Nitric Oxide and the Prevention of Birth Defects, 9/2005 

SUMMARY:
Inhallation of nitric oxide is a newly introduced intervention in infants with low birth weights who experience respiratory distress despite standard treatment. The first of two studies reports it does little to improve survival or to prevent lung abnormalities. The second had previously reported some improvement in survival and now reports the follow-up of survivors. Those who received nitric oxide had fewer neurodevelopmental defects, mostly in the intellectual realm. The incidence of cerebral palsy was essentially the same in the two groups, but the types were different.

Neonatologists (Pediatricians specializing in the care of newborn children) are constantly striving to improve the survival and quality of life of prematurely born children. This month we will review two articles published in the July 7, 2005 New England Journal of Medicine. Although the results are not very encouraging, they do show some benefit. It is also useful to note that those responsible for the well being of premature children keep working to improve outcomes.

Van Meurs and her associates¹ did a multi-center controlled study of the benefits of adding small amounts of nitric oxide to the gasses breathed by infants between 401 and 1500 grams (about 1-3 pounds) who were suffering respiratory distress that had not been relieved by standard means. They found across the range of premature infants that nitric oxide did not improve the rate of survival nor did it prevent the development of pulmonary dysfunction. However, it did improve oxygenation of the infants’ blood. They did note that in a subset of infants weighing more than 1000 grams (about 2 pounds) there was a small improvement in both survival and prevention of later pulmonary complications.

In another study, Mesten² and her colleagues reported the neurodevelopmental outcome of children enrolled in a single center, randomized, placebo controlled trial where about half of the infants were given nitric oxide and half had not (the “placebo arm”). This study³ of 207 infants was previously published and described the results of treatment on the survival and pulmonary complications of children receiving nitric oxide. In that report, they noted that 24% of the children in the placebo arm, but only 9% in the nitric oxide group, developed white mater disease or bleeding surrounding the cerebral ventricles (periventricular leucomalacia or PVL).

In the present study, they compared 70 children in the treated group with 69 children in the placebo group at 2 years of age. There were many dropouts in the study but most could be accounted for. Overall in the nitric oxide group, 24% were found to have neurodevelopmental disorders while in the control group 46% were found to have neurodevelopmental disorders. There was little difference in the incidence of cerebral palsy between the two groups, but a considerable difference in the number of children who had Mental Development Index Scores better than 70 and in developmental delay without disability.

Among the children who developed cerebral palsy, there were differences in the types of disability between the two groups. In the nitric oxide group, all six children with CP were diplegic. Among the eight in the control group, four were hemiparetic (one sided spasticity), one quariparetic (4 limb spasticity), and two diplegic (both lower limb spasticity). The type of cerebral palsy in one child was unstated.

Comment:
Very often medical progress proceeds by small steps rather than by giant bounds. Mental retardation commonly accompanies cerebral palsy. Although nitric oxide did not produce a decrease in the overall incidence of cerebral palsy, who could deny that improvement in their intellectual domain would not be a benefit for those children? This issue was not specifically addressed in the article due to the small numbers of children with cerebral palsy. It is also interesting that the types of cerebral palsy were different. There is no evident explanation for this difference.

¹Van Muers, KP et al. Inhaled nitric oxide for premature infants with severe respiratory failure. New England Journal of Medicine. 2005 (July 7); 353:13-22.
²Mesten, KL et al. Neurodevelopmental outcomes of premature infants treated with inhaled nitric oxide. New England Journal of Medicine. 2005 (July 7); 353:23-32.
³Schreiber, MD et al. Inhaled nitric oxide in infants with respiratory distress syndrome. New England Journal of Medicine. 2003; 349:2099-2107.

© UCP Research & Educational Foundation, September 2005

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