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.