Secondary outcomes
| Placebo N=24* | Caffeine citrate 5 mg/kg/day N=24 | Caffeine citrate 10 mg/kg/day N=27 | Caffeine citrate 15 mg/kg/day N=27 | Caffeine citrate 20 mg/kg/day N=27 | Any dose of caffeine N=105 | ||||||
| Summary data | Summary data | Mean difference (95% CI), p value vs placebo | Summary data | Mean difference (95% CI), p value vs placebo | Summary data | Mean difference (95% CI), p value vs placebo | Summary data | Mean difference (95% CI), p value vs placebo | Summary data | Mean difference (95% CI), p value vs placebo | |
| Weight growth velocity (birth to term equivalent) (g/kg/day)*, †; mean (SD) | 8.8 (3.1) | 8.4 (3.4) | −0.45 (−2.55 to 1.65); 0.67 | 7.5 (3.4) | −1.51 (−3.59 to 0.56); 0.15 | 9.1 (3.4) | 0.02 (−2.10 to 2.15); 0.98 | 9.1 (3.5) | −0.32 (−2.51 to 1.88); 0.78 | 8.5 (3.4) | −0.62 (−2.27 to 1.04); 0.46 |
| Length growth velocity (birth to term equivalent) (cm/week)*, †; mean (SD) | 0.7 (0.6) | 0.7 (0.4) | −0.08 (−0.39 to 0.23); 0.61 | 0.7 (0.6) | 0.02 (−0.28 to 0.33); 0.89 | 1.0 (0.4) | 0.20 (−0.11 to 0.52); 0.20 | 0.6 (0.4) | −0.08 (−0.41 to 0.25); 0.62 | 0.8 (0.5) | 0.02 (−0.23 to 0.26); 0.89 |
| Head circumference growth velocity (birth to term equivalent) (cm/week)*, †; mean (SD) | 0.6 (0.3) | 0.4 (0.2) | −0.23 (−0.40 to –0.07); 0.006 | 0.5 (0.3) | −0.12 (−0.28 to 0.04); 0.15 | 0.5 (0.2) | −0.16 (−0.33 to 0.00); 0.05 | 0.5 (0.2) | −0.16 (−0.34 to 0.01); 0.07 | 0.5 (0.2) | −0.17 (−0.30 to –0.04); 0.010 |
| Failure to regain birth weight by 2 weeks postnatal age; N (%)‡ | 2 (8.3%) | 2 (8.3%) | 1.03 (0.13 to 8.21); 0.98 | 4 (14.8%) | 1.91 (0.28, 13.29); 0.51 | 7 (25.9%) | 4.33 (0.72 to 26.16); 0.11 | 6 (21.4%) | 3.50 (0.55 to 22.30); 0.18 | 19 (17.9%) | 2.58 (0.51 to 13.11); 0.25 |
| Sleep score; mean (SD)§,¶ | |||||||||||
| Two weeks | 4.2 (0.6) | 4.3 (0.3) | 0.11 (−0.17 to 0.38); 0.45 | 4.3 (0.5) | 0.02 (−0.25 to 0.29); 0.87 | 4.2 (0.3) | 0.01 (−0.27 to 0.29); 0.94 | 4.1 (0.5) | −0.09 (−0.38 to 0.20); 0.53 | 4.2 (0.4) | 0.02 (−0.20 to 0.23); 0.87 |
| Term | 4.4 (0.5) | 4.4 (0.3) | 0.05 (−0.21 to 0.31); 0.70 | 4.5 (0.4) | 0.16 (−0.09 to 0.42); 0.21 | 4.3 (0.4) | −0.03 (−0.30 to 0.23); 0.80 | 4.2 (0.4) | −0.18 (−0.44 to 0.09); 0.19 | 4.4 (0.4) | 0.01 (−0.20 to 0.22); 0.94 |
| Gastro-oesophageal symptoms; I-GERQ-R mean (SD)§ | |||||||||||
| Two weeks | 29.7 (4.3) | 27.6 (4.2) | −2.35 (−5.56 to 0.85); 0.15 | 25.3 (6.1) | −3.80 (−6.96 to –0.64); 0.019 | 26.1 (5.1) | −3.27 (−6.46 to –0.08); 0.045 | 27.5 (6.3) | −2.75 (−6.13 to 0.63); 0.11 | 26.6 (5.5) | −3.07 (−5.54 to –0.60); 0.015 |
| Term | 27.5 (5.6) | 25.2 (4.7) | −2.38 (−5.60 to 0.84); 0.15 | 25.4 (4.9) | −2.27 (−5.41 to 0.86); 0.15 | 25.8 (5.7) | −2.16 (−5.36 to 1.05); 0.18 | 25.9 (4.1) | −2.76 (−5.99 to 0.46); 0.09 | 25.6 (4.8) | −2.39 (−4.85 to 0.08); 0.06 |
| Duration of tube feeding (days); median (IQR) (geometric mean) | 7.0 (2.0, 13.0) (2.6) | 6.0 (3.5, 14.5) (5.6) | 1.67 (0.48 to 5.89); 0.42 | 13.0 (4.0, 15.0) (6.2) | 1.34 (0.39 to 4.68); 0.64 | 6.0 (1.0, 12.0) (2.5) | 0.77 (0.22 to 2.65); 0.68 | 13.5 (1.5, 17.5) (6.1) | 0.79 (0.23 to 2.70); 0.71 | 9.0 (2.0, 15.0) (3.4) | 1.07 (0.40 to 2.87); 0.89 |
| Length of stay (number of days); median (IQR) (geometric mean) | 9.0 (5.0, 15.0) (8.2) | 7.5 (6.5, 20.0) (8.6) | 1.06 (0.76 to 1.48); 0.73 | 15.0 (8.0, 18.0) (10.8) | 1.31 (0.94 to 1.83); 0.11 | 11.0 (6.0, 16.0) (10.5) | 1.29 (0.95 to 1.75); 0.10 | 14.0 (6.0, 20.0) (11.1) | 1.36 (0.98 to 1.87); 0.06 | 12.0 (6.0, 18.0) (10.3) | 1.26 (0.99 to 1.59); 0.06 |
*Number of infants with at least one anthropometric measurement at 2 weeks and term, respectively, are: 22 and 20 in placebo group; 21 and 19 in 5 mg/kg/day group; 26 and 21 in 10 mg/kg/day group; 21 and 19 in 15 mg/kg/day group and 22 and 18 in 20 mg/kg/day group.
†Growth velocity for weight was calculated using an exponential model43 for weight and linear models for length, and head circumference.
‡Estimated group comparisons for failure to regain birth weight are ORs.
§Number of infants with feeding and sleeping data at 2 weeks and term, respectively, are: 22 and 20 in placebo group; 21 and 19 in 5 mg/kg/day group; 25 and 21 in 10 mg/kg/day group; 21 and 19 in 15 mg/kg/day group and 21 and 18 in 20 mg/kg/day group.
¶Sleep score was calculated using subscale nine on the Infant Behaviour Questionnaire-Revised, modified for neonates.31