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JAMA. 2012 Jan 18;307(3):275-82. doi: 10.1001/jama.2011.2024.

Survival without disability to age 5 years after neonatal caffeine therapy for apnea of prematurity.

Collaborators (165)

Schmidt B, D'Ilario J, Cairnie J, Dix J, Adams B, Warriner E, Kim MH, Anderson P, Davis P, Doyle L, Argus B, Callanan K, Davis N, Duff J, McDonald M, Asztalos E, Hohn D, Lacy M, Haslam R, Barnett C, Goodchild L, Lontis R, Fraser S, Keng J, Saunders K, Opie G, Kelly E, Woods H, Marchant E, Turner AM, Davis N, Magrath E, Williamson A, Bairam A, BĂ©langer S, Fraser A, Lemyre B, Frank J, Solimano A, Synnes A, Grunau RE, Hubber-Richard P, Rogers M, Mackay M, Petrie-Thomas J, Butt A, van Wassenaer A, Nuytemans D, Houtzager B, van Sonderen L, Regev R, Itzchack N, Arnon S, Chalaf A, Ohlsson A, O'Brien K, Hamilton AM, Chan ML, Sankaran K, Morgan S, Proctor P, Golan A, Goldsch-Lerman E, Reynolds G, Dromgool B, Meskell S, Parr V, Maher C, Broom M, Kecskes Z, Ringland C, McMillan D, Schaab D, Spellen E, Sauve RS, Christianson H, Anseeuw-Deeks D, Creighton D, Heath J, Alvaro R, Chiu A, Porter C, Turner G, Moddemann D, Granke N, Penner K, Bow J, Mulder A, Wassenberg R, van der Hoeven M, Clarke M, Parfitt J, Parker K, Nwaesei C, Ryan H, Saunders C, Schulze A, Wermuth I, Hilgendorff A, Flemmer AW, Herlenius E, Legnevall L, Lagercrantz H, Matthew D, Amos W, Tulsiani S, Tan-Dy C, Turner M, Phelan C, Shinwell E, Levine M, Juster-Reicher A, Khairy M, Grier P, Vachon J, Perepolkin L, Barrington KJ, Sinha S, Tin W, Fritz S, Walti H, Royer D, Halliday H, Millar D, Berry A, Mayes C, McCusker C, McLaughlin O, Fahnenstich H, Tillmann B, Weber P, Wariyar U, Embleton N, Swamy R, Bucher HU, Fauchere JC, Dietz V, Harikumar C, Tin W, Fritz S, Schmidt B, Anderson PJ, Asztalos EV, Barrington KJ, Davis PG, Dewey D, Doyle LW, Grunau RE, Moddemann D, Ohlsson A, Roberts RS, Solimano A, Tin W, Gent M, Fraser W, Hey E, Perlman M, Thorpe K, Gray S, Roberts RS, Chambers C, Costantini L, Yacura W, McGean E, Scapinello L.

Author information

Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Canada.



Very preterm infants are prone to apnea and have an increased risk of death or disability. Caffeine therapy for apnea of prematurity reduces the rates of cerebral palsy and cognitive delay at 18 months of age.


To determine whether neonatal caffeine therapy has lasting benefits or newly apparent risks at early school age.


Five-year follow-up from 2005 to 2011 in 31 of 35 academic hospitals in Canada, Australia, Europe, and Israel, where 1932 of 2006 participants (96.3%) had been enrolled in the randomized, placebo-controlled Caffeine for Apnea of Prematurity trial between 1999 and 2004. A total of 1640 children (84.9%) with birth weights of 500 to 1250 g had adequate data for the main outcome at 5 years.


Combined outcome of death or survival to 5 years with 1 or more of motor impairment (defined as a Gross Motor Function Classification System level of 3 to 5), cognitive impairment (defined as a Full Scale IQ<70), behavior problems, poor general health, deafness, and blindness.


The combined outcome of death or disability was not significantly different for the 833 children assigned to caffeine from that for the 807 children assigned to placebo (21.1% vs 24.8%; odds ratio adjusted for center, 0.82; 95% CI, 0.65-1.03; P = .09). The rates of death, motor impairment, behavior problems, poor general health, deafness, and blindness did not differ significantly between the 2 groups. The incidence of cognitive impairment was lower at 5 years than at 18 months and similar in the 2 groups (4.9% vs 5.1%; odds ratio adjusted for center, 0.97; 95% CI, 0.61-1.55; P = .89).


Neonatal caffeine therapy was no longer associated with a significantly improved rate of survival without disability in children with very low birth weights who were assessed at 5 years.

[Indexed for MEDLINE]

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