Relationship of caffeine regimen with osteopenia of prematurity in preterm neonates: A cohort retrospective study

Document Type



Paediatrics and Child Health


Background: Caffeine is a routinely prescribed pharmacological active compound in neonatal intensive care units (NICU) for treating apnea of prematurity (AOP), which also decreases the risk of bronchopulmonary dysplasia and cerebral palsy in neonates. Caffeine-induced excessive calcium loss can promote the development of metabolic bone disease (MBD) in preterm neonates. This study aimed to evaluate the effect of the caffeine regimen on the development of osteopenia of prematurity (OOP), using serum alkaline phosphatase (serum-ALP) concentrations as a surrogate marker at the 4th week of life.
Methods: This retrospective cohort study was conducted including neonates of < 32 weeks gestational age (GA) and birth weight < 1500 g, admitted to NICU from April-2017 to December-2018 and received caffeine therapy till 28 days of life for AOP. Based on serum-ALP levels, formed the high and low-ALP groups. Neonatal characteristics, caffeine regimen, risk factors for OOP, including duration of parenteral nutrition (PN), exposure to medicines associated with MBD, and intake of essential vitamins and minerals, were compared in both groups. Predictors of OOP were analyzed through logistic regression.
Results: From the total of 268 participants, 52 (19%) developed OOP, mostly female (61.5%). In the high ALP group, the serum-ALP levels were significantly higher than in the low-ALP group (725.0 ± 143.8 vs 273.6 ± 55.0 units/L, p < 0.001). The high-ALP group received significantly (p < 0.001) higher daily and cumulative caffeine doses and were associated with a higher likelihood of developing OOP in this study cohort [cumulative dose (mg) (AOR = 1.082 95% CI 1.011 to 1.157) and daily dose (mg/kg/day) (AOR = 2.892 95% CI 1.392 to 6.007)]. Smaller GA was found directly related to OOP. Among the other medical risk factors, phosphorus intake was significantly low in the high-ALP group. No, significant relationship between duration of PN and use of steroids and diuretics, and intake of vitamins and minerals were identified.
Conclusion: The daily and cumulative doses of caffeine and smaller GA are associated with the development of OOP in this study cohort. Clinical randomized control studies are needed to validate the outcomes and determine the range of safest and most effective caffeine doses for treating AOP in preterm neonates.


Pagination are not provided by the author/publisher

Publication (Name of Journal)

BMC pediatrics

Creative Commons License

Creative Commons Attribution 4.0 International License
This work is licensed under a Creative Commons Attribution 4.0 International License.