Eur J Pediatr (2009) 168:1081–1090 It is well known that lower stage neuroblastoma can regress spontaneously over time and therefore these neuroblastoma might never have come into clinical attention without the thorough investigations after detection of CHD. This may artificially increase the difference between prevalence of CHD in neuroblastoma patients and controls. Indeed, in the study of George et al. [11] neuroblastoma was detected during workup for CHD in three patients. George et al. found a relatively high proportion of patients with neural crest-derived CHD. Five of 14 (36%) patients with CHD had neural crest-derived CHD, which is more than expected when considering the normal distribu- tion of CHD [13]. This seems in favour of a possible association between the two conditions, with its source in the common neural crest origin. However, numbers were very small in the study of George et al. The 16 other studies on CHD in neuroblastoma patients reviewed here, showed prevalence rates much lower than the 20% reported by George et al. In these studies it was not mentioned how patients were evaluated for the presence of CHD, but it is unlikely that the majority of patients underwent echocardiography or other imaging techniques. CHD might thus have been missed. In all of these studies information was lacking on other items of validity as well. The validity of a study addresses the issue of whether the researcher actually measures what is said to be measured. It concerns the extent to which the results of a study can be interpreted adequately and the extent to which we can trust these results. A lack of information on validity items might lead to invalid results; the studies reviewed here might have been subject to various types of bias. For example, a well-defined definition of CHD was not given in the studies, which led to difficulties in interpretation of what exactly had been considered as CHD. The use of a non-representative sample of patients from the original study group may have led to either over- or under- estimation of the true prevalence of CHD, depending on whether patients with a higher or a lower risk profile were selected for the study. In addition, cancer registries, birth certificates and medical charts might not contain all medical information and therefore CHD could be under-reported. In studies were data from these registries served as control data, the significance of a higher prevalence of CHD in neuroblas- toma patients might have been overestimated [7, 9, 15]. In studies based on parental interviews, recall bias may have led to overestimation of CHD in neuroblastoma patients. In addition, studies in tertiary care centres might have been subject to referral bias. Non-accuracy of the control group can be a source of bias as well. We used the consecutive ALL cohort presented by George et al. as a control group [11]. We chose this control group because all consecutive children in this cohort had undergone echocardiography, like the patients in our study group. A concern might be that the 1089 control group comprises patients from another country. We therefore also compared the prevalence of CHD in our cohort to data from EUROCAT Northern Netherlands, with non-significant results. As mentioned above, use of data from a health registry for comparison may lead to bias as well. However, because data in health registries might be prone to under-representation of anomalies in the general population [7, 9, 15], this would imply that the significance of the difference is even less than described. In conclusion, although several studies have addressed the prevalence of CHD in neuroblastoma patients, only the present study and the study of George et al. [11] used adequate methodology and had reasonable validity to determine the prevalence of CHD in these patients. However, the results differed largely between these two studies. The difference may in part be explained by differences in methodology and patient characteristics, but may be due to chance as well. Therefore, the association between neuroblastoma and CHD remains unclear. To confirm or reject the true existence of such an association, further research in a large and complete cohort of neuroblastoma patients is needed. Our study and systematic review have shown, however, that clear evidence of an association between neuroblastoma and CHD is lacking. Standard cardiac screening in all patients with neuroblasto- ma is therefore not supported by current evidence. Acknowledgements We thank Edith Leclercq for her support in the construction of the search strategies and Jeroen Vis for help in the arrangement and performance of the cardiologic examinations. 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