Pulsed arterial spin labeling (PASL) perfusion MRI has unique advantages for measuring cerebral blood flow (CBF) in the pediatric population. In neonates with congenital heart defects (CHDs), however, a considerable number of negative CBF values were observed in PASL perfusion images. A set of specific physiological and biophysical conditions were proposed as plausible explanations for this phenomenon, including small body size, low blood flow, prolonged tracer life time (blood T1) and the "shunt" between pulmonary and systemic circulations in CHD. An optimized PASL scheme with a restricted label volume was proposed, and experimental data demonstrated reduced spurious negative values and lower intersubject variability of perfusion measurements in neonates with CHD as compared to standard PASL sequences.