Global, Regional, and National Burden of Ectopic Pregnancy: A 30-Year Observational Database Study

Objective To estimate global, regional, and national trends due to ectopic pregnancy as part of the 2019 Global Burden of Disease study. Methods We systematically reviewed trends in ectopic pregnancy burden using data from the Global Burden of Disease (GBD) database, including 21 regions, 195 countries, and territories over the past 30 years. The trends of ectopic pregnancy-related incidence, mortality, and disability-adjusted life years (DALYs) attributable to all known risk factors were also analyzed. Age-standardized rates (ASRs) and their estimated annual percentage changes (EAPCs) were also calculated. Results Incident cases, deaths, and DALYs of ectopic pregnancy increased worldwide in the past 30 years. The age-standardized incidence rate (ASIR) was decreasing (EAPC = −1.14, 95% confidence interval (CI): −1.29 to −0.98), and the age-standardized death (EAPC = −0.9, 95% CI: −1.03 to −0.76) and DALY rate decreased generally (EAPC = −0.83, 95% CI: −0.98 to −0.68). In addition, the burden of ectopic pregnancy is lower in areas with higher socioeconomic development, and significant positive correlations between ASRs and sociodemographic index (SDI) were observed, especially among low-middle SDI, and low SDI quintiles carried the majority burden of ectopic pregnancy. Conclusion Globally, the incidence, mortality, and DALY rate of ectopic pregnancy had been decreasing from 1990 to 2019. Compared with lower and decreasing ASIR in the high SDI region, ASIR in the low SDI region was always high, indicating the need for ectopic pregnancy treatment improvement and the establishment of more targeted and specific strategies in low SDI countries to reduce the incidence of ectopic pregnancy.


Introduction
Worldwide, ectopic pregnancy, as one of the common acute disease occurring at abdomen in obstetrics and gynecology, is the main cause of maternal death [1,2].Once the ectopic pregnancy site ruptures, it may cause serious complications such as bleeding, or even shock, which may endanger life [3,4].Nowadays, with the development of the social economy and the change in people's lifestyles, the incidence rate and clinical treatment of ectopic pregnancy have also changed greatly, and the mortality of ectopic pregnancy is also decreasing [5,6].Of these, actively tracking changes in the burden of ectopic pregnancy is quite necessary, which can provide relevant data support for better implementation of prevention and treatment, especially for the improvement of health decision-making and disease management in various countries and regions.
Previous studies mainly focused on regional studies, and most of them were single-center studies [7][8][9][10].Limited by population sample size and time span, it was difcult to accurately trace the incidence trend of ectopic pregnancy, so more comprehensive and extensive data were urgently needed as support.Nowadays, with the increasing improvement of public databases, making full use of data mining technology can search for potentially valuable knowledge from a large amount of data, thereby better serving clinical applications [11,12].Fortunately, the global burden of disease meets the needs of time and space span analysis of ectopic pregnancy, especially from the relevant robust indicators of epidemiology (such as age-standardized incidence rate (ASIR) and age-standardized death rate (ASDR)), which can more accurately assess the incidence of ectopic pregnancy and its prevention and treatment efects, thus providing an important basis for the formulation of future public health strategies related to ectopic pregnancy [13,14].Given this situation, this study reviewed the progress related to the epidemiology of ectopic pregnancy in the past 30 years in order to provide a theoretical basis for clinical workers to treat and care for ectopic pregnancy.

Data Resources.
To obtain detailed information on the global disease burden database of ectopic pregnancy, we obtained it with the help of the Global Health Data Exchange (GHDx) query tool (download address: https://ghdx.healthdata.org/gbd-results-tool).According to the sociodemographic index (SDI), regions and countries were divided into fve levels: low SDI, low-middle SDI, middle SDI, high-middle SDI, and high SDI.In addition, according to geographical characteristics, there were twenty-one geographical regions including East Asia, South Asia, and Western Europe.

Evaluation Index for Ectopic Pregnancy.
In short, from this database, we can obtain detailed data on the number of cases and deaths in the world, countries, and regions in the current year and calculate the relevant "age-standardized rate (ASR)" and its estimated annual percentage changes (EAPCs) through the number of cases and deaths of ectopic pregnancy from 1990 to 2019.
In this formula, a represents the specifc age rate of the ith age group, wi represents the population (or weight) of the corresponding ith age subgroup in the selected reference standard population, and A represents the number of age groups.Tese indicators can better evaluate the changing trend related to the incidence and death of ectopic pregnancy in the past 30 years.In addition, disability-adjusted life years (DALYs) refer to all the years of healthy life lost from illness to death, including years of life lost due to early death and years of healthy life lost due to disability.In this study, the DALYs were the sum of the years of lost life (YLL) and the years lived with disability (YLD).

Statistical Methods.
In this study, the EAPC calculation formula was 100 × [exp(β) − 1], and 95% confdence interval (CI) was calculated with a linear regression model.When the EAPC value and its 95% CI > 0, it was defned as a trend increase.On the contrary, when the EAPC value and its 95% CI < 0, it indicated that the trend decreases.Others represent that ASR was relatively stable in a period.To explore the infuencing factors of EAPC, the Pearson correlation analysis in R software (download address: https://www.rproject.org/)was used to evaluate the correlation between EAPCs and ASR in 1990 and the correlation between EAPCs and Human Development Index (HDI) in 2019, as well as to draw a Choropleth chart.2).In addition, from the perspective of diferent SDI divisions, the declining trend of EAPC in high SDI (EAPC � −0.74, 95 CI%: −0.8∼−0.67)regions was generally lower than that in low SDI (EAPC � −1.46, 95 CI%: −1.55∼−1.37)and low-middle SDI regions (EAPC � −2.25, 95 CI%: −2.29∼−2.21)(Supplementary Figures 1 and 2).Consistent with the results, the three countries with the most signifcant decline in EAPC were Qatar, Afghanistan, and Somalia.Te three countries with the lowest decline in EAPC were the Northern Mariana Islands, Albania, and Puerto Rico (Figure 3, Supplementary Tables 1 and 3).However, from the regional perspective, the decline of EAPC in East Asia, high-income North America, and Central Europe was the slowest, while the declining trend of EAPC in Oceania, Western Sub-Saharan Africa, and Central Sub-Saharan Africa ranked in the top three (Supplementary Table 2 and Supplementary Figure 3).In addition, we also found a negative correlation between EAPC and ASIR (ρ � −0.23 and p < 0.01) and a positive correlation between EAPC and the SDI (ρ � 0.36 and p < 0.01) (Figure 4).Collectively, the incidence of ectopic pregnancy was quite diferent in various countries and regions, and the overall trend of incidence rate in developed countries was lower than that in less developed countries, although the decline of EAPC in the past three decades was less than that in less developed countries and regions.

Trends in Ectopic
Pregnancy-Related Deaths.At the global level, ectopic pregnancy-related deaths cannot be ignored.As shown in Table 2 and Figure 1, the annual deaths decreased gradually and there were 64.52 (95% UI, 54.96∼75.13)× 10 2 deaths in 2019 and 57.49(95% UI, 51.07∼64.35)× 10 2 deaths in 1990.In the past 30 years, the ASDR was stable with 0.11/100,000 persons (95% UI, 0.09∼0.12) in 1990 to 0.08/100,000 persons (95% UI, 0.07∼0.09) in 2019.Fortunately, the EAPC of ectopic pregnancy still maintained a weak downward trend, which indicated that the mortality rate was efectively controlled.In addition, from the perspective of diferent SDI regions, the 2 International Journal of Clinical Practice  2 and Supplementary Figures 1 and 2).From the national and regional level, as shown in Figure 3 and Supplementary Table 1, the three countries with the highest and lowest decline in EAPC were Ecuador, Belize, Jamaica, Estonia, Czechia, and Hungary.However, the three regions with the largest and lowest decline in EAPC were the Caribbean, Andean Latin America, Central Sub-Saharan Africa, Eastern Europe, Central Europe, and East Asia (Supplementary Tables 2 and 4 and Supplementary Figure 3).In addition, we also found a positive correlation between EAPC and ASDR (ρ � 0.15, p < 0.05) and a negative correlation between EAPC and the SDI (ρ � −0.37, p < 0.01) (Figure 4).In general, the mortality due to ectopic pregnancy in both developed and underdeveloped areas was on the decline, which also refected the global eforts to control ectopic pregnancy-related deaths.3 and Figure 1).On analysis from the SDI level, we found that the age-standardized DALY rate in all the SDI regions declined, and the decline of EAPC with high-middle SDI increased, followed by middle SDI (Supplementary Figures 1 and 2).On observation from the GBD regions and countries level, the three countries with the highest age-   1).In terms of regions, the three regions with the largest and lowest number of DALY were the Caribbean, Andean Latin America, Central Sub-Saharan Africa, Eastern Europe, Central Europe, and East Asia (Supplementary Tables 2 and 5 and Supplementary Figure 3).In addition, we also found a nonsignifcant correlation between EAPC and ASDR (ρ � 0.1, p � 0.18) and a negative correlation between EAPC and the SDI (ρ � −0.26, p < 0.01) (Figure 4).In summary, the declining trend of DALYs in various countries and regions around the world refected that the loss of ectopic pregnancy on women's healthy life span was gradually narrowing.

Distribution of Related Risk Factors among SDI Quintiles.
According to the potential threat factors provided by GBD, we conducted an attributable risk factor analysis, which showed that iron defciency was signifcantly associated with ectopic pregnancy-related deaths and DALYs.As shown in Figure 5, compared with 1990, the risk factors of iron defciency in a few regions in 2019, such as South Asia and Western Europe, have been signifcantly reduced.Meanwhile, from the perspective of diferent SDI regions, iron defciency in low-grade SDI regions was the most signifcant, followed by middle and low-middle SDI regions, while the risk factors for iron defciency in the middle, high-middle, and high SDI regions were relatively stable (Figure 6).However, the factors of death and DALYs caused by iron defciency in the overall SDI region in the past 30 years also showed a downward trend, even in underdeveloped regions.

Discussion
Tis study systematically elaborated the latest trends and models of global incidence rate, mortality, and DALY of ectopic pregnancy from 1990 to 2019, based on the results of GBD 2019.Compared with the previous research reports, we have made a comprehensive summary based on the incidence trend of ectopic pregnancy in various countries and regions around the world, and we frmly believe that this has a very cutting-edge guiding signifcance for the timely follow-up of the prevention and control of ectopic pregnancy.
Although ectopic pregnancy is a benign gynecological disease, its sudden onset may bring high-risk factors such as hemorrhagic shock, which will pose a potential threat to the lives of patients.Worldwide, the early identifcation and management of ectopic pregnancy still show great diferences, which are closely related to the health policies of various countries and regions.For example, the total proportion of ectopic pregnancy reported in North America and other regions is 19.7/1000, which is the main cause of death for women in early pregnancy, accounting for 10% to 15% of all women's deaths [1].In the past 30 years, for every 1000 pregnancies in Northern Europe, ectopic pregnancy has increased from 11.2 to 18.8.In 1970, 17800 cases of ectopic pregnancy were hospitalized in the   International Journal of Clinical Practice United States, which rose to 88400 in 1989.More than 10000 ectopic pregnancies are admitted to hospital every year in the UK (the incidence rate is about 11.5/1000 pregnancies) [15,16].Te burden of the disease varies greatly across the globe, and this imbalance is mainly affected by population structure and socioeconomic status [17,18].In this study, the number of morbidity and ectopic pregnancy-related deaths in developed regions is signifcantly lower than that in underdeveloped regions.As for the change range of ASIR and ASDR, even though the decline in developed regions is not signifcant, compared with the overall population base, the prevention, and control of the fatal risk of ectopic pregnancy tends to be more stable, which also suggests that early management strategies for ectopic pregnancy, especially in underdeveloped regions.Because of the existing limitations of medical resources and health systems, the burden of ectopic pregnancy remains an important challenge in the world and a few underdeveloped regions.
Ectopic pregnancy is still a clear public health burden and a public health issue [19].So far, people have insufcient knowledge of ectopic pregnancy, especially in underdeveloped countries and regions, and there is often greater neglect of the risk factors of ectopic pregnancy.Previous studies have demonstrated that the occurrence of ectopic pregnancy is the result of a combination of one or more factors, which may be related to reproductive system infection, abortion, fallopian tube surgery, history of ectopic pregnancy, the use of intrauterine devices, cesarean section, emergency contraception, and other factors [1, [20][21][22].Many unknown potential risk factors are still worth discussing.For example, this study found that iron defciency may become a high-risk factor for ectopic pregnancy, especially in regional distribution.
Previous studies have shown that menstruation loss and a signifcant increase in iron demand during pregnancy are the main reasons for negative iron balance in women of childbearing age and pregnant women [23,24].For example, the World Health Organization recommends that pregnant women take 300 micrograms of iron and 400 micrograms of folic acid daily.Studies on iron supplementation showed that the risk of anemia in pregnant women at term was reduced by 70%, and the risk of iron defciency at term was reduced by 57%.At the same time, the level of hemoglobin per liter of women receiving iron therapy at term or in the near future was signifcantly higher than that of women not receiving supplements [25].Terefore, the risk of iron defciency during pregnancy and lactation mainly stems from insufcient iron reserves in women of childbearing age before pregnancy.We speculate that this may also lead to the abnormal development of fertilized eggs, which increases the risk of ectopic pregnancy.
Our research also inevitably has the following limitations.First, there was a lack of data for countries with low socioeconomic status and the least data sources, which may ofset the assessment of the disease burden of these countries and regions.In the future, it is still necessary to strengthen the data-sharing policy to expand the accurate assessment of the burden of ectopic pregnancy in all regions of the world.Second, because the GBD database did not report the disease burden of ectopic pregnancy by type, it is necessary to carefully evaluate the pregnancy risk of diferent ectopic parts in the future, especially the ectopic International Journal of Clinical Practice pregnancy in the ampulla and interstitial parts.We believe that the disease burden of ectopic pregnancy in diferent parts is also diferent.Tird, the lack of data on some other potential risk factors of ectopic pregnancy may hinder the interpretation of this association.Terefore, it is still necessary to expand the screening of risk factors of ectopic pregnancy, and the risk factors in diferent regions depend on each other, so it is necessary to treat with caution and formulate corresponding policies.Notwithstanding, our study provides an updated estimate of the burden of ectopic pregnancy and its causes, which will be useful for public health policymakers.International Journal of Clinical Practice      12 International Journal of Clinical Practice

Conclusion
In summary, ectopic pregnancy is a major public health problem worldwide, but there are great diferences among countries and regions.Although the prevalence rate of agestandardized point and DALY rate caused by ectopic pregnancy has decreased in the past 30 years, the burden is still heavy, especially in less-developed countries.In addition, despite the multifactorial nature of the disease, dietary iron defense is still an important factor that cannot be ignored in all regions of ectopic pregnancy.Terefore, it is necessary to pay more attention to nutritional interventions, formulate comprehensive interventions, give priority to the highest-risk group, and strengthen the early prevention and treatment of ectopic pregnancy to improve the prognosis of patients.

Figure 4 :
Figure 4: Te correlations between EAPC and age-standardized incidence (ASIR) (a), death (ASDR) (c), and DALY (e) rate in 1990 and correlations between EAPC of incidence (b), death (d), DALY (f ), and HDI in 2019.Each circle represents a country and the size represents number of ectopic pregnancy patients.Te r value is the correlation coefcient of Pearson's correlation.EAPC: estimated annual percentage change and HDI: human development index.

Figure 6 :
Figure 6: Te trends of age-standardized DALYs (a) and deaths (b) attributable to iron defciency from 1990 to 2019.

Table 1 :
Te incident cases and ASIR in 1990 and 2019 and its temporal trends.

Table 2 :
Te death cases and ASDR in 1990 and 2019 and its temporal trends.

Table 3 :
Te DALY and age-standardized DALY rate in 1990 and 2019 and its temporal trends.