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Neurodevelopmental delay is frequently encountered in children with congenital heart defects (CHD). Recent cohorts show slightly smaller head circumferences (HC) in isolated CHD, irrespective of type of CHD, altered cerebral flow or brain oxygenation. [Extracted from the article]

Congenital heart defects (CHD) are still frequently missed in prenatal screening programs, which can lead to life-threatening situations or brain damage. This study shows that differences in circumstances do not explain that CHD are being missed. The 20% with correct planes and normal anatomy included mainly septal defects and aortic arch anomalies. [Extracted from the article]

A letter to the editor is presented in response to the article "Prevalence of prenatal brain abnormalities in fetuses with congenital heart disease: a systematic review," by A. Khalil and colleagues in the 2016 issue.

An abstract of the article "A prenatal detection rate of 85% is achieved for transposition of the great arteries after introduction of the three-vessel view," by S. M. Everwijn and colleagues is presented.

An abstract of the article "Premature birth and fetal demise rates in singleton pregnancies with isolated fetal heart defects," by C. Velzen and colleagues is presented.

The article describes the case of a patient with membraneous pulmonary atresia and ventricular septal defect who underwent transcatheter heart valve surgery in native pulmonary valve position.

After surgery for congenital heart disease in children and adolescents, an active lifestyle is important to achieve and maintain good physical fitness. This study aimed to describe physical activity, as well as the use of patients' and parents' preferences for rehabilitative care after surgery for congenital heart disease. This cross-sectional study included patients aged 4–16 years old, who had undergone surgery for congenital heart disease 2 years prior to the study onset. Patients and/or parents were invited to complete questionnaires on physical activity, and on their preferences for, and -use of, rehabilitative care after surgery. Forty-five of the 92 eligible patients and/or parents completed the questionnaires. The median age of the children was 12.2 years (IQR 7.8–16.1). Two children (4%) met the recommendations for taking part in moderate physical activity and 13 (29%) having done so for vigorous physical activity. Postoperatively 15 children (33%) had had physical therapy in primary care. More than 50% of the patients/parents would have preferred to have had more information on physical activity and to have taken part in an individual exercise program delivered during their primary care. The majority of eligible patients do not meet public health recommendations for engaging in physical activity and do not use physical therapy after surgery for congenital heart disease. The majority of patients and parents preferred more information as well as individual physical therapy treatments. Two years after surgery for congenital heart disease children and adolescents are less active compared to typically developing peers. Patients with a congenital heart disease and their parents need more information and support regarding stimulation of physical activity and physical fitness after heart surgery. In the postoperative process, a well-structured and supportive (individual) rehabilitation program should be introduced to improve physical activity and physical fitness. [ABSTRACT FROM AUTHOR]

Recent studies in erythroid cells have shown that autophagy is an important process for the physiological clearance of mitochondria during terminal differentiation. However, autophagy also plays an important role in removing damaged and dysfunctional mitochondria. Defective mitochondria and impaired erythroid maturation are important characteristics of low-risk myelodysplasia. In this study we therefore questioned whether the autophagic clearance of mitochondria might be altered in erythroblasts from patients with refractory anemia (RA, n=3) and RA with ringed sideroblasts (RARS, n=6). Ultrastructurally, abnormal and iron-laden mitochondria were abundant, especially in RARS patients. A large proportion (52±16%) of immature and mature myelodysplastic syndrome (MDS) erythroblasts contained cytoplasmic vacuoles, partly double membraned and positive for lysosomal marker LAMP-2 and mitochondrial markers, findings compatible with autophagic removal of dysfunctional mitochondria. In healthy controls only mature erythroblasts comprised these vacuoles (12±3%). These findings were confirmed morphometrically showing an increased vacuolar surface in MDS erythroblasts compared to controls (P<0.0001). In summary, these data indicate that MDS erythroblasts show features of enhanced autophagy at an earlier stage of erythroid differentiation than in normal controls. The enhanced autophagy might be a cell protective mechanism to remove defective iron-laden mitochondria.Leukemia (2009) 23, 886–891; doi:10.1038/leu.2008.389; published online 15 January 2009 [ABSTRACT FROM AUTHOR]

We have developed an entirely sequence-based method that identifies and integrates relevant features that can be used to assign proteins of unknown function to functional classes, and enzyme categories for enzymes. We show that strategies for the elucidation of protein function may benefit from a number of functional attributes that are more directly related to the linear sequence of amino acids, and hence easier to predict, than protein structure. These attributes include features associated with post-translational modifications and protein sorting, but also much simpler aspects such as the length, isoelectric point and composition of the polypeptide chain. [Copyright &y& Elsevier]

This study presents an improved approach to common‐conversion point stacking of converted body waves that incorporates scattering kernels, accurate and efficient measurement of stack uncertainties, and an alternative method for estimating free surface seismic velocities. To better separate waveforms into the P and SV components to calculate receiver functions, we developed an alternative method to measure near‐surface compressional and shear wave velocities from particle motions. To more accurately reflect converted phase scattering kernels in the common‐conversion point stack, we defined new weighting functions to project receiver function amplitudes only to locations where sensitivities to horizontal discontinuities are high. To better quantify stack uncertainties, we derived an expression for the standard deviation of the stack amplitude that is more efficient than bootstrapping and can be used for any problem requiring the standard deviation of a weighted average. We tested these improved methods on Sp phase data from the Anatolian region, using multiple band‐pass filters to image velocity gradients of varying depth extents. Common conversion point stacks of 23,787 Sp receiver functions demonstrate that the new weighting functions produce clearer and more continuous mantle phases, compared to previous approaches. The stacks reveal a positive velocity gradient at 80–150 km depth that is consistent with the base of an asthenospheric low‐velocity layer. This feature is particularly strong in stacks of longer period data, indicating it represents a gradual velocity gradient. At shorter periods, a lithosphere‐asthenosphere boundary phase is observed at 60–90 km depth, marking the top of the low‐velocity layer. Plain Language Summary: This paper presents a new method that more accurately incorporates the physics of seismic scattering into how the wave records are combined to form images of gradients in seismic velocity structure. This method was tested on data from the Anatolian region, where the asthenosphere is known to have low seismic wave velocities, consistent with high mantle temperatures and possibly small fractions of partial melt, as suggested by the presence of volcanic fields at the surface. However, the depth of the asthenospheric low‐velocity layer is not well known. In this study, we locate this low‐velocity mantle layer by applying the newly developed imaging method to seismic shear waves that convert to compressional waves at the velocity gradients that mark the layer boundaries. This study is the first to clearly resolve both the lower and upper margins of the asthenosphere for the whole region. The top of the layer corresponds to the lithosphere‐asthenosphere boundary at 60–90 km depth, and this velocity gradient is localized in depth. However, the bottom boundary, which lies at depths of 80–150 km, occurs over a broader depth range. Key Points: A new approach to common conversion point stacking based on scattering kernels is developedA fast and accurate quantification of the standard deviation of the weighted stack average is derivedAn anomalously low‐velocity asthenosphere beneath Anatolia is indicated by velocity discontinuities imaged with multifrequency data [ABSTRACT FROM AUTHOR]

Objective: Congenital heart defects (CHD) are still missed frequently in prenatal screening programs, which can result in severe morbidity or even death. The aim of this study was to evaluate the quality of fetal heart images, obtained during the second-trimester standard anomaly scan (SAS) in cases of CHD, to explore factors associated with a missed prenatal diagnosis.Methods: In this case-control study, all cases of a fetus born with isolated severe CHD in the Northwestern region of The Netherlands, between 2015 and 2016, were extracted from the PRECOR registry. Severe CHD was defined as need for surgical repair in the first year postpartum. Each cardiac view (four-chamber view (4CV), three-vessel (3V) view and left and right ventricular outflow tract (LVOT, RVOT) views) obtained during the SAS was scored for technical correctness on a scale of 0 to 5 by two fetal echocardiography experts, blinded to the diagnosis of CHD and whether it was detected prenatally. Quality parameters of the cardiac examination were compared between cases in which CHD was detected and those in which it was missed on the SAS. Regression analysis was used to assess the association of sonographer experience and of screening-center experience with the cardiac examination quality score.Results: A total of 114 cases of isolated severe CHD at birth were analyzed, of which 58 (50.9%) were missed and 56 (49.1%) were detected on the SAS. The defects comprised transposition of the great arteries (17%), aortic coarctation (16%), tetralogy of Fallot (10%), atrioventricular septal defect (6%), aortic valve stenosis (5%), ventricular septal defect (18%) and other defects (28%). No differences were found in fetal position, obstetric history, maternal age or body mass index (BMI) or gestational age at examination between missed and detected cases. Ninety-two cases had available cardiac images from the SAS. Compared with the detected group, the missed group had significantly lower cardiac examination quality scores (adequate score (≥ 12) in 32% vs 64%; P = 0.002), rate of proper use of magnification (58% vs 84%; P = 0.01) and quality scores for each individual cardiac plane (4CV (2.7 vs 3.9; P < 0.001), 3V view (3.0 vs 3.8; P = 0.02), LVOT view (1.9 vs 3.3; P < 0.001) and RVOT view (1.9 vs 3.3; P < 0.001)). In 49% of missed cases, the lack of detection was due to poor adaptational skills resulting in inadequate images in which the CHD was not clearly visible; in 31%, the images showed an abnormality (mainly septal defects and aortic arch anomalies) which had not been recognized at the time of the scan; and, in 20%, the cardiac planes had been obtained properly but showed normal anatomy. Multivariate regression analysis showed that the volume of SAS performed per year by each sonographer was associated significantly with quality score of the cardiac examination.Conclusions: A lack of adaptational skills when performing the SAS, as opposed to circumstantial factors such as BMI or fetal position, appears to play an important role in failure to detect CHD prenatally. The quality of the cardiac views was inadequate significantly more often in undetected compared with detected cases. Despite adequate quality of the images, CHD was not recognized in 31% of cases. A high volume of SAS performed by each sonographer in a large ultrasound center contributes significantly to prenatal detection. In 20% of undetected cases, CHD was not visible even though the quality of the images was good. © 2019 Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Objective: Neurodevelopmental delay is frequently encountered in children with a congenital heart defect (CHD). Fetuses with major CHD have a smaller head circumference (HC), irrespective of altered cerebral flow or brain oxygenation. This cohort study compared head growth in cases with isolated vs those with non-isolated CHD to evaluate the effect of additional pathology on head size in these fetuses.Method: All CHD cases diagnosed prenatally in the period January 2002-July 2014 were selected from our regional registry, PRECOR. Cases of multiple pregnancy, and those affected by maternal diabetes, severe fetal structural brain anomalies or functional CHD were excluded. Subjects were divided into groups according to whether the CHD was isolated, and the non-isolated group was subdivided into three groups: cases with genetic anomaly, extracardiac malformation or placental pathology. In both isolated and non-isolated CHD groups, CHDs were also grouped according to their potential effect on aortic flow and oxygen saturation. Mean HC Z-scores at 20 weeks and increase or decrease (Δ) of HC Z-scores over the course of pregnancy were compared between isolated and non-isolated groups, using mixed linear regression models.Results: Included were 916 cases of CHD diagnosed prenatally, of which 378 (41.3%) were non-isolated (37 with placental pathology, 217 with genetic anomaly and 124 with extracardiac malformation). At 20 weeks, non-isolated cases had significantly lower HC Z-scores than did isolated cases (Z-score = -0.70 vs -0.03; P < 0.001) and head growth over the course of pregnancy showed a larger decrease in this group (Δ HC Z-score = -0.03 vs -0.01 per week; P = 0.01). Cases with placental pathology had the lowest HC Z-score at 20 weeks (Z-score = -1.29) and the largest decrease in head growth (Δ HC Z-score = -0.06 per week). In CHD subjects with a genetic diagnosis (Z-score = -0.73; Δ HC Z-score = -0.04 per week) and in those with an extracardiac malformation (Z-score = -0.49; Δ HC Z-score = -0.02 per week), HC Z-scores were also lower compared with those in subjects with isolated CHD. CHDs that result in low oxygenation or flow to the brain were present more frequently in isolated than in non-isolated cases.Conclusions: Smaller HC in fetuses with CHD appears to be associated strongly with additional pathology. Placental pathology and genetic anomaly in particular seem to be important contributors to restricted head growth. This effect appears to be irrespective of altered hemodynamics caused by the CHD. Previously reported smaller HC in CHD should, in our opinion, be attributed to additional pathology. Neurodevelopment studies in infants with CHD should, therefore, always differentiate between isolated and non-isolated cases. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Objective: Cardiac ventricular size disproportion is a marker for aortic coarctation (CoA) in fetal life, but approximately 50% of fetuses do not have CoA after birth. The aim of this study was to evaluate the postnatal outcome of cases with fetal ventricular size disproportion in the absence of CoA after birth.Methods: All cases with fetal isolated ventricular size disproportion diagnosed between 2002 and 2015 were extracted from a prenatal congenital heart defects regional registry. Cases were stratified according to presence or absence (non-CoA) of aortic arch anomalies after birth. Postnatal outcome of non-CoA cases was evaluated by assessing the presence of cardiac and other congenital malformations, genetic syndromes and other morbidity after birth. Non-CoA cases were further classified according to whether they had cardiovascular pathology requiring medication or intervention.Results: Seventy-seven cases with fetal ventricular size disproportion were identified, of which 46 (60%) did not have CoA after birth. Of these, 35 did not require cardiovascular intervention or medication, whereas 11 did. Of the 46 non-CoA cases, six presented with clinical pulmonary hypertension requiring treatment after birth, cardiac defects were present in 24 cases and syndromic features were seen in four. Overall, 43% of all non-CoA children were still under surveillance at the end of the study period.Conclusions: The postnatal course of cases with fetal ventricular size disproportion is complicated by prenatally undetected congenital defects (46%) and pulmonary or transition problems (35%) in a significant number of cases that do not develop CoA. Proper monitoring of these cases is therefore warranted and it is advisable to incorporate the risks for additional morbidity and neonatal complications in prenatal counseling. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

Objectives: Congenital heart defects (CHDs) are reported to be associated with a smaller fetal head circumference (HC) and neurodevelopmental delay. Recent studies suggest that altered intrauterine brain hemodynamics may explain these findings. Our objectives were to evaluate the pattern of head growth in a large cohort of fetuses with various types of CHD, analyze these patterns according to the type of CHD and estimate the effect of cerebral hemodynamics with advancing gestation in the second and third trimesters.Methods: Singleton fetuses with an isolated CHD were selected from three fetal medicine units (n = 436). Cases with placental insufficiency or genetic syndromes were excluded. CHD types were clustered according to the flow and oxygen saturation in the aorta. Z-scores of biometric data were constructed using growth charts of a normal population. HC at different gestational ages was evaluated and univariate and multivariate mixed regression analyses were performed to examine the patterns of prenatal HC growth.Results: Fetuses with severe and less severe types of CHD demonstrated statistically significant HC growth restriction with increasing gestational age (slope of -0.017/day); however, there was no statistically significant effect of fetal hemodynamics on HC growth. Fetuses with CHD but normal brain oxygenation and normal aortic flow showed a significant decrease in HC growth (slope of -0.024/day). Only fetuses with isolated tetralogy of Fallot demonstrated a smaller HC z-score at 20 weeks of gestation (-0.67 (95% CI, -1.16 to -0.18)).Conclusions: Despite the decline in head growth in fetuses with a prenatally detected isolated CHD, HC values were within the normal range, raising the question of its clinical significance. Furthermore, in contrast to other studies, this large cohort did not establish a significant correlation between aortic flow or oxygen saturation and HC growth. Factors other than altered fetal cerebral hemodynamics may contribute to HC growth restriction with increasing gestational age, such as (epi)genetic or placental factors. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

Objective: To examine the accuracy of fetal echocardiography in diagnosing congenital heart disease (CHD) at the fetal medicine units of three tertiary care centers.Methods: This was a multicenter cohort study of tertiary echocardiography referrals between 2002 and 2012. Prenatal and postnatal diagnoses were compared and the degree of agreement was classified as 'correct' (anatomy correct and the postnatal diagnosis led to a similar outcome as expected), 'discrepant' (anatomical discrepancies present but the severity and prognosis of the defect were diagnosed correctly) or 'no similarity' (the pre- and postnatal diagnoses differed completely).Results: We included 708 cases with CHD for which both prenatal and postnatal data were available. The prenatal diagnosis was correct in 82.1% of cases and discrepancies present were present in 9.9%; however, these did not result in a different outcome. In 8.1% there was no similarity between prenatal and postnatal diagnoses. Disagreement between pre- and postnatal diagnoses occurred significantly more frequently in cases that presented with a normal four-chamber view than in those with an abnormal four-chamber view (5.5% vs 1.9%). Incorrect identification of the outflow tracts and incorrect differentiation between unbalanced atrioventricular septal defect and hypoplastic left heart syndrome were relatively commonly encountered. In many cases with disagreement, trisomy 21, extracardiac anomaly or a high maternal body mass index was present.Conclusions: The prenatal diagnosis and estimated prognosis of fetal echocardiography in our tertiary referral centers were appropriate in 92% of cases. Some types of CHD remain difficult to diagnose or rule-out prenatally, therefore awareness and education are of considerable importance. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

ABSTRACT Objectives To evaluate the prenatal detection of transposition of the great arteries ( TGA), after the introduction of a Dutch screening program in 2007, as well as the effect of prenatal detection on pre- and postsurgical mortality and morbidity. Methods In a geographical cohort study, all infants with TGA who were born between 1 January 2002 and 1 January 2012 were included. The cases were divided into two groups: those with and those without a prenatal diagnosis. Pre- and postsurgical mortality was assessed, with a follow-up of 1 year. Presurgical morbidity was assessed in terms of cardiovascular compromise, metabolic acidosis, renal and/or hepatic dysfunction and closure of the duct before initiation of therapy. Results Of all cases ( n = 144), 26.4% were diagnosed prenatally, with detection rates of 15.7% and 41.0% in the first and last 5 years of the study period, respectively. First-year mortality was significantly lower in cases with a prenatal diagnosis of TGA than in those without (0.0% vs 11.4%, respectively). Presurgical mortality (4.9%) only occurred in undetected simple TGA cases. Closure of the duct before treatment, renal dysfunction and hypoxia occurred significantly more often in the group without a prenatal diagnosis. Conclusions The prenatal detection rate of TGA has increased significantly since the introduction of the screening program in 2007. Prenatal diagnosis is an important factor that contributes to survival of the infant in the first postnatal year. Furthermore, some morbidity indicators were significantly higher in the group without a prenatal diagnosis. These results justify efforts to improve prenatal screening programs. Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

The objective of this multicenter study was to evaluate psychological functioning and disease-related quality of life (DRQoL) in pediatric patients with an implantable cardioverter defibrillator (ICD) in The Netherlands. Thirty patients were investigated; the mean age was 16.3 years, and the mean duration of implantation was 3.6 years. To assess psychological problems, three domains of the Symptom Checklist (SCL-90-R) were administered to the 25 patients >13 years old. DRQoL was assessed with a disease-specific pediatric questionnaire, the short-form 11-item Worries About (WA)ICDs Scale. Patients ≥13 years old scored significantly higher than the reference group on the domains of anxiety, depression, and sleeping problems of the SCL-90-R ( T = 7.5, p < 0.001; T = 5.4, p < 0.001; and T = 7.8, p < 0.001, respectively). Patients who had received an (in)appropriate shock reported more depressive symptoms ( T = 2.1, p < 0.03). Patients with >2 years implant duration ( N = 19) or who had received an (in)appropriate shock ( N = 13) showed lower DRQoL scores on the modified WAICD ( T = 2.1, p < 0.04; T = 2.1, p < 0.5, respectively). Age at implantation or underlying disease did not influence psychological problems or DRQoL. Young ICD patients showed more anxiety, depression, and sleeping disorders. Worries were increased among patients with ICD shocks and in those who had their ICD implanted for >2 years. To determine psychological problems and help children to learn to cope with shocks, proper guidance and monitoring of young ICD patients are recommended. [ABSTRACT FROM AUTHOR]

Background: Cardiac resynchronisation therapy (CRT) is increasingly used in children in a variety of anatomical and pathophysiological conditions, but published data are scarce. Objective: To record current practice and results of CRT in paediatric and congenital heart disease. Design: Retrospective multicentre European survey. Setting: Paediatric cardiology and cardiac surgery centres. Patients: One hundred and nine patients aged 0.24-73.8 (median 16.9) years with structural congenital heart disease (n = 87), congenital atrioventricular block (n = 12) and dilated cardiomyopathy (n = 10) with systemic left (n = 69), right (n = 36) or single (n = 4) ventricular dysfunction and ventricular dyssynchrony during sinus rhythm (n = 25) or associated with pacing (n = 84). Interventions: CRT for a median period of 7.5 months (concurrent cardiac surgery in 16/109). Main outcome measures: Functional improvement and echocardiographic change in systemic ventricular function. Results: The z score of the systemic ventricular end-diastolic dimension decreased by median 1.1 (p<0.001). Ejection fraction (EF) or fractional area of change increased by a mean (SD) of 11.5 (14.3)% (p<0.001) and New York Heart Association (NYHA) class improved by median 1.0 grade (p<0.001). Non-response to CRT (18.5%) was multivariably predicted by the presence of primary dilated cardiomyopathy (p = 0.002) and poor NYHA class (p = 0.003). Presence of a systemic left ventricle was the strongest multivariable predictor of improvement in EF/fractional area of change (p<0.001). Results were independent of the number of patients treated in each contributing centre. Conclusion: Heart failure associated with ventricular pacing is the largest indication for CRT in paediatric and congenital heart disease. CRT efficacy varies widely with the underlying anatomical and pathophysiological substrate. [ABSTRACT FROM AUTHOR]

A sinus venosus defect is a form of interatrial communication associated with abnormal drainage of the right pulmonary veins. Its morphogenesis still remains unclear. We therefore studied the normal development of pulmonary veins in human embryos in relation to the sinus venosus and the dorsal mesocardium using graphic reconstructions and HNK-1 immunohistochemistry. Twenty embryos, ranging from 4 to 7 weeks' gestation, were examined. At 4 weeks, the orifice of the nonlumenized common pulmonary vein is visible as an endothelial invagination within the sinus venosus segment. Development of the muscular septum primum and the ventral proliferation of extracardiac mesenchyme from the dorsal mesocardium positions the common pulmonary vein (CPV) eventually into the left atrium. The right wall of the CPV contributes to the posterior part of the atrial septum and is continuous with the dorsal sinuatrial fold (the future left venous valve). With the use of HNK-1 antigen expression as a marker for sinus venosus myocardium, this common wall between the right-sided sinus venosus and the CPV is demonstrated, and at 7 weeks the proximal part of the right upper pulmonary vein also becomes part of this common wall. This study demonstrates that the CPV develops within the sinus venosus segment and that later a common myocardial wall is present between the sinus venosus in the right atrium and the CPV. A deficiency of this wall explains the development of sinus venosus defects. [ABSTRACT FROM AUTHOR]

This study focused on the incidence of these variants in second trimester fetuses with CHD and follow-up from a prenatal perspective, as this currently lacks, but is essential for prenatal counselling. We assessed the incidence of genetic variants amongst specific CHD types and its association with extra-cardiac malformations (ECM). After aneuploidy is ruled out, the yield of genetic variants in severe CHD fetuses is 25.1%, of which 15.6% pathogenic. [Extracted from the article]