Global and regional burden of neonatal disorders (preterm birth, encephalopathy, jaundice, and sepsis), 1990–2021 and projections to 2050

1. GBD 2021 overview

We used data from the GBD 2021 to assess the global burden of neonatal disorders from 1990 to 2021 across 204 countries [10]. A detailed overview of the geographical classifications applied in this study are available in Supplementary Table 1. Within the GBD framework, we ensured both methodological consistency and comprehensive geographical representation in our assessment. Key metrics, including incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life years (DALYs) were stratified by age, sex, SDI levels, and region [10]. ASIR referred to the number of new cases per 100,000 population per year, adjusted to a standard age distribution, while ASMR was defined as the number of deaths per 100,000 population per year, also adjusted for age. ASDR was a combined measure of premature death and disability, standardized by age to allow for comparisons across populations. All analytical procedures were aligned with the Guidelines for Accurate and Transparent Health Estimates Reporting framework (Supplementary Table 2). The Global Burden of Diseases study used deidentified data, approved by the University of Washington Institutional Review Board (Study Number 9060) and Kyung Hee University for secondary analysis. Ethical considerations were upheld, adhering to the Declaration of Helsinki. Statistical analyses were performed using Python ver. 3.10.4 (Python Software Foundation) and R ver. 4.2.1 (R Foundation for Statistical Computing, Austria).

2. Case definition

In this study, neonatal disorders were classified according to the GBD 2021 guidelines using the International Classification of Diseases (ICD) codes. The relevant ICD-10 codes included B95.1, P00-P22.9, P24-P34.2, P36-P36.9, P38-P92.9, P94-P96, P96.3-P96.4, P96.8-P99.9 [11]. These codes were consistently applied to both mortality and incidence estimates, to ensure temporal and cross-regional comparability [9]. Neonates were defined as infants within 28 days after birth. Morbidity from neonatal disorders was modeled as 5 individual causes: neonatal preterm birth, neonatal encephalopathy due to birth asphyxia and trauma, neonatal sepsis and other neonatal infections, hemolytic disease and other neonatal jaundice, and other neonatal disorders, due to their differences in data availbility and pathology. Neonatal preterm birth was defined as any newborn baby born less than 37 completed weeks of gestation [11]. Neonatal encephalopathy due to birth asphyxia and birth trauma was defined as injury to the brain in the first few moments or days of life in an infant born at term [11]. Neonatal sepsis and other neonatal infections are referred to infections during the neonatal period that advance to a systemic bloodstream infection (sepsis) and infections that occur during the neonatal period [11]. Hemolytic disease of the newborn and other neonatal jaundice described several etiologies by which an infant develops extreme hyperbilirubinemia and can then go on to develop kernicterus [11]. The residual category of “other neonatal disorders” included diverse perinatal conditions such as intracranial hemorrhage, cardiovascular disorders of the newborn, and conditions related to maternal complications. However, congenital anomalies were not included in this category, as they were modeled separately within the GBD framework [11].

3. Input data

In GBD 2021, data sources used to estimate the number of deaths attributable to each condition were derived from vital registration and surveillance systems. Mortality modeling was limited to males and females under 5 years of age, categorized into 4 age groups: early neonatal, late neonatal, postneonatal, and 1–4 years [12]. Data points were flagged as outliers and excluded if they were implausibly high or low, or if they substantially conflicted with established age-specific or temporal patterns [13]. Since GBD 2019, estimates for neonatal disorders have incorporated data from the Child Health and Mortality Prevention Surveillance program, which operates in Bangladesh, Kenya, Mozambique, South Africa, and Mali. This program provides data on causes of death in children under 5 years of age through minimally invasive tissue sampling, a technique that allows tissue-level diagnosis in settings where full autopsy is not available [14]. Although verbal autopsy data were available, validation studies have shown that this method tends to be less accurate in determining causes of death among neonates [14]. As a result, the majority of verbal autopsy data were excluded from the GBD 2021. An exception was made for Indian states, where verbal autopsy data were retained due to the absence of alternative data sources [13,14].

4. Sociodemographic index

The SDI is a composite indicator that reflects the influence of social and economic development on health outcomes across populations. It is derived as the geometric mean of 3 key components: the total fertility rate among females under the age of 25, the mean years of educational attainment in the population aged 15 years and older, and lag-distributed income per capita, a smoothed measure of income adjusted over time to reflect long-term economic conditions [15].

5. Estimating the burden of neonatal disorders

Cause-specific mortality estimates for neonatal disorders were generated using the Cause of Death Ensemble model (CODEm) within the analytical framework of the GBD 2021 [16]. Estimates were stratified by sex, age group, geographic location, and calendar year. Prior to model implementation, input data were disaggregated by age and sex, and a meta-regression–Bayesian, regularized, trimmed (MR-BRT) approach was applied.

The CODEm framework employed 4 model classes, including linear mixed-effects regression and spatiotemporal Gaussian process regression. Ninety-five percent uncertainty intervals (UIs) were derived from 1,000 posterior draws with replacement. This modeling strategy enabled the generation of consistent and robust estimates of mortality and DALYs attributable to neonatal disorders, while accounting for variations in data quality and availability across countries and time periods.

6. Assessment of risk factor contributions to the neonatal disorders burden

The GBD 2021 evaluates the impact of modifiable risk factors on disease burden by estimating changes in DALYs under a TMREL. In GBD 2021 [11], the number and types of risk factors assessed for neonatal disorders varied depending on the strength of epidemiological evidence and the availability of exposure data. For each risk factor, exposure levels were estimated by location, age, sex, and year using regression-based modeling approaches. Relative risks were derived from pooled analyses of multiple study designs, including cohort studies, case-control studies, and interventional trials, for each risk–outcome pair. Population attributable fractions were then calculated using exposure estimates and relative risks, enabling the quantification of DALYs attributable to each risk factor. Attributable DALYs represent the estimated reduction in disease burden that would occur if the population were exposed to the theoretical minimum risk level. Mediation effects among multiple risk factors were accounted for; however, potential synergistic interactions were not included in the final estimates.

7. Annual percentage change

Temporal trends in the burden of neonatal disorders were evaluated using the annual percentage change (APC) [17]. A log-linear regression model was employed, specified as follows:

where y represents the natural logarithm of the neonatal disorders burden metric, x denotes the calendar year, β is the estimated regression coefficient, α is the intercept, and ε is the error term. The analysis was conducted using ASMR, ASIR, and age-standardized DALY rate (ASDR).

The APC was derived using the following equation:

Statistical significance was determined using a 2-sided P value threshold of ≤0.05 [8].

8. Projections to 2050

DALYs attributable to neonatal disorders were forecasted through 2050 by incorporating independent health determinants, sociodemographic metrics, and intervention-related variables [18]. Core covariates included the SDI, immunization coverage, and access to essential maternal and neonatal healthcare services. The forecasting framework was designed to reflect historical patterns, recent temporal shifts, and external shocks. Future risk factor trends were projected using summary exposure values (SEVs), which were subsequently used to estimate population attributable fractions and condition-specific DALY multipliers. A generalized ensemble modeling strategy was implemented, integrating 12 submodels based on 2 principal approaches: annualized rate of change models and a 2-stage spline model informed by MR-BRT methodology. To avoid inflation of risk estimates attributable to mediator effects, mediator SEVs were also computed using an ensemble approach.

1. Global burden of neonatal disorders

Fig. 1 presents the ASIR, ASMR, and ASDR for neonatal disorders across 204 countries in 2021. In a cross-sectional analysis of 2021 burden estimates, the ASIR, ASMR, and ASDR of neonatal disorders were estimated at 437.43 (95% UI, 433.20–441.95), 29.57 (25.37–34.26), and 2,941.98 (2,547.76–3,384.20) per 100,000 population, respectively, with neonatal preterm birth contributing the largest burden of neonatal disorders among the 5 subtypes. Regionally, the highest ASMR and ASDR were observed in Western Sub- Saharan Africa, showing rates of 56.74 (95% UI, 48.04–66.23) and 5,286.87 (4,504.47–6,147.67) per 100,000 population, respectively, whereas the highest ASIR was exhibited in South Asia (645.70 [636.10–656.13]). Detailed results of the ASIR, ASMR, and ASDR across different regions and nations are described in Supplementary Tables 1–4.

Fig. 1.

Global distribution of neonatal disorders burden for both sexes: (A) age-standardized mortality, DALYs, and incidence rate per 100,000 population in 2021; and (B) average APC in mortality, DALYs, and incidence rates of 1990–2021. DALYs, disability-adjusted life years; APC, annual percentage change.

Fig. 1 illustrates the APC of the ASIR, ASMR, and ASDR for neonatal disorders across 204 countries from 1990 to 2021. Throughout the study period, the ASIR, ASMR, and ASDR of neonatal disorders indicated a statistically significant downward trend. Regionally, East Asia exhibited the most substantial APCs in ASIR, ASMR, and ASDR for neonatal disorders among 21 GBD regions, presented as -0.31 (95% UI, -0.33 to -0.29), -0.81 (-0.84 to -0.76), and -0.75 (-0.79 to -0.70) per 100,000 population, respectively. Detailed results of the APC of ASIR, ASMR, and ASDR across different regions are described in Supplementary Tables 5–7.

2. Burden of neonatal disorders according to sex

Fig. 2 presents the ASIR, ASMR, and ASDR of major subtypes of neonatal disorders stratified by sex from 1990 to 2021. The ASIR for neonatal disorders was significantly higher in males (489.90 [95% UI, 484.15–495.69] per 100,000 population) compared to females (381.24 [376.42–385.90]) in 2021. Notably, ASDR of neonatal encephalopathy due to asphyxia and trauma was significantly higher in males (3,258.94 [95% UI, 2,780.65–3,785.91] per 100,000 population) than females (2,603.09 [2,274.86–2,954.93]) in 2021. Detailed results of the ASIR, ASMR, and ASDR for neonatal disorders are presented in Supplementary Tables 8–16.

Fig. 2.

Trends in age-standardized mortality, DALYs, and incidence rates of neonatal disorders by sex and cause in 1990–2021. DALYs, disability-adjusted life years; ASR, age-standardized rate.

3. Burden of neonatal disorders according to SDI

Fig. 3 describes the ASIR, ASMR, and ASDR for neonatal disorders including 5 subtypes in 2021, categorized by SDI. Among the 5 subtypes, neonatal encephalopathy exhibits the most pronounced disparities in both mortality and DALY rates across SDI levels, with mortality rates ranging from 17.77 (95% UI, 14.77–21.58) per 100,000 population in low-SDI countries to 0.66 (95%, 0.58–0.72) in high-SDI countries. The ASDR exhibited a similar pattern, ranging from 1,653.75 (95% UI, 1,388.53–1,994.40) per 100,000 population in low-SDI levels to 99.37 (86.55–112.88) in high-SDI levels. In contrast, the disparity in ASIR across SDI levels was most pronounced for neonatal preterm birth. Detailed results of the ASIR, ASMR, and ASDR for all neonatal disorders subtypes stratified by SDI groups are presented in Supplementary Tables 17–19.

Fig. 3.

Age-standardized mortality, DALYs, and incidence rates of neonatal disorders by SDI level and cause. DALYs, disabilityadjusted life years; SDI, sociodemographic index.

4. Burden of neonatal disorders risk factors

Table 1 presents the ASDR of neonatal disorders and its 5 subtypes in 2021, categorized by each risk factor. The highest ASDR of neonatal disorders was 2,227.54 (95% UI, 1,939.96–2,563.52) per 100,000 population by low birthweight, followed by short gestation (1,693.35 [1,463.77–1,941.92]), household air pollution from solid fuels (518.10 [410.06–641.68]), and ambient particulate matter pollution (204.81 [121.31–311.25]). Similar patterns were observed for 5 subtypes of neonatal disorders. In particular, preterm births attributable to both low birthweight and short gestation shared an identical ASDR of 1,253.53 (95% UI, 1,089.75–1,462.17) per 100,000 population. Detailed results of the ASDR for all neonatal disorders subtypes, stratified by risk factors, are presented in Table 1.

Table 1.

Age-standardized DALYs per 100,000 with 95% uncertainty intervals for neonatal disorders by risk factor

Supplementary Fig. 1 presents the percentage change in ASDR of neonatal disorders attributable to risk factors from 1990 to 2021, stratified by SDI levels and 21 GBD regions. The ASDRs attributable to all risk factors showed an overall decrease or stable trend across all SDI levels and regions. Among the 4 identified risk factors, household air pollution exhibited the greatest percentage change in ASDR. At the regional scale, the High-income Asia Pacific region experienced the greatest reduction in ASDR (-1.00 [95% UI, -1.00 to -0.99] per 100,000 population) associated with household air pollution. Detailed outcomes of the percentage change of ASDR for neonatal disorders according to risk factors, categorized by SDI and 21 GBD regions, are presented in Supplementary Table 20.

Supplementary Fig. 1 illustrates the proportion of ASDR attributable to risk factors for neonatal disorders. Among the 4 identified risk factors, low birthweight was the leading contributor to the inclusive burden of neonatal disorders from 1990 to 2021. At the regional scale, low birthweight contributed most substantially to the ASDR burden in the South Asia region by accounting for 0.84 (95% UI, 0.82–0.85) per 100,000 population. Detailed outcomes of the proportion of ASDR for neonatal disorders according to risk factors, classified by SDI and 21 GBD regions, are presented in Supplementary Table 21.

5. Forecasts of the burden of neonatal disorders in 2050

Fig. 4 presents the projected burden of neonatal disorders and their subtypes through 2050. The ASDR for neonatal disorders is forecasted to decrease substantially, from 2,361.65 (95% UI, 2,053.43–2,716.04) per 100,000 population in 2021 to 1,230.57 (950.09–1,590.15) in 2050. A similar pattern is projected across all 5 subtypes, with the most pronounced reduction for neonatal preterm birth, decreasing from 1,018.02 (95% UI, 885.47–1,187.59) per 100,000 population in 2021 to 457.21 (337.28–597.27) in 2050. Detailed projections for neonatal disorders and each subtype are presented in Supplementary Table 22.

Fig. 4.

Global trends in and projections for age-standardized DALYs per 100,000 for neonatal disorders by cause in 1990–2050 based on GBD 2021 estimates. DALYs, disability-adjusted life years; GBD, Global Burden of Disease Study.

1. Key findings

We investigated the global and regional burden of neonatal disorders and 5 subtypes using estimates from the GBD 2021. From 1990 to 2021, the ASIR initially increased slightly but then showed a sustained decline, while ASMR and ASDR consistently decreased across all subtypes and both sexes. Males have consistently exhibited a higher ASIR burden than females. Countries with lower SDI levels experienced a higher burden of neonatal disorders. Among the 5 subtypes (neonatal preterm birth, neonatal encephalopathy due to asphyxia and trauma, neonatal sepsis and other infections, hemolytic disease and other neonatal jaundice), neonatal preterm birth consistently accounted for the highest ASIR, ASMR, and ASDR across all SDI levels. Among the 4 identified risk factors (low birthweight, short gestation, household air pollution, ambient particulate matter), low birthweight contributed the most to the ASDR of neonatal disorders and their subtypes. It is forecasted that the ASDR of neonatal disorders and their subtypes will continue to decline by 2050.

2. Plausible mechanism

Males have consistently experienced a higher ASIR of neonatal disorders than females. The disparity was particularly pronounced in neonatal encephalopathy due to asphyxia and trauma, primarily due to different immunologic mechanisms among sexes [19]. Compared to females, males exhibit greater microglial activation, along with increased infiltration of peripheral leukocytes, elevated secretion of proinflammatory cytokines (i.e., tumor necrosis factor alpha and interleukin 1 beta), reactive oxygen species, and reactive nitrogen species [19]. Moreover, males show a greater association with perinatal risk factors, including emergency cesarean delivery and amniotic fluid contamination [20].

This study shows that disparities across SDI levels were more pronounced for ASMR and ASDR than for ASIR, emphasizing the importance of effective disease management in low-SDI countries. In these regions, where home births are still common, limited access to medical facilities such as emergency obstetric services and neonatal intensive care units is closely linked to higher neonatal mortality [8]. These disparities are driven by clinical factors such as maternal malnutrition, infections, lack of prenatal screening and vaccination, and limited medical resources, alongside socioepidemiological factors including rapid population growth, young maternal age, low educational attainment, and poverty [2,21]. Low birthweight contributed most significantly to the ASDR of neonatal disorders in low-SDI countries, largely due to its notable association with maternal health conditions such as malnutrition, anemia, and inadequate antenatal care [22]. It is also linked to increased risk of chronic conditions later in life, including breast cancer, hypothyroidism, adult-onset asthma, and cardiac hypertrophy, further contributing to the DALY burden [23].

The projected decline in neonatal disorders attributable to preterm birth by 2050 may be explained with improvements in maternal health, education, and healthcare access modeled in the GBD 2021 forecasts. These projections reflect long-term trends in SDI and other structural determinants that are expected to reduce the incidence and impact of preterm birth globally [15].

3. Clinical and policy implications

While overall mortality from neonatal disorders has steadily declined in recent decades, the rate of deaths attributable to low birthweight and short gestation remained markedly high in low-SDI countries. Despite the establishment of SDG 3.2 to reduce preventable child deaths, projections indicate that over 60 countries are unlikely meet the target by 2030 [24]. Therefore, practical implementation in these regions requires sustained international efforts that cover both epidemiological patterns and cultural contexts.

Given the inverse relationship between hospital delivery rates and neonatal mortality, the limited availability of emergency obstetric care and neonatal intensive care units in low-SDI countries presents a significant challenge [25]. Despite World Health Organization recommendations for universal emergency obstetric care access within 1 hour, coverage in sub-Saharan Africa remains as low as 37 percent [26]. Achieving global targets requires equitable health financing and improved quality of emergency obstetric care, including free antenatal and contraceptive services [27]. Concurrently, as 33.6% of births in sub-Saharan Africa still occur outside health facilities, policies should also prioritize supporting safe home deliveries through strategies such as community health worker visits, emergency referral systems, and the distribution of clean delivery kits [28]. Additionally, broader implementation of Kangaroo Mother Care, involving skin-to-skin contact and early breastfeeding, is essential to reduce infections and improve neonatal outcomes [29].

4. Comparison with previous studies

While previous studies have examined the global burden of neonatal disorders, their standpoint often has been limited. Most of the prior studies have focused on single causes such as neonatal preterm birth [8], sepsis [7], and hemolytic disorders [6], or have considered individual risk factors including low birthweight [30] and PM2.5 [5]. Moreover, previous studies provided a restricted understanding of the GBD, limiting their analysis to specific regions such as China [4] or Africa [3]. This narrow focus has restricted the multifaceted understanding of neonatal disorders across epidemiological and sociodemographic dimensions.

5. Strengths and limitations

This study is the first to systematically analyze the burden of all 5 subtypes of neonatal disorders attributable to risk factors using GBD 2021, with forecasts up to 2050. However, our study has several limitations to be considered. First, although this research primarily focuses on low-SDI countries due to their higher disease burden, the analysis includes all SDI levels to provide a balanced and comprehensive perspective. Second, this study underexamined subtypes with relatively lower burden in its analysis, such as neonatal sepsis and other neonatal infections, hemolytic disease and other neonatal jaundice, and other neonatal disorders, despite their growing epidemiological significance [31]. Third, the absence of incidence data for other neonatal disorders in the GBD 2021 dataset reduces the accuracy of statistical analysis for ASIR between different SDI levels. Moreover, grouping heterogeneous conditions under a single category may lead to misleading estimates. Fourth, the age weighting method in many national burden of disease studies used in the GBD statistics may underrepresent neonatal-specific determinants [32]. Additionally, sociodemographic factors such as marriage age, education, and cultural norms are often insufficiently represented as risk factors in the GBD framework, restricting a comprehensive understanding of disease causation [33]. Fifth, this research has disproportionately focused on low birthweight and short gestation, with less attention given to environmental factors such as air pollution [5]. Sixth, neonatal morbidity and mortality statistics are susceptible to reporting bias, particularly in low-SDI countries. Accurate diagnosis and documentation of neonatal illnesses and deaths are often challenging, especially in cases of non-institutional delivery [34]. Finally, the analysis was conducted primarily at the SDI and regional levels, with limited consideration of individual countries.

Despite these limitations, this study offers several remarkable strengths. To our knowledge, this is the first study to comprehensively quantify the burden of neonatal disorders attributable to risk factors across 5 subtypes using the GBD 2021. It incorporates multiple outcomes stratified by sex, risk factors, and SDI, enabling a multifactorial assessment of neonatal disorders. By examining age-standardized incidence, mortality, and DALY rates simultaneously, the study enhances comprehensive understanding of disease burden across different SDI levels and projects trend through 2050. Consistent with international targets such as SDG 3.2, this study offers foundational insights to inform future global strategies aimed at reducing the burden of neonatal disorders.

In conclusion, we are the first to comprehensively estimate the burden of neonatal disorders attributable to risk factors across 5 subtypes using GBD 2021, stratified by sex, causes, risk factors, SDI levels and GBD regions. Given that neonatal preterm births attributable to low birthweight and short gestation remain the leading cause in lower SDI regions, targeted interventions should be prioritized accordingly. Although the overall burden is projected to decline by 2050, the persistent disparities across SDI levels highlight the need for context-specific and practical policy responses.