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J Pediatr. 2010 Mar;156(3):382-7. doi: 10.1016/j.jpeds.2009.09.069. Epub 2009 Nov 18.

Caffeine for Apnea of Prematurity trial: benefits may vary in subgroups.

Collaborators (150)

Schmidt B, D'Ilario J, Cairnie J, Dix J, Adams B, Faber B, Callanan K, Davis N, Duff J, Ford G, Golec L, Lacy M, Hohn D, Barnett C, Goodchildt L, Lontis R, Fraser S, Keng J, Saunders K, Opie G, Kelly E, Bairam A, Ferland S, Laperriere L, BĂ©langer S, St Amand P, Blayney M, Davis D, Frank J, Lemyre L, Solimano A, Singh A, Chalmers M, Ramsay K, Synnes A, Whitfield M, Rogers M, Tomlinson J, Offringa M, Nuytemans D, Vermeulen E, Kok J, van Wassenaer A, Arnon S, Chalaf A, Regev R, Netter I, Ohlsson A, Nesbitt K, O'Brien K, Hamilton AM, Sankaran K, Morgan S, Proctor P, LaCorte M, LeBlanc P, Braithwaite A, Golan A, Barabi T, Goldstein E, Reynolds G, Dromgool B, Meskell S, McMillan D, Schaab D, Spellen L, Sauve R, Christianson H, Anseeuw-Deeks D, Alvaro R, Chiu A, Porter C, Turner G, Moddemann D, Granke N, Penner K, Mulder T, Ghys A, van der Hoeven M, Clarke M, Parfitt J, MacLean H, Nwaesei C, Kuhn L, Ryan H, Saunders C, Schulze A, Pudenz P, Muller M, Lagercrantz H, Bhiladvala M, Legneval L, Herlenius E, Matthew D, Amos W, Tulsiani S, Tan-Dy C, Turner M, Shinwell E, Levine R, Juster-Reicher A, Barrington K, Kokkotis T, Khairy M, Grier P, Vachon J, Tin W, Fritz S, Walti H, Royer D, Halliday H, Millar D, Berry A, Mayes C, Cummings C, Fahnenstich H, Philipp K, Tillmann B, Weber P, Canning R, Wariyar U, Tin W, Fritz S, Embleton N, Bucher HU, Fauchere JC, Tin W, Fritz S, Pfister R, Launoy V, Huppi P, Poets C, Urschitz-Duprat P, Barrington K, Davis P, Doyle LW, Ohlsson A, Solimano A, Tin W, Gent M, Fraser W, Hey E, Perlman M, Thorpe K, Gray S, Roberts RS, Chambers C, Costantini L, McGean L, Scapinello L.

Author information

Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, Australia.



To determine whether the benefits of caffeine vary in three subgroups of 2006 participants in the Caffeine for Apnea of Prematurity (CAP) trial.


Post-hoc subgroup analyses were performed on the basis of: (1) indication for commencement of study drug: treat apnea, prevent apnea, or facilitate extubation; (2) positive pressure ventilation (PPV) at randomization: endotracheal tube (ETT), noninvasive ventilation, or none; and (3) timing of commencement of study drug: early or late (< or =3 versus >3 days). Outcomes assessed were those showing treatment effects in the original analyses. We investigated the consistency of caffeine effects by using regression models that incorporated treatment/subgroup factor interactions.


There was little evidence of a differential treatment effect of caffeine in subgroups defined by the clinical indication for starting study drug. The size and direction of the caffeine effect on death or disability differed depending on PPV at randomization (P = .03). Odds ratios (95% CI) were: no support, 1.32 (0.81-2.14); noninvasive support, 0.73 (0.52-1.03); and ETT, 0.73 (0.57-0.94). Adjustment for baseline factors strengthened this effect (P = .02). Starting caffeine early resulted in larger reductions in days of respiratory support. Postmenstrual age at time of discontinuing PPV was shorter with earlier treatment (P = .01). Mean differences (95% CI) were: early, 1.35 weeks (0.90-1.81); and late 0.55 weeks (-0.11-0.99). Adjustment for baseline factors weakened this effect (P = .03).


There is evidence of variable beneficial effects of caffeine. Infants receiving respiratory support appeared to derive more neurodevelopmental benefits from caffeine than infants not receiving support. Earlier initiation of caffeine may be associated with a greater reduction in time on ventilation.

[Indexed for MEDLINE]

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