.6-3517.6) (P = .02). Those with prenatal diagnosis had an earlier estimated gestational age at delivery (mean, 38.6 weeks; 95% CI, 38.2-38.9) than those with postnatal diagnosis (mean, 39.1 weeks; 95% CI, 38.8-39.5) (P = .03). CONCLUSIONS AND RELEVANCE: Newborns with prenatal diagnosis of single ventricle physiology and transposition of the great arteries demonstrate less preoperative brain injury and more robust microstructural brain development than those with postnatal diagnosis. These results are likely secondary to improved cardiovascular stability. The impact of these findings on neurodevelopmental outcomes warrants further study.

Integrity signals

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Crossref · 10.1001/jamapediatrics.2015.4450

Cites

47 of 47 references verified0 citation errors · 0 not checkable

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Claims the paper makes

0 of 51 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    The postnatally diagnosed TGA group had low preoperative oxygen saturation (mean 58.3%).

    “However, the group with postnatally diagnosed TGA appeared to have low preoperative oxygen saturation (mean, 58.3%).”
    Quote in the paperNot a substantial claim
  • Findingown data

    The rate of decrease in white matter ADC did not differ significantly between the prenatal and postnatal diagnosis groups (0.3%; 95% CI, -0.7% to 1.2%; P = .55).

    “The rate of decrease in ADC in white matter was not significantly different between the groups (0.3%; 95% CI, −0.7% to 1.2%; P = .55).”
    Quote in the paperNot a substantial claim
  • Findingown data

    There was a trend toward earlier operation in the prenatal group.

    “However, there was also a trend toward an earlier operation in the prenatal group.”
    Quote in the paperSubstantial claim
  • Findingown data

    The study found a 50% (gray matter) to 70% (white matter) increase in the rate of brain development in prenatally diagnosed patients from preoperative to postoperative imaging.

    “Specifically, there was a 50% (gray matter voxels) to 70%(white matter voxels) increase in the rate of brain development in patients with prenatal diagnosis in this very short period from preoperative to postoperative imaging.”
    Quote in the paperSubstantial claim
  • Findingown data

    Prenatally diagnosed patients had lower birth weight than postnatally diagnosed patients (mean 3184.5 g vs 3397.6 g; P = .02).

    “Patients with prenatal diagnosis had lower birth weight (mean, 3184.5 g; 95%CI, 3050.3–3318.6) than those with postnatal diagnosis (mean, 3397.6 g; 95%CI, 3277.6–3517.6) (P = .02).”
    • Also stated in: § Results · plain
      “and had a lower birth weight (prenatal: mean 3184.5 g; 95% CI, 3050.3–3318.6; postnatal: 3397.6g; 95% CI, 3277.6–3517.6; P = .02)”
    Quote in the paperNot a substantial claim
  • The quote only partly states this claim. 1
  • May combine two claims. 19
  • Classified as probably not a substantial claim. 13

  • The quote only partly states this claim.

    Findingown data

    In a subanalysis of SVP patients excluding those with pulmonary outflow tract obstruction, the same pattern of lower preoperative brain injury with prenatal diagnosis was observed.

    “A subanalysis of patients with SVP excluding those with pulmonary outflow tract obstruction revealed the same pattern.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Analysis by specific lesion (TGA and SVP) showed identical trends but no meaningful differences by prenatal diagnosis because of smaller sample size.

    “Analysis of the data by specific lesion (TGA and SVP) demonstrated identical trends but no meaningful differences by prenatal diagnosis as a result of smaller sample size.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The cohort comprised 153 infants, 96 with TGA and 57 with SVP, and 67% were male.

    “Among 153 patients (67% male), 96 had transposition of the great arteries and 57 had single ventricle physiology.”
    • Also stated in: § Results · plain
      “A total of 153 infants were included in the study, 96 with TGA and 57 with SVP, with a slight male predominance (67%).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The lower preoperative brain injury prevalence in prenatally diagnosed patients remained true among patients with TGA and among those with SVP.

    “This remained true among patients with TGA and SVP.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The postnatally diagnosed SVP group had low preoperative pH (mean 7.22), low base excess (mean -7.0 mEq/L), and 3 cases of cardiac arrest.

    “Similarly, the group with postnatally diagnosed SVP appeared to have low preoperative pH (mean, 7.22), low base excess (mean, −7.0 mEq/L [to convert to millimoles per liter, multiply by 1.0]), and 3 cases of cardiac arrest.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Among the 86 patients with postnatal diagnosis, 80 (93%) were born at hospitals outside the study centers.

    “Among the 86 patients with postnatal diagnosis, 80(93%) were born at hospitals outside the study centers.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    No adverse events occurred during the MRI protocol.

    “No adverse events occurred during this protocol.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The earlier MRI and earlier operation support the hypothesis that prenatally diagnosed patients are healthier, have less preoperative brain injury, and are better candidates for earlier operation.

    “Although this may influence our findings, the earlier MRI and earlier operation support our hypothesis that patients with prenatal diagnosis are “healthier,” thus having less preoperative brain injury, and are better candidates for an earlier operation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    In this cohort, the postnatal diagnosis group had low preoperative oxygen saturations, which may explain the increased brain injury in that group.

    “In our cohort, the postnatal diagnosis group had low preoperative oxygen saturations, thus explaining the possible mechanism behind increased brain injury in the postnatal group”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Patients with a prenatal diagnosis appear healthier in the preoperative period, likely due to early initiation of prostaglandin E1.

    “Patients with a prenatal diagnosis appear to be healthier in the preoperative period, likely secondary to the early initiation of prostaglandin E1, as seen in prior studies.7,9”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [7]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [9]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Early studies of prenatal diagnosis found no benefits in long-term neurodevelopmental outcome, a finding potentially explained by early preterm delivery and higher rates of preoperative intensive care therapies.

    “Similarly, early studies of prenatal diagnosis found no benefits in long-term neurodevelopmental outcome, a finding potentially explained by early preterm delivery and higher rates of preoperative intensive care therapies.39”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

    Premisecitation

    Multiple studies have demonstrated that newborns with complex CHD have immature brains, using techniques including semiquantitative morphologic scoring and quantitative MRI measures.

    “Multiple studies have demonstrated that newborns with complex CHD have immature brains, using a wide range of techniques including semiquantitative morphologic scoring (ie, total maturation score)18 and quantitative magnetic resonance measures such as diffusion tensor imaging and magnetic resonance spectroscopy.17”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [18]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [17]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Initial studies of prenatal diagnosis have not shown improved surgical outcomes and have even been associated with worse survival.

    “Despite these apparent benefits, initial studies of prenatal diagnosis have not shown improved surgical outcomes and have even been associated with worse survival.12”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

    Study design and conductnone given

    Clinical data were prospectively collected by trained neonatal research nurses and reviewed by a pediatric intensivist blinded to all neuroimaging findings.

    “Clinical data were prospectively collected from the medical records by a team of trained neonatal research nurses and reviewed by a pediatric intensivist (P.M.) blinded to all neuroimaging findings.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    The diffusion analyses included an interaction term for site by region of interest.

    “an interaction term for site (UCSF or UBC) by region of interest was included in all analyses of MRI diffusion data.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Lower preoperative oxygen saturation and longer time to surgery have been identified as risk factors for white matter injury or periventricular leukomalacia.

    “Lower preoperative oxygen saturation and longer time to surgery have been identified as risk factors for WMI or periventricular leukomalacia.26”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Correct region of interest placements were confirmed by neuroradiologists at each site.

    “Correct region of interest placements were confirmed by neuroradiologists at each site (A.J.B. and K.J.P.).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    The study adjusted for center and gestational age at MRI in the diffusion analyses.

    “In these models, we adjusted for center (UCSF or UBC) and gestational age at MRI.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Fetal brain imaging studies show that delayed brain development begins in the third trimester, coincident with rapid increases in brain blood flow as a percentage of total cardiac output.

    “Fetal brain imaging studies show that delayed brain development begins in the third trimester, coincident with rapid increases in brain blood flow as a percentage of total cardiac output that occur normally to support increases in brain electrical activity.25”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Prenatal diagnosis often leads to earlier gestational age at birth and lower birth weight.

    “In addition, prenatal diagnosis often leads to earlier gestational age at birth and lower birth weight,9”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    Generalized estimating equations with a robust variance estimator were used to account for within-patient correlation.

    “Generalized estimating equations with a robust variance estimator were used to account for within-patient correlation.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Study methods, including brain imaging, were consistent across the duration of the study.

    “Study methods, including brain imaging, were consistent across the duration of the study”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    With increasing microstructural brain development, the magnitude of water diffusion motion decreases (ADC) and the regional directionality of water motion increases (FA).

    “With increasing microstructural brain development, the magnitude of water diffusion motion decreases (apparent diffusion coefficient [ADC]) and the regional directionality of water motion increases (fractional anisotropy [FA]).22”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Prenatal detection of critical CHD has been shown to improve the perioperative clinical condition of neonates, with preserved preoperative hemodynamics and fewer life-threatening events for ductal-dependent lesions such as TGA and hypoplastic left heart syndrome.

    “Prenatal detection of critical CHD has been shown to improve the perioperative clinical condition of these neonates, with preserved preoperative hemodynamics and fewer life-threatening events for ductal-dependent lesions such as transposition of the great arteries (TGA) and hypoplastic left heart syndrome.7–11”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [7]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [8]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [9]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [10]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [11]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

    Study design and conductnone given

    Institutional committees on human research at both UCSF and UBC approved the study protocol.

    “Institutional committees on human research at both UCSF and UBC approved the study protocol.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Earlier gestational age at birth and lower birth weight are associated with poor clinical outcomes such as mortality and increased length of stay for neonates with critical CHD.

    “both associated with poor clinical outcomes such as mortality and an increased length of stay for neonates with critical CHD.13”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

    Premisecitation

    In a prior study, no association was found between preoperative brain maturity and newly acquired postoperative brain injury.

    “In a prior study, no association was found between preoperative brain maturity and newly acquired postoperative brain injury.19”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Reduced cerebral oxygenation and impaired brain growth were observed in fetuses with CHD using novel in utero MRI approaches.

    “More recently, reduced cerebral oxygenation and impaired brain growth were observed in fetuses with CHD using novel in utero MRI approaches.31”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Multiple studies have shown that acquired brain injury is common in neonates prior to corrective surgery and is related to clinical risk factors similar to those influenced by prenatal diagnosis.

    “Multiple studies have shown that acquired brain injury is common in neonates prior to corrective surgery14 and is related to a set of clinical risk factors similar to those influenced by prenatal diagnosis.15”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [14]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [15]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

29 of 29

  • The paper relies on this without support.

    Before this study, the association between prenatal diagnosis of critical congenital heart disease and postnatal brain injury or brain maturation had not been established.

    “The relationship of prenatal diagnosis of critical congenital heart disease (CHD) with brain injury and brain development is unknown.”

  • The paper relies on this without support.

    No prior study had demonstrated improved brain development with prenatal diagnosis in a large, well-characterized cohort across two centers.

    “however, this is the first report, to our knowledge, demonstrating improved brain development with prenatal diagnosis in a large cohort of well-characterized patients across 2 centers.”
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?

  • Antenatal diagnosis has been associated with reduced brain injury and more advanced microstructural and metabolic brain maturation across the pre- and postoperative periods in infants with congenital heart disease, including transposition of the great arteries.

    “Antenatal diagnosis has been associated with reduced brain injury and more advanced microstructural and metabolic brain maturation across the pre-and postoperative periods in infants with CHD, including those with TGA. 8”

    From Antenatal diagnosis, neonatal brain volumes, and neurodevelopment in transposition of the great arteries (2024) · cites this paper as [8]

    Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • Infants with antenatal diagnosis of CHD, including those with TGA, had faster microstructural white matter and grey matter maturation between pre- and postoperative MRIs compared with infants with postnatal diagnosis.

    “we previously observed that infants with antenatal diagnosis of CHD, including those with TGA, had faster microstructural white matter and grey matter maturation between pre-and postoperative MRIs compared with infants with postnatal diagnosis.8”

    From Antenatal diagnosis, neonatal brain volumes, and neurodevelopment in transposition of the great arteries (2024) · cites this paper as [8]

  • Antenatal diagnosis has been associated with a reduced risk of preoperative brain injury in infants with CHD, which may have been related to more favourable preoperative clinical characteristics including higher oxygen saturations in the subset of infants with TGA diagnosed antenatally.

    “Antenatal diagnosis has also been associated with a reduced risk of preoperative brain injury in infants with CHD, which may have been related to more favourable preoperative clinical characteristics including higher oxygen saturations in the subset of infants with TGA diagnosed antenatally.8”

    From Antenatal diagnosis, neonatal brain volumes, and neurodevelopment in transposition of the great arteries (2024) · cites this paper as [8]

  • White matter injury was evaluated using a previously described grading system.

    “white matter injury (WMI) was evaluated based on the size and number of focal white matter lesions according to our previously described grading.18”

    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 [18]

  • Brain microstructure is less disrupted in cases with a prenatal diagnosis, possibly because of earlier use of prostaglandin E1 to maintain the ductus arteriosus.

    “In contrast, brain microstructure is less disrupted in those cases with a prenatal diagnosis, which may result from earlier use of prostaglandin E1 (to maintain the ductus arteriosus).59”

    From Neuroimaging, cardiovascular physiology, and functional outcomes in infants with congenital heart disease (2017) · cites this paper as [59]

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Authors
Peyvandi, S., De Santiago, V., Chakkarapani, E., Chau, V., Campbell, A., Poskitt, K. J., Xu, D., Barkovich, A. J., Miller, S., & McQuillen, P.
Affiliations
  • University of California, San Francisco (US)
  • Department of Pediatrics, University of California, San Francisco, Benioff Children’s Hospital, San Francisco
  • School of Clinical Sciences, University of Bristol and St Michael’s Hospital, Bristol, England3Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada
  • University of Toronto (CA)
  • University of British Columbia (CA)
Corresponding author
Peyvandi, Shabnam
Venue
JAMA Pediatrics
Publisher
American Medical Association (AMA)
Published
2016-04-04
Volume
170
Issue
4
Pages
e154450
ISSN
  • 1072-4710 (ISSN-L)
  • 2168-6203
DOI
10.1001/jamapediatrics.2015.4450
PMC
PMC5083633
OpenAlex
W2288039448
Cited by
167
References
47
Citations by year
2026: 12 · 2025: 19 · 2024: 19 · 2023: 24 · 2022: 18 · 2021: 12 · 2020: 18 · 2019: 11 · 2018: 15 · 2017: 14 · 2016: 4
FWCI
9.94
Type
journal article
Language
en
Open access
Locations
  • Archives of Pediatrics and Adolescent Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • Explore Bristol Research (submittedVersion, other-oa)
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
critical congenital heart disease, prenatal diagnosis, postnatal diagnosis, neonatal brain injury, brain development, transposition of the great arteries, single ventricle, fractional anisotropy
MeSH terms
Brain, Brain Injuries, Female, Heart Defects, Congenital, Humans, Infant, Newborn

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