Global, regional, and national burden of neonatal infectious diseases from 1990 to 2021

Introduction

Neonatal infectious diseases, caused by bacterial, viral, or fungal pathogens, represent a major global health concern due to their significant morbidity and mortality rates among both term and preterm infants. Newborns are particularly vulnerable to infections due to their immature immune systems and underdeveloped barrier defenses. Pathogens can invade through multiple routes, including the skin, umbilical cord, conjunctiva, oropharynx, as well as gastrointestinal and respiratory tracts. Infants requiring prolonged hospitalization and advanced medical interventions, such as indwelling devices including intravenous lines, endotracheal tubes, urinary catheters, and shunts, are at an elevated risk of infection (1).

Severe systemic infections, classified as neonatal sepsis, can lead to life-threatening organ dysfunction and are the third leading cause of neonatal mortality, affecting 4 to 22 per 1,000 live births globally (2,3). Neonatal sepsis is categorized based on the timing of onset into early-onset sepsis (EOS) and late-onset sepsis (LOS). EOS typically manifests within the first 72 hours post-delivery, often resulting from vertical transmission from mother to infant, occurring either in utero or during delivery. In contrast, LOS arises from postnatal exposure to infectious agents within the community or hospital setting, typically emerging after 72 hours of life. Occasionally, pathogens acquired during delivery may only become symptomatic later (4,5).

Neonatal infectious diseases remain a critical public health challenge worldwide, contributing substantially to neonatal morbidity and mortality. Prior researches have indicated that the disease burden varies significantly across different regions. Low- and middle-income countries experience a disproportionately higher burden due to factors such as limited access to quality healthcare, inadequate sanitation, and higher rates of maternal infections (6,7). This study aims to elucidate the global, regional, and national trends in the incidence and disability-adjusted life years (DALYs) associated with neonatal infectious diseases from 1990 to 2021, stratifying these trends by sex, age, socio-demographic index (SDI), region, and country. We present this article in accordance with the STROBE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-57/rc).

Methods

Data source

The 2021 Global Burden of Disease (GBD) study, utilizing the latest epidemiological data and enhanced standardized methodologies, comprehensively assessed the health detriments associated with 369 diseases, injuries, and impairments, as well as 88 risk factors, encompassing 204 nations and territories (8). In this study, we extracted data on the incidence and DALYs for neonatal infectious disease from 1990 to 2021, categorized by country and region, using the Global Health Data Exchange Query Tool (http://ghdx.healthdata.org/gbd-results-tool). Regional and national stratification in this study was conducted based on the standard classification framework used by the GBD Study. Age-standardized rates (ASRs) were calculated based on the GBD global standard population to ensure comparability across regions and over time. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Joinpoint regression analysis

The study employed the Joinpoint regression analysis model, a statistical methodology widely used in epidemiological research to assess temporal trends in disease. This model effectively identifies and quantitatively characterizes significant change points in temporal datasets related to neonatal infectious disease incidence and DALYs. The model facilitated the computation of the annual percentage change (APC) and average APC (AAPC), including their 95% confidence intervals (CIs). A log-linear model was specified, and the number of joinpoints was determined based on the Bayesian Information Criterion (BIC), allowing for a maximum of four joinpoints. Statistical significance of trend changes was tested using a Monte Carlo Permutation method, with a significance threshold set at P<0.05. The joinpoint model thus enabled identification of critical time points where significant shifts in disease trends occurred and provided a robust quantitative assessment of temporal patterns.

SDI

The SDI is a composite measure developed by researchers from the GBD study to assess the socio-economic development level of a country or region. It integrates three key indicators: lag-distributed income per capita, average years of schooling, and the fertility rate among females under age 25 years. Each component is rescaled using selected health indicators to a uniform scale ranging from 0 to 1. A higher SDI value indicates better socio-economic conditions and is generally associated with improved health outcomes. Based on SDI quintiles, countries are categorized into five levels of development: low, low-middle, middle, high-middle, and high SDI.

Statistics analysis

The main objective of this study was to estimate the global trends in neonatal infectious diseases incidence and DALYs. We stratified global trends by sex, age and reported regional and national trends. Rates in our projections were displayed/100,000 people.

The estimated APCs (EAPCs) were calculated to evaluate the annual average change in ASRs using a generalized linear regression model. This model characterizes the temporal dynamics of ASR by establishing a relationship between the natural logarithm (ln) of ASR and time through the equation: Y=αβX+ε. Here, Y represents ln (ASR), α is the intercept, X corresponds to the calendar year, ε denotes the error term, and β reflects a linear positive or negative trend in ASR. The EAPC and its 95% CI are computed using this formula: EAPC = 100 × [exp (β) − 1]. Trend significance is evaluated through 95% CIs, an upward trend is inferred when the lower CI boundary exceeded 0, while a downward trend is concluded if the upper CI boundary fell below 0. Trends are considered statistically non-significant when the 95% CI encompassed 0 (8).

All statistical analysis and graphical representations were conducted using R software (version 4.3.2) and the Joinpoint Regression Program (version 5.2.0).

Results

Global trends

Globally, the incidence cases of neonatal infectious diseases decreased from 4,654,910 [95% uncertainty interval (UI): 4,590,168 to 4,726,630] in 1990 to 3,634,421 (95% UI: 3,580,612 to 3,694,913) in 2021 and the rate decreased from 46,365.63 (95% UI: 45,720.76 to 47,080.01)/100,000 in 1990 to 37,294.43 (95% UI: 36,742.27 to 37,915.17)/100,000 in 2021, AAPC −0.71 (95% CI: −0.76 to −0.65). The DALYs cases decreased from 23,935,968 (95% UI: 21,127,958 to 26,691,398) in 1990 to 18,579,984 (95% UI: 15,702,408 to 21,843,560) in 2021 and the rate decreased from 238,416.27 (95% UI: 210,446.84 to 265,861.96)/100,000 in 1990 to 190,657.60 (95% UI: 161,129.49 to 224,146.63)/100,000 in 2021, AAPC −0.70 (95% CI: −0.83 to −0.57) (Table 1).

Joinpoint regression analysis of the incidence and DALYs rate of neonatal infectious diseases from 1990 to 2021 were shown in Figure 1. We found the incidence rate significantly increased from 1994–1999 (APC =0.59). Since 2003, the incidence rate significantly decreased (Figure 1A). For DALYs, the rate significantly increased from 1990–1996 (APC =0.44), and decreased from 1999–2017 (1999–2005 APC =−0.77, 2005–2008 APC =−1.98, 2008–2013 APC =−1.03, 2013–2017 APC =−1.76) (Figure 1B).

Figure 1 Joinpoint regression analysis of the incidence and DALYs rate of neonatal infectious diseases from 1990 to 2021. (A) Incidence rate. (B) DALYs rate. *, the APC is significantly different from zero at the alpha =0.05 level. APC, annual percentage change; DALYs, disability-adjusted life years.

Sex and age groups

Figure 2 showed the trends in incidence and DALYs of neonatal infectious diseases by sex and age from 1990 to 2021. We found incidence and DALYs rate were decreasing overall. And there were gender and age differences, males and 0–6 days neonates had higher risk in neonatal infectious diseases.

Figure 2 Trends in incidence and DALYs of neonatal infectious diseases by sex and age from 1990 to 2021. (A) Incidence number and rate by sex. (B) DALYs number and rate by sex. (C) Incidence number and rate by age. (D) DALYs number and rate by age. DALYs, disability-adjusted life years.

SDI region

In 2021, the highest cases and rates of incidence and DALYs in neonatal infectious diseases were shown in the low SDI regions (Table 2, Figure 3A). And from 1999 to 2019, all SDI regions showed a decreasing trend in both incidence and DALYs rates, the most rapid decreases of incidence rate were low SDI region (EAPC =−1.14), of DALYs rate were high SDI region (EAPC =−2.78) (Table 2, Figure 3B).

Figure 3 Incidence and DALYs rates in 2021 and their EAPC from 1990 to 2021 by SDI. (A) Incidence and DALYs rates in 2021 by SDI. (B) EAPC of incidence and DALYs rates from 1990 to 2021 by SDI. DALYs, disability-adjusted life years; EAPC, estimated annual percentage change; SDI, socio-demographic index.

Regional trends

Across the regional level, we found in 2021, Southern Sub-Saharan Africa had the highest incidence rate (90,810.01/100,000), Western Sub-Saharan Africa had the highest DALYs rate (440,999.84/100,000) (Table 3, Figure 4A). In most regions, the incidence and DALYs rates of neonatal infectious diseases were decreasing, except Andean Latin America, Caribbean, Central Asia and Southern Sub-Saharan Africa. The most rapid decreases of incidence rate were High-income Asia Pacific (EAPC =−1.51), and of DALYs rate were Central Europe (EAPC =−5.82) (Table 3, Figure 4B).

Figure 4 Incidence and DALYs rates in 2021 and their EAPC from 1990 to 2021 in 21 regions. (A) Incidence and DALYs rates in 2021 in 21 regions. (B) EAPC of incidence and DALYs rates from 1990 to 2021 in 21 regions. DALYs, disability-adjusted life years; EAPC, estimated annual percentage change.

National trends

Across the national level, we found in most countries, the incidence and DALYs rates of the neonatal infectious diseases were decreasing (Figure 5). Africa had higher disease burden with lower SDI values. The most rapid decreases of incidence rate were Slovakia (EAPC =−2.51) and Israel (EAPC =−2.01), both were high SDI countries. The most rapid decreases of DALYs rate were Poland (EAPC =−8.54) and Serbia (EAPC =−6.43), also both were high SDI countries (Figure 5).

Figure 5 Incidence and DALYs rate in 2021 and their EAPC from 1990 to 2021 in 204 countries. (A) Incidence rate in 2021 in 204 countries. (B) EAPC of incidence rate from 1990 to 2021 in 204 countries. (C) DALYs rate in 2021 in 204 countries. (D) EAPC of DALYs rate from 1990 to 2021 in 204 countries. DALYs, disability-adjusted life years; EAPC, estimated annual percentage change; NA, not applicable.

Discussion

We used GBD database to analyze the worldwide distribution, regional variances, temporal trends, and socio-economic associations of neonatal infectious disease incidence and DALYs. Our study indicated that the trend in the burden of neonatal infectious diseases from 1990 to 2021 by incidence and DALYs is decreasing overall. Except Andean Latin America, Caribbean, Central Asia and Southern Sub-Saharan Africa, other regions defined by the GBD reported declines in incidence and DALY rates of neonatal infectious diseases. Among the 204 countries analysed, Slovakia showed the most decrease in incidence rate and Poland showed the most decrease in DALYs rate. In terms of SDI regions, both the highest cases and rates for neonatal infectious diseases were shown in the low SDI regions in 2021.

Severe systemic infections, classified as neonatal sepsis, is a life-threatening disease and associated with adverse neurodevelopmental outcome (9-11). A recent resolution by World Health Organization (WHO) listed sepsis as a key health-care priority for the coming decade and peak sepsis incidence occur in the extreme age groups, with newborn babies, young children, and elderly people at highest risk (12). Many previous studies have described the incidence of neonatal sepsis and the GBD. Studies have shown the incidence of neonatal sepsis was 1.8-fold higher in middle-income countries and 3.5-fold higher in low-income countries compared with high-income countries. And the incidence and mortality of EOS were higher than LOS (13). However, other neonatal infectious diseases such as enteric infections, upper respiratory infections, lower respiratory infections, and tetanus can also cause severe harm (14-17). Previous studies have shown that neonatal infectious diseases affect nearly 3.9 million neonates (18,19), but in our study we found in 2021, the number of incident cases of neonatal infectious diseases is 3,634,421, which is lower than previous studies, reflecting significant strides in neonatal health over recent decades. With advances in medical and socio-economic development, the burden of neonatal infectious diseases is decreasing.

From a global perspective, three-quarters of newborn deaths occur in the first week after birth, and the incidence of EOS were higher than LOS, therefore, conducting age-stratified research on incidence and DALYs associated with neonatal infectious diseases is significant importance. Our study indicated that 0–6 days have higher risk in neonatal infectious diseases, which aligns with the outcomes of previous studies.

There is also a gender difference, males have higher risk in neonatal infectious diseases. Previous multiple studies highlight a significant role of sex chromosome complement on overall immunity, many genes with immunomodulatory function are encoded on the X chromosome, lead males are generally more susceptible than females to infections (20,21). And this is consistent with our findings, male newborns have a higher burden of disease.

Additionally, significant variations were observed across different regions and countries. Previous studies have mentioned that in developing countries, the incidence of neonatal infectious diseases is higher, especially in Africa (22-25), and our study also confirm this. Through the analysis of SDI, regions and countries, we find the burden of neonatal infectious diseases is related to socio-economic development. With better socio-economic development have relatively lower disease burdens.

Neonatal infections have non-specific symptoms, thus diagnosing neonatal infectious disease can be challenging (26), repeated clinical assessments and laboratory investigations may help rule out infection and avoid unnecessary antibiotic treatment, but they are often unfeasible in low-income countries (24,27).

Health system coverage can affect neonatal health outcomes (28). Low- and middle-income countries are more likely to face challenges such as inadequate drinking water, poor sanitation, incorrect hygiene behaviours and weak healthcare infrastructure, and that remain critical determinants of the global disease burden, particularly among young children (29-33). Additionally, vaccine inequality exacerbates disparities in infectious disease outcomes, high-income countries secured vaccines faster, while low- and middle-income nations faced delays. Vaccination plays a critical role in preventing infectious diseases by stimulating the immune system to recognize and combat pathogens such as viruses and bacteria, is one of the most effective public health interventions.

Education and religion are related to disease prevention and treatment (34). In low- and middle-income countries, families and healthcare workers often lack the necessary knowledge and training to identify infections at an early stage, leading to delays in treatment (35,36). Certain religious practices may increase the risk of infectious diseases, for example, by rejecting vaccinations, refusing medical interventions, or promoting unhealthy dietary habits.

Antibiotic resistance has become a persistent global health threat (37). Low- and middle-income countries have misuse of antibiotics and population level resistance, that cause high resistance to antibiotics (38,39). Antibiotics resistance can lead to poor treatment of infectious diseases.

The data in the article are all sourced from the GBD database, this time-trends data can be used to monitor disease patterns and identify long-term trends by tracking the incidence and DALYs over time. In addition, can reveal disparities among different demographic groups and help forecast future disease burdens, guiding targeted interventions. This study provided a comprehensive analysis of the global, regional, and national burden of neonatal infectious diseases from 1990 to 2021 using the latest GBD 2021 data. The insights were valuable for policymakers and healthcare providers in developing more effective health policies, optimizing resource allocation, and implementing tailored healthcare interventions. This research made a contribution to global efforts aimed at reducing neonatal mortality and improving long-term child health outcomes, ultimately supporting the achievement of Sustainable Development Goal targets related to child survival and public health improvement.

There are several limitations to this study. Firstly, diagnosis of neonatal infections is challenging. Neonatal infections often manifest with a wide range of non-specific clinical signs, such as feeding intolerance, respiratory distress, episodes of apnea, bradycardia, increased oxygen requirement, lethargy, hypotension, temperature dysregulation, rash and prolonged inconsolable crying. These ambiguous presentations potentially resulting in both misdiagnosis and overdiagnosis, especially in Low- and middle-income countries (40). Secondly, the accuracy of burden estimation relies on the availability and quality of data from the GBD database, there may be a lack of access to the raw/original data for some countries, particularly in low- and middle-income countries. Thirdly, variations in the diagnosis and detection protocols across countries and over time may potentially impact the comparability of results.

Conclusions

Overall, the burden of neonatal infectious diseases has decreased worldwide. Males and 0–6 days neonates have higher risk. And the burden of neonatal infectious diseases is related to SDI values, high SDI countries have a relatively lower disease burden. Though the burden of disease is decreasing, regional and national differences are still significant, improving socio-economic levels and enhancing disease management are very important.

Acknowledgments

We highly appreciate the efforts of the GBD 2021 collaborators.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-57/rc

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-57/prf

Funding: This work was supported by The Key Laboratory for Screening and Diagnosis of Maternal and Child Genetic Disease of the Health Commission of Jiangxi Province.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-57/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.

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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