Escalating global burden of female infertility

Abstract

This study explores the global burden of female infertility across 204 countries and 21 regions from 1990 to 2021. The population-based study analyzed was conducted using data from the Global Burden of Disease 2021. We assessed age-standardized prevalence rate (ASPR), age-standardized incidence rate, disability-adjusted life years rate, and trends via average annual percent change, with projections to 2035 using the Bayesian age-period-cohort model. The outcomes revealed that female infertility sustained a global rise in ASPR (0.66% annually) and disability-adjusted life years (0.68% annually), driven by population growth and aging. Notably, while the 35 to 39 age group exhibited the highest prevalence, the 20 to 29 age group showed the fastest growth rate (average annual percent change = 1.04%), signaling a younger-onset trend. Socioeconomic disparities were prominent: low-middle sociodemographic index regions experienced the steepest ASPR increases (1.23% annually), contrasting with high sociodemographic index areas. During 2019 to 2021, ASPR stabilized, potentially linked to COVID-19-related population shifts rather than direct biological effects. Projections indicate a persistent burden, with ASPR reaching 6458.26/100,000 by 2035. These findings underscore the urgent need for targeted interventions addressing socioeconomic inequities, younger demographic risks, and sustainable reproductive health policies to mitigate the escalating global challenge of female infertility.

1. Introduction

Infertility refers to the situation where couples who desire to have children are unable to conceive after at least 12 months of unprotected intercourse.^[1,2] Millions of couples worldwide are afflicted by infertility. Both female and male factors can contribute to infertility, among which female factors are more prevalent.^[2] The causes of female infertility encompass pathological alterations in the female reproductive system, metabolic diseases, aging, unhealthy lifestyles, and others.^[3–7] Female infertility exerts a significant impact on patients’ physical and mental well-being.^[8,9] Female infertility often involves hormone imbalances and metabolic disorders, such as polycystic ovary syndrome, obesity, diabetes, and other conditions, which may indirectly shorten life expectancy and increase the risk of female reproductive system tumors due to hormonal abnormalities and therapeutic drugs such as clomiphene.^[10,11] Surgical procedures and exogenous hormone therapy can lead to abdominal discomfort, hot flashes, mood swings, and even ovarian hyper-stimulation syndrome, causing disappointment or anxiety. Meanwhile, family emotional distress is accompanied by social pressure and stigmatization.^[3,12,13]

Affected by the economy, social customs, religion, environment, and climate, the prevalence of female infertility varies significantly and exhibits an upward trend in different regions and countries. Approximately 8% of the world’s women of reproductive age are affected, which directly impedes the sustainable development of the global population.^[13–15] Women in developed countries delay childbearing due to career planning and life stress, while those in developing countries face challenges in prevention, diagnosis, and management caused by insufficient health, nutrition, and medical resources.^[10] A study of French women reveals that there is considerable expenditure on infertility treatment for reproductive-aged women, with an annual disease-related expense of 70 million euros for every 10,000 women.^[16] Sun et al discovered that the age-standardized prevalence rate and disability-adjusted life growth rate of female infertility from 1990 to 2017 were higher than those of males.^[17] Female infertility has a profound influence on labor supply, economic development, and social structure, imposing a heavy burden on individuals and society. There is an urgent need for global attention and in-depth research to confront this severe challenge.

In recent years, especially after the outbreak of COVID-19, there have been few epidemiological studies on female infertility from a global perspective. Many studies have focused on the impact of the severe acute respiratory syndrome coronavirus 2 virus on the reproductive system, indicating that virus infection might have a negative effect on fertility.^[18,19] Studies have shown that the severe acute respiratory syndrome coronavirus 2 virus can affect female follicle formation, reduce ovarian reserve function, cause abnormal ovulation, and affect the hypothalamus–pituitary–gonad axis in multiple ways, leading to menstrual disorder.^[20–22] The quality of the embryo may be compromised if fertilization occurs during the acute infective period.^[23] It remains unclear whether COVID-19 is the cause or a contributing factor to female infertility. The assessment of the global trend of female infertility prevalence and disease burden during the COVID-19 epidemic may provide indirect evidence for this issue. Therefore, it is essential to reevaluate the prevalence and trend of female infertility in the post-COVID era and clarify the current global burden, thereby guiding the prevention, intervention, and management of female infertility.

2. Methods

2.1. Data sources

The data for this study were obtained from the global burden of disease (GBD) 2021, which encompasses epidemiological data on 371 diseases and injuries in 21 GBD regions and 204 countries and territories during the period from 1990 to 2021. These data are freely accessible via the Global Health Data Exchange platform (https://ghdx.healthdata.org/gbd-2021/sources).

2.2. Study population

Female subjects aged between 15 and 49 years with infertility were included in the study. Information such as prevalence, incidence, disability-adjusted life years (DALYs), and DALYs attributable to each risk factor (with 95% uncertainty intervals [UIs]) was extracted.

2.3. Burden assessment indicators

The burden of female infertility was evaluated using 3 indicators: incidence, prevalence, and DALYs. Age-standardized rates were employed to eliminate the influence of age distribution differences, and weighted averages were calculated for comparative purposes. DALYs, a comprehensive metric for quantifying the burden of disease, consist of years lived with disability and years of life lost. The age-standardized rate (ASR) was computed per 100,000 individuals utilizing the subsequent formula:

$$\begin{array}{c}{\displaystyle }ASR=\frac{{\sum }_{i=1}^A{a}_i{w}_i}{{\sum }_{i=1}^A{w}_i}\times 100,000\end{array}$$

where a_i and w_i denote age-specific rates and the number of persons (or weight) in the same age subgroup of the chosen reference standard population (where i denotes the ith age class), respectively.

2.4. Age groups and dociodemographic index (SDI)

Data on female infertility in 21 GBD regions, composed of geographically adjacent countries with similar epidemiological characteristics, were analyzed. These regions were divided into 7 age groups: 15 to 19, 20 to 24, 25 to 29, 30 to 34, 35 to 39, 40 to 44, and 45 to 49 years. The SDI of each country was calculated to investigate the association between the burden of female infertility and socioeconomic development. The SDI, a composite indicator of social and economic conditions affecting health outcomes, ranges from 0 to 1 and is divided into 5 quintiles: low, low-middle, middle, high-middle, and high.

2.5. Statistical analysis

Descriptive analyses on females only were conducted to compare the age-standardized prevalence rates (ASPR), age-standardized incidence rates (ASIR), age-standardized death rates (ASDR), and DALYs of infertility across different age groups, regions, and countries. The average annual percent change (AAPC) was used to represent the average annual change rate of a specific variable over a specific period. It was calculated as the weighted average of the slope coefficients of the underlying Joinpoint regression model. Joinpoint regression analysis was performed with a maximum of 3 Joinpoints. Model selection was based on the Bayesian information criterion, and log-linear models were used for the estimation of time trends. Based on the GBD data, the ASPR and 95% UI for the world’s standardized population in 2021 were calculated for regional comparisons, and the AAPC was estimated by joinpoint regression to measure the time trend. Additionally, a decomposition analysis of the burden of female infertility from 1990 to 2021 was performed using the method developed by Das Gupta to identify the contributions of population growth, population age structure, and epidemiological changes to the burden changes. The calculation formula of AAPC is as follows:

$$\begin{array}{c}{\displaystyle }AAPC=(e^{\left(\frac{{\sum }_{i-1}^k{b}_i{w}_i}{{\sum }_{i-1}^k{w}_i}\right)}-1)\times 100\end{array}$$

b_i is the slope coefficient of the ith segment (i.e., the APC). w_i is the length of time for each segment (usually measured in years). “k” is the total number of segments. $\sum$ represents the summation.

A prediction of female infertility in 2035 was also carried out using the Bayesian age-period-cohort model. This model was applied to project the potential trends and changes in the incidence, prevalence, and other relevant indicators of female infertility in different regions and age groups in 2035, based on historical data and patterns of female infertility from 1990 to 2021.

3. Results

Globally, the ASPR of female infertility among reproductive-aged women (15–49 years) was 4581.22/100,000 (95% UI: 1334.59–10,445.33) in 1990 and 5586.19/100,000 (95% UI: 1580.25–12,917.2) in 2021, with an annual growth rate of about 0.66% (95% confidence interval [CI]: 0.57–0.76) (Table 1). In 2021, the incidence was highest in the 35 to 39 age group. The AAPC for 20 to 24 and 25- to 29-year-olds was higher, with scores of 1.04% and 1.02%, respectively. The incidence of female infertility demonstrated an increasing tendency regardless of SDI, of which the low-middle SDI had the highest annual growth rate of 1.23% (95% CI: 0.92–1.54).

Table 1.

The prevalence cases and ASPR of female infertility in 1990 and 2021 and its trends.

	Prevalence
	1990 counts (95% UI)	2021 counts (95% UI)	1990 ASR (95% UI)	2021 ASR (95% UI)	AAPC (95% CI)
Global	59,689,999.8 (17,523,491.21–135,943,503.17)	110,089,459.28 (31,051,019.39–254,716,760.01)	4581.22 (1334.59–10,445.33)	5586.19 (1580.25–12,917.2)	0.66 (0.57–0.76)
High SDI	5,090,008.07 (1,127,203.24–14,033,772.21)	7,476,943.46 (1,328,133.86–20,976,789.87)	2120.83 (469.04–5852.22)	2860.77 (501.78–8060.92)	1.03 (0.86–1.21)
High-middle SDI	16,546,620.6 (4,803,408.26–37,046,249.01)	21,200,265.94 (5,677,838.67–49,662,886.16)	5859.23 (1690.62–13,124.53)	6425.88 (1729.47–15,084.33)	0.3 (0.27–0.33)
Middle SDI	22,576,312.93 (6,532,011.33–50,626,394.46)	39,038,802.27 (10,528,473.47–90,881,602.27)	5384.83 (1552.92–12,053.94)	6117.68 (1650.98–14,246.1)	0.41 (0.34–0.49)
Low-middle SDI	10,739,459.55 (3,157,911.66–24,828,743.02)	30,053,932.7 (9,339,735.08–68,093,929.66)	4136.12 (1186.67–9646.29)	5941.61 (1828.32–13,492.45)	1.23 (0.92–1.54)
Low SDI	4,687,800.56 (1,598,354.63–10,186,699.41)	12,249,743.98 (3,851,922.54–27,475,785.78)	4486.02 (1524.52–9792.92)	4715.98 (1455.75–10,644.77)	0.22 (−0.01 to 0.45)
Age group
15–19 yr	791,658.25 (97,993.25–2,338,496.68)	1,014,988.54 (69,015.93–3,271,028.2)	309.8 (38.35–915.12)	334.26 (22.73–1077.24)	0.26 (0.13–0.38)
20–24 yr	7,957,251.01 (2,863,602.4–16,004,113.11)	13,082,607.56 (4,616,283.93–26,411,135.7)	3259.37 (1172.96–6555.44)	4453.62 (1571.49–8990.96)	1.04 (0.88–1.19)
25–29 yr	10,618,577.77 (3,352,786.48–26,006,674.29)	19,170,379.45 (6,129,767.61–46,190,158.91)	4824.44 (1523.3–11,815.87)	6588.05 (2106.54–15,873.6)	1.02 (0.93–1.11)
30–34 yr	13,279,983.89 (3,429,389.11–30,328,858.3)	26,866,482.92 (6,932,323.82–64,075,581.85)	6985.46 (1803.91–15,953.4)	8987.52 (2319.04–21,434.92)	0.93 (0.59–1.27)
35–39 yr	17,089,875.28 (5,157,052.04–38,349,601.04)	30,599,403.42 (8,491,887.74–69,339,499.29)	9852.72 (2973.16–22,109.47)	11,014.8 (3056.8–24,959.98)	0.36 (0.21–0.51)
40–44 yr	9,834,566.32 (2,599,135.64–22,294,902.33)	19,070,838.95 (4,763,495.84–43,742,361.28)	7013.4 (1853.54–15,899.33)	7687.07 (1920.07–17,631.66)	0.32 (0.22–0.42)
45–49 yr	118,087.28 (23,532.29–620,857.42)	284,758.44 (48,244.52–1,686,994.78)	103.77 (20.68–545.57)	120.84 (20.47–715.91)	0.31 (−0.83 to 1.46)

AAPC = average annual percentage change, ASPR = age-standardized prevalence rate, ASR = age-standardized rate, CI = confidence interval, SDI = sociodemographic index, UI = uncertainty interval.

The global incidence of female infertility is shown in Figure 1, with an upward tendency in 16 regions (Fig. 1A). Eastern Asia, Southern Asia, Southeastern Asia, Eastern Europe, and parts of Sub-Saharan Africa are areas with a high incidence of female infertility, and the DALYs burden in these areas remains high (Fig. 1B and C). Although the incidence of ASDR and ASPR is relatively low in parts of Latin America and along the Mediterranean coast, the growth rate is rather pessimistic (Fig. 1D). From the perspective of AAPC distribution, the prevalence of female infertility shows an increasing trend in 115 countries and regions. Three countries/regions with relatively faster growth are Peru (10.61%), Ecuador (5.15%), and Togo (4.77%), while those with declines are Malawi (−6.61%), Uganda (−4.30%), and Burundi (−3.92%) (Fig. 1B and Table S1, Supplemental Digital Content 1).

Figure 1.

Global epidemiological traits of female infertility in 201 countries and territories. (A) The age-standardized prevalence of female infertility between 1990 and 2021; (B) The estimated annual percentage change of female infertility age-standardized prevalence between 1990 and 2021; (C) The DALYs of female infertility between 1990 and 2021; and (D) The estimated annual percentage change of female infertility age-standardized death rates between 1990 and 2021. AAPC = average annual percent change, ASDR = age-standardized death rates, ASPR = age-standardized prevalence rate, DALYs = disability-adjusted life years.

The ASR-DALYs of female infertility in 1990 was 24.89/100,000 (95% UI: 5.23–72.3), and in 2021, it reached 30.55/100,000 (95% UI: 6.32–87.18), with an annual growth rate of approximately 0.68% (95% CI: 0.58–0.79) (Table 2). In 2021, the ASR-DALYs of patients aged 35 to 39 was the highest, which was 57.95 (95% CI: 12.88–167.42). The APC of ASR-DALYs in patients aged from 25 to 29 years old was the highest, which was 1.05 (95% CI:0.95–1.14).

Table 2.

The incidence cases and ASIR of female infertility in 1990 and 2021 and its trends.

	DALYs
	1990 counts (95% UI)	2021 counts (95% UI)	1990 ASR (95% UI)	2021 ASR (95% UI)	AAPC (95% CI)
Global	325,936.79 (68,632.89–943,171.24)	601,133.51 (124,293.13–1,716,290.98)	24.89 (5.23–72.3)	30.55 (6.32–87.18)	0.68 (0.58–0.79)
High SDI	28,319.99 (4542.51–94,060.33)	41,100.93 (5491.76–136,766)	11.82 (1.89–39.25)	15.82 (2.08–52.54)	1.01 (0.83–1.18)
High-middle SDI	88,610.77 (18,863.33–255,699.43)	112,846.18 (22,510.04–326,067.83)	31.33 (6.65–90.69)	34.43 (6.84–99.81)	0.31 (0.28–0.34)
Middle SDI	121,994.02 (25,327.11–349,883.27)	211,708.41 (42,256.7–612,214.88)	28.9 (6.04–83.16)	33.28 (6.63–96.2)	0.45 (0.38–0.52)
Low-middle SDI	60,815.36 (13,275.96–171,051.06)	167,400.47 (36,219.01–462,514.88)	23.14 (5–65.61)	33.01 (7.1–91.6)	1.24 (0.92–1.57)
Low SDI	25,921.95 (6368.83–69,920.9)	67,696.06 (15,475.22–183,700.06)	24.49 (6.02–66.61)	25.86 (5.86–70.74)	0.27 (−0.03 to 0.56)
Age group
15–19 yr	5074.38 (468.79–17,951.64)	6162.18 (316.19–23,164.36)	1.99 (0.18–7.03)	2.03 (0.1–7.63)	0.09 (−0.04 to 0.22)
20–24 yr	48,663.08 (11,823.48–133,351.57)	78,481.71 (19,500.61–207,846.34)	19.93 (4.84–54.62)	26.72 (6.64–70.76)	0.97 (0.79–1.15)
25–29 yr	60,406.22 (11,757.15–172,481.36)	109,615.3 (22,334.45–309,836.91)	27.44 (5.34–78.37)	37.67 (7.68–106.48)	1.05 (0.95–1.14)
30–34 yr	70,119.21 (13,340.58–189,815.29)	142,815.18 (26,432.98–384,260.94)	36.88 (7.02–99.85)	47.78 (8.84–128.55)	0.96 (0.62–1.3)
35–39 yr	89,176.03 (20,855.05–261,596.73)	160,994.61 (35,789.9–465,101.96)	51.41 (12.02–150.82)	57.95 (12.88–167.42)	0.39 (0.2–0.58)
40–44 yr	51,867.62 (10,292.63–164,619.55)	101,534.89 (19,710.24–317,436.65)	36.99 (7.34–117.4)	40.93 (7.94–127.95)	0.36 (0.26–0.46)
45–49 yr	630.25 (95.21–3355.1)	1529.64 (208.76–8643.82)	0.55 (0.08–2.95)	0.65 (0.09–3.67)	0.33 (−0.81 to 1.48)

AAPC = average annual percentage change, ASIR = age-standardized incidence rate, ASR = age-standardized rate, CI = confidence interval, DALYs = disability-adjusted life years, SDI = sociodemographic index, UI = uncertainty interval.

The global DALYs of female infertility and its changes are depicted in Fig. 1C, where 15 regions and 114 countries demonstrate an upward trend in ASR-DALYs (Fig. 1C and Table S2, Supplemental Digital Content 2). The 3 countries and regions with the most rapid growth are Peru (10.54%), Ecuador (5.10%), and Togo (4.68%). By contrast, the 3 countries and regions with the most significant declines are Malawi (−6.56%), Uganda (−4.36%) and Armenia (−3.81%). The global distribution of ASDR of female infertility is presented in Figure 1D, which is basically in line with the trend of age-standardized morbidity.

Female infertility showed an increasing tendency worldwide, especially after 2010 (Figs. 2 and 3A), and DALYs changed concurrently (Fig. 3B). The AAPC of the incidence and mortality has exhibited 5 stages of rapid decline, slow increase, slow decline, rapid rise, and slow rise over the past 20 years, and is currently at a high level of ASPR and ASDR (Fig. 3C and D).

Figure 2.

Correlation of SDI level with ASPR and ASDR and its trend. (A) ASPR trends of different SDI levels from 1990 to 2021. (B) ASDR trends at different SDI levels from 1990 to 2021. (C) ASPR is negatively correlated with SDI. (D) ASDR is negatively correlated with SDI. ASDR = age-standardized death rates, ASPR = age-standardized prevalence rate, SDI = sociodemographic index.

Figure 3.

Global trends in female infertility prevalence, mortality, and DALYs, 1990 to 2021. (A) Prevalence; (B) DALYs; (C) trend of annual growth rate of ASPR; and (D) trend of annual growth rate of ASDR. AAPC = average annual percent change, APC = annual percent change, ASDR = age-standardized death rates, ASPR = age-standardized prevalence rate, DALYs = disability-adjusted life years.

Regardless of different SDI levels, the ASR-DALYs displayed an increasing tendency, with the highest annual growth rate of 1.01% (95% CI: 0.83–1.18) in high SDI. ASDR and ASPR in the high-middle SDI were consistently high, and the growth is currently slow, while the low-middle SDI have been experiencing a period of rapid growth after 2010 (Figs. 2A, B and 4). According to the tendency of ASPR, ASDR, and SDI in 21 regions, there is a negative correlation between ASPR and SDI (r = −0.27), and between ASDR and SDI (r = −0.27) (Figs. 2C, D and 5).

Population growth is one of the most crucial reasons for the increasing prevalence, contributing 51.82% (Fig. 6). The increase in the incidence caused by population growth is particularly prominent in low and low-middle SDI, with a contribution of 150.29% and 107.18%, respectively. Low-middle SDI is also affected by epidemiological change (66.2%), while the impact of aging in middle SDI cannot be disregarded (12.13%).

Figure 6.

Relative contribution of aging, population, and epidemiological change to the prevalence (A) and DALYs (B) of female infertility at different SDI levels. DALYs = disability-adjusted life years, SDI = sociodemographic index.

Figure 4.

Average annual percentage change (AAPC) among women of reproductive age (15–49 years) in regions with different sociodemographic index (SDI) levels. (A) Prevalence of female infertility and (B) DALYs of female infertility.

Figure 5.

The negative relationship between ASPR, ASDR, and SDI. ASDR = age-standardized death rates, ASPR = age-standardized prevalence rate, SDI = sociodemographic index.

The incidence and DALYs of female infertility patients with different SDI levels varied in different age groups. The incidence and DALYs of all age groups in middle SDI were significantly higher than those in other SDI. In low-middle SDI, the increase in the incidence and DALYs among those aged 15 to 39 years old was higher than that among those aged 40 to 49 years old, especially after 2010 (Fig. 7). Female infertility patients in high SDI and high-middle SDI were mainly 25 to 49 years old, and the proportion of those aged 15 to 25 years old in low-middle SDI and low SDI is higher than that in other SDI (Fig. 8).

Figure 7.

Trends of female infertility prevalence and DALYs in different age groups and SDI levels from 1990 to 2021. DALYs = disability-adjusted life years, SDI = sociodemographic index.

Figure 8.

The distribution of prevalence and DALYs of female infertility with different SDI levels and different age groups in 2021. DALYs = disability-adjusted life years, SDI = sociodemographic index.

The global incidence of female infertility and DALYs burden remained relatively stable from 1990 to 2010, increasing at a low annual rate. Since 2010, the incidence and DALYs burden have been increasing rapidly. According to the model prediction, the growth momentum of the incidence and DALYs burden will slow down slightly from 2021 to 2035, but the overall number of patients is considerable. It is estimated that the global ASPR of female infertility will increase from 6171.82/100,000 in 2030 to 6458.26/100,000 by 2035 (Fig. 9, Table S3, Supplemental Digital Content 3).

Figure 9.

Global trends of female infertility prevalence and DALYs from 1990 to 2021 and forecast trend for 2035. ASR = age-standardized rate, DALYs = disability-adjusted life years.

4. Discussion

For a long time, global public health policies and plans have mainly focused on controlling population growth, thereby paying less attention to infertility intervention in many countries.^[1] This study revealed that the global ASPR and DALYs burden of female infertility among reproductive-aged women increased significantly from 1990 to 2021, with a pronounced acceleration after 2010. Peak incidence and disease burden were concentrated in the 35 to 39 age group, while relatively rapid annual increases were observed among women aged 20 to 29 years. Consistent upward trends were detected across all SDI levels, with the most rapid growth in the low-middle SDI and a significant inverse association between SDI level and ASPR as well as DALYs rates worldwide. Population growth emerged as the leading contributor to the rising burden, and although the projected growth rate is expected to moderate slightly by 2035, the overall disease burden will remain high, underscoring that female infertility poses a persistent and increasingly prominent global public health challenge.

The WHO 2023 report indicates a high global prevalence of infertility, particularly in countries and regions along the western Pacific Ocean (23.2%), while it is lower in the coastal areas of the eastern Mediterranean (10.7%).^[24] In contrast, this study found that the global ASPR of female infertility in 2021 was 5586.19/100,000, with an annual growth rate of approximately 0.66% compared to 1990. Yet, the estimated overall incidence was lower than that reported by the WHO. This disparity may be attributed to the different inclusion criteria for female infertility and the lack of male data.^[25,26] The absolute number of female infertility cases is increasing along with population growth.^[26–29] Compared to a few years ago, the prevalence of female infertility in some countries and regions has changed significantly. Among them, Peru (10.61%), Ecuador (5.15%), and Togo (4.77%) have higher rates than before, and the incidence rate increases rapidly along the Mediterranean coast and parts of Latin America. From the attribution analysis, rapid population growth could be an important factor contributing to the increase in female infertility.

From 1990 to 2021, the incidence of infertility among women aged 35 to 39 has always been the highest, which could be associated with various factors.^[17] Individually, ovarian reserve function declines with age, and the success rate of natural conception or assisted pregnancy decreased along with a thinner endometrium.^[30,31] Reasons such as late marriage, career pursuit, and anxiety can also lead to the postponement of the 1st childbearing age, thereby gradually revealing the age-related social problem of female infertility.^[32–34]

4.1. Global burden of female infertility

Over the past 3 decades, the burden of female infertility has increased, regardless of the level of SDI. The growth rate of SDI varies at different levels. It is worth noting that high SDI represents the lightest burden, but its annual growth rate cannot be ignored; while high-middle SDI experiences a more challenging burden. In 2021, the 3 regions with the heaviest burden were South Asia, East Asia, and Southeast Asia, and the countries were Indonesia, Pakistan, and India, while Peru, Ecuador, and Togo were in a rapid growth phase. South, East, and Southeast Asia are densely populated areas worldwide, with a large base and a high incidence of female infertility; the limitation of social and economic development may lead to a lack of knowledge regarding reproductive health popularization and inadequate medical conditions. The varied management in these countries and regions is influenced by numerous factors, such as national social and cultural values, economic and political situations, education levels, reproductive health policies, medical conditions, and others.^[35,36] Regardless of a country’s development level, only approximately 50% of infertile couples seek for medical assistance, and the inequality of medical resources and the willingness to seek medical help also contribute to the worrying situation in another way.^[37–40]

Consistent with the trend of incidence, the disease burden was greatest among women aged 35 to 39. In the 3rd decade of women’s lives, the contradictions are more prominent, such as the decline of ovarian reserve function, occupational stress, anxiety about seeking medical treatment for infertility, limited access to medical treatment, and high treatment expenses, all of which pose significant challenges to women struggling with infertility.^[41]

Overall, the prevalence of female infertility remained stable during the COVID-19 pandemic, which may be related to multiple factors. The expression of the angiotensin converting enzyme receptor in follicles is the theoretical basis that COVID-19 may affect the function of the female reproductive system.^[42] Mahdian et al. found that COVID-19 may interfere with embryo implantation through the Basigin receptor, which suggests avoiding fertilization in the acute stage of infection.^[43] COVID-19 has little impact on reconverted women’s reproduction, and there is no clear causal relationship between them.^[44] Regarding the vaccine, studies have demonstrated that vaccination was not related to female hormone levels, implantation rates, or pregnancy outcomes.^[45–47] Since COVID-19 or vaccines do not affect the occurrence and treatment of female infertility, the stability of female infertility may be due to the abnormal population reduction during the COVID-19 epidemic.^[48]

Yu et al predict that by 2030, the global ASPR of female infertility will be 3725.51/100,000, and the ASDR will reach 19.96/100, 000.^[41] In contrast, our prediction model indicates that the global ASPR of female infertility is expected to increase from 6171.82 per 100,000 in 2030 to 6458.26 per 100,000 by 2035. This discrepancy from Yu et al.‘s findings may stem from differences in the datasets and prediction models used. It is essential to prioritize and employ scientific approaches to address the issue of infertility to promote sustainable human development, ensure healthy lives, and advance gender equality.^[24]

5. Limitation

This study’s data are based solely on estimates of infertility prevalence among reproductive-aged women, lacking information on specific causes. Consequently, estimating the particular circumstances contributing to female infertility is challenging. Additionally, this analysis relies exclusively on the GBD 2021 database, which provides insight into trends only over the past 3 years and does not integrate broader data analyses.

6. Conclusion

The global burden of female infertility has been increasing from 1990 to 2021, and there will be a tough challenge in the next decade. Population growth, population aging, and uneven social development have led to great differences in the burden across different regions. Public health departments should highlight the management strategy of female infertility to promote female reproductive health and sustainable population development.

Acknowledgments

We extend our gratitude to the contributors of the Global Burden of Diseases, Injuries, and Risk Factors Study 2021 for their invaluable work. We also express our sincere appreciation to the Institute for Health Metrics and Evaluation (IHME) for making the GBD data available for this research. The study funders did not participate in the design of the study, data collection, analysis, interpretation, or report writing.

Author contributions

Formal analysis: Lizhi Lu, Chao Xiao.

Data curation: Wenwen Zhou, Jiyu Meng.

Writing – original draft: Qigui Chen.

Writing – review & editing: Gang Liu.