Orofacial clefts (OFCs) are most common facial birth defects in the world (1). There are two types of OFCs; a majority of them are simple cleft lips, cleft palates, or facial clefts without any additional birth defects, termed the nonsyndromic type. The other category is the syndromic type, which is frequently associated with other birth defects,account for 15%–30% of cases (2). OFCs severely affect the patient's diet and, speech, facial, dental and other developmental issues; despite advances in medical knowledge and increasingly updated methods of effective prevention and treatment, OFCs remain a serious public health problem that imposes a significant burden on patients and society (3, 4). Furthermore, OFCs are associated with an elevated risk of death caused by congenital defects (5).

The aetiology of OFCs remains unclear, although genetic and environmental factors are currently considered the main causes (6). Recent genome-wide association studies have demonstrated that many genes and variants are associated with OFCs (7, 8). Environmental factors, including prominent drug use, alcohol consumption, smoking, parental age, and environmental toxins, may also influence the development of OFCs (9, 10). Therefore, supplementation of folic acid before pregnancy and during pregnancy, smoking cessation, alcohol withdrawal, avoidance of teratogenic drugs, reduction of air pollution, prohibition of recent marriage, prenatal genetic testing, genetic counseling, etc., can reduce the incidence of OFC (9, 10).

Epidemiological studies reveal significant geographic, ethnic disparities. Global data have shown that the overall incidence of OFCs in the world is one in 700 live births. Another recent systematic review revealed that in low- and middle-income countries, approximately one in 730 children was born with OFCs (11). Furthermore, the birth prevalence of OFCs worldwide has been reported to vary significantly. A previous systematic review showed that the OFC birth rate was higher in Asia than in other regions, at about 1.57 (1.54–1.60)/1,000 live births (12). However, these studies are only on the prevalence of OFC in regions or countries, and global data on all countries and regions is rare.To date, little global research has been done to assess the world's burden of OFCs across all countries and regions (13, 14). The previous studies focused on more developed countries or regions, and large gaps existed in registry data from low-income countries (13, 14). Further, there are no updated global studies on OFCs that provide comprehensive data on its epidemiology and burden. Moreover, the trends in prevalence, deaths, and DALYs of OFCs over time remain unexplored at these levels. Therefore, there is an urgent need to acquire precise data on OFCs worldwide and to allocate adequate resources for disease control and preventive purposes.

We analyzed data from the Global Burden of Disease Study (GBD) 2021 to obtain comprehensive information on the burden of OFCs, including prevalence, mortality, and DALYs by socio-demographic indices (SDIs), counts, and age-standardized rates (ASRs) at the global, regional, and national levels. This accurate information on the burden of OFCs can help to formulate appropriate policies to reduce the OFCs burden.

OFCs are one of the most common craniofacial birth defects in the world, posing a severe burden on infants, family and society. In the present research we reported the prevalence, death, DALYs, and their temporal trends over a 31-year period from 1990–2021 based on the latest data extracted from GBD 2021 at the global, regional, and national levels. Globally, the ASPR, ASMR, and ASDR of OFCs decreased from 1990–2021, demonstrated effectiveness of current preventive measures. However, the disease burden is unevenly distributed worldwide; some regions and countries continue to face increasing burdens, as evidenced by rising ASPR in Southeast Asia, the Caribbean, and Oceania, while ASMR remains on an upward trajectory in Afghanistan, Trinidad and Tobago, and Uzbekistan. In this study, the SDI index indicates a country's position on the development spectrum, which considers education, fertility, and poverty levels. The burden of OFCs varies with the SDI level; our findings reveal that 81.0% of the prevalence and 96.1% of deaths occurred in low- and middle-SDI countries. This is similar to the results of previous studies. Regions with high SDI exhibited the lowest burdens and the most significant decreasing trends in prevalence. Recent studies have also indicated that lower socioeconomic status correlates with a higher incidence of OFCs (18). Children with OFCs may have severe speech disorders, hearing loss, scar repair, nutrition, and mental and social developmental disorders. Therefore, OFCs needs to be solved through multidisciplinary sequential therapy starting from the neonatal period and running through the entire growth and development stage of patients. This requires the collaboration of orthopedic surgeons, plastic surgeons, dentists, pediatricians, otolaryngologists, physical therapists, etc., to gradually repair anatomical defects, restore function, and improve appearance (19). Areas with high SDIs are equipped with high-quality medical resources and team that provide targeted, sequential, and effective treatment for OFCs patients, compared to areas with a low SDI, therefore, they experience lower burdens.

The estimated overall global birth prevalence of 0.45 per 1,000 live births was calculated from a recent meta-data analysis (5). Our study estimated a global ASPR of OFCs at 53.42 cases per 100,000 population, higher than the previously published data. However, the prevalence of OFCs conditions varies across geographic areas and ethnic groupings. The low prevalence of OFCs in previous studies may be due to lack of information in areas with a higher prevalence, inclusion of countries or incomplete data (5)Previous reports of birth prevalence of OFCs vary considerably from different African populations. The prevalence of OFC is low in Africa with 0.5/1,000 cases in Nigeria (20), 0.44/1,000 cases in Ethiopia (21), and and 0.31/1,000 cases in South Africa (22). I In our research, sub-Saharan Africa had the lowest prevalence, with1.03/1,000 cases.

A review of the prevalence of OFCs in Africa and the Middle East showed an average prevalence of 1.25/1,000 live births (23). The prevalence of OFCs in the regions of Saudi Arabia ranges from 0.65–1.9/1,000 live births (24). Parental consanguineous marriage was the highest prevalent risk factor for OFCs cases in the included studies (24). In our study, the ASPR of OFCs in North Africa and the Middle East was 85.22 per 10,000 population. The prevalence of births of OFCs in Africa is lower than in other parts of the world. It is possible that inadequate monitoring systems and research programs for OFCs have undermined the accuracy of birth rate estimates in low- and middle-income countries.

Previous literature has indicated that drugs and air pollution, maternal tobacco smoking, and environmental tobacco smoke exposure, along with prenatal alcohol exposure, can increase the risk of OFCs at birth (2, 9, 10, 25, 26). The highest prevalence of OFCs has been reported in South and South-East Asia, with Pakistan having an OFC prevalence of 1.91/1000 (27)., 1.94/1,000 population in the Philippines (28), 1.90/1,000 population in Japan (22, 29), 1.4/1,000 livebirths in China (30), 0.73/1,000 births in India, and 1.64/1,000 live birth in Nepal (31). In our study, the ASPR of OFCs was notably higher in South Asia, with 109.09 (88.36–135.28) cases per 100,000 populations, and in East Asia, with 53.06 (43.39–64.75) cases per 100,000 populations. Moreover, A meta-analysis showed that smoking is an important risk factor for OFCs, and that smoking is significantly more strongly associated with the risk of OFCs in Asia and South America than in Europe and North America. Therefore, stringent restrictions on smoking are imperative in Asia (32).

The mortality rate of OFCs significantly decreased across most countries from 1990–2021. The primary cause of death is the syndromic type of OFCs (33). This notable reduction in mortality primarily resulted from the widespread adoption of universal prenatal diagnosis; earlier diagnosis and subsequent termination of foetuses with OFCs lessened the adverse impacts of pregnancy termination on the mother and her family (34). At present, many OFCs can be detected by B-ultrasonography, a universal and effective prenatal detection and diagnosis of congenital anomalies early in pregnancy, advanced ultrasonography (such as 3D/4D imaging) at 11 and 13 + 6 weeks of gestation can detect OFCs early, with a sensitivity of 90%–100% (35). Consequently, most mothers terminate their pregnancy as soon as possible after diagnosed with nonsyndromic OFCs. If the family decides to terminate the pregnancy, it is recommended to complete the pregnancy before 24 weeks to reduce the risk of surgery and ethical controversy. Nevertheless, in some countries, death rates are rising because of religious beliefs prohibiting abortion or poor economic conditions (36). As selective termination of pregnancy is sensitive and controversial, parents can still benefit from prenatal screening to prepare in advance for the birth of a child with orofacial clefts. In our study, the highest number of deaths cases in 2021 was also found in Western Sub-Saharan Africa, North Africa and the Middle East, and Eastern Sub-Saharan Africa.

We used DALYs to measure the burden of disease for the OFCs from 1990–2021 in 204 countries and territories. In 2021, at least 408,775 (95% UI: 252,320–671,120) OFCs per 100,000 population globally. The GBD data likely underestimates the global burden of disease since it fails to take into consideration other diseases related to OFCs, such as dental caries, facial dysmorphism, and malocclusion. We found that the high SDI region showed the biggest downward trend and the least ASRs of prevalence, as well as DALYs. Moreover, an negative linear relationship inverse relationship was noted between SDI values and both ASMR and ASDR in 21 geographic regions. Recent studies have also indicated that lower socioeconomic status correlates with a higher incidence of OFCs (18, 36, 37). Lower SDI may be associated with nutritional deficiencies, inadequate prenatal folic acid intake, limited access to health care, insufficient health infrastructure, inadequate levels of education, and lack of knowledge and awareness of environmental risk factors that can lead to adverse pregnancy outcomes (18, 38).Although the prevalence of OFCs is high in some high SDI regions, such as the Republic of Korea, Japan, Finland, Switzerland, and Germany, the ASMR and ASDR of the disease remains low. Thus, a high level of treatment of OFCs is associated with a low burden of disease.

The major barriers to care for OFCs in patients from low- and middle-income countries were: patient travel costs, lack of patient awareness, and insufficient financial support. Patient travel costs emerged as the most frequently reported barrier in sub-Saharan Africa, the Middle East and North Africa, and South and Southeast Asia. In a survey of 68 multidisciplinary practitioners of OFCs care in 17 countries in Africa, “Patient travel costs” was the most commonly reported barrier to OFCs care (39). Patient travel costs, also represents one of the largest out-of-pocket expenditures encountered when seeking healthcare. Patients may need to travel long distances to receive care and poor infrastructure may make in-country travel prohibitively expensive. They often struggle to afford additional nonmedical costs like travel, accommodation and meals. In contrast, inadequate financial support is the main barrier in the Eastern Europe and East Asia (39). In low- and middle-income areas of sub-Saharan Africa, where infrastructure is often inadequate, international assistance is important for controlling OFCs (40). International mission assistance organisations should focus on enhancing local medical capacity to ensure sustainability (41). Effective collaborations between international host countries' assistance and visiting organisations are crucial in addressing the complex challenges associated with OFCs care in these regions (42). Additionally, strengthening censuses at the national level to establish accurate health data on OFCs and dynamic monitoring of the burden can help further OFCs prevention and treatment. In addition, there is limited search for medical information on OFCs, so there is a need to utilize social media to provide educational resources for families with OFCs (4). Therefore, enhanced nutritional intake, emphasis on health care worker training, improved public awareness of preventive health care and allocation of health care resources in low-income countries may effectively reduce the disease burden of OFCs.

Our study has few limitations. First, this research is a secondary analysis of the GBD study data, and the accuracy and reliability of the estimates are still insufficient. Many low - and middle-income countries, particularly in Africa, South Asia and elsewhere, have inadequate disease surveillance systems, variations in healthcare reporting systems, missing or incomplete data, the registration of orofacial clefts may be missed in the low economic regions, leading to an underestimation of the disease burden. Second, in the GBD 2021 database, cleft lip and cleft palate are combined as OFCs, and in this study we were unable to distinguish whether it was unilateral or bilateral cleft lip or cleft palate, and whether there was a combined cleft. It is hoped that more detailed data on the types of cleft lip will be collected in the future to better understand the epidemiological characteristics of different types of cleft lip and palate. Thirdly, the risk factors are not sufficiently identified to explain the regional differences and temporal patterns in the disease burden of orofacial clefts. More data on risk factors are needed for further research.

OFCs represent a significant public health challenge globally, yet the geographical distribution of this burden varies. The global burden of OFCs decreased from 1990–2021. However, some countries continuing to experience increasing burdens. The greatest burden of OFCs was noted in South Asia, North Africa, the Middle East, and East Asia, where over 80% of the burden is borne by patients in low- and middle-income countries. Enhanced public awareness of OFCs prevention, stringent restrictions on smoking, control of air pollution, improved healthcare infrastructure, and increased training for healthcare workers in low- and middle-income countries are essential to mitigate the future burden of this disease.