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Therapy for Apnoea of Prematurity: A Retrospective Study on Effects of Standard Dose and Genetic Variability on Clinical Response to Caffeine Citrate in Chinese Preterm Infants



Apnoea of prematurity (AOP) is among the most common diagnoses in the neonatal intensive care unit. Caffeine treatment is a preferred treatment choice. However, neonatal caffeine therapy results in significant intersubject variability. This study aimed to determine the effects of plasma caffeine levels based on standard dose and genetic variability on clinical response to caffeine citrate in Chinese preterm infants.


This single-center and retrospective study examined data from 112 preterm infants (< 35 weeks gestational age) between July 2017 and July 2018. Subjects were divided into apnoea-free (n = 48) and apnoeic (n = 64) groups, and their clinical outcomes were summarized. Liquid chromatography-tandem mass spectrometry was used to measure levels of caffeine and its primary metabolites. Eighty-eight single-nucleotide polymorphisms were chosen for genotyping by a MassARRAY system.


Preterm infants in the apnoea-free group were associated with a reduction in the incidence of bronchopulmonary dysplasia and a reduced requirement for patent ductus arteriosus ligation. No significant association was observed between plasma-trough-concentration-to-dose (C0/D) ratio and birth weight, gestational age, or postnatal age in either group. Polymorphisms in CYP1A2 and aryl hydrocarbon receptor (AHR) genes did not affect plasma caffeine levels. Polymorphisms in adenosine receptor genes ADORA1 (rs10920568 and rs12744240), ADORA2A (rs34923252 and rs5996696), and ADORA3 (rs10776727 and rs2298191), especially in AHR (rs4410790) and adenosine deaminase (rs521704), play critical roles in the interindividual response to caffeine therapy.


Genetic polymorphisms in caffeine’s target receptors, but not the exposure levels based on the standard dosing, were associated with variable responses to caffeine therapy in preterm neonates. Future studies are needed to uncover how these genetic variants affect responses to caffeine therapy in this patient population.

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This research was supported by the Scientific Research Foundation for Young Scholars at the Children’s Hospital of Nanjing Medical University (ETYYQM2014024), the Specially Appointed Medical Expert Project of Jiangsu Commission of Health (2019) and Special fund for clinical research of Wu Jieping Medical Foundation (320.6750.2020-04-07). This study was also supported by Nanjing Medical University Science and Technology Development Foundation (NMUB2019195). The journal’s Rapid Service Fees for this article were funded by the Specially Appointed Medical Expert Project of Jiangsu Commission of Health (2019).

Medical Writing Assistance

Medical writing support, under the guidance of the authors, was provided by Elsevier's WebShop, a company registered in Kidlington (UK). The medical writing assistance fee was funded by Nanjing Medical University Scienceand Technology Development Foundation (NMUB2019195).


All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Authorship Contributions

Xin He, Jin-Chun Qiu, Ke-Yu Lu, Feng Chen, Rui Cheng: Principal investigators who designed the study, analysed the data, and wrote the paper. Xin He, Ke-Yu Lu, Hong-Li Guo: Performed the data collection and analysis. Wei-Wei Jia: Performed the caffeine assay. Ling Li, Ming-Ming Ni, Yun Liu, Jing Xu: Assisted with the study and data analysis. Feng Chen, Xin He, Ling Li, Hong-Li Guo: Wrote the paper. Xin He, Jin-Chun Qiu and Ke-Yu Lu contributed equally to this work.


Xin He, Jin-Chun Qiu, Ke-Yu Lu, Hong-Li Guo, Ling Li, Wei-Wei Jia, Ming-Ming Ni, Yun Liu, Jing Xu, Feng Chen and Rui Cheng have nothing to disclose.

Compliance with Ethics Guidelines

The study was conducted in accordance with the Helsinki Declaration and the study protocol was approved by the Children’s Hospital of Nanjing Medical University ethics committee (Protocol number 201902082-1). The informed consent was obtained from a parent of each infant.

Data Availability

The datasets generated during and/or analyzed during the present study are available from the corresponding author on reasonable request.

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Corresponding authors

Correspondence to Feng Chen or Rui Cheng.

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He, X., Qiu, JC., Lu, KY. et al. Therapy for Apnoea of Prematurity: A Retrospective Study on Effects of Standard Dose and Genetic Variability on Clinical Response to Caffeine Citrate in Chinese Preterm Infants. Adv Ther 38, 607–626 (2021).

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  • Adenosine receptors
  • AHR
  • AOP
  • Caffeine
  • CYP1A2
  • Phosphodiesterase
  • Polymorphism
  • Therapeutic drug monitoring