In China, the risk of morbidity and mortality remains high for VLBW infants and particularly high for ELBW infants. As the survival rates for these high-risk neonates continue to rise, so too does the frequency of RBC transfusions in these patients. As shown in Table 2, transfusions were conducted earlier and more often in infants with a BW < 1,250 g. In addition, infants with a GA < 30 weeks, a BW < 1,250 g, and comorbidities exhibited greater transfusion needs. Transfusion requirements are also indicative of disease severity, and while RBC transfusions can effectively treat neonatal anemia, they can also result in a number of potentially serious adverse outcomes.
There are multiple significant clinical implications to the results of this study, as this was a comprehensive analysis of data pertaining to adverse outcomes in 408 VLBW infants in our hospital in China. There have been few reports published to date regarding the relationships between RBC transfusion and various diseases including sepsis, PIVH 3–4, BPD, ROP, NEC, PDA, and death in China.
The risk of NEC associated with transfusion has become an increasing concern in recent years, given that temporal correlations between RBC transfusion and NEC incidence in premature neonates have been observed. Those newborns exhibiting NEC have often undergone one or more RBC transfusions, and one study suggested that a higher total RBC transfusion volume was specifically linked to an elevated NEC risk in VLBW infants[10]. Some researchers have employed near-infrared spectroscopy (NIRS) as a tool for monitoring altered mesenteric tissue oxygen saturation (StO2) prior to and after blood transfusion, revealing a significant decrease in such saturation after transfusion [11]. RBC transfusion has the potential to alter intestinal perfusion and to thereby cause intestinal injury, thus increasing the risk of feeding intolerance or NEC development. However, we did not detect any significant relationship between NEC and blood transfusion herein, in line with the results of other recent observational analyses. Indeed, a meta-analysis of 13 studies detected no significant relationship between transfusion and NEC occurrence in the 48 h post-transfusion (OR: 1.13, 95% CI: 0.99–1.29), and high heterogeneity among included studies was detected in their analysis [12]. Other reports suggest that NEC onset following transfusion may be linked to severe underlying anemia [13], and there is some evidence that transfusion may be protective for the intestines [14, 15]. Arthur et al. identified severe anemia as an independent risk factor associated with NEC development, and detected correlations in premature infants between anemia severity and the levels of the inflammatory cytokine interferon gamma (IFNg), which is potentially linked to a higher NEC risk. Anemia can increase local inflammation within the intestines, altering local macrophage function and thereby disrupting barrier integrity, thus predisposing infants to intestinal injury and NEC[16].
It is also important to examine the potential relationship between RBC transfusion and PIVH. Baer et al. and others have found RBC transfusion in premature infants with a Grade 1 IVH to be related to extension to Grade 3 or 4 hemorrhages (OR 2.29: 95% CI: 2.19–3.90)[17]. Reactive oxygen species, endothelial activation, and increased capillary pressure as consequences of differences in the mechanical and biochemical properties of transfused RBCs all have the potential to influence the risk of transfusion-associated IVH[18]. In the present study, we found that infants with a combined IVH grade of 3–4 had higher RBC transfusion needs, but we are unable to evaluate the temporal correlation between these two events with our present dataset.
RBC transfusion has the potential to increase the risk of ROP [7, 19]. Transfusion can increase retinal oxygen delivery owing to the lower oxygen affinity of adult hemoglobin relative to that normally found in neonates. Repeated transfusions can also result in the accumulation of free iron, which can facilitate the generation of free hydroxyl radicals via the Fenton reaction, causing further retinal damage [20]. The free hemoglobin that is inevitably present within transfused units of blood can also induce small vessel vasoconstriction through the capture and fixing of nitric oxide. Indeed, ROP severity is related to the number of RBC transfusions [21], and RBC transfusion frequency is independently associated with ROP risk with an adjusted OR of 2.4 (95% CI: 1.4–4.1) for individuals undergoing 2 or more transfusions relative to individuals undergoing 0 or 1 transfusions [22]. The number of transfusions was also associated with an increased risk of iron overload (OR: 2.07, 95% CI: 1.36–2.14), and ferritin levels were positively correlated with transfusions (r = 0.53; P < 0.001) [23].
Other reports suggest that plasma non-transferrin-bound iron levels are significantly elevated in premature infants following RBC transfusion, resulting in reactive oxygen species production and oxidative damage that can drive BPD and ROP development [24, 25].Indeed, RBC transfusions are associated with BPD risk, and stored RBCs can contain a number of pro- and anti-inflammatory mediators that can influence BPD pathology [26]. The transfusion of greater RBC volumes is associated with higher BPD risk (adjusted relative risk per 20-mL increase, 1.05; 95% CI, 1.02– 1.07; p < 0.001) [27]. Our results indicated that undergoing > 3 transfusions could significantly increase the composite risk of BPD, ROP, and death (OR: 3.275, 95% CI: 1.707–6.275). Other studies have also found RBC transfusion to adversely impact VLBW infant survival, with one study having reported a correlation between the number of transfusions within 7 days of birth and the odds of mortality within 1 month (OR: 1.54, 95% CI: 1.04–2.27, p = 0.03)[7]. We found RBC transfusion to be linked to increased VLBW infant mortality, in line with the findings of Dos Santos et al., who determined that undergoing any number of RBC transfusions within 28 days of birth was associated with a 50% increase in the risk of in-hospital mortality relative to individuals that did not undergo transfusion [28].
While the results of this observational do not indicate that RBC transfusions are independently associated with the risk of death, BPD, or ROP in newborns, they do indicate a strong correlation between the number of transfusions and the composite risk of these outcomes. As infants with more comorbidities are more likely to necessitate transfusions, this may explain the biological basis for our results. However, there are certain limitations to our analysis. For one, this was a retrospective analysis and it cannot account for potential confounding variables not included in patient medical records. In addition, we were unable to directly assess the relationship between the time of RBC transfusion and the time of individual disease onset. Furthermore, as this was a single-institution study, the RBC transfusion thresholds discussed herein may not align with those of other institutions. However, the results of this study are nonetheless of clinical significance, indicating that a greater number of RBC transfusions is related to a higher composite risk of adverse outcomes. As such, alternative active efforts to reduce iatrogenic blood loss, delay umbilical cord ligation, apply recombinant erythropoietin, and provide active nutritional support should be taken in an effort to prevent anemia and to decrease neonate requirements for RBCtransfusion, thereby reducing their composite risk.