High CRP and white blood cell counts are not reliable indicators of early-onset neonatal infection in full-term infants

Background: Diagnosing neonatal early-onset sepsis (EOS) is challenging, making it difficult to determine infection indicator characteristics and cutoff values in full-term infants. This study retrospectively analyzed full-term infants with high-risk factors for neonatal EOS but tested negative for EOS, aiming to identify infection indicator characteristics and their association with perinatal factors without antibiotic intervention.

Methods: Full-term infants at high risk for EOS who were admitted to rooming-in from 1 July 2023 to 29 February 2024 were included in the study. Blood routine examinations and C-reactive protein (CRP) levels were dynamically monitored after birth. All demographic data and medical records were collected from the electronic medical records system.

Results: Among 103 neonates, only 2 had normal infection indicators. Within 24–48 h after birth, an additional 28 displayed normal infection indicators. Although most of the infants exhibited normal WBC within 24–48 h, 33 patients still had higher neutrophil percentages, and 62 had higher CRP levels. Moreover, several high-risk perinatal factors for abnormal infection indicators have been identified.

Conclusions: This study demonstrates that infection indicators frequently showed abnormalities in full-term infants at high risk for EOS who tested negative. Few infants had normal infection indicators within 24 h, and although WBC levels normalized by 24–48 h, CRP levels remained elevated. Specific perinatal factors were also associated with abnormal infection markers. These findings reinforce the need for cautious interpretation of isolated biomarker elevations and support antimicrobial stewardship by highlighting the high frequency of abnormal indicators in uninfected infants, thereby reducing unnecessary antibiotic exposure.

1 Introduction

Neonatal early-onset sepsis (EOS) is one of the leading causes of neonatal mortality (1, 2). Prophylactic antibiotic use in neonates with high-risk factors can effectively prevent neonatal sepsis and reduce both mortality and morbidity (3–6). However, antibiotic overuse also warrants attention, as it can disrupt the intestinal microbiome, contribute to antibiotic resistance, and lead to future metabolic disorders and immune dysregulation-related diseases (7–13). The World Health Organization has already prioritized antibiotic resistance as part of its global action plan (14).

The gold standard for diagnosing EOS is the positive identification of a pathogenic organism from sterile body fluid (4–6). However, current studies have demonstrated that pathogen cultures have low sensitivity, making the diagnosis of neonatal sepsis challenging (15–19). Furthermore, although many laboratories provide preliminary blood culture results within 36–48 h, final pathogen identification and susceptibility testing often require additional time (15–19). If antibiotic administration is based solely on this gold standard, suspected sepsis may rapidly progress to life-threatening outcomes by the time culture results become available. In recent years, molecular diagnostic techniques such as polymerase chain reaction (PCR) have been increasingly utilized to aid in the rapid detection of pathogens, although their integration into routine neonatal sepsis evaluations varies across settings. Consequently, clinical suspicion and infection indicators often guide antibiotic treatment decisions (20–23). Common blood infection indicators include white blood cell (WBC) count, neutrophil percentage, C-reactive protein (CRP), procalcitonin (PCT), and interleukin-6 (IL-6). However, these indicators can also respond to early acute stress events, such as delivery, respiratory distress, and hypoxic stress in neonates, which, in turn, may influence infection indicators (24–28). This makes it difficult to decide whether antibiotics should be used in these cases. To date, there are no definitive inflammatory markers or cutoff values for infection indicators in neonatal EOS that clearly indicate whether antibiotics should be administered (3, 4, 16). Once antibiotics are used, these neonates are hospitalized, separated from their mothers, and face increased healthcare costs.

In fact, research in this field is particularly challenging because infection markers in infants suspected of having, but not actually diagnosed with, EOS may be affected by prior antibiotic use. Therefore, in the present study, we took an alternative approach. We retrospectively collected data on full-term infants with high-risk factors for EOS who were ultimately EOS-negative and did not receive antibiotics. We analyzed their infection indicators and relevant perinatal factors, aiming to offer valuable insights for guiding future antibiotic use in this population.

2 Methods

The Ethics Review Committee of Tianjin Central Hospital of Gynecology Obstetrics approved this study (No. 2024KY072). All study protocols adhered to the principles of the Declaration of Helsinki. The requirement for written informed consent was waived due to the retrospective nature of the clinical data collection. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines.

2.1 Study population

This observational study included all full-term live-born newborns at Tianjin Central Hospital of Gynecology Obstetrics (He Ping District) from 1 July 2023 to 29 February 2024. The following newborns were excluded: (1) infants admitted to the NICU after birth, (2) infants admitted to rooming-in but with a gestational age of <37 weeks; (3) infants without a high risk of EOS and without infection indicator monitoring after birth; (4) infants without follow-up information to confirm the presence or absence of EOS; and (5) infants diagnosed with sepsis, suspected sepsis, or clinical sepsis, and who received any antibiotics within the first 7 days postnatally.

2.2 Study definitions

Sepsis was defined as a positive culture of bacteria in blood or other body fluids, along with infectious clinical signs and symptoms and abnormal infection indices. Suspected sepsis was defined as the presence of infectious clinical signs and symptoms or maternal chorioamnionitis. Clinical sepsis was defined as abnormal infection indices with infectious clinical signs and symptoms, but with negative bacterial cultures. All newborns were followed up within the first 7 days after birth to exclude sepsis, suspected sepsis, and clinical sepsis. Feeding intolerance was defined as the presence of one or more of the following: gastric residuals >50% of the previous feeding volume, abdominal distension requiring interruption or reduction of feeding, vomiting, or clinically significant regurgitation (29). In accordance with standard clinical microbiology protocols, positive blood cultures would have been reviewed for potential contamination based on organism identity (e.g., coagulase-negative staphylococci), time to positivity, clinical correlation, and serial infection markers. Any culture deemed a contaminant in the absence of clinical or laboratory evidence of infection would have led to exclusion from the sepsis-positive group. In this study, all blood cultures were negative, and thus no such exclusions were necessary.

Newborns admitted to rooming-in with high-risk factors for EOS were monitored for infection indicators and clinical signs and symptoms. The infection indicators included in this study were blood routine examinations and CRP levels. High-risk factors for EOS included meconium staining of amniotic fluid, premature rupture of membranes for >18 h, application of vacuum extractor during delivery, maternal fever within 48 h before delivery, and maternal group B streptococcus (GBS) colonization with adequate intrapartum antibiotic prophylaxis (≥4 h before delivery). An abnormal WBC count was defined as >30 × 10⁹/L or <5 × 10⁹/L. An abnormal neutrophil percentage was defined as >70%, and an abnormal CRP level was defined as >10 mg/L (20, 30–32). Absolute neutrophil counts (ANC) were interpreted using established neonatal reference ranges rather than those applied to older infants or children. Specifically, neonatal neutrophil values were evaluated according to the widely used reference ranges described by Manroe et al. (32). All demographic data including maternal complications, maternal white cell count (WCC) before delivery, and medical records were collected from the electronic medical records system. White blood cell counts were obtained from automated complete blood count analysis and were not manually corrected for nucleated red blood cells, consistent with routine clinical reporting in our institution.

Operational definition of EOS-negative status for study inclusion: For the purposes of this analysis, an infant was considered definitively EOS-negative and eligible for inclusion if they fulfilled all of the following criteria during the 7-day postnatal follow-up period—(1) absence of clinical signs of sepsis; (2) receipt of no antibiotic therapy; and (3) either (a) a negative blood culture result (if obtained) or (b) in the absence of blood culture, documented normalization of initial laboratory abnormalities (WBC, neutrophil%, CRP) concurrent with sustained clinical well-being.

Blood culture protocol: Blood culture was not routinely performed for all asymptomatic high-risk infants in the rooming-in ward, consistent with local antimicrobial stewardship practices. It was obtained based on clinical judgment for a subset of infants (23/103, 22.3%) when specific concerns arose; all cultures were negative.

2.3 Statistical analysis

R software 4.2.2 was used to conduct the statistical analysis. To characterize the features of the study neonates, categorical data were presented as frequencies (percentages) and continuous variables as medians (interquartile ranges). As outcome variables, WBC, neutrophil percentage, CRP, and composite infection indicators were evaluated. Univariate analysis was conducted between outcome variables and neonatal baseline characteristics including perinatal factors and general clinical symptoms. Pearson's chi-squared test was used to evaluate differences in distribution between groups, and Fisher's exact test was used when any expected cell frequency was 5 or less. Independent infectious risk factors were determined using a multiple binary logistic regression model. All variables were entered simultaneously into the logistic regression models and treated as categorical variables. Odds ratios and 95% confidence intervals (CI) were calculated. A significance level of p < 0.05 was used.

3 Results

As shown in Figure 1, from July 2023 to February 2024, a total of 3,162 newborns were born at Tianjin Central Hospital of Gynecology Obstetrics (He Ping District), of whom 2,528 were full-term newborns admitted to rooming-in care. Among them, 2,418 infants had no high-risk factors for EOS and/or lacked infection indicator data and were cared for routinely, while 110 infants were identified as having risk factors for EOS. All 110 infants underwent blood routine examinations and CRP testing within 24 h of birth and were closely monitored for clinical symptoms within the first 48 h. Of them, seven infants lacked follow-up information regarding whether they developed infections during the neonatal period. Finally, 103 infants with high risk factors for EOS but ultimately negative for EOS and who did not receive any antibiotics within the first week after birth were included in the present study. Of these 103 infants, blood culture was obtained in 23 (22.3%) based on the doctor’s judgment; all cultures were negative.

Figure 1

Figure 1. Flowchart for enrolled neonates.

As shown in Table 1, the clinical characteristics of the 103 newborns were listed, including not only information about the newborns but also details about their mothers, pregnancy-related factors, and other information closely related to EOS. Information on whether the mother experienced infections during the entire gestation was also included.

Table 1

Table 1. Characteristics of full-term infants with infectious risk factors during the perinatal period.

All infants included in the present study underwent blood routine examinations and CRP testing within 24 h and were followed up until their infection indicators normalized. The main infection indicator results, including WBC, neutrophil percentage, and CRP, were shown in Figure 2 and Table 2. Among the 103 neonates, only 2 had completely normal WBC, neutrophil percentage, and CRP results at the initial screening, while the remaining 101 exhibited varying degrees of abnormalities. Specifically, 28 infants had WBC levels above normal (27.7%), 90 had elevated neutrophil percentages (89.1%), and 61 had CRP levels above normal (60.4%).

Figure 2

Figure 2. Comparison of neonatal WBC count, neutrophil percentage, and CRP levels between “0–24 h” and “24–48 h” after birth. (a) WBC counts (×10⁹/L), (b) neutrophil percentage (%), and (c) CRP levels (mg/L) were displayed in box plots for neonates measured at two time intervals: 0–24 h (blue) and 24–48 h (red). Each dot represented an individual data point. The central line in each box indicated the median value, the box edges represented the interquartile range, and the whiskers denoted the maximum and minimum values observed within each group. The dotted horizontal lines at 30 × 10⁹/L in panel a, 70% in panel b, and 10 mg/L in panel c indicated clinically relevant thresholds. Observations suggested changes in WBC count, neutrophil percentage, and CRP levels between the two time intervals.

Table 2

Table 2. Levels of major infection indicators in newborns within 48 h after birth.

We planned to reexamine blood routine tests and CRP levels in the 101 infants with abnormal results within 24 h after birth. However, 5 of 101 infants were reexamined >48 h after birth due to various reasons. Ultimately, 96 infants were reexamined within 24–48 h after birth. Among these 96 infants, 28 had normal infection indicators. Including the two infants who had normal indicators within the first 24 h, the proportion of infants with normal infection indicators within 48 h after birth was only 29.2%.

In the second examination conducted within 24–48 h after birth, 68 infants still had abnormal infection indicators. Among them, 3 had WBC levels above normal (3.1%), 33 had elevated neutrophil percentages (34.4%), and 62 had CRP levels above normal (64.6%). As shown in Figure 2, WBC and neutrophil percentages exhibited a decreasing trend from 0–24 h to 24–48 h, while CRP levels showed an increasing trend.

As previously mentioned, in this cohort, only 30 infants had normal infection indicators within 48 h of birth, with 70.9% showing abnormal indicators. Therefore, we explored the relationship between infection indicators and perinatal factors. As shown in Tables 3 and 4 and Figure 3, within the first 24 h after birth, premature rupture of membranes for >18 h was identified as a high-risk factor for abnormal WBC levels, while neonatal feeding intolerance or weight loss exceeding 3% was a high-risk factor for abnormal CRP levels. According to current studies and recommendations, WBC and CRP are often used together as indicators of infection (33, 34), so we defined composite infection indicator abnormality as having both WBC and CRP outside normal ranges and analyzed the associated outcomes. The study revealed that weight loss exceeding 3% in the first 24 h was a high-risk factor for abnormal composite infection indicators. Additionally, within the 24–48 h after birth, maternal infection during pregnancy was a high-risk factor for abnormal neutrophil percentages and composite infection indicators (WBC + CRP).

Table 3

Table 3. Univariate analysis of the association between perinatal factors, general clinical symptoms, and blood indices within 24 h of birth.

Table 4

Table 4. Univariate analysis of the association between perinatal factors, general clinical symptoms, and blood indices between 24 and 48 h after birth.

Figure 3

Figure 3. Forest plots showed the odds ratios (OR) for factors associated with neonatal WBC count, neutrophil percentage, and CRP levels at various post-birth time intervals. Panels a through d presented the ORs with 95% CI for maternal and neonatal factors affecting the following abnormality indicators: (a) abnormal WBC count (defined as >30 × 10⁹/L or <5 × 10⁹/L); (b) abnormal neutrophil percentage (defined as >70%); (c) abnormal CRP levels (defined as >10 mg/L); (d) abnormal composite blood index (defined as both WBC > 30 × 10⁹/L and CRP > 10 mg/L). Each panel compared the impact of these factors on neonatal outcomes across specified time intervals (“0–24 h” and “24–48 h”). Multivariate models were fitted using logistic regression. Statistical significance was indicated as follows: *p < 0.05; **p < 0.01. Factors marked as “NA” represented instances where abnormal indicators occurred exclusively within specific subgroups, leading to insufficient sample sizes for accurate estimation of odds ratios.

4 Discussion

This study highlights that infection indicators such as WBC count, neutrophil percentage, and CRP levels often show abnormalities in full-term infants at high risk for EOS who test negative, questioning their reliability as sole diagnostic markers. Relying solely on these indicators for antibiotic therapy in high-risk newborns may lead to overuse, emphasizing the need for more targeted approaches in neonatal care.

In diagnosing infections in children and adults, common blood infection indicators such as WBC, neutrophil percentage, and CRP are generally reliable (35–38). However, these indicators are not entirely applicable to neonatal EOS (37). Neonatologists often encounter abnormal infection indicators in well-appearing infants, creating a dilemma about whether to use antibiotics. Many studies have focused on determining cutoff values for various infection indicators to guide antibiotic use (39–43). Despite current guidelines and expert consensus suggesting that antibiotics should not be solely relied upon (21, 33), neonatologists still use these indicators to make decisions about antibiotic therapy due to the high mortality associated with EOS. Consequently, antibiotic overuse remains a significant issue in neonates. In the present study, we included 103 neonates with high-risk factors for EOS who were ultimately confirmed not to have true EOS and did not receive antibiotics during follow-up. By examining the changes in infection indicators and their relationship with perinatal factors, this study provides valuable insights into the management of neonates at risk for EOS.

In this study, 103 neonates with high-risk factors for EOS had their infection indicators tested within 24 h after birth. We found that only two neonates had normal infection indicators within this period. Relying solely on these results for antibiotic use would significantly increase the number of neonates exposed to antibiotics. The remaining 101 neonates with abnormal infection indicators at their initial assessment did not receive any antibiotics. This study reaffirms that it is not appropriate to base antibiotic treatment solely on infection indicators, as it can lead to unnecessary antibiotic exposure. Some studies have even suggested using physical examination alone to determine the need for antibiotics (22). For instance, Berardi et al. (22) compared the use of antibiotics between a group receiving laboratory evaluations plus simplified physical examination and a group receiving only physical examinations. The results showed that the group receiving only physical examinations used fewer unnecessary antibiotics and had a shorter length of stay. While in many centers, neonatologists cannot rely solely on physical examinations due to variability in the interpretation of symptoms and signs, our study at least suggests that for asymptomatic newborns, infection indicator results should not be overinterpreted.

In addition to monitoring infection indicators within the first 24 h, we continued to track these newborns until their infection indicators returned to normal. For infants with abnormal infection indicators in the first 24 h, we reexamined them within 24–48 h to rule out infection. As shown in Figure 2, while most newborns had normal white blood cell counts within 24–48 h, CRP levels exhibited different patterns. Both WBC and neutrophil percentages showed a decreasing trend from 0–24 h to 24–48 h, whereas CRP levels increased during the same period. Perrone et al. (24) examined CRP in 859 healthy term newborns during the first 48 h of life. The CRP mean values were significantly higher at 48 h. The 95th centiles for CRP at 48 h were 13.3 mg/L. This is consistent with the reference intervals established by Chiesa et al. (44), who reported that CRP levels in healthy term neonates peak during the first 48 h. In our study, the median CRP value during 24–48 h was 13.1 mg/L. This high level can be attributed to the fact that all newborns in our study had high-risk factors for infection.

Several studies have reported higher CRP levels in infants delivered vaginally compared with those delivered by cesarean section, likely reflecting increased physiological stress during labor and delivery. Vaginal delivery is associated with elevated fetal stress hormones, such as cortisol and catecholamines, which may contribute to transient increases in inflammatory markers including CRP and white blood cell indices (24, 44–49). In line with these observations, our data showed that although WBC counts and neutrophil percentages generally decreased between 24 and 48 h after birth, CRP levels often rose during the same period. Notably, 28 infants had normal CRP levels within the first 24 h but developed elevated CRP values at 24–48 h, despite the absence of clinical infection. Therefore, isolated CRP elevation, particularly in the context of improving WBC indices, should be interpreted with caution in clinical decision-making.

Despite their limited specificity, inflammatory markers such as CRP and white blood cell indices are still widely used by neonatologists to guide decisions regarding antibiotic initiation, given the potentially high mortality associated with early-onset sepsis. However, De Rose et al. (50) reported that CRP levels at admission were similar in neonates with positive and negative blood cultures and demonstrated that, in clinically stable infants, antibiotic therapy may be safely discontinued when blood cultures remain negative after 36–48 h. Together, these findings underscore the challenge of interpreting isolated or delayed CRP elevation in high-risk but clinically well-term infants.

To further explore potential non-infectious contributors to this pattern, we examined the role of delivery mode on inflammatory markers. Perrone et al.'s (24) study also noted that newborns delivered vaginally had elevated CRP levels, which aligns with our findings regarding WBC (p = 0.052, Figure 3). This is consistent with previous reports indicating that the physiologic stress of labor and vaginal delivery may contribute to a more pronounced acute-phase response in the newborn, even in the absence of infection. Furthermore, a similar trend was observed between vacuum-assisted delivery and elevated neutrophil percentages (p = 0.074). It should be noted that these associations are observational in nature and, as indicated by their p-values, are suggestive rather than statistically conclusive. Although these specific associations did not reach conventional statistical significance in our cohort, they collectively suggest that the mode of delivery, including operative vaginal delivery, may act as a non-infectious stressor influencing early neonatal hematological indices. These findings suggest that vacuum-assisted delivery may be associated with transient elevations in inflammatory markers reflecting physiological stress, rather than indicating true neonatal infection. Thus, these findings are best interpreted as generating hypotheses for future investigation. Such physiological elevations underscore the challenge of interpreting isolated CRP increases in the early neonatal period, particularly in high-risk but clinically well infants. Previous studies have shown that up to 20% of healthy newborns may exhibit a physiological rise in CRP above 10 mg/L, and even up to 20 mg/L, during the first days after birth. Benitz et al. (51) and Hengst (52) reported that such transient CRP elevations may occur in the absence of infection and should be interpreted in conjunction with the infant's overall clinical condition rather than in isolation. This physiological pattern further supports cautious interpretation of elevated CRP values in clinically well neonates.

However, it should be noted that neonatal weight loss >3% on the first day after birth is not an established risk factor or indicator of neonatal infection. Beyond the mode of delivery, other perinatal factors were also linked to abnormalities in infection markers. For instance, premature rupture of membranes for >18 h was identified as a risk factor for abnormal WBC levels within the first 24 h. Similarly, feeding intolerance or weight loss exceeding 3% in newborns emerged as a significant factor associated with elevated CRP. While these perinatal conditions do not definitively rule out infection—and infants exhibiting such factors alongside abnormal markers warrant close observation—their association with altered hematological indices serves as an important clinical reminder. These findings suggest that the possibility of a non-infectious etiology should be actively considered in such scenarios, which could help mitigate unnecessary antibiotic use.

According to the NICE guideline (20, 21), symptoms such as breathing difficulties, tachycardia, and seizures are considered significant indicators or red flags for sepsis. In line with this, our protocol involved active monitoring for a comprehensive set of EOS symptoms across all major organ systems (respiratory, cardiovascular, neurological, gastrointestinal, metabolic, and thermoregulatory). In our study, we also examined these symptoms to explore their relationship with EOS. However, aside from digestive symptoms (such as feeding intolerance or weight loss exceeding 3%), these other symptoms were not observed in any of the 103 newborns, resulting in an incidence rate of 0%. This is consistent with our cohort's defining characteristic: All infants were clinically well-appearing and managed in the rooming-in ward. Per our clinical protocol, any neonate exhibiting systemic signs of illness (e.g., apnea, tachycardia, and respiratory distress) would have been transferred to the NICU for evaluation and thus excluded from this analysis. This absence of symptoms is likely because infants presenting with such signs would have been admitted to the NICU for further evaluation of potential systemic diseases. In the NICU, these infants would have undergone more rigorous monitoring and additional assessments to determine the presence of EOS.

In addition, jaundice within the first 24 h after birth is also considered an indicator or high-risk factor for EOS. We included jaundice in our evaluation of the 103 neonates. For the diagnosis of jaundice, our data included the expert consensus of Chinese local experts (53). The standard for 24 h jaundice is based on the hourly bilirubin curve, and any value above this standard is defined as 24 h jaundice. However, this factor did not show any significant association with the abnormalities in the three infection indicators. The latest guidelines from the American Academy of Pediatrics (54) have updated the criteria for jaundice, and what was previously considered abnormal is no longer classified as jaundice. According to these updated guidelines, only two newborns met the criteria for 24 h jaundice. Due to the small sample size and its minimal impact, we did not include this factor in our study.

Widely accepted high-risk factors for EOS include GBS colonization, chorioamnionitis, and preterm birth (3–6). In this study, all mothers who tested positive for GBS received adequate antibiotics before delivery. Infants whose mothers had not received sufficient antibiotics were closely monitored in the NICU, rather than in rooming-in. Infants diagnosed with chorioamnionitis were also monitored in the NICU. For preterm birth, only partially preterm infants with >36 gestation weeks were admitted to rooming-in. If infants are born at <36 weeks, they would admit in NICU for further monitoring in our center. Consequently, we explored the application of antibiotics in all late preterm infants due to the differing care practices between the NICU and rooming-in settings. Therefore, preterm births were not included in the present study.

Some guidelines recommend managing multiple positive risk factors for EOS (33, 55). In this study, we analyzed maternal GBS positivity, intrapartum fever, and premature rupture of membranes for >18 h. However, there were no cases with maternal GBS positivity combined with both premature rupture of membranes for >18 h and intrapartum fever. We identified two cases with any two of these risk factors. According to the local guideline (33), the presence of two positive risk factors suggests transferring neonates to a specialized department and considering antibiotic use. Although antibiotics were not administered in these two cases, no definitive conclusions can be drawn from such a small sample. This finding warrants further investigation with a larger sample size in future studies.

Several limitations must be acknowledged when interpreting our findings: Firstly, the relatively small sample size limited statistical power, particularly in multivariate analyses. Observed correlations should therefore be interpreted as hypothesis-generating and require validation in larger cohorts. Secondly, the single-center retrospective design introduces a risk of selection bias, which may compromise the external validity of the statistical inferences. Thirdly, although efforts were made to adjust for known confounders, there remains a possibility that unmeasured biases and confounders were not sufficiently addressed in the statistical models. Fourthly, our study specifically focused on neonates at high risk for EOS who were ultimately confirmed to be uninfected and managed in the rooming-in ward. While this design allowed us to characterize infection indicators in the absence of antibiotic confounding, it also means that our cohort comprised infants who were, in retrospect, truly low risk for developing EOS. This may limit the direct generalizability of our findings to all high-risk infants, particularly those who present with more equivocal clinical signs. Nevertheless, this population remains highly relevant to clinical practice. In many settings, including numerous NICUs in developing countries, the decision to initiate antibiotics in asymptomatic or minimally symptomatic high-risk infants is still heavily influenced by abnormal laboratory indicators. Our findings directly address this common clinical dilemma by demonstrating the high frequency of such abnormalities in infants who do not have infection, thereby underscoring the potential for antibiotic overuse in this specific group.

Our findings directly inform antimicrobial stewardship efforts by demonstrating that abnormal WBC, neutrophil%, and CRP values are common in high-risk but uninfected term infants. This underscores the risk of antibiotic overuse when these markers are interpreted in isolation, supporting a more conservative, clinically integrated approach to antibiotic initiation in asymptomatic neonates. In conclusion, this study reaffirms that relying solely on blood infection indicators is insufficient for accurately diagnosing neonatal EOS. In newborns identified as high-risk for EOS but ultimately confirmed not to have the condition, only a few exhibited normal WBC count, neutrophil percentage, and CRP levels within 24 h after birth. While WBC levels may return to the normal range within 24–48 h, CRP levels often remain elevated. Additionally, certain perinatal factors, such as feeding intolerance, have been identified as risk factors for abnormalities in blood infection indicators. Further exploration is needed to determine the significance of multiple positive risk factors for EOS as an indication for antibiotic administration.

Data availability statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Ethics statement

The studies involving humans were approved by the Ethics Committee of Tianjin Central Hospital of Gynecology Obstetrics. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation in this study was provided by the participants' legal guardians/next of kin.

Author contributions

LL: Data curation, Investigation, Resources, Writing – original draft, Writing – review & editing. XL: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Software, Supervision, Validation, Writing – original draft, Writing – review & editing. LZ: Funding acquisition, Investigation, Resources, Writing – original draft. JM: Investigation, Resources, Writing – original draft. FD: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Resources, Supervision, Validation, Writing – original draft, Writing – review & editing.

Funding

The author(s) declared that financial support was received for this work and/or its publication. FD is sponsored by Tianjin Health Research Project (grant number: TJWJ2025XK009), Tianjin Science and Technology Committee (grant number: 21JCQNJC01650), and China International Medical Foundation (grant number: Z-2019-41-2101-04). LZ is sponsored by Tianjin Health Research Project (grant number: TJWJ2022QN087).

Acknowledgments

We acknowledge support from Tianjin Key Medical Discipline Construction Project (TJYXZDXK-3-029C). We thank all resident doctors in the Department of Neonatology of Tianjin Central Hospital of Gynecology Obstetrics for collecting information. FD thanks Lei Gao and Mo Ding for their care and support.

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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