Oxygen for Newborns: When There Is Too Much of a Necessary Thing

Oxygen supplementation is often a critical part of neonatal care. Newborns, especially those born prematurely, may need oxygen supplementation during resuscitation and for stabilization afterward.

But exposure to high levels of oxygen can also have as a byproduct the generation of tissue-damaging “oxidative stress” if unstable reactive oxygen-containing molecules — also called oxygen free radicals — get too high. Oxygen supplementation is also associated with the creation of unstable nitrogen-containing molecules, such as nitric oxide and peroxynitrite, that can damage a variety of tissues.

In a recent review article published in the open-access journal Children, Serafina Perrone of the University of Parma in Italy and colleagues discussed some of “free radical diseases” that occur in newborns, primarily those born prematurely, and the decades of research seeking to identify the safest level of oxygen supplementation.

“Despite recent clinical studies, oxygen can still be considered a double-edged sword since higher levels may increase survival, although with increased risk of severe sequelae,” they wrote.

Vitamin E is an antioxidant that “soaks up” oxygen free radicals but, but Perrone and her colleagues note that data from clinical trials of vitamin E supplementation in preterm infants provided little supporting evidence for the supplementation.

The 17-page review article discusses some of the back-and-forth about the optimum levels of oxygen supplementation and the trade-offs between high and low levels.

In 1992, the American Heart Association guidelines for newborn resuscitation said that “100% oxygen should be used, it is not toxic and there are no reasons to be concerned,” according to Perrone and her colleagues.

But the review also notes that the potential toxicity of oxygen was identified in the early 1950s by Kate Campbell, an Australian pediatrician, who was the first to report a possible connection between oxygen supplementation and blindness in infants, a condition that has is now known as retinopathy of prematurity (ROP).

Here some of the other conditions related to oxygen and oxidative stress discussed in the review:

Bronchopulmonary dysplasia is a major cause of chronic lung disease and morbidity in preterm infants. The review says one of the main causes of the condition is oxidative stress sustained by inflammation due to exposure to high oxygen levels (“hyperoxia exposure”). High oxygen levels may spur on fibrotic process in lung tissue and interfere with the production of surfactant, a mixture of fats, proteins and carbohydrate that coats lung tissue and keeps them functioning.

Necrotizing enterocolitis is a potentially life-threatening condition characterized by inflammation and bacterial invasion of the wall of the large intestine. Some researchers have proposed that it is at least partially caused by inability of epithelial cells in the gut to cope with oxidative stress.

Patent ductus arteriosusoccurs when a hole in the aorta, which is normal in newborns, fails to close up in the several days after birth. Normally, exposure to oxygen after birth helps trigger the process that leads to the closure of the ductus arteriosus The link between oxidative stress and patent ductus arteriosus isn’t direct, but oxidative stress may interfere with the signaling that results in tissue growing and closing the hole.

Studies conducted in the mid-20th century showed that more limited use of oxygen resulted in fewer deaths, decreased respiratory failure and decreased lung disease, according to the Perrone and her co-authors. But researchers and clinicians also had to weigh the evidence reduced oxygen supplementation was associated with a higher risk of cerebral palsy. The review cites a 1961 study published in the New York State Journal of Medicine which showed that supplemental oxygen exposure of less than two days was associated with a 17% incidence of cerebral palsy and an 8.7% incidence of ROP whereas exposure to supplementation for more than 10 days was associated with a lower incidence (5.8%) of spastic diplegia (a form of cerebral palsy) but greater incidence (21.7%) incidence of ROP.

That was far from the last word, though, as researchers continued to try to figure out the safest and most effective oxygen level. Results from the Supplemental Therapeutic Oxygen for Prethreshold-ROP (STOP-ROP) study showed that high levels of oxygen did not prevent the progression of ROP but were associated with pneumonia, chronic lung disease and hospitalization.

A definitive meta-analysis called the Neonatal Oxygen Prospective Meta-Analysis (NeOProM) that was published in 2011 in the BMC Pediatrics concluded there was no difference in death, disability and neurodevelopmental impairment, such as cerebral palsy or cognitive impairment, between high- and low-exposure oxygen groups. But this meta-analysis showed again that there may be some tradeoffs: low oxygen saturation (the proportion of hemoglobin bound to oxygen) was associated with 25% reduced risk of ROP, according to the meta-analysis but a 25% increase in necrotizing enterocolitis.

Perrone and her colleagues say results from STOP-ROP and NeOProM studies suggested a mid-range target level for oxygen saturation.

“Extreme excess supplementation of oxygen is not administered in modern NICUs (neonatal intensive care units),” they wrote in the review article. “This means that ROS (reactive active species)-mediated injuries due to hyperoxia may be reduced in the recent era.”