Invasive group B Streptococcus (GBS) diseases in neonates and infants are categorized into two types: those occurring within the first week of birth (0–6 days) are defined as early-onset disease (EOD), while those developing between one week and three months after birth (7–89 days) are referred as late-onset disease [1, 2]. Risk factors for EOD include central venous catheters, other invasive medical devices, prolonged hospitalization, preterm membrane rupture, amnionitis, multiple (more than three) vaginal examinations during labor, maternal fever during labor, or any other infection during labor, and neonates with aspiration of meconium, low, very low, and extremely low birth weights, and preterm birth [3]. Most EOD cases result from the ascending spread of GBS colonizing the maternal genitourinary tract into the amniotic fluid [4], which can lead to severe infections such as bacteremia and meningitis [5]. Because these GBS EOD infections likely result in severe infection in neonates, intrapartum antibiotic chemoprophylaxis (IAP) was introduced in the United States in 1996 and revised in 2002 to prevent infection [6]. IAP, recommended by the Centers for Disease Control and Prevention, has significantly contributed to reducing the incidence of GBS EOD in the United States from 0.37 to 0.23 per 1,000 live births [1, 5].

Preterm birth neonates are at high risk of EOD [3], and recent guidelines have prioritized the use of noninvasive respiratory support for preterm neonates; however, mechanical ventilation is still considered for completion of brain maturation [7, 8]. However, this procedure has been performed with great caution due to the inevitable physiological instability that occurs during the intubation process and the continued risk of ventilator-associated pneumonia even upon successful intubation [9, 10].

Currently, routine antenatal GBS screening is not recommended; instead, clinical risk-based IAP is used in South Korea [11]. The epidemiology of infant GBS infections, including the overall prevalence and incidence of EOD, has not been studied recently, making it difficult to determine their current status. This longitudinal, long-term, retrospective study aimed to investigate the incidence and distribution of GBS-related EOD in a tertiary care hospital in Wonju, South Korea.

Laboratory data were reviewed for all neonates aged <7 days admitted to the Wonju Severance Christian Hospital (WSCH) from January 2001 to December 2022. Additionally, the electronic medical records (EMRs) of the 12 neonates from whom GBS was isolated were specifically examined. The numbers of live births from 2001 to 2022 were also extracted for analysis. All the data were automatically decoded. For GBS detection, plausible colonies on 5% blood agar plates were tested for the Christie-Atkins-Munch-Peterson reaction and agglutination using the Streptex GBS reagent (Wellcome Diagnostics, Dartford, England). Antimicrobial susceptibility tests were performed using the CLSI-recommended disk diffusion and microbroth dilution tests, as appropriate. If GBS was identified in different specimen types from the same patient, each case was analyzed separately. The EOD was defined as GBS occurring within the first week of birth (0–6 days). Neonates born at 37 or more completed weeks of gestation were categorized as full-term, and those born below that point were defined as premature. If a bacterium other than GBS was identified within seven days of life, it was defined as a co-infection. This study was approved by the Institutional Review Board of the Yonsei University WSCH for simple data analysis (CR322158). Data analysis was performed using the R statistical software (R Foundation for Statistical Computing, Vienna, Austria). Statistical differences between the dead and live neonates were also examined. The Fisher’s exact test was used for nominal variables, and the Wilcoxon signedrank test was used for continuous variables.

The number of live births in WSCH decreased from 842 in 2001 to 401 in 2022. The average incidence of GBS EOD per 1,000 live births in inborn neonates over 22 years of age was 0.38. When applying the incidence based on the birth rate of the research institution to outborn neonates, the overall incidence increased to 1.14 (Fig. 1). In 2001, 2012, 2013, 2016, and 2021, one neonate each year tested positive for GBS EOD infection. In contrast, in 2010, 2011, and 2015, two neonates each year were confirmed positive. The neonates labeled 6, 9, 10, and 12 were born at WSCH, while the remaining patients were born at other hospitals. The remaining neonates were transferred shortly after birth or a few days later. Among the 12 neonates who tested positive for GBS EOD, the sex ratio was 1:1, and five of them were premature. All neonates were admitted to the neonatal intensive care unit (NICU), and among those born prematurely, three died. Dead and live neonates showed significant differences in gestational age (P=0.018), maturity (P=0.045), birth weight (P=0.018), and ventilation therapy (P=0.018) (Table 1).

GBS was identified simultaneously in the intubation tube and blood of neonate 12, whereas other neonates had GBS in only one specimen. There was no significant difference in the presence of GBS in blood samples between dead and live neonates; however, a significant difference was observed in the intubation tubes (P=0.045). Neonates 8 and 11, in whom GBS was identified in urine, were confirmed to have Staphylococcus aureus (SAU) and Escherichia coli (ECO) in urine simultaneously, but neonates survived. In contrast, neonate 1, in whom SAU was concurrently identified in the blood, and neonate 12, who had ECO coinfection in both the intubation tube and blood, died. There was no significant difference between the dead and live groups in the presence of co-infections (P=0.236). However, the simultaneous identification of other pathogens with GBS in the blood was significantly different between the two groups (P=0.028) (Table 1).

The antimicrobial susceptibility test (AST) conducted for GBS from 2001 to 2022 included penicillin (PEN), ceftriaxone (CRO), vancomycin (VAN), erythromycin (ERY), clindamycin (CLI), and levofloxacin (LFX). All GBS isolates were susceptible to PEN, CRO, and VAN. Among the GBS isolates identified in the nine live neonates, resistance to ERY and CLI was observed in one and two cases, respectively. Resistance to LFX was observed in two of the three dead and nine live neonates. Antimicrobial resistance was not significantly associated with survival (Table 1).

Among the five premature neonates, four were female. Neonate 10 had a gestational age of 35+2 (week+day), with birth weight in the 10–25th percentile range, but survived. Neonate 6 had a gestational age of 28+5 and birth weight in the 75–90th percentile range, leading to survival. Both neonates 1 and 12, who died, had birth weights below the 10th percentile, with neonate 12 having GBS identified in the intubation tube. Neonate 9, a male, had a birth weight in the 50–75th percentile range but died after GBS was identified in the intubation tube.

Park et al. [11] investigated GBS infections in newborns aged 0–90 days at 14 university hospitals in South Korea from 1996 to 2005. They found that the number of EOD cases increased gradually from one case in 1996 to six in 2005. However, in a study on neonatal sepsis by Shim et al. [12] at a centrally located university hospital in the capital city from 1980 to 2005, there were no cases of EOD. Our study investigated GBS EOD patients over 22 years at a tertiary hospital since 2001. GBS EOD cases were sporadic but increased as the year progressed. The mortality rate of infants infected with GBS EOD in the United States from 2006 to 2015 was 6.9% [1]. Another study in Norway conducted during 1996–2012 reported a one-year mortality rate of 7.0% for infants infected with GBS, with rates of 13.9% for premature and 4.1% for full-term infants [13]. One study with 37 infants at two Korean university hospitals reported four deaths, a mortality rate of 10.8%, with three of the deaths occurring prematurely and one in full-term [14]. Another study revealed the mortality rate of Korean GBS EOD over ten years in a study by Park et al. was 20.7% (6/29) [11]. In the current study, 3 of the 12 infants examined died, resulting in a mortality rate of 25%, which is the highest mortality rate in similar studies. All 3 patients were premature infants, which is also the highest mortality rate for GBS infection in premature infants. The small number of children studied may explain these results. Still, a similar Korean study showed a mortality rate of 10.8%, suggesting that GBS mortality in Korea is not low compared to the worldwide rate.

In this study, four neonates acquired polymicrobial infections with different strains. Neonates 1 and 12, who developed polymicrobial infections in the blood, died, but neonates 8 and 11, who developed in urine, survived. Polymicrobial infections are generally associated with high mortality rates [15-17]. Although studies have shown that polymicrobial infections in urinary tract infections are linked to increased mortality [18], research specifically focusing on neonates is limited. Despite the small sample size in this study, two neonates survived despite developing polymicrobial infections in the urinary tract, highlighting the need for further research on polymicrobial urinary tract infections among neonates.

According to data analyzed by Madrid et al. [19] regarding the GBS EOD incidence per 1,000 live births worldwide, the incidence was 0.41 globally; in Asia, it was even lower, at 0.32. The case fatality rate (CFR), a measure of mortality, was 10.0% globally, ranging from 5.0 to 27.0% [19]. In Japan, which is geographically close to Korea, the nationwide institution-based GBS EOD incidence per 1,000 live births was 0.08, 0.09, and 0.09 for the periods 2004–2010, 2011–2015, and 2016–2020, respectively. The CFR during the same periods was 13.6, 4.5, and 6.5%, respectively [20]. Matsubara et al. [20] investigated nationwide institutional data and revealed that when the data were extrapolated to the entire population, the GBS EOD incidence decreased to 0.04. In this study, the GBS EOD incidence was higher than that in Japan but closer to the Asian average, whereas the GBS EOD CFR was much higher than Japan’s average of 7.4% (30/407) [19, 20]. As a tertiary hospital, the research institution encountered many GBS EOD neonates delivered outside the hospital during the study period. Compared to previous research findings, the results of this study should be interpreted as regional outcomes in South Korea to avoid overestimation.

The gestational age-specific birth weight curves are based on the data compiled by Lim et al. [21] from 2008 to 2012, involving 2,249,804 normal neonates. EOD infections are influenced by birth weight, which is a crucial factor [3]. In this study, all the deceased GBS EOD neonates were preterm neonates. Specifically, the birth weights of the two female neonates did not reach the 10th percentile, and their gestational ages were <29 weeks. The CFR for preterm GBS EOD in this study was 60.0%, higher than Japan’s 17-year average of 24.7% (22/89) [20].

Davidesko et al. [22] investigated 220,594 newborns and found that preterm infants had significantly higher morbidity from invasive bacterial and respiratory infections than full-term infants. Additionally, a study by Muhe et al. [23] examining the causes of death in 3,852 NICU-admitted preterm neonates found that respiratory distress syndrome was the most common cause of death. It can be inferred that preterm neonates requiring ventilation therapy and admission to the NICU inherently have compromised respiratory function due to immaturity of the lung and higher morbidity from infections. This was confirmed by the fact that all neonates with GBS identified in the intubation tube died during the study.

This study has several limitations. First, it was based on results from a single institution, and the number of patients with GBS EOD was too small to analyze the statistical significance effectively. Additionally, while maternal conditions significantly influenced GBS EOD, the data used for the analysis primarily focused on GBS-identified cases. This has led to a lack of information regarding maternal antenatal care. Furthermore, the lack of additional data on GBS serotypes or sequence types blocked investigations beyond GBS EOD case analysis. In this study, we did not examine the cause of death in preterm infants without GBS infection.

Further research should explore all causes of mortality in premature infants, not just those linked to GBS EOD infection. Our study included proportional information on GBS EOD in South Korea. However, this highlights the fact that GBS EOD continued to be detected and was associated with neonatal mortality. This indicates the importance of ongoing research on various factors that can protect newborns from infections beyond GBS EOD. In this regard, our study emphasizes the need for continuous research efforts to protect newborns from infections.