Comparison 2. High‐ versus standard‐dose strategies for prevention of apnea.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 All‐cause mortality prior to hospital discharge	2	152	Risk Ratio (M‐H, Fixed, 95% CI)	1.32 [0.50, 3.53]
2.2 Major neurodevelopmental disability in children aged three to five years	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.2.1 High‐loading and high‐maintenance dose versus standard‐loading and standard‐maintenance dose	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.3 Failure to extubate within one week of commencing treatment	1	78	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.34, 2.69]
2.4 Apnea: number of infants with at least one episode (defined as interruption of breathing for more than 20 seconds) after 24 hours from commencing treatment, in a 24‐hour period and over one week	1	78	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.59, 1.75]
2.5 Side effects (tachycardia, agitation, or feed intolerance) leading to a reduction in dose or withholding of caffeine	1	78	Risk Ratio (M‐H, Fixed, 95% CI)	1.19 [0.34, 4.09]
2.6 Bronchopulmonary dysplasia/chronic lung disease at 36 weeks' postmenstrual age	2	152	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.61, 1.30]
2.7 Number of days using mechanical ventilation	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
2.8 Intraventricular hemorrhage, any grade	1	74	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.41, 1.69]
2.9 Intraventricular hemorrhage, grade 3 to 4	2	152	Risk Ratio (M‐H, Fixed, 95% CI)	0.68 [0.22, 2.15]
2.10 Cerebellar hemorrhage at brain ultrasound (yes/no)	1	74	Risk Ratio (M‐H, Fixed, 95% CI)	3.33 [1.00, 11.15]
2.11 Magnetic resonance imaging (MRI) abnormalities at term equivalent age (yes/no), defined as white matter lesions (i.e. cavitations [Rutherford 2010]) and punctate lesions (Cornette 2002); germinal matrix‐intraventricular hemorrhage (Parodi 2015); or cerebellar hemorrhage (Limperopoulos 2007)	1	74	Risk Ratio (M‐H, Fixed, 95% CI)	0.50 [0.10, 2.56]
2.12 Periventricular leukomalacia	2	152	Risk Ratio (M‐H, Fixed, 95% CI)	1.64 [0.41, 6.59]
2.13 Necrotizing enterocolitis (proven = Bell stage of 2 or greater) (Bell 1978)	2	152	Risk Ratio (M‐H, Fixed, 95% CI)	1.23 [0.51, 2.93]
2.14 Patent ductus arteriosus (PDA) requiring treatment (cyclo‐oxygenase inhibitors or surgical ligation)	1	74	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.66, 1.52]
2.15 Retinopathy of prematurity (ROP) (any ROP) (International Committee 2005)	1	78	Risk Ratio (M‐H, Fixed, 95% CI)	1.66 [0.53, 5.23]
2.16 Retinopathy of prematurity (ROP) (severe ROP [stage 3 or greater]) (International Committee 2005)	1	74	Risk Ratio (M‐H, Fixed, 95% CI)	0.50 [0.10, 2.56]
2.17 Seizures (clinically diagnosed; diagnosed by electroencephalography)	1	74	Risk Ratio (M‐H, Fixed, 95% CI)	1.42 [0.79, 2.53]
2.18 Developmental delay (Bayley Mental Developmental Index or Griffiths Mental Development Scale in children aged 18 to 24 months	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.18.1 High‐loading and high‐maintenance dose versus standard‐loading and standard‐maintenance dose	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.19 Bayley‐III cognitive score in children at 18 to 24 montsh CA	1	42	Mean Difference (IV, Fixed, 95% CI)	‐1.90 [‐8.60, 4.80]
2.20 Cerebral palsy in children aged 18 to 24 months	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.20.1 High‐loading and high‐maintenance dose versus standard‐loading and standard‐maintenance dose	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.21 Blindness in children aged 18 to 24 months	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.21.1 High‐loading and high‐maintenance dose versus standard‐loading and standard‐maintenance dose	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.22 Deafness in children aged 18 to 24 months	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2.22.1 High‐loading and high‐maintenance dose versus standard‐loading and standard‐maintenance dose	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected