MINNEAPOLIS – Caffeine therapy for apnea of prematurity did not prevent the development of persistent and significant obstructive apnea in children by the time they were 9 years old.
"Apnea of prematurity occurs in more than three-quarters of infants born at under 30 weeks’ gestation, and more than half of these apneas are actually obstructive in nature," reported Dr. Carole Marcus, who is director of the sleep center at the Children’s Hospital of Philadelphia, at the annual meeting of the Associated Professional Sleep Societies. "Caffeine is now the most commonly used drug [to treat apnea of prematurity] in the NICU in infants less than 32 weeks’ gestation," she said.
Dr. Carole L. Marcus
Apnea of prematurity is commonly treated with therapeutic caffeine administration, but the long-term effects of caffeine on sleep in the developing brain are not well understood. In particular, it is not known whether neonatal caffeine administration has permanent adverse effects on sleep architecture and ventilatory control, perhaps increasing the risk of later sleep disorders such as insomnia and obstructive sleep apnea.
In the earlier CAP (Caffeine for Apnea of Prematurity) trial, 793 premature infants with birthweights of 500-1250 g were randomly assigned to receive either caffeine or placebo until therapy for apnea of prematurity was no longer needed.
Caffeine therapy was shown to improve the rate of survival without neurodevelopmental disability at 18 to 21 months in these babies compared to placebo (P = .008) (N. Engl. J. Med. 2007;357:1893-902).
The subsequent axillary long-term CAP-S (Sleep) trial involved 201 CAP subjects and looked at whether neonatal caffeine administration resulted in later sleep abnormalities. The investigators assessed the ex-premature children between ages 5-11 years (mean age, 9 years) using sleep questionnaires, actigraphy, and full ambulatory (home-based) polysomnography.
Of note, the patients assessed in CAP-S were from either Canada or Australia, with a high proportion of white patients, high maternal education, and high socioeconomic status, "which is relevant to our obstructive sleep apnea outcomes," noted Dr. Marcus (SLEEP 2014 abstract supplement;37:abst.#0862).
No significant differences were noted in children who had received caffeine, compared with those who did not in terms of subjective measures of sleep quality or quantity. Total recording time and total sleep time on polysomnography were somewhat longer in the caffeine arm, but there was no difference seen in sleep efficiency between groups (P = .91).
However, obstructive sleep apnea (apnea-hypopnea index of more than two episodes/hour) was common in both groups (8.2% of the caffeine group and 11% of the placebo group; P = .22). In contrast, the prevalence of obstructive sleep apnea in the general pediatric population is between 1%-4%.
Also, 24% of the caffeine group and 29% of the placebo group had either obstructive sleep apnea on polysomnography and/or a history of adenoidectomy/tonsillectomy, again with no difference between groups (P = .35).
A large proportion of subjects in both arms had elevated periodic limb movements (17.5% in the caffeine group and 11% in the placebo groups; P = .27), a proportion that was markedly higher than was the normal prevalence in cases in which the child had more than five episodes of periodic limb movement/hour, which lies between 5% and 8%.
"We think that this study further supports the use of caffeine for apnea of prematurity as it has been shown to have quite a number of beneficial effects and no long-term adverse effects," said Dr. Marcus. "However, further study is needed on the mechanisms underlying the high prevalence of sleep disorders, both [obstructive sleep apnea] and [periodic limb movement syndrome], in ex-preterm infants."
In response to a comment, Dr. Marcus added that there is also a long-term behavioral and neurocognitive outcomes study ongoing on the CAP cohort, but they were unable to combine those results with the sleep study results because the data were collected too far apart.
The study was supported by an National Institutes of Health R01 grant and by the Canadian Institute for Health Research. Philips Respironics provided actigraphy equipment. Dr. Marcus reported that she gets unrelated research support from Philips Respironics and Ventus.