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

Barbara Schmidt, Robin S Roberts, Peter J. Anderson, Elizabeth V. Asztalos, Lorrie Costantini, Peter G. Davis, Deborah Dewey, Judy D'ilario, Lex W. Doyle, Ruth E. Grunau, Diane Moddemann, Harvey Nelson, Arne Ohlsson, Alfonso Solimano, Win Tin, Caffeine for Apnea of Prematurity (CAP) Trial Group

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)564-572
Number of pages9
JournalJAMA Pediatrics
Volume171
Issue number6
DOIs
Publication statusPublished - 1 Jun 2017
Externally publishedYes

Cite this

Schmidt, Barbara ; Roberts, Robin S ; Anderson, Peter J. ; Asztalos, Elizabeth V. ; Costantini, Lorrie ; Davis, Peter G. ; Dewey, Deborah ; D'ilario, Judy ; Doyle, Lex W. ; Grunau, Ruth E. ; Moddemann, Diane ; Nelson, Harvey ; Ohlsson, Arne ; Solimano, Alfonso ; Tin, Win ; Caffeine for Apnea of Prematurity (CAP) Trial Group. / 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. In: JAMA Pediatrics. 2017 ; Vol. 171, No. 6. pp. 564-572.
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title = "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",
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.",
author = "Barbara Schmidt and Roberts, {Robin S} and Anderson, {Peter J.} and Asztalos, {Elizabeth V.} and Lorrie Costantini and Davis, {Peter G.} and Deborah Dewey and Judy D'ilario and Doyle, {Lex W.} and Grunau, {Ruth E.} and Diane Moddemann and Harvey Nelson and Arne Ohlsson and Alfonso Solimano and Win Tin and {Caffeine for Apnea of Prematurity (CAP) Trial Group}",
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Schmidt, B, Roberts, RS, Anderson, PJ, Asztalos, EV, Costantini, L, Davis, PG, Dewey, D, D'ilario, J, Doyle, LW, Grunau, RE, Moddemann, D, Nelson, H, Ohlsson, A, Solimano, A, Tin, W & Caffeine for Apnea of Prematurity (CAP) Trial Group 2017, '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' JAMA Pediatrics, vol. 171, no. 6, pp. 564-572. https://doi.org/10.1001/jamapediatrics.2017.0238

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. / Schmidt, Barbara; Roberts, Robin S; Anderson, Peter J.; Asztalos, Elizabeth V.; Costantini, Lorrie; Davis, Peter G.; Dewey, Deborah; D'ilario, Judy; Doyle, Lex W.; Grunau, Ruth E.; Moddemann, Diane; Nelson, Harvey; Ohlsson, Arne; Solimano, Alfonso; Tin, Win; Caffeine for Apnea of Prematurity (CAP) Trial Group.

In: JAMA Pediatrics, Vol. 171, No. 6, 01.06.2017, p. 564-572.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Academic performance, motor function, and behavior 11 years after neonatal caffeine citrate therapy for apnea of prematurity

T2 - An 11-year follow-up of the CAP randomized clinical trial

AU - Schmidt, Barbara

AU - Roberts, Robin S

AU - Anderson, Peter J.

AU - Asztalos, Elizabeth V.

AU - Costantini, Lorrie

AU - Davis, Peter G.

AU - Dewey, Deborah

AU - D'ilario, Judy

AU - Doyle, Lex W.

AU - Grunau, Ruth E.

AU - Moddemann, Diane

AU - Nelson, Harvey

AU - Ohlsson, Arne

AU - Solimano, Alfonso

AU - Tin, Win

AU - Caffeine for Apnea of Prematurity (CAP) Trial Group

PY - 2017/6/1

Y1 - 2017/6/1

N2 - 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.

AB - 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.

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DO - 10.1001/jamapediatrics.2017.0238

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