Lukas Augustinus Johannes Rammeloo

Background: Passive leg raising is used to predict who will benefit from fluid therapy in critically ill patients, including children. Patients with a Fontan circulation may have a different haemodynamic response to a fluid challenge by passive leg raising. Methods: The haemodynamic response of 31 paediatric patients with a Fontan circulation from the outpatient clinic (median age 14.0 years) and 35 healthy controls (median age 12.8 years) to passive leg raising was evaluated non-invasively by echocardiography for the assessment of, e.g., velocity time integral across the (neo)aortic valve, blood pressure measurements, and respiration. Participants were considered responders when the velocity time integral increased ≥ 10.0%. Results: Overall, patients and controls did not differ in the haemodynamic response. Twelve patients (38.7%) and 8 controls (22.9%) were responders, which was not statistically different ( P = 0.22). Responders in the patient and control group also had a similar echo-estimated velocity time integral increase of + 18.9% and + 15.2%, respectively ( P = 0.91). There was no difference in echo-estimated velocity time integral change between patient and control non-responders with a decrease of −1.4% and −6.4%, respectively ( P = 0.70) and no difference in the amount of patients who were negatively affected by passive leg raising, ith a decrease of ≤−10.0% in 7 patients (22.6%) and 9 controls (25.7%)( P = 0.77). Conclusion: The haemodynamic response of ambulatory paediatric patients with a Fontan circulation to passive leg raising is like that of healthy controls. Patients who did not respond were similarly affected as healthy controls. Whether the haemodynamic response is different in critically ill patients warrants further investigation. Trail registration: The Netherlands National Trial Register (NTR), Trial: NL6415; date of registration 20-07-2017; Trial information: https://www.trialregister.nl/trial/6415.

Background: Cardiopulmonary exercise testing (CPET) has an important prognostic value in adults with different congenital heart defects (CHDs) and is a useful tool for risk stratification and clinical decision-making. In this retrospective study, we studied the prognostic value of CPET in paediatric patients with CHD. Methods: 411 CPET performed by paediatric patients with different CHDs were evaluated in this retrospective study. Medical records were reviewed to determine the presence of cardiac events. Participants were classified using the 2018 AHA/ACC guideline for the management of adults with CHD that combines anatomical complexity and current physiological stage. Results: 411 patients with a median age at test of 12 years, 51 patients with simple CHD, 170 patients with moderate complexity CHD and 190 with high complexity CHD underwent CPET. Overall, CPET parameters were lower than the reference values (%predicted VO_2peak=75% and %predicted oxygen uptake efficiency slope (OUES)=79%), showing worst exercise capacity in the most complex types of CHD (Group III: %predicted VO_2peak=72% and %predicted OUES=75%). Seventy-one patients presented with cardiac events at a median time from CPET to first event of 28 months. Patients with cardiac events had lower exercise performance as compared with patients without cardiac events as determined by the submaximal variables (%predicted OUES: HR=2.6 (1.5–4.4), p2: HR=2.2 (1.4–3.5), p=0.001). Conclusion: Reduced exercise capacity at young age is related to a higher probability of future cardiovascular events in paediatric patients with CHD. Submaximal exercise variables can be used instead when maximal exercise cannot be achieved.

The total uptake of prenatal aneuploidy screening for Down syndrome (DS) is increasing worldwide. As a result of increasing prenatal diagnosis of DS and subsequent termination of pregnancy, livebirth prevalence of DS is decreasing. The aim of this study is to explore the impact of an increasing uptake of prenatal aneuploidy screening on the neonatal mortality and morbidity in DS. This is a retrospective cohort study of 253 neonates with DS born between 2012 and 2018 that were seen at the outpatient clinic of five hospitals in the Netherlands. The medical files were reviewed for maternal and neonatal characteristics and neonatal morbidities. The Dutch national birth registry (Perined) provided mortality numbers of neonates with DS. The results were interpreted in the context of other published studies. Neonatal mortality in DS remained stable, ranging from 1.4 to 3.6%. A congenital heart defect (CHD) was found in 138 of the 251 neonates (55.0%) with atrial septal defect, atrioventricular septal defect, and ventricular septal defect being the most common. The type of CHD in DS did not change over time. Gastro-intestinal defects were present in 22 of the 252 neonates with DS (8.7%), with duodenal atresia as the most reported anomaly. Persistent pulmonary hypertension of the neonate (PPHN) was found in 31 of the 251 infants (12.4%).  Conclusions: Although uptake of prenatal aneuploidy screening increased, neonatal mortality and morbidity in DS appears to be stable. An increased incidence of PPHN was found. What is Known:• The total uptake of prenatal aneuploidy screening for Down syndrome is increasing worldwide.• As a result of increasing prenatal diagnosis of Down syndrome and subsequent termination of pregnancy, the livebirth prevalence of Down syndrome is decreasing. What is New:• Although uptake of prenatal aneuploidy screening increased, neonatal mortality and morbidity in Down syndrome appears to be stable.• An increased incidence of persistent pulmonary hypertension of the neonate was found.

Background: This study aimed to describe the current practice and results of genetic evaluation in Dutch children with dilated cardiomyopathy and to evaluate genotype-phenotype correlations that may guide prognosis. Methods: We performed a multicenter observational study in children diagnosed with dilated cardiomyopathy, from 2010 to 2017. Results: One hundred forty-four children were included. Initial diagnostic categories were idiopathic dilated cardiomyopathy in 67 children (47%), myocarditis in 23 (16%), neuromuscular in 7 (5%), familial in 18 (13%), inborn error of metabolism in 4 (3%), malformation syndrome in 2 (1%), and “other” in 23 (16%). Median follow-up time was 2.1 years [IQR 1.0–4.3]. Hundred-seven patients (74%) underwent genetic testing. We found a likely pathogenic or pathogenic variant in 38 children (36%), most often in MYH7 (n = 8). In 1 patient initially diagnosed with myocarditis, a pathogenic LMNA variant was found. During the study, 39 patients (27%) reached study endpoint (SE: all-cause death or heart transplantation). Patients with a likely pathogenic or pathogenic variant were more likely to reach SE compared with those without (hazard ratio 2.8; 95% CI 1.3–5.8, P = 0.007), while transplant-free survival was significantly lower ( P = 0.006). Clinical characteristics at diagnosis did not differ between the 2 groups. Conclusions: Genetic testing is a valuable tool for predicting prognosis in children with dilated cardiomyopathy, with carriers of a likely pathogenic or pathogenic variant having a worse prognosis overall. Genetic testing should be incorporated in clinical work-up of all children with dilated cardiomyopathy regardless of presumed disease pathogenesis.

A single 6-min walk test (6MWT) can be used to identify children with dilated cardiomyopathy (DCM) with a high risk of death or heart transplantation. To determine if repeated 6MWT has added value in addition to a single 6MWT in predicting death or heart transplantation in children with DCM. Prospective multicenter cohort study including ambulatory DCM patients ≥ 6 years. A 6MWT was performed 1 to 4 times per year. The distance walked was expressed as percentage of predicted (6MWD%). We compared the temporal evolution of 6MWD% in patients with and without the study endpoint (SE: all-cause death or heart transplantation), using a linear mixed effects model. In 57 patients, we obtained a median of 4 (IQR 2–6) 6MWTs per patient during a median of 3.0 years of observation (IQR 1.5–5.1). Fourteen patients reached a SE (3 deaths, 11 heart transplantations). At any time during follow-up, the average estimate of 6MWD% was significantly lower in patients with a SE compared to patients without a SE. In both patients groups, 6MWD% remained constant over time. An absolute 1% lower 6MWD% was associated with an 11% higher risk (hazard) of the SE (HR 0.90, 95% CI 0.86–0.95 p < 0.001). Children with DCM who died or underwent heart transplantation had systematically reduced 6MWD%. The performance of all patients was stable over time, so repeated measurement of 6MWT within this time frame had little added value over a single test.

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.

Cardiopulmonary exercise testing is an important tool to predict prognosis in children and adults with heart failure. A much less sophisticated exercise test is the 6 min walk test, which has been shown an independent predictor for morbidity and mortality in adults with heart failure. Therefore, we hypothesized that the 6 min walk test could be predictive for outcome in children with dilated cardiomyopathy. We prospectively included 49 children with dilated cardiomyopathy ≥6 years who performed a 6 min walk test. Median age was 11.9 years (interquartile range [IQR] 7.4–15.1), median time after diagnosis was 3.6 years (IQR 0.6–7.4). The 6 min walk distance was transformed to a percentage of predicted, using age- and gender-specific norm values (6MWD%). For all patients, mean 6MWD% was 70 ± 21%. Median follow-up was 33 months (IQR 14–50). Ten patients reached the combined endpoint of death or heart transplantation. Using univariable Cox regression, a higher 6MWD% resulted in a lower risk of death or transplantation (hazard ratio 0.95 per percentage increase, p = 0.006). A receiver operating characteristic curve was generated to define the optimal threshold to identify patients at highest risk for an endpoint. Patients with a 6MWD% < 63% had a 2 year transplant-free survival of 73%, in contrast to a transplant-free survival of 92% in patients with a 6MWD% ≥ 63% (p = 0.003). In children with dilated cardiomyopathy, the 6 min walk test is a simple and feasible tool to identify children with a higher risk of death or heart transplantation.