Caffeine for Apnea of Prematurity Trial: Benefits May Vary in Subgroups

Peter G. Davis, MD, Barbara Schmidt, MD, Robin S. Roberts, MSc, Lex W. Doyle, MD, Elizabeth Asztalos, MD,
Ross Haslam, MD, Sunil Sinha, PhD, and Win Tin, MD for the Caffeine for Apnea of Prematurity Trial Group*
Objective To determine whether the benefits of caffeine vary in three subgroups of 2006 participants in the
Caffeine for Apnea of Prematurity (CAP) trial.
Study design 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 (#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.
Results 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).
Conclusions 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. (J Pediatr 2010;156:382-7).

he Caffeine for Apnea of Prematurity (CAP) trial compared short- and long-term outcomes of preterm infants treated
with caffeine with those of infants receiving a placebo. Infants were eligible for inclusion when their clinicians considered
them to be candidates for methylxanthine therapy during the first 10 days of life.1,2
Earlier trials and systematic reviews examined the safety and efficacy of methylxanthines in relation to the specific clinical
indication for commencement of treatment. Cochrane reviews evaluated methylxanthines for treatment of apnea (5 trials,
192 infants),3 prophylaxis for infants at risk of apnea (2 trials, 104 infants),4 and pre-extubation treatment (6 trials, 197 infants).5 The small numbers of subjects included in the 3 pooled analyses limited the statistical power to evaluate the safety
and efficacy of methylxanthines.
The mechanisms of the short- and long-term beneficial effects of caffeine are not clearly understood. In human infants, methylxanthines reduce apneic events, increase minute volumes, improve respiratory system compliance,6 reduce diaphragmatic
fatigue,7 and act as a diuretic.8 However, methylxanthines reduce survival of weanling mice exposed to a period of anoxia.9
Therefore, the benefits and risks of caffeine may vary according to the respiratory status and postnatal age of the infant.
The broad inclusion criteria of the CAP trial meant that infants were randomized and commenced study drug at varying levels
of respiratory support. Moreover, some infants commenced the study drug immediately after birth, and others received their
first dose of study drug after they reached their second week of life.
We conducted these post hoc analyses of the CAP trial to determine the short- and long-term effects of caffeine according to
the clinical subgroups of: (1) indication for commencing study medication; (2) level of respiratory support at randomization;
and (3) age of starting treatment.

Methods
The trial design and the short- and long-term outcomes of the CAP trial have
been reported previously.1,2 The research ethics boards of all participating centers approved the trial. Written parental consent was obtained prior to study enCAP
ETT
PDA
PMA
PPV

Caffeine for Apnea of Prematurity

Endotracheal tube
Patent ductus arteriosus
Postmenstrual age
Positive pressure ventilation

From the Department of Obstetrics and Gynaecology,

University of Melbourne, Melbourne, Australia (P.D.,
L.D.); Departments of Clinical Epidemiology and
Biostatistics, McMaster University, Hamilton, Ontario,
Canada (B.S., R.R.); Department of Pediatrics, University
of Toronto, Toronto, Ontario, Canada (E.A.); Womens
and Childrens Hospital, Adelaide, Australia (R.H.); and
Department of Pediatrics, James Cook University
Hospital, Middlesbrough, United Kingdom (S.S., W.T.)
*Additional members of the Caffeine for Apnea of Prematurity Trial Group are available at www.jpeds.com
(Appendix).
Funded by the Canadian Institute of Health Research and
the National Health and Medical Research Council of
Australia. The authors declare no conflicts of interest.
0022-3476/$ - see front matter. Copyright 2010 Mosby Inc.
All rights reserved. 10.1016/j.jpeds.2009.09.069

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Vol. 156, No. 3  March 2010

try. In summary, infants with a birth weight between 500 and
1250 g were randomized to receive either caffeine citrate (n =
1006) or normal saline placebo (n = 1000). A computer-generated randomization scheme with variable block sizes was
used, and a designated pharmacist at each center prepared
vials of study solution. A loading dose of 20 mg of caffeine
citrate per kilogram of body weight was followed by a daily
maintenance dose of 5 mg/kg. Caregivers and those assessing
study outcomes were masked to the treatment group. The
dose of study drug could be increased to 10 mg/kg/day
when symptoms of apnea persisted or withheld or reduced
when there were clinical signs of toxicity. Caffeine levels
were not measured. Open label use of caffeine or other methylxanthines was strongly discouraged and occurred in 9.5%
of infants overall. The study drug was commenced at a median age of 3 days and discontinued before a median of 35
weeks postmenstrual age (PMA).
Infants receiving caffeine had reduced rates of bronchopulmonary dysplasia and spent approximately 1 fewer week
with an endotracheal tube (ETT), any positive pressure ventilation (PPV), and supplemental oxygen.1 The primary outcome of the trial was death before a corrected age of 18 to 21
months or survival with $1 of these conditions: cerebral
palsy, cognitive delay, hearing loss requiring amplification,
or bilateral blindness. Caffeine reduced the rate of the primary outcome and 2 of its components, cerebral palsy and
cognitive delay.2
Subgroup analyses
We documented why each infant was considered to be a candidate for methylxanthines as 1 of the following mutually exclusive reasons: to prevent apnea, to treat apnea, or to
facilitate removal of an ETT. Analyses of a subset of outcomes
were conducted for each indication subgroup. In addition,
we performed subgroup analyses on the basis of the level of
respiratory support at randomization (no support, non-invasive respiratory support, or ventilation via an ETT) and the
time of commencing study drug (< median age versus $
median age).
We assessed these outcomes: Death or major disability; cerebral palsy; cognitive delay; broncopulmonary dysplasia,
any retinopathy of prematurity (ROP); severe ROP; drug
therapy for closure of patent ductus arteriosus (PDA); PDA
ligation; use of postnatal corticosteroids; PMA at last use of

oxygen treatment, last use of ETT, and last use of PPV. All
these outcomes showed an overall treatment effect in the
original analyses of the 2 randomly allocated CAP trial
groups. Definitions of outcomes are provided in full in earlier
publications.1,2 Bronchopulmonary dysplasia was defined as
the need for supplemental oxygen at a PMA of 36 weeks. Cerebral palsy was diagnosed when the child had a non-progressive motor impairment characterized by abnormal muscle
tone and decreased range or control of movements. Cognitive delay was defined as a Mental Development Index score
<85 on the Bayley II Scales of Infant Development.10
For each dichotomous outcome, logistic regression models
were fitted separately to each subgroup. This yielded a point
estimate and a 95% CI for the subgroup treatment effect expressed as an odds ratio. The subgroup treatment effects for
continuous outcomes such as PMA of last respiratory support were expressed as mean differences between the treatment groups with 95% CIs. For dichotomous outcomes,
we determined the statistical significance of the observed heterogeneity of treatment effect with logistic regression models
incorporating treatment/subgroup interactions. Multiple linear regression models were used for continuous outcomes.
Each analysis was then adjusted for prognostically important
variablesgestational age, sex, level of maternal education,
antenatal steroid treatment, and multiple births. A P value
for the test of heterogeneity (treatment x subgroup interaction) <.05 was considered to represent statistically important
evidence of a subgroup effect.

Results
Adequate data for an analysis of the primary composite outcome were available for 1869 (93.2%) of the infants who
were enrolled in the study. The characteristics of these 1869
children were similar in the 2 groups at birth (Table I; available at www.jpeds.com). There were no important differences
in these characteristics between the subgroups (Table II).
The number of infants in each subgroup with an adverse
outcome (n), the total number in each group (N), the odds
ratios, and their 95% CIs are shown in Figure 1, A,
Figure 2, A, and Figure 3, A (available at www.jpeds.
com). Continuous outcomes expressed as means (SD)
and the mean differences between caffeine and placebo

Table II. Baseline characteristics by subgroup

Respiratory support
at randomization

Reason for caffeine

Baseline characteristics
Mothers education college/university
Antenatal steroids
Gestational age (weeks), mean (SD)
Singleton birth
Female

Time of Randomization

Apnea
treatment

Apnea
prophylaxis

Extubation

No PPV

PPV,
no ETT

PPV
with ETT

Early
3 days

Late
>3 days

54.2%
89.8%
27.8
(1.76)
69.9%
52.7%

53.3%
86.3%
27.3
(1.84)
67.4%
45.2%

47.5%
87.3%
26.8
(1.69)
76.3%
45.4%

48.8%
89.4%
28.8
(1.54)
68.5%
54.6%

53.2%
90.4%
27.8
(1.55)
68.7%
49.9%

51.6%
86.3%
26.7
(1.69)
74.3%
45.5%

48.9%
89.7%
27.4
(1.67)
71.9%
48.4%

53.5%
86.9%
27.3
(1.91)
71.6%
48.3%
383

THE JOURNAL OF PEDIATRICS

A

www.jpeds.com

Caffeine
n/N

Vol. 156, No. 3

Placebo
n/N

OR (fixed)
95% CI

OR (fixed)
95% CI

Death or major disability

Apnea treatment
Apnea prophylaxis
Pre-extubation

141/400
94/219
141/316

153/367
88/204
189/360

0.76 [0.57, 1.02]

0.99 [0.67, 1.46]
0.73 [0.54, 0.99]
0.80 [0.66, 0.96]

117/341
66/189
145/327

0.80 [0.58, 1.09]

1.13 [0.75, 1.70]
0.73 [0.53, 1.01]
0.84 [0.69, 1.02]

18/361
9/200
39/339

0.56 [0.26, 1.19]

1.04 [0.41, 2.60]
0.51 [0.29, 0.91]
0.60 [0.40, 0.90]

141/392
94/211
212/350

0.62 [0.46, 0.84]

0.74 [0.50, 1.08]
0.63 [0.46, 0.85]
0.65 [0.54, 0.78]

40/400
23/220
66/378

0.35 [0.19, 0.64]

0.38 [0.18, 0.83]
0.28 [0.16, 0.48]
0.32 [0.23, 0.46]

Test for heterogeneity: P = 0.44

Cognitive delay
Apnea treatment
Apnea prophylaxis
Pre-extubation

110/374
78/207
105/285

Test for heterogeneity: P = 0.25

Cerebral palsy
Apnea treatment
Apnea prophylaxis
Pre-extubation

11/388
10/215
19/305

Test for heterogeneity: P = 0.43

BPD
Apnea treatment
Apnea prophylaxis
Pre-extubation

107/413
84/226
158/322

Test for heterogeneity: P = 0.76

PDA ligation
Apnea treatment
Apnea prophylaxis
Pre-extubation

16/427
10/233
19/339

Test for heterogeneity: P = 0.77

0.1

0.2

0.5

Favors caffeine

10

Favors placebo

Caffeine
Mean (SD)

Placebo
Mean (SD)

MD (fixed)
95% CI

MD (fixed)
95% CI

33.1(4.9)
34.4(5.8)
35.3(4.5)

387
208
347

34.0(4.3)
35.0(4.4)
36.8(5.4)

-0.84 [-1.48, -0.19]

-0.61 [-1.66, 0.37]
-1.53 [-2.29, -0.77]
-1.02 [-1.45, -0.58]

387
208
349

30.4(3.1)
30.6(3.4)
31.2(3.6)

-0.61 [-1.04, -0.19]

-0.64 [-1.28, -0.09]
-0.88 [-1.41, -0.34]
-0.69 [-0.99, -0.40]

387
208
348

32.2(3.1)
32.5(3.4)
33.0(3.6)

-0.86 [-1.29, -0.43]

-1.02 [-1.63, -0.40]
-1.03 [-1.57, -0.49]
-0.98 [-1.28, -0.69]

PMA at last oxygen treatment

Apnea treatment
Apnea prophylaxis
Pre-extubation

410
223
319

Test for heterogeneity: P = 0.24

PMA at last ETT

Apnea treatment
Apnea prophylaxis
Pre-extubation

410
224
319

29.8(3.1)
30.0(3.3)
30.3(3.3)

Test for heterogeneity: P = 0.72

PMA at last positive pressure ventilation

Apnea treatment
Apnea prophylaxis
Pre-extubation

410
224
319

31.3(3.0)
31.5(3.2)
31.9(3.5)

Test for heterogeneity: P = 0.86

-4
-2
Favors caffeine

2
4
Favors placebo

Figure 1. A, Neonatal morbidities and long-term impairments by reason for treatment. B, PMA at last use of respiratory supports
by reason for treatment. Each black diamond represents the overall treatment effect for that outcome.

groups and their 95% CIs are shown in Figure 1, B,

Figure 2, B, and Figure 3, B. For dichotomous and continuous outcomes, the point estimates and their 95% CIs are
384

expressed as forest plots for each subgroup. The overall

treatment effect of caffeine on each outcome is expressed
as a diamond at the bottom of each graph.
Davis et al

ORIGINAL ARTICLES

March 2010

Caffeine
n/N

Placebo
n/N

OR (fixed)
95% CI

OR (fixed)
95% CI

Death or major disability

No PPV
Non-invasive vent
Endotracheal tube

61/167
100/285
216/485

41/135
118/278
271/518

1.32 [0.81, 2.14]

0.73 [0.52, 1.03]
0.73 [0.57, 0.94]
0.80 [0.66, 0.96]

33/129
91/260
204/468

1.49 [0.90, 2.49]

0.77 [0.53, 1.11]
0.74 [0.57, 0.97]
0.83 [0.69, 1.02]

4/138
13/274
49/488

0.61 [0.13, 2.77]

0.61 [0.25, 1.49]
0.59 [0.37, 0.95]
0.60 [0.40, 0.89]

32/151
107/293
308/509

1.08 [0.64, 1.82]

0.58 [0.41, 0.83]
0.60 [0.47, 0.78]
0.65 [0.54, 0.78]

6/154
23/302
101/542

0.27 [0.05, 1.36]

0.33 [0.14, 0.75]
0.33 [0.22, 0.49]
0.33 [0.23, 0.46]

Test for heterogeneity: P = 0.03, adjusted 0.02

Cognitive delay
No PPV
Non-invasive vent
Endotracheal tube

55/162
77/263
161/442

Test for heterogeneity: P = 0.02, adjusted 0.01

Cerebral palsy
No PPV
Non-invasive vent
Endotracheal tube

3/168
8/273
29/468

Test for heterogeneity: P = 0.97

BPD
No PPV
Non-invasive vent
Endotracheal tube

41/182
73/290
236/491

Test for heterogeneity: P = 0.09

PDA ligation
No PPV
Non-invasive vent
Endotracheal tube

2/184
8/303
36/514

Test for heterogeneity: P = 0.94

0.1

0.2

0.5

Favors caffeine

Caffeine
Mean (SD)

10

Favors placebo

Placebo
Mean (SD)

MD (fixed)
95% CI

MD (fixed)
95% CI

PMA at last oxygen treatment

No PPV
Non-invasive vent
Endotracheal tube

184
303
518

32.5(5.4)
33.4(5.6)
35.0(5.1)

154
302
541

32.59(3.82)
34.0(4.1)
36.3(5.5)

-0.06 [-1.07, 0.96]

-0.65 [-1.43, 0.13]
-1.32 [-1.96, -0.67]
-0.85 [-1.29, -0.40]

154
302
543

30.1(2.6)
29.8(2.8)
31.4(3.9)

-0.53 [-1.04, -0.01]

-0.38 [-0.83, 0.08]
-0.78 [-1.26, -0.31]
-0.55 [-0.83, -0.27]

154
302
542

31.4(3.0)
32.0(3.0)
33.1(3.9)

-0.83 [-1.43, -0.24]

-0.68 [-1.21, -0.16]
-0.93 [-1.40, -0.46]
-0.88 [-1.18, -0.57]

Test for heterogeneity: P = 0.11

PMA at last ETT
No PPV
Non-invasive vent
Endotracheal tube

184
303
519

29.6(2.3)
29.5(3.0)
30.7(4.0)

Test for heterogeneity: P = 0.47

PMA at last positive pressure ventilation
No PPV
Non-invasive vent
Endotracheal tube

184
303
519

30.5(2.5)
31.3(3.6)
32.1(3.9)

Test for heterogeneity: P = 0.80

-4

-2

Favors caffeine

Favors placebo

Figure 2. A, Neonatal morbidities and long-term impairments by level of respiratory support at randomization B, PMA at last use
of respiratory supports by level of respiratory support at randomization. Each black diamond represents the overall treatment
effect for that outcome.

Caffeine for Apnea of Prematurity Trial: Benefits May Vary in Subgroups

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Outcomes by reason for treatment with study drug

There was little evidence of heterogeneity of treatment effect
for any outcome assessed on either the unadjusted (Figure 1)
or adjusted analyses (data not shown).
Outcomes by level of respiratory support
There was evidence of heterogeneity of caffeine effect for the
outcomes death or major disability (P = .03) and cognitive
delay (P = .02; Figure 2, A). These effects remained statistically significant after adjustment for prognostically important baseline variables. Infants receiving respiratory support
at the time of randomization appeared to derive greater
long-term neurological benefit from caffeine than infants
not receiving any respiratory support. There was
little evidence of heterogeneity for any other outcome
(Figure 2).
Outcomes by age at randomization
The median age at randomization was 3 days; the early
group comprised infants randomized at <3 days, and the
late group comprised infants randomized at $3 days. Unadjusted analysis showed evidence of significant heterogeneity for the outcomes of broncopulmonary dysplasia (P
= .02), PMA at last oxygen treatment (P = .03; Figure 3,
B), PMA at last endotracheal intubation (P = .02), and
PMA at last PPV (P = .01; Figure 3, B). After adjustment,
only PMA at last endotracheal intubation (P = .04) and
PMA at last PPV (P = .03) remained statistically significant.
Infants whose treatment commenced before 3 days of age
appeared to derive greater short-term respiratory benefit
from caffeine than infants commencing treatment at $3
days.
There was little evidence of any subgroup effects in the adjusted analyses for any of the following outcomes: any ROP;
severe ROP; drug therapy for closure of PDA, and use of
postnatal corticosteroids (data not shown).

Discussion
The CAP study showed that caffeine significantly improved
survival without neurodevelopmental disability at a corrected
age of 18 to 21 months.2 Caffeine also reduced the incidence
of bronchopulmonary dysplasia and shortened the duration
of supplemental oxygen therapy and assisted ventilation.1
The eligibility criteria were broad and pragmatic. Infants
with birth weights from 500 to 1250 g could be randomized
in the first 10 days of life when their caregivers considered
them to be candidates for methylxanthine therapy. Earlier
trials and meta-analyses split the question of efficacy of respiratory stimulants according to the clinical indication for
commencing therapy. The numbers of patients enrolled
were small, and important clinical outcomes were not measured.
Mindful of the earlier trials, we recorded the clinical
indication for considering methylxanthine therapy. This
provided an opportunity to explore the potential for differ386

Vol. 156, No. 3

ential effectiveness of methyxanthines in these subgroups.
However, caution should be exercised in the interpretation
of these subanalyses. We did not stratify for clinical indication, time of study drug commencement, or level of respiratory support, and we did not undertake sample size
calculations for these subgroups.
Although effect sizes and directions of effect of caffeine
varied in the subgroups, we found no evidence of harm
reaching statistical significance. However, the power to detect
differences in the size of treatment effect in subgroups is relatively low. Similarly, although not directly addressed here,
the power to make statements about the presence or absence
of a treatment effect within any specific subgroup is much
less than for the trial overall. Rather than focus on the point
estimates of treatment effects for each subgroup, we stress the
importance of looking for consistency of treatment effects
across the subgroups.
The stated clinical indication for the use of methylxanthines appeared to have little effect on the benefits of caffeine. However, the effectiveness of caffeine varied
significantly depending on the level of respiratory support
at time of study commencement. In relation to the 2 outcomes, death or major disability and cognitive delay, it appears that infants not requiring any PPV derived less
benefit than infant receiving support via continuous positive airway pressure or an ETT. This is consistent with
our post hoc analysis of possible mechanisms of action of
the effect of caffeine on the rate of survival free of disability.2 Earlier discontinuation of any positive airway pressure
was the most powerful of 6 mechanisms explored and explained 49% of the beneficial long-term drug effect. There
were some interesting trends suggesting that early commencement of caffeine was associated with improved
short-term pulmonary outcomes. However, only PMA at
last endotracheal intubation and the last use of any positive
airway pressure remained statistically significant after adjustment for prognostically important variables. Caution
should be applied in interpreting this subanalysis because
infants who started the study drug early were likely to
have been seen by their clinicians as more ready to wean
from respiratory support than infants who were enrolled
later.
The CAP study provides a unique resource because of
its methodological strengths and large number of subjects
enrolled. Lagakos cautioned against over-interpretation of
the results of subgroup analyses, but suggested that when
well planned and executed, such analyses could make
a valuable contribution to the literature.11 One pitfall to
be avoided is that of multiple testing. We conducted 36
comparisons and would therefore expect that 2 nominally
significant interaction terms would occur by chance
alone.12
The message of the CAP trial for clinicians remains clear.
Caffeine improves neurodevelopmental outcomes to 2 years
of age. Follow-up of infants at 5 years is ongoing and may
further refine estimates of effect of caffeine on neurodevelopmental outcome. Infants who start receiving caffeine
Davis et al

ORIGINAL ARTICLES

March 2010
while they are receiving respiratory support appear to experience the greatest improvements in neurodevelopmental
outcome. n
Submitted for publication Feb 17, 2009; last revision received Aug 20, 2009;
accepted Sep 25, 2009.
Reprint requests: Dr Peter G. Davis, The Royal Womens Hospital, Locked Bag
300, Cnr Grattan St & Flemington Rd, Parkville, Victoria, 3052 Australia. E-mail:
pgd@unimelb.edu.au.

References
1. Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, et al.
Caffeine therapy for apnea of prematurity. N Engl J Med 2006;354:2112-21.
2. Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A,
et al. Long-term effects of caffeine therapy for apnea of prematurity. N
Engl J Med 2007;357:1893-902.
3. Henderson-Smart DJ, Steer P. Methylxanthine treatment for apnea in
preterm infants. Cochrane Database Syst Rev 2001;CD000140.
4. Henderson-Smart DJ, Steer PA. Prophylactic methylxanthine for preventing of apnea in preterm infants. Cochrane Database Syst Rev 2000;
CD000432.

5. Henderson-Smart DJ, Davis PG. Prophylactic methylxanthines for

extubation in preterm infants. Cochrane Database Syst Rev 2003;
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6. Davi MJ, Sankaran K, Simons KJ, Simons FE, Seshia MM, Rigatto H.
Physiologic changes induced by theophylline in the treatment of apnea
in preterm infants. J Pediatr 1978;92:91-5.
7. Heyman E, Ohlsson A, Heyman Z, Fong K. The effect of aminophylline on the excursions of the diaphragm in preterm neonates. A
randomized double-blind controlled study. Acta Paediatr Scand
1991;80:308-15.
8. Rieg T, Steigele H, Schnermann J, Richter K, Osswald H, Vallon V.
Requirement of intact adenosine A1 receptors for the diuretic and natriuretic action of the methylxanthines theophylline and caffeine. J Pharmacol Exp Ther 2005;313:403-9.
9. Thurston JH, Hauhard RE, Dirgo JA. Aminophylline increases cerebral
metabolic rate and decreases anoxic survival in young mice. Science
1978;201:649-51.
10. Bayley N. Bayley Scales of Infant Development:Manual. San Antonio:
The Psychological Corporation, Harcourt Brace & Company; 1993.
11. Lagakos SW. The challenge of subgroup analysesreporting without
distorting. N Engl J Med 2006;354:1667-9.
12. Wang R, Lagakos SW, Ware JH, Hunter DJ, Drazen JM. Statistics in
medicinereporting of subgroup analyses in clinical trials. N Engl J
Med 2007;357:2189-94.

Caffeine for Apnea of Prematurity Trial: Benefits May Vary in Subgroups

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Appendix
In addition to the authors, these investigators, research
nurses, and hospitals participated in the Caffeine for Apnea
of Prematurity Trial (study sites are listed according to the
number of infants they enrolled): McMaster University Medical Center, Hamilton, Ontario, CanadaB. Schmidt, J.
DIlario, J. Cairnie, J. Dix, B. Adams; Royal Womens Hospital, Melbourne, AustraliaB. Faber, K. Callanan, N. Davis, J.
Duff, G. Ford; Sunnybrook Health Sciences Center, Toronto,
CanadaL. Golec, M. Lacy, D. Hohn; Womens and Childrens Hospital, Adelaide, AustraliaC. Barnett, L. Goodchild, R. Lontis; Mercy Hospital for Women, Melbourne,
AustraliaS. Fraser, J. Keng, K., Saunders, G. Opie, E. Kelly;
Centre Hospitalier Universitaire de Quebec, Quebec City,
Quebec CanadaA. Bairam, S. Ferland, L. Laperriere,
S. Belanger, P. St. Amand; Ottawa Hospital, Ottawa, Ontario,
CanadaM. Blayney, D. Davis, J. Frank, B. Lemyre; British
Columbia Childrens Hospital, Vancouver, British Columbia,
CanadaA. Solimano, A. Singh, M. Chalmers, K. Ramsay,
A. Synnes, M. Whitfield, M. Rogers, J. Tomlinson; Academic
Medical Center, Amsterdam, The NetherlandsM. Offringa,
D. Nuytemans, E. Vermeulen, J. Kok, A. van Wassenaer; Meir
General Hospital, Kfar-Saba, IsraelS. Arnon, A. Chalaf, R.
Regev, I. Netter; Mount Sinai Hospital, Toronto, Ontario,
CanadaA. Ohlsson, K. Nesbitt, K. OBrien, A.M. Hamilton;
Royal University Hospital, Saskatoon, Saskatchewan,
CanadaK. Sankaran, S. Morgan, P. Proctor; The Brooklyn
Hospital Center, Brooklyn, New YorkM. LaCorte, P. LeBlanc , A. Braithwaite; Soroka University, Beer Sheva, IsraelA. Golan, T. Barabi, E. Goldstein; The Canberra
Hospital, Canberra, AustraliaG. Reynolds, B. Dromgool,
S. Meskell; Foothills Hospital, Calgary, Alberta, CanadaD.
McMillan,D. Schaab, L. Spellen, R. Sauve, H. Christianson,
D. Anseeuw-Deeks; St. Boniface, Winnipeg, Manitoba,
CanadaR. Alvaro, A. Chiu, C. Porter, G. Turner, D.

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Moddemann, N. Granke, K. Penner; University Hospital
Maastricht, Maastricht, The NetherlandsT. Mulder, A.
Ghys, M. van der Hoeven; Kingston General Hospital, Kingston, Ontario, CanadaM. Clarke, J. Parfitt, H. MacLean;
Windsor Regional Hospital, Windsor, Ontario, CanadaC.
Nwaesei, L. Kuhn, H. Ryan, C. Saunders; Ludwig Maximilian
University, Munich, GermanyA. Schulze, P. Pudenz, M.
Muller; Astrid Lindgren Childrens Hospital, Stockholm,
SwedenH. Lagercrantz, M. Bhiladvala, L. Legnevall, E. Herlenius; Victoria General Hospital, Victoria, British Columbia,
CanadaD. Matthew, W. Amos, S. Tulsiani, C. Tan-Dy, M.
Turner; Kaplan Medical Center, Rehovot, IsraelE. Shinwell,
R. Levine, A. Juster-Reicher; Royal Victoria Hospital, Montreal, Quebec, CanadaK. Barrington, T. Kokkotis, M.
Khairy, P. Grier, J. Vachon; James Cook University Hospital,
Middlesbrough, United KingdomW. Tin, S. Fritz; University of Sherbrooke, Sherbrooke, Quebec, CanadaH. Walti,
D. Royer; Royal Maternity Hospital Belfast, Northern Ireland,
United KingdomH. Halliday, D. Millar, A. Berry, C. Mayes,
C. Cummings; Basel Childrens Hospital, Basel, SwitzerlandH. Fahnenstich, K. Philipp, B. Tillmann, P. Weber;
Moncton Hospital, Moncton, New Brunswick, CanadaR.
Canning; Royal Victoria Infirmary, Newcastle upon Tyne,
United KingdomU. Wariyar, W. Tin, S. Fritz, N. Embleton;
University Hospital Zurich, Zurich, SwitzerlandH-U.
Bucher, J-C. Fauchere; Northern Neonatal Initiatives, Middlesbrough, United KingdomW. Tin, S. Fritz; University
Hospitals of Geneva, Geneva, SwitzerlandR. Pfister, V. Launoy, P. Huppi; University of Tuebingen, Tuebingen, GermanyC. Poets, P. Urschitz-Duprat. Steering Committee:
K. Barrington, P. Davis, L.W. Doyle, A. Ohlsson, A. Solimano,
W. Tin. External Safety Monitoring Committee: M. Gent
(Chair), W. Fraser, E. Hey, M. Perlman, K. Thorpe. Consultant Pharmacist: S. Gray. Coordinating and Methods Center
in Hamilton, Ontario, Canada: R.S. Roberts, C. Chambers,
L. Costantini, E. McGean, L. Scapinello.

Davis et al

ORIGINAL ARTICLES

March 2010

Caffeine
n/N

Placebo
n/N

OR (fixed)
95% CI

OR (fixed)
95% CI

Death or major disability

Early
Late

152/375
225/562

206/408
225/524

0.67 [0.50, 0.89]

0.89 [0.70, 1.13]
0.79 [0.66, 0.95]

151/372
178/486

0.80 [0.59, 1.08]

0.84 [0.65, 1.09]
0.82 [0.68, 1.00]

34/395
32/506

0.45 [0.24, 0.85]

0.72 [0.42, 1.23]
0.58 [0.39, 0.88]

190/426
257/528

0.48 [0.36, 0.65]

0.77 [0.61, 0.98]
0.64 [0.53, 0.77]

Test for heterogeneity: P = 0.33

Cognitive delay
Early
Late

123/348
170/519

Test for heterogeneity: P = 0.80

Cerebral palsy
Early
Late

15/367
25/542

Test for heterogeneity: P = 0.27

BPD
Early
Late

111/396
239/567

Test for heterogeneity: P = 0.02, adjusted 0.06

PDA ligation
Early
Late

11/413
35/588

54/444
76/555

0.20 [0.10, 0.38]

0.40 [0.26, 0.61]
0.32 [0.22, 0.45]

Test for heterogeneity: P = 0.08

0.1

0.2

0.5

Favors caffeine

Caffeine
Mean (SD)

10

Favors placebo

Placebo
Mean (SD)

MD (fixed)
95% CI

WMD (fixed)
95% CI

PMA at last oxygen treatment

Early
Late

413
592

33.5(5.2)
34.4(5.5)

442
556

35.1(4.6)
35.0(5.4)

-1.58 [-2.24, -0.92]

-0.57 [-1.21, 0.07]
-1.06 [-1.51, -0.60]

Test for heterogeneity: P = 0.03, adjusted 0.10

PMA at last ETT
Early
Late

413
593

29.5(2.9)
30.5(3.8)

444
556

30.6(3.5)
30.9(3.5)

-1.08 [-1.51, -0.65]

-0.37 [-0.79, 0.05]
-0.72 [-1.02, -0.42]

Test for heterogeneity: P = 0.02, adjusted 0.04

PMA at last positive pressure ventilation
Early
Late

413
593

31.2(3.0)
31.8(4.0)

443
556

-1.35 [-1.81, -0.90]

-0.55 [-0.99, -0.11]
-0.99 [-1.30, -0.67]

32.6(3.7)
32.4(3.5)

Test for heterogeneity: P = 0.01, adjusted 0.03

-4

-2

Favors caffeine

Favors placebo

Figure 3. A, Neonatal morbidities and long-term impairments by age at commencement of study drug. B, PMA at last use of
respiratory supports by age at commencement of study drug. Each black diamond represents the overall treatment effect for that
outcome.

Caffeine for Apnea of Prematurity Trial: Benefits May Vary in Subgroups

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www.jpeds.com

Vol. 156, No. 3

Table I. Baseline characteristics of the infants and their

mothers
Caffeine
(n = 937)

Placebo
(n = 932)

Baseline characteristics
Maternal college/university education 454 (52%) 438 (50%)
Antenatal steroids
829 (89%) 817 (88%)
Gestational age (weeks)
27.4 (1.8) 27.3 (1.8)
Singleton
672 (72%) 668 (72%)
Female
468 (50%) 435 (47%)

P value
.51
.62
.45
1.00
.17

These data are for the 1869 children with adequate information for the ascertainment of the
composite primary outcome at a corrected age of 18 to 21 months.

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Davis et al