Global, regional, and national incidence and mortality of neonatal sepsis and other neonatal infections, 1990–2019

Background Neonatal infections, especially neonatal sepsis, are one of the major causes of incidence and mortality in pediatrics. However, the global burden of neonatal sepsis and other neonatal infections (NSNIs) remains unclear. Methods From the 2019 global disease burden study, we collected annual incident cases, deaths, age-standardized incidence rates (ASIRs), and age-standardized deaths rates (ASDRs) of NSNIs in the past 30 years. Analysis indicators included the percentage of relative changes in incident cases and deaths, and the estimated annual percentage changes (EAPCs) of ASIRs and ASDRs. Correlations were assessed between the EAPCs of ASIRs and ASDRs and social evaluation indicators, including sociodemographic index (SDI) and universal health coverage index (UHCI). Results Globally, the number of incident cases of NSNIs grew by 12.79% per year, and the number of deaths dropped by 12.93% per year. During this period, global ASIR of NSNIs increased by 46% annually on average, while ASDR decreased by 53% annually on average. The ASIR and ASDR of female NSNIs were consistently lower than that of male NSNIs. The EAPC of female ASIR was 0.61, nearly twice that of male ASIR, and female ASIR was growing rapidly. The same declining trends of ASDR were noted in males and females. The ASIR of NSNIs in high-SDI regions grew by an average of 14% annually from 1990 to 2019. Except for high-SDI regions, the ASIRs of other 4 SDI regions maintained a rising trend at a high level, and were improved in the past 10 years. The ASDRs of all 5 SDI regions generally showed a downward trend. The region with the highest ASIR of NSNIs was Andean Latin America, and Western Sub-Saharan Africa had the highest mortality. We found a negative correlation between EAPCs of ASDRs and UHCI in 2019. Conclusion The global health situation was still not optimal. The incidence of NSNIs remained high, and continues to rise. The mortality of NSNIs has decreased, especially in the countries/territories with high UHCI. Therefore, it is crucial to improve the overall awareness and management of NSNIs, and take interventions for NSNIs worldwide.


Introduction
Neonatal infections refer to the disease caused by the infection of pathogenic microorganisms (bacterial, viral, or fungal) in newborns, including neonatal sepsis, neonatal pneumonia and other neonatal infections, the most common pathogens of which include group B Streptococcus (GBS), Escherichia coli, and herpes simplex virus (HSV) (1,2). In the past decades, the mechanism of neonatal susceptibility to infection has been extensively studied. Neonatal immature immunity has been implicated for the higher neonatal infection rate (3). Preterm infants, compared with term infants, showed more immature immune responses and had a higher risk of infection (1,4,5). Another risk factor was neonatal environmental exposure, such as the maternal history of exposure to infectious diseases and bacterial colonization (6,7).
Neonatal infections, especially neonatal sepsis, are one of the major causes of incidence and mortality in pediatrics (2). In 2015, 600,000 of newborns died of infection worldwide (8). The 2016 Global Burden of Disease Study illustrated that neonatal sepsis and other neonatal infections (NSNIs) ranked third in neonatal deaths (243,000 deaths per year), and also ranked at the forefront of years of lost life across all age groups (9). It was reported that South Asia and Sub-Saharan Africa had the highest burden of neonatal sepsis, and the total incidence of culture-positive sepsis reported by South Asian hospitals was 15.8 per 1,000 live births (10). This was about 2-4 times higher than the rate reported in the United Kingdom and the United States (1,11). To reduce the incidence and mortality of NSNIs, measures should be taken based on national and regional incidence and mortality data for NSNIs and related factors.
As far as we know, there is no detailed and systematic study to illustrate the incidence and mortality of NSNIs, and the relationship with national socio-economic status and medical health level. Therefore, we collected Global Burden of Disease 2019 data to assess the global incidence and mortality characteristics of NSNIs and the relationship with national socio-economic status and medical health level, so as to provide a more comprehensive view for the development of global and regional interventions to prevent and control NSNIs health care policies.

Data source
The GBD 2019 study performed an all-round epidemiological assessment of 369 diseases and injuries (by age and sex) in 204 countries and territories worldwide in the past 30 years (12). The details of the GBD study have been reported before (12-14). The specific protocols are available in the GBD website (https://www. healthdata.org/gbd/about/protocol).
From the Global Health Data Exchange (GHDx) query tool, we collected annual incident cases, deaths, age-standardized incidence rates (ASIRs), and age-standardized deaths (ASDRs) of NSNIs in the past 30 years. A total of 204 countries and territories were included, which were divided into 5 sociodemographic index (SDI) regions and 21 GBD regions.

SDI
The SDI can quantitatively reveal the development status of the country/territory, and it is obtained by comprehensive evaluation of the overall fertility rates of women under the age of 25, the average education level of women aged 15 and above, and the per capita income (15). The SDI values range from 0 to 1. The smaller the SDI, the lower the level of sociodemographic development. The SDIs are provided in the GHDx. The SDIs of 204 countries and territories in 2019 (SDI 2019) are used for subsequent analyses.

UHCI
Universal health coverage (UHC) refers to the access of all people to the quality health services they need without experiencing financial hardship (16). The UHCI comprises 23 indicators, of which 4 are used to measure intervention coverage, and 19 are based on mortality to measure the quality of care obtained (16). The UHCI is scored on a scale of 0 (less developed) to 100 (most developed). The UHCIs are provided in the GHDx. The UHCIs of 204 countries and territories in 2019 (UHCI 2019) are used for subsequent analyses.

Statistical analysis
Analysis indicators included the percentage of relative changes in incident cases and deaths, and the estimated annual percentage changes (EAPCs) of ASIRs and ASDRs to characterize the trends in the incidence and mortality of NSNIs. The percentage of relative change in the number of incidents cases and deaths was calculated as reported (17). The formulas for ASIR and ASDR have been described previously (18,19). EAPC is a measure that reflects trends in the age-standardized rate (ASR) in a certain interval, and its calculation method was described before (20). The EAPC and lower boundary of 95% confidence interval (CI) both >0 indicated an upward trend. Conversely, when both the EAPC and the upper boundary of the 95% CI were lower than 0, ASR showed a downward trend.
In addition, the correlations between the EAPCs of ASIRs and ASDRs and social evaluation indicators (SDI 2019; UHCI 2019) were assessed by Pearson correlation analysis in 204 countries and territories to identify potential factors affecting EAPCs. All analyses were conducted using in R (version 4.1.2). The threshold value of P is 0.05.

Global trend in NSNIs from to
On a global scale, the number of incident cases of NSNIs showed a rise of 12.79% (5.59 million in 1990 to 6.31 million in 2019), and the number of deaths of NSNIs declined by 12.93% (260,000 in 1990 to 227,000 in 2019) ( Table 1). In males, the number of global incident cases of NSNIs grew by 10.09% annually, and the number of deaths dropped by 12.54% annually. In females, the number of global incident cases of NSNIs grew by 19.52%     Table 2). Overall, the ASIR showed an increasing trend year by year worldwide, with similar trend in males and females, and the ASIR of females was lower than that of males ( Figure 1A). It can be noted that the ASIR of male NSNIs (ASIR: 99.74 per 100,000) was higher than that of females (ASIR: 94.96 per 100,000) in 2019 ( Table 2). The EAPC of female ASIR was 0.61, nearly twice that of male ASIR, indicating that female ASIR increased rapidly. From 1990 to 2019, the global ASDR initially rose, plateaued between 1999 and 2005, and then declined ( Figure 1B). The trend was the same for males and females, with males having higher ASDR than females ( Figure 1B).

Regional trend in NSNIs from to
In high-SDI regions, the number of incident cases of NSNIs decreased by 9.17%, and the number of deaths of NSNIs decreased by 56.38% from 1990 to 2019 (Table 1) Table 2). The ASIRs of other 4 SDI regions all maintained a rising trend at a high level except for high-SDI regions, and there were heterogeneous trends between ASIRs and SDIs, for example, the ASIR of middle-SDI regions was not lower than that of low-SDI regions (Table 2, Figure 1C, Supplementary Figure 1A). The ASDR in all 5 SDI regions showed a downward trend on the whole, and the higher the SDI, the smaller the ASDR (Table 2, Figure 1D, Supplementary Figure 1B).
Among the 21 GBD regions, the number of incident cases increased in 10 regions and decreased in 11 regions; the number of deaths increased in seven regions and decreased in 14 regions ( Table 1). The regions where both incident cases and deaths were increasing were Southern Sub-Saharan Africa, Eastern Sub-Saharan Africa, Western Sub-Saharan Africa, Central Sub-Saharan Africa, and Oceania (Table 1). The largest increase in incident cases was in Central Sub-Saharan Africa (relative change = 80.75%), and in deaths in Oceania (relative change = 88.84%; Table 1). Besides, the number of incident cases (relative change = −42.38%) presented the most rapid decline in Central Europe, as did the number of deaths (relative change = −78.02%; Table 1). The region with the highest incidence of NSNIs was Andean Latin America (2019 ASIR: 174.90 per 100,000), and Central Latin America ranked second (2019 ASIR: 160.76 per 100,000) ( Table 2). In terms of NSNIs mortality, the threat was most severe in Western Sub-Saharan Africa (2019 ASDR: 8.18 per 100,000), and Eastern Sub-Saharan Africa ranked second (2019 ASDR: 6.88 per 100,000; Table 2 Figure 2A]. The ASIRs of Western Europe and Highincome Asia Pacific remained stable (Table 2, Figure 2A). The ASDR generally showed a downward trend, with only three regions showing an upward trend, including Central Asia, Southern Sub-Saharan Africa, and the Caribbean (Table 2, Figure 2B). The largest decrease in ASDR was noted in Central Europe (Table 2, Figure 2B).
In order to show the recent changes in the ASIRs and ASDRs of NSNIs, we obtained data from the past 10 years (2010-2019; Supplementary Table 1). In recent 10 years, the ASIRs in regions with high-middle and low-middle SDI were still on the rise, while those in regions with high SDI, middle SDI and low SDI tended to be stable and improved compared with the overall trend (the ASIRs of all SDI regions were on the rise from 1990 to 2019; Figures 2A,  C). The short-term and long-term trends of ASDRs in the 5 SDI regions were the same, showing a downward trend (Figures 2B,  D). In the 21 GBD regions, East and South Asia remained the top 2 in the rapid growth of ASIRs, while Central Europe and Southern Latin America maintained a continuous decline of ASIRs ( Figure 2C). Central Latin America, Eastern Sub-Saharan Africa, Tropical Latin America and Caribbean performed well. While the overall ASIRs (1990-2019) showed an upward trend, effective measures were taken in the past 10 years to successfully curb the upward trend of ASIRs, showing a downward trend (Figures 2A,  C). In Southern Sub-Saharan Africa, ASIR stopped growing and remained stable over the past decade ( Figure 2C). The ASDRs declined in all 21 GBD regions from 2010 to 2019, indicating that infant death caused by NSNIs has attracted attention in some regions where ASDR was still growing ( Figure 2D).

National trend in NSNIs from to
Among 204 countries and territories, China (1.11 million) and India (0.75 million) ranked the top 2 in the number of incident cases of NSNIs in 2019, accounting for about 29% of the number of global incident cases (6.31 million; Supplementary Table 2). The countries with the highest number of deaths were India (36,900) and Nigeria (27,200), accounting for 28% of the number of global deaths (226,500; Supplementary Table 2).
. /fpubh. .  Table 4). The ASDRs of eight countries or territories had a downward trend, and Mauritius had the largest increase [EAPC = 2.98 (95% CI, 1.23 to 4.77)], followed by Austria, Greenland and Singapore (Supplementary Table 4 Table 4). Compared with the data of the past 30 years, the ASIRs and ASDRs of NSNIs in some countries and territories were under control from 2010 to 2019.

Discussion
To the best of our knowledge, we for the first time comprehensively assessed global and regional long-term and shortterm characteristics in incidence and mortality of NSNIs. In this study, we found that the number of incident cases of NSNIs in the world grew by 12.79% per year, and the number of deaths dropped by 12.93% per year from 1990 to 2019. During this period, global ASIR of NSNIs increased by 46% annually on average, while ASDR decreased by 53% annually on average. The ASIR and ASDR of female NSNIs were consistently lower than that of male NSNIs. The EAPC of female ASIR was 0.61, nearly twice that of male ASIR, and female ASIR was growing rapidly. The same declining trends of ASDR were noted in males and females. For SDI regions, the ASIR of NSNIs in high-SDI regions grew by an average of 14% annually from 1990 to 2019. Except for high-SDI regions, the ASIRs in other 4 SDI regions maintained a rising trend at a high level. The ASDRs of all 5 SDI regions generally showed a downward trend. The largest decline was in the high-SDI regions. The highest ASIR of NSNIs was in Andean Latin America NSNIs are one of the major causes of 2.6 million newborn deaths worldwide every year (21). It is necessary and significant to improve the current situation of NSNIs. We need to better understand the characteristics of NSNIs, and actively enhance newborn care. In this study, we found that the global incidence of NSNIs showed rapid growth, and the mortality was generally declining. The incidence and mortality of males and females were in line with global trends. The incidence and mortality of NSNIs in females were lower than in males. The continuous increase in global incidence of NSNIs may indicate that the global health environment still needs to be improved. However, the decline of global mortality of NSNIs in the short term showed that the current maternal and newborn health care has achieved positive results (22).
We found that in high SDI regions, the ASIR showed the lowest increase, while the ASDR exhibited the highest decline. In other 4 SDI regions, we found no relationship between ASIR and SDI levels. For example, the ASIR in the middle-SDI regions was higher than that in the low-SDI regions. The ASDRs of all 5 SDI regions were generally decreasing, and the higher the SDI, the smaller the ASDR. This finding indicated that NSNIs had a high ASIRs and was growing rapidly, and the mortality of NSNIs was related to the educational level and economic level of the SDI regions. Although the ASIRs of Western Sub-Saharan Africa and Eastern Sub-Saharan Africa were not the highest (the highest was Andean Latin America and Central Latin America), the ASDRs were the highest. Consistent with our findings, Sub-Saharan Africa topped the list for the mortality of NSNIs (23). One possible reason was the high antimicrobial resistance of pathogens in Sub-Saharan Africa, and the efficacy of treatment was reduced (24). Ranjeva et al. evaluated the public health burden and economic pressure caused by neonatal sepsis in Sub-Saharan Africa, and believed that it was necessary to provide reasonable and appropriate health care for neonatal infections (25).
The high incidence and its high growth rate of NSNIs may indicate that infants are generally susceptible to pathogens and their infection capacity is increasing. The death of NSNIs may be related to the lack of timely diagnosis and treatment, and antibiotic resistance (26,27). Our findings illustrated that the mortality of NSNIs was relatively high in low-and middle-income countries. Families and health workers in low-and middle-income countries lack relevant knowledge and training to identify the early stage of infections, and the corresponding laboratory equipment is only available in hospitals, delaying the time of treatment (27,28). In addition, many people in low-and middle-income countries may not go to hospitals due to financial hardship, or may not have access to medical care. It was estimated that there were 8 million curable deaths in 2015, of which 96% occurred in lowand middle-income countries (29). A study estimated the quality of care in 81 low-and middle-income countries, and when highquality care was provided, it was believed that neonatal mortality would be reduced by 28% (30). UHCI is an indicator reflecting health coverage and nursing quality (16). Efforts to improve UHC can overcome these issues and promote health equity. From our results, it was observed that the UHCI was negatively correlated with the trend of ASDRs, that is, when the level of UHCI was high, the ASDR was generally in a downward trend. This was consistent with previous report (31). There is no doubt that the use of antibiotics is crucial to the treatment of infections. It is known that there is a clear correlation between antibiotic use and antibiotic resistance, and antibiotic resistance has become a persistent global health threat (32,33). On the one hand, there is the misuse of antibiotics and population-level resistance in lowand middle-income countries (34). On the other hand, low-and middle-income countries showed high resistance to antibiotics recommended by World Health Organization (WHO) (35). These are not conducive to neonatal outcomes. Therefore, we need to improve the overall awareness, timely diagnosis and management of NSNIs.
Finally, special attention should be paid to countries or territories where ASDR is still growing, including Mauritius, Austria, and Greenland (Supplementary Table 4). In these countries and territories with ASDR on the rise, it was imperative to accelerate the promotion of universal health coverage and strengthen antibiotic management.

Limitations
This study fills a gap in this area by providing the first comprehensive assessment of global and regional long-term and short-term characteristics of incidence and mortality of NSNIs, and the relationship with socioeconomic status and medical health level. However, we should recognize several limitations. First of all, the quality of the data limited our accurate description of the results. The possible bias made the results less robust. Second, the causes of NSNIs were notoriously complex. There was no specific pathogen infection data in the GBD study, so we could not estimate the contribution of different causes.

Conclusions
To sum up, the ASIR of global NSNIs gradually increased and the ASDR gradually declined from 1990 to 2019. In addition, the ASIR and ASDR of males were higher than those of females. Except for high-SDI regions, the ASIRs of other 4 SDI regions remained at a high level in this period. The ASDRs declined in all SDI regions. The ASDRs in Western Sub-Saharan Africa and Eastern Sub-Saharan Africa were the highest. The ASDRs were still growing in some countries and territories. Therefore, it is essential to improve the overall awareness and management of NSNIs, and reduce the morbidity and mortality of NSNIs worldwide.

Data availability statement
The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author.