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Association of early versus late caffeine administration on neonatal outcomes in very preterm neonates

Caffeine is commonly used for preterm infants with apnoea of prematurity. The caffeine for apnoea of prematurity trial (CAP) was launched to determine whether survival without neurodevelopmental disability at a corrected age of 18 months is improved if apnoea of prematurity is managed without methylxanthines in infants at a high risk of apnoeic attacks (1). Infants had to be within 10 days of birth. Forty per cent of the patients assigned to caffeine died or survived with a neurodevelopmental disability compared with 46% assigned to placebo (OR 0.77, 95% CI 0.64–0.93; p = 0.008). Physicians were not asked to alter their own prescribing indications for caffeine. However, only 22.5% of the neonatologists in the trial started caffeine to prevent apnoea (2). Thus, the risk–benefit ratio of caffeine administered exclusively for prophylaxis and therefore likely earlier remains unclear. This was emphasised by Schmidt in a recent editorial (3) commenting upon a large observational cohort study that showed that early administration decreased the incidence of BPD in their US group of NICUs (4). This is in line with another retrospective data analysis by Taha et al. (5). In addition, a subgroup analysis of the CAP trial demonstrated that early caffeine treatment correlated with a larger reduction in days of respiratory support compared to late caffeine (6). In this third large-scale observational study of the Canadian Neonatal Network, Lodha et al. retrospectively investigated the effect of early versus late initiation of caffeine therapy on neonatal short-term outcomes of very preterm infants. The nationwide participation resulted in an impressive number of included infants. Nevertheless, there are a few comments to make. First, the diagnosis of a PDA was based on clinical signs, with or without echocardiography. However, several studies have demonstrated that echocardiograms are required for the diagnosis of a PDA in preterm infants, as clinical signs are not reliable in the first few days of life (7,8). Second, there are imbalances between the infants of the early and those of the late treatment groups. We also suggest that some baseline characteristics should rather be declared as outcomes and/or co-interventions (table 3) due to their timely relation to the intervention. The late treatment group, for example, showed a more frequent use of postnatal steroids and an increased occurrence of air leak syndromes. The differences in baseline characteristics may have resulted in an early administration of caffeine in those babies without and a late administration in those with major risk factors for adverse outcomes, such as BPD for example. Despite adjustments for known imbalances between groups, observational studies do not have the ability to completely eliminate selection bias and observational studies investigating the effect of drug treatments are prone to confounding by indication. Thirdly, information concerning the indication to start caffeine is lacking, and no information on dosages is provided. In conclusion, this is an important study, but more data from randomised controlled trials on the optimal timing of caffeine administration are needed before introducing early prophylactic caffeine into routine clinical practice (9).