Summary of retrospective studies, post hoc analyses, randomised controlled trials (RCTs) and systematic reviews and meta-analyses comparing early versus late caffeine treatment in preterm infants

First author, year [ref.]Study characteristics, regimen, limitationsPatient characteristicsMain significant findings
Early caffeineLate caffeineBenefits of early caffeineDrawbacks or no effect of early caffeine
Davis, 2010 [34]Post hoc subgroup analysis of the CAP trial
Caffeine citrate
20 mg·kg−1 load ≤3 DoL versus >3 DoL
Post hoc analysis for treatment indication, not as primary outcome
Larger reduction in days of respiratory support (p=0.02)
Lower PMA at time of discontinuing PPV (mean difference 1.35 weeks (0.90–1.81) versus 0.55 weeks (−0.11–0.99))
Abbasi, 2010 (abstract) [65]Retrospective cohort study
Early caffeine (0–2 DoL) versus late caffeine (≥3 DoL)
Retrospective, many data not available; Newcastle–Ottawa score for risk of bias 4
166 case/control pairs, BW 500–1250 gReduced odds of IVH (OR 0.37)
Patel, 2013 [61]Retrospective cohort study
Caffeine initial dose <3 DoL versus ≥3 DoL
Retrospective, single-centre; indication for caffeine therapy unknown; no protocol on caffeine use
83 neonates
BW 940 (730–1100) g
GA 27.3 (25.6–28.7) weeks
57 neonates
BW 910 (715–1035) g
GA 26.6 (25.3–27.7) weeks
Decreased incidence of death or BPD (25.3% versus 52.6%) by a reduced rate of BPD (23.6% versus 50.9%)
Reduced need for treatment of PDA (10.4% versus 36.4%)
Lower duration of MV (6 versus 22 days)
Saeidi, 2014 (abstract) [69]RCT
Caffeine citrate 20 mg·kg−1 load within first 3 DoL versus ≥3 DoL
Single-centre; small sample size; many data not available
16 neonates
BW 1123±244 g
GA 29.5±2.0 weeks (BW and GA for all 36 included infants)
20 neonatesMarginal reduction in BPD and significant reduction in apnoea
Dobson, 2014 [32]Retrospective analysis
Caffeine initial dose <3 DoL versus ≥3 DoL
Retrospective; variable indications for early caffeine use among centres (hypothetically: apnoea, prophylactically, weaning from MV and reduction in BPD); possible changes in clinical practice during the study period
14 535 neonates
BW 1055 (630–1447) g
GA 28.1 (25.0–31.0) weeks
14 535 neonates
BW 1054 (590–1460) g
GA 28 (24.0–32.0) weeks
Reduced risk of BPD by 7.6% (23.1% versus 30.7%);
Reduction in MV days at 36 weeks PMA (median 11 versus 17 days)
Reduction in PDA requiring treatment (12.3% versus 19%)
Higher odds of death (OR 1.23, 95% CI 1.05–1.43; 4.5% versus 3.7%)
Lodha, 2015 [57]Retrospective cohort study (Canadian Neonatal Network)
Caffeine initial dose <3 DoL versus ≥3 DoL
Retrospective; variations and inconsistency in the protocol for early caffeine use at various centres and unknown indications for caffeine use; potential variations in maintenance dose of caffeine
3806 neonates
BW 1070 (850–1310) g
GA 28 (26–29) weeks
1295 neonates
BW 1050 (790–1360) g
GA 28 (26–30) weeks
Reduction in BPD or death (aOR 0.81), stemming on BPD (aOR 0.79)
Reduced incidence of PDA (40.5% versus 46.2%) and of surgical treatment for PDA (13.3% versus 25%)
Reduced duration of MV, HFV and CPAP on day 2; reduction in the use of postnatal steroids
No difference in mortality (aOR 0.98)
No difference in NEC ≥stage 2, ROP ≥stage 3, severe neurological injury (presence of parenchymal echolucency, periventricular echogenicity or PVL)
Taha, 2014 [66]Retrospective data analysis (Alere Neonatal Database)
Caffeine initial dose <3 DoL (0–2) versus ≥3 DoL (3–10)
Retrospective; unknown indications for use of early caffeine
1986 neonates
BW 938±201 g
GA 27.5±2.0 weeks
965 neonates
BW 899±216 g
GA 27.2±2.1 weeks
Reduced incidence of BPD (36.1% versus 46.7%, OR 0.69) and rate of BPD or death (45.5% versus 54.9%, OR 0.77)
Lower age at first extubation (7.1 versus 10.8 days), decreased duration of MV (16.7 versus 23.7 days) and PMA to room air (34.7 versus 35.6 days)
Lower odds of severe IVH and PDA
Higher odds of NEC (OR 1.41)
Dekker, 2017 [12]Unblinded RCT
Caffeine in the delivery room versus caffeine in the NICU
Small sample size; no placebo-controlled group
13 neonates
BW 870 (767–1198) g
GA 27 (26–28) weeks
10 neonates
BW 960 (731–1450) g
GA 28.5 (27–29) weeks
Increased minute volumes (189±74 versus 162±70 mL·kg−1·min−1) and tidal volumes (5.2, IQR 3.9–6.4 mL·kg−1) versus 4.4, IQR 3.0–5.6 mL·kg−1) at 7–9 min after birthNo differences in short-term clinical outcomes (intubation rates, surfactant administration) and IVH
Katheria, 2015 [40]Pilot RCT
Caffeine citrate
20 mg·kg−1 load within the first 2 h of life versus at 12 h of life
Small sample size underpowered to achieve differences in the outcome of reducing intubation
11 neonates
BW 1007±169 g
GA 27±0.9 weeks
10 neonates
BW 1005±239 g
GA 27±0.9 weeks
Reduced incidence of intubation in the first 12 h (27% versus 70%, p=0.08)
Reduced vasopressor requirement in the first 24 h (0% versus 20%, p=0.21)
Higher SVC flow (101±25 mL·kg−1·min−1 versus 77±24 mL·kg−1·min−1) and RVO (273±62 mL·kg−1·min−1 versus 219 ± 43 mL·kg−1·min−1)
Similar duration of oxygen treatment, MV, IVH, PDA requiring treatment
Park, 2015 [64]Systematic review and meta-analysis
Early caffeine (0–2 DoL) versus late caffeine (≥3 DoL)
Only one RCT included; one retrospective study in the meta-analysis; no analysis on the effect of caffeine on apnoea as the studies did not report it as an outcome
30 974 neonates for primary outcomes23 873 neonates for primary outcomesReduced mortality (3.8% versus 4.2%, OR 0.90), incidence of BPD (20% versus 34.6%, OR 0.5) and rate of BPD or death (23.7% versus 37.9%, OR 0.52)
Reduced risk of IVH, PVL, ROP requiring photocoagulation, PDA requiring treatment
Risk of NEC and NEC requiring surgery not associated with the early use of caffeine (OR 0.97 and 1.06, respectively)
Kua, 2017 [67]Systematic review and meta-analysis
Early caffeine (initiated <3 DoL) in preterm infants
No information on the indications for early versus late caffeine treatment from the studies; most of the RCTs had small sample size
Meta-analysis of cohort studies and RCTs:
  • - Reduction of BPD 20–33%

  • - 29% reduction in the incidence of PDA (cohort studies)

  • - 59% decrease in the need for surgical closure of PDA (cohort studies)

  • - Shorter duration of MV (WMD −7.5 days)

Increase in absolute risk of mortality with early caffeine therapy (4.7% versus 3.9%).
No difference in rates of NEC, need for surfactant, home oxygen
Borszewska-Kornacka, 2017 [63]Prospective cohort study
Early (initial dose on DoL 1)
and late (initial dose on DoL ≥2) caffeine therapy
Possible differences in local practices between centres; no randomisation
143 neonates
BW 1130 (895–1450) g
GA 29 (27–30) weeks
143 neonates
BW 1100 (850–1485) g
GA 29 (27–30) weeks
Significant lower incidence of PDA (25% versus 37%, OR 0.56)
Reduced incidence of IVH (42.1% versus 60.1%, OR 0.48)
Reduced duration of MV (IQR 0–4 versus IQR 1–15.9)
No statistically significant difference in the incidence of BPD (36.4% versus 45.8%, p=0.31) and mortality rates (8.6% versus 8.5%, nonsignificiant)
Patel, 2017 [73]Multicentre, observational cohort study
Early caffeine (initiation on DoL 0) versus late caffeine (initiation on DoL 1–6)
No adjustment for factors possibly associated with doctor's decision to start caffeine; highly selected infants excluding those with need of surfactant or lower Apgar score
4528 neonates
BW <1500 g
GA 29 (28–30) weeks
6605 neonates
BW <1500 g
GA 30 (29–31) weeks
Similar incidence of CPAP failure (22% versus 21%, OR 1.05)
No difference in exposure to a max FiO2 >0.3 (27% versus 32%, OR 1.05)
No difference in duration of CPAP therapy (3 versus 2 days, OR 1.02)

CAP: Caffeine for Apnoea of Prematurity; DoL: day of life; PMA: post-menstrual age; PPV: positive pressure ventilation; BW: birthweight; IVH: intraventricular haemorrhage; GA: gestational age; BPD: bronchopulmonary dysplasia; PDA: patent ductus arteriosus; MV: mechanical ventilation; aOR: adjusted odds ratio; HFV: high-frequency ventilation; CPAP: continuous positive airway pressure; NEC: necrotising enterocolitis; ROP: retinopathy of prematurity; PVL: periventricular leukomalacia; NICU: neonatal intensive care unit; IQR: interquartile range; SVC: superior vena cava; RVO: right ventricular output; WMD: weighted mean difference; FiO2: fraction of inhaled oxygen.