I was privileged to be part of the CAP trial group, a pivotal neonatal trial that showed improved Bayley scores and improved motor function at 18 to 21 months corrected age, among infants randomized before 10 days of age, with a birthweight under 1251 g, and considered eligible for caffeine therapy.
By 5 years of age there continued to be some advantages of caffeine treatment, compared to placebo, mostly in the motor domain.
Schmidt B, et al. Academic Performance, Motor Function, and Behavior 11 Years After Neonatal Caffeine Citrate Therapy for Apnea of Prematurity: An 11-Year Follow-up of the CAP Randomized Clinical Trial. JAMA Pediatr. 2017. A new publication presents data from 920 of 1200 of the originally enrolled patients. Quite a remarkable achievement. There were actually 2000 in the original trial but for various reasons (mostly language issues for the standardized testing, and centers who decided not to participate in the longer follow-up) there were 1200 of them eligible for this follow-up.
Functional impairment was less frequent with caffeine than with placebo, but the 95% confidence intervals of the adjusted Odds Ratio were 0.59 to 1.02, which means we can ‘only’ have about 93% confidence that the Odds of escaping impairment are improved by caffeine compared to placebo.
That might be “not significant” in some terms, but I think that’s a pretty significant degree of confidence, for a treatment lacking in any serious side effects.
This new publication confirms that there is no sign of adverse impact at this age of caffeine. The academic achievement mean scores are almost identical between caffeine and placebo groups, with slightly more caffeine children being more than 2SD below the mean.
The motor scores (movement ABC) showed more subjects below -2SD for the various subscales, which was described as being “motor impaired”, in the control group compared to the caffeine treated subjects. I don’t know much about the movement ABC, so I am not sure if “motor impairment” by this measure really has an impact on the child’s life. Only one third of the children with “motor impairment” had cerebral palsy, which was more frequent among placebo babies, 6% compared to 4.3% with caffeine.
We can be re-assured that there has never been evidence of adverse effects of caffeine, now up to 11 years of age, when given as in the CAP trial. It would be great to know if longer durations of treatment (up to term, or even after), or higher doses, could further improve these outcomes. I would be a bit reticent to try higher doses, especially following these publications (Vesoulis ZA, et al. Early High-Dose Caffeine Increases Seizure Burden in Extremely Preterm Neonates: A Preliminary Study. Journal of Caffeine Research. 2016;6(3):101-7. McPherson C, et al. A pilot randomized trial of high-dose caffeine therapy in preterm infants. Pediatr Res. 2015;78(2):198-204), which showed potential serious harm.
But a trial of prolonging caffeine therapy, at the point when it would normally be considered to be stopped, would really be worthwhile. Caffeine would probably, at least temporarily, reduce hypoxic events. Hypoxic events leading up to discharge, and beyond, have been associated with worse developmental outcomes. I think a large multi-center RCT, randomizing children to caffeine or placebo when they have their clinically indicated caffeine stopped, and continuing to term, with dose adjustments to take into account the accelerating clearance of caffeine at this developmental stage, could have real benefits for future babies in our care.