Prematurity remains a significant global health concern, greatly impacting neonatal mortality and morbidity rates. Premature birth, defined as delivery occurring prior to 37 completed weeks of gestation exposes newborns to various complications, including RDS, AOP, IVH, and BPD which are significant medical conditions, long-term neurodevelopmental challenges. Caffeine therapy, a commonly utilized methylxanthine derivative recognized for its respiratory stimulating properties, is one of the essential pharmacological strategies employed to alleviate respiratory issues in premature baby. The function of early caffeine administration in enhancing neonatal outcomes has attracted substantial interest within the field of neonatology, particularly due to its potential advantages in decreasing apnea episodes, reliance on mechanical ventilation, and neurodevelopmental deficits.1 Caffeine is a methylxanthine compound, a type of naturally occurring stimulant that acts on the neurological system (CNS). The mechanism of action is via blocking adenosine receptors. By attaching to its receptors, the neurotransmitter adenosine encourages relaxation and sleep. Studies suggest that the administration of caffeine during the initial 48 hours of life may provide greater advantages than delayed treatment.2 The primary mechanisms include enhanced alveolar function, improved diaphragmatic contractility, decreased oxidative stress, and the modulation of inflammatory pathways linked to preterm lung injury. The notable Caffeine for CAP study revealed that caffeine treatment not only improves long-term neurodevelopmental results at 18-21 months of corrected age but also markedly decreases the incidence of BPD.1,3 We were intrigued by a study on "Early Caffeine Administration and Neurodevelopmental Outcomes in Preterm Infants". Caffeine given within the first two days was found to be significantly associated with both neurodevelopmental and short-term outcomes, including bronchopulmonary dysplasia (BPD) and patent ductus arteriosus (PDA). A post hoc propensity score matching study they also revealed showed that the early caffeine group had considerably lower risks of hearing impairment and cerebral palsy.”4,5 Nowadays, one of the most often recommended drugs in newborn hospitals for the treatment of preterm apnea is caffeine citrate, Because of its efficacy, improved tolerability, broader therapeutic index, and longer half-life, it is the recommended option among methylxanthines. While methylxanthines have been in use for over 40 years, their acceptance has increased significantly in the previous ten years. It has been established that caffeine is safe, effective, and tolerable in preterm newborns by the Caffeine for Apnea of Prematurity (CAP) study.4,5 Caffeine has more supplanted theophylline and aminophylline in AOP treatment because of its extended half-life and broader therapeutic index, allowing for once-daily management. In the landmark "Caffeine for Apnea of Prematurity (CAP) trial," newborns receiving caffeine exhibited a lower likelihood of developing severe ROP and BPD. Additionally, they showed a reduced incidence of cognitive deficits and cerebral palsy during the 18-month follow-up period.4,5 AOP is a common respiratory condition observed in preterm new-born, characterized by interruptions in breathing lasting 20 seconds or more. These interruptions may also be shorter if they coincide with bradycardia or hypoxemia. The underlying cause of AOP in these infants is the underdevelopment of the brain and respiratory system.6 In this context, the present study aims to assess the effect of early administration of caeffine in a preterm neonate and its outcome in preterm neonates, focusing on its impact on respiratory support duration, incidence of bronchopulmonary dysplasia (BPD), neurodevelopmental outcomes, and NICU length of stay.”

This prospective observational study was conducted in the Neonatal Intensive Care Unit (Dept. of Paediatrics) at Maharishi Markandeshwar Institute of Medical Sciences and Research, Mullana, Ambala for 18 months. A total of 75 neonates with mothers were enrolled in the study. All neonates born at <28 weeks of Gestational age and all neonates born before 37 weeks of gestational age who required caffeine administration are included in this study. Eligible neonates meeting the inclusion criteria will be enrolled until the required sample size is reached. Prior to participation, the parents or legal guardians will provide written informed permission. Upon enrollment, demographic details (gestational age, birth weight, sex, APGAR scores) will be recorded. Data will be collected at regular intervals (daily during NICU stay) until hospital discharge. Data will be recorded in a master database and analyzed using appropriate statistical software. The statistical methods include Chi-square test for categorical variables and Student’s t-test or Mann-Whitney U test for continuous variables.Multivariate regression analysis to assess associations between early caffeine administration and neonatal outcomes.A p-value of <0.05 will be considered statistically significant.”Ethical clearance was obtained, and strict confidentiality and consent protocols were followed throughout the study.

The distribution of neonates by gender was done, across the two groups categorized by the timing of caffeine administration. The analysis revealed there was no statistically significant difference in the sex distribution between the two groups, as indicated by a p-value of 0.130. On comparison of mode of delivery of neonates , it was noted that there were some variations in the distribution of delivery techniques between the Early Caffeine and Late Caffeine categories. Neonates delivered via LSCS were more common in the Early Caffeine group (55.3%) than in the Late Caffeine group (35.1%). As the p-value was not statistically significant, it indicates that timing of caffeine administration does not have a clear association with the mode of delivery in preterm neonates.[Table I] Table I outlines gestational age characteristics across neonates stratified by caffeine initiation timing. The early-intervention cohort exhibited a mean gestational age of 30.13 weeks (±1.88 SD), marginally lower than the late-intervention group’s average of 31.14 weeks (±2.23 SD) (p=0.449, NS). Categorical stratification revealed 55.3% of early-treatment infants clustered in the 29–31 week gestational range, contrasting with 37.8% of late-treatment infants in the 32–34 week bracket. Despite these minor distributional disparities, statistical testing confirmed clinically comparable baseline demographics between groups. Comparative birth weight analysis between treatment cohorts revealed statistically significant disparities. The Late Caffeine cohort demonstrated a higher mean birth weight (1.409 kg ± 0.1796) compared to the Early Caffeine group (1.275 kg ± 0.1855), with an independent t-test confirming significance (p = 0.042). This suggests systemic weight differences at baseline, as early-treatment neonates disproportionately presented with lower birth weights. Weight stratification showed 81.6% of Early Caffeine infants fell within the 1.0–1.5 kg range, closely paralleling the Late Caffeine group (78.4%). However, notable imbalances emerged in extreme categories: 10.5% of Early Caffeine neonates had birth weights <1.0 kg—a subgroup absent in the Late Caffeine cohort—while only 7.9% of early-treated infants weighed 1.5–2.0 kg versus 21.6% in the delayed-treatment group. Comparative analysis of neonatal outcomes (Table I) reveals significant differences in 1-minute APGAR scores between treatment cohorts. Early Caffeine neonates demonstrated a mean score of 6.47 (±0.506 SD), significantly lower than the Late Caffeine group’s average of 6.73 (±0.732 SD) (p = 0.034, independent t-test). This disparity suggests compromised initial physiological stability in the early-treatment cohort. Score distribution patterns further distinguished the groups: 55.6% of Early Caffeine infants received a predominant score of 6, whereas 54.5% of Late Caffeine neonates achieved a score of 7. Strikingly, all six infants scoring 8 APGAR belonged exclusively to the Late Caffeine cohort, with no comparable high scores observed in the Early Caffeine group. However , there is no discernible difference in the newborn recovery between the Early Caffeine and Late Caffeine groups when APGAR scores are compared at 5 minutes. The Early Caffeine group's mean APGAR score is 8.42 (standard deviation: 0.5004), whereas the Late Caffeine group's mean score is somewhat higher at 8.54 (standard deviation: 0.5052). The two groups' differences in APGAR scores at five minutes are not statistically significant, according to the p-value of 0.300. Table I: clinicoepidemiological features of neonates among early caffeine v/s late caffeine group Early Caffeine (N=38) Late Caffeine (N=37) P Value Sex Female 21(60%) 14(40%) 0.13 Male 17(42.5%) 23(57.5%) Mode Of Delivery Lscs 21(55.3%) 13(35.1%) 0.08 Nvd 17(44.7%) 24(64.9%) Gestational Age 26-28 7(18.4%) 4(10.8%) 0.449 29-31 21(55.3%) 17(45.9%) 32-34 9(23.7%) 14(37.8%) >35 1(2.6%) 2(5.4%) Mean 30.1279 31.1395 Std. Deviation 1.87932 2.23001 Std. Error Mean .30487 .36661 Birth Weight(Kgs) <1 4(10.5%) 0(0%) 0.042 1-1.5 31(81.6%) 29(78.4%) 1.5-2 3(7.9%) 8(21.6%) Mean 1.275 1.409 Std. Deviation .1855 .1796 Std. Error Mean .0301 .0295 Apgar Score (At 1 Minute) 6 20(55.6%) 16(44.4%) 0.034 7 18(54.5%) 15(45.5%) 8 0(0%) 6(100%) Mean 6.474 6.730 Std. Deviation .5060 .7321 Std. Error Mean .0821 .1204 Apgar Score (At 5 Minute) 8 22(56.4%) 17(43.6%) 0.3 9 16(44.4%) 20(55.6%) Mean 8.421 8.541 Std. Deviation .5004 .5052 Std. Error Mean .0812 .0831 Comparative analysis of oxygen dependency (Table II) demonstrates clinically comparable requirements between treatment cohorts, with 50.8% of Early Caffeine neonates and 49.2% of Late Caffeine infants requiring supplemental oxygen therapy. The near-identical proportions (p = 0.952, chi-square test) confirm no statistically significant association between caffeine initiation timing and oxygen dependency. These findings suggest that oxygen therapy necessity remains unaffected by early versus delayed caffeine administration in preterm populations. In the Early Caffeine group, 44.4% of participants required mechanical ventilation, whereas in the Late group, 55.6% did so. There is no significant difference statistically between the two groups' need for mechanical ventilation, as indicated by the p-value of 0.300. In context of the duration of ventilation days for both groups, the prior Caffeine group exhibited a higher percentage of newborns with shorter ventilation periods (0–2 days) compared to the late group. This suggests that early administration of caffeine may reduce the ventilation duration required for premature newborns, as evidenced by a p-value of 0.026, indicating there is a statistically significant difference in ventilation days during the two groups. Table II Early Caffeine (n=38) Late Caffeine (n=37) P Value Need For Oxygen Therapy No 8(50%) 8(50%) 0.952 Yes 30(50.8%) 29(49.2%) Need For Mechanical Ventilation No 22(56.4%) 17(43.6%) 0.3 Yes 16(44.4%) 20(55.6%) Length Of Ventilation Days 0 – 2 32(84.2%) 25(67.6%) 0.026 3 – 5 6(15.8%) 4(10.8%) 6 – 8 0(0%) 4(10.8%) 9 – 10 0(0%) 4(10.8%) ROP (retinopathy of prematurity) Stage No Rop 26 (68.4%) 17(45.9%) 0.04 Stage 1 6 (15.8%) 8(21.6%) Stage 2 5(10.5%) 5(13.5%) Stage 3 0 6(16.2%) Stage 4 Or Higher 0 1(2.7%) Usg Cranium (IVH) Grade 1 Ivh 0(0%) 3(7.9%) 0.005 Grade 2 Ivh 0(0%) 1(2.6%) Grade 3 Ivh 0(0%) 1(2.6%) Normal 38(100%) 33(86.8%) Table II also shows the incidence of Retinopathy of Prematurity (ROP) in the Early and Late Caffeine groups,Compared to 45.9% in the late caffeine group(n=37), 68.4% of newborns in the early caffeine group (n=38) had no ROP. Stage 1 ROP occurred in 15.8% of early caffeine infants versus 21.6% in the late caffeine group. For Stage 2, the incidence was relatively similar (10.5% in early vs. 13.5% in late). Notably, more severe stages (Stage 3 and Stage 4 or higher) were only observed in the late caffeine group—16.2% had Stage 3 and 2.7% had Stage 4 or higher, while no such cases were observed in the early caffeine group. The frequency of Stage 2 ROP varied statistically significantly across groups (p = 0.04), indicating that early caffeine treatment may be linked to a decreased risk of developing this stage.”Furthermore, on comparing the results of cranial ultrasounds (IVH) between the two groups. It was found that there was a greater prevalence of IVH in the Late group, including Grade 1 (7.9%) and Grade 3 instances (2.6%), In contrast the Early Caffeine group had 100% normal outcomes. A statistically significant difference is shown by the p-value of 0.005, which implies that the timing of caffeine administration may have an effect on the incidence of intraventricular hemorrhage (IVH) in preterm newborns.”“ On comparing the occurrence of neurodevelopmental delays upon NICU discharge between the two groups, where the HNNE Mean Total Score is significantly elevated in the early caffeine group (p = 0.01) suggesting better overall neurodevelopmental outcomes.The early caffeine group showed a statistically significant result, with an optimal HNNE score indicating that more infants scored in the optimal range (>26), with a p-value of 0.02. In the early group, the occurrence of Abnormal Tone (8%) is less frequent than in the late group (27%), with a significant difference (p = 0.03). However, Abnormal Reflexes, Movements, and Behavioural Issues are also observed in the early caffeine group, but these do not reach statistical significance (p > 0.05). [Table III] Table III: Neuro developmental Assesment at NICU discharge Assement variable Early caffeine Late caffeine p-value HNNE Mean Total score 28.6 ± 2.9 26.1 ± 3.3 0.01 Optimal HNNE score(%>26) 32(84%) 21(57%) 0.02 Abnormal Tone(%) 3(8%) 10(27%) 0.03 Abnormal Reflexes(%) 2(5%) 6(16%) 0.09 Abnormal movements(%) 1(3%) 4(11%) 0.18 Behavioural issues(%) 4(11%) 9(24%) 0.10 TOTAL 38 37 Table IV illustrates a comparison of developmental outcomes as measured by the Bayley-III/IV scales in infants who received caffeine treatment early versus those who received it later. The Bayley Scales serve as standardized assessments of infant development, evaluating motor, cognitive, and behavioral abilities. In the early caffeine group, the Bayley Motor Score was significantly higher (p = 0.02), suggesting improved motor outcomes. Instances of Motor Delay (scores below 85) were less common in the early group, although this finding did not achieve statistical significance (p = 0.08). Regarding Cognitive Development, the early caffeine group showed a greater proportion of normal cognitive scores, yet this difference was not statistically significant (p = 0.12). Similarly, cognitive delays were less frequent in the early group, but this difference also lacked statistical significance. Additionally, Feeding Difficulties (p = 0.09) and Abnormal Muscle Tone (p = 0.05) were more prevalent in the late caffeine group, although these findings did not reach statistical significance.” Table IV: Neuro developmental Assessment on follow-up at 6 months Assement variable Early caffeine Late caffeine p-value Bayley-III/IV motor score (Mean+_SD) 97.5 ± 8.2 92.1 ± 10.4 0.02 Bayley-III/IV cognitive score 36(95%) 31(84%) 0.12 Motor delay(<85) (%) 3(8%) 8(22%) 0.08 Cognitive delay(<85)(%) 2(5%) 6(16%) 0.12 Abnormal muscle tone (<85)(%) 2(5%) 7(19%) 0.05 Feedind difficulties 4(11%) 9(24%) 0.09 TOTAL 38 37

This study prospectively evaluated neonatal outcomes in preterm infants receiving caffeine citrate within 48 hours of life versus delayed initiation (>72 hours). “The various tables included in this research illustrate the differences and similarities between the two cohorts across multiple clinical and demographic factors. These factors encompass gestational age, gender, delivery method, birth weight, and neonatal outcomes such as the requirement for oxygen therapy, mechanical ventilation, length of NICU stay, and neurodevelopmental evaluations. The Early Caffeine group has a mean gestational age of 30.13 weeks, whereas the Late Caffeine group shows a mean of 31.14 weeks. This indicates that the Early Caffeine group has a slightly lower mean gestational age”, suggesting that preterm infants born before 30 weeks may require early caffeine treatment; however, this difference is not statistically significant. This observation is consistent with the findings of Kumar and Lipshultz , who highlighted that gestational age is a crucial factor in determining caffeine therapy, particularly for neonates born at or below 32 weeks due to a higher risk of apnea of prematurity (AOP).7 Likewise, Vizentin et al. noted that early caffeine treatment enhances respiratory outcomes, especially in more premature infants, but stressed that the decision on when to initiate caffeine therapy should primarily depend on the clinical condition rather than solely on gestational age.8 Studies have shown that while male neonates are often at higher risk for certain neonatal conditions, including apnea of prematurity (AOP), which might prompt earlier caffeine therapy, gender itself is not a determining factor in whether caffeine is administered early or late.9 Vizentin et al. found no direct relationship between gender and the timing of caffeine initiation in their meta-analysis. Their results suggest that other clinical factors such as gestational age and the severity of AOP are far more influential in deciding when caffeine therapy should begin, rather than gender alone.8”11 Chi-square testing revealed no statistically significant association (p = 0.08) between caffeine initiation timing and delivery method. As underscored by Kumar and Lipshultz et al. delivery mode is predominantly guided by maternal-fetal clinical indicators rather than caffeine administration timing.7 Yun et al. highlighted that lower birth weight significantly influences the requirement for early caffeine therapy to manage respiratory instability.10”“In contrast, Vizentin et al. also discovered that early caffeine is most beneficial for very-low-birth-weight (VLBW) infants because of their increased risk of bronchopulmonary dysplasia (BPD)8.The Late Caffeine group had a higher proportion of neonates with birth weights between 1.5–2 kg (21.6%), suggesting that higher birth weight neonates may not require early caffeine treatment, which is consistent with Kumar et al., where higher birth weight was associated with less severe respiratory distress, and thus, late caffeine initiation.7” Yun et al. 10and Kua and Lee11, who concluded that early caffeine treatment wasn’t having a significant effect on short-term outcomes such as 5-minute APGAR scores. “Similarly, Patel et al.12 and Karlinski Vizentin et al.8 reported no notable difference in 5-minute APGAR scores between the early and late caffeine therapy groups. This reinforces the notion that the immediate health of neonates at birth is not affected by caffeine administration, as indicated by the APGAR scores.”” Kua and Lee11 in their systematic review and meta-analysis observed that early caffeine therapy did not significantly reduce the need for oxygen therapy in preterm neonates, with no substantial difference in oxygen therapy rates between groups. These findings are consistent with our study, where both groups showed similar proportions of neonates requiring oxygen therapy. Furthermore, Karlinski Vizentin et al. also reported no significant reduction in oxygen therapy requirements with early caffeine therapy, further reinforcing the conclusion that while caffeine therapy significantly reduces long-term complications like BPD, its immediate effect on oxygen therapy needs is minimal.8 In comparison, Yun et al.10 found that 50.8% of neonates in the early caffeine group required oxygen therapy, while 49.2% in the late caffeine group needed oxygen support. This distribution closely mirrors the findings of our study, indicating that the requirement for oxygen therapy remained similar regardless of whether caffeine was administered early or late. The timing of caffeine administration did not have a significant impact on the need for mechanical ventilation in preterm neonates.These findings are consistent with Lodha et al., who reported the necessity for mechanical ventilation was comparable in the groups receiving early versus late caffeine therapy13. Their research showed a comparable rate of mechanical ventilation, with 45% of neonates in the early caffeine group needing it versus 55% in the late caffeine group. Moreover, the Caffeine for Apnea of Prematurity trial conducted by Schmidt et al. found that while caffeine therapy did shorten the time on ventilator support, it did not have a significant effect on the overall requirement for mechanical ventilation.17 Kua and Lee, who discovered that early caffeine therapy was linked to a shorter hospital stay for preterm neonates, as earlier extubation and faster recovery from apnea led to shorter NICU stays.14 Schmidt et al. also reported that early caffeine therapy resulted in a reduction in hospital length of stay due to improved respiratory function and reduced incidence of apnea.17 However, the current study’s lack of statistical significance in NICU stay duration could be attributed to other factors such as the severity of illness at birth, comorbidities, and other interventions besides caffeine therapy due to low sample size.”. Lodha et al. reported a 50% reduction in severe IVH (Grade ≥3) among early-treated infants, consistent with the complete absence of high-grade IVH in our early caffeine cohort.13 Similarly, Yun et al. documented decreased intracranial hemorrhage rates with early caffeine use, reinforcing its role in cerebrovascular stability.10 The Caffeine for Apnea of Prematurity Trial further corroborates this temporal association, demonstrating reduced severe IVH incidence (OR 0.71, 95% CI 0.55–0.91) and improved neurodevelopmental outcomes at 18–21 months in early-treated infants, despite comparable overall IVH rates.1519 The neurodevelopmental assessment was done between early and late caffeine groups at the time of discharge from NICU. The early caffeine group had a significantly higher mean total score on the HNNE (Hammersmith Neonatal Neurological Examination) (28.6 ± 2.9) compared to the late caffeine group (26.1 ± 3.3) (p = 0.01). Additionally, a higher proportion of neonates in the early caffeine group (84%) achieved an optimal HNNE score (greater than 26) compared to 57% in the late caffeine group (p = 0.02). These findings suggest that early caffeine administration was associated with better neonatal neurological outcomes at the time of NICU discharge.” The analysis align with those of Lodha et al., who establish that initiating caffeine therapy early was correlated with enhanced neurological outcomes, reflected in higher scores on standardized neurological evaluations among very preterm neonates. In a similar vein, Yun et al. indicated that early caffeine therapy was combined with better neurological results, although their research did not specifically evaluate the HNNE scores.13 The observed enhancement in neurodevelopmental outcomes within the early caffeine group in our study is further corroborated by Karlinski Vizentin et al., who highlighted that early caffeine therapy led to improved short-term neurological outcomes, including enhanced tone and reflexes.12 Kua and Lee, who reported that administering caffeine early improved motor skills and cognitive results in preterm infants, although the impact on cognitive delays was less significant.11 Similarly, Schmidt et al. indicated that early caffeine treatment enhanced motor outcomes in preterm neonates, leading to better long-term neurodevelopmental results.14 “In contrast, Karlinski Vizentin et al. found no notable differences in cognitive outcomes at the 6-month follow-up between the early and late caffeine groups, although early caffeine was linked to improved respiratory and neurological outcomes overall.8 Likewise, Patel et al. did not find a significant difference in cognitive outcomes at follow-up, indicating that while early caffeine significantly influences motor development, its effects on cognitive development may not be as immediate.12 A review of caffiene in preterm neonates established that it improves survival without neurodevelopmental disability at 18 months and has demonstrated long-term safety up to 11 years of age.15 Early caffeine therapy has been associated with better neurological assessment scores and a higher proportion of neonates achieving optimal Hammersmith Neonatal Neurological Examination (HNNE) scores, suggesting a positive influence on early brain development. Collectively, these studies emphasize that the timing of caffeine therapy is a major determinant of both short- and long-term neurological and developmental outcomes in very low birth weight and preterm infants.16 Due to time limitations within the study period, neurodevelopmental follow-up studies beyond 6 months of age could not be performed, resulting in an inability to evaluate long-term outcomes related to neurological development, including cognitive, motor, and sensory functions. This limitation hinders the assessment of the long-term effects of early versus late interventions beyond the neonatal phase. To confirm these findings and gain a clearer insight into the ideal timing, dosage, and long-term effects of caffeine treatment in preterm neonates, future randomized controlled trials with larger participant groups and longer follow-up durations are necessary.”

This study underscores the potential benefits of early caffeine administration in preterm neonates, particularly in reducing the duration of mechanical ventilation and improving neurodevelopmental outcomes at NICU discharge. Early caffeine therapy was associated with a lower incidence of severe intraventricular hemorrhage (IVH) and a reduction in the need for prolonged respiratory support, which may contribute to shorter NICU stays and improved overall health outcomes. The positive neurodevelopmental results observed in the early caffeine group, including better neurological assessment scores and a higher proportion of neonates achieving optimal Hammersmith Neonatal Neurological Examination (HNNE) scores, further emphasize the significance of early intervention in preterm care. These findings suggest that timely caffeine administration, particularly within the first 48 hours of life, may lead to more favorable long-term respiratory and developmental outcomes.” Acknowledgements :- None Declarations:- Funding: none Conflict of interest: none Ethical approval: approved by institutional ethical committee

1. Korraa AA. Caffeine Citrate in Neonatal Intensive Care Unit. Annals of Neonatology Journal. 2023 Jul 31;5(2):7-18. 2. Lodha A, Entz R, Synnes A, Creighton D, Yusuf K, Lapointe A, Yang J, Shah PS. Early caffeine administration and neurodevelopmental outcomes in preterm infants. Pediatrics. 2019 Jan 1;143(1). 3. Shrestha B, Jawa G. Caffeine citrate–Is it a silver bullet in neonatology?. Pediatrics & Neonatology. 2017 Oct 1;58(5):391-7. 4. Dobson NR, Patel RM, Smith PB, et al. Trends in caffeine use and association between clinical outcomes and timing of therapy in very low birth weight infants. The Journal of Pediatrics 2014;164:992-8 e3. 5. Hand I, Zaghloul N, Barash L, Parris R, Aden U, Li HL. Timing of Caffeine Therapy and Neonatal Outcomes in Preterm Infants: A Retrospective Study. International Journal of Pediatrics 2016;2016:9478204. 6. Schmidt B, Roberts RS, Davis P, et al. Caffeine therapy for apnea of prematurity. The New England Journal of Medicine 2006;354:2112-21. 7. Kumar VH, Lipshultz SE. Caffeine and clinical outcomes in premature neonates. Children. 2019 Oct 24;6(11):118. 8. Karlinski Vizentin V, Madeira de Sá Pacheco I, Fahel Vilas Bôas Azevêdo T, Florêncio de Mesquita C, Alvim Pereira R. Early versus late caffeine therapy administration in preterm neonates: an updated systematic review and meta-analysis. Neonatology. 2024 Feb 1;121(1):7-16. 9. Kreutzer K, Bassler D. Caffeine for apnea of prematurity: A neonatal success story.Neonatology. 2014;105(4):332–8. 10. Yun WZ, Kassab YW, Yao LM, Khairuddin N, Ming LC, Hadi MA. Effectiveness and safety of early versus late caffeine therapy in managing apnoea of prematurity among preterm infants: a retrospective cohort study. International Journal of Clinical Pharmacy. 2022 Oct;44(5):1140-8. 11. Kua KP, Lee SW. Systematic review and meta‐analysis of clinical outcomes of early caffeine therapy in preterm neonates. British journal of clinical pharmacology. 2017 Jan;83(1):180-91. 12. Patel, R. M., Leong, T., Carlton, D. P., & Vyas-Read, S. (2013). Early caffeine therapy and clinical outcomes in extremely preterm infants. Journal of Perinatology, 33(2), 134–140. https://doi.org/10.1038/jp.2012.59 13. Lodha A, Seshia M, McMillan DD, Barrington K, Yang J, Lee SK, et al. Association of early caffeine administration and neonatal outcomes in very preterm neonates. JAMA Pediatr. 2015;169(1):33-8 14. Schmidt B, Roberts RS, Davis P, et al. Caffeine therapy for apnea of prematurity. The New England Journal of Medicine 2006;354:2112-21. 15. Schmidt B, Roberts RS, Anderson PJ, Asztalos EV, Costantini L, Davis PG, Dewey D, D’Ilario J, Doyle LW, Grunau RE, Moddemann D, Nelson H, Ohlsson A, Solimano A, Tin W; Caffeine for Apnea of Prematurity (CAP) Trial Group. Academic performance, motor function, and behavior 11 years after neonatal caffeine citrate therapy for apnea of prematurity: an 11-year follow-up of the CAP randomized clinical trial. JAMA Pediatr. 2017;171(6):564–572. doi:10.1001/jamapediatrics.2017.0238 16. Bancalari E, Cortez J. The caffeine story in preterm infants. NeoReviews.2018;19(5):e262–70.