TABLE 1.
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, limitations | Patient characteristics | Main significant findings | ||
| Early caffeine | Late caffeine | Benefits of early caffeine | Drawbacks 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)) |
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| 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 g | Reduced 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 neonates | Marginal 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 birth | No 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 outcomes | 23 873 neonates for primary outcomes | Reduced 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:
|
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 |
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| 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.