Use of caffeine for apnea of prematurity also has long-term neurodevelopmental benefits

Article Outline

• Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, et al, for the Caffeine for Apnea of Prematurity Trial Group. Long-term effects of caffeine therapy for apnea of prematurity. N Engl J Med 2007;357:1893-902
  • Question
  • Design
  • Setting
  • Participants
  • Intervention
  • Outcome
  • Main results
  • Conclusions
  • Comment
• Copyright

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Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, et al, for the Caffeine for Apnea of Prematurity Trial Group. Long-term effects of caffeine therapy for apnea of prematurity. N Engl J Med 2007;357:1893-902 

Question 

Among preterm infants, does treatment with caffeine for apnea of prematurity have any long-term effects on neurodevelopment and growth?

Design 

Randomized controlled trial.

Setting 

Multiple centers in the United States, Canada, Europe, Australia, and Israel.

Participants 

2006 infants with birth weights of 500 to 1250 g.

Intervention 

Infants received either caffeine or placebo until therapy for apnea of prematurity was no longer needed. Participants were followed to a corrected age of 18 to 21 months.

Outcome 

A composite of death, cerebral palsy, cognitive delay (defined as a Mental Development Index score of <85 on the Bayley Scales of Infant Development), deafness, or blindness.

Main results 

Of the 937 infants assigned to caffeine for whom adequate data on the primary outcome were available, 377 (40.2%) died or survived with a neurodevelopmental disability, as compared with 431 of the 932 infants (46.2%) assigned to placebo for whom adequate data on the primary outcome were available (odds ratio adjusted for center, 0.77; 95% confidence interval [CI], 0.64 to 0.93; P = .008, number needed to treat [NNT] = 17). Treatment with caffeine as compared with placebo reduced the incidence of cerebral palsy (4.4% vs 7.3%; adjusted odds ratio, 0.58; 95% CI, 0.39 to 0.87; P = .009, NNT = 35) and of cognitive delay (33.8% vs 38.3%; adjusted odds ratio, 0.81; 95% CI, 0.66 to 0.99; P = .04, NNT = 23). The rates of death, deafness, and blindness and the mean percentiles for height, weight, and head circumference at follow-up did not differ significantly between the 2 groups.

Conclusions 

Caffeine therapy for apnea of prematurity improves the rate of survival without neurodevelopmental disability at 18 to 21 months in infants with very low birth weight.

Comment 

Methylxanthines have been a mainstay of treatment for apnea of prematurity for over 3 decades. They reduce the frequency of apnea episodes, but evidence of favorable effects on long-term outcomes has been lacking. Central nervous system effects might actually adversely impact neurological development. This report, along with the short-term outcomes from the same trial, lays those concerns to rest. More than 2000 infants were enrolled in this multicenter, randomized, placebo-controlled trial. Infants treated with caffeine were extubated, weaned from continuous positive air pressure, and weaned from supplemental oxygen sooner, and fewer required oxygen at 36 weeks gestation. At 18 to 21 months of age, fewer treated infants had died or survived with neurodevelopmental impairment, with an estimated number needed to treat of 17 to avoid one such outcome. In particular, rates of cerebral palsy and cognitive delay were reduced. Because of these data, we now know that our time-honored reliance on methylxanthines for management of apnea of prematurity was not misguided, and in fact appears to be beneficial. Moreover, we know who (infants with birth weights of 500 to 1250 g), when (within 10 days after birth), how (loading dose of 20 mg/kg of caffeine citrate followed by daily maintenance doses of 5 mg/kg, increased to 10 mg/kg if apneas persisted), and how long (until apneas resolve, or to median gestational age of 35 weeks) to treat, and that monitoring of caffeine levels is unnecessary. Criteria for initiation of treatment (which were “treatment or prevention of apnea or to facilitate endotracheal tube removal” in this trial) remain imprecise.