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J Res Med Sci 2019,  24:64

Identification of associated risk factors for the severity of generalized anxiety disorder among Iranian infertile people: An ordinal regression analysis with a flexible link function

1 Department of Biostatistics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
2 Department of Epidemiology and Reproductive Health, Reproductive Epidemiology Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran

Date of Submission14-Oct-2018
Date of Decision23-Jan-2019
Date of Acceptance16-May-2019
Date of Web Publication24-Jul-2019

Correspondence Address:
Prof. Fatemeh Mohammadzadeh
xDepartment of Biostatistics, Faculty of Medical Sciences, Tarbiat Modares University, Jalal AleAhmad, Nasr, Tehran
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jrms.JRMS_790_18

Clinical trial registration NCT02075749

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Background: Generalized anxiety disorder (GAD) is a common disorder in infertile people. The aim of this study was the identification of associated risk factors for the severity of GAD in infertile people using an ordinal model with a flexible link function. Materials and Methods: This cross-sectional study was conducted on 1146 individuals with a couple's infertility problem selected from an infertility center in Tehran, Iran. Data collected using self-administered questionnaires include demographic/clinical information and GAD-7. We used a Bayesian-ordered symmetric power logit (splogit) model to identify the risk factors for the severity of GAD. Furthermore, we implemented standard ordinal models to compare with the ordered splogit model. Results: Female gender (B coefficient 0.48, 95% credible interval [CrI]: 0.34–0.62), longer duration of infertility (B coefficient 0.03, 95% CrI: 0.01–0.04), previous treatment failure (B coefficient 0.17, 95% CrI: 0.03–0.30), and self-cause of infertility (B coefficient 0.12, 95% CrI: 0.01–0.23) were associated factors with the severity of GAD. The splogit model had a better fit and performance to determine the associated risk factor for the severity of GAD as compared to standard models. It provided more precise estimates of risk factors and one more significant risk factor. Conclusion: Infertile people with female gender, longer duration of infertility, failure in previous treatments, and self-cause infertility are more likely to experience higher severity levels of GAD and require additional psychological, and support interventions. Furthermore, it can be argued that the ordinal splogit model is more powerful to identify the associated risk factors for the severity of GAD.

Keywords: Anxiety, Bayesian analysis, generalized anxiety disorder-7, infertility, risk factors

How to cite this article:
Mohammadzadeh F, Hajizadeh E, Rasekhi A, Omani-Samani R. Identification of associated risk factors for the severity of generalized anxiety disorder among Iranian infertile people: An ordinal regression analysis with a flexible link function. J Res Med Sci 2019;24:64

How to cite this URL:
Mohammadzadeh F, Hajizadeh E, Rasekhi A, Omani-Samani R. Identification of associated risk factors for the severity of generalized anxiety disorder among Iranian infertile people: An ordinal regression analysis with a flexible link function. J Res Med Sci [serial online] 2019 [cited 2020 Aug 4];24:64. Available from: http://www.jmsjournal.net/text.asp?2019/24/1/64/263365

  Introduction Top

Infertility is the failure to become pregnant after 1 year or more of regular sexual intercourse without using protected methods.[1],[2] Annually, an estimated 60–80 million couples are affected by infertility worldwide.[3] Infertility is an unpleasant and stressful occasion in the life of a person and may lead to psychological disorders such as depression and anxiety in both men and women.[4]

Generalized anxiety disorder (GAD) is one of the psychological disorders which is often happening in infertile people.[5] People with GAD experience extreme, persistent, and unrealistic worry about different events or activities.[6] The current estimate of the prevalence of GAD in the general population is about 1.6%–5.0%.[7] Although there is a lack of information about the prevalence of GAD among infertile people, most studies which are limited to some infertility centers suggest a much higher of GAD prevalence in the infertile population than the general population.[8],[9] GAD is highly comorbid with major depression, other anxiety disorders, and also physical disorders such as diabetes, peptic ulcer disease, and irritable bowel syndrome, cardiac, and other somatic symptoms.[10],[11] Patients with GAD commonly experience lower levels of two dimensions of physical and psychological aspects of health-related quality of life, including physical functioning, role physical, role emotional, bodily pain, general health, vitality, social functioning, and mental health.[10] Studies show that the direct and indirect costs of GAD are very high,[12] and the comorbidity between GAD and other psychiatric disorders results in an increase of around 65% in the direct economic costs.[13] Moreover, as the severity of GAD increases, so does the financial burden.[14]

In people with GAD, levels of symptom severity may impact on the levels of physical functioning.[7],[15] Furthermore, the likelihood of full remission, the treatment plan of GAD, and choice of drug(s) depend on the severity of the problem.[16],[17] In infertile people, more severity levels of anxiety could lead to higher cortisol level and therefore lower successful pregnancy rate in infertility treatments.[18]

Not with standing the importance of GAD in infertile people and its negative consequences, there is little information about it in this group. Identification of associated risk factors for the severity of GAD in this population may aid clinicians to obtain a more accurate understanding of GAD among infertile people and identifying patients at greater demand for psychological support and treatments.

In clinical practice and research, GAD-7 is one of the most common rating scales used for screening, diagnosis, and severity assessment of GAD. In GAD-7, the clinically meaningful GAD severity levels are defined as an ordinal scale based on predetermined threshold values to denote normal, mild, moderate, and severe levels.[5],[19] Ordinal regression models with traditional link functions including probit, logit, and complementary log-log (cloglog) are most commonly using methods for the analysis of such data in the statistical literature. In recent years, it has been proposed the using of flexible link functions in the modeling of the ordinal dependent variables to avoid link misspecification, the bias in the parameter estimations and inferior fit in the model.[20] Evaluation of the usefulness of recently proposed ordinal models in health researches could be valuable to determine the best method for model fitting and parameter estimation.

The current study was an effort to identify the associated risk factors for the severity of GAD as one of the most common psychological disorders in infertile people using an ordinal model with a flexible link function.

  Materials and Methods Top

Study design

A cross-sectional study was conducted from May to August 2017 at the Infertility Treatment Center of Royan Institute in Tehran, Iran. Participants of the study were men or women with couple's infertility problem which met the following inclusion criteria: (a) the willingness to participate in the study; (b) age >18 years; and (c) ability to reading, writing, and understanding Persian. A total of 1146 eligible people completed and returned questionnaires. Data collection was conducted using the GAD-7 questionnaire. Information about demographic/clinical factors including gender, age, educational level, infertility duration, infertility cause, history of abortion, and failure of previous treatment was also collected.

Generalized anxiety disorder-7 questionnaire

The Gad-7 is a measurement scale to assess the respondents' anxiety symptoms for the past 2 weeks. It contains 7 Likert scale items from 0 (not at all) to 3 (nearly every day) and can be used to determine the risk of GAD based on Diagnostic and Statistical Manual of Mental Disorders, 4th Edition criteria. Scores for the whole scale range from 0 to 21, and a higher total score reflects more severe symptoms of GAD. A cut-off point of 10 is typically employed for clinical diagnosis of GAD, and cut-off points of 5, 10, and 15 describe mild, moderate, and severe anxiety symptoms, respectively. The reliability and validity of the Persian version of GAD-7 in the Iranian infertility population were assessed by Omani-Samani et al.,[5] with a Cronbach alpha of 0.876.


The study was approved by the Iranian Ethics Committee of Royan Institute (Approval number: IR.ACECR.ROYAN.REC.1395.187), and written informed consent to participate in the study was obtained from all individuals.

Statistical analysis

Data analyses were done using GNU PSPP (a free alternative to SPSS) and R version 3.5.0. Continuous and categorical variables were summarized as mean ± standard deviation (SD) and frequency (percentage), respectively. Categorical data were compared between categories of GAD using the Kruskal–Wallis test. Correlation between severity of GAD and continuous variables were assessed using the Spearman's rank-order correlation. Furthermore, a simple ordinal regression model was performed on potential risk factors for the severity of GAD and those with P < 0.2 were subjected to multivariate analysis. Multivariate analysis was conducted using a Bayesian ordinal splogit model, and a 95% credible interval (CrI) not including zero was considered as the statistical significance.

Ordered symmetric power logit model

Let Y denotes the severity level of GAD (1 = no/minimal, 2 = mild, 3 = moderate, and 4 = severe) and J represents the number of severity levels (here J = 4). Postulating the existence of a latent (unobserved) variable associated with each response is a natural way for statistical inference about an ordinal model.[14] The latent variable can be modeled as a linear function of the covariates as follows:[21],[22]

For each individual i, xi is the values of a set of predictor variables, β is a vector of coefficients of the predictors, Exi) = 0, ϵi~ F and F is a cumulative distribution function (cdf). The response variable is determined by discretization of the data into J ordered categories through a series of unknown thresholds which can be stated mathematically as:

where −∞ = γ0 < γ1<… < γj− 1 < γj= ∞. To guarantee that the parameters of the model are identifiable and without loss of generality, γ1 can be fixed at 0. The probability of observed yi= j, conditional on xi, β, and γ = (γ1,… γJ− 1)' can expressed as

P (yi= j) = Fjxi'β) − Fj− 1xi'β)

Therefore, the likelihood function for the model can be written as

where I {yi= j} is the indicator function that takes the value 1 if yi= j, and 0 otherwise. The probability of observing yi= j is associated with the F-distribution. The distribution behind the splogit model is a flexible distribution that permits for both positive and negative skewness and also enables detecting the measure of skewness required.[18] The cdf of splogit distribution can be written as

where F0 is a logit baseline distribution.

Priors, computational issues, and assessment of splogit model

We assigned a normal prior on β and a truncated normal prior distribution on γ. We used a mean 0 and a large diffuse SD 1000 for normal priors, reflecting the lack of information. Jiang et al.[23] proposed a proper gamma prior with mean 1 and reasonable large variance for the power parameter r of the splogit model. In this study, we assigned the power parameter r with a Gamma (αr, αr) prior distribution, where αr= 2. The program Just Another Gibbs Sampler (JAGS) was used to perform all the Bayesian computations using the R2jags providing interface utilities. For more details on the sampling method see Jiang et al.[23] Assessment of the ordered splogit model was performed using the deviance information criteria (DIC) in comparison to the traditional models including probit, logit, and complementary log-log. The model with the smallest value of DIC was chosen as the best model.

  Results Top

[Table 1] presents descriptive statistics of the characteristics of the study's participants.
Table 1: Characteristics of the participants in the present study

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Findings indicated that 19.5% of males and 36.6% of females with couple's infertility problem had moderate to severe levels of GAD. Simple ordinal regression showed that age, duration of infertility, sex, previous treatment failure, and cause of infertility had a significant relationship with the GAD severity (P < 0.2). We showed only the results of the ordinal logit model in [Table 2]. The ordered splogit model had the smallest DIC value and therefore the best fit among ordinal models. Furthermore, we obtained more precise estimates of predictors (narrower 95% CrI) and one more significant predictor under the splogit model. [Table 2] shows the posterior mean of regression coefficients, 95% CrI, and the DIC values for the ordinal models.
Table 2: Simple and multiple ordinal regression model's results on factors related to the severity of generalized anxiety disorder

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The results showed that people who experienced a longer duration of infertility suffered higher severity levels of GAD (B coefficient 0.03, 95% CrI: 0.01–0.04). Females were more likely to experience higher severity levels of GAD than males (B coefficient 0.48, 95% CrI: 0.34–0.62). Furthermore, individuals with previous treatment failure were more likely to have higher severity levels of GAD (B coefficient 0.17, 95% CrI: 0.03–0.30). On the other hand, results demonstrated that people with self-cause of infertility had higher levels of GAD than others (regression coefficient 0.12, 95% CrI: 0.01–0.23). We found no significant relationship between age and the severity levels of GAD (regression coefficient – 0.01, 95% CrI:-0.02–0.01). The bold-faced values in [Table 2] indicate statistically significant results.

  Discussion Top

The present study was developed to identify associated risk factors for the severity of GAD. The results showed that individuals with longer infertility duration suffered from higher severity levels of GAD. This finding supports previous researches conducted by Yang et al.[24] and Ramezanzadeh et al.[25] However, some studies demonstrated that there is no association between the duration of infertility and anxiety or depression.[26],[27] People with longer infertility duration may repeatedly refer to physicians and receive different treatments and so fluctuate between hope and hopelessness and experience more concern and anxiety about the difficulty of having a baby.[28]

Another important finding was that females experienced higher severity levels of GAD than males. This finding was in accordance with findings reported by Galundia[4] and Maroufizadeh et al.[29] This relation may be related to the different reaction of men and women toward infertility.[30] On the other hand, in Iranian culture, women may have more encounter with social pressure than men due to frequently consider them as responsible for infertility.[4] Furthermore, it is typical for women to be more influenced because of involving profoundly in investigations and infertility treatment procedures.[4],[25] Male infertility evaluation usually initiated after evaluation of infertility in female.[31] On the other hand, the procedures and tests for infertility problems are more complex, invasive, and costly for females than males.[31],[32] Moreover, it has been demonstrated that women more involved in the process of trying to have a baby such as treatment seeking, and selection of the tests or therapies they can take when pregnancy attempts are failed, even when the male is the cause of infertility.[33]

We also found that people who have experienced failure in the previous treatments suffered from higher levels of GAD than others. A study demonstrated that anxiety and depression in patients experiencing infertility and undergoing assisted reproductive technology (ART) increase after infertility treatment failure.[26] Furthermore, a systematic review examined the association between psychological outcomes and having treatment failure in both men and women and showed increased levels of anxiety and depression after an ART treatment failure.[34]

We observed that patients with self-cause of infertility were more likely to experience higher GAD severity levels than others. A similar result was reached by Dhaliwal et al.[28] An explanation for this might be that a diagnosis of infertility problem in a man or woman may lead them to feel lacking in self-confidence, and feeling worthless as a spouse, and fear of being abandoned by her/his partner and being alone.[35]

In this study, the ordinal regression models with different link functions were used to determine the risk factors for severity of GAD. The splogit model had a better fit and performance to determine significant factors associated with the severity of GAD as compared to standard models including logit, probit, and cloglog models. It provided more precise estimates of risk factors (narrower 95% Crl) and one more significant risk factor. These results indicated the power of the splogit model for handling the data in this study.

This study provides valuable insights into risk factors for severity levels of GAD among infertile people using a large sample size in both men and women and a validated instrument to assess the severity of GAD. However, it has some limitations: (i) its cross-sectional design provides no evidence for causality, (ii) the study was only conducted in one infertility treatment center in Iran; so, generalizing the results to other populations has to be performed with caution, and (iii) some confounding factors such as having any comorbidity or previous history of psychiatric disorders and using medications were not evaluated within the study.

  Conclusion Top

The present study revealed that infertile people with female gender, longer duration of infertility, failure in previous treatments, and self-cause infertility are more likely to experience higher severity levels of GAD and require additional psychological, and support interventions. Moreover, in this study, the ordinal splogit model was more powerful to identify the associated risk factors for the severity of GAD.


Ethical approval for this study was obtained from the Iranian Ethics Committee of Royan Institute (Approval number: IR.ACECR.ROYAN.REC.1395.187). The authors express their gratitude to the infertile patients who participated in this study and to the Royan Institute, Tehran, Iran for its kind cooperation in data collection.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Kazandi M, Gunday O, Mermer TK, Erturk N, Ozkınay E. The status of depression and anxiety in infertile Turkish couples. Iran J Reprod Med 2011;9:99-104.  Back to cited text no. 1
Drosdzol A, Skrzypulec V. Evaluation of marital and sexual interactions of polish infertile couples. J Sex Med 2009;6:3335-46.  Back to cited text no. 2
Pasi AL, Hanchate MS, Pasha MA. Infertility and domestic violence: Cause, consequence and management in Indian scenario. Biomed Res 2011;22:255-8.  Back to cited text no. 3
Galundia R. To Understand the impact of anxiety and depression amongst infertile males and females: Gender issues. Int J Humanit Soc Sci 2016;6:135-40.  Back to cited text no. 4
Omani-Samani R, Maroufizadeh S, Ghaheri A, Navid B. Generalized anxiety disorder-7 (GAD-7) in people with infertility: A reliability and validity study. Middle East Fertil Soc J 2018;23:446-9.  Back to cited text no. 5
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington DC: American Psychiatric Association; 2013.  Back to cited text no. 6
Spitzer RL, Kroenke K, Williams JB, Löwe B. A brief measure for assessing generalized anxiety disorder: The GAD-7. Arch Intern Med 2006;166:1092-7.  Back to cited text no. 7
Chen TH, Chang SP, Tsai CF, Juang KD. Prevalence of depressive and anxiety disorders in an assisted reproductive technique clinic. Hum Reprod 2004;19:2313-8.  Back to cited text no. 8
Volgsten H, Skoog Svanberg A, Ekselius L, Lundkvist O, Sundström Poromaa I. Prevalence of psychiatric disorders in infertile women and men undergoingin vitro fertilization treatment. Hum Reprod 2008;23:2056-63.  Back to cited text no. 9
Hoffman DL, Dukes EM, Wittchen HU. Human and economic burden of generalized anxiety disorder. Depress Anxiety 2008;25:72-90.  Back to cited text no. 10
Culpepper L. Generalized anxiety disorder and medical illness. J Clin Psychiatry 2009;70 Suppl 2:20-4.  Back to cited text no. 11
Goldstein S, DeVries M. Handbook of DSM-5 Disorders in Children and Adolescents. Switzerland: Springer; 2017.  Back to cited text no. 12
Souêtre E, Lozet H, Cimarosti I, Martin P, Chignon JM, Adès J, et al. Cost of anxiety disorders: Impact of comorbidity. J Psychosom Res 1994;38 Suppl 1:151-60.  Back to cited text no. 13
Toghanian S, Dibonaventura M, Järbrink K, Locklear JC. Economic and humanistic burden of illness in generalized anxiety disorder: An analysis of patient survey data in Europe. Clinicoecon Outcomes Res 2014;6:151-63.  Back to cited text no. 14
Matza LS, Morlock R, Sexton C, Malley K, Feltner D. Identifying HAM-A cutoffs for mild, moderate, and severe generalized anxiety disorder. Int J Methods Psychiatr Res 2010;19:223-32.  Back to cited text no. 15
Yonkers KA, Dyck IR, Warshaw M, Keller MB. Factors predicting the clinical course of generalised anxiety disorder. Br J Psychiatry 2000;176:544-9.  Back to cited text no. 16
Davidson JR, Feltner DE, Dugar A. Management of generalized anxiety disorder in primary care: Identifying the challenges and unmet needs. Prim Care Companion J Clin Psychiatry 2010;12. pii: PCC.09r00772.  Back to cited text no. 17
Smeenk JM, Verhaak CM, Eugster A, van Minnen A, Zielhuis GA, Braat DD. The effect of anxiety and depression on the outcome ofin vitro fertilization. Hum Reprod 2001;16:1420-3.  Back to cited text no. 18
Jordan P, Shedden-Mora MC, Löwe B. Psychometric analysis of the generalized anxiety disorder scale (GAD-7) in primary care using modern item response theory. PLoS One 2017;12:e0182162.  Back to cited text no. 19
Wang X, Dey DK. Generalized extreme value regression for ordinal response data. Environ Ecol Stat 2011;18:619-34.  Back to cited text no. 20
Boes S, Winkelmann R. Ordered response models. In: Hübler OO, Frohn J, editors. Modern Econometric Analysis: Surveys on Recent Developments. New York: Springer-Verlag; 2006. p. 167-81.  Back to cited text no. 21
Johnson VE, Albert JH. Ordinal Data Modeling. New York: Springer; 2006.  Back to cited text no. 22
Jiang X, Dey DK, Prunier R, Wilson AM, Holsinger KE. A new class of flexible link functions with application to species co-occurrence in cape floristic region. Ann Appl Stat 2013;7:2180-204.  Back to cited text no. 23
Yang B, Zhang J, Qi Y, Wang P, Jiang R, Li H. Assessment on occurrences of depression and anxiety and associated risk factors in the infertile Chinese men. Am J Mens Health 2017;11:767-74.  Back to cited text no. 24
Ramezanzadeh F, Aghssa MM, Abedinia N, Zayeri F, Khanafshar N, Shariat M, et al. Asurvey of relationship between anxiety, depression and duration of infertility. BMC Womens Health 2004;4:9.  Back to cited text no. 25
Maroufizadeh S, Karimi E, Vesali S, Omani Samani R. Anxiety and depression after failure of assisted reproductive treatment among patients experiencing infertility. Int J Gynaecol Obstet 2015;130:253-6.  Back to cited text no. 26
Ogawa M, Takamatsu K, Horiguchi F. Evaluation of factors associated with the anxiety and depression of female infertility patients. Biopsychosoc Med 2011;5:15.  Back to cited text no. 27
Dhaliwal LK, Gupta KR, Gopalan S, Kulhara P. Psychological aspects of infertility due to various causes – Prospective study. Int J Fertil Womens Med 2004;49:44-8.  Back to cited text no. 28
Maroufizadeh S, Ghaheri A, Almasi-Hashiani A, Mohammadi M, Navid B, Ezabadi Z, et al. The prevalence of anxiety and depression among people with infertility referring to Royan Institute in Tehran, Iran: A cross-sectional questionnaire study. Middle East Fertil Soc J 2017;23:103-6.  Back to cited text no. 29
Hjelmstedt A, Andersson L, Skoog-Svanberg A, Bergh T, Boivin J, Collins A. Gender differences in psychological reactions to infertility among couples seeking IVF-and ICSI-treatment. Acta Obstet Gynecol Scand 1999;78:42-8.  Back to cited text no. 30
Sethi P, Sharma A, Goyal LD, Kaur G. Prevalence of psychiatric morbidity in females amongst infertile couples – A hospital based report. J Clin Diagn Res 2016;10:VC04-VC07.  Back to cited text no. 31
Bolin A, Whelehan P. Perspectives on Human Sexuality. Albany: State University of NewYork; 1999.  Back to cited text no. 32
Pasch LA, Dunkel-Schetter C, Christensen A. Differences between husbands' and wives' approach to infertility affect marital communication and adjustment. Fertil Steril 2002;77:1241-7.  Back to cited text no. 33
Milazzo A, Mnatzaganian G, Elshaug AG, Hemphill SA, Hiller JE; Astute Health Study Group. Depression and anxiety outcomes associated with failed assisted reproductive technologies: A systematic review and meta-analysis. PLoS One 2016;11:e0165805.  Back to cited text no. 34
Hocaoglu C. The psychosocial aspect of infertility. In: Sheriff DS, editors. Infertility, Assisted Reproductive Technologies and Hormone Assays. London: IntechOpen; 2018.  Back to cited text no. 35


  [Table 1], [Table 2]


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