Impact of extracardiac pathology on head growth in fetuses with congenital heart defect.

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.

Fluorinated steroids do not improve outcome of isolated atrioventricular block.

INTRODUCTION: Congenital atrioventricular block (CAVB) is a rare disorder with a significant morbidity and mortality. Consensus regarding the prescription and efficacy of prenatal corticosteroids is lacking. This nationwide study was initiated to evaluate the effects of prenatal treatment with corticosteroids on the outcome of CAVB in The Netherlands. METHODS: All fetuses identified with isolated congenital AVB-II° or AVB-III° in any of the eight academic fetal heart centers of The Netherlands between 2003 and 2013 were included and reviewed. RESULTS: Fifty-six fetuses were included. Fourteen (25%) fetuses were treated with dexamethasone. We found no differences between the steroid-treated and untreated cases regarding in utero progression of the AVB (63% vs 67% respectively), survival to birth (86% vs 84%), pacemaker implantations (74% vs 58%) or long-term dilated cardiomyopathy (13% vs 17%). Steroid treated fetuses demonstrated more in utero growth restriction (38% vs 11%). CONCLUSION: No benefit from prenatal corticosteroid treatment was demonstrated for fetuses with isolated CAVB in this study. However, we found negative side effects. Our data provide no evidence to support the routine administration of corticosteroids for the treatment of fetal CAVB.

KinCor, a national registry for paediatric patients with congenital and other types of heart disease in the Netherlands: aims, design and interim results.

OBJECTIVE: Studies in children with heart disease have been hampered by a lack of easily identifiable patient groups. Currently, there are few prospective population-based registries covering the entire spectrum of heart disease in children. KinCor is a Dutch national registry for children with heart diseases. This paper presents the aims, design and interim results of the KinCor project. METHODS: All children presenting at a Dutch university medical centre with a diagnosis of heart disease from 2012 onwards were eligible for registration in the KinCor database. Data entry is through a web-based portal. Entry codes have been synchronised with the European Paediatric Cardiac Coding system, allowing coupling with similar databases for adults, such as CONCOR. RESULTS: Between June 2012 and July 2015, 8421 patients were registered (76 % of those eligible). Median age of the patients was 9.8 years, 44.7 % were female; 6782 patients had morphological congenital heart disease. The most prevalent morphological congenital heart defects were ventricular septal defects (18 %), Tetralogy of Fallot (10 %) and transposition of great arteries (9 %). For 42 % of the patients additional diagnoses were registered. Sixty percent of patients had undergone at least one intervention (catheter intervention or surgery). CONCLUSION: The KinCor database has developed into a large registry of data of children with all types of heart disease and continues to grow. This database will provide the opportunity for epidemiological research projects on congenital and other types of heart disease in children. Entry codes are shared with the CONCOR database, which may provide a unique dataset.

Development of major aorto-pulmonary collateral arteries in vegf120/120 isoform mouse embryos with tetralogy of fallot.

The degree of right ventricular outflow tract obstruction, pulmonary stenosis (PS) and the development of major aorto-pulmonary collateral arteries (MAPCAs) in patients with tetralogy of Fallot (TOF) is related to clinical outcome. Vegf120/120 mutant mouse embryos develop TOF with various degrees of PS, comparable to humans. We aimed to study the ontogeny of the development of MAPCAs in this mouse model. The development of the right ventricular outflow tract, pulmonary arteries, and ductus arteriosus (DA) and formation of MAPCAs were studied in both wild type as well as Vegf120/120 mice from embryonic day 10.5 until day 19.5. Of the 49 Vegf120/120 embryos, 35 embryos (71%) had ventral displacement of the outflow tract and a subaortic ventricular septal defect. A time-related development in severity of PS to pulmonary atresia (PA) was observed. From embryonic day 12.5, hypoplasia of the DA was seen in 13 (37%) and absent DA in 12 (37%) of these embryos. The 3 (6%) embryos with PA and absent DA developed MAPCAs, after day 15.5. In all, the MAPCAs arose from both subclavian arteries, running posterior in the thoracic cavity, along the vagal nerve. The MAPCAs connected the pulmonary arteries at the site of the hilus. A time-related development of PS to PA can lead, in combination with absent DA, to the development of MAPCAs later in embryonic life as an alternative route for pulmonary perfusion in this mouse model. This finding contributes to a better understanding of the consecutive morphological changes in the development toward MAPCAs in humans.

Evaluation of the diagnostic work-up in children with myocarditis and idiopathic dilated cardiomyopathy.

The underlying etiology of dilated cardiomyopathy (DCM) in children varies, 14-22% is secondary to myocarditis, and the majority remains idiopathic. Etiology has prognostic value; however, 'a clinical diagnosis of myocarditis' has been frequently used because the gold standard [endomyocardial biopsy (EMB)] is often not performed. Therefore, a consistent diagnostic approach and interpretation is needed. In this multicenter study, we evaluated the diagnostic approach and interpretation of the viral results in children with myocarditis and idiopathic DCM. We included 150 children with DCM, of whom 103 were assigned the diagnosis myocarditis (n = 21) or idiopathic DCM (n = 82) by the attending physician. Viral tests were performed in 97/103 patients, in only 34% (n = 35) some of the tests were positive. Of those patients, we evaluated the probability of the assigned diagnosis using the viral test results. We classified viral test results as reflecting definite or probable myocarditis in 14 children and possible or unlikely myocarditis in 21 children. Based on this classification, 23% of patients were misclassified. We found that in children with DCM, the diagnostic approach varied and the interpretation was mainly based on viral results. Since a 'clinical diagnosis of myocarditis' has been frequently used in daily practice because of the lack of EMB results, a uniform protocol is needed. We propose to use viral test results in several steps (blood PCR, serology, PCR and/or cultures of the gastro-intestinal and respiratory tract, and EMB results) to estimate the probability of myocarditis.

The Dutch Childhood Oncology Group guideline for follow-up of asymptomatic cardiac dysfunction in childhood cancer survivors.

BACKGROUND: The Late Effects of Childhood Cancer task force of the Dutch Childhood Oncology Group (DCOG LATER) developed a guideline for follow-up of asymptomatic cardiac dysfunction in childhood cancer survivors (CCS). In this paper, we present the methods, available evidence and final recommendations of our guideline. MATERIALS AND METHODS: A multidisciplinary working group specified clinical questions that should be answered to get to recommendations for the guideline. We carried out short or extensive evidence summaries and determined methodological quality of studies and levels of evidence in order to answer all clinical questions. When evidence was lacking for CCS, we carefully extrapolated evidence from other populations. Final recommendations were based on evidence and consensus. RESULTS: There was high-level evidence for the increased risk of cardiac dysfunction in CCS and its main risk factors. Evidence was lacking regarding the prognosis, diagnosis and treatment of cardiac dysfunction in CCS. We recommended echocardiographic screening for asymptomatic cardiac dysfunction in CCS treated with cardiotoxic treatments and counseling about potential advantages and disadvantages of our screening recommendations. CONCLUSION: The DCOG LATER guideline recommends risk-based screening for asymptomatic cardiac dysfunction in CCS, but it should be noted that recommendations are not completely supported by evidence in CCS.

[Complete atrioventricular septal defect in children with Down's syndrome: good results of surgical correction at younger and younger ages]. / Compleet atrioventriculair septumdefect bij kinderen met het syndroom van Down: goede resultaten van chirurgische correctie op steeds jongere leeftijd.

OBJECTIVE: To evaluate the results of cardiosurgical treatment of children with Down's syndrome and a complete atrioventricular septal defect (cAVSD). DESIGN: Retrospective. METHOD: Data were collected from the records of all patients with Down's syndrome who had been subjected to primary corrective surgery for cAVSD in the period 1980-2003 in Leiden, The Netherlands. Exclusion criteria were: concomitant tetralogy of Fallot or interruption of the aortic arch and palliative banding of the pulmonary artery. Children with an abnormal shape of the ventricle making it impossible to correct biventricularly were not considered in the study. Data on mortality >30 days after the operation and on repeated surgery were included in the analysis if the duration of follow-up was at least 5 years. RESULTS: The group comprised 148 children: 75 girls and 73 boys. The median age at time of surgery was 20 weeks (range: 6 weeks to 3.7 years) and showed a statistically significant decrease during the period under investigation. Of 4 children lost to clinical follow-up actual data could be obtained. The median duration offollow-up was 6 years and 7 months (range: 38 days to 23 years and 11 months). 28 children (19%) died. The mortality within 30 days after the operation decreased from 0-38% in the period 1980-1989 via 0-30% in the period 1990-1999 to 0% in 2000-2003. The percentage ofreoperations related to the correction ofcAVSD (14%; 14/98) did not seem to increase. Of the correction-related reoperations, 14% (2/14) were followed by a second reoperation. Conclusion. In the period 1980-2003, children with Down's syndrome and a cAVSD were corrected surgically at a younger and younger age. The early mortality decreased to 0% in the years 2000-2003. Echocardiography in the first weeks of life for all children with Down's syndrome makes it possible to diagnose those with a cAVSD early enough for surgical repair.

Low-dose daunorubicin in induction treatment of childhood acute lymphoblastic leukemia: no long-term cardiac damage in a randomized study of the Dutch Childhood Leukemia Study Group.

BACKGROUND: To investigate late cardiotoxicity in childhood acute lymphoblastic leukemia (ALL) survivors after induction treatment with or without daunorubicin (DNR; 25 mg/m(2), i.v., weekly, x4, cumulative dose 100 mg/m(2)). PROCEDURE: Cardiac function was assessed in 90 event-free survivors of childhood ALL, 11.4-17.8 years (median 14.8 years) after treatment according to the DCLSG protocol ALL V. In this protocol patients were randomized to receive (group B) or not to receive (group A) DNR 25 mg/m(2)/week i.v. during the first 4 weeks of induction treatment. Age at diagnosis was 1.2-14.9 years (median 4.5 years). The cardiac evaluation consisted of a history, physical examination, electrocardiogram (ECG), 24 hr ambulatory ECG, and echocardiography. RESULTS: Electrocardiographic data, arrhythmias, left ventricular dimensions, left ventricular contractility, wall stress, and diastolic function were within normal limits in both groups. No difference could be shown between data from group A (n = 40) and group B (n = 50). CONCLUSIONS: No late cardiac damage was demonstrated in childhood ALL survivors after induction treatment including a cumulative dose of 100 mg/m(2) DNR, compared to survivors who received the same treatment but without DNR. DNR 100 mg/m(2) given in 4 doses of 25 mg/m(2)/week appears to be a safe dose in induction treatment of ALL.

Academic career after treatment for acute lymphoblastic leukaemia.

AIM: To evaluate academic career in long term survivors of childhood acute lymphoblastic leukaemia (ALL), in comparison to their healthy siblings. PATIENTS: Ninety four children treated for ALL with cranial irradiation 18 or 25 Gy and intrathecal methotrexate as CNS prophylaxis. Median age at evaluation was 20 years; median follow up since diagnosis was 15 years at the time of the study. METHODS: Patients and their 134 siblings completed a questionnaire on school career. The percentage of referrals to special primary schools for learning disabled, and the final level of secondary education in patients and siblings were compared, using a six point classification. Within the patient group, the effect of possible risk factors (age at diagnosis, irradiation dose, and gender) was investigated. RESULTS: Significantly more patients than siblings were placed in special educational programmes. A significant difference was found for level of secondary education. No effect of gender or irradiation dose was found, but younger age at diagnosis was significantly related to both referrals and school levels. CONCLUSION: Treatment for childhood ALL with cranial irradiation and chemotherapy at a young age is clearly associated with poorer academic career.