Term pregnancy has been defined as one in which 37 to 41^6/7 weeks have elapsed since the first day of the last menstrual period, referred to as postmenstrual age (PMA).¹ Neonates born during this 5-week period have traditionally been considered a homogeneous low-risk group. Categorizing groups of newborns is of value to focus attention on negative outcomes and to develop strategies to address the causes.² For example, the late-preterm neonate emerged as a newly described group in the last decade, defined in part to draw attention to the significantly higher than perceived risk for morbidity and mortality. This resulted in efforts such as the 2005 workshop of the Eunice Kennedy Shriver National Institute of Child Health and Human Development on late-preterm infants (34-36^6/7 weeks’ PMA), which served as a platform for raising awareness and effecting prevention.^3,4 The designation of early-term infants (37-38^6/7 weeks’ PMA) was more recently coined to focus attention on the risk for morbidity and mortality in such infants compared with other term infants born at 39 to 41^6/7 weeks’ gestational age.^1,2,5 Morbidity among early-term infants is considerably less than that among late-preterm infants.⁶ However, early-term infants outnumber late-preterm infants by 3 to 1 in the United States (27.6% vs 8.7% of all births in 2009).⁷ Studies linking gestational age to outcomes among term neonates have focused on the presence of labor and mode of delivery and have provided limited description of neonatal outcomes^8,9 or are based on admissions to a tertiary care center and not a specific geographic area.¹⁰

Normal neonatal lung growth requires a substantial increase in microvascular endothelial cells. Oxygen injury to neonatal lung destroys endothelial cells and alters the normal process of alveolarization, including development of the microvasculature. The mechanisms that regulate lung alveolar capillary growth and development are not known. Vascular endothelial growth factor (VEGF) is a specific mitogen for endothelial cells that is often expressed by epithelial cells in close proximity to capillary beds. VEGF expression is induced by hypoxia and may be inhibited by hyperoxia. We examined the cell-specific expression of VEGF during normal postnatal lung development and the effects of hyperoxic lung injury on VEGF mRNA and protein in vivo. Normal newborn rabbits between 1 day and 5 wk of age had VEGF transcripts located mainly in alveolar epithelial cells, with little or no VEGF mRNA noted in smooth muscle or endothelial cells. A subpopulation of freshly isolated, normal type II cells, but not mesenchymal cells, expressed VEGF mRNA. Newborn rabbits exposed to 100% oxygen for 4 days had no change in VEGF mRNA abundance, transcript location, or immunostaining. Animals exposed to 100% oxygen for an average of 9 days had an 80% decrease in lung VEGF mRNA abundance, decreased alveolar epithelial cell VEGF expression, and decreased VEGF immunostaining. Recovery of VEGF expression to control levels occurred during a 5-day recovery period. We conclude that alveolar epithelial cells in postnatal lung express VEGF, suggesting epithelial regulation of alveolar capillary formation. Furthermore, hyperoxic injury decreases neonatal lung VEGF mRNA and protein, which may be a contributory mechanism of impaired postnatal microvascular development in oxygen injury.

Objective. To test the hypothesis that high-frequency jet ventilation (HFJV) will reduce the incidence and/or severity of bronchopulmonary dysplasia (BPD) and acute airleak in premature infants who, despite surfactant administration, require mechanical ventilation for respiratory distress syndrome. Design. Multicenter, randomized, controlled clinical trial of HFJV and conventional ventilation (CV). Patients were to remain on assigned therapy for 14 days or until extubation, whichever came first. Crossover from CV to HFJV was allowed if bilateral pulmonary interstitial emphysema or bronchopleural fistula developed. Patients could cross over to the other ventilatory mode if failure criteria were met. The optimal lung volume strategy was mandated for HFJV by protocol to provide alveolar recruitment and optimize lung volume and ventilation/perfusion matching, while minimizing pressure amplitude and O₂ requirements. CV management was not controlled by protocol. Setting. Eight tertiary neonatal intensive care units. Patients. Preterm infants with birth weights between 700 and 1500 g and gestational age 0.30 at 2 to 12 hours after surfactant administration, received surfactant by 8 hours of age, were <20 hours old, and had been ventilated for <12 hours. Outcome Measures. Primary outcome variables were BPD at 28 days and 36 weeks of postconceptional age. Secondary outcome variables were survival, gas exchange, airway pressures, airleak, intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), and other nonpulmonary complications. Results. A total of 130 patients were included in the final analysis; 65 were randomized to HFJV and 65 to CV. The groups were of comparable birth weight, gestational age, severity of illness, postnatal age, and other demographics. The incidence of BPD at 36 weeks of postconceptional age was significantly lower in babies randomized to HFJV compared with CV (20.0% vs 40.4%). The need for home oxygen was also significantly lower in infants receiving HFJV compared with CV (5.5% vs 23.1%). Survival, incidence of BPD at 28 days, retinopathy of prematurity, airleak, pulmonary hemorrhage, grade I–II IVH, and other complications were similar. In retrospect, it was noted that the traditional HFJV strategy emphasizing low airway pressures (HF-LO) rather than the prescribed optimal volume strategy (HF-OPT) was used in 29/65 HFJV infants. This presented a unique opportunity to examine the effects of different HFJV strategies on gas exchange, airway pressures, and outcomes. HF-OPT was defined as increase in positive end-expiratory pressure (PEEP) by ≥1 cm H₂O from pre-HFJV baseline and/or use of PEEP of ≥7 cm H₂O. Severe neuroimaging abnormalities (PVL and/or grade III–IV IVH) were not different between the CV and HFJV infants. However, there was a significantly lower incidence of severe IVH/PVL in HFJV infants treated with HF-OPT compared with CV and HF-LO. Oxygenation was similar between CV and HFJV groups as a whole, but HF-OPT infants had better oxygenation compared with the other two groups. There were no differences in Paco₂ between CV and HFJV, but the Paco₂ was lower for HF-LO compared with the other two groups. The peak inspiratory pressure and ΔP (peak inspiratory pressure-PEEP) were lower for HFJV infants compared with CV infants. Conclusions. HFJV reduces the incidence of BPD at 36 weeks and the need for home oxygen in premature infants with uncomplicated RDS, but does not reduce the risk of acute airleak. There is no increase in adverse outcomes compared with CV. HF-OPT improves oxygenation, decreases exposure to hypocarbia, and reduces the risk of grade III–IV IVH and/or PVL.