An Overview on the Respiratory Stimulant Effects of Caffeine and Progesterone on Response to Hypoxia and Apnea Frequency in Developing Rats

  • Aida BairamEmail author
  • NaggaPraveena Uppari
  • Sébastien Mubayed
  • Vincent Joseph
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 860)


The respiratory stimulant caffeine is the most frequently used xanthine (theophylline or aminophylline) for the treatment of apnea in premature infants. It decreases but does not eliminate apnea. In most cases such decreases is insufficient to prevent the use of artificial ventilation. Progesterone is a respiratory stimulant in adult mammals including human, and it decreases sleep apnea in menopausal women. Whether progesterone as an adjunct to caffeine therapy could be effective in further reducing the frequency of apnea in premature infants is not known because its respiratory effect in newborns has not been well studied. Using rat pups at different postnatal ages, we first determined whether the respiratory stimulant effects of acute caffeine (10 mg/kg, i.p.) or progesterone (4 mg/kg i.p.) are age dependent. These studies showed that caffeine enhances the ventilatory response to hypoxia in 1 and 4 days-old rats while it decreases apnea frequency in 12-days-old. In contrast, progesterone enhances the ventilatory response to hypoxia in less than 7-days-old but decreases apnea in 1-day-old rats. Preliminary experiments show that administration of progesterone (4 mg/kg i.p.) to newborn rats that are chronically treated with caffeine (mimicking its clinical uses – 7.5 mg/kg once/day by gavage) enhances the respiratory stimulant effects of caffeine. Surprisingly, acute injection of progesterone enhances apnea frequency and reduces hypoxic ventilatory response in 12-day-old rats.


Caffeine Progesterone Newborn Rats Breathing Apnea 



Studies founded by a grant from the Canadian Institute for Health Research to Aida Bairam (MOP-119272).


  1. Al-Matary A, Kutbi I, Qurashi M et al (2004) Increased peripheral chemoreceptor activity may be critical in destabilizing breathing in neonates. Semin Perinatol 28(4):264–272PubMedGoogle Scholar
  2. Bairam A, Lumbroso D, Joseph V (2013a) Effect of progesterone on respiratory response to moderate hypoxia and apnea frequency in developing rats. Respir Physiol Neurobiol 185(3):515–525PubMedGoogle Scholar
  3. Bairam A, Niane LM, Joseph V (2013b) Role of ATP and adenosine on carotid body function during development. Respir Physiol Neurobiol 185(1):57–66PubMedGoogle Scholar
  4. Behan M, Thomas CF (2005) Sex hormone receptors are expressed in identified respiratory motoneurons in male and female rats. Neuroscience 130(3):725–734PubMedGoogle Scholar
  5. Behan M, Wenninger JM (2008) Sex steroidal hormones and respiratory control. Respir Physiol Neurobiol 164(1–2):213–221PubMedPubMedCentralGoogle Scholar
  6. Darnall RA, Ariagno RL, Kinney HC (2006) The late preterm infant and the control of breathing, sleep, and brainstem development: a review. Clin Perinatol 33(4):883–914PubMedGoogle Scholar
  7. Davis JM, Bhutani VK, Stefano JL et al (1989) Changes in pulmonary mechanics following caffeine administration in infants with bronchopulmonary dysplasia. Pediatr Pulmonol 6(1):49–52PubMedGoogle Scholar
  8. Davis PG, Schmidt B, Roberts RS et al (2010) Caffeine for Apnea of Prematurity trial: benefits may vary in subgroups. J Pediatr 156(3):382–387PubMedGoogle Scholar
  9. Dobson NR, Patel RM, Smith PB et al (2014) Trends in caffeine use and association between clinical outcomes and timing of therapy in very low birth weight infants. J Pediatr 164(5):992–998PubMedPubMedCentralGoogle Scholar
  10. Edwards BA, Sands SA, Berger PJ (2013) Postnatal maturation of breathing stability and loop gain: the role of carotid chemoreceptor development. Respir Physiol Neurobiol 185(1):144–155PubMedGoogle Scholar
  11. Eichenwald EC, Zupancic JA, Mao WY et al (2011) Variation in diagnosis of apnea in moderately preterm infants predicts length of stay. Pediatrics 127(1):53–58Google Scholar
  12. Finer NN, Higgins R, Kattwinkel J et al (2006) Summary proceedings from the apnea-of-prematurity group. Pediatrics 117(3 Pt 2):S47–S51PubMedGoogle Scholar
  13. Greer JJ (2012) Control of breathing activity in the fetus and newborn. Compr Physiol 2(3):1873–1888PubMedGoogle Scholar
  14. Haywood SA, Simonian SX, van der Beek EM et al (1999) Fluctuating estrogen and progesterone receptor expression in brainstem norepinephrine neurons through the rat estrous cycle. Endocrinology 140(7):3255–3263PubMedGoogle Scholar
  15. Heyman E, Ohlsson A, Heyman Z et al (1991) The effect of aminophylline on the excursions of the diaphragm in preterm neonates. A randomized double blind controlled study. Acta Paediatr Scand 80(3):308–315PubMedGoogle Scholar
  16. Janvier A, Khairy M, Kokkotis A et al (2004) Apnea is associated with neurodevelopmental impairment in very low birth weight infants. J Perinatol 24(12):763–768PubMedGoogle Scholar
  17. Joseph V, Doan VD, Morency CE et al (2006) Expression of sex-steroid receptors and steroidogenic enzymes in the carotid body of adult and newborn male rats. Brain Res 1073–1074:71–82PubMedGoogle Scholar
  18. Julien C, Bairam A, Joseph V (2008) Chronic intermittent hypoxia reduces ventilatory long-term facilitation and enhances apnea frequency in newborn rats. Am J Physiol Regul Integr Comp Physiol 294(4):R1356–R1366PubMedGoogle Scholar
  19. Julien CA, Joseph V, Bairam A (2010) Caffeine reduces apnea frequency and enhances ventilatory long-term facilitation in rat pups raised in chronic intermittent hypoxia. Pediatr Res 68(2):105–111PubMedGoogle Scholar
  20. Julien CA, Joseph V, Bairam A (2011) Alteration of carotid body chemoreflexes after neonatal intermittent hypoxia and caffeine treatment in rat pups. Respir Physiol Neurobiol 177(3):301–312PubMedGoogle Scholar
  21. Kassim Z, Greenough A, Rafferty GF (2009) Effect of caffeine on respiratory muscle strength and lung function in prematurely born, ventilated infants. Eur J Pediatr 168(12):1491–1495PubMedGoogle Scholar
  22. Kawai A, Okada Y, Muckenhoff K et al (1995) Theophylline and hypoxic ventilatory response in the rat isolated brainstem-spinal cord. Respir Physiol 100(1):25–32PubMedGoogle Scholar
  23. Lefter R, Morency CE, Joseph V (2007) Progesterone increases hypoxic ventilatory response and reduces apneas in newborn rats. Respir Physiol Neurobiol 156(1):9–16PubMedGoogle Scholar
  24. MacFarlane PM, Ribeiro AP, Martin RJ (2013) Carotid chemoreceptor development and neonatal apnea. Respir Physiol Neurobiol 185(1):170–176PubMedGoogle Scholar
  25. Martin RJ, Di Fiore JM, Macfarlane PM et al (2012) Physiologic basis for intermittent hypoxic episodes in preterm infants. Adv Exp Med Biol 758:351–358PubMedGoogle Scholar
  26. Mathew OP (2011) Apnea of prematurity: pathogenesis and management strategies. J Perinatol 31(5):302–310PubMedGoogle Scholar
  27. Mayer CA, Ao J, Di Fiore JM et al (2013) Impaired hypoxic ventilatory response following neonatal sustained and subsequent chronic intermittent hypoxia in rats. Respir Physiol Neurobiol 187(2):167–175PubMedGoogle Scholar
  28. Milerad J, Lagercrantz H, Lofgren O (1985) Alveolar hypoventilation treated with medroxyprogesterone. Arch Dis Child 60(2):150–155PubMedPubMedCentralGoogle Scholar
  29. Mironov SL, Langohr K, Richter DW (1999) A1 adenosine receptors modulate respiratory activity of the neonatal mouse via the cAMP-mediated signaling pathway. J Neurophysiol 81(1):247–255PubMedGoogle Scholar
  30. Montandon G, Kinkead R, Bairam A (2008) Adenosinergic modulation of respiratory activity: developmental plasticity induced by perinatal caffeine administration. Respir Physiol Neurobiol 164(1–2):87–95PubMedGoogle Scholar
  31. Nock ML, Difiore JM, Arko MK et al (2004) Relationship of the ventilatory response to hypoxia with neonatal apnea in preterm infants. J Pediatr 144(3):291–295PubMedGoogle Scholar
  32. Peng YJ, Rennison J, Prabhakar NR (2004) Intermittent hypoxia augments carotid body and ventilatory response to hypoxia in neonatal rat pups. J Appl Physiol 97(5):2020–2025PubMedGoogle Scholar
  33. Picard N, Guenin S, Larnicol N et al (2008) Maternal caffeine ingestion during gestation and lactation influences respiratory adaptation to acute alveolar hypoxia in newborn rats and adenosine A2A and GABA A receptor mRNA transcription. Neuroscience 156(3):630–639PubMedGoogle Scholar
  34. Potvin C, Rossignol O, Uppari N et al (2014) Reduced hypoxic ventilatory response in newborn mice knocked-out for the progesterone receptor. Exp Physiol 99(11):1523–1537PubMedGoogle Scholar
  35. Ren J, Greer JJ (2006a) Modulation of respiratory rhythmogenesis by chloride-mediated conductances during the perinatal period. J Neurosci 26(14):3721–3730PubMedGoogle Scholar
  36. Ren J, Greer JJ (2006b) Neurosteroid modulation of respiratory rhythm in rats during the perinatal period. J Physiol 574(Pt 2):535–546PubMedPubMedCentralGoogle Scholar
  37. Rhein LM, Dobson NR, Darnall RA et al (2014) Effects of caffeine on intermittent hypoxia in infants born prematurely: a randomized clinical trial. JAMA Pediatr 168(3):250–257PubMedGoogle Scholar
  38. Rhoda J, Corbier P, Roffi J (1984) Gonadal steroid concentrations in serum and hypothalamus of the rat at birth: aromatization of testosterone to 17 beta-estradiol. Endocrinology 114(5):1754–1760PubMedGoogle Scholar
  39. Saaresranta T, Polo O (2003) Sleep-disordered breathing and hormones. Eur Respir J 22(1):161–172PubMedGoogle Scholar
  40. Schoen K, Yu T, Stockmann C et al (2014) Use of methylxanthine therapies for the treatment and prevention of apnea of prematurity. Paediatr Drugs 16(2):169–177PubMedGoogle Scholar
  41. Shahar E, Redline S, Young T et al (2003) Hormone replacement therapy and sleep-disordered breathing. Am J Respir Crit Care Med 167(9):1186–1192PubMedGoogle Scholar
  42. Taha D, Kirkby S, Nawab U et al (2014) Early caffeine therapy for prevention of bronchopulmonary dysplasia in preterm infants. J Matern Fetal Neonatal Med 27(16):1698–1702PubMedGoogle Scholar
  43. Trotter A, Maier L, Grill HJ et al (1999a) Effects of postnatal estradiol and progesterone replacement in extremely preterm infants. J Clin Endocrinol Metab 84(12):4531–4535PubMedGoogle Scholar
  44. Trotter A, Maier L, Grill HJ et al (1999b) 17Beta-estradiol and progesterone supplementation in extremely low-birth-weight infants. Pediatr Res 45(4 Pt 1):489–493PubMedGoogle Scholar
  45. Yoder B, Thomson M, Coalson J (2005) Lung function in immature baboons with respiratory distress syndrome receiving early caffeine therapy: a pilot study. Acta Paediatr 94(1):92–98PubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Aida Bairam
    • 1
    • 2
    Email author
  • NaggaPraveena Uppari
    • 1
  • Sébastien Mubayed
    • 1
  • Vincent Joseph
    • 1
  1. 1.Pediatric DepartmentLaval University, Research Center of Centre Hospitalier, Universitaire de QuebecQuebec CityCanada
  2. 2.Centre de recherche du CHUQHSFAQuébecCanada

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