Global, regional, and national burden and trends of congenital birth defects from 1990 to 2021: epidemiological trends, health inequalities, and COVID-19 impact

Introduction

Birth defects encompass a broad range of structural, functional, or metabolic abnormalities that arise during prenatal development, affecting any part of the body and sometimes only becoming evident later in life. The World Health Organization (WHO) delineates hundreds of birth defects in the International Classification of Diseases (ICD), which lead to approximately 410,000 child deaths annually and impact over 60 million people globally (1). Birth defects represent one of the primary causes of mortality and disability of younger populations worldwide (2-4). Alleviating the burden of these defects is essential for achieving the goal of United Nations Sustainable Development Goal (SDG) 3.2, which targets a reduction in the global neonatal mortality rate to no more than 12 per 1,000 live births and the under-five mortality rate to no more than 25 per 1,000 live births by the year 2030 (5,6). Although the etiology of most birth defects remains unknown, for those with identified causes, their management is heavily contingent upon the accessibility of healthcare resources (7). Therefore, a comprehensive global assessment of the disease burden and epidemiological profiling of birth defects is essential for optimizing medical resource allocation and informing targeted public health interventions.

The phenotypic diversity and the intricate interplay of environmental, genetic and social factors in the etiology of birth defects pose significant challenges to global management due to birth defects (8). Consequently, monitoring the epidemiological trends of congenital birth defects across various global regions is an essential aspect of efforts to mitigate the burden of these conditions. Previous research has evaluated the epidemiological data of birth defects, but these studies have predominantly focused on geographic areas, neglecting a comprehensive global view. The mortality and disability rates associated with birth defects in different organs vary widely, making it essential to identify the optimal allocation of medical resources—whether for prevention, screening, treatment, or rehabilitation—for effective short-term and long-term medical planning. Existing global birth defect studies have not adequately analyzed the variance among different subtypes (9,10). Therefore, global epidemiological studies focusing on birth defects across various organ systems are indispensable for reducing the disease burden of birth defects. Over the past two decades, there has been a global call to action to eliminate health inequality in birth defect incidence between countries of differing income levels; however, the specific outcomes of these equity efforts remain largely unknown (11,12). A more nuanced quantification of health inequality in birth defects across nations with diverse socio-demographic development levels is imperative to inform the strategic distribution of medical resources. Moreover, the impact of viruses as teratogenic agents and the epidemiological shifts in birth defects amidst the global coronavirus disease 2019 (COVID-19) pandemic are fields that are not well understood and require further investigation (13).

The Global Burden of Disease (GBD) database, initiated in the early 1990s by the WHO and the World Bank, was created to offer a comprehensive framework for assessing global health. The most recent iteration of this database, published in The Lancet, facilitates global epidemiological trend analyses across a spectrum of diseases through an open, collaborative methodology (14). The GBD 2021 serves as an invaluable resource for epidemiological research (4). By extracting data from the GBD, the study can track the epidemiological impact of birth defects, measure regional disparities in their disease burden, and assess health inequities. The most recent edition of the GBD incorporates crucial data post-COVID-19 pandemic, offering insights that can inform the development of targeted programs, practices, and policies designed to alleviate the disease burden of birth defects.

Drawing on data from the GBD, this study delineates the epidemiological profiles of overall birth defects and 10 specific subtypes to assess the urgent prevention and treatment needs of each condition across diverse regions, age groups, and genders. Employing the health inequalities analysis, slope index of inequality (SII) and concentration index (CI), endorsed by the WHO, the study conducted a cross-national inequality analysis to shed light on the health disparities in birth defects linked to socio-demographic index (SDI). Lastly, this research scrutinized the incidence trends of birth defects before and after the advent of the COVID-19 pandemic. These comprehensive investigations offer a nuanced understanding essential for guiding the more strategic deployment of medical resources in the future.

Methods

Data acquisition from GBD study

The 2021 GBD database (https://ghdx.healthdata.org/gbd-2021), employing the latest epidemiological data and sophisticated statistical methodologies, comprehensively documented and estimated the disease burden attributable to 369 diseases, injuries, and impairments across 204 countries and territories (4). Core data sources include vital registration systems and birth certification records, standardized ICD-coded hospital discharge datasets, health insurance claims data, national and international population-based birth defect surveillance registries, high-quality epidemiological data from systematic literature reviews, as well as verbal autopsy and representative household survey data for low- and middle-income regions with incomplete civil registration systems, covering the full spectrum of birth defect prevalence and mortality outcomes. The GBD study has established a rigorous standardized methodological framework to ensure cross-country data equivalence and comparability. All cases are uniformly mapped to the ICD-10 coding range Q00–Q99 to unify diagnostic and case definition standards globally. The GBD team uses the Meta-Regression Bayesian, Regularized, Trimmed (MR-BRT) model to correct ascertainment bias caused by cross-country differences in data sources, diagnostic capacity and case collection, adopts the DisMod-MR 2.1 Bayesian hierarchical meta-regression model to generate consistent national-level estimates, and incorporates the SDI and Healthcare Access and Quality Index as covariates to adjust for systematic bias from health system disparities, ensuring the comparability of estimates across all included regions. The GBD study applies strict, uniform inclusion criteria for birth defects. First, included cases are strictly limited to structural or functional developmental abnormalities present at birth, in full accordance with the ICD-10 Q00–Q99 classification of congenital malformations, deformations and chromosomal abnormalities. Second, only birth defects causing premature death or long-term disability are included, while minor anomalies without significant health loss are excluded. Third, estimates uniformly cover live birth cases across the full life course in all included regions, with stillbirths and terminations of pregnancy for fetal anomaly excluded consistently across all countries to ensure denominator consistency for core indicators. Finally, only population-representative raw data for the corresponding geographic unit are included, with non-representative subpopulation data excluded. Data for specific GBD components, causes, and locations are accessible via the results tool (https://vizhub.healthdata.org/gbd-results/). Based on the data format of the GBD database, prevalence, incidence, death, and years lived with disability (YLD) represent absolute numbers, unless reported as age-standardized rates per 100,000 population, including age-standardized prevalence rate (ASPR), age-standardized incidence rate (ASIR), age-standardized YLD rate (ASYR), and age-standardized death rate (ASDR) (15). This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Disease burden definitions

We employed prevalence, ASPR per 100,000 populations, incidence, ASIR per 100,000 populations, death, ASDR per 100,000 populations, YLD, and ASYR per 100,000 populations to evaluate disparities in disease burden across various regions, age groups, and genders. The GBD study provides detailed methodologies for calculating prevalence, incidence, deaths, and YLD (1). Briefly, prevalence is estimated using the DisMod-MR 2.1 model or alternative modeling strategies, integrating multiple data sources, including survey data, disease registries, and case reports, to ascertain the prevalence of specific diseases at defined ages, genders, regions, and years. Incidence refers to the proportion of new cases occurring within a specified time frame relative to the total population. Within the GBD, incidence is typically derived from disease registries, case reports, or survey data, employing methods analogous to those for prevalence but focusing on new cases. Death rate denotes the number of fatalities due to specific diseases. Mortality data in the GBD are generally sourced from national death registration systems, cause of death surveillance systems, or death reports from the WHO. Where mortality data are inaccessible, the mortality-to-incidence ratio (MIR) model is applied to estimate deaths from incidence data. YLD, measuring health loss attributable to disease, is calculated by multiplying prevalence by the corresponding disability weight. Disability weight, reflecting the severity of health impact of a disease, ranges from 0 (full health) to 1 (equivalent to death). The formula for calculating YLD is: YLD = prevalence × disability weight. Additionally, the GBD study includes adjustments to data, such as crosswalking and bias adjustment, to ensure consistency across different data sources. For YLD calculations, corrections for comorbidity are also made by simulating the likelihood of individuals having multiple diseases concurrently across each age, gender, region, and year. The 95% uncertainty intervals (UIs) from the GBD study are used to present all statistical values, with the lower and upper bounds of the UIs displayed in parentheses after the estimates. For each sampled dataset, estimates are derived using statistical models (such as DisMod-MR 2.1 or other models), yielding a range of values. The lower bound of the 95% UI represents the 2.5th percentile of the estimates, and the upper bound represents the 97.5th percentile.

Regional division

The GBD categorizes major global regions based on geographical location and SDI. Geographically, the world is divided into 21 GBD regions, encompassing the most continents and their subregions. The SDI is a composite indicator that measures socio-economic background conditions affecting health outcomes by calculating the geometric mean of the total fertility rate for women under 25 years, the average education level for those over 15 years, and per capita income distribution lagged. Its value ranges from 0 to 1, reflecting the level of socio-demographic development in a region, with higher values indicating higher socio-economic, demographic, and developmental status, and vice versa for lower values. Based on the SDI, the world is divided into five quintiles, including high SDI, high-middle SDI, middle SDI, low-middle SDI, and low SDI.

Health inequality analysis

The study employed the SII and the CI, both recommended by the WHO, to evaluate the absolute and relative health inequalities of birth defects across countries and regions with varying SDI levels. The SII quantifies the change in age-standardized rates across the spectrum of SDI, represented as the regression coefficient of the incidence rate on the SDI scale. This coefficient reflects the gradient of health outcomes with respect to socio-economic status, indicating how health outcomes vary as SDI changes. The CI, on the other hand, sorts countries and regions by SDI, calculates the cumulative share of the health outcome for each segment, and then computes the twice the difference between this cumulative share and that which would be expected if the outcome were evenly distributed, standardized to range between −1 and 1. A positive CI value suggests that the health outcome is more prevalent among populations with higher socio-economic status, whereas a negative value indicates a higher prevalence among those with lower status. The magnitude of the absolute value signifies the degree of inequality.

Statistical analysis

All statistical analyses were conducted using R version 4.4.2 and the GBD online visualization platform (https://www.healthdata.org/research-analysis/gbd-data). Age-standardized rates reported are per 100,000 populations, with 95% UIs. T-tests were employed to compare the average annual percentage change (AAPC) in incidence of 10 types of birth defect from 2015 to 2020 across 21 GBD regions and the incidence in 2020–2021, to assess whether the COVID-19 pandemic affected the incidence of birth defect. Data on newborns for the global, 21 GBD regions, and 204 countries and territories were sourced from GBD demographic statistics.

Results

Global trends in the burden of congenital birth defects

The disease burden of birth defects is closely associated with birth rates. In 2021, the global birth cohort was recorded at 129.38 million, marking a 1.82% decline from 1990 levels. The number of male and female births was 66.94 million and 62.44 million, respectively, indicating decreases of 1.99% and 1.65% from 1990 (table available at https://cdn.amegroups.cn/static/public/tp-2025-1-849-1.xlsx). The global prevalence of birth defects in 2021 was estimated at 53,228,605.40 (95% UI: 47,858,994.11 to 59,376,385.81), and the ASPR was 865.75 (95% UI: 772.79 to 976.44) per 100,000 population, reflecting 52.95% increase and 12.13% decrease from 2019, respectively. The incidence of birth defects diagnosed in newborns in 2021 was 7,198,542.23 (95% UI: 6,203,686.76 to 8,356,382.81), with the ASIR of 5,563.72 (95% UI: 4,794.80 to 6,458.61) per 100,000 population, demonstrating a 6% decrease and a 4.26% decrease from 1990 (Table S1, table available at https://cdn.amegroups.cn/static/public/tp-2025-1-849-2.xlsx, Figure 1A,1B). The global death burden of birth defects in 2021 showed a significant reduction compared to 1990. There were 530,946.58 (95% UI: 454,278.97 to 642,418.94) deaths attributed to birth defects, with the ASDR of 6.73 (95% UI: 5.76 to 8.14) per 100,000 population, representing a 44.05% and 62.17% decrease from 1990, respectively. In 2021, the YLD due to birth defects was 52,325,332.69 (95% UI: 45,186,944.83 to 62,682,127.14), with the ASYR of 663.07 (95% UI: 572.61 to 794.31) per 100,000 population, showing a 40.89% and 60.05% decrease from 1990 (Table S1, Figure 1C,1D).

Figure 1 Temporal trends in the burden of birth defects and their subtypes. (A) Prevalence and ASPR. (B) Incidence and ASIR. (C) Death and ASDR. (D) YLD and ASYR. ASDR, age-standardized death rate; ASIR, age standard incidence rate; ASPR, age-standardized prevalence rate; ASYR, age-standardized YLD rate; YLD, years lived with disability.

In 2021, among the 10 types of birth defects, congenital musculoskeletal and limb anomalies, congenital heart anomalies, and other congenital birth defects had the highest prevalence, reaching 18,549,408.27 (95% UI: 15,159,832.56 to 22,636,856.78), 15,774,456.86 (95% UI: 14,041,228.96 to 17,389,519.74), and 12,829,860.16 (95% UI: 6,842,606.87 to 20,559,607.83), respectively. The ASPRs were 235.06 (95% UI: 192.11 to 286.86), 199.90 (95% UI: 177.93 to 220.36), and 162.58 (95% UI: 86.71 to 260.53) per 100,000 population, respectively. The highest incidence of new cases in 2021 was still congenital musculoskeletal and limb anomalies, 2,437,890.12 (95% UI: 1,737,729.85 to 3,355,568.45), and congenital heart anomalies, 2,300,327.37 (95% UI: 1,813,141.51 to 2,967,225.21), with ASIRs of 1,884.23 (95% UI: 1,343.08 to 2,593.50) and 1,777.91 (95% UI: 1,401.37 to 2,293.36) per 100,000 population, respectively, showing a 1.53% and 0.84% decrease from 1990. Neural tube defects, Down syndrome, and orofacial clefts were well-controlled, with ASIR decreases of 35.79%, 28.76%, and 24.79%, respectively. However, the outlook for preventing other anomalies remains bleak, with the ASIR of Klinefelter syndrome in 2021 even exhibiting a modest increase of 3% compared to 1990 (Figure 1A,1B, Table S1, table available at https://cdn.amegroups.cn/static/public/tp-2025-1-849-2.xlsx).

Congenital heart anomalies had the highest ASDR of 3.18 (95% confidence interval: 2.63–3.85) per 100,000 population, followed by other congenital birth defects, neural tube defects, and digestive congenital anomalies, with ASDRs of 1.29 (95% confidence interval: 1.01–1.78), 0.71 (95% confidence interval: 0.57–0.88), and 0.61 (95% confidence interval: 0.46–0.77), respectively (Table S1). Considering the disparate incidence rates of different birth defect subtypes, we utilized the death/incidence ratio for children aged <1 year to ascertain the annual neonatal mortality rate. Neural tube defects had the highest mortality propensity among birth defects, at 36.91%, followed by Down syndrome, digestive congenital anomalies, and congenital heart anomalies, with respective ratios of 22.92%, 9.12%, and 7.30% (table available at https://cdn.amegroups.cn/static/public/tp-2025-1-849-3.xlsx). Over the past three decades, there has been a remarkable improvement in the management of orofacial clefts, resulting in a staggering 91.3% reduction in the ASDR. This is succeeded by congenital heart anomalies and neural tube defects, which have witnessed declines in ASDR of 67.94% and 66.03%, respectively. Contrary to the ASDR, the ASYR is most pronounced for Congenital musculoskeletal and limb anomalies, peaking at 34.46 (95% confidence interval: 22.64–49.55). Other congenital birth defects and congenital heart anomalies trial behind, with ASYRs of 23.33 (95% confidence interval: 13.00–40.43) and 13.22 (95% confidence interval: 7.58–20.39), respectively. It is noteworthy that, despite the relatively low burden of Turner syndrome in ASIR and ASDR, the disease carries a substantial burden in the ASYR. This underscores the significant disabling impact of Turner syndrome (Figure 1B-1D). Over the last 30 years, the most significant decrease in ASYR has been noted in Down syndrome, with a reduction of 35.66%, while the ASYR for other congenital birth defects has risen by 10.92% (Table S1, Figure 1C,1D).

The disease burden across different age and gender groups

In 2021, males exhibited a higher disease burden of birth defects compared to females (Table S1, Figure 2). The burden of birth defects was consistently greater in males than in females across the 21 GBD regions. Exceptions were noted in certain regions, such as Western Sub-Saharan Africa, Latin America, Sub-Saharan Africa, the Caribbean, and select European and Asian areas, where females showed slightly higher ASIR, ASPR, and ASYR than males (Figure 2, table available at https://cdn.amegroups.cn/static/public/tp-2025-1-849-4.xlsx).

Figure 2 Regional and sex distribution of birth defect disease burden across 21 GBD regions. (A) ASPR. (B) ASIR. (C) ASDR. (D) ASYR. ASDR, age-standardized death rate; ASIR, age standard incidence rate; ASPR, age-standardized prevalence rate; ASYR, age-standardized YLD rate; GBD, Global Burden of Disease; YLD, years lived with disability.

The disease burden attributable to birth defects is predominantly concentrated within the 0–14-year age group. Among all diseases, birth defects are ranked second in terms of the ASIR for neonates, eighth in the ASPR for children under 5 years, and decline further to rank 21st in the ASPR for children aged 5–14 years (Figure 3). The ASDR for birth defects consistently occupies the first position among all-cause ASDRs in both children under 5 years and those in the 5–14 years age group (Figure S1). The ASYR for birth defects is ranked first for children under 5 years and eighth for those aged 5–14 years (Figure S2). Although infants within the first 2 years post-birth have the lowest prevalence, they display the highest ASPR, ASDR, and the absolute number of deaths compared to other age groups (Figure 4, table available at https://cdn.amegroups.cn/static/public/tp-2025-1-849-5.xlsx). This underscores that the first 2 years after birth, and particularly the first week, represent a pivotal period for mortality due to birth defects, with a substantial disability burden for those who survive.

Figure 3 Ranking of birth defect disease burden within all-cause mortality. (A) Ranking of ASIR for birth defects among all-cause diseases in neonates. (B) Ranking of ASPR for birth defects among all-cause diseases in children under 5 years of age. (C) Ranking of ASPR for birth defects among all-cause diseases in children aged 5–14 years. ASIR, age-standardized incidence rate; ASPR, age-standardized prevalence rate.

Figure 4 Age-stratified trends in birth defect-related (A) prevalence, (B) mortality, (C) YLD, (D) ASPR, (E) ASDR, and (F) ASYR among individuals aged 0–95 years. ASDR, age-standardized death rate; ASPR, age-standardized prevalence rate; ASYR, age-standardized YLD rate; YLD, years lived with disability.

Between 1990 and 2021, the ASDR attributable to birth defects has shown a consistent annual increase as a proportion of the total ASDR. This trend is particularly pronounced among children and adolescents aged <14 years (Figure 5). This pattern implies that, compared to other diseases, medical investments in the treatment of birth defects among adolescents remain inadequate. Furthermore, projections warn that if current trends continue unabated, the ASMR due to birth defects in adolescents under 14 years is expected to rise further by 2050, notably among infants aged between 7 days and 1 year, where the proportion of deaths attributed to birth defects is anticipated to exceed 15% of all-cause mortality (Figure S3).

Figure 5 Proportion of birth defect death burden within all-cause disease mortality across different age groups.

More than 90% of the disease burden of birth defects is concentrated in children under the age of 14 years (Figure 4). Our comparative analysis of the disease burden for 10 types of birth defects in children under 5 years and those aged 5 to 14 years revealed that congenital musculoskeletal and limb anomalies had the highest prevalence in the younger group, followed by congenital heart anomalies and urogenital congenital anomalies. Congenital heart anomalies were the leading cause of death, followed by other birth defects and neural tube defects. The highest burden of YLD was attributed to congenital musculoskeletal and limb anomalies, congenital heart anomalies, and other congenital birth defects. In the 5 to 14 years age group, the prevalence of congenital heart anomalies dropped to third place, neural tube defects emerged as the primary cause of death, and orofacial clefts became the third leading cause of mortality. In terms of YLD burden, congenital heart anomalies also dropped to third place (Figure S4, table available at https://cdn.amegroups.cn/static/public/tp-2025-1-849-6.xlsx).

The disease burden across 204 regions and countries

Among the 21 GBD regions and territories, South Asia recorded the highest number of births, Western Sub-Saharan Africa witnessed the most significant population increase from 1990 to 2021, and East Asia experienced the most pronounced decline in birth rates (table available at https://cdn.amegroups.cn/static/public/tp-2025-1-849-1.xlsx). Further analysis based on the 21 GBD regions revealed that Western Sub-Saharan Africa, Central Sub-Saharan Africa, and the North Africa and Middle East region had the highest prevalence of birth defects, reaching 5,736,740.72 (95% confidence interval: 5,082,144.52–6,597,660.02), 1,482,906.23 (95% confidence interval: 1,320,572.77–1,678,596.67), 6,590,554.89 (95% confidence interval: 5,903,701.09–7,396,211.42) (Table S2). The ASPR were 1,171.17 (95% confidence interval: 1,037.54–1,346.93), 1,082.98 (95% confidence interval: 964.43–1,225.89), and 1,057.87 (95% confidence interval: 947.62–1,187.19) per 100,000 population, respectively (Table S2). In 2021, Western Sub-Saharan Africa had the highest incidence of new birth defects, with an ASIR, ASDR, and ASYR of 238.07 (95% confidence interval: 202.13–280.68), 22.75 (95% confidence interval: 16.18–28.86), and 123.52 (95% confidence interval: 89.24–168.31) per 100,000 population, respectively. This was followed by Central Sub-Saharan Africa, with ASIR, ASMR, and ASYR rates of 213.72 (95% confidence interval: 180.86–251.62), 13.69 (95% confidence interval: 9.50–20.88), and 116.58 (95% confidence interval: 83.81–160.16) per 100,000 population, respectively and Eastern Sub-Saharan Africa had ASIR, ASMR, and ASYR rates of 198.30 (95% confidence interval: 168.73–232.68), 15.89 (95% confidence interval: 11.12–24.92), and 110.39 (95% confidence interval: 79.37–152.00) per 100,000 population, respectively (Table S2, table available at https://cdn.amegroups.cn/static/public/tp-2025-1-849-7.xlsx). Although Oceania had a lower ranking in ASIR and ASPR burdens, the ASMR and ASYR burdens were relatively high, indicating that therapeutic approaches in this region necessitate enhancement (table available at https://cdn.amegroups.cn/static/public/tp-2025-1-849-8.xlsx).

Among the 204 countries and territories, India had the highest number of births, the State of Qatar experienced the greatest increase in birth rates from 1990 to 2021, and Puerto Rico saw the most significant decline (table available at https://cdn.amegroups.cn/static/public/tp-2025-1-849-1.xlsx). Due to their substantial population bases, China and India had the highest number of prevalence and incidence of birth defects in 2021, a demographic effect that not even high SDI regions like the United States could avoid (Figure 6). Madagascar, Afghanistan, and Mali had the highest ASPR. Compared to 1990, all countries except Austria and Papua New Guinea experienced a decrease in ASPR, with the Republic of Korea, Mexico, and Maldives showing the most significant reductions. The Central African Republic, Tajikistan, and Brunei Darussalam had the highest ASIR in 2021. Encouragingly, 148 countries saw a decrease in ASIR compared to 1990, with Saudi Arabia, Canada, the Republic of Korea, and Iran experiencing the most considerable reductions, while Spain, Dominica, and Georgia reported increases (tables available at https://cdn.amegroups.cn/static/public/tp-2025-1-849-9.xlsx, https://cdn.amegroups.cn/static/public/tp-2025-1-849-10.xlsx, Figure 6). The demographic effect remained significant in terms of death numbers and YLD, with India having the highest number of deaths and YLD due to birth defects, followed by Nigeria and China. Interestingly, unlike death numbers, the United States significantly rose in YLD rankings. High ASDR and ASYR were predominantly concentrated in African and Western Asian regions, including countries such as Madagascar, Afghanistan, Chad, and Niger (tables available at https://cdn.amegroups.cn/static/public/tp-2025-1-849-9.xlsx, https://cdn.amegroups.cn/static/public/tp-2025-1-849-10.xlsx, Figure S5).

Figure 6 Global burden of birth defects across 204 countries and territories. (A) Prevalence, (B) ASPR, (C) incidence, and (D) ASIR of birth defects in 204 countries and territories. ASIR, age-standardized incidence rate; ASPR, age-standardized prevalence rate.

Disease burden and SDI

Previous research indicates that the majority of the burden of birth defect diseases is concentrated in regions of Africa, underscoring the importance of socio-economic development levels in the prevalence of birth defects. Indeed, the ASIR, ASPR, ASDR, and ASYR across the five SDI regions all exhibit a declining trend with increasing SDI. The lowest SDI regions carry the heaviest burden, with ASIR, ASDR, and ASYR reaching 640.45 (95% confidence interval: 547.39–748.64), 18.65 (95% confidence interval: 14.30–24.90), and 1,749.88 (95% confidence interval: 1,367.08–2,296.47) per 100,000 individuals, respectively. In contrast, the highest SDI regions have the lowest burdens, with ASIR, ASDR, and ASYR rates of 704.42 (95% confidence interval: 648.15–766.62), 1.98 (95% confidence interval: 1.86–2.09), and 209.06 (95% confidence interval: 186.73–234.17), respectively (Figure 5, Table S1). Subsequently, we employed the SII and the CI to evaluate health inequity among countries with varying SDI levels. Over the past three decades, there has been a significant disparity in the burden of birth defects between low and high SDI regions. Apart from the SII of ASDR improving from −67 in 1990 to −33 in 2021, there has been no significant change for ASPR, ASIR, and ASYR. The CI for incidence, prevalence, deaths, and YLD group in both 1990 and 2021 were all less than 0, and have not undergone substantial changes over the past 30 years. This suggests that the burden of birth defects is concentrated in low SDI regions, with very limited improvements over the three-decade period (Figure 7).

Figure 7 Health inequalities in birth defects across 204 countries and territories worldwide. SII and CI curves for (A,B) prevalence, (C,D) incidence, (E,F) death, and (G,H) YLD from 1990 to 2021. CI, concentration index; SII, slope index of inequality; TFR, total fertility rate; YLD, years lived with disability.

The impact of COVID-19

Beyond genetic variations, environmental factors, particularly viral infections, are recognized as risk factors for birth defects. Consequently, we conducted a further assessment of the disease burden during the COVID-19 pandemic. Isolating the impact of the COVID-19 from underlying trends by directly comparing the disease burden from 2019 to 2021 is challenging. To evaluate the medical challenges posed by the COVID-19 infection in the context of birth defects, we compared the changes in the ASIR from 2020 to 2021 with the average annual ASIR change observed over the past 5 years. At the global level, the COVID-19 infection did not significantly amplify the medical burden of birth defects. From 2015 to 2020, there were 14 regions, such as Australasia, where the ASIR of birth defects exhibited a positive growth trend, and in 2021, only five of these regions sustained positive growth (Figure 8, Figure S6, table available at https://cdn.amegroups.cn/static/public/tp-2025-1-849-11.xlsx). However, the change of ASIR for Down syndrome, orofacial clefts, and other chromosomal abnormalities in 2021 was significantly higher than the average ASIR from 2015 to 2020 across the 21 GBD regions globally (Figure S6). This suggests that the COVID-19 infection may be associated with an increased risk of birth defects caused by chromosomal abnormalities.

Figure 8 Temporal trends in ASIR of birth defects and their 10 subtypes across 21 GBD regions over three decades. ASIR, age-standardized incidence rate; GBD, Global Burden of Disease.

Discussion

Global burden and trends of congenital birth defects

This study reveals that from 1990 to 2021, the ASIR and ASDR for birth defects have declined, with the reduction in incidence largely outpaced by the decrease in mortality. This trend suggests significant advancements in birth defect treatment over the past three decades, attributed to improved medical technologies and healthcare policies. However, prenatal screening and prevention strategies have lagged behind. Morphological screening exhibits favorable preventive effects on multiple birth defects; however, it is mostly performed after embryonic formation, which poses certain challenges to prenatal reproductive counseling. In addition, some occult defects, such as phenylketonuria, often require genetic screening for detection. Genetic screening can complete the detection at the early stage of embryo establishment, thereby providing an intervention window for reproductive counseling. This gap likely reflects inadequate research into the genetic causes of birth defects. Early screening for birth defects focused on Down syndrome and aneuploidy. With the popularization of second-generation sequencing technology, more than 5,000 genetic variations of monogenic genetic diseases have been discovered successively (16). However, a significant proportion of birth defects are attributed to multifactorial genetic disorders, with unclear etiologies, and even within the same condition, there may be varying genetic backgrounds. Consequently, current effective screening methods are no longer limited to mutations at a single site but have expanded to panel-based genetic screening, which necessitates a deeper understanding of the causes of multifactorial birth defects. During the past decades of industrialization and urbanization, PM2.5 pollution in middle- and high-income regions and soil and water contamination in low-income areas have increased the risk of birth defects (17). High-income and low-income regions alike have an urgent need for economic development strategies that are based on environmental governance and ecological protection. Despite current calls to control the proportion of drug use during pregnancy, the abuse of drugs during pregnancy for reproductive system infections in some low-income areas, remains a common phenomenon (18). Recent studies have reported that offspring of pregnant women exposed to fluconazole have an increased risk of specific birth defects, including a threefold increase in the risk of tetralogy of Fallot, a sevenfold increase in the risk of transposition of the great arteries, and a fivefold increase in the risk of cleft lip and palate (19). This underscores the necessity for preventive strategies to bolster women’s health during pregnancy, thereby mitigating the risk of urinary and reproductive system infections, given the complex trade-offs between managing maternal infections and averting fetal birth defects.

During the study, we confirmed that birth defects are the most significant cause of death in children aged <14 years, and over the past 30 years, the proportion of deaths in adolescents aged 0–14 years due to birth defects has been increasing annually as a percentage of all-cause mortality. This indicates the substantial healthcare burden that birth defects impose during adolescence and suggests a significant shortfall in related medical resource allocation. On one hand, the devastating impact of birth defects poses a considerable challenge to survival, and on the other hand, the substantial burden of disability faced by survivors over the subsequent decades leads to a loss of confidence in treatment among family members and physicians (20). However, this study indicates that a negative medical strategy is not advisable, and if left uncontrolled, by 2050, the proportion of all-cause mortality due to birth defects in patients aged 0–14 years will continue to increase. This highlights the urgent need for prenatal screening and improvements in subsequent medical technology levels. Concurrently, birth defects, being lifelong conditions, exhibit a rising prevalence and YLD as the patient pool grows. This trend underscores the enduring and substantial medical burden birth defects impose on individuals and families, often resulting in physical and cosmetic disabilities that diminish quality of life. Enhancing therapeutic interventions and fostering a supportive social milieu for these patients is essential for advancing social equity and stability.

Global burden in various congenital birth defects subtypes

In this study, congenital heart anomalies and congenital musculoskeletal and limb anomalies were identified as the birth defect categories with the highest ASIR burden. Congenital heart anomalies frequently result in mortality, whereas congenital musculoskeletal and limb anomalies often lead to chronic disability. The negligible decline in ASIR for these conditions over three decades indicates a plateau in prenatal screening and prevention. Severe congenital heart anomalies can result in rapid neonatal death after the umbilical cord blood supply is interrupted, whereas certain occult cardiac abnormalities allow for a more prolonged therapeutic intervention (21,22). Although congenital heart anomalies are the primary cause of mortality across 10 birth defect subtypes, they have shown a notable decrease in ASDR over the past three decades, likely due to improvements in cardiac surgery and neonatal care (23). Nonetheless, survivors face a heightened risk of cardiovascular diseases, with early cardiac dysfunction and tissue degeneration being nearly inevitable (24). Thus, while enhanced survival rates due to aggressive treatment are encouraging, preventing congenital heart anomalies remains the most effective strategy to alleviate the associated burden. Congenital musculoskeletal and limb anomalies primarily result in musculoskeletal deficiencies or limb absence, such as Poland syndrome, congenital myopathies, and spina bifida. These conditions seldom lead to mortality unless severe organ malformations are also present (25-27). Given the critical role of limbs and motor function in normal human social capabilities, congenital musculoskeletal and limb anomalies inevitably impose a significant disability burden. These anomalies can be screened using imaging methods; thus, enhancing the development of high-precision imaging equipment is an essential approach to eradicating these conditions. However, economic barriers prevent many pregnant women from accessing such screening, and healthcare disparities make the task of screening still challenging.

Turner syndrome is a genetic disorder that affects only females, resulting from the complete or partial absence of one X chromosome in all or some somatic cells. Individuals with this condition face not only growth and developmental restrictions and gonadal dysgenesis but also comorbidities involving multi-organ functional abnormalities (28). Our study indicates that despite its low incidence, Turner syndrome accounts for a significant burden of YLD, second only to patients with congenital musculoskeletal and limb anomalies. This highlights the profound disruption Turner syndrome can cause to normal life. Turner syndrome often necessitates long-term treatment, including extended growth hormone therapy and sex hormone replacement therapy. However, most individuals with Turner syndrome are diagnosed around the age of 15 years, thus missing the optimal timing for hormone therapy (29). Due to the heterogeneity of chromosomal deletions, screening and early diagnosis of Turner syndrome are challenging, especially in low-income regions where developmental delays and restricted sexual maturation in children may be mistakenly attributed to nutritional issues. This makes it difficult to reduce the disease burden.

The groundbreaking discovery linking folic acid deficiency to neural tube defects, coupled with the widespread implementation of free folic acid supplementation in most regions, has led to a significant reduction in the incidence of neural tube defects over the past three decades (6). This highlights the potency of disease prevention as the most effective strategy for reducing the disease burden of birth defects, emphasizing the critical role of etiological screening. However, the death rate of neural tube defects remains the highest among all birth defects, partly due to their inherently high fatality rate and partly because their devastating impact and clear prevention methods can lead to a sense of pessimism regarding advancements in therapeutic techniques among medical professionals (30). Considering the significant effects of prevention, costs, and mortality rates, prenatal prevention continues to be the most crucial approach to eliminating neural tube defects. It is encouraging to note that the ASDR due to cleft lip and palate has significantly declined, while the ASIR has seen a relatively smaller decrease. Thus, although advancements in medical methods have greatly reduced mortality among patients with cleft lip and palate, treatment costs remain a substantial burden, particularly in low-income areas (31). Studies have reported the importance of folic acid supplementation in preventing cleft lip and palate, emphasizing the need to strengthen prenatal prevention to completely eradicate the disease burden caused by these conditions (32). In summary, the effective control of neural tube defects through oral folic acid supplementation has confirmed the priority of prenatal screening and prenatal prevention in reducing the disease burden of birth defects. However, for polygenic birth defects without appropriate screening methods, the focus in the short term should remain on improving survival rates and reducing the burden of disability.

Social development level and health inequality

This study reports a clustered burden of birth defects in three African regions: Western Sub-Saharan Africa, Central Sub-Saharan Africa, and North Africa and the Middle East. Although birth defects caused by genetic variations are highly correlated with ethnicity (33), it is not appropriate to simplistically assume that ethnic groups in African regions have a genetic predisposition for a higher burden of birth defect diseases. Such racial bias can easily lead to unfairness. For instance, the exclusion of certain groups in marital and reproductive decisions can lead to health disparities and raises ethical concerns. In fact, regional clustering is partly due to the lower level of socio-economic development in these areas, which is confirmed by our findings that regions with a lower burden of birth defect are located in higher socio-economic development areas such as High-income North America, Western Europe, and Australasia. On the other hand, the proportion of consanguineous marriages in the Middle East and Africa is relatively high, a social custom that exacerbates the burden of birth defects caused by genetic variations (34,35). This is also reflected at the national level, with countries such as the Central African Republic, Tajikistan, and Brunei Darussalam, which have the highest ASIR, also having higher rates of consanguineous marriages (36-39). In summary, the low level of socio-economic development and consanguineous marriages greatly exacerbate the burden of birth defects. We should emphasize the importance of human intervention from a sociological perspective to reduce the medical burden of birth defects, rather than genetic background, which is of great significance for us to allocate medical resources objectively and reduce racial prejudice. On the other hand, the burden of birth defects caused by population size should not be overlooked. India, China, and the United States have successively increasing levels of the SDI, and although there is a large gap in ASIR, the total population burden of new birth defects is still very heavy.

As the regional analysis demonstrates, it is the level of socio-economic development, rather than racial differences that is the primary driver of inequality in the burden of birth defects. The top 20 countries with the highest neonatal ASIRs are located in low socio-economic development regions across Africa, Asia, and the Americas. The GBD study stratifies global regions into quintiles based on the SDI, and our analysis confirms an inverse relationship between SDI and the incidence of birth defects. The CI indicates that the burden of birth defects is disproportionately higher in populations with lower SDI, a pattern that has remained largely invariant over the past three decades. The SII further underscores significant disparities in disease burden, as reflected by ASPR, ASIR, ASDR, and ASYR, between regions of high and low SDI. While there has been a notable reduction in ASDR inequalities over the last 30 years, disparities in other health metrics have persisted. Despite global calls for the elimination of health disparities in congenital birth defects over the past three decades, the outcomes still fall short of the intended goals (40,41). This implies that strategic medical resource allocation has historically neglected the health inequities in lower SDI regions, necessitating a concerted effort to ameliorate the socio-economic disparities contributing to the burden of birth defects.

The impact of COVID-19 on congenital birth defects

Although genetic mutations are important in the pathogenesis of birth defects, a considerable proportion of birth defects are caused by environmental factors (e.g., viral infection, medications, etc.). Evidence currently indicates that Zika virus infection during pregnancy can lead to microcephaly, neural tube defects, early brain malformations, eye structure abnormalities, congenital deafness, and limb contracture development in fetuses (42-44). In developed regions, cytomegalovirus is the most common viral infection causing birth defects (45). These viruses impact fetal development through the virus itself or antibodies produced by the mother, crossing the placental barrier. During the study period, the COVID-19 pandemic has caused illness and death in 2.2 billion and 7.89 million people globally, with the COVID-19 targeting multiple organs and profoundly affecting human health. The impact of COVID-19 on birth defects is primarily related to the virus infection itself and vaccination. Most current studies suggest that vaccination is not associated with birth defects, and COVID-19 vaccination during pregnancy is recommended as a protective measure for pregnant women (46-48). Additionally, there is no evidence supporting an association between COVID-19 infection and birth defects (49). It is noteworthy that there is still controversy over whether COVID-19 can cause intrauterine infection. Some studies have found that syncytiotrophoblast cells are often infected with the COVID-19, yet the fetus is not always infected, with only a few cases reporting possible fetal infection (50-52). This study also did not find a significant impact of COVID-19 infection on the overall incidence of birth defects. However, we observed a possible impact on birth defects associated with two types of chromosomal abnormalities (Down syndrome and other chromosomal abnormalities) and cleft lip or palate. To date, no studies have supported an association between COVID-19 infection and chromosomal abnormalities. Chromosomal screening is a common method for birth defect screening, thus this difference may be due to the impact of COVID-19 infection on the healthcare system, leading to a reduction in newborn screening efforts. However, some studies have reported an increased risk of cleft lip or palate in infants born to mothers infected with COVID-19 during pregnancy (53). Of particular importance, a case report has documented a 34-year-old unvaccinated pregnant woman who contracted severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the first gestational month, delivered preterm at 34 weeks’ gestation, and whose fetus presented with congenital heart disease and hydrops fetalis (54). Furthermore, a comparative analysis revealed that the prevalence of echocardiographic abnormalities in neonates born to pregnant women with COVID-19 was significantly higher than that in the control group (55). In our study, although no significant change in the incidence of congenital heart anomalies was observed at the global level, a significant elevation in its incidence was detected in several specific regions in 2020 and 2021. This finding may be attributed to the asynchronous progression timeline of the COVID-19 pandemic across different regions, which warrants further in-depth investigation. Therefore, the potential impact of COVID-19 on birth defects cannot be entirely ruled out, and further in-depth research is needed to confirm the exact results in this area.

Our study presents several strengths: (I) we performed a comprehensive epidemiological analysis of the disease burden characteristics for birth defect of 10 distinct organs, stratified by gender and age, offering a systematic review of trends over the past three decades. This analysis revealed a higher predisposition for birth defect burden among adolescents aged 0–14 years, males, and populations in African regions; (II) by employing the SII and the CI, we quantified significant health disparities in birth defects across nations with varying socio-economic development levels, noting no substantial improvement in these inequalities over the 30-year period; (III) leveraging the most recent 2021 GBD data, we evaluated changes in the incidence rates of birth defects overall and its 10 subtypes before and during the COVID-19 pandemic. These investigations provide insights into the discordance between the direct needs for prevention and treatment of various birth defects, which is crucial for the strategic allocation of healthcare resources.

This study also acknowledges several limitations that require consideration. Firstly, the diagnosis of birth defects, particularly those not involving overt limb deficiencies or malformations, is heavily reliant on advanced genetic technologies and medical imaging techniques. Our findings highlight significant disparities in health outcomes related to birth defects, and in less developed countries, undiagnosed cases may lead to an underestimation of the disease burden, implying that actual health inequalities could be even more pronounced. Secondly, the GBD database, while a comprehensive source of epidemiological statistics for 369 diseases, injuries, and impairments across 204 countries and regions, is incomplete in its assessment of certain specific diseases. It lacks data on risk factors for birth defects and parental exposure to specific factors, which are crucial for informing medical decisions to prevent and intervene in birth defects. Future research should prioritize addressing health inequalities and enhancing screening and prevention efforts in low-income areas. Such initiatives are essential for alleviating the medical burden of birth defects and for accurately quantifying the actual burden. Furthermore, the establishment of a comprehensive birth defect database is imperative. This database should record environmental factors and genetic backgrounds to further strengthen etiological investigations and the development of prevention strategies for birth defects. Finally, it is important to note that the GBD results are substantially dependent on modeled data. This dependency inherently involves estimations of data completeness, healthcare access, and disease prevalence. Such estimates may not accurately mirror real-world scenarios and could potentially introduce systematic biases. These limitations should be carefully considered when interpreting the results of our study.

Conclusions

In summary, this study proposes four key aspects for the global management of congenital birth defects (birth defects): firstly, while birth defect-related mortality and disability have declined, the incidence of new cases remains high, underscoring the necessity for intensified etiological research and prenatal screening to bolster birth population quality. Secondly, congenital heart anomalies and congenital musculoskeletal and limb anomalies are the two most burdensome birth defects in terms of incidence, with the highest burdens of mortality and disability, respectively. The incidence of neural tube defects has significantly decreased with the widespread use of folic acid, although the mortality rate remains high. This indicates that resource allocation for prevention and treatment should be prioritized according to the different subtypes. Thirdly, the burden of birth defects is higher in Africa, the Middle East, and countries with higher rates of consanguineous marriages. There is a significant clustering of birth defect burdens in low SDI regions, emphasizing the persistence of health inequalities over the past three decades. Greater efforts are needed to address inter-regional health disparities. Finally, there is no clear evidence to suggest that COVID-19 infection increases the overall incidence of birth defects, but susceptibility to certain subtype defects in the context of the COVID-19 pandemic requires attention. This study provides a comprehensive epidemiological map of birth defects and their subtypes globally, and these findings are guiding for further strategic allocation of medical resources.

Acknowledgments

We express our profound gratitude to the Global Burden of Disease (GBD) team for their invaluable assistance in data collection, collation, analysis, and sharing. Their contributions have been instrumental in facilitating our research endeavors.

Footnote

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-1-849/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-1-849/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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