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Academic Performance, Motor Function, and Behavior 11 Years After Neonatal Caffeine Citrate Therapy for Apnea of Prematurity: An 11-Year Follow-up of the CAP Randomized Clinical Trial.

Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada2Division of Neonatology, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia. Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada. Murdoch Childrens Research Institute, Melbourne, Victoria, Australia4Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, Victoria, Australia5Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia. Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada. Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, Victoria, Australia5Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia7Royal Women's Hospital, Melbourne, Victoria, Australia. Alberta Children's Hospital Research Institute for Child and Maternal Health, Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada9Alberta Children's Hospital Research Institute for Child and Maternal Health, Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada. Murdoch Childrens Research Institute, Melbourne, Victoria, Australia4Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, Victoria, Australia5Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia7Royal Women's Hospital, Melbourne, Victoria, Australia. Child and Family Research Institute, Vancouver, British Columbia, Canada11Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada. Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada. Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada. Department of Pediatrics, James Cook University Hospital, Middlesbrough, England.

JAMA pediatrics. 2017;(6):564-572
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Abstract

IMPORTANCE Caffeine citrate therapy for apnea of prematurity reduces the rates of bronchopulmonary dysplasia, severe retinopathy, and neurodevelopmental disability at 18 months and may improve motor function at 5 years. OBJECTIVE To evaluate whether neonatal caffeine therapy is associated with improved functional outcomes 11 years later. DESIGN, SETTING, AND PARTICIPANTS A follow-up study was conducted at 14 academic hospitals in Canada, Australia, and the United Kingdom from May 7, 2011, to May 27, 2016, of English- or French-speaking children who had been enrolled in the randomized, placebo-controlled Caffeine for Apnea of Prematurity trial between October 11, 1999, and October 22, 2004. A total of 1202 children with birth weights of 500 to 1250 g were eligible for this study; 920 (76.5%) had adequate data for the main outcome. INTERVENTIONS Caffeine citrate or placebo until drug therapy for apnea of prematurity was no longer needed. MAIN OUTCOMES AND MEASURES Functional impairment was a composite of poor academic performance (defined as at least 1 standard score greater than 2 SD below the mean on the Wide Range Achievement Test-4), motor impairment (defined as a percentile rank of ≤5 on the Movement Assessment Battery for Children-Second Edition), and behavior problems (defined as a Total Problem T score ≥2 SD above the mean on the Child Behavior Checklist). RESULTS Among the 920 children (444 females and 476 males; median age, 11.4 years [interquartile range, 11.1-11.8 years]), the combined rates of functional impairment were not significantly different between the 457 children assigned to receive caffeine compared with the 463 children assigned to receive placebo (145 [31.7%] vs 174 [37.6%]; adjusted odds ratio, 0.78; 95% CI, 0.59-1.02; P = .07). With all available data, including those from up to 24 Swedish trial participants, the rates of poor academic performance on 1 or more of 4 subtests (66 of 458 [14.4%] vs 61 of 462 [13.2%]; adjusted odds ratio, 1.11; 95% CI, 0.77-1.61; P = .58) and behavior problems (52 of 476 [10.9%] vs 40 of 481 [8.3%]; adjusted odds ratio, 1.32; 95% CI, 0.85-2.07; P = .22) were broadly similar between the group that received caffeine and the group that received placebo. However, caffeine therapy was associated with a reduced risk of motor impairment compared with placebo (90 of 457 [19.7%] vs 130 of 473 [27.5%]; adjusted odds ratio, 0.66; 95% CI, 0.48-0.90; P = .009). CONCLUSIONS AND RELEVANCE Caffeine therapy for apnea of prematurity did not significantly reduce the combined rate of academic, motor, and behavioral impairments but was associated with a reduced risk of motor impairment in 11-year-old children with very low birth weight. At the doses used in this trial, neonatal caffeine therapy is effective and safe into middle school age. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00182312; isrctn.org Identifier: ISRCTN44364365.

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