Necrotizing enterocolitis (NEC) is a serious complication of prematurity, often associated with long-term consequences and increased mortality. This study aimed to analyze the risk of NEC development in premature infants exposed to inflammatory syndromes, by examining the role of inflammatory cytokines detected postnatally, as well as the influence of maternal inflammation on NEC risk. Cytokines play a key modulatory role in intestinal inflammation and can contribute to intestinal injury. Among these, interleukins (IL1, IL3, IL6, IL8) are frequently studied to assess inflammation in newborns. Although these interleukins are not specific to intestinal inflammation, their association with other markers may help establish an early diagnosis of NEC [19,20,21].

In this study, the value of IL3 was assessed in premature infants, but no statistically significant difference was found between those who developed NEC and those who did not (p = 0.165). However, maternal chorioamnionitis and elevated maternal C-reactive protein (CRP) were associated with a higher neonatal inflammatory status. Newborns of mothers with chorioamnionitis had significantly higher IL3 levels compared to those whose mothers did not have chorioamnionitis (p = 0.044).

While we did not find a direct significant association between chorioamnionitis and NEC incidence, our findings suggest that the inflammatory pathway might still be relevant. The absence of a direct relationship between chorioamnionitis and NEC, despite the relationship between chorioamnionitis and elevated IL3 levels, highlights the complex multifactorial nature of NEC pathogenesis. It is possible that chorioamnionitis creates a pro-inflammatory environment that predisposes one to NEC, but additional factors are necessary for NEC to develop.

Fetal exposure to intrauterine inflammation can lead to a sustained postnatal inflammatory response, increasing the risk of sepsis or NEC in newborns. Previous studies have described an inflammatory phenotype in these infants that increases their risk of complications [12, 22, 23]. In the studied cohort, biomarkers supported this pro-inflammatory status, with higher IL3 levels suggesting a state of sustained inflammation in newborns of mothers with chorioamnionitis, as described by Humberg et al. [24]. Approximately half of premature births are triggered by inflammation, leading to premature labor or premature rupture of membranes, often associated with or without chorioamnionitis.

Pan et al. demonstrated in their study on preterm pigs that prenatal inflammation alters the expression of genes related to both innate and adaptive immunity in the neonatal intestine, with marked immune cell infiltration observed at birth. In premature infants, pro-inflammatory cytokines like IL1, IL3, IL6, IL8, tumor necrosis factor (TNF)-α, and other inflammation-related proteins, such as CRP and intercellular adhesion molecules (ICAM- 1), are often overexpressed. The immune system’s insufficient regulation of these inflammatory markers may contribute to the development of NEC [18, 25, 26].

Evennett et al. found that CRP, while sensitive to NEC, lacks specificity and typically rises 12–24 h after NEC onset. However, it is still used routinely in neonatal care to assess treatment response. In this study, maternal CRP levels were predictive of neonatal inflammation and NEC risk. The study found CRP to have a specificity of 98% for neonatal inflammation and 30% for maternal CRP, with maternal CRP sensitivity at 82%. These findings align with other studies highlighting the high sensitivity of CRP in premature infants with NEC [27].

PCT (procalcitonin) was found to have a sensitivity of 47% and a specificity of 58% in this study. PCT, produced by thyroid parafollicular cells, regulates calcium homeostasis and rises significantly during sepsis but less so in mild NEC cases. Turner et al. found similar results. In this study, PCT levels correlated significantly with IL3 in premature infants (p < 0.001). The presence of elevated PCT and IL3 from birth indicates an ongoing inflammatory state, increasing the risk of NEC [15].

MMP9, a chemokine, demonstrated a specificity of 83% but a sensitivity of only 22%. Other chemokines, including MMP- 10, CCL20, and CXCL1, have also been studied in diagnosing NEC and differentiating it from neonatal sepsis. Dong et al. found that combining multiple biomarkers (IL- 8, IL- 24, CCL20) improved NEC diagnosis and sepsis differentiation [12].

Diagnosing NEC, particularly in its early stages, is challenging because symptoms often overlap with sepsis. Biomarkers like those mentioned may not be NEC-specific, but combining several of them could improve early detection. Multiple studies have evaluated the role of inflammatory biomarkers in NEC, but few have investigated the link between perinatal inflammation and NEC development in preterm infants [4, 20, 25, 28, 29].

Cetinkaya et al. analyzed SAA, PCT, and CRP in 152 preterm infants with NEC and found PCT to have the highest specificity (98%) and PPV (97%) but the lowest sensitivity (92%) [14]. Elfarargy et al. reported increased fecal calprotectin and serum levels of CRP, PCT, and ENA- 78 in the NEC group [11]. Dong et al. also found the combination of IL- 8, IL- 24, and CCL20 to be highly valuable in identifying preterm infants at high risk of NEC [12].

These studies support the idea that using multiple biomarkers could facilitate earlier NEC detection. Developing an inflammatory model with predictive value for NEC diagnosis and implementing early treatment strategies may reduce the incidence and severity of NEC in premature infants. Given the association of severe NEC with increased mortality and long-term complications, identifying high-risk groups could improve outcomes. A limitation of our study is the relatively small sample size of 82 preterms, with only 20 developing NEC. This may explain why some relationships, such as the association between IL3 levels in NEC neonates with and without chorioamnionitis exposure, approached but did not reach statistical significance (p = 0.063). We believe that, with a larger sample size, more definitive associations might be established. The correlation between maternal and neonatal inflammatory factors remains a key strength of this study. Further research is needed to explore inflammatory factors before and after NEC onset.