Critical issues with clinical research in children: the example of premature infants

Research in pediatrics has led to marked improvements in survival in pediatric patients. In no other age group have these improvements been more dramatic than in neonatology, where antenatal steroid administration to mothers and postnatal utilization of surfactant have led to marked improvements in survival so that infants born at 24 weeks gestation now have a greater than 50% chance of survival. Unfortunately, more than 50% of these patients develop significant complications of prematurity with potential long-term impact on the health of these infants. Therefore, additional research must be done in these patients to prevent these complications or reduce the impact of these complications. There are many practical and some ethical issues that could impede research in the area. Interventional studies have succeeded because literally decades of research defined unequivocally the pathophysiology of diseases such as surfactant deficiency in RDS. Unfortunately, the pathophysiology leading to the complications of prematurity has been extrapolated from old concepts without verification as the population has become smaller and more premature than the previous era. Thus, an extremely important practical issue in pediatric research is whether to design interventions to address the extrapolated pathophysiology risking misinterpretations of the results of such studies. Or should our efforts be focused on defining endpoints associated with the development of diseases and complications which may define pathophysiology more completely but delay the design of interventions to improve the outcomes of patients. Another crucial practical issue in pediatric research is how to power studies so that interventions can be studied adequately. In the US, large neonatal networks have been formed so that large databases can be created and large multi-center trials can be performed. The practical issues associated with these network studies is the center to center variability in patient care may dwarf the beneficial effect of the intervention on the disease process, so that a "negative" study of an intervention may not represent the true effect of the intervention in the disease process. These practical issues among others will be the focus of this review.