Skip to main content

Thank you for visiting nature.com. 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.

  • Comment
  • Published:

Caffeine for prostaglandin E1-induced apnea in neonates with ductal dependent congenital heart disease: integrating evidence into practice

Journal of Perinatology (2026)Cite this article

Subjects

In clinical practice, PGE₁ is initiated to maintain ductal dependency in certain critical congenital heart lesions, typically at starting dose of 0.01–0.03 micrograms/kilograms/min (mcg/kg/min) [10]. In infants diagnosed postnatally, when the ductus may already be constricting, higher doses or dose escalation may be needed to achieve adequate ductal reopening [10]. PGE₁ and adenosine pathways appear to interact functionally, reflecting cross-talk or downstream convergence rather than through direct receptor binding to adenosine receptors [7, 11]. Much of the mechanistic data on suppression of respiratory rhythmogenesis and diminished ventilatory response to carbon dioxide with central adenosine receptors is linked to PGE2 [2]. Specifically, PGE2 exerts central nervous system effects by binding to the EP family of PGE receptors and modulating respiratory drive through receptor-specific, second-messenger–dependent mechanisms [4]. Four EP receptor subtypes (EP1–EP4) have been identified, each with distinct G-protein coupling patterns that determine downstream signaling pathways underlying the biphasic, context-dependent modulation of respiratory drive [12]. Cyclic adenosine monophosphate (cAMP) is a critical mediator of many PGE-related effects on neural and respiratory physiology [13]. EP2 and EP4 primarily couple to the Gαs subunit, stimulating adenylyl cyclase and increasing intracellular cAMP [13]. In contrast, EP1 signals through Gαq to mobilize intracellular calcium, while EP3 couples to Gαi to inhibit adenylyl cyclase, with additional receptor-specific signaling variety [13]. These receptor-dependent pathways explain the diverse respiratory effects of PGE, including regulation of bronchomotor tone, airway inflammation, and respiratory rhythm [13]. Understanding these pathways provides a physiologic basis for how caffeine, through its effects on adenosine signaling and respiratory stimulation, may mitigate apnea associated with PGE₁ administration.

Given caffeine’s function as a nonselective adenosine receptor antagonist, it represents a logical candidate for the prevention or treatment of PGE₁-induced apnea, a form of pharmacologically induced central apnea that shares clinical features with apnea of prematurity. Preclinical work by Mitchell et al. [7] demonstrated that caffeine reverses PGE₁-induced respiratory instability in neonatal rat models, providing support for its therapeutic potential in this setting. Caffeine is one of the most extensively studied neurostimulants in neonatology [6]. Preterm infants have delayed maturation of respiratory control and impaired brainstem-mediated homeostatic control. The Caffeine for Apnea of Prematurity (CAP) trial demonstrated that caffeine reduces apnea, facilitates extubation, shortens the duration of mechanical ventilation, and improves long-term neurodevelopmental outcomes in preterm infants [14]. As a methylxanthine, caffeine exerts primary effects through adenosine receptor antagonism, resulting in enhanced ventilatory responses and improved neuromuscular performance [6].

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1

References

  1. Lewis AB, Freed MD, Heymann MA, Roehl SL, Kensey RC. Side effects of therapy with prostaglandin E1 in infants with critical congenital heart disease. Circulation. 1981;64:893–8.

    Article  CAS  PubMed  Google Scholar 

  2. Ballanyi K, Lalley PM, Hoch B, Richter DW. cAMP-dependent reversal of opioid- and prostaglandin-mediated depression of the isolated respiratory network in newborn rats. J Physiol. 1997;504:127–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Hofstetter AO, Saha S, Siljehav V, Jakobsson PJ, Herlenius E. The induced prostaglandin E2 pathway is a key regulator of the respiratory response to infection and hypoxia in neonates. Proc Natl Acad Sci USA. 2007;104:9894–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Siljehav V, Shvarev Y, Herlenius E. Il-1β and prostaglandin E2 attenuate the hypercapnic as well as the hypoxic respiratory response via prostaglandin E receptor type 3 in neonatal mice. J Appl Physiol. 2014;117:1027–36.

    Article  CAS  PubMed  Google Scholar 

  5. Lim DS, Kulik TJ, Kim DW, Charpie JR, Crowley DC, Maher KO. Aminophylline for the prevention of apnea during prostaglandin E1 infusion. Pediatrics. 2003;112:e27–29.

    Article  CAS  PubMed  Google Scholar 

  6. Marques KA, Bruschettini M, Roehr CC, Davis PG, Fiander M, Soll R. Methylxanthine for the prevention and treatment of apnea in preterm infants. Cochrane Database Syst Rev. 2023;10:Cd013830.

    PubMed  PubMed Central  Google Scholar 

  7. Mitchell LJ, Mayer CA, Mayer A, Di Fiore JM, Shein SL, Raffay TM, et al. Caffeine prevents prostaglandin E(1)-induced disturbances in respiratory control in neonatal rats: implications for infants with critical congenital heart disease. Am J Physiol Regul Integr Comp Physiol. 2020;319:R233–r242.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Higgins KL, Buck ML. Caffeine citrate for the prevention of apnea associated with alprostadil infusions. J Pediatr Pharmacol Ther. 2020;25:235–40.

    PubMed  PubMed Central  Google Scholar 

  9. Salamati L, Dehghan B, Sabri MR, Ahmadi A, Ghaderian M, Mahdavi C, et al. Caffeine treatment for prostaglandin E1-induced apnea prevention in congenital heart disease neonates: a randomized clinical trial. Crit Care Res Pract. 2025;2025:4923280.

    PubMed  PubMed Central  Google Scholar 

  10. Marino BS, Tabbutt S, MacLaren G, Hazinski MF, Adatia I, Atkins DL, et al. Cardiopulmonary resuscitation in infants and children with cardiac disease: a scientific statement from the American Heart Association. Circulation. 2018;137:e691–e782.

    Article  PubMed  Google Scholar 

  11. Ruangkittisakul A, Ballanyi K. Reversal by phosphodiesterase-4 blockers of in vitro apnea in the isolated brainstem-spinal cord preparation from newborn rats. Neurosci Lett. 2006;401:194–8.

    Article  CAS  PubMed  Google Scholar 

  12. Breyer RM, Bagdassarian CK, Myers SA, Breyer MD. Prostanoid receptors: subtypes and signaling. Annu Rev Pharmacol Toxicol. 2001;41:661–90.

    Article  CAS  PubMed  Google Scholar 

  13. Lebender LF, Prünte L, Rumzhum NN, Ammit AJ. Selectively targeting prostanoid E (EP) receptor-mediated cell signalling pathways: Implications for lung health and disease. Pulm Pharmacol Ther. 2018;49:75–87.

    Article  CAS  PubMed  Google Scholar 

  14. 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;354:2112–21.

    Article  CAS  PubMed  Google Scholar 

  15. Naiyananon F, Dissaneevate S, Thatrimontrichai A, Janjindamai W, Maneenil G, Praditaukrit M, et al. Predictors of high maintenance prostaglandin E1 doses in neonates with critical congenital heart disease-ductal-dependent pulmonary circulation during preoperative care. Pediatr Neonatol. 2024;65:464–8.

    Article  PubMed  Google Scholar 

  16. Haughey BS, Elliott MR, Wiggin JY, Conaway MR, White SC, Swanson JR, et al. Standardizing prostaglandin initiation in prenatally diagnosed ductal-dependent neonates; a quality initiative. Pediatr Cardiol. 2023;44:1327–32.

  17. Hallidie-Smith KA. Prostaglandin E1 in suspected ductus dependent cardiac malformation. Arch Dis Child. 1984;59:1020–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departamento de Pediatria, Divisão de Terapia Intensiva Neonatal, Hospital das Clínicas de Ribeirão Preto da Universidade de São Paulo, Ribeirão Preto, SP, Brazil

    Thais Iwashita Lages

  2. Division of Neonatology, Rady Children’s Health, Orange County, University of California Irvine, Irvine, CA, USA

    Shawn Sen

  3. Department of Pediatrics, Division of Neonatology, Indiana University School of Medicine, Riley Hospital for Children, Indianapolis, IN, USA

    Paulomi M. Chaudhry

  4. Division of Neonatology and Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA

    Molly K. Ball

  5. Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA

    Martina A. Steurer

  6. Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA

    Martina A. Steurer

  7. Department of Pediatrics, Division of Neonatology, New York-Presbyterian Morgan Stanley Children’s Hospital, Columbia University Irving Medical Center, New York, NY, USA

    Ganga Krishnamurthy

  8. Department of Pediatrics, Harvard Medical School and Division of Newborn Medicine, Boston Children’s Hospital, Boston, MA, USA

    Philip T. Levy

Authors
  1. Thais Iwashita Lages
    View author publications

    Search author on:PubMed Google Scholar

  2. Shawn Sen
    View author publications

    Search author on:PubMed Google Scholar

  3. Paulomi M. Chaudhry
    View author publications

    Search author on:PubMed Google Scholar

  4. Molly K. Ball
    View author publications

    Search author on:PubMed Google Scholar

  5. Martina A. Steurer
    View author publications

    Search author on:PubMed Google Scholar

  6. Ganga Krishnamurthy
    View author publications

    Search author on:PubMed Google Scholar

  7. Philip T. Levy
    View author publications

    Search author on:PubMed Google Scholar

Contributions

PL and TIL conceptualized and designed the study. TIL drafted the initial manuscript, and critically reviewed and revised the manuscript. TIL, SS, PMC, MKB, MAS, GK, and PL assisted with study design and/or provided expert input. All authors critically reviewed and revised the manuscript for important intellectual content. All authors approved the final manuscript as submitted.

Corresponding author

Correspondence to Philip T. Levy.

Ethics declarations

Competing interests

Levy received speaking honorarium for Abbot Structural Heart.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Iwashita Lages, T., Sen, S., Chaudhry, P.M. et al. Caffeine for prostaglandin E1-induced apnea in neonates with ductal dependent congenital heart disease: integrating evidence into practice. J Perinatol (2026). https://doi.org/10.1038/s41372-026-02639-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Version of record:

  • DOI: https://doi.org/10.1038/s41372-026-02639-4

Search

Advanced search

Quick links