Influence of Caffeine Therapy in Preterm Infants
Influence of Caffeine Therapy in Preterm Infants
The development of sleep wake cycles is indicative of child's neurocognitive functions.
 Caffeine therapy is commonly used in neonatal intensive care units for treatment of apnea of
 prematurity (AOP), to reduce mechanical ventilation, and improve the success of extubation.
 In addition, it is suggested to be associated with positive long-term outcomes on pulmonary
 function and neurodevelopment. However, it is still not clear how caffeine therapy affects
 the sleep architecture and neurodevelopment of preterm infants. Furthermore, optimal dosing
 and timing of caffeine therapy is controversial.

 We aimed to evaluate the effects of caffeine therapy on sleep architecture and
 neurodevelopment in preterm infants during the first year of life.

 A prospective observational case-control study will be conducted. Forty preterm infants aged
 between 28 to 34 gestational weeks admitted to the Marmara University Neonatal Intensive Care
 Unit (NICU) from May 2020 to May 2021 will be included. Infants with neonatal risk factors
 for poor neurodevelopmental outcomes will be excluded. Duration, timing and cumulative dosage
 of caffeine therapy will be calculated. Follow up outcome for neurodevelopment and sleep
 architecture of preterm infants who received caffeine therapy will be compared with those who
 did not receive caffeine therapy.

 Sleep and activity behavior recorded by actigraphy, sleep diary and polysomnography at 6, and
 12 months corrected age will be compared to noncaffeine group. Neurodevelopment will be
 assessed by neurological examination defined by Hammersmith, Ages and Stages Questionnaire
 (ASQ-2), and Bayley Scales of Infant and Toddler Development.
Methylxanthines have been prescribed in preterm infants to treat and prevent Apnea of
 Prematurity (AOP), for extubation success, for reduction of incidence of BPD, need for
 treatment of PDA, retinopathy of prematurity, IVH, and for neuroprotective effects. Caffeine
 is the most common drug of choice. Despite its frequent use there are no standardized
 protocols for optimal timing and dosage. It is suggested to have a neuroprotective effect,
 and associated with reduction of neurological disabilities, cognitive delay. However, there
 are studies which found no difference in poor neurological outcomes compared to control.

 Premature infants have more active sleep compared to term infants, and their sleep patterns
 mature gradually. Studies about the effects of caffeine therapy on sleep of premature infants
 are few. It is known that sleep is associated with child's neurodevelopmental outcomes.
 Identifying the impact of caffeine therapy on sleep will help clinicians to identify and
 improve neurodevelopmental problems in this vulnerable study population.

 The aim of this study is to evaluate the effects of caffeine therapy on sleep, activity
 patterns and neurodevelopment in preterm infants during the first year of life.

 Based on the assumption that each year approximately 20 infants receive neonatal caffeine
 therapy in the unit, forty preterm infants aged between 28 to 34 gestational weeks admitted
 to the Marmara University Neonatal Intensive Care Unit (NICU) from May 2020 to May 2021 will
 be included. Duration, timing and cumulative dosage of caffeine therapy will be calculated.
 The routine practice of Marmara University NICU protocol is to administer caffeine
 prophylaxis to infants born at less than 30 weeks of gestational age and/or infants with less
 than 1250 grams gestational weight. Infants born between 30 to 34 weeks of gestational age
 who has AOP are treated with caffeine therapy with the commonly prescribed dose of 20 mg/kg
 loading, and 5-10 mg/kg/day maintenance. Neonatal caffeine therapy continues until the
 infants are 34 weeks corrected gestational age and free of any apnea episodes for at least 7
 days. Infants with neonatal risk factors for poor neurodevelopmental outcomes such as infants
 with perinatal asphyxia, intraventricular hemorrhage grade 3 or higher, retinopathy of
 prematurity(ROP) of stage 3 or higher, infants using sedative or anticonvulsant drugs at the
 time of data collection will be excluded.

 Follow up outcome for sleep architecture and neurodevelopment of preterm infants who received
 caffeine therapy will be compared with those who did not receive caffeine therapy.

 Actigraphy Sleep and activity behavior recorded by sleep diary, actigraphy and
 polysomnography at 6, and 12 months corrected age will be compared to noncaffeine group.
 Sleep wake patterns will be assessed by Philips Respironics Mini-Mitter Actiwatch-2 for at
 least 3 days at home environment and sleep diaries within 5-minute intervals will be filled
 out by parents simultaneously. Actigraphy is a validated wristwatch-like device that
 distinguishes sleep from wakefulness based on accelerometer measured movement. The actiwatch
 weighs 16 grams and will be placed on the infant's left ankle. For actigraphy interpretation,
 if the activity count exceeds a predefined threshold value the epoch is scored as wake state.
 10 minutes with no movements on autograph will be determined as sleep phase. High frequency
 movements with >40 movements in each epoch lasting >10 minutes will be determined as wake
 state. According to the frequency of infants' movements, a number of sleep-wake variables
 will be calculated for analyses with Philips Actiware 6.1.8 software. Mean total sleep
 duration, mean sleep duration during the day, mean sleep duration at night, sleep onset
 latency (SOL: time taken to fall asleep after reported lights out), wake after sleep onset
 (WASO: number of minutes recorded as wake between sleep onset and sleep offset), longest
 consolidated sleep period at night (midnight and 6 am), number of night waking, and sleep
 efficiency (TST/ time in bed, reported as percent) will be determined.

 Polysomnography Infants will undergo 3-4 hours polysomnography (Embla Systems N7000) in the
 pediatric sleep laboratory. Further validation of the actigraphy will be performed by an
 epoch-by-epoch comparison of actigraphy and simultaneous polysomnography data. The following
 variables will be monitored: electroencephalography, electromyography, electrocardiography,
 heart rate and respiratory rate. Respiration will be monitored with a nasal-cannula- pressure
 transducer, thoracic and abdominal inductive plethysmography bands and pulse-oximetry.
 Polysomnography will be recorded with Embla RemLogic software. For polysomnography scoring,
 recommendations of the American Academy of Sleep Medicine Guidelines-2017 will be followed.
 The polysomnography data will be analyzed by an expert physician blinded to the actigraphy
 results or the newborn infant's clinical data, except for gestational age and days of life.
 Apnea-hypopnea index (AHI) will be determined.

 Our secondary objective is to assess neurodevelopment of these infants. Neurodevelopment will
 be assessed by neurological examination defined by Hammersmith, Ages and Stages Questionnaire
 (ASQ), and Bayley Scales of Infant and Toddler Development at 6, and 12 months corrected age
 and will be compared to noncaffeine group.

 Neurological examination will be performed with Hammersmith Neurological Examination.
 Hammersmith Neurological Examination is a quick examination for 3 to 24 months old infants.
 It consists of 26 items assessing neurological function in 5 groups: cranial nerve function
 (max 15 points), posture (maximum 18 points), movements (maximum 6 points), tone (maximum 24
 points) and reflexes and reactions (maximum 15 points). Each subgroup is scored from 0 to 3
 points and all scores are summed at the end of the examination.

 Ages and Stages Questionnaire helps to evaluate developmental progress in children between
 the ages of 1 month and 66 months. Ages and Stages Questionnaire lasts approximately 10-15
 minutes and assess the child development in 5 developmental areas: gross motor, fine motor,
 communication, problem solving and personal- social. Each area consists of 6 questions and
 the questions are answered in 3 simple responses: yes, sometimes or not yet. The
 questionnaire is scored with a simple 0, 5- and 10-point scoring system (yes: 10 points,
 sometimes: 5 points, not yet: 0 points) in 2-3 minutes by parents and the results are
 interpreted according to standardized cutoffs by professionals. Ages and Stages
 Questionnaire-2 (ASQ-2) is a parent-friendly developmental scale with 0.86 sensitivity, 0.85
 specifity, 0.92 test-retest reliability and 0.93 inter-rater reliability. If the score on any
 domain is <2SDs below the cut-off point for the Turkish reference group, the child is defined
 as at risk for neurodevelopmental delay.

 The Bayley Scales of Infant and Toddler Development, 3rd Edition produces three composite
 scores: the Cognitive Scale (range 55-145), the Language scale (range 45-155) which has
 receptive and expressive communication subtests, and the Motor scale (range 45-155), which
 consists of Fine Motor, and Gross Motor subtests.

 Child's scores will be compared to the standardized age norms.
Inclusion Criteria:

 -  Preterm infants born between 28 to 34 gestational weeks admitted to the Marmara
 University Neonatal Intensive Care Unit (NICU)

 Exclusion Criteria:

 -  perinatal asphyxia intraventricular hemorrhage grade 3 or higher retinopathy of
 prematurity(ROP) of stage 3 or higher major congenital anomalies infants using
 sedative or anticonvulsant drugs at the time of data collection