Sensitivity analysis and publication bias
We performed a sensitivity analysis of each outcome by removing each study one by one, and we discovered that the meta-analysis results were relatively stable. We calculated publication bias using tools like funnel plots for all outcomes, and there was no obvious asymmetry (S Figure). Moreover, Begg’s and Egger’s tests revealed no clear publication bias for all outcomes (P >0.05).
Discussion
Caffeine citrate is a medication that is extensively used in neonatology and is regarded as the gold standard in the prevention and treatment of apnea of prematurity. The 2019 European consensus guidelines on the management of neonatal respiratory distress syndrome emphasized that prophylactic caffeine administration was associated with improving newborn prognosis[21]. But there were also reviews against the support of the use of prophylactic caffeine for preterm infants at risk of apnea[22]. Therefore, the purpose of this meta-analysis was to explored the effect of prophylactic caffeine on AOP and related complications in very low infants. Prophylactic caffeine use, as compared to the control group, was found to be substantially linked with a lower incidence of apnea, duration of mechanical ventilation and oxygen therapy, BPD, PDA, and ROP. The incidence of NEC, IVH and death before hospital discharge were similar in the two groups. In this review, strong evidence from multiple randomized trials supports prophylactic caffeine for the prevention of AOP and related complications. Firstly, we found that the caffeine-prevented group had fewer apnea events than the control group, which was consistent with several previous studies[23, 24]. Caffeine’s primary effects on apnea prevention are respiratory center stimulation, increased minute ventilation, improved carbon dioxide sensitivity, and decreased periodic breathing[25]. It also was demonstrated to be a neuroprotective anti-inflammatory medication that may reduce premature infants’ lung inflammation and prevent AOP by activating the pro-inflammatory cascade reaction in newborns[26]. Furthermore, Armanian[11] discovered that caffeine prophylaxis had a greater benefit on the occurrence and severity of apnea in more immature newborns. However, because our study only focuses on the impact on very low birth weight infants, further research is needed to classify the newborn weight.
Our results indicated that prophylactic initiation of caffeine significantly reduce the time for mechanical ventilation and oxygen therapy. Such findings were consistent with the current guideline and Park’s previous reviews[27]. The rationale for prophylactic caffeine administration is to maintain spontaneous ventilation by boosting the infant’s respiratory drive[28]. Caffeine may also improve respiratory function via bronchodilation, improved diaphragmatic contractility, a mild diuretic effect, and cyclic adenosine-induced transcription of surfactant protein B[29]. This may increase the efficacy rate of noninvasive ventilation while decreasing the need for and duration of invasive ventilation. At the same time, it is a manifestation of positive long-term effects on newborns, since mechanical ventilation and protracted oxygen therapy constitute risk factors for both BPD and poor neurodevelopmental outcomes[30]. Notably, we did not describe the effects of prophylactic caffeine use on the duration of nasal continuous positive airway pressure and CPAP due to a lack of original data, additional research is required to examine the relationships.
According to this meta-analysis, prophylactic caffeine use was associated with a significant reduction in the incidence of BPD. Our findings were consistent with those of Davis et al.[12], who discovered infants whose caffeine was initiated prophylactically showed a 52% decrease in the rate of BPD compared with only 23% in the therapeutic caffeine group. Patel et al. [31] also proposed that prophylactic caffeine use (earlier than 3 days of life) could reduce the risk of BPD or death, particularly in high-risk infants weighing less than 750 g. It was possible that the number of neutrophils in bronchoalveolar lavage fluid increases fastest shortly after birth and within 4 days of life[32], whereas preventive caffeine could reduce neutrophil infiltration in lung tissue, lower levels of CINC-1, MIP-2, McP-1, TNF-0, and IL-6, and thus block the onset of BPD development[33]. Another speculation is that caffeine reduces hyper oxygen lung damage by lowering the production of reactive oxygen species[34]. Furthermore, Chen[35] discovered that a high maintenance dose of prophylactic caffeine use appears to be more efficient in promoting lung maturity of premature infants. However, our study lacked original data and was not discussed, more research is needed to assess the safety of different maintenance doses of caffeine.
We have shown the prophylactic use of caffeine significantly reduced the incidence of PDA compared to the control group. The effect of caffeine on PDA may benefit from the fact that caffeine could stabilize hemodynamic changes in infants, such as improving cardiac output and blood pressure[36]. Another speculation is that the diuretic effect and prostaglandin antagonistic properties of caffeine could promote the closure of arterial catheter and reduce the intervention rates of PDA[37]. Although observed in several trials[28], the mechanism of the decline of PDA incidence is difficult to explain, additional research on the prophylactic mechanism of caffeine on PDA is required. Furthermore, our study has demonstrated that caffeine has benefits decrease the incidence of ROP. Pharmacologic agents with anti-VGEF properties are ordinarily used for the prevention and treatment for ROP[38]. Caffeine has been shown in preliminary animal studies to prevent ROP by upregulating the sonic hedgehog signaling pathway through vascular endothelial growth factor and insulin-like growth factor, resulting in the conservation of retinal development and angiogenesis[39]. A previous systematic review[8] also found that infants given prophylactic caffeine had a significantly lower risk of PDA and ROP.
Caffeine prophylaxis was not related with a difference in the occurrence of NEC, IVH, and death before hospital discharge when compared to the control group. The conclusions of our systematic review were in accordance with previous studies on the same topic[27, 40]. NEC is an injury to the intestinal mucosa caused by blood flow redistribution under hypoxia stress. Although prophylactic caffeine use can reduce the occurrence of neonatal hypoxia stress, it will also increase gastric juice secretion, resulting in increased intestinal reflux and decreased peristalsis[41]. Caffeine also has both a direct neuroprotective effect as well as adverse effects on the developing brain[42]. As a result, the benefits and drawbacks for premature infants may be balanced. Nevertheless, Kua[8] has been conducted to suggest that prophylactic caffeine use would increase mortality rate. We speculate that the level of newborn care varies across countries. Another possible explanation is survival bias, which occurs when the overall survival rates of very low birth weight infants are low. It highlights the need for future research with more rigorous study design to explore the effects of prophylactic caffeine before strong conclusions can be made.