Neonatal mortality rates serve as a key indicator of a nation's healthcare quality and socioeconomic development [1]. The World Health Organization (WHO) estimates that approximately 2.5 million neonates die each year, with many of these deaths occurring in low- and middle-income countries [2]. Since 2000, the Millennium Development Goals (MDGs) have been adopted to reduce deaths from communicable diseases such as HIV, tuberculosis, and malaria (MDG 6); maternal mortality (MDG 5); and child mortality (MDG 4). Furthermore, Sustainable Development Goal (SDG) 3.2 specifically aims to quantify the preventable portion of child mortality. It states, “By 2030, end preventable deaths of newborns and children under 5 years of age, with all countries aiming to reduce neonatal mortality to at least as low as 12‰ LB (live births) and under-5 mortality to at least as low as 25‰ LB” [3,4]. Although neonatal deaths have decreased by 44 % since 2000, they accounted for a larger proportion (47 %) of all deaths among children under-5 in 2022 [5]. Globally, the mortality rate of children under-5 decreased from 71.2‰ LB in 2000 to 37.1 in 2019; however, the mortality rate of neonates declined at a slower pace [1].

Analyzing the factors contributing to neonatal mortality, high-risk elements can be identified, leading to the development of targeted preventive measures and intervention strategies aimed at reducing the neonatal mortality rate. Numerous studies have been conducted to highlight the multifaceted nature of this public health challenge [6–10], and to address the leading causes of neonatal deaths, which include preterm birth, birth asphyxia, and neonatal infections [11–13]. Recent analyses indicate that, while progress has been made in reducing neonatal mortality rates, disparities persist across different regions of the world [1,8,14].

The Global Burden of Disease Study (GBD), a collaborative initiative led by the Institute for Health Metrics and Evaluation (IHME) at the University of Washington, has been instrumental in tracking health trends and disparities worldwide [15]. To address this critical gap, this study provides an in-depth analysis of neonatal mortality from 2000 to 2021 using the latest data from the GBD 2021 [16,17]. The authors examine all-cause and cause-specific mortality rates across global, regional, and national levels, analyze temporal trends, identify leading causes, and assess their correlation with socioeconomic development. The findings would provide critical insights for formulating and optimizing public health policies to reduce global neonatal mortality rates.

In order to achieve the SDG 3.2 target, this study provided a comprehensive, multi-level analysis of all-cause and cause-specific neonatal mortality from 2000 to 2021. These findings reveal persistent and profound disparities: by 2021, only half of all countries had achieved the target neonatal mortality rate (≤12‰ LB), underscoring the urgent need for redoubled global effort. The analysis generates a detailed, evidence-based overview of the challenges by integrating cause-specific and HDI data across 204 countries. It also helps pinpoint where progress has changed by identifying key inflection points in the mortality trend around 2011 and 2017. These insights are vital for policymakers and health organizations, clarifying that overcoming the stagnation in neonatal survival requires tailored, dual-track strategies that address both the immediate biomedical causes of death and the underlying social determinants of health.

The global all-cause neonatal mortality rate has declined by an average of 2.1 % per year since 2000, with all regions reporting a decrease. Notably, while 92.6 % of countries experienced a reduction in mortality rates, nine countries maintained stable rates, and five countries saw an increase. This pattern of uneven progress is exemplified in Latin America as well. Despite a steady regional decline since 2000, a persistent gap remains compared to Europe and other high-income regions, alongside profound heterogeneity within the continent. By 2021, countries such as Brazil, Chile, and Uruguay had achieved the SDG 3.2 target, while others like Bolivia, Venezuela, and Paraguay still reported rates exceeding 12‰ LB. In this context of a concurrent global decline in fertility rates [23], ensuring the survival of every newborn becomes even more critical, underscoring the need to sustain and accelerate efforts to reduce neonatal mortality.

Although most regions experienced a broad decline in cause-specific neonatal mortality from 2000 to 2021, several high-income regions reported counterintuitive increases in specific infectious causes. For instance, sexually transmitted infections excluding HIV rose significantly in Australasia and Western Europe, and diarrheal diseases increased in Australasia, Western Europe, and Central Europe. In fact, sexually transmitted infections continue to be the most frequently reported condition to the Australian National Notifiable Diseases Surveillance System, and the numbers continue to rise [24]. The observed increase in mortality from specific infections in several high-income regions is notable and warrants consideration. One possible contributor is the growing challenge of antimicrobial resistance, which can complicate treatment and worsen outcomes for neonatal infections [13]. Additionally, improvements in disease surveillance and diagnostic capabilities over the study period may have led to more complete identification and reporting of cases that were previously undetected. Shifts in maternal demographic and health profiles — such as increasing maternal age and rising prevalence of chronic conditions — may also influence neonatal susceptibility to infection [25].

Neonatal disorders, particularly preterm birth and birth asphyxia, remained the leading causes of death globally in 2021, consistent with prior estimates [1]. However, in the Republic of Moldova, neonatal sepsis and other infections emerged as the primary causes. Although a decreasing trend in the mortality rate of neonatal sepsis and other infections was observed globally from 1990 to 2019, an increasing trend in incidence was noted among neonates [26]. These findings highlight the need to strengthen infection prevention, antimicrobial stewardship, and access to essential treatments, especially in regions where infectious causes remain predominant.

The joinpoint regression identified 2011 and 2017 as significant inflection points in the global decline of neonatal mortality. This nonlinear trajectory suggests that the drivers of progress may have shifted around these periods. The initial steeper decline (pre-2011) likely reflects broad successes in scaling up fundamental interventions, such as skilled birth attendance, neonatal resuscitation, and immunization against major infectious diseases [14]. The slowdown or change in trend thereafter may indicate that further gains are increasingly dependent on tackling more complex and resource-intensive causes, such as preterm birth complications and congenital anomalies, which are now leading causes of death and have seen slower progress [1]. This underscores that sustaining progress requires a strategic evolution from broad, foundational programs to more specialized, integrated care systems capable of addressing the residual burden of disease [27].

The present findings reinforce the critical link between socioeconomic development and neonatal survival, as evidenced by the strong correlation with HDI [28,29]. This association highlights a fundamental inequity in the capacity to tackle major causes of death. For instance, managing complex conditions like congenital anomalies depends on advanced medical resources more accessible in high-HDI settings [30], while preventing deaths from infections or birth asphyxia through basic interventions relies on robust primary healthcare and community systems — core components of human development itself [31]. Thus, elevating HDI is not a separate endeavor but a prerequisite that enables the effective implementation of cause-specific interventions across all settings.

Several limitations should be considered when interpreting the present findings. First, the present analysis is based on modeled estimates from the GBD 2021 study. Although GBD employs rigorous methods to integrate diverse data, the accuracy of estimates in regions with limited vital registration depends on modeling assumptions, as indicated by the wide UI in these areas. Second, the ecological design of the present study limits causal inference. The use of population-level data prevents us from examining individual risk factors or directly attributing mortality changes to specific interventions. Third, while the authors report cause-specific mortality, this analysis does not explore the underlying socioeconomic, behavioral, or health-system drivers of these causes, which are essential for designing fundamental interventions. Finally, the present data extends only to 2021 and therefore do not account for the potential effects of the COVID-19 pandemic on neonatal health systems and outcomes.

In conclusion, this study is poised to make a significant contribution to the field of neonatal health by providing a comprehensive analysis of all-cause and cause-specific mortality rates. The results indicate that, although there has been a significant reduction in neonatal mortality since the 21st century, the absolute number of neonatal deaths remained at 2.19 million globally in 2021. By that year, only 58.8 % of countries had achieved the SDG 3.2 goal. These findings emphasize the need for continued efforts to reduce neonatal mortality, particularly in low- and middle-income countries.

The data on all-cause and cause-specific neonatal was obtained from GBD 2021 (https://vizhub.healthdata.org/gbd-results/). The data of HDI at the national level were collected from the United Nations Development Programme (https://hdr.undp.org/data-center/human-development-index#/indicies/HDI).

The study used publicly available data and did not involve identified human information; therefore, no ethics approval or informed consent was needed.

This work was supported by the Senior Medical Talents Program of Chongqing for Young and Middle-aged (No. YXGD202401), and CQMU Program for Youth Innovation in Future Medicine (W0182). The funder has no role in the conceptualization, design, data collection, analysis, decision to publish, or preparation of the manuscript.

Dongqing Gu: Writing – original draft, Data curation, Methodology, Formal analysis, Funding acquisition. Xiaofei Zheng: Writing – original draft, Validation, Methodology, Formal analysis. Yan Zhou: Data curation. Fengjie Tan: Data curation. Rui Gui: Writing – review & editing, Validation, Methodology. Linna Wei: Writing – review & editing, Validation, Methodology. Lubin Liu: Writing – review & editing, Validation, Project administration.