Feasibility of neurosonography in CHD-fetuses and controls in a clinical tertiary setting.

Objective: Ultrasonographic examination is the first-tier test to detect abnormal development of central nervous system (CNS). In optimal conditions, neurosonography can detect all important hallmarks of CNS development. It is, however, not known how the performance of this modality is in a routine setting. We aimed to evaluate the feasibility of neurosonography in a time-limited routine setting. Study design: We have performed a prospective study in which we have included a group of pregnant women carrying a fetus with an isolated congenital heart defect (CHD), and a control group of fetuses without structural anomalies. We have performed basic neurosonography examination according to the guideline 'how to perform a basic screening examination of the CNS', published by the international society of ultrasound in obstetrics and gynecology in both groups. In all these examinations, 9 brain structures were scored in 3 different planes, by researchers that were blinded for group allocation. A sufficient neurosonogram was performed when 7 or more out of 9 CNS structures were clearly visible during the off-line scoring of the examination. Results: A total of 574 neurosonographic examinations were performed in 151 fetuses, 90 in the CHD-group and 61 in the control group. A sufficient neurosonogram could be performed in 79% (234/294) of cases in a clinical setting (CHD cases) and in 90% (253/280) of control pregnancies. Higher maternal BMI (>30), maternal age, fetal cephalic position, fetal gender and placental position did not significantly influence neurosonography scores. Conclusion: In clinical setting, basic fetal neurosonography can be sufficiently performed in the majority of cases. This was not significantly influenced by maternal or fetal factors. The optimal gestational age for neurosonography is between 22 and 34 weeks.

Biallelic loss of LDB3 leads to a lethal pediatric dilated cardiomyopathy.

Autosomal dominant variants in LDB3 (also known as ZASP), encoding the PDZ-LIM domain-binding factor, have been linked to a late onset phenotype of cardiomyopathy and myofibrillar myopathy in humans. However, despite knockout mice displaying a much more severe phenotype with premature death, bi-allelic variants in LDB3 have not yet been reported. Here we identify biallelic loss-of-function variants in five unrelated cardiomyopathy families by next-generation sequencing. In the first family, we identified compound heterozygous LOF variants in LDB3 in a fetus with bilateral talipes and mild left cardiac ventricular enlargement. Ultra-structural examination revealed highly irregular Z-disc formation, and RNA analysis demonstrated little/no expression of LDB3 protein with a functional C-terminal LIM domain in muscle tissue from the affected fetus. In a second family, a homozygous LDB3 nonsense variant was identified in a young girl with severe early-onset dilated cardiomyopathy with left ventricular non-compaction; the same homozygous nonsense variant was identified in a third unrelated female infant with dilated cardiomyopathy. We further identified homozygous LDB3 frameshift variants in two unrelated probands diagnosed with cardiomegaly and severely reduced left ventricular ejection fraction. Our findings demonstrate that recessive LDB3 variants can lead to an early-onset severe human phenotype of cardiomyopathy and myopathy, reminiscent of the knockout mouse phenotype, and supporting a loss of function mechanism.

Serial neurosonography in fetuses with congenital heart defects shows mild delays in cortical development.

INTRODUCTION: Neurodevelopmental delay is more common in children born with congenital heart defects (CHD), even with optimal perinatal and peri-operative care. It is hypothesized that fetuses with CHD are prone to neurological impairment in utero due to their cardiac defect, possibly leading to delayed cortical development. METHODS: Cerebral cortical maturation was assessed with advanced neurosonographic examinations every 4 weeks in fetuses with CHD and compared to control fetuses. Five different primary fissures and four areas were scored (ranging 0-5) by blinded examiners using a cortical maturation scheme. RESULTS: Cortical staging was assessed in 574 ultrasound examinations in 85 CHD fetuses and 61 controls. Small differences in grading were seen in Sylvian and cingulate fissures. (Sylvian fissure: -0.12 grade, 95% CI (-0.23; -0.01) p = 0.05, cingulate fissure: -0.24 grade, 95% CI (-0.38; -0.10) p = <0.001. Other cortical areas showed normal maturation as compared to control fetuses. CONCLUSION: Small differences were seen in three of the nine analyzed cortical areas in CHD fetuses, in contrast to previous reports on progressive third-trimester delay. The clinical implications of the small differences however, remain unknown.

The association between flow and oxygenation and cortical development in fetuses with congenital heart defects using a brain-age prediction algorithm.

OBJECTIVES: Presumably, changes in fetal circulation contribute to the delay in maturation of the cortex in fetuses with congenital heart defect (CHD). The aim of the current study is to analyze fetal brain development based on hemodynamic differences, using novel brain-age prediction software. METHODS: We have performed detailed neurosonography, including acquiring 3D volumes, prospectively in cases with isolated CHD from 20 weeks onwards. An algorithm that assesses the degree of fetal brain-age automatically was used to compare CHD cases to controls. We stratified CHD cases according to flow and oxygenation profiles by lesion physiology and performed subgroup analyses. RESULTS: A total of 616 ultrasound volumes of 162 CHD cases and 75 controls were analyzed. Significant differences in maturation of the cortex were observed in cases with normal blood flow toward the brain (-3.8 days, 95%CI [-5.5; -2.0], P = <.001) and low (-4.0 days, 95% CI [-6.7; -1.2] P = <.05; hypoplastic left heart syndrome[HLHS]) and mixed (-4.4 days, 95%CI [-6.4; -2.5] p = <.001) oxygen saturation in the ascending aorta (TGA) and in cardiac mixing (eg, Fallot) cases. CONCLUSION: The current study shows significant delay in brain-age in TGA and Fallot cases as compared to control cases. However, the small differences found in this study questions the clinical relevance.

Cortical development in fetuses with congenital heart defects using an automated brain-age prediction algorithm.

INTRODUCTION: Congenital heart defects are associated with neurodevelopmental delay. It is hypothesized that fetuses affected by congenital heart defect have altered cerebral oxygen perfusion and are therefore prone to delay in cortical maturation. The aim of this study was to determine the difference in fetal brain age between consecutive congenital heart defect cases and controls in the second and third trimester using ultrasound. MATERIAL AND METHODS: Since 2014, we have included 90 isolated severe congenital heart defect cases in the Heart And Neurodevelopment (HAND)-study. Every 4 weeks, detailed neurosonography was performed in these fetuses, including the recording of a 3D volume of the fetal brain, from 20 weeks onwards. In all, 75 healthy fetuses underwent the same protocol to serve as a control group. The volumes were analyzed by automated age prediction software which determines gestational age by the assessment of cortical maturation. RESULTS: In total, 477 volumes were analyzed using the age prediction software (199 volumes of 90 congenital heart defect cases; 278 volumes of 75 controls). Of these, 16 (3.2%) volume recordings were excluded because of imaging quality. The age distribution was 19-33 weeks. Mixed model analysis showed that the age predicted by brain maturation was 3 days delayed compared with the control group (P = .002). CONCLUSIONS: This study shows that fetuses with isolated cases of congenital heart defects show some delay in cortical maturation as compared with healthy control cases. The clinical relevance of this small difference is debatable. This finding was consistent throughout pregnancy and did not progress during the third trimester.