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Neuroprotection for premature infants?: another perspective on caffeine.

APPROXIMATELY 85% OF INFANTS BORN WEIGHING LESS than 1500 g at birth (approximately 30 weeks’ gestational age) survive to hospital discharge. However, these surviving preterm infants, especially those at the threshold of viability (23 to 25 weeks’ gestational age) often have major developmental deficits or minor functional morbidities that interfere with daily living. One-third of children with birth weight less than 1000 g who had no neurosensory problems detected at hospital discharge had an IQ of less than 85, learning problems, or poor motor skills at 8 to 9 years of age, and two-thirds had behavioral problems; those with abnormalities identified in the newborn period had an even greater rate of adverse outcome. In the United States, preterm infants contribute more than half of all new cases of cerebral palsy and contribute disproportionately to cognitive impairment as well, although the extent is more difficult to evaluate. The resulting burden on family and societal resources is substantial. On average, a child with cerebral palsy born in 2000 incurs an estimated lifetime medical and nonmedical direct and indirect cost of nearly $1 million in 2003 dollars. The combined cost for all children with cerebral palsy, deafness, and blindness was estimated at $16 billion in 2003. Other costs that cannot easily be measured are reflected in the high rates of depression, anxiety, and behavioral problems of children with cerebral palsy and their families. An intervention that could reduce the effect of disability in preterm infants would be beneficial for the children, their families, and society as a whole. However, with the exception of antenatal corticosteroids and surfactant replacement therapy, the results of most clinical trials aimed at improving outcomes of prematurity have been disappointing. Promising short-term results are often not sustained through infancy or childhood. For example, in the Trial of Indomethacin Prophylaxis in Preterms, indomethacin administered to extremely low-birthweight infants significantly decreased the incidence of patent ductus arteriosus and periventricular and intraventricular hemorrhage. However, the rate of survival without neurosensory impairment at 18 months of age, the primary outcome of the trial, was similar in both groups. In another study that compared vitamin A supplementation with placebo, vitamin A supplementation reduced the rate of chronic lung disease in extremely low-birth-weight infants, but respiratory and neurodevelopmental outcomes were similar in both groups at 18 to 22 months of age. In this issue of JAMA, Schmidt and colleagues report the results of their 5-year follow-up of infants enrolled in the Caffeine for Apnea of Prematurity (CAP) trial. This publication is the third report from a large international trial to assess the long-term effects on neurodevelopment and growth of an agent widely used to treat apnea in preterm infants. In the CAP trial, infants with a birth weight of 500 to 1250 g whose clinicians considered treatment with a methylxanthine during the first 10 days of age were randomly assigned to receive caffeine or placebo. The indications for treatment were to prevent or treat apnea or to facilitate endotracheal extubation; treatment was continued until the clinicians thought it was no longer needed. The 18-month neurodevelopmental outcomes were measured using the Bayley Scales of Infant Development, Second Edition (BSID-II), which was the gold standard for neurodevelopmental assessment when the study was conducted. As reported previously, the primary outcome of the trial—a composite of death before 18 months and cerebral palsy, cognitive delay, severe hearing loss, or bilateral blindness at a corrected age of 18 to 21 months—occurred in 40.2% of the caffeine group compared with 46.2 percent of the placebo group (odds ratio adjusted for center, 0.77; 95% CI, 0.640.93, P=.008). Treatment with caffeine nearly halved the rate of cerebral palsy, and resulted in a modest decrease in cognitive delay. Among short-term outcomes, caffeine substantially reduced the rate of bronchopulmonary dysplasia but did not affect the rates of death, brain injury detected by ultrasonography, or necrotizing enterocolitis. In the current study, neurobehavioral, neuropsychological, and motor outcomes were comprehensively evaluated at 5 years of age. The Wechsler Preschool and Primary School Scale of Intelligence III, Child Behavior Checklist, and Move-