Neonates with infections face significant challenges, as the outcomes for this population can be quite poor. ¹ Neonatal infections, particularly systemic infections known as neonatal sepsis, remain a prevalent concern. ² Neonatal sepsis is characterized by a systemic inflammatory response syndrome (SIRS) triggered by infection within the first four weeks of life. ^{3, 4} Due to the non-specific nature of initial clinical signs—such as tachycardia, fever, and drowsiness—neonatal sepsis can often be misdiagnosed as other neonatal conditions, including metabolic diseases, respiratory distress syndrome, and intracranial hemorrhage. ³ Furthermore, clinical manifestations such as respiratory distress, hypothermia, cyanosis, apnea, convulsions, and prolonged capillary refill time are closely associated with mortality related to neonatal sepsis, possibly linked to metabolic derangements and cardiovascular collapse. ^{5, 6}

Neonatal sepsis is a major health concern in neonatal health care units worldwide. ⁴ Neonatal infections account for more than one-third (36%) of all neonatal mortalities worldwide. ^{7, 8} The mortality rate of neonatal sepsis ranges from 9% to 65%. ⁹ Sepsis is the main cause of neonatal mortality, accounting for more than one million deaths each year worldwide. ^{7, 8} According to the World Health Organization (WHO), 2.4 million neonates die from neonatal sepsis, ¹⁰ with developing countries accounting for 40% of these deaths. ¹¹ In developed countries, mortality rates range from 5% to 20%, resulting in significant disability. ^{12– 15}

All organ systems undergo discernible physiological transitions and learn to respond to various external stimuli during the neonatal period, which means that this period is a period of high exposure, as they perform tasks necessary for survival outside the womb. ¹⁶ The immaturity of the immune system at this time, especially in premature neonates, lends different clinical, physical, and outcome characteristics to infections compared to other age groups. Furthermore, inherent factors such as poorly established and immature skin barriers, mucosal defense mechanisms, and blood-brain barriers contribute to the increased vulnerability of neonates to infection. Therefore, neonates are more susceptible to various pathogens. ¹⁷

Preterm birth, low birth weight, and prolonged rupture of membranes are known risk factors that increase the likelihood of neonatal sepsis-related mortality. ^{3, 18} In addition to these risk factors, studies have shown that low socioeconomic conditions can further increase the likelihood of neonatal sepsis mortality. This could be due to poor access to healthcare facilities or a lack of awareness of preventive measures for neonatal sepsis. ¹⁹ Clinicians should recognize these risk factors and take measures to prevent, diagnose, and treat neonatal sepsis to reduce morbidity and mortality. Herein, we performed a systematic review and meta-analysis to assess the risk factors of mortality in patients with neonatal sepsis.

This systematic review and meta-analysis were conducted following the reporting guidelines provided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) in 2020. ²⁰ Our research protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO), with registration number CRD42023456164.

Our analysis showed that history of invasive ventilation, requirement for inotropic support, low 1 ^st minute Apgar score, convulsive, poor feeding episodes, preterm birth, low birth weight, early onset sepsis, and lethargy was identified as significant risk factors for neonatal sepsis mortality ( Figure 3).

As proven in this study, neonates who experienced early onset sepsis (EOS) were approximately two times more at risk of mortality. This finding could be attributed to the rapid and severe progression of the condition leading to septic shock and eventual death, commonly seen in cases of EOS. ⁴² Nevertheless, a few studies have documented a higher mortality rate due to late-onset sepsis (LOS). ^{43, 44} The increased mortality rates observed in the LOS group were attributed to the performance of invasive procedures, extended hospital stay, and prolonged administration of antibiotics. ^{40, 45, 46} Neonates with sepsis and a history of invasive ventilation were 35 times more at risk for death, as observed in this meta-analysis.

Neonates with sepsis and a history of poor feeding were at risk of mortality four times. Breast milk, as a source of vitamin A and antibodies, helps fight infections in neonates. Sepsis in poorly fed neonates has been shown to engender hypoglycemia through the inhibition of gluconeogenesis, lactic acidosis, and increased glucose requirements. Thus, the risk of death was high in this group of neonates. ¹⁷ Neonates with sepsis who developed multiple organ failure were at a high risk of death. These neonates require inotropic drugs to support their cardiovascular system. ¹⁸ In our study, neonates who required inotropic support were 18 times at risk of mortality. The Apgar score is clinically used to evaluate hemodynamic impairment. It was performed in the 1 ^st minute as a screening tool to determine the need for early intervention. Low Apgar scores were correlated with increased mortality in neonates without congenital anomalies. ⁴⁷ Neonates with sepsis a low 1 ^st minute Apgar score were five times more at risk for mortality in this study.

As observed in this study, preterm birth and low birth weight (LBW) septic neonates increased the risk of neonatal sepsis mortality by three times each. The prevalence of sepsis was higher in preterm and LBW neonates, with a mortality rate of 17.6%. Preterm neonates with sepsis face higher complication risks due to their immature immune systems, leading to impaired humoral immunity and vulnerability in their early days. ⁴⁸ Mortality in this group of neonates is due to insufficient immunoglobulin synthesis, complement systems (C3 and C5), phagocytosis, and opsonization. ⁴⁹ The risk of mortality in preterm neonates with sepsis increases as birth weight decreases. ⁵⁰ LBW neonates are more vulnerable to sepsis due to the insufficiency of the immune system and the number of invasive and therapeutic procedures performed, leading to nosocomial infections. ⁵¹

Neonates with sepsis who presented with lethargy were twice at risk for mortality, while those who had convulsive episodes were four times at risk of death. Our conclusions are in accordance with those of previous studies. ^{5, 46} Similar to the observations of other authors, we found that sepsis neonates with lethargic and convulsive episodes had significantly higher mortality rates, which may be attributed to cardiovascular collapse and metabolic derangements. ^{41, 52– 55} Structural brain lesions, such as brain infarctions and hemorrhage, are aggravated by convulsive episodes, which govern the overall physiological and hemodynamic stability. Other conditions such as acute neonatal encephalopathy can also increase mortality in patients with sepsis ¹⁷

Our study has some limitations. Some of the limitations are: 1) The inclusion criteria of the studies, which were published exclusively in English, may limit their representativeness; and 2) Data regarding the risk of various adverse outcomes were derived from a limited number of studies. There is a need for large prospective studies with appropriate controls to further explore these issues.

In summary, we found through a meta-analysis that neonates with sepsis who had a history of using invasive ventilation, required inotropic support, had a low 1st minute Apgar score, had convulsive and poor feeding episodes, preterm birth, low birth weight, early onset sepsis, and lethargy were more at risk for death. Clinicians must be alert about this risk factor and employ early and personalized treatment strategies to increase effectiveness and minimize mortality.

Not applicable.