Our results demonstrated that the maximum RDW and RDW fluctuation were associated with neonatal sepsis. RDW fluctuation showed better accuracy than maximum RDW, with a sensitivity of 92.10% and specificity of 71.70%. Further, for every 1% relative increase in the maximum RDW during the NICU stay, the likelihood of sepsis rose by 61% (OR 1.61); for every 1% relative increase in RDW fluctuation, the likelihood of sepsis rose by 13% (OR 1.13).
Our results indicated that RDW values varied widely with GA. RDW values at 34–37 weeks in the control group were higher than in the other GAs. Similarly, a large-scale cohort study of 8089 individuals found a strong association between RDW and age, but not sex . Another study of RDW values showed that RDW reference intervals for neonates are higher than older children and adults. The lower reference limit for RDW at birth for term and late preterm neonates is 15.5% and the upper reference limit is 20%, slightly higher (up to 23%) in preterm neonates. The study also found that the reference interval at birth does not change appreciably over the first two weeks, except for those receiving a blood transfusion where the RDW increases . Moreover, another study showed that blood parameters of preterm neonates depend on both the degree of prematurity, postnatal age, and perinatal treatments . An observational study of 1594 normal newborns whose samples were taken on the first day of life demonstrated that the normal range for RDW values at GA 32–34 weeks was higher than at 35–36 weeks and 37–42 weeks (P = 0.002 and 0.003) . Similarly, another study showed that RDW and GA at birth were negatively correlated . Also, a study showed that the RDW values of newborns at 28 ± 2 gestational weeks with PDA and non-PDA were (15.75 ± 1.15) and (16.85 ± 1.49) respectively, with no significant difference . A high RDW in neonates is likely due to reticulocytosis , possibly explaining the correlation between RDW and GA. In future studies, we will recruit a larger sample size to further explore the association between RDW and PDA and explain the greater change in RDW.
Similar to other studies , we found that RDW values varied by ethnicity. Mean and elevated RDW has progressively increased from 1999–2012 among adults in the United States, as observed among non-Hispanic Whites, Blacks, and Mexican Americans . Another study showed that the median RDW was distributed differently among various ethnicities . This is another aspect to investigate in future studies.
Recognition of biomarkers with high sensitivity and specificity is important for the early diagnosis and for prognosticating neonatal sepsis. Several biomarkers such as procalcitonin, CRP, and interleukin 6 have been reported for the auxiliary diagnosis of neonatal sepsis, with a 72.3–90.8% sensitivity [18–20]. CRP is an acute-phase protein mostly produced by the liver following the onset of inflammation, but it rises after 12 h from the onset of sepsis and other non-infectious inflammatory diseases . However, these biomarkers require extensive laboratory support systems and are difficult to perform when a limited volume of blood is available, as in the case of extremely preterm infants. RDW is a practical, simple, and accessible biomarker as a parameter of the routine complete blood count, which has a strong positive correlation with CRP .
Here, we found that the RDW value in the sepsis group was higher than that in the control group. Similarly, a prospective study measured RDW in 251 cases of neonatal sepsis that showed significantly higher RDW (19.9% vs. 18.9%, P < 0.001) than age-matched healthy controls . Additionally, the diagnostic value of RDW was studied recently for early-onset neonatal sepsis cases, and it was found that the mean RDW values was higher (19.2 ± 2.9) in the sepsis group than in the control group (16.9 ± 1.3, P < 0.01) . These findings suggest that elevated RDW was associated with neonatal sepsis.
Our study found that an RDW cut-off of 18.15% was associated with a sensitivity of 78.70% and a specificity of 69.30% for predicting neonatal sepsis (P < 0.01). Previous studies have shown that RDW has high diagnostic accuracy for sepsis . A cut-off value of > 19.50% had a sensitivity of 87% and a specificity of 81% for late-onset Gram-negative sepsis (P < 0.001). They enrolled 47 infants with Gram-positive sepsis and 39 infants with Gram-negative sepsis, whose median GA was 28 (range 26–31) weeks. In our study, the median GA was 33.50 (range 30–34.5) weeks. They found that RDW levels remained unchanged in infants with Gram-positive sepsis (P = 0.4). We did not compare RDW values between infants with Gram-positive and Gram-negative infections. Future studies should investigate the effect of different pathogens on RDW. High RDW may indicate high-risk newborns .
In our study, RDW fluctuation was found to be more useful for diagnosing neonatal sepsis than the maximum RDW. The sensitivity of the RDW fluctuation with a cut-off value of 1.94 was 92.10%, and its specificity was 71.70%. For long-term hospitalized premature infants, RDW fluctuations were more readily obtainable than blood culture results without collecting additional blood for testing. Using RDW allows early identification of sepsis for prompt treatment, thus improving the prognosis and decreasing patient mortality. Furthermore, multivariable logistic regression analysis of RDW fluctuation, birth weight, WBC, hemoglobin, and platelet count showed a positive independent association between RDW fluctuation and sepsis diagnosis (OR, 1.13; 95%CI, 1.08–1.18). Kim et al. (2013) found that, in adults, an increase in RDW from baseline during the first 72 hours of hospitalization is significantly associated with adverse clinical outcomes and suggested that a combination of baseline RDW value and an increase in RDW can be a potential independent prognostic marker in patients with severe sepsis or septic shock . Nevertheless, the pathogenesis between RDW and outcomes of RDW is still unclear. Inflammation and organ dysfunction are two possible mechanisms . Inflammation impairs RBC maturation, accelerating the entry of immature RBCs into the circulation . RDW is determined by the life span of RBC . The half life span of RBC is about 120 days, thus RDW may serve as a long-term inflammatory marker. In contrast, traditional markers such as CRP are only short-term markers. For patients with sepsis, higher RDW would indicate probable organ dysfunction, which may have worse outcomes.
To the best of our knowledge, this was the first study in which the relationship between RDW fluctuation and diagnosis of neonatal sepsis has been evaluated using data from the MIMIC-Ⅲ database. Our study, however, still has some limitations. First, weaknesses of our study are inherent to its retrospective nature. The MIMIC III database has some incomplete data, thus, analysis for confounding factors is incomplete. Second, we used the search terms “bacteremia of newborn” and “septicemia [sepsis] of newborn” for sepsis; therefore, the blood culture results were unclear. Finally, other risk factors such as erythrocyte transfusions , were not included in our study; thus, residual confounding factors remain possible. To increase the credibility of our results, we compared the RDW of patients with sepsis with those of matched controls based on GA, sex, and ethnicity. Future studies should include a larger sample size and prospective design to validate the findings of the present study.