NEW ZEALAND: According to research reported in Archives of Disease in Childhood – Fetal and Neonatal Edition, BMC Journal, doses of 10 or 20 mg/kg/day of caffeine citrate are beneficial in reducing intermittent hypoxemia in late preterm infants. These doses have no negative effects on gastrointestinal reflux or sleep, but they do cause an increase in tachycardia.

In comparison to term newborns, late preterm infants have a higher risk of morbidity and mortality in the neonatal period because they are physiologically and metabolically immature. Late preterm infants make up the majority of preterm deliveries.

Episodic hypoxaemia is more common in late preterm newborns than their term-born peers, and it is linked to poor cognitive and neurodevelopmental outcomes in preterm infants.

The team lead by Dr.Jane M Alsweiler, Department of Paediatrics: Child and Youth Health, The University of Auckland, reported that, “the neurodevelopmental results of very preterm newborns are improved by caffeine, which also lessens episodes of prematurity apnoea and intermittent hypoxemia (IH)”.

“Caffeine is often well tolerated in extremely preterm neonates, while it can impair neonatal weight gain and occasionally causes infants to become tachycardic and feed intolerant,”.Unknown is the ideal caffeine dosage for treating IH in infants born late in the pregnancy, they asserted.

To lower IH in late preterm newborns, the researchers endeavored to determine the caffeine citrate dose that was both most efficacious and most tolerated.

A Phase IIB, double-blind, five-arm, parallel, randomised controlled study was carried out in Auckland, New Zealand, at two maternity hospitals in the neonatal and postnatal wards Between February 2019 and December 2020. Within 72 hours of birth, late preterm infants who were born at 34+0–36+6 weeks’ gestation were enrolled for the trial. A loading dose of 10, 20, 30, or 40 mg/kg was given to 132 infants with mean (SD) birth weights of 2561 (481) g and gestational ages of 35.7 (0.8) weeks. They were then randomly assigned to receive either a placebo or 5, 10, 15, or 20 mg/kg/day of equivolume enteral caffeine citrate until term corrected age. The primary endpoint was IH (events/hour with oxygen saturation concentration 10% below baseline for 2 min), 2 weeks after randomization. Neonatal development, tachycardia, and salivary caffeine levels were predetermined secondary outcomes.

Key results of the trial:

In comparison to placebo, caffeine decreased the rate of IH at two weeks after randomization (geometric mean (GM): 4.6, 4.6, 2.0, 3.8, and 1.7 events/hour for the placebo, 5, 10, and 15 mg/kg/day, respectively), with differences statistically significant for the 10 mg/kg/day (GM ratio (95% CI] 0.39 (0.20 to 0.76]; p=0.006) and the 20 mg/kg/day (GM ratio (95% CI] 0.33 (0.17 to 0.68]; p=0.003). Without having a significant negative impact on growth rate or sleep, the 20 mg/kg/day dose raised mean (SD) pulse oximetry oxygen saturation (SpO2) (97.2 (1.0) vs placebo 96.0 (0.8); p0.001), and decreased median (IQR) percentage of time SpO2 90% (0.5 (0.2-0.8) vs 1.1 (0.6-2.4); p0.001) at 2 weeks.

The authors concluded that broad use of caffeine might result in long-term advantages for brain development in this significant patient population if it is shown to improve neurodevelopmental outcomes in late preterm newborns.

A crucial step in achieving this objective and enabling the creation of a larger and longer trial of effectiveness is determining an effective dose that is linked with few side effects, they added.


Oliphant EA, McKinlay CJ, McNamara D, et al;Caffeine to prevent intermittent hypoxaemia in late preterm infants: randomised controlled dosage trial, Archives of Disease in Childhood – Fetal and Neonatal Edition Published Online First: 29 August 2022. doi: 10.1136/archdischild-2022-324010

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