Evidence map›Paper›PMID 40542101›Full record

ReviewPediatric research2026

Caffeine and preterm infants: multiorgan effects and therapeutic creep: scope to optimise dose and timing.

Michael O'Shea, Luke Butler, Sam Holohan, Kate Healy, Rebecca O'Farrell, Amreena Shamit, Ruth Cusack, Mai Elhadi, Sinead Lynch, Megan Gilcrest and 9 more

Abstract readReview
In one paragraph

Review in Pediatric research, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.

0numbers the graph read from it
0cells of the map it votes in
7citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

7 citing papers in PubMed.

  1. Article
  2. Article
  3. Observational
  4. Review
  5. Article
  6. Article
  7. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

19 authors.

Michael O'Shea *Paediatrics, School of Medicine, Trinity College, The University of Dublin, Dublin, Ireland.
Luke Butler *Paediatrics, School of Medicine, Trinity College, The University of Dublin, Dublin, Ireland.
Sam Holohan *Paediatrics, School of Medicine, Trinity College, The University of Dublin, Dublin, Ireland.
Kate HealyPaediatrics, School of Medicine, Trinity College, The University of Dublin, Dublin, Ireland.
Rebecca O'FarrellPaediatrics, School of Medicine, Trinity College, The University of Dublin, Dublin, Ireland.
Amreena ShamitPaediatrics, School of Medicine, Trinity College, The University of Dublin, Dublin, Ireland.
Ruth CusackPaediatrics, School of Medicine, Trinity College, The University of Dublin, Dublin, Ireland.
Mai ElhadiPaediatrics, School of Medicine, Trinity College, The University of Dublin, Dublin, Ireland.
Sinead LynchSchool of Medicine, University College Dublin, Dublin, Ireland.
Megan GilcrestNeonatology, Coombe Hospital, Dublin, Ireland.
Jana SemberovaPaediatrics, School of Medicine, Trinity College, The University of Dublin, Dublin, Ireland.
Aoife BranaganPaediatrics, School of Medicine, Trinity College, The University of Dublin, Dublin, Ireland.
Mary Isabel O'DeaPaediatrics, School of Medicine, Trinity College, The University of Dublin, Dublin, Ireland.
Peter DuddyPharmacy, Coombe Hospital, Dublin, Ireland.
Namasivayam AmbalavananUniversity of Alabama at Birmingham, Birmingham, AL, USA.
Karel AllegaertDepartment of Development and Regeneration, KU Leuven, Leuven, Belgium.
Cynthia F BearerUH Rainbow Babies & Children's Hospital, Cleveland, OH, USA.
Judith MeehanPaediatrics, School of Medicine, Trinity College, The University of Dublin, Dublin, Ireland.
Eleanor J MolloyPaediatrics, School of Medicine, Trinity College, The University of Dublin, Dublin, Ireland. eleanor.molloy@tcd.ie.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Caffeine is a methylxanthine used for nearly 50 years in the treatment of apnoea of prematurity (AOP). Caffeine citrate is effective in the treatment of AOP using standard dosing (loading dose 20 mg/kg, maintenance 5-10 mg/kg/day) and is associated with long-term neurological benefits and other improved organ outcomes as well as immunomodulatory effects. Therapeutic creep has been noted in the use of caffeine in preterm infants differing from the criteria in randomised controlled trials. A Cochrane review showed insufficient evidence to support prophylactic use of caffeine citrate in preterm neonates to prevent AOP, although it is still recommended in many national and local guidelines. Concerns about adverse reactions exist with high-dose caffeine regimens with one high-dose trial reporting statistically significant increases in abnormal neurological outcomes compared with standard doses (80 mg/kg compared to 20 mg/kg). International clinical guidelines vary from clinical trials regarding timing, dose, and duration of caffeine therapy. Further clinical research could help to understand optimal doses for different indications, such as peri-extubation, early postnatal use while ventilated, multiorgan and psychoactive effects, and long-term neurodevelopmental outcomes. This review describes the mechanism and multiorgan effects of caffeine highlighting areas of therapeutic creep and uncertainty requiring further research, such as comparative effectiveness trials. IMPACT: Caffeine citrate is indicated for the management of apnoea of prematurity. Therapeutic creep is evident in international guidelines for the use of caffeine citrate in preterm infants. Caffeine has multiorgan effects involving renal, respiratory, and inflammatory responses, which, by optimising dosing and timing, may improve outcomes. Optimising indications, dose, and timing of caffeine citrate in preterm infants in further large-scale trials is warranted and may have other multiorgan benefits.

Indexed as

ApneaCaffeineCitratesInfant, PrematureHumansInfant, NewbornCaffeinecaffeine citrateCitrates

Identifiers

PMID40542101
PMCPMC12956565

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.