{"paper_id":"8acc8154-da6a-48af-960d-9857cd9cebc6","body_text":"Infertility is a serious worldwide health problem affecting\nalmost 8-10% of couples global ( 1 ). According to the World\nHealth Organization (WHO), 186 million ever-married\nwomen in sexual age in developing countries are affected\nby infertility ( 2 ). This serious problem requires urgent\naction, especially where most infertility cases are avoidable.\nAccording to the latest global described as failure to reach\nclinical pregnancy after regular unprotected intercourse for\ntwelve months omore. Having regular sexual intercourse is\na key factor in pregnancy. Primary infertility is the lack of\nability to give birth either because of not having the ability\nto get pregnant or carry a baby till live birth, which can\nencompass miscarriage or stillbirth. Secondary infertility\nis the lack of ability to conceive or give birth despite a\nprevious pregnancy or a live birth ( 3 ).\nInfertility is a very important part of sexual health and\nefforts that have often been ignored ( 4 ) in this regard.\nFailure to give birth to an infant influences many couples\naround the world. The United State Centers for Disease\nControl and Prevention emphasize that infertility is\nbeyond just a problem that affects the quality of life with\nsignificant consequences for public health, such as mental\ndiscomfort, social stigma, economic stress and marital\nseparation. According to the results comparing stressful\nlife events, after mother’s death, father’s death and\nspouse's infidelity, infertility is ranked as fourth stressful\nlife event ( 5 ). Not considering the emotional afflictions\nof infertile men and women and secondary signs of\ninfertility (interpersonal problems, marital discontent and loss of libido) may lead to a flawed cycle that increases\ninfertility incidence ( 6 ). On the other hand, in recent\nyears, factors such as changes in women’s role in social\nactivities, delaying marriage, changes in childbearing age,\nincreasing use of contraceptive methods, liberal abortion\nlaws, and undesirable economic status have decreased\nfertility rates and increased infertility ( 7 ).\nThere are over one million infertile couples living\nin Iran, and since childbearing is so important in the\nreligious, historical, and cultural context of Iranian society,\ninfertility can be one of the causes of divorce ( 8 ). Gaining\naccurate information about the prevalence, and infertility\ntrends is the first main step in providing evidence-based\nmeasures and policies for decreasing the difficulties of\nthis issue worldwide. There have been numerous studies\nin Iran on the prevalence and etiology of infertility and\nthe results vary widely ( 9 - 43 ), and a systematic review\nof the original studies now seems necessary. The metaanalyses combine various studies with similar objectives,\nwhich involves increasing the number of samples and\ndecreasing the confidence interval, and this can provide a\nmore reliable estimate ( 44 ,  45 ). The purpose of this metaanalysis was to assess the prevalence and etiologic factors\nassociated with infertility in Iran.\n\nThe protocol of the present study was posted on International\nProspective Register of Systematic Reviews (PROSPERO\n2020) prior to implementation (CRD42020170926\nAvailable from: https://www.crd.york.ac.uk/prospero/\ndisplay_record.php?ID=CRD42020170926). We made\nsure that the implementation of study and reporting\nthe results were consistent with the Meta-analyses Of\nObservational Studies in Epidemiology (MOOSE) ( 46 )\nand Preferred Reporting Items for Systematic Reviews and\nMeta-Analysis (PRISMA) guidelines, respectively ( 47 ).\nAll stages of the research were conducted by two authors,\nand the disagreement at each stage of the research was\nresolved by consensus.\nOn January 1, 2020, we started a detailed literature\nsearch on international databases of Web of Science (ISI),\nOvid, Scopus, EMBASE, PubMed/Medline, Cochrane\nLibrary, EBSCO, CINAHL, and Iranian Online databases\nScientific Information Database (SID), elmnet , Civilica,\nRegional Information Center for Science and Technology\n(RICST), , IranDoc , Magiran Barakat Knowledge\nNetwork System, and Iranian National Library, as well\nas specialized journals, several authentic international\npublishers including Wiley online library, Science Direct,\nand Springer and search engines such as Google Scholar.\nWe reviewed the reference list of identified articles for\nmissed articles and then searched online for them.\nThe following search strategy is an example of what\nwas used in PubMed: (“prevalence” OR “frequency” OR\n“incidence” OR “rate” OR “epidemiology” OR “etiology”\nOR “cause”) AND (“infertility”) AND Iran.\nAfter excluding duplicate studies, the two writers reviewed\nthe title and abstract of the studies independently. In case of\ndisagreement, a third author was consulted or it resolved\nthrough consensus. Then, the full text of each study was\nreviewed based on the target inclusion criteria ( Fig .S1 , See\nSupplementary Online Information at www.ijfs.ir).\nEligible studies according to PECOS (population,\nexposure, comparison/comparator, outcome and study\ntype) criteria: i. Population: Iranian population, ii.\nExposure: infertility, iii. Comparison/comparator: type\nof infertility and its cause, iv. Outcome: prevalence of\ninfertility, and v. Study type: cross-sectional study.\nInfertility was defined as failure to achieve pregnancy\nafter unprotected intercourse for 12 months. Primary\ninfertility was defined as not experiencing a previous\npregnancy and secondary infertility was defined as having\na previous pregnancy ( 48 ). Infertility is considered as\nlifetime when a couple has experienced infertility in their\nwhole lives. However, current infertility is defined as\nhaving the problem of infertility at present ( 49 ).\nTwo researchers extracted the required data from all studies\nbased on data encryption list. The following variables were\nobtained for each article: i. Study information (authors,\npublication year, place of study and completion year), ii.\nDesign of the study, iii. Sample selection, iv. Reliability\ncoefficient of the instrument, v. Sample size, vi. Prevalence\n(lifetime infertility, current infertility, primary infertility,\nsecondary infertility, and etiology of infertility).\nNewcastle-Ottawa Scale adapted for cross-sectional\nresearch was used to assess the quality of articles ( 50 ).\nThe highest achievable score was 9. Three categorizations\nwere defined for the quality of studies with a score of less\nthan 6, 6-7, and 8-9 as low, medium and high quality,\nrespectively.\nThe program used here was Comprehensive Metaanalysis Software ver. 2, and the results\nwere shown as forest plot. The heterogeneity of the data was evaluated using I 2 \nindex. This test evaluates the percent of variability in estimating the effect of\nheterogeneity. Significant heterogeneity exists if I 2  values are above 50%\n( 51 ). Meta-analysis was performed to estimate the prevalence using a random effects model\nby DerSimonian and Laird for point estimation and 95% confidence interval (CI).\nPublication bias was assessed according to regression asymmetry tests ( 52 ). Sensitivity\nanalysis was used to investigate the effect of individual studies on overall prevalence.\nSubgroup-analysis and meta-regression were conducted to determine the source of\nheterogeneity. Significance level was defined less than 0.05 in all tests.\n\nThe lifetime infertility prevalence (in 14 studies with\n46,466 samples) ( Table 1 ) was 11.3% (95% CI: 8.6-14.7)\nand current infertility (in 34 studies with 30,069 samples)\nestimated to be 3.7% (95% CI: 3.2-4.3) ( Fig .1 ).\nThe subgroup analysis regarding the prevalence of lifetime\ninfertility according to the region (P=0.069), year (P=0.069)\nand studies quality (P=0.069) was insignificant ( Fig .S2 ,\nSee Supplementary Online Information at www.ijfs.ir).\nSubgroup analysis of current infertility prevalence was\nsignificant based on year (P<0.001) but not significant based\non region (P=0.321) and studies quality (P=0.593,  Fig .S3 ,\nSee Supplementary Online Information at www.ijfs.ir).\nSummary of characteristics in studies into a meta-analysis\nThe primary infertility prevalence (in 45 studies\nwith 51,021 samples) and secondary infertility (in\n13 studies with 35,683 samples) in Iran was 18.3%\n(95% CI: 15.4-21.6) and 2.5% (95% CI: 1.6-4.0),\nrespectively ( Fig .2 ).\nPrevalence of infertility.  A.  Lifetime infertility and  B.  Current\ninfertility. Red rhombus; Overall estimate.\nSubgroup analysis of primary infertility prevalence\nwas significant based on year (P<0.001) and studies\nquality (P=0.069) but not significant based on region\n(P=0.430) ( Fig .S4 , See Supplementary Online\nInformation at www.ijfs.ir). Subgroup analysis of\nsecondary infertility prevalence according to region\n(P=0.321), and studies quality (P=0.593) was not\nsignificant, but was significant based on year (P<0.001,\n Fig .S5 , See Supplementary Online Information at\nwww.ijfs.ir).\nThe prevalence of female, male, both and unexplained\ncauses was estimated to be 32.0% (95% CI: 27.6-\n36.8), 43.3% (95% CI: 38.2-48.6), 12.5% (95% CI:\n9.6-16.2) and 13.6% (95% CI: 10.2-17.8), respectively\n( Fig .3 ).\nThe prevalence of causes related to ovulation, uterine\ntubes, and endometriosis in infertile women was estimated\nto be 54.0% (95% CI: 45.6-62.2), 15.5% (95% CI: 11.3-\n21.0), 6.2% (95% CI: 3.5-10.6), and 5.4% (95% CI: 2.5-\n11.3), respectively ( Fig .4 ).\nAbnormal semen analysis was estimated to be 55.6%\n(95% CI: 45.7-65.2) among infertile men ( Fig .S6 , See\nSupplementary Online Information at www.ijfs.ir).\nMeta-regression based on year was not significant in\nterms of lifetime infertility prevalence (coefficient:- 0.000,\n95% CI:-0.057 to 0.055, P=0.976) and current infertility\n(coefficient: 0.057, 95% CI:-0.005 to 0.119, P=0.073),\nprimary infertility (coefficient:-0.021, 95% CI:-0.084\nto 0.040, P=0.496), and secondary infertility (coefficient:-0.017, 95% CI:-0.106 to 0.071, P=0.700,  Fig .5 ).\nSensitivity analysis with individual study elimination\nfor all meta-analyzes showed a strong overall result\n( Fig .S7 - Fig S9 , See Supplementary Online Information at\n  www.ijfs.ir ).\nPublication bias tests were not significant for studies\nabout the prevalence of lifetime, current, primary, and\nsecondary infertility ( Fig .S10 , See Supplementary Online\nInformation at www.ijfs.ir).\nPrevalence of infertility.  A.  Primary infertility and  B.  Secondary\ninfertility. Red rhombus; Overall estimate.\nThe prevalence of infertility.  A.  Female,  B.  Male,  C.\n Both, and  D.  Unexplained causes. Red rhombus; Overall\nestimate.\nThe prevalence of causes related to infertility.  A.  Ovulation,  B.\n Uterine tubes, and  C.  Endometriosis in infertile women. Red\nrhombus; Overall esti- mate.\nMeta-regression based on year for the prevalence of infertility.  A.  Lifetime,\n B.  Current infertility,  C.  Primary infertility,\nand  D.  Secondary infertility.\n\nInfertility is a common situation with complex socioeconomic and health outcomes for the individuals and\nthe whole society. In spite of the important outcomes\nof infertility, estimating its prevalence is faced with\nlimitations. In this systematic meta-analysis, the lifetime\ninfertility prevalence was estimated at 11.1%, while\n3.7% had current infertility. The estimated incidence of\ninfertility is between 3.5 and 30% in various countries,\nand this variety is probably due to the population under\nstudy, the definitions of infertility and the estimation\nmethod ( 4 ). Therefore, the major challenges in evaluating\nthe true infertility burden include the lack of populationbased researches and the variety of definitions. In addition,\nadvancements in diagnosing, treating and preventing\ninfertility in recent decades have caused great changes\nin infertility prevalence worldwide. In least developed\ncountries, the prevalence of 12-month infertility varies\nfrom 6.9 to 9.3%. Significant geographic diversities have\nbeen noted in its prevalence, and the diversities are mostly\nexplained by the difference in cultural, environmental,\nand socioeconomic effects and having evaluate to the\nhealth-care system ( 54 ). The prevalence varies widely\nfrom 9% in Gambia to 11.8% in Ghana compared to\n21.2% in northwest Ethiopia and between 20 and 30% in\nNigeria ( 3 ,  8 ,  55 - 57 ). We do not have much information\nabout Asian countries and Latin America. Based on the\nstatistics provided by WHO, infertility prevalence in these\nareas varies from 8 to 12% in women of childbearing ages\n( 2 ). Universally, the age-standardized female infertility\nprevalence has elevated by 14.96% (from 1366.85 per\n100,000 in 1990 to 1571.35 per 100,000 in 2017) ( 58 ).\nBased on a previous meta-analysis in 2013, lifetime\ninfertility and current infertility prevalence in Iran was\nreported to be 10.9 and 3.3%, respectively ( 59 ), and our\nestimate shows a slight increase compared to the previous\nestimate.\nSearching for assistive behaviors related to infertility\nservices is common in Iranians. In one study, more than\n75% of people with fertility problems sought medical\nhelp. An international survey reported that 56% of women\nin more advanced countries seek help from infertility\ntreatment systems ( 54 ), and a Trävä study ( 60 ) found\nthat 57% of all infertile women did so. The popularity of\nseeking help for infertility treatment in Iran may be owing\nto the present perception that in Iran, having a child is\nthe only way to improve one’s position in the family and\nsociety ( 61 ). There have been several explanations for not\nseeking (or following up) infertility assistance, including\nlack of understanding or acknowledgment of the problem\n( 62 ), fear of being labeled infertile, worrying about the\ncost of treatment , having no intention to provoke , and the\nphysical and psychological burden of treatment.\nDecrease in fertility rates does not imply that infertility\nhas elevated. Despite the reports of increased infertility\nrates in some parts of the world, the evidence suggests the\ntotal prevalence of infertility has not changed significantly\nover the past thirty years. In this study, no significant\nchange was found in the prevalence of infertility in Iran\nbased on the meta-regression models over time (between\n1990-2016). The important point is the noteworthy\nreduction in total fertility rate (TFR) in Iran; TFR in\nIran was 7 children per woman in 1960, 6.5 in 1980,\n2.06 in 2000, 1.83 in 2010, and 2.11 in 2017 ( 1 ). TFR is\ndecreasing in the world. Europe has the lowest level of\nfertility rate among all regions of the world. Partnership\ninstability, better cooperation of women in education and\noccupations, postponement of parenthood, changes in\nvalues and economic burdens impose significant effects\non fertility rates ( 63 ). On the other hand, infertility is more commonly experienced by married people,\nreflecting the fact that people in stable relationships are\nmore likely to become pregnant and are hence aware of\nfertility problems ( 62 ). Much lower prevalence among\nyoung people somewhat indicates that they may never\nattempt to become pregnant. Previous studies have shown\nprolonged transition to adulthood and increase in the\ninterval between important reproductive events such as\nfirst sexual relationship, marriage, and birth of first child\n( 64 ). On the other hand, much of the literature describes\nthe tendency of women in developed countries to delay\nhaving children ( 65 ) and it is suggested that this tendency\nis rapidly becoming a global phenomenon ( 66 ).\nIn the previous meta-analysis, the primary infertility\nprevalence was 10.6% and secondary infertility prevalence\nwas 2.7% ( 59 ), which was higher in our study. A global\nstudy in 2010 among one hundred and ninety countries,\namong pregnant women aged 20-44, primary infertility\nwas 1.9% and secondary one was 10.5%. Some regions\nhave a high incidence of primary infertility, but secondary\ninfertility is low, like North Africa and the Middle East,\nespecially Adetoro and Ebomoyi ( 3 ). However, some\nareas have a high incidence of secondary infertility, but\nthe incidence of primary infertility is low, such as in\nCentral and Eastern Europe and Central Asia. In addition,\nseveral previous studies provided information on the\nprevalence of gender-related infertility. For instance, the\nprevalence of infertility in England was 12.5% in women,\nbut it was 10.1% in men ( 62 ). It is worth noting that in\nthese published studies, some only examined women ( 42 ).\nOthers only evaluated the records of men in infertility\nclinics ( 67 ). Likewise, these articles are performed on\nfairly small groups which do not represent the majority of\nthe infertile population ( 36 ).\nResults of the causes of infertility in Iran showed that\nthe causes of infertility were as follows: 32.0% male\ncause, 43.3% female cause, 12.5% both genders and\n13.6% unknown. This calculated percentage is consistent\nwith reported estimates of major causes of infertility in\nother studies ( 6 ).\nResearch shows that different studies provide different\ndefinitions of infertility, which may lead to misunderstanding\nof the actual situation ( 68 ). Some sources define infertility\nas lack of pregnancy after two years of unprotected\nintercourse , while others consider the couple infertility if\npregnancy does not occur after unprotected intercourse for\n12 months ( 69 ). We only provided studies with a 12-month\ndefinition. Therefore, we even excluded good-quality\nstudies with more than 12 months of measurement (such as\nthe study of Safarinejad) ( 70 ).\nThere was a high heterogeneity among articles across\nall of meta-analyses, and by considering the present\ndata, we were able to ascribe this difference to the\ngeographical area and year based on subgroup analysis.\nOther differences, including the partnership instability,\nincreased cooperation of women in better education and\noccupations, postponement of parenthood, changes in\nvalues and economic burdens could not be investigated\nby using available data.\nThe strengths of the present study included the use of\na comprehensive search strategy, selection of studies,\nextracting data and even analyzing the data by two\nindependent researchers based on MOOSE guidelines,\nwhile the diversities were sorted out via group discussion.\nIn case of any doubt of duplicate publications or more\ninformation that was required, we contacted the first or\ncorresponding authors. We performed a conservative\nestimate using the random effects model, adopted a\nsubgroup analysis and a meta-regression model to\ndiscover the heterogeneity causes. In the present study,\nin addition to updating previous meta-analyses to\nestimate the prevalence of lifetime and current infertility\nwith a much higher sample size, we meta-analyzed the\netiological details of infertility for the first time. The\nweaknesses of our study included the restricted search in\ninternal databases and exclusion of studies with different\ninfertility definitions.\n\nIn summary, the estimate of infertility burden in Iran\ndid not change between 1990 and 2017 and its prevalence\nremains high. This study provides a comprehensive and upto-date understanding of the that we need prevention and\nmanagement interventions to alleviate infertility in Iran.\nFurther research is required to evaluate the risk factors\nof infertility for developing effective prevention and\nmanagement strategies to decrease the burden of this issue.","source_license":"public-domain-us","license_restricted":false}