The Global Burden of Sexually Transmitted Infections Estimated from 1990 to 2019


 Background:To explore the burden of sexually transmitted infections at national, regional, and global levels from the 2019 Global Burden of Disease Study database. Methods: The number of cases and age-standardized rate of prevalence, incidence, and disability-adjusted life years were used for a descriptive study of sexually transmitted infections burden from 1990 to 2019, and secular trends were assessed by counting the estimated annual percentage change. Finding:The global prevalence of sexually transmitted infections in 2019 was 128.82 million. There were 58.15% new cases than in 1990. The disability-adjusted life year burden of sexually transmitted infections was lower among males than females and peaks among under 5 and 15- to 44-year-olds. In 2019, the global disability-adjusted life year loss was mostly attributed to years of life lost (88.23%), the higher the social development index developed, the more the number of years lived with disability contributed. In 21 regions, the age-standardized rates of disability-adjusted life year (per 100, 000 population) showed that the Caribbean remained on top. At a national level, a decreasing trend of the estimated annual percentage change of disability-adjusted life year rate had been observed. Syphilis was proved as a leading cause of heavy disease burden, which carried almost 85.9% of it. The age-standardized rates of disability-adjusted life year were in positive correlation with the human development index in 2019 and had a negative correlation with the estimated annual percentage change in 1990. Conclusion: A declining trend of sexually transmitted infections was observed globally; prevention of syphilis remained a crucial strategy in the course of reducing sexually transmitted infections burden. The findings from this research can help to establish appropriate health policy and reduce the disease burden further.


Abstract
Background: To explore the burden of sexually transmitted infections at national, regional, and global levels from the 2019 Global Burden of Disease Study database.

Methods:
The number of cases and age-standardized rate of prevalence, incidence, and disability-adjusted life years were used for a descriptive study of sexually transmitted infections burden from 1990 to 2019, and secular trends were assessed by counting the estimated annual percentage change.

Conclusion:
A declining trend of sexually transmitted infections was observed globally; prevention of syphilis remained a crucial strategy in the course of reducing sexually transmitted infections burden. The ndings from this research can help to establish appropriate health policy and reduce the disease burden further.

Plain English Summary:
As we all know, sexually transmitted diseases have a great impact on sexual and reproductive health and maternal-infant well-being.
However, a few studies have reported long-term trends in the global burden of them, systematic analysis of the disability-adjusted life year is still lacking.
This study described the prevalence of sexually transmitted infections at the global, regional and national levels in 2019 and the change trend of STIs from 1990 to 2019. It aims to provide a theoretical basis for resource allocation and policy adjustment of sexually transmitted diseases, so as to better control its transmission. We found that the global burden of STIs in 2019 decreased by 11.35% compared with 1990, and the overall situation of sexually transmitted infections in the world has been signi cantly improved. But the burden of STIs in low SDI regions, especially in sub-Saharan Africa, has decreased, it still accounts for a large proportion. Syphilis, which still accounts for the heaviest burden of STIs in the world.
In conclusion, the world's efforts to reduce the burden of sexually transmitted diseases over the years have yielded impressive results, but we still cannot ignore the fact that some regions are still ghting a protracted war.

Background
Sexually transmitted infections (STIs) are developed by viruses or bacteria which can result in sexually transmitted diseases (STDs) through sexual activity 1 . STDs are less likely to be fatal even in the acute phase, however, it poses a signi cant and constant public health threat for high-risk groups 2 . The World Health Organization (WHO) had estimated that over 340 million people live with STIs worldwide every year 3 . Previously published researches mostly focused on the prevalence and incidence of STIs. In addition to traditional and intuitive methods for investigating the prevalence and incidence and performing a comparative study, the analysis of STIs burden becomes a distinct eld of research needed to be focused on. Making use of the disability-adjusted life year (DALY) method as a tool for assessment of health hazards to enhance comparability of results across diverse countries was jointly developed by WHO, etc 4 . STIs have a great impact on sexual and reproductive health and maternal-infant well-being, what's more, they can lead to long-lasting health problems. 40% of untreated syphilis patients can develop tertiary syphilis, in severe cases, even damage the cardiovascular and system nervous system 5 .
Congenital syphilis can cause severe local and systemic complications and even lead infant death 6 . Chlamydial and gonococcal infections can result in infertility, or adverse pregnancy outcomes 7,8 . Several human papillomavirus types are related to cervical, anogenital, or oropharyngeal cancer 9 . STIs are associated with HIV infection. The incidence of HIV had been reported to be up to 20% after ten years from syphilis diagnosis 10 . Additionally, STDs impose a social, psychological, and economical burdens. In 2018, the direct medical costs related to STD diagnosis and treatment of 19.7 million patients exceeded $3 billion annually in the United States alone 11 .
Grasping the essence of public health burden macroscopically, was the essential foundation for the development and implementation of the health strategies.
Having access to DALY data on STIs is of great importance for public health policy development, health system planning, and resource allocation. Although a few studies have reported long-term trends in the global burden of STIs 12 , systematic analysis of DALY is still lacking. We used DALY data from 2019 Global Burden of Disease Study (GBD2019) to precisely assess the loss of health from STIs at national, regional, and global levels and understood resource utilization of the allocated budget, which can place more emphasis and timely adjust.

Methods
The research dates of STIs were derived from the Health Metrics and Evaluation (IHME) o cial website (http://ghdx.healthdata.org/gbdresults-tool), through the GBD Results Tool. Our research obtained data on global human STI burden from GBD2019, from 1990 to 2019. Calculating DALY, age-standardized rate (ASR), and estimated annual percentage change (EAPC) values to quantify the burden of STIs. DALYs include years lived with disability (YLD) and the years of life lost (YLL). ASR was calculated based on the following formula: (a i the age-speci c proportion, where the subscript i represents the ith age group and w i denotes the number of cases or weight among select reference standard population for same age subgroup i) 13 . The natural logarithm of ASR (ln ASR) was supposed to be linear together with time, EAPC was introduced to indicate the variation tendency of ASRs at speci c time intervals which imply the growth speed of the ASR during the observation period. y = α + βx + , where y refers to ln (ASR), x represents calendar year, ε means the error term. EAPC was estimated as 100×(exp(β)-1), with the 95% UIs acquired from the linear model 14,15 . ASR presents an increasing trend as EAPC is positive and 95% UI > 0. Oppositely, it shows a descending trend 16 . Socio-demographic Index (SDI) is a composite measure of income, education, and total fertility rate in the GBD country, which is used to divide 204 countries into 5 classes: high, high-middle, middle, lowmiddle, low. Each country's human development index (HDI) values were obtained from the World Bank. We evaluated the association between EAPC and ASRs of DALY in 1990, EAPC and HDIs in 2019 at the national level via Pearson correlational analyses.
The data were cleaned and collated in O ce Excel. Because the overall age-standardized rate and 95%UI were given directly by GBD2019, all statistical procedures and data visualization were taken advantage of the R program (version 4.1.0) with packages Maps and ggplot2, etc. P-value less than 0.05 was de ned as statistically signi cant.  Table 1 Absolute numbers and age-standardized rates of prevalence, incidence, and the disability-adjusted life-years of sexually transmitted infections excluding HIV in 1990 and 2019 and their temporal trend from 1990 to 2019 at global and regional levels. 2 Changes in DALYs due to STIs at the global, regional, and national level   The ASRs were all found to have declined at all the SDI quintiles levels ( Figure S1b), the EAPC of the Low-SDI quintile was the lowest   (Figure 3).    Figure S2a), age-standardized DALY rates of females were higher compared with males, but it's the opposite in 2019 ( Figure S2b). The ASR of DALY of syphilis always accounted for the largest proportion in both genders. DALYs of total STIs displayed an overall decrease over 30 years, especially syphilis ( Figure S3).

Global prevalence status of STI
The same trend as that of the total DALY rate of sexually transmitted diseases, at SDI quintiles level, Low SDI quintile always had the higher ASR of DALY of syphilis (Supplementary Table 2 Table 3).

Relations among DALY burden estimates of STIs and SDI and HDI levels
The SDIs had raised in all 21 global burdens of STIs regions from 1990 to 2019 ( Figure 5). As SDI values increased, ASRs remained a downward trend. ASRs were higher at the low SDI quintile than the high SDI quintile. The regions whose baseline SDI was relatively high showed remarkably minor magnitude in ASR from 1990 to 2019. The ASRs of DALY always kept dramatically higher in Southern sub-Saharan Africa, central sub-Saharan Africa, and Oceania than expected based on SDI. There had a negative correlation between EAPC and ASRs of DALY (ρ=-0.2844932, P=0.00003724, Figure S4a), however, it had a positive correlation with HDI (ρ = 0.3055735, P=0.00001905, Figure S4b).

Discussion
The number and ASR of STIs prevalence all increased in 2019 compared with 1990 at the global level, providing further evidence to understand that STIs remained a major public health concern globally. With economic development and medical improvements, some conditions inversely increase high-risk sexual behavior and the potential risk of STIs. These include: increased opportunities to travel to countries where the sex tourism industry is more accessible; the introduction and utilization of drugs focusing on sexual dysfunction; divorce rates as well as numbers of sexual partners have increased with lifespan extension and health conditions improvement; the increasing internet coverage and opening sexual awareness 17 . Not unexpectedly, in addition to the substantial disease burden, the humongous numbers of STIs have also been associated with the improvement of the sensitivity of the detection method and the number of reported cases. Although there still have a heavy STIs burden in 2019, the ASR of DALY had decreased from 1990 to 2019, because of the extension of the availability of prevention strategies, scaling up treatment service and the provision and promotion of free condoms reduce the risk of some STIs. The burden of STIs varied greatly among different SDI regions. The ASRs of DALY in all SDI quintiles showed the falling trend apart from the low-middle SDI quintile, one of the reasons for that is coverage rate remains unchanged with the number of current people increased 18 . Adjusting medical resources will be needed to control the epidemics.
Decreased trends in the absolute number and ASRs of DALY of STIs have shown the obvious better overall health from a global perspective, which proved that it's worthy of making efforts to lighten STIs burden by the health care system work. In 2019, STIs occupied the tenth position among the leading reasons of disease burden for childhood under 10 years (congenital syphilis accounted for 100%) 12 .
Based on the results of our research, although DALY numbers declined to a certain degree for all age groups, the high ASRs of DALY were associated with children under 5. Considering this population have so inactive sexual life, the possible reasons for this phenomenon were due to limited access to maternal health services and failure to get adequately screening and treatment. National and regional public health sectors should strengthen the monitoring in women of childbearing age and carry out emergency interventions about mother and fetus during the pregnant and puerperal period to inhibit vertical transmission of the infection 19 . STIs data suggested age was signi cantly associated with the DALY burden of STIs, though it's likely to spread at all ages. The greatest dramatic increase of DALY was for persons in the 15-30-year age group from 1990 to 2019, because of the unregular sexual partner and increment sexual life. With the change of period, DALY rates decreased at all ages, but at different rates, and the peak was slightly shifted posteriorly, which may be due to improvements of the aging population. Public data are taken from the Centers for Disease Control and Prevention also brings thinking for a high-risk population like homosexual or bisexual males 20 . We notice the STI DALY burden for the age group more than 60 years also wasn't relaxed.
The need for sex is often overlooked in the elderly, there was limited factual knowledge and relevant source regarding STIs for them, perhaps, future multiple media campaigns may improve the current situation 21 .
As we observed the number of YLLs accounted for 88.23% of DALYs, efforts to control premature mortality still seems to be a leading goal.
The higher the SDI, the larger the YLDs, which is in line with the results reported in the literature 12  Indeed, from the initial stage of low-level medical resources and the degree of social civilization gradually developed, the heavy STIs burden of low SDI level region is already alleviated to a large extent, which also explained why its EAPC had a greater decline than the developed areas with relatively perfect economic level.
The spread, prevalence, and burden of sexually transmitted diseases are unequal between the sexes, what's more, the prevalence was much higher among women than men ( Caribbean was the fastest-growing DALY burden region, globally. When EAPC decreased in other regions, only the Caribbean and the highincome Asia Paci c were positive, which means effective management needs to be greatly strengthened among those areas. Black/minority ethnic groups carry a considerable proportion STIs burden in many high-income countries. High STI diagnoses rates occurred among the black Caribbean in England. This phenomenon is the result of interaction among cultural, socioeconomic, and sexual characteristics, and varied from region to region as well as from race to race 28 . a survey of the 11161 general population residents in Britain found people of black Caribbean had a high number of lifetime sex partners and active sexual activities, which result in an increased risk 29 . The STI burden is serious in sub-Saharan Africa countries, which account for 60% of global disease-adjusted life years. The ASR of several countries like Mozambique, Ethiopia, and Liberia is high, may because Sub-Saharan Africa still faces a multiple disease burden now, especially AIDS 22 ; remote areas far away from primary health care services are di cult to achieve well-developed health services, and screening covers a small area of people 30 . Sub-Saharan Africa had a high YLLs proportion, meaning that the leading cause of heavy DALY burden in the region is premature deaths attributable to STIs. For countries with great control of sexually transmitted infections, solving the problem of the rebound in the transmission is a great challenge, which needs denser routine screening of STD. Specialized service of STIs depends heavily on the HIV funds, however, without abundant nancial support to maintain investment in primary prevention, the government can make screening and treatment of STIs part of the minimum basic service package provided by social health insurance for outpatients through recognized service providers (public, private or non-governmental institutions), which will greatly contribute to the screening of sexually transmitted infections and increase selectivity 31 . Some scholars believe that under the above circumstances, the method of home sampling STI testing services can also be adopted for screening, which not only saves costs but also is more acceptable 32 .
In several sexually transmitted diseases, syphilis has the highest DALY rate and greatest in uence. Data on syphilis are more easily acquired and reliable, tracking syphilis trends contributed to monitoring overall control efforts for sexually transmitted infections 31 . longeracting penicillin G formulations are the cornerstone of syphilis treatment. Since the discovery of penicillin in the 1940s, syphilis prevalence had continued to decline 5 . Although syphilis decreased more signi cantly than other sexually transmitted infections, it still attracts a lot of attention due to its high DALY rate. To in uence the burden of global STIs, it looks that the focus should be more on the control of syphilis, in the meantime, nor should we ignore the importance of addressing other sexually transmitted infections 19 . When the DALY rate of several sexually transmitted diseases all decreased, gonococcal infection and genital herpes increased slightly, which ought to be another key point of the prevention and control of the disease. This abnormal phenomenon maybe because of the development of drug resistance that complicates effective treatment. What we ought to do is to develop a novel type of antibacterial agent and timely optimizing treatment.
STIs prevention and interventions can be expanded positively in the current health promotion framework, integrating standardized reproductive services into primary care, includes: strengthen sexual health education and condom use publicity; optimize the diagnosis and screening of sexually transmitted infections and implement effective partner treatment strategies; develop the vaccine against sexually transmitted infections is also a key research area 11,33 .
The limitation of this study is that it analyzes the burden of sexually transmitted infections only at a macro level. As a result of limited availability of data, there is a lack of relevant etiology and risk factors.

Conclusion
In our study, the GBD2019 database was used to comprehensively describe the global burden of STIs. In 2019, the global burden of STIs decreased by 11.35% compared with 1990, and the overall situation of sexually transmitted infections in the world has been signi cantly improved. However, although the burden of STIs in low SDI regions, especially in sub-Saharan Africa, has decreased, it still accounts for a large proportion. The Caribbean showed an increasing trend when the global age-standardized annual disability-adjusted life rate showed an overall downward trend. Syphilis, which accounts for the heaviest burden of STIs in the world, has the same trend as the total DALY rate of sexually transmitted diseases. The lower the SDI levels, the higher the DALY rate of syphilis and the high-income areas have also increased slightly in recent years. In general, the world's efforts to reduce the burden of sexually transmitted diseases over the years have yielded impressive results, but we still cannot ignore the fact that some regions are still ghting a protracted war. When formulating global health goals, policymakers need to make reasonable and e cient resource allocation and support and formulate appropriate health strategies by taking into account the burden differences of regions, gender, and countries.