Neonatal Sepsis: Within and Beyond China
Neonatal sepsis remains a significant cause of morbidity and mortality among newborns globally, with varying epidemiological and clinical characteristics across different regions. This article provides a comprehensive review of neonatal sepsis, focusing on its epidemiology, pathogen profiles, diagnostic approaches, and treatment strategies, with a particular emphasis on the context of China in comparison to other industrialized and non-industrialized countries.
Introduction
Neonatal sepsis is a critical condition that can lead to severe complications and death if not promptly diagnosed and treated. The global incidence of neonatal sepsis is estimated at 2202 per 100,000 live births, with mortality rates ranging from 11% to 19%. In China, the incidence is reported to be 25.6 per 1000 live births, with a decreasing trend in mortality from 0.4 to 0.1 per 1000 live births between 1996 and 2015. Despite this improvement, significant disparities in mortality rates exist across different regions in China.
Neonatal sepsis can be classified into early-onset sepsis (EOS) and late-onset sepsis (LOS) based on the timing of infection. EOS typically occurs within the first 3 to 6 days of life, while LOS occurs after 4 to 7 days and can extend up to the first 3 months of life. The pathogens responsible for sepsis can be acquired through in utero infection, maternal microbiota during delivery, or postnatal exposure to hospital or community environments.
Early-Onset Neonatal Sepsis
Incidences and Pathogen Profiles
In industrialized countries such as the United States, the incidence of EOS has remained relatively stable at around 0.8 cases per 1000 live births over the past two decades. Group B Streptococcus (GBS) and Escherichia coli are the predominant pathogens, accounting for 36% and 25% of EOS cases, respectively. However, there has been a marked reduction in GBS-related EOS and an increase in E. coli-related cases.
In contrast, the incidence of GBS-related EOS has plateaued or slightly increased in some other developed countries, such as the UK and the Netherlands. This variation may be attributed to differences in population structure, the emergence of new GBS clones, and modified diagnostic criteria.
In non-industrialized countries, the incidence of GBS-related EOS is less clear due to limitations in detection methodologies and difficulties in defining population denominators. However, studies in Asia have shown a steady decline in the overall and pathogen-specific incidence of EOS from 2005 to 2009, with a corresponding decrease in case fatality rates.
In China, the incidence of EOS among preterm infants less than 34 weeks’ gestation was reported to be 9.7 cases per 1000 live births. The leading pathogens were Gram-negative bacteria (GNB) such as E. coli (20.3%) and coagulase-negative staphylococci (CoNS) (16.5%), with GBS being relatively rare (2.5%). The case fatality rate of EOS in China was 19%.
Intrapartum Antibiotic Prophylaxis (IAP)
In the United States, the American College of Obstetricians and Gynecologists (ACOG) recommends universal maternal screening for GBS between 36 and 38 weeks of gestation and intrapartum antibiotic prophylaxis (IAP) for colonized women to prevent GBS-related EOS. This approach has significantly reduced the incidence of GBS-related EOS.
In Europe, a risk-based stratification approach is often used instead of universal screening. Despite IAP guidelines, the incidence of GBS-related EOS has slightly increased in some countries, such as the UK and the Netherlands.
In China, there are no standard guidelines for maternal GBS screening and neonatal GBS disease prevention. Some hospitals follow a risk-based strategy, while others adopt universal screening. The maternal GBS colonization rate in China ranges from 5.7% to 14.5%, and the incidence of invasive GBS disease in infants under 3 months of age is estimated to be 0.31 cases per 1000 live births. The majority of invasive GBS cases occur in term infants, and only 13.2% of GBS-case mothers received GBS screening during pregnancy.
Late-Onset Neonatal Sepsis
Maternal Postpartum Transmission of GBS
Late-onset sepsis (LOS) accounts for about one-third of neonatal GBS sepsis, with a higher case fatality rate compared to EOS (7.7% vs. 5.2%). Maternal postpartum transmission is an important source of GBS-related LOS. Studies have shown that infants born to GBS-colonized mothers who received IAP are less likely to be colonized at discharge but may become colonized later, highlighting the need for continued vigilance.
Gram-Negative Bacteria and Severe Neonatal LOS
Gram-negative bacteria (GNB) are associated with more severe clinical manifestations of LOS, including meningitis, and have a higher mortality rate, especially in very low birth weight (VLBW) infants. E. coli is the most common cause of bacterial meningitis in preterm infants and the second most common in term neonates in the UK. In France, E. coli meningitis is seven times more frequent in preterm than in term infants, with a median age at diagnosis of 14 days.
Pathogen Profiles of Community- and Hospital-Acquired Neonatal LOS
The pathogen profiles of community-acquired and hospital-acquired LOS differ significantly. In Switzerland, GBS and E. coli are the predominant pathogens in community-acquired LOS, while CoNS, Staphylococcus aureus, and other GNB are more common in hospital-acquired LOS.
In developing countries, the burden of neonatal infections is highly variable due to the lack of vital registries and surveillance systems. In South Asia and Southeast Asia, Salmonella enterica serotype Typhi, Streptococcus pneumoniae, and Haemophilus influenzae are commonly isolated pathogens, reflecting the lack of large-scale vaccination.
Neonatal Viral Sepsis
Viruses are common but underappreciated pathogens of neonatal sepsis. In a population-based study in South Asia, the mean incidence of viral infections was 10.1 per 1000 live births, with respiratory syncytial virus (RSV) being the leading pathogen.
Herpes Simplex Virus (HSV)
HSV can cause severe infections in neonates, with a frequency of 0.4% among infants tested for HSV. Most cases occur in the first four weeks of life, and prompt administration of acyclovir is critical for treatment.
Enteroviruses
Enteroviruses are increasingly recognized as causes of meningitis, sepsis-like disease, and fever without source in neonates. In China, enterovirus infection is common among febrile neonates, with PCR results being positive in 99.2% of stool samples and 44.3% of cerebrospinal fluid (CSF) samples.
Infectious Work-up of Neonatal Sepsis
A prompt and adequate infectious work-up is essential for the timely diagnosis of neonatal sepsis. Blood cultures remain the standard for diagnosing bacteremia, with 1-2 mL of blood recommended for optimal yield. Urine and CSF samples should also be collected in stable infants.
Biological markers such as procalcitonin (PCT), C-reactive protein (CRP), white blood cell count, and absolute neutrophil count (ANC) are not specific to bacterial infection but can aid in diagnosis. The Lab-score based on PCT levels, CRP levels, and urine dipstick results has been shown to be highly predictive of urinary tract infections (UTI).
Lumbar puncture (LP) is mandated in young febrile infants if sepsis is highly suspected. Direct examination of CSF samples under a microscope is crucial for determining the bacterial type and guiding empirical antibiotic therapy.
Empirical Treatment of Neonatal Sepsis
Empirical antibiotic treatment should be initiated as soon as neonatal sepsis is suspected. Amoxicillin/ampicillin combined with gentamicin is commonly recommended for treating EOS. If GBS is confirmed, amoxicillin/ampicillin should be continued, and gentamicin should be discontinued after 48 hours to prevent toxicity.
For hospital-acquired LOS, vancomycin is recommended due to the prevalence of methicillin-resistant CoNS. In cases of GNB infection, aminoglycosides are preferred, with escalation to third-generation cephalosporins or carbapenems based on local epidemiology and clinical presentation.
The duration of antibiotic treatment should be guided by culture results and clinical response. Antibiotic therapy should be discontinued if cultures are sterile, and non-specific biological markers alone do not justify prolonged use of antibiotics.
Antimicrobial Resistance
The overuse and misuse of antibiotics have led to the emergence of multi-resistant bacteria, particularly extended-spectrum beta-lactamase (ESBL) Enterobacteriaceae, in neonatal sepsis in China. Resistance rates to third-generation cephalosporins and carbapenems are alarmingly high, complicating both initial empirical treatment and secondary antibiotic strategies.
Supportive Treatment of Neonatal Sepsis
Supportive treatment for neonatal sepsis includes volume loading and vasopressors in cases of septic shock. However, unnecessary volume loading should be avoided to prevent complications such as brain and lung edema. Intravenous immunoglobulins (IVIG) have not been shown to be effective in reducing sepsis episodes or improving outcomes in neonates.
Conclusions
The epidemiology and pathogen profiles of neonatal sepsis vary significantly between countries and regions, necessitating tailored approaches to diagnosis and treatment. In China, the high antimicrobial resistance rate poses a substantial challenge, emphasizing the need for continuous monitoring and appropriate antibiotic stewardship. Early diagnosis, adequate empirical therapy, and prompt cessation of antibiotics in non-bacterial infections are crucial for optimizing neonatal health care.
doi.org/10.1097/CM9.0000000000000935
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