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EBNEO review of the study by Oliphant EA, McKinlay CJ, McNamara D, Cavadino A, Alsweiler JM. Caffeine to prevent intermittent hypoxaemia in late preterm infants: randomised controlled dosage trial. Arch Dis Child Fetal Neonatal Ed. 2023 Mar;108(2):106-113. doi: 10.1136/archdischild-2022-324010. Epub 2022 Aug 29. PMID: 36038256 reviewed for EBNeo by Ayat Mohamed and Hassanein Moustafa from the Department of Neonatology, Newcross Hospital, Wolverhampton, United Kingdom. 

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Acta Paediatrica commentary by Ayat Mohamed and Hassanein Moustafa:

Acta Paediatrica - 2024 - Mohamed - EBNEO commentary Caffeine to prevent intermittent hypoxaemia in late preterm infants .pdf


Caffeine citrate is considered to be the drug of choice of apnea of prematurity. Caffeine therapy reduces the incidence of intermittent hypoxaemia, duration of mechanical ventilation and lung damage in preterm babies who are born before 28 week gestation (1).


Intermittent hypoxemia is the brief and repetitive episodes of dropped haemoglobin oxygen saturation from the normal oxygenation state, which are followed by returning to normal oxygenation baseline state. Preterm babies are more likely to have more frequent episodes of Intermittent hypoxia until term-equivalent age with no clear potential clinical triggers of developing apnea (2). The frequent occurrence of these episodes of desaturations in preterm infants have been suggested to be associated with later poor neurodevelopmental outcomes (3).


Late preterm infants, who are born between 34 0/7 and 36 6/7 weeks gestational age, account for an important proportion of newborn babies requiring admission to the neonatal unit because of respiratory morbidity (4). Nearly one third (28.6%) of late preterm newborns were reported to have apnea of prematurity which was attributed to both lung and respiratory centre immaturity, and hence required treatment (5) Furthermore, a prospective cohort observational study showed that there is a great risk of having intermittent hypoxemia in late preterm babies (6). Therefore, preventing or reducing intermittent hypoxemia episodes in late preterm infants could be associated with improving the neurodevelopmental outcomes.


This study was published in a reputable journal and declared no conflict of interest. It started with a large sample size and clear primary and prespecified secondary outcomes. However, there was a high rate of withdrawal of significant number of eligible babies in the higher dose caffeine. This was because of poor tolerability and administration difficulty, which may be attributed to the bitter solution taste as caffeine was received orally, in addition to the difficulty to give big volume in higher doses. The optimal dosage of caffeine citrate for reducing intermittent hypoxia in late preterm infants was not clear. This study used different dosages, and it is important to determine the most effective dose without adverse effects. It might be worth conducting longer and larger trials using more palatable caffeine formulation to assess the efficacy and safety of caffeine therapy in high doses, in addition to recording concurrent use of other medication that may interact with caffeine citrate. This would be very beneficial alongside with comparing early prophylactic versus late caffeine therapy and duration of caffeine treatment in late preterm infants in order to come to a definitive conclusion regarding its routine use on this population.


Chavez L, Bancalari E. Caffeine: Some of the Evidence behind Its Use and Abuse in the Preterm Infant. Neonatology. 2022;119(4):428-432.

Rhein LM, Dobson NR, Darnall RA, Corwin MJ, Heeren TC, Poets CF, McEntire BL, Hunt CE; Caffeine Pilot Study Group. Effects of caffeine on intermittent hypoxia in infants born prematurely: a randomized clinical trial. JAMA Pediatr. 2014;168(3):250-7.

Pillekamp F, Hermann C, Keller T, von Gontard A, Kribs A, Roth B. Factors influencing apnea and bradycardia of prematurity – implications for neurodevelopment. Neonatology. 2007;91(3):155-61.

Consortium on Safe Labor. Hibbard JU, Wilkins I, Sun L, Gregory K, Haberman S, et al. Respiratory morbidity in late preterm births. JAMA 2010; 304:419–25.

Olivier F, Nadeau S, Caouette G, Piedboeuf B. Association between Apnea of Prematurity and Respiratory Distress Syndrome in Late Preterm Infants: An Observational Study. Front Pediatr. 2016 Sep 26;4:105.

Williams LZJ, McNamara D, Alsweiler JM. Intermittent Hypoxemia in Infants Born Late Preterm: A Prospective Cohort Observational Study. J Pediatr. 2019; 204:89-95.e1.

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