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Andrew B. Kairalla MD, Editor

Saleh Al-Alaiyan,  MD, Guest Editor


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Long-Term Effects of Caffeine

Schmidt B,  Roberts R, Davis P, et al.  Long-Term Effects of Caffeine Therapy for Apnea of Prematurity. N Engl J Med 357:1893, November 8, 2007.  [Full Text ]  | [PDF]

Background. Methylxanthine therapy is commonly used for apnea of prematurity but in the absence of adequate data on its efficacy and safety. It is uncertain whether methylxanthines have long-term effects on neurodevelopment and growth.

Methods.  We randomly assigned 2006 infants with birth weights of 500 to 1250 g to receive either caffeine or placebo until therapy for apnea of prematurity was no longer needed. The primary outcome was 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 at a corrected age of 18 to 21 months.   
       
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=0.008). 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=0.009) and of cognitive delay (33.8% vs. 38.3%; adjusted odds ratio, 0.81; 95% CI, 0.66 to 0.99; P=0.04). 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 two 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.


Comments. This study is a follow up at 18-21 months of infants previously reported by these authors (N Engl J Med 2006).  The original study showed that infants randomly assigned to caffeine had a significant reduction in BPD as well diminished weight gain during the first 3 weeks.  In the present study, the authors found that the rate of survival without neurodevelopmental disability, particularly CP and cognitive delay, improved in infants randomly assigned to caffeine therapy as compared with the placebo group. Furthermore, the rates of death, deafness, and blindness and growth parameters did not differ significantly between the two groups. The incidence of severe ROP was reduced by caffeine treatment, even though the overall incidence of retinopathy of prematurity was not altered by caffeine use. Overall, the authors estimated that the number of infants who would need to be treated with caffeine to prevent one adverse outcome was 16.  Infants assigned to caffeine had earlier discontinuation of positive airway pressure as compared with placebo which put the placebo group at risk of ventilator-induced lung injury that results in the development of bronchopulmonary dysplasia, which in turn is an important risk factor for neurodevelopmental disability. On the other hand, longer follow-up is necessary, since the neurodevelopmental outcome at 18 to 21 months is not entirely prognostic of later neurodevelopmental outcome. SAA.
 

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