Caffeine, standard treatment for apnea of prematurity, improves brainstem auditory processing. We hypothesized that caffeine also improves cortical differentiation of complex speech sounds. We used event-related potential methodology to measure responses to speech-sound contrasts in 45 intensive care neonates, stratified by cumulative exposure as no-, low-, and high-caffeine groups. Sound differentiation in the low-caffeine group and near-term no-caffeine infants was similar with repeated measures analysis of variance controlling for gestational and postnatal age. However, a generalized estimating equation approach demonstrated that, at equivalent postnatal age, differentiation was reduced in the high-caffeine (gestational age 25 weeks) compared to the low-caffeine group (gestational age 28 weeks), reflecting the importance of maturity at birth (Z = 2.77, P < .006). We conclude that caffeine improves measures of auditory processing associated with improved neurodevelopmental outcomes in preterm infants. However, current usage of caffeine for apnea of prematurity cannot fully compensate for the effects of brain immaturity on speech sound processing.
EichenwaldECAinaAStarkAR. Apnea frequently persists beyond term gestation in infants delivered at 24 to 28 weeks. Pediatrics. 1997;100(3 pt 1):354–359.
2.
LorchSASrinivasanLEscobarGJ. Epidemiology of apnea and bradycardia resolution in premature infants. Pediatrics. 2011;128:e366–e373.
3.
YamamotoAYokoyamaNYonetaniM. Evaluation of change of cerebral circulation by SpO2 in preterm infants with apneic episodes using near infrared spectroscopy. Pediatr Int. 2003;45:661–664.
4.
UrlesbergerBKaspirekAPichlerG. Apnoea of prematurity and changes in cerebral oxygenation and cerebral blood volume. Neuropediatrics. 1999;30:29–33.
5.
SinhaSKD'SouzaSWRivlinEChiswickML. Ischaemic brain lesions diagnosed at birth in preterm infants: clinical events and developmental outcome. Arch Dis Child. 1990;65(10 Spec No):1017–1020.
6.
KhairyMKokkotisACormierCMessmerD. Apnea is associated with neurodevelopmental impairment in very low birth weight infants. J Perinatol. 2004;24:763–768.
7.
PerlmanJMVolpeJJ. Episodes of apnea and bradycardia in the preterm newborn: impact on cerebral circulation. Pediatrics. 1985;76:3333–338.
8.
MartinRJAbu-ShaweeshJM. Control of breathing and neonatal apnea. Biol Neonate. 2005;87:288–295.
9.
RugginsNR. Pathophysiology of apnoea in preterm infants. Arch Dis Child. 1991;66(1 Spec No):70–73.
10.
SchmidtBRobertsRSDavisP. Caffeine therapy for apnea of prematurity. N Engl J Med. 2006;354:2112–2121.
11.
SchmidtBRobertsRSDavisP. Long-term effects of caffeine therapy for apnea of prematurity. N Engl J Med. 2007;357:1893–1902.
12.
HowarthTMBorkDDinuIA. Permanent bilateral sensory and neural hearing loss of children after neonatal intensive care because of extreme prematurity: a thirty-year study. Pediatrics. 2009;123:e797–e807.
13.
DoyleLWLCheongJJHuntRWR. Caffeine and brain development in very preterm infants. Ann Neurol. 2010;68:734–742.
14.
ChenYJLiouCSTsaiCHYehTF. Effect of aminophylline on brain stem auditory evoked potentials in preterm infants. Arch Dis Child Fetal Neonatal Ed. 1994;71:F20–F23.
15.
BisiacchiPSMentoGSuppiejA. Cortical auditory processing in preterm newborns: an ERP study. Biol Psychol. 2009;82:176–185.
16.
CeponieneRKushnerenkoEFellmanVRenlundMSuominenKNäätänenR. Event-related potential features indexing central auditory discrimination by newborns. Brain Res Cogn Brain Res. 2002;13:101–113.
17.
KushnerenkoECeponieneRBalanPFellmanVHuotilaineMNäätäneR. Maturation of the auditory event-related potentials during the first year of life. Neuroreport. 2002;13:47–51.
18.
deRegnierR-A. Neurophysiologic evaluation of brain function in extremely premature newborn infants. Semin Perinatol. 2008;32:2–10.
19.
MaitreNLSlaughterJCAschnerJLKeyAP. Hemisphere differences in speech-sound event-related potentials in intensive care neonates: associations and predictive value for development in infancy. J Child Neurol. 2013.
20.
MaitreNLLambertWEAschnerJLKeyAP. Cortical speech sound differentiation in the neonatal intensive care unit predicts cognitive and language development in the first 2 years of life. Dev Med Child Neurol. 2013;55:834–839.
21.
KeyAPFLambertEWAschnerJLMaitreNL. Influence of gestational age and postnatal age on speech sound processing in NICU infants. Lit Discuss. 2012;49:720–731.
22.
PapileL-AMunsick-BrunoGSchaeferA. Relationship of cerebral intraventricular hemorrhage and early childhood neurologic handicaps. J Pediatr. 1983;103:273–277.
23.
StevensKNBlumsteinSE. Invariant cues for place of articulation in stop consonants. J Acoust Soc Am. 1978;64:1358–1368.
24.
KeyAPFDoveGOMaguireMJ. Linking brainwaves to the brain: an ERP primer. Dev Neuropsychol. 2005;27:183–215.
25.
NichCCarrollK. Now you see it, now you don't: a comparison of traditional versus random-effects regression models in the analysis of longitudinal follow-up data from a clinical trial. J Consult Clin Psychol. 1997;65:252–261.
26.
GardnerWMulveyEPShawEC. Regression analyses of counts and rates: Poisson, overdispersed Poisson, and negative binomial models. Psychol Bull. 1995;118:392–404.
RheinLMDobsonNRDarnallRA. Effects of caffeine on intermittent hypoxia in infants born prematurely: a randomized clinical trial. JAMA Pediatr. 2014;168:250–257.
29.
BackSASCraigAALuoNLN. Protective effects of caffeine on chronic hypoxia-induced perinatal white matter injury. Ann Neurol. 2006;60:696–705.
30.
TchekalarovaJKubovaHMarešP. Postnatal caffeine exposure: effects on motor skills and locomotor activity during ontogenesis. Behav Brain Res. 2005;160:99–106.
31.
TchekalarovaJKubováHMarešP. Effects of early postnatal caffeine exposure on seizure susceptibility of rats are age-and model-dependent. Epilepsy Res. 2010;88:231–238.
32.
LondosCCooperDMWolffJ. Subclasses of external adenosine receptors. Proc Natl Acad Sci U S A. 1980;77:2551–2554.
