Fetal MRI detects early alterations of brain development in Tetralogy of Fallot

doi:10.1016/j.ajog.2015.05.046

American Journal of Obstetrics and Gynecology

Volume 213, Issue 3, September 2015, Pages 392.e1-392.e7

https://doi.org/10.1016/j.ajog.2015.05.046 Get rights and content

Objective

Prenatal imaging has identified alterations of brain growth in fetuses with congenital heart disease. However, little is known about the timing of altered brain development and its occurrence in specific congenital heart disease subgroups. This magnetic resonance imaging study aimed to identify early (median, 25 gestational weeks [GW]) changes in fetal total brain (TBV), gray matter (GMV), and subcortical brain (SBV) volumes in Tetralogy of Fallot (TOF) cases in utero.

Study Design

Fetal magnetic resonance imaging (1.5 Tesla) was performed in 24 fetuses who were diagnosed with TOF and 24 normal age-matched control fetuses (20-34 GW). TBV, GMV, SBV, intracranial cavity, cerebellar, ventricular, and external cerebrospinal fluid volumes were quantified by manual segmentation based on coronal T2-weighted sequences. Mixed model analyses of variance and t-tests were conducted to compare cases and control fetuses.

Results

TBV was significantly lower (P < .001) in early (<25 GW) and late TOF cases. Both GMV (P = .003) and SBV (P = .001) were affected. The GMV-to-SBV ratio declined in fetuses with TOF (P = .026). Compared with normal fetuses, ventricular volume was increased (P = .0048). External cerebrospinal fluid was enlarged in relation to head size (P < .001). Intracranial cavity volume (P = .314) and cerebellar volume (P = .074) were not significantly reduced in fetuses with TOF.

Conclusion

TOF is associated with smaller volumes of gray and white matter and enlarged cerebrospinal fluid spaces. These changes are present at ≤25 GW and indicate altered fetal brain growth in this pathophysiologic entity during early stages of human brain development.

Section snippets

Test subjects

A total of 58 fetal MRI datasets that were acquired between March 2004 and April 2014 were studied retrospectively. The data were obtained from pregnant women who had been informed about the procedure and the possible risks of the examination and who had given written, informed consent for a prenatal MRI study before the examination. MRI was performed at a median gestational age (GA) of 25 GW (20-34 GW).

The retrospective study was approved by the local ethics committee (registration no.

Results

Mean TBV in fetuses with TOF was significantly lower (P < .001) than in normal control fetuses, with reduced GMV (P = .003) and SBV (P = .001). TOF fetuses and normal control fetuses at ≥25 GW had larger TBV (P < .001) than those at <25 GW, with a significant increase of GMV (P < .001) and SBV (P < .001). Neither GMV (P = .056) nor SBV (P = .976) showed significant interaction between the within-subjects (group) or between-subjects (age group) variables (Figure 2, Figure 3). In contrast,

Comment

TOF fetuses showed abnormally low total brain, cortical, and subcortical volumes and enlarged CSF spaces as early as 20 GW. Altered brain development in this CHD entity originates in the early second- or, presumably, even first-trimester stages. An equally distributed reduction of GMV and SBV at this GA points towards alterations of all major processes of cortical development (proliferation, migration, and organization²⁸).

A declining ratio of GMV to SBV in fetuses with TOF indicates reduced

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Antenatal assessment of congenital heart disease and associated anomalies by ultrasound has improved perinatal care. Fetal cardiovascular MRI and fetal brain MRI are rapidly evolving for fetal diagnostic testing of congenital heart disease. We give an overview on the use of fetal cardiovascular MRI and fetal brain MRI in congenital heart disease, focusing on the current applications and diagnostic yield of structural and functional imaging during pregnancy. Fetal cardiovascular MRI in congenital heart disease is a promising supplementary imaging method to echocardiography for the diagnosis of antenatal congenital heart disease in weeks 30–40 of pregnancy. Concomitant fetal brain MRI is superior to brain ultrasound to show the complex relationship between fetal haemodynamics in congenital heart disease and brain development.
Brainstem and cerebellar volumes at magnetic resonance imaging are smaller in fetuses with congenital heart disease
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Congenital heart disease is associated with an increased risk of smaller brain volumes and structural brain damage, and impaired growth of supratentorial brain structures in utero has been linked to poor neurodevelopmental outcomes. However, little is known on brainstem and cerebellar volumes in fetuses with congenital heart disease. Moreover, it is not clear whether impaired infratentorial growth, if present, is associated with only certain types of fetal cardiac defects or with supratentorial brain growth, and whether altered biometry is already present before the third trimester.
This study aimed to investigate brainstem and cerebellar volumes in fetuses with congenital heart disease and to compare them to infratentorial brain volumes in fetuses with normal hearts. Secondarily, the study aimed to identify associations between infratentorial brain biometry and the type of cardiac defects, supratentorial brain volumes, and gestational age.
In this retrospective case-control study, 141 magnetic resonance imaging studies of 135 fetuses with congenital heart disease and 141 magnetic resonance imaging studies of 125 controls with normal hearts at 20 to 37 gestational weeks (median, 25 weeks) were evaluated. All cases and controls had normal birthweight and no evidence of structural brain disease or genetic syndrome. Six types of congenital heart disease were included: tetralogy of Fallot (n=32); double-outlet right ventricle (n=22); transposition of the great arteries (n=27); aortic obstruction (n=24); hypoplastic left heart syndrome (n=22); and hypoplastic right heart syndrome (n=14). First, brainstem and cerebellar volumes of each fetus were segmented and compared between cases and controls. In addition, transverse cerebellar diameters, vermian areas, and supratentorial brain and cerebrospinal fluid volumes were quantified and differences assessed between cases and controls. Volumetric differences were further analyzed according to types of cardiac defects and supratentorial brain volumes. Finally, volume ratios were created for each brain structure ([volume in fetus with congenital heart disease/respective volume in control fetus] × 100) and correlated to gestational age.
Brainstem (cases, 2.1 cm³ vs controls, 2.4 cm³; P<.001) and cerebellar (cases, 3.2 cm³ vs controls, 3.4 cm³; P<.001) volumes were smaller in fetuses with congenital heart disease than in controls, whereas transverse cerebellar diameters (P=.681) and vermian areas (P=.947) did not differ between groups. Brainstem and cerebellar volumes differed between types of cardiac defects. Overall, the volume ratio of cases to controls was 80.8% for the brainstem, 90.5% for the cerebellum, and 90.1% for the supratentorial brain. Fetuses with tetralogy of Fallot and transposition of the great arteries were most severely affected by total brain volume reduction. Gestational age had no effect on volume ratios.
The volume of the infratentorial brain, which contains structures considered crucial to brain function, is significantly smaller in fetuses with congenital heart disease than in controls from midgestation onward. These findings suggest that impaired growth of both supra- and infratentorial brain structures in fetuses with congenital heart disease occurs in the second trimester. Further research is needed to elucidate associations between fetal brain volumes and neurodevelopmental outcomes in congenital heart disease.
Abnormal Extracardiac Development in Fetuses With Congenital Heart Disease
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Citation Excerpt :
Cases with fetal arrhythmia (but without structural heart defect), atrial septal defect (ASD) II (isolated or with persistent left superior vena cava), myocardial hypertrophy, or with isolated aberrant right subclavian artery were not included in the analysis. In total, 24 fetuses with a tetralogy of Fallot (TOF) (14) and 53 fetuses with mixed CHD (15), previously published by our group, were also included. Inclusion criteria comprised the diagnosis of a fetal structural CHD; the final diagnosis of cardiac anomaly confirmed or corrected at autopsy, postnatal imaging, or surgery; and completion of at least 1 fetal MRI.
Knowledge about extracardiac anomalies (ECA) in fetal congenital heart disease (CHD) can improve our understanding of the developmental origins of various outcomes in these infants. The prevalence and spectrum of ECA, including structural brain anomalies (SBA), on magnetic resonance imaging (MRI) in fetuses with different types of CHD and at different gestational ages, is unknown.
The purpose of this study was to evaluate ECA rates and types on MRI in fetuses with different types of CHD and across gestation.
A total of 429 consecutive fetuses with CHD and MRI between 17 and 38 gestational weeks were evaluated. ECA and SBA rates were assessed for each type of CHD and classified by gestational age (<25 or ≥25 weeks) at MRI.
Of all 429 fetuses with CHD, 243 (56.6%) had ECA on MRI, and 109 (25.4%) had SBA. Among the 191 fetuses with normal genetic testing results, the ECA rate was 54.5% and the SBA rate 19.4%. Besides SBA, extrafetal (21.2%) and urogenital anomalies (10.7%) were the most prevalent ECA on MRI in all types of CHD. Predominant SBA were anomalies of hindbrain-midbrain (11.0% of all CHD), dorsal prosencephalon (10.0%) development, and abnormal cerebrospinal fluid spaces (10.5%). There was no difference in the prevalence or pattern of ECA between early (<25 weeks; 45.7%) and late (≥25 weeks; 54.3%) fetal MRI.
ECA and SBA rates on fetal MRI are high across all types of CHD studied, and ECA as well as SBA are already present from midgestation onward.
Brain growth in congenital heart disease from prenatal environment to adulthood
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Over the past several decades, improved survival for children with moderate–severe congenital heart defects has led to heightened recognition of the long-term neurodevelopmental sequelae associated with this diagnosis. Magnetic resonance imaging studies have identified that abnormal brain growth is common in congenital heart disease and is associated with impaired cognitive and motor outcomes. Deficits in brain growth begin prenatally, progress along an altered trajectory after birth, and continue to be present in adolescents and adults with congenital heart disease. Global disturbances in cerebral white and gray matter development contribute to impaired brain growth and result from altered prenatal cardiac physiology, postnatal hemodynamic changes, surgical and perioperative clinical factors, and genetic variants.
Fetal postmortem imaging: an overview of current techniques and future perspectives
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Fetal death because of miscarriage, unexpected intrauterine fetal demise, or termination of pregnancy is a traumatic event for any family. Despite advances in prenatal imaging and genetic diagnosis, conventional autopsy remains the gold standard because it can provide additional information not available during fetal life in up to 40% of cases and this by itself may change the recurrence risk and hence future counseling for parents. However, conventional autopsy is negatively affected by procedures involving long reporting times because the fetal brain is prone to the effect of autolysis, which may result in suboptimal examinations, particularly of the central nervous system. More importantly, fewer than 50%–60% of parents consent to invasive autopsy, mainly owing to the concerns about body disfigurement.
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Postmortem magnetic resonance imaging using 1.5-Tesla magnets is the most studied technique and offers an overall diagnostic accuracy of 77%–94%. It is probably the best choice as a virtual autopsy technique for fetuses >20 weeks’ gestation. However, for fetuses <20 weeks’ gestation, its performance is poor. The use of higher magnetic resonance imaging magnetic fields such as 3-Tesla may slightly improve performance. Of note, in cases of fetal maceration, magnetic resonance imaging may offer diagnoses in a proportion of brain lesions wherein conventional autopsy fails. Postmortem ultrasound examination using a high-frequency probe offers overall sensitivity and specificity of 67%–77% and 74%–90%, respectively, with the advantage of easy access and affordability. The main difference between postmortem ultrasound and magnetic resonance imaging relates to their respective abilities to obtain images of sufficient quality for a confident diagnosis. The nondiagnostic rate using postmortem ultrasound ranges from 17% to 30%, depending on the organ examined, whereas the nondiagnostic rate using postmortem magnetic resonance imaging in most situations is far less than 10%. For fetuses ≤20 weeks’ gestation, microfocus computed tomography achieves close to 100% agreement with autopsy and is likely to be the technique of the future in this subgroup. The lack of histology has always been listed as 1 limitation of all postmortem imaging techniques. Image-guided needle tissue biopsy coupled with any postmortem imaging can overcome this limitation.
In addition to describing the diagnostic accuracy and limitations of each imaging technology, we propose a novel, stepwise diagnostic approach and describe the possible application of these techniques in clinical practice as an alternative or an adjunct or for triage to select cases that would specifically benefit from invasive examination, with the aim of reducing parental distress and pathologist workload. The widespread use of postmortem fetal imaging is inevitable, meaning that hurdles such as specialized training and dedicated financing must be overcome to improve access to these newer, well-validated techniques.

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: Supported in part by the Austrian National Bank Anniversary Fund (FETALMORPHO, 14812) to G.K.

: The authors report no conflict of interest.

: Cite this article as: Schellen C, Ernst S, Gruber GM, et al. Fetal MRI detects early alterations of brain development in Tetralogy of Fallot. Am J Obstet Gynecol 2015;213:392.e1-7.

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ResearchObstetricsFetal MRI detects early alterations of brain development in Tetralogy of Fallot

Objective

Study Design

Results

Conclusion

Section snippets

Test subjects

Results

Comment

J Pediatr

J Thorac Cardiovasc Surg

Eur J Paediatr Neurol

Ann Thorac Surg

Ann Thorac Surg

J Pediatr

Lancet

J Am Coll Cardiol

Am J Obstet Gynecol

Neuroimage

Magn Reson Imaging

J Pediatr

Pediatr Neurol

J Pediatr

Semin Cell Dev Biol

Prog Cardiovasc Dis

Am J Obstet Gynecol

Am J Obstet Gynecol

Clin Perinatol

Brain volume and metabolism in fetuses with congenital heart disease: evaluation with quantitative magnetic resonance imaging and spectroscopy

Circulation

Delayed cortical development in fetuses with complex congenital heart disease

Cereb Cortex

Impaired brain growth of intracranial structures in fetuses with complex congenital heart disease as measured by 3D ultrasonography

Ultrasound Obstet Gynecol

Regional alterations in cerebral growth exist preoperatively in infants with congenital heart disease

J Thorac Cardiovasc Surg

Congenital heart disease and brain injury

N Engl J Med

Research
Obstetrics
Fetal MRI detects early alterations of brain development in Tetralogy of Fallot