Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The effects of caffeine on heart rate variability in newborns with apnea of prematurity



Apnea of prematurity is a common complication in premature newborns and caffeine is a widespread medication used to treat this complication. Caffeine may have adverse effects on the cardiovascular and central nervous system, yet its effects on the autonomic nervous system modulation of heart rate have not been studied in premature newborns, which was the objective of our study.

Study Design:

We prospectively studied 21 premature newborns who were treated with caffeine. We analyzed heart rate variability by power spectral density and by dynamic nonlinear analyses methods.


There were no changes in heart rate, blood pressure or the autonomic nervous system tone following administration of caffeine, nor were the nonlinear dynamical properties of the system altered by caffeine.


Caffeine does not have detrimental effects on heart rate variablility, heart rate or blood pressure in conventional doses given to premature newborns.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1
Figure 2


  1. Barrington K, Finer N . The natural history of the appearance of apnea of prematurity. Pediatr Res 1991; 29: 372–375.

    CAS  Article  Google Scholar 

  2. Henderson-Smart DJ, Steer P . Methylxanthine treatment for apnea in preterm infants. Cochrane Database Syst Rev 2001; 3: CD000140.

    Google Scholar 

  3. Martin RJ, Abu-Shaweesh JM, Baird TM . Apnoea of prematurity. Paediatr Respir Rev 2004; 5 (Suppl A): S377–S382.

    Article  Google Scholar 

  4. Arnaud MJ . The pharmacology of caffeine. Prog Drug Res 1987; 31: 273–313.

    CAS  PubMed  Google Scholar 

  5. Saliba E, Autret E, Gold F, Bloc D, Pourcelot L, Laugier J . Effect of caffeine on cerebral blood flow velocity in preterm infants. Biol Neonate 1989; 56: 198–203.

    CAS  Article  Google Scholar 

  6. Walther FJ, Erickson R, Sims ME . Cardiovascular effects of caffeine therapy in preterm infants. Am J Dis Child 1990; 144: 1164–1166.

    CAS  Google Scholar 

  7. Fredholm BB, Bättig K, Holmén J, Nehlig A, Zvartau EE . Actions of Caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol Rev 1999; 51: 83–133.

    CAS  Google Scholar 

  8. Pelchovitz DJ, Goldberger JJ . Caffeine and cardiac arrhythmias: A review of the evidence. Am J Med 2011; 124: 284–289.

    CAS  Article  Google Scholar 

  9. Tuzcu V, Nas S, Ulusar U, Ugur A, Kaiser JR . Altered heart rhythm dynamics in very low birth weight infants with impending intraventricular hemorrhage. Pediatrics 2009; 123: 810–815.

    Article  Google Scholar 

  10. Lemmerling P, Van Huffel S, Naulaers G, Daniels H, Devlieger H . Nonlinear analysis of heart rate variability in infants with apparent life-threatening events. Adv Exp Med Biol 2003; 510: 369–373.

    Article  Google Scholar 

  11. Pincus SM, Cummins TR, Haddad GG . Heart rate control in normal and aborted-SIDS infants. Am J Physiol 1993; 33: R638–R646.

    Google Scholar 

  12. Goldberger AL, Amaral LA, Hausdorff JM, Ivanov PCh, Peng CK, Stanley HE . Fractal dynamics in physiology: alterations with disease and aging. Proc Natl Acad Sci USA 2002; 99: 2466–2472.

    Article  Google Scholar 

  13. Aranda JV, Cook CE, Gorman W, Collinge JM, Loughnan PM, Outerbridge EW et al. Pharmacokinetic profile of caffeine in the premature newborn infant with apnea. Pediatrics 1979; 94: 663–668.

    CAS  Article  Google Scholar 

  14. Weissman A, Zimmer EZ, Aranovitch M, Blazer S . Heart rate dynamics during acute pain in newborns. Pflugers Arch 2012; 464: 593–599.

    CAS  Article  Google Scholar 

  15. Weissman A, Berkowitz E, Smolkin T, Blazer S . Effect of phototherapy on neonatal heart rate variability and complexity. Neonatology 2009; 95: 41–46.

    Article  Google Scholar 

  16. Heart rate variability: Standards of measurement, physiological interpretation, and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Circulation 1996; 93: 1043–1065.

  17. Pincus SM . Approximate entropy as a measure of system complexity. Proc Natl Acad Sci USA 1991; 88: 2297–2301.

    CAS  Article  Google Scholar 

  18. Kamen PW, Tonkin AM . Application of the Poincare plot to heart rate variability: a new measure of functional status in heart failure. Aust N Z J Med 1995; 25: 18–26.

    CAS  Article  Google Scholar 

  19. Peng CK, Havlin S, Stanley HE, Goldberger AL . Quantification of scaling exponents and crossover phenomena in nonstationary heartbeat time series. Chaos 1995; 1: 82–87.

    Article  Google Scholar 

  20. Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A et al. Caffeine therapy for apnea of prematurity. N Engl J Med 2006; 354: 2112–2121.

    CAS  Article  Google Scholar 

  21. Saul JP . Beat-to-beat variations of heart-rate reflect modulation of cardiac autonomic outflow. Physiology 1990; 5: 32–37.

    Article  Google Scholar 

  22. Levy MN . Autonomic interactions in cardiac control. Ann N YAcad Sci 1990; 601: 209–221.

    CAS  Article  Google Scholar 

  23. Corti R, Binggeli C, Sudano I, Spieker L, Hänseler E, Ruschitzka F et al. Coffee acutely increases sympathetic nerve activity and blood pressure independently of caffeine content: Role of habitual versus nonhabitual drinking. Circulation 2002; 106: 2935–2940.

    Article  Google Scholar 

  24. Jee SH, He J, Whelton PK, Suh I, Klag MJ . The effect of chronic coffee drinking on blood pressure: a meta-analysis of controlled clinical trials. Hypertension 1999; 33: 647–652.

    CAS  Article  Google Scholar 

  25. Periti M, Salvaggio A, Quaglia G, Di Marzio L . Coffee consumption and blood pressure: an Italian study. Clin Sci 1987; 72: 443–447.

    CAS  Article  Google Scholar 

  26. MacDonald TM, Sharpe K, Fowler G, Lyons D, Freestone S, Lovell HG et al. Caffeine restriction: effect on mild hypertension. BMJ 1991; 303: 1235–1238.

    CAS  Article  Google Scholar 

  27. Steer P, Flenady V, Shearman A, Charles B, Gray PH, Henderson-Smart D et al. The caffeine collaborative study group steering group. Arch Dis Child Fetal Neonatal Ed 2004; 89: F499–F503.

    CAS  Article  Google Scholar 

Download references


Part of the present manuscript has been submitted for the partial fulfillment of the requirements for the Degree of Doctor of Medicine in the Rappaport Faculty of Medicine, Technion—Israel Institute of Technology.

Author information

Authors and Affiliations


Corresponding author

Correspondence to A Weissman.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Ulanovsky, I., Haleluya, N., Blazer, S. et al. The effects of caffeine on heart rate variability in newborns with apnea of prematurity. J Perinatol 34, 620–623 (2014).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

Further reading


Quick links