The prevalence of depression among Iranian infertile couples: an update systematic review and meta-analysis

Depression is a common mental disorder. Infertility can lead to depression. The current systematic review and meta-analysis were conducted to estimate the pooled prevalence of depression among Iranian infertile couples. Seven electronic databases (Google Scholar, MagIran, SID, Science Direct, PubMed, Scopus, Web of Science) were searched, up to August 2019, for relevant published studies. The pooled prevalence of depression also pooled mean of depression score was determined using a random-effects model with a 95% confidence interval (95% CI). All analyses performed using Stata ver11 (Stata Corporation, College Station, TX, USA). The 0.05 was considered a significant level. Totally, 230 studies were retrieved and 31 studies included in the meta-analysis. The pooled prevalence of depression among infertile couples was about 35.3% (95 % CI 24.1–46.5), and the prevalence of depression among females and males was 48.7% (95% CI 24.0–73.3) and 9% (95% CI 0% to 23.7%), respectively. Our findings suggest a high prevalence of depression in infertile couples. The results can highlight an important and growing mental disorder among infertile couples that may be overlooked.


Background
Infertility is a reproductive system deficiency defined by the "failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse" [1, 2]. The overall burden of subfertility/infertility is high globally, and it seems the trend of this deficiency does not have a decreasing trend. According to reports of the World Health Organization, over 10% of women are affected by infertility [2].. Also, according to results of Demographic and Health Surveys (DHS) data (2004), about 186 million married women at reproductive age have infertility deficiency in developing countries [3]. In Iran, the prevalence of primary infertility based on the WHO's clinical, epidemiological, and demographic definitions was 20.2, 12.8, and 9.2%, respectively. In addition, the prevalence of secondary infertility was about 4.9% [4]. Infertility affects various aspects of life including mental, social, and physical aspects [5,6]. Also, this disorder can lead to shame, stigma, anxiety, depression, and low feelings of selfesteem and guilt [7]. One of the more prevalent disorders among infertile couples especially among females is depression [8][9][10]. About 86% of infertile couples experience it [11]. Depression is defined by a sense of persistent sadness and a loss of enjoyment in activities, accompanied by an inability to carry out daily activities, for at least 2 weeks [12]. This mental disorder has a negative impact on the process of infertility treatment, the follow-up stage also the hope for treatment [13]. Feeling depressed and frustrated can reduce infertile women's satisfaction with the past, present, and future lives [14]. It is estimated that about 25 to 60% of infertile couples suffered at least one psychological disorder [15] and globally depression affected more than 300 million people of all ages [16]. The prevalence of depression among Iranian infertile couples was estimated 0.47 in 2013 [11]. Many studies have been conducted to estimate the prevalence of depression among Iranian infertile couples, which are widely reported. Also, a systematic review conducted up to 2011 [11] the prevalence of this mental disorder among Iranian infertile couples maybe change over time. Therefore, the purpose of the current systematic review and meta-analysis was to estimate a pooled measure of the prevalence of depression among Iranian infertile couples between 2005 and 2019.

Materials and methods
The current meta-analysis was performed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) and Meta-analysis of Observational Studies in Epidemiology (MOOSE).

Search strategy
In this study, articles published from January 2005 to August 2019 through 7 electronic databases (Google Scholar, MagIran, SID, Science Direct, PubMed, Scopus, Web of Science) were searched. The keywords were as follows: Infertility, Sterility, Sterile, Iran, Depressions, Depressive Disorder, Bipolar Disorder, Unipolar Disorder, Emotional Depressions, Depressive Symptom Were examined. The search was conducted in Persian and English languages. The search strategy of the databases was done independently by two researchers, and the dispute was resolved by a third person.

Screening and selection criteria
We included all published cross-sectional studies between 2005 and 2019 that estimated the prevalence of depression or mean and standard deviation of depression score among Iranian infertile couples. Also, the casecontrol, cohort, clinical trial, case reports, and case series studies were excluded. In addition, studies that did not  provide an accurate report about the prevalence of depression (or mean and standard deviation of the depression score) in the infertile population, as well as studies that did not use a standard questionnaire to measure depression, were excluded.

Quality and risk of bias assessment
An 8-item checklist was used for critical appraisal and risk of bias assessment of the studies. This checklist includes items such as Clearly define depression, clearly definite infertility, Give the eligibility, Give precision of the estimates, indicate the study's design, Explain sample size calculation, describe the locations, and describe the dates [11].

Data extraction
The data extraction form was included (1) author's name, (2) country, (3) year of performing and publication, (4) sex, (5) mean and standard deviation of age, (6) measuring tools, (7) sample size, (8) sampling method, (9) mean and standard deviation of duration infertility, (10) mean and standard deviation of duration marriage, and (11) and mean and standard deviation or prevalence of depression in infertile couples. All data were extracted independently by two authors. Also, some studies estimated different types of depression (mild, moderate, severe) among infertile couples. So the pooled prevalence of the mentioned subgroup was calculated separately.

Statistical analysis
The heterogeneity between studies was assessed using I 2 and T 2 (Tau2) statistics. Due to the presence of heterogeneity between studies (I 2 more than 90% and T 2 statistic), the pooled prevalence of depression also pooled mean of depression score was determined using a random-effects model with 95% confidence interval (CI). The weight of each study was determined using the inverse variance model. The univariate meta-regression was conducted to determine the probable cause of heterogeneity between studies. Also, the pooled estimate was estimated according to different subgroups. Begg and Egger's tests were used to assess publication bias. All analyses performed using Stata ver11 (Stata Corporation, College Station, TX, USA). The 0.05 was considered a significant level.

Results
As it is shown in Fig. 1, a total of 230 articles were found in the databases. After eliminating duplicates, screening the titles and abstracts of the articles, 51 articles were selected for full-text review. Of these, 20 studies were excluded because did not report the prevalence and were not cross-sectional study. Finally, 31 articles with 47 records were included in the study (Fig. 1). The general characteristics of the articles are listed in    Tables 2 and 3 and Fig. 2. Some studies calculated the mean and standard deviation of depression scores among understudy cases. The overall mean of depression score among Iranian couples was 7.74 [(95% CI 5.52-9.93), I 2 86.7, T 2 21.21, P heterogeneity < 0.001] (Fig. 3). Also, the mean of depression score according to different used tools was shown in Table 4. In terms of heterogeneity, the publication year, sex, and sample size does not have any significant effect on heterogeneity of between studies, but the depression measuring tools had a significant effect on heterogeneity between studies in the estimation of pooled prevalence. Also, in estimation pooled mean of depression score, the publication year, sex, measuring tools, and sample size had no effect on heterogeneity between studies (Table 5). According to Fig.  4, the prevalence of depression had an increasing trend with the increase in sample size and publication year. Also, the mean of depression score among infertile couples had an increasing trend with the increase in sample size, but this score had a decreasing trend with the increase in a publication year.

Publication bias
The results of Begg and Egger's tests for prevalence were statistically significant (p = 0.001 for both tests), whereas the tests for estimation mean of depression score were not statistically significant (p = 0.11 for both tests). It means for prevalence, the results of the Egger and Begg's test indicating that there is publication bias but for estimation mean of depression score there is no publication bias.

Discussion
Depression in infertile couples has been considered as one of the psychological problems in recent years. It cannot be denied that infertility is a concern for many people and should be taken into consideration.
The results of this meta-analysis revealed that 35.3% of Iranian infertile couples had depression, a disorder that can affect other aspects of health. In a systematic study by Masoumi in 2013 reported the prevalence of depression in infertile couples was 0.44 [11]. The  Studies in other countries also show a high prevalence of depression in infertile women. Recent researches showed that prevalence can range from 11 [48] to 18 [49] and 27 [50] and 73% [41]. Dimitner et al. [51] reported that 19% of patients before the IVF cycle reported symptoms of moderate to severe depression, and 54% reported mild symptoms. Omu et al. [52] in Kuwait showed that the prevalence of depression in infertile women was 5.2% and 14.9% in men. A study in Taiwan [50] found that 40.2% of infertile women suffer from mental disorders, and 17% suffer from severe depression. Another study in Sweden [48] reported that major depression was the most common mood disorder among infertile couples with a prevalence of 10.9% in women and 5.1% in men. In a study on infertile women in Nigeria [53], Upkong and colleagues showed that the prevalence of anxiety and depression in infertile women was 37.5% and 42.9%, respectively. Similar studies have been done in different countries, and our study has been done in Iran. Consequently, the reason for the differences between the results of these studies and the present study may be due to differences in the place of study. Infertility seems to increase depression in women and men by affecting their moods, which is a serious health challenge. This should be considered a serious warning that threat the mental health of the infertile couples and should be the focus of special attention, particularly by the psychologist.
Some studies have reported a mean depression score based on the type of questionnaire used. In studies that used the BDI (Beck Depression Inventory) questionnaire to measure depression, the mean depression score was 20.95, based on the scoring [54]; participants had moderate depression. In studies using the PHQ (Patient Health Questionnaire), the mean depression score was 6.13, which according to the scoring [55]. Depression was moderate. Also, in studies using the HADS (Hospital Anxiety and Depression Scale) questionnaire, the mean depression score was 6.14, based on the scoring of this questionnaire [56]. In terms of depression, participants had normal status. As observed, studies have included this metaanalysis showed that depression has been mild in infertile couples, which is consistent with existing studies [57,58]. Studies using other questionnaires to measure depression in infertile couples almost showed that depression is moderate or mild in participants.
This study showed that the prevalences of depression in infertile men and women were 9% and 48.7%, respectively. These findings are consistence with the Samani et al. [59], Maroufizadeh et al. [57], and Hariri et al. [60] studies. In a study by Ahmadi [17], the prevalence of depression in infertile men in Tehran was 42%, which is inconsistent with our study. It seems that because women are more involved with fertility and different aspects of infertility can affect women's mental health, women are more likely to be depressed than men.
There were a few limitations and potential biases in this study. Included studies may vary in the duration of the depression period of the study participants. So, the severity of depression cannot be the same across all included studies. Another limitation of this study is that studies may vary in quality and instrumentation used, making comparability difficult. Different questionnaires have also been used to measure depression, which makes it difficult to compare studies in terms of results.

Conclusion
Our study showed that 35.3% of infertile couples suffer from depression. The results can highlight an important and growing mental disorder among infertile couples that may be overlooked. Depression, as a major mental disorder, should be of particular concern to gynecologists, midwives, and physicians who manage infertile couples for fertility and related issues. However, many individuals, social, and cultural characteristics play an important role in the onset and exacerbation of depression, especially among infertile couples. Depression can occur in people of any age, gender, or background. It is predicted that in the whole world, depression alone will take second place in the disease burden until 2030. Also, according to this prediction, depression and anxiety disorders will be the main cause of the five factors that cause loss of life due to disability [61].