Evaluation of clinical and laboratory parameters for recognition and diagnosis of neonatal sepsis: a retrospective analysis of a cross-sectional study

Introduction

Background

Sepsis, severe sepsis, and septic shock are significant global healthcare issues. Neonatal septicemia is a leading cause of mortality and morbidity in newborns, with an estimated 4 million infants dying within the first 28 days of life each year. It has become a global healthcare challenge that accounts for 1.5–2.0 million deaths annually in underdeveloped countries, and the incidence rate is increasing annually (1,2).

Early-onset of neonatal sepsis (EONS) occurs when microorganisms cross physical and biochemical immune barriers within the first 72 hours of life. The tendency of EONS rises with increasing amounts of risk factors, such as maternal factors like early membrane rupture >18 h, dribbling, intrapartum maternal fever, chorioamnionitis, vaginal Group B streptococcus colonization, candidiasis, gestational diabetes mellitus, prenatal steroid exposure, anemia, and urinary tract infections (3). Late onset of neonatal sepsis (LONS), occurring after 72 hours of life up to 28 days, is typically acquired from the environment after delivery. LONS risk factors include preterm birth and hospital-acquired infections (4). The most common neonatal clinical manifestations of sepsis include prematurity, low Apgar scores, fetal distress caused by lack of oxygen or nutrient supply, anemia, meconium aspiration, and metabolic disorders (5).

Diagnosis of neonatal sepsis relies on both clinical symptoms and laboratory findings. Clinical manifestations in neonates range from non-specific signs and symptoms like temperature instability and metabolic acidosis to severe conditions like septic shock. Cardiac, respiratory, gastrointestinal, and skin changes are also observed in neonates with sepsis. Symptoms are typically more severe in gram-negative infections compared to gram-positive ones. Neonatal sepsis can lead to serious complications, including increased mortality, organ failure, metabolic acidosis, coagulation disorders, empyema, and pulmonary hypertension (6).

The diagnosis of sepsis is made when a patient with a suspected or confirmed infection meets at least two Systemic Inflammatory Response Syndrome (SIRS) criteria, which includes Body temperature over 38 or under 36 degrees Celsius, heart rate greater than 90 beats/minute, Respiratory rate greater than 20 breaths/minute or partial pressure of CO₂ less than 32 mmHg, leukocyte count greater than 12,000 or less than 4,000/microliters or over 10% immature forms or bands (7).

Full blood count (FBC) count is a common laboratory investigation aiding in the diagnosis of sepsis, specifically characterized by leukocytosis or leucopenia, reduced absolute neutrophil counts and thrombocytopenia. Moreover, infection markers like C-reactive protein (CRP) and procalcitonin also contribute to the diagnosis (8).

Blood culture is the gold standard for diagnosing bacteremia but detecting it in neonates requires a blood volume of >0.25 mL due to commonly low bacteremia levels. Even though it is the most reliable method there are some limitations of blood cultures including delayed processing (>48 hours to obtain results), sensitivity varies according to blood volume and bacterial load in the blood, potential for culture contamination, very high percentage of false negatives (ex-intrapartum antibiotic prophylaxis), not available in majority of developing countries and rural areas and whether the causative pathogen grows on standard blood culture media (9). CRP has both diagnostic and prognostic significance. However, it should not be used as the sole indicator due to its elevation from other fetomaternal conditions, such as complications during labor and delivery, intravascular hemorrhage, fetal distress, perinatal asphyxia, and meconium aspiration (10). Only an upper cutoff value of CRP has been established for the neonates having clinical symptoms of sepsis, and generally, a CRP level greater than 10 mg/L is considered to be a positive indicator of neonatal sepsis (11). FBC is commonly used to assess suspected neonatal sepsis, but a single FBC shortly after admission is not very diagnostically useful. A low white blood cell (WBC) count with low neutrophils correlates better with positive blood cultures, and mortality is higher when septicemia is associated with severe thrombocytopenia. FBC is more effective when combined with other biomarkers rather than using alone (12).

Rationale and knowledge gap

Infected neonates must be promptly identified and distinguished from non-infectious conditions to initiate targeted antibiotic therapy. Unlike adults, neonates show wide variability in clinical signs and symptoms, with many appearing even with negative blood cultures. Currently, there is a lack of a clear and defined clinical picture for neonatal sepsis, highlighting the need for specific diagnostic criteria. This would help reduce excessive empirical antimicrobial therapy, which can promote antimicrobial resistance and higher healthcare costs.

Objectives

The study aimed to identify the incidence of confirmed sepsis patients among suspected patients at Colombo South Teaching Hospital and Castel Street Hospital for Women, to identify maternal clinical conditions and neonatal clinical features associated with sepsis, and to identify specific or combinative parameters and develop clinical guidelines to diagnose neonatal sepsis. We present this article in accordance with the STROBE reporting checklist (available at https://pm.amegroups.com/article/view/10.21037/pm-25-14/rc).

Methods

Research design and research setting

A cross-sectional study was conducted from January to December 2022, using medical records of 219 neonates aged 0–28 days, registered at the premature baby unit, postnatal wards, and pediatric wards of Castle Street Hospital for Women, and Colombo South Teaching Hospital, Sri Lanka. All neonates who underwent sepsis screening as a result of being suspected of sepsis were included, but those with major congenital anomalies and administered with antibiotics before admission were excluded (Figure 1).

Figure 1 Flow diagram for study population selection.

Subjects were categorized into two subpopulations: those with positive blood culture results, along with the clinical diagnosis confirmed by the consultant pediatrician as the sepsis group, and those with negative blood culture results as the non-sepsis group. Altogether, 116 sepsis neonates and 103 non-sepsis neonates were enrolled in the study.

Data collection methods and tools

Demographic information on mother and neonate (gender, gestational age, delivery mode, birth weight), delivery complications of mother (early membrane rupture >18hrs, dribbling, intrapartum maternal fever, Group B streptococcus colonization), neonatal clinical conditions (Apgar score, body temperature, heart rate, blood pressure, respiratory rate) were obtained from the medical records and other relevant clinical reports. The 1-, 5-, and 10-minute Apgar scores were assessed using the standard criteria, which evaluate heart rate, respiratory effort, muscle tone, reflex irritability, and skin color. Each component was scored from 0 to 2, with the total score ranging from 0 to 10 (13). All assessments were performed at the respective time points (1, 5, and 10 minutes after birth) by a consultant pediatrician with extensive experience in neonatal care.

The results of blood culture, FBC, and CRP on days 0 (the day before the blood culture was taken) and 1 (the day the blood culture was taken), and other biochemical investigations (creatinine, urea, sodium, potassium, bilirubin) were recorded. Blood culture and clinical guidelines (SIRS) were taken as the gold standard for the confirmation of neonatal sepsis.

Statistical analysis

Statistical analysis was performed using the Statistical Package for Social Sciences (SPSS) version 20.0. All statistical tests were two-sided, and a probability value of P<0.05 was considered to be statistically significant. Demographic and clinical data of mother and neonate, fetomaternal conditions, FBC parameters, and results of biochemical investigations were descriptively analyzed among the two study groups. An independent sample t-test was used to compare parameters between sepsis and non-sepsis groups. The association between different categorical variables was evaluated using the Chi-Square test. The results of the univariate analysis were validated and evaluated for potential interactions among variables. To eliminate confounding factors and identify independent determinants of neonatal sepsis, a binary logistic regression model was developed. Finally, a receiver operating characteristic (ROC) curve analysis was conducted to evaluate the discriminatory power of the model.

Ethical considerations

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by institutional ethics committees of Colombo South Teaching Hospital, Kalubowila and Castle Street Hospital for Women, Sri Lanka (Ethical number: 875) and individual consent for this retrospective analysis was waived.

Results

Demography

A total of 219 neonates with clinical suspicion of neonatal sepsis that fulfilled the inclusion and exclusion criteria were selected for the study. Out of 217 neonates with clinical suspicion of sepsis, 21 were included in the less than 28-week gestational age category. Among them, 95.20% (20/21) had sepsis. Twenty-five neonates were observed in the less than 1kg birth weight category, in which 88% had sepsis (Table 1).

Out of the observed maternal clinical conditions, prenatal steroid exposure was observed in 70.70% of neonates with sepsis (Table 2).

Out of 180 neonates, 57 had an Apgar score <7 in 1st minute, and of those, 42 developed sepsis, which is stated as 73.60%. Similarly, 18 neonates had a 5th minute of <7 min, and of those, 15 (83.30%) developed sepsis. For the 10th minute, there were only 11 neonates with <7 min, and ten neonates had sepsis (91%) (Table 3).

Temperature instability (66.67%), bradycardia (60%), and hypotension (77%) were observed in neonates with sepsis compared to the non-sepsis group (Table 3).

Laboratory investigations

An independent sample t-test analysis was performed for the sepsis and non-sepsis study groups. The significant differences in renal function, liver function, and hematological parameters were statistically measured using paired sample t-test analysis, and P values were obtained between laboratory parameters of sepsis and non-sepsis patients (Table 4).

A statistically significant difference was observed in total bilirubin (P=0.001), indirect bilirubin (P<0.001), and percentage of monocyte count (P<0.001) between sepsis and non-sepsis patients. CoNS was the most predominant organism (57.80%) isolated from positive blood cultures of the sepsis population, followed by Acinetobacter spp (11.20%). Group A streptococci (1.70%), diphtheroid, and Micrococcus spp. were the least isolated organisms (1.72%) (Table 5).

Comparison of categorical variables among the study groups (Chi-squared test)

According to the association of maternal gestational age with sepsis, 95.20% of neonates with a gestational age of less than 28 weeks developed sepsis, while only 4.80% of neonates did not develop sepsis (P<0.001). Prenatal steroid exposure was more commonly observed among neonates with sepsis (70.70%) when compared with the non-sepsis group of neonates. (29.30%) (P=0.01). In the low-birth-weight category of less than 1 kg (very low birth weight), 88% of neonates had sepsis while 12% had non-sepsis (P=0.005). Of the neonates with sepsis, 48.80% had jaundice, while 66.60% did not have jaundice (P=0.03).

Sepsis was more common among neonates with Apgar scores <7 in the 1^st, 5^th, and 10^th minutes. A statistically significant association (P=0.007) was observed among study groups and the Apgar score. Of the patients who were noted as sepsis, 64.40% had a CRP level of more than 5 mg/L (P=0.03). The fatality rate was found to be (89.50%) in the sepsis group, in which two deaths (10.50%) were reported in the non-sepsis population (P<0.001)

Logistic regression model of predictors for sepsis

Binary logistic regression was applied due to the dichotomous nature of the dependent variable (sepsis vs. non-sepsis). The analysis aimed to assess the relationship between multiple independent variables, both continuous and categorical, and the likelihood of sepsis. Continuous variables that showed statistical significance in prior independent sample t-tests were included in the model. These included total bilirubin, indirect bilirubin, monocyte percentage, and MCHC. Categorical variables such as gestational age, birth weight, Apgar scores at 1, 5, and 10 minutes, and day 0 CRP levels identified as significant in chi-square tests were also included. The model was developed using the Backward: likelihood ratio (LR) method. Of the seven models generated, the final model included only variables with P values less than 0.05 and was selected for predicting sepsis. From the Omnibus tests of model coefficients, the model was statistically significant, χ² (6) =33.17, P<0.001. From the Hosmer and Lemeshow Test, which analyzes the goodness of fit statistics determined that the model was adequately fitting the data (P=0.52). The model explained 20.30% (Nagelkerke R Square) of the variance in sepsis. The model correctly classified 69.20 % of cases. The sensitivity of the model was 72.50%, specificity was 65 %, positive predictive value was 71.60% and negative predictive value was 66%. Gestational age 1 (<28 weeks), gestational age 3 (34–37 weeks), CRP value of day 0 (>5), and monocyte percentages were statistically significant (P=0.03) in the binary logistic regression model. Though the Apgar score 5^th min (>7) variable contributed to the model, according to the analysis, it was not statistically significant, as the P=0.11. The prediction equation or binary logistic model for sepsis is mentioned below:

log[P/(1−P)]=−1.18+2.30∗Gestationalage(1)−0.26∗Gestationalage(2)−1.12∗Gestationalage(3)+1.42∗Apgarscore5thmin+0.83∗CRPvalueofday0(1)+0.10∗Monocyte%[1]

Odd ratio (Exp B) >1 describes a positive relationship. Gestational age >37 weeks was selected as the reference category in the gestational age variable. Being in gestational age group 1 (<28 weeks) makes a neonate at 9.93 greater odds of being sepsis. Gestational age 2 (28–33 weeks) and gestational age 3 (34–37 weeks) decrease the likelihood of sepsis, 1.30 (1/0.78) and 3.08 (1/0.33) are the odds ratios, respectively.

Apgar score 5th min (≥7) was selected as the reference category, and the odds ratio of 4.13 indicates that neonates who have Apgar score 5th min <7 have a higher chance of being sepsis compared to neonates with Apgar score 5th min ≥7. CRP value of day 0 (<5) was selected as the reference category. Being in the CRP value of day 0 (≥5) group makes a neonate 2.29 times of likely to develop sepsis. For every one unit increase in monocyte%, the odds of being sepsis (vs. non-sepsis) increased by a factor of 1.10 (Table 6).

ROC analysis

The ROC curve analysis for the final binary logistic regression model demonstrated an area under the curve (AUC) of 0.69 (95% CI: 0.62–0.79) (Figure 2).

Figure 2 ROC curve. ROC, receiver operating characteristic.

Discussion

Neonatal sepsis, a clinical syndrome that manifests within the first 28 days of life, presents with a range of signs and symptoms of infection. However, due to its non-specific presentation, diagnosing neonatal sepsis in hospital settings remains quite challenging. Neonates, in contrast to older patients, frequently have symptoms that can be confused with non-infectious conditions, making it difficult to quickly and precisely diagnose sepsis.

Difficulty in diagnosis has significant consequences since early and accurate diagnosis of newborn infections is crucial for improving outcomes and minimizing potential risks associated with extended or unnecessary antibiotic therapy (14).

An estimated 4 million newborn deaths occur annually as a result of neonatal sepsis, with the highest fatality rates primarily occurring in sub-Saharan Africa and South-Central Asia (5). These figures highlight the critical need for a highly sensitive, rapid, and affordable diagnostic method to reliably identify newborn illnesses. Given this, the current study attempted to determine specific parameters, or combinations of parameters, derived from laboratory tests and clinical presentations, that might be used as reliable indicators for the diagnosis of newborn sepsis. By establishing clearer diagnostic criteria, this study seeks to contribute to a more targeted approach to neonatal infection management, which may ultimately reduce neonatal mortality rates and lower the reliance on broad-spectrum antibiotics, helping to lower the spread of antimicrobial resistance.

The study included 219 clinically suspicious patients for neonatal septicemia below the age of 28 days. The clinical profile of the mother and neonate, fetomaternal sepsis risk factors, sepsis screen, and outcomes were studied. Out of the total suspected cases,116 neonates were positive for sepsis, and 103 were negative for sepsis based on blood culture results, along with the clinical guidelines.

Almost every neonate showed a single neonatal clinical sign associated with sepsis. There were 53% of neonates identified as having sepsis, with a majority of the male population (58.50%). The male-to-female ratio was 1.28:1. The reason behind this sex-linked factor is the genetic difference between males and females. Host susceptibility mainly depends on the gamma globulins, which are synthesized by X-linked immune regulatory genes. Males have only one X chromosome, so they may be more prone to infections than females (15).

The results of this study indicate that preterm neonates, particularly those born before 28 weeks of gestation, are at significantly higher risk of developing sepsis, with an observed incidence rate of 95.20%. This may be the result of preterm newborns’ underdeveloped immune systems and organ function, which make them vulnerable (16). Furthermore, 88% of neonates who had sepsis were categorized as having a very low birth weight (less than 1 kg), indicating a negative relationship between the risk of sepsis and birth weight. Low birth weights, which are often linked to preterm births, make it more difficult for the newborn to establish an effective immune defense, making them more susceptible to infection (16).

Moreover, the study revealed that 62.80% of neonates with sepsis required resuscitation at birth, while 60% experienced meconium aspiration. These results imply that some particular delivery issues, either because of impaired respiratory function or extended exposure to potentially infectious substances during resuscitation efforts, may predispose newborns to sepsis. Meconium aspiration in neonates can cause inflammation of the lungs and airway obstruction, making the environment more prone to infection. To facilitate early intervention and lower sepsis-related morbidity, it is important to monitor at-risk neonates, particularly those who are pre-term, have low birth weight, or have complications during delivery (17).

The results of this study indicate that a significant proportion of neonates (82%) were born to mothers with at least one maternal risk factor. These results highlight the significant impact that maternal health has on neonatal outcomes, especially the onset of sepsis. Among the conditions observed, prenatal steroid exposure was the most common, affecting 70.70% of neonates with sepsis. Preterm mothers often get prenatal steroids to promote the development of fetal lungs. Depending on the dosage and timing, prenatal steroids may have both beneficial and negative effects (18).

In this study, several clinical signs were notably more common in neonates with sepsis compared to those without. Apgar scores <7 in 1^st minute (73.60%), <7 in 5^th minute (83.30%), and <7 in 10^th minute (91%) in the sepsis group. Apgar score is a key indicator of neonatal adaptation to life outside the womb. A score below 7 is often indicative of poor cardiovascular and respiratory performance, and this may be the reason why they are more prone to sepsis conditions than others. Temperature instability was seen in 66.67% of sepsis neonates, further emphasizing the systemic nature of the infection, as neonates with sepsis often struggle with maintaining normal body temperature (19). Similarly, bradycardia, observed in 60% of neonates with sepsis, is another common manifestation in septic infants and can result from systemic inflammation and circulatory compromise. Hypotension, noted in 77% of sepsis cases, shows a severe decline in cardiovascular function, often due to the systemic inflammatory response triggered by infection. These clinical findings highlight the need for monitoring and early intervention in neonates, as these signs are critical for the timely identification and management of sepsis, which can significantly affect neonatal outcomes if not addressed promptly.

In this study, Coagulase-negative Staphylococci (CoNS) were the most predominant organisms isolated from positive blood cultures in neonates with sepsis (57.80%), followed by Acinetobacter spp. (11.20%). Acinetobacter is an emerging pathogen in neonatal sepsis, particularly in intensive care units, where it can cause severe infections due to its resistance to multiple antibiotics (20). Group A Streptococcus (1.70%), diphtheroid, and Micrococcus spp. were among the least isolated organisms (1.72%).

Except for total bilirubin (P<0.001) and indirect bilirubin (P<0.001) levels, none of the other biochemical investigations showed statistically significant differences between the two study groups. A statistically significant difference was observed in the percentage of monocyte count with that of the non-sepsis group. The present study depicted that 64.40% of the patients suspected of sepsis have a CRP level of more than 5 mg/L. CRP levels have been widely used as a diagnostic tool in infections and inflammatory conditions, with higher levels often correlating with the severity of sepsis. CRP is known to rise quickly in response to bacterial infections, making it a useful marker for early detection of neonatal sepsis.

The fatality rate was found to be 89.50% in the sepsis group, while two deaths (10.50%) were reported in the non-sepsis population. Regarding infant mortality, there was a significant association between extremely low birth weight <1 kg and gestational age <28 weeks of life.

Applying binary logistic regression analysis, the following showed a significant effect on the risk of neonatal sepsis: gestational age 1 group (<28 weeks), Apgar score <7 at 5 minutes, CRP values (<5) of day 0, and monocyte percentage.

The diagnostic performance of the final logistic regression model was evaluated using ROC curve analysis, which yielded an AUC of 0.69 with a 95% confidence interval of 0.62–0.79. This indicates a fair level of discrimination between neonates with and without sepsis. Although the AUC falls within the modest range, the upper bound of the confidence interval approaches the level of good diagnostic performance, suggesting that the model has potential for early sepsis identification and risk stratification in clinical settings. With further validation in larger and more diverse populations, the model may be refined to enhance its predictive accuracy and contribute meaningfully to clinical decision-making in neonatal care settings. In conclusion, the findings of this study provide information that can be interpreted to assist pediatricians in making decisions when treating neonates suspected of sepsis. Healthcare professionals can evaluate the severity of infection and decide the most suitable course of treatment by detecting important clinical and biochemical markers such as gestational age, Apgar scores, CRP levels, and monocyte percentage. For high-risk newborns with extremely low birth weight or prematurity, early detection of sepsis is essential to enhance survival rates and reduce complications. These results further highlight the significance of timely and targeted measures, such as supportive care and antibiotic therapy, to improve outcomes in neonatal sepsis. The overall prognosis of infants can be enhanced, and mortality will be lowered by implementing these diagnostic and treatment procedures into practice.

Conclusions

Out of 219 cases studied, 52.96% were blood culture positive. Prematurity, preterm labor (<28 weeks), prenatal steroid exposure, extremely low birth weight (<1 kg), increased total and indirect bilirubin levels, and neonates who had low Apgar scores at 1st, 5th, and 10th minutes were more prone to neonatal sepsis. The current study found that signs and symptoms of neonatal sepsis were generally nonspecific and may be clinically indistinguishable from those occurring in non-infectious conditions during the neonatal period. Gram-positive bacteria were more common than gram-negative bacteria, which caused sepsis.

Hematological parameters showed limited value in the diagnosis of bacterial sepsis. Gestational age (<28 weeks), Apgar score <7 at five minutes, CRP values (<5) of day 0, and monocyte% were identified as the best predictors of neonatal sepsis in a significant binary logistic model.

Limitations

The study has several limitations. Incomplete or missing data from laboratory and clinical records posed a practical challenge and may have introduced selection bias or reduced statistical power. Although the study included 219 neonates from two centers, this sample size may not fully capture the variability in larger, more diverse populations. In addition, procalcitonin testing was not performed for all neonates due to cost limitations. If it had been included, it may have improved the sensitivity and overall accuracy of sepsis diagnosis.

Recommendations

It is recommended to perform essential newborn care for neonates suspected of sepsis and arrange appropriate follow-ups until the end of the neonatal period. Furthermore, early detection using sensitive and specific laboratory markers and the management of infection/inflammatory conditions appropriately are recommended. In addition, studies in different epidemiological regions with different epidemiological settings should confirm the generalizability of these study findings.

Acknowledgments

We wish to express our sincere gratitude to the Director, Medical Officers, Nursing Officers, Medical Laboratory Technologists, staff, department head, and the staff of the medical record room of the Castle Street Hospital for Women and Colombo South Teaching Hospital for their guidance and unwavering support in carrying out our study at their hospitals. We are also thankful to all the research participants and everyone else who contributed to the success of this research.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://pm.amegroups.com/article/view/10.21037/pm-25-14/rc

Data Sharing Statement: Available at https://pm.amegroups.com/article/view/10.21037/pm-25-14/dss

Peer Review File: Available at https://pm.amegroups.com/article/view/10.21037/pm-25-14/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://pm.amegroups.com/article/view/10.21037/pm-25-14/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by institutional ethics committees of Colombo South Teaching Hospital, Kalubowila and Castle Street Hospital for Women, Sri Lanka (Ethical number: 875) and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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