Caffeine therapy in preterm infants: effects in 2^nd and 3^rd childhood

To the Editor,

The immediate postnatal period is the moment for the individual's cardiopulmonary adaptation. It is necessary for the neonate's organic systems to mature so that the hemodynamic and respiratory transformation occurs in a physiological manner.¹ The cardiopulmonary and neurological immaturity of premature newborns requires caffeine to reduce the need for invasive ventilatory support, facilitate extubation and promote better cognitive outcomes. It is worth noting that the action of caffeine occurs due to its structural similarity to adenosine, acting as a competitive antagonist against the depressant effects of this molecule, through its binding to adenosine A1 and A2A receptors, which leads to beneficial results, especially in cardiac, lung and brain development.²

While reading the manuscript "Late effects of caffeine use on sleep of infants born prematurely" by Oliveira et al.,³ volume 42, 2024, methodological gaps were found in the analysis of variables regarding wake-up time and total daily sleep time in premature babies undergoing caffeine therapy in the neonatal period.

Therefore, we identified in the study by Oliveira et al.³ that the comparison of groups regarding the variables mentioned above is done through variance analysis with Tukey post-hoc, which is considered inadequate due to the imbalance between the groups. This may inflate the type I error due to the post-hoc selection, which should be Hochberg's GT2.⁴

Oliveira et al.³ also do not present an effect measure for findings with significant differences, which limits understanding of their clinical usefulness. It is necessary to develop a measure of effect in order to expose the relevance of the findings. Based on this, using the descriptive statistics of the variables "wake-up time" and "total daily sleep time", an effect measure called Cohen's d was created for unbalanced groups.⁵ It reveals that the difference between the preterm (PCG) and at term (TG) groups presents d=1.78, equivalent to a very large effect. The same was evident for the variable "total daily sleep time", with d=1.69.

In view of the above, the considerable differences in effect magnitudes indicate that caffeine administered to neonates may have considerable long-term effects on sleep in childhood. In addition to confirming these findings, it would also be interesting to observe the likely implications related to social interaction and learning that could arise in school-going children due to the longer duration of their sleep. These are the imaginable paths for future investigations into the therapeutic use of caffeine.

REFERENCES

• ¹
  Wu TW, Azhibekov T, Seri I. Transitional hemodynamics in preterm neonates: clinical relevance. Pediatr Neonatol. 2016;57:7-18. https://doi.org/10.1016/j.pedneo.2015.07.002
  » https://doi.org/10.1016/j.pedneo.2015.07.002
• ²
  Moschino L, Zivanovic S, Hartley C, Trevisanuto D, Baraldi E, Roehr CC. Caffeine in preterm infants: where are we in 2020? ERJ Open Res. 2020;6:00330-2019. https://doi.org/10.1183/23120541.00330-2019
  » https://doi.org/10.1183/23120541.00330-2019
• ³
  Oliveira AC, Leão AP, Goulart AL, Oliveira AC, D'Almeida V. Late effects of caffeine use on sleep of infants born prematurely. Rev Paul Pediatr. 2024;42:e2022224. https://doi.org/10.1590/1984-0462/2024/42/2022224
  » https://doi.org/10.1590/1984-0462/2024/42/2022224
• ⁴
  Field A. Discovering statistics using IBM SPSS statistics. Thousand Oaks: Sage Publications; 2013.
• ⁵
  Lopes JM, Andrade AS, Brito BS, Costa IG. Clinically significant differences: what to choose? Arq Neuropsiquiatr. 2020;78:387-8. https://doi.org/10.1590/0004-282x20200011
  » https://doi.org/10.1590/0004-282x20200011

Reply: Late effects of caffeine use on sleep of infants born prematurely

Authorship SCIMAGO INSTITUTIONS RANKINGS

We fully agree with the positive impact of caffeine on the cardiorespiratory function of preterm infants. However, we would like to highlight that its widespread use precedes most of the evidence on the latter positive effects in neurodevelopment.¹,² Even though positive neurodevelopment outcomes can be related to caffeine effects beyond adenosine receptor antagonism, this inhibition could have specific and unpredictable effects on sleep neuronal circuitry development, much less explored.³

We were surprised by the criticism regarding using the Tuckey posthoc test due to different groups’ sample sizes. We use it in normally distributed samples with homogeneous variances between groups. Levene test was applied in both wake-up time (p=0.133) and total daily sleep time (p=0.248) analysis. We recognize the impact of group sample size on the homogeneity of the distributions, but we could not find any references supporting the prioritization of one criterion over the other.

As for the in-between group comparisons, differences observed between individuals born at term (TG) and those born preterm and exposed to caffeine in the neonatal period (PCG) do not equal the caffeine effect.

Although the differences in "wake-up time" and "total daily sleep time" reached statistical significance, we did not interpret these differences as clinically significant, not justifying additional statistical analysis, which we judge, in this case, to be statistical preciosity.

Our results regarding total daily sleep time are in accordance with the normal populational sleep time distribution,⁴ and it is unlikely that in-between group differences in the normal range of sleep time duration would affect social interaction and learning in the studied population.

REFERENCES

• ¹
  Kumar P, Walker JK, Hurt KM, Bennett KM, Grosshans N, Fotis MA. Medication use in the neonatal intensive care unit: current patterns and off-label use of parenteral medications. J Pediatr. 2008;152:412-5. https://doi.org/10.1016/j.jpeds.2007.07.050
  » https://doi.org/10.1016/j.jpeds.2007.07.050
• ²
  Krzyzaniak N, Pawlowska I, Bajorek B. Review of drug utilization patterns in NICUs worldwide. J Clin Pharm Ther. 2016;41:612-20. https://doi.org/10.1111/jcpt.12440
  » https://doi.org/10.1111/jcpt.12440
• ³
  Gvilia I, Suntsova N, Kostin A, Kalinchuk A, McGinty D, Basheer R, et al. The role of adenosine in the maturation of sleep homeostasis in rats. J Neurophysiol. 2017;117:327-35. https://doi.org/10.1152/jn.00675.2016
  » https://doi.org/10.1152/jn.00675.2016
• ⁴
  Williams JA, Zimmerman FJ, Bell JF. Norms and trends of sleep time among US children and adolescents. JAMA Pediatr. 2013;167:55-60. https://doi.org/10.1001/jamapediatrics.2013.423
  » https://doi.org/10.1001/jamapediatrics.2013.423

Publication Dates

• Publication in this collection
  08 July 2024
• Date of issue
  2025

History

• Received
  17 Feb 2024