Journal of Developmental Origins of Health and Disease


Prematurity and programming: contribution of neonatal Intensive Care Unit interventions

S. C. Kalhana1a2 c1 and D. Wilson-Costelloa3

a1 Department of Molecular Medicine, Cleveland Clinic, Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA

a2 Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA

a3 Department of Neonatology, Rainbow Babies and Children's Hospital, Case Western Reserve University, Cleveland, OH, USA


Contemporary clinical practice for the care of the prematurely born babies has markedly improved their rates of survival so that most of these babies are expected to grow up to live a healthy functional life. Since the clinical follow-up is of short duration (years), only limited data are available to relate non-communicable diseases in adult life to events and interventions in the neonatal period. The major events that could have a programming effect include: (1) intrauterine growth restriction; (2) interruption of pregnancy with change in redox and reactive oxygen species (ROS) injury; (3) nutritional and pharmacological protocols for clinical care; and (4) nutritional care in the first 2 years resulting in accelerated weight gain. The available data are discussed in the context of perturbations in one carbon (methyl transfer) metabolism and its possible programming effects. Although direct evidence for genomic methylation is not available, clinical and experimental data on impact of redox and ROS, of low protein intake, excess methionine load and vitamin A, on methyl transfers are reviewed. The consequences of antenatal and postnatal administration of glucocorticoids are presented. Analysis of the correlates of insulin sensitivity at older age, suggests that premature birth is the major contributor, and is compounded by gain in weight during infancy. We speculate that premature interruption of pregnancy and neonatal interventions by affecting one carbon metabolism may cause programming effects on the immature baby. These can be additive to the effects of intrauterine environment (growth restriction) and are compounded by accelerated growth in early infancy.

(Received December 29 2011)

(Revised August 15 2012)

(Accepted September 11 2012)

(Online publication October 11 2012)

Key words

  • insulin resistance;
  • methionine;
  • parenteral nutrition;
  • prematurity;
  • programming


c1 Address for correspondence: Dr S. C. Kalhan, Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, NE-40, 9500 Euclid Avenue, Cleveland, OH 44195, USA. Email