Infertility is a significant reproductive health issue with significant physical, emotional, social, and economic implications.[1] In addition to its inability to bring about pregnancy, infertility has a negative impact on marital relations, self-esteem, social functioning, and quality of life.[2] Infertility is a significant public health problem; roughly one in six women and men of reproductive age are infertile at some point in their lives.[3] The psychological impact might be more significant for women, as childbearing is also associated with one's sense of social identity, family expectations, and marital satisfaction.[4] In a systematic review and meta-analysis of more than 124,000 women, the overall prevalence of infertility was 46.25%, and 51.5% of the cases of infertility were related to primary infertility among the populations analyzed.[5]

Infertile women can suffer various psychological conditions, such as anxiety and depression. The process of uncertainty around conception, frequent medical appointments, extended treatment, financial burden, fear of treatment failure, and familial and societal demands can be a gradual escalation in psychological distress. According to a systematic review and meta-analysis of 44 studies in 53,300 infertile women published in 2024, mental-health issues were significantly more common among women from Asia, with depressive symptoms being the most common disorder (22.9%), followed by generalized anxiety (13.3%) and depression (31.6%).[6] Another meta-analysis reported that the prevalence of depression among infertile women differed depending on the assessment instrument (pooled estimates from 21.0% to 52.2%), with higher prevalence observed in low- and middle-income countries compared to high-income countries.[7] This study highlights the need to view infertility not just as a reproductive problem, but as a psychological condition that has consequences.

However, the psychological implications may be even more significant in cultures of South Asia where motherhood is often considered a part of marriage, and women may feel significant pressure to become mothers.[8] This concern is supported by evidence from Pakistan. A recent multicentre study on women referred for fertility treatment in Pakistan has revealed significant psychiatric morbidity, and previous Pakistani comparative studies have shown significant depression, anxiety, and stress in infertile women compared to fertile women.[9, 10] Moreover, a recent study of women suffering from primary infertility in Pakistan found that the psychological aspects of their condition were a significant cause of anxiety and depression, further highlighting the importance of addressing psychological well-being in the context of infertility treatment.[11] The majority of the literature available, however, has focused either exclusively on infertile women, or on applying a variety of psychological assessment techniques, or on including primary and secondary infertility together, which makes it hard to compare and contrast the psychological burden of primary infertility with that of women who have been able to conceive.

In light of this background, it is important to differentiate the anxiety and depression of primary infertile women from that of fertile women. Identifying if women who have primary infertility suffer from a more severe psychological burden than fertile women could help to move the management of infertility from a reproductive-only to a holistic, reproductive and mental-health framework. This evidence can also help with early psychological screening, counselling, and timely referral for women who are undergoing an evaluation and treatment for infertility. Hence, the present study was undertaken to compare the level of anxiety and depression between primary infertile women and fertile women, to find out the extent of psychological difference between the two groups, and to emphasize the need for providing appropriate psychosocial support to women as a part of comprehensive infertility treatment.

The comparative analytical cross sectional study was carried out in department of obstetrics and gynaecology of Mardan Medical College, Mardan during six months period 1st November 2025 to 30th April 2026. Sample size was determined using OpenEpi version 3.01 for the comparison of two proportions using a 95% confidence level and 80% power. The expected prevalence of psychological distress among women with infertility was set at 76.0%, while the prevalence among fertile women was set at 42.3% based on a recent prospective case-control study evaluating psychological morbidity using the Hospital Anxiety and Depression Scale (HADS).[10, 12, 13] Based on the proportions, the calculated sample size for each group was about 47 participants. With a non-response/incomplete-response rate of 10%, the sample size was expanded to 52 women per group (n=104). A total of 120 subjects (60 women with primary infertility and 60 fertile controls) were finally enrolled to increase the statistical power and allow comparisons between the subgroups. Non-probability consecutive sampling was used to select participants. The women who attended the infertility and gynecological outpatient clinics during the study period were consecutively assessed for their eligibility, and the required sample size was obtained. The women who were not infertile were married, living with their husbands, and had experienced at least 12 months of regular unprotected sexual intercourse without a clinically recognized pregnancy. Only primary infertile women, who had no documented pregnancy before, were included. The fertile control group comprised women aged 20–40 years, married, living with their husband, with at least one previous naturally conceived and clinically recognized pregnancy that ended with a live birth, and had no current clinical history of infertility. Women who had previously been diagnosed with a major psychiatric disorder, women on psychiatric and/or antidepressant treatment, women taking anxiolytics or antipsychotic drugs, and women with severe medical and/or chronic systemic conditions which would likely significantly affect psychological wellbeing were excluded. Additionally, women with cognitive impairment who could not complete the questionnaire, women who refused to participate, and women who gave only partial responses were excluded. Eligible participants were approached and informed of the aims and procedures of the study after obtaining approval from the institutional ethical review committee. Informed written consent was obtained from all participants before enrollment. A structured data collection proforma was used to collect sociodemographic and clinical data. Demographic factors, such as age, place of birth, education, occupation, socioeconomic status, years married, years of infertility, and clinical and reproductive factors, were noted. The length of time the women had been infertile and information regarding the underlying factor of infertility were also recorded for women with primary infertility. The Hospital Anxiety and Depression Scale (HADS) was used to measure anxiety and depression. There were 14 items across two subscales of the HADS, HADS-Anxiety (HADS-A) and HADS-Depression (HADS-D). Each item was scored from 0 to 3, giving a possible score of 0–21 for each subscale. Those with scores 0-7 were normal, 8-10 were borderline or possible cases, and 11-21 were probable cases of clinically significant anxiety or depression.[14] The questionnaire was administered in a private setting to reduce social desirability and confidentiality issues. If necessary, a validated Urdu version was used. Clinically concerning psychological scores participants were counselled and referred to proper psychological/psychiatric assessment, as per institutional policy. The data collected were then entered and analyzed in IBM SPSS Statistics version 26. The Shapiro–Wilk test was used to test the normality of continuous variables. The

A total of 120 women were involved in the study; 60 women were primary infertile, and 60 were fertile. Among the continuous variables, there was no statistically significant difference between the groups in terms of age, duration of marriage, occupation, educational status, or socioeconomic status and no difference between the groups in terms of residence (Table 1).

The median time to achieve a successful pregnancy was 3.0 years (IQR: 2.0-5.0) for women with primary infertility. The most common cause of female infertility was age-related (35.0%), then unexplained (25.0%), male (23.3%), and combined (16.7%). All women in the fertile group reported having had one or more previous pregnancies and live births, as would be expected (Table 2).

The psychological morbidity was significantly higher among women with primary infertility compared to fertile women. The mean scores for the HADS-Anxiety and the HADS-Depression were 10.2 ± 3.7 and 8.7 ± 3.5 respectively, as compared to 6.8 ± 3.1 and 5.6 ± 2.8, respectively; both of which were statistically significant (p<0.001) (Table 3).

The proportion of women with primary infertility who had probable anxiety was 38.3% compared to 10.0% of fertile women; for probable depression, 23.3% of women with primary infertility were compared to 5.0% of fertile women. The fertile participants had much higher normal anxiety and depression (Table 4).

The factors significantly associated with clinically significant anxiety were urban place of residence, housewife status, and duration of infertility more than 5 years, while age, education, and socioeconomic status were not significantly associated. The longer the duration of infertility, the higher the psychological distress level (Table 5).

Primary infertility was associated with anxiety and depression separately from the potential confounders. The odds of clinically significant anxiety (p<0.001) and depression (p=0.003) were 4.82 and 4.67 times greater in females with primary infertility, respectively. Infertility duration >5 years was additionally associated with anxiety (p=0.046) and depression (p=0.048) (Table 6).

Table 1. Sociodemographic characteristics of women with primary infertility and fertile women

Table 2. Reproductive and clinical characteristics of study participants

Table 3. Comparison of anxiety and depression scores between the two groups

Table 4. Severity categories of anxiety and depression according to HADS

Table 5. Association of sociodemographic and clinical variables with clinically significant anxiety

Table 6. Binary logistic regression analysis of factors associated with clinically significant anxiety and depression

The present study showed that primary infertile women experienced a significantly higher psychological burden than fertile women. There were significant mean HADS-Anxiety and HADS-Depression scores and more marked differences in the prevalence of probable anxiety and depression scores among women with primary infertility compared to fertile controls. The results corroborate the idea that infertility is a reproductive disease as well as a significant psychological stressor. The difference observed is striking in contexts where motherhood has a strong connection to social and marital roles. \ The results of the study were in agreement with Ashrafi et al. 2021 comparative cross-sectional study which compared a group of infertile women with fertile control group with each other and found significant differences between the anxiety, depression, self-esteem, body image, sexual function, and quality of life of the two groups. The authors found that there was significant loss across several psychosocial areas, which confirmed our findings that women with infertility are psychologically vulnerable in comparison to fertile women.[15] Likewise, a 2021 longitudinal study of women undergoing their first IVF/ICSI cycle showed that there were distinct trajectories of anxiety and depression, with 19% of women having persistently high psychological symptoms across the whole IVF/ICSI treatment. This indicates that psychological stress may not only be a temporary phenomenon that happens in one clinical event, but it can also occur repeatedly. [16] Our findings were also consistent with the findings of a comparative study in 2022 from Bahawalpur, Pakistan, that showed greater depression, anxiety, and stress levels in both women and men who were infertile than in those who were fertile. The uniformity of our results with this study conducted in Pakistan does indicate that the psychological effects of infertility are especially important in the local sociocultural context.[17] In Pakistan, the psychological, social, and financial impact of infertility, such as family pressure, social questioning, marital concerns, and stigma, can increase levels of anxiety and depressive symptoms that are greater than the physiological consequences of infertility alone. Our results are supported by a systematic review published in 2023 on social determinants of mental health in women with infertility. The prevalence of anxiety ranged from 21.8% to 27.5%, and it was noted that the prevalence of anxiety was higher in primary than secondary infertile women (23.5% vs. 18.4%). The prevalence of depression was significantly different across the population and assessment method, reflecting the significant variation in psychological morbidity within the infertile women.[18] This may therefore be a reflection of the psychological strain or weight imposed because of the lack of previous reproductive success and the uncertainty about the likelihood that a first pregnancy would be successful in our primary-infertility group. This was confirmed by Bahadur et al (2024), who carried out a case-control study of 100 infertile and 100 fertile women. Despite both primary and secondary infertility and the inclusion of DASS-21, not HADS, infertile women suffered from significantly increased anxiety, depression, stress, and reduced quality of life compared to fertile controls. Like in our study, there were no differences between groups in their baseline characteristics, which bolsters the interpretation that psychological morbidity is strongly associated with the condition of being infertile.[19] A 2024 study done specifically on women undergoing fertility treatment also found that infertile women experienced more psychological problems than control women (12.9% with clinically significant anxiety and 32.3% with clinically significant depression on HADS). Although the absolute prevalence differed from our study, the direction of association was similar.[20] The results were in line with the overall findings of Salari et al. in a 2024 systematic review and meta-analysis of 44 studies with 53,300 infertile women. Major depressive disorder was the most prevalent mental-health condition, pooled prevalence at 22.9%, generalized anxiety also had a high pooled prevalence of 13.3% and the pooled prevalence of depression was 31.6%, especially high among women from Asian populations.[6] The increased prevalence of probable depression and anxiety in our infertility group may then be indicative of the high psychological and social burden of women in South Asian cultures. Our findings are also supported by the evidence from studies with a focus on specific infertility diagnoses. Anxiety levels in women undergoing fertility treatment were comparable across the entire study group of women (n = 1,025) and women with PCOS, with about one third of women having clinically relevant anxiety in 2024. It indicates that anxiety is not limited to a specific etiology of infertility, but could also be linked to the overall experience of infertility and fertility treatment.[21] Similarly, a study by Hecht et al. reported that female factor infertility was associated with anxiety, depression, and infertility-specific distress, even if a female reproductive factor had been discovered.[22] A major advantage of the present study was the direct comparison between women of primary infertility and women who had been known to be fertile, excluding previous pregnancy from the group of women with primary infertility. This enabled a more specific evaluation of the psychological impact of specifically failing to conceive a first pregnancy. Our results are consistent with recent comparative studies and large systematic reviews, which further support the inclusion of anxiety and depression into the routine assessment of infertility. However, there are variations in psychological instruments, diagnostic criteria, etiology of infertility, treatment status, and sociocultural environments that help to account for the difference in prevalence rates reported in various studies. The results overall suggest that primary infertility was independently related to significantly higher levels of anxiety and depression than fertility. This association grew stronger as the length of the infertility increased, meaning that psychological evaluations must not be overlooked as a component of infertility management. Rather, routine screening, counselling, psychosocial support, and appropriate psychiatric referral, along with reproductive investigations and treatment, should be integrated into infertility clinics. Recent evidence also indicates that the reduction of psychological distress may be of clinical relevance: elevated anxiety and depression have been linked to poorer IVF/ICSI results, supporting an integrated biopsychosocial approach to IVF/ICSI treatment. Limitations There were some limitations in the study. It was not possible to determine the temporal or causal relationship between the existence of infertility and psychological morbidity with its cross-sectional design. The study sample was relatively small and single-center, which may have restricted the findings from studies conducted in other healthcare settings and/or with women of other socioeconomic and cultural backgrounds. Structured psychiatric diagnostic interview data were not used to assess anxiety and depression, but rather a self-reported screening instrument, potentially leading to misclassification. In addition, psychological outcomes were not assessed in detail, and other factors (e.g., history of infertility treatment, previous treatment failure, marital satisfaction, family pressure, social support, and specific infertility diagnosis) may have contributed to psychological outcomes. Lastly, there is the possibility of selection bias in using consecutive sampling.

Women with primary infertility showed significantly higher anxiety and depression compared with fertile women, and longer duration of infertility appeared to be associated with greater psychological burden. Anxiety and depression, when considered separately, were still associated with primary infertility, even after adjusting for potential confounding factors. The results underlined the need to use routine psychological screening, counseling, and mental health referral in the services. A biopsychosocial model may enhance overall health and health care of women being evaluated and treated for infertility.

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