Background

Infertility is a worldwide health concern, affecting approximately 168 million people of reproductive age, globally [1]. Infertility is defined as the inability to consume a child after 12 or more months of unprotected intercourse [1]. Involuntary childlessness can be considered a life crisis with a great impact on physical, social, emotional, and psychological aspects of life [1,2,3,4]. Social stigma, domestic violence, divorce, decrease in self-esteem, stress, anxiety, and depression are amongst the adverse psychosocial effect of infertility [1, 4,5,6]. Even though fertility treatments have evolved during the past decades, these procedures often cause patients physical and or mental distress [2, 5, 7]. The emotional tension experienced by infertile women may lead to changes in endocrine system regulation and probably result in adverse pregnancy outcomes [5, 6, 8].

A pandemic occurs when a disease spread worldwide, passing international borders and infecting a large number of people [9]. Pandemics and the measures that are taken to control or suppress them such as patient isolation, social distancing, and quarantine can increase mental distress and perceived risk of disease, which leads to psychological consequences including stress, anxiety, depression, delirium, and even post-traumatic stress disorder [10].

In December 2019, cases of infection with the new coronavirus were reported in Wuhan, China [11]. Soon after, the virus was spread across the world, and in May 2020 it was declared a pandemic by World Health Organization [12, 13]. The majority of people infected with this virus through droplet transmission have mild to moderate symptoms, but in some cases, the severity of symptoms may lead to death [13]. Until now 767,984,989 people were infected by the virus and more than 6.9 million people lost their lives [14]. In addition to physical effects, coronavirus can affect the psychological well-being of individuals [11, 24,25].

The results of systematic reviews indicate that treatment suspension or postponement has a negative effect on patients' mental health. In a systematic review on the mental health and treatment impacts of covid-19 on neurocognitive disorders, an increase in mental health disorders in patients whose treatments were suspended due to the coronavirus pandemic was reported [26]. Similarly, another systematic review reported a negative relationship between mental health and treatment suspension in cancer patients [27].

As it was mentioned, both infertility and the coronavirus pandemic have negative mental outcomes, so that if the impact of treatment suspension is added, the severity of adverse mental health effects on infertile patients would be increased. Although different studies have been conducted regarding the relationship between treatment suspension due to the coronavirus pandemic and the mental health of infertile patients; to the best of our knowledge, no systematic review has been conducted in this relation. It is noteworthy that two systematic reviews have been published with respect to fertility treatment during the Covid-19 pandemic. One systematic review examined the challenges of oncofertility and fertility preservation treatment and the importance of telemedicine during the Covid-19 pandemic [28]. Another systematic review was conducted on the psychological impact of the Covid-19 pandemic on fertility care, and its finding suggested that the covid-19 pandemic causes negative psychological impacts on fertility care [29]; but because of the heterogeneity of studies, the researchers were not able to perform a meta-analysis. In their review, patients were also heterogeneous, with some studies conducted on patients receiving treatment, and some on patients whose treatment was halted or postponed.

Based on the studies conducted prior to the Covid-19 pandemic [2, 30, 31], it is clear that infertile patients suffer from psychological disorders resulted from their infertility. Also, as it was mentioned, systematic reviews on patients other than those who undergo fertility care, suggest that suspension or postponement of treatment has a negative effect on patients' mental health [26, 27]. Therefore, it seems that infertile patients who face treatment suspension or postponement can be at higher risk for mental disorders. Consequently, the mental health status of an infertile patient, who is undergoing fertility treatment might be different from those who experienced treatment postponement. This difference can affect their quality of life and satisfaction with treatment. Therefore, it was decided to conduct a systematic review in this regard. On the other hand, since meta-analyses help with improvement in precision by summarizing and synthesizing of quantitative data from independent yet comparable studies included in a systematic review [32,33,34,35], it will be easier and more practical for the audiences to grasp the results of different studies by viewing the results of meta-analysis. In order to reach a precise, clear and summarized result from the findings of the reviewed studies, this systematic review and meta-analysis was conducted to assess the mental health of infertile patients facing treatment suspension due to the Covid-19 pandemic.

Materials and methods

To do this study, MOOSE Guidelines for Meta-Analyses and Systematic Reviews of Observational Studies was followed [35]. The protocol is registered in PROSPERO (International prospective register of systematic reviews) under the code of CRD42023399725. Also, the study was approved by the Local Research Ethics Committee, Mashhad University of Medical Sciences, Mashhad, Iran (Code of ethics: IR.MUMS.NURSE.REC.1401.056).

Search strategy and data sources

Two researchers (EI, AY), independently, searched PubMed, Web of Science, Scopus, PsycINFO, Embase, and Cochrane library databases using keywords including coronavirus, covid-19, sars-cov-2, infertility, assisted reproductive technique, psychological distress, stress, anxiety, depression, psychological status, psychological problems/issues, mental health, suspension, and postponement with no time limit until 31 December 2022 (see Additional File 1). Search results of each database was imported to a library created by Endnote reference management software version 9. The software was also used to manage the studies, including identification and removal of duplicated studies, and screening of the titles and abstracts. References of articles which met the inclusion criteria were also searched manually. Since all the relevant articles found by manual search were already included in the study, no records were added by manual search.

Using appropriate keywords, the search of different databases was conducted. At first, duplicate articles were removed. In the next step, the titles and abstracts of the remaining articles were carefully reviewed and the irrelevant articles were excluded. Then the full text of the remaining articles was sought, and articles without access to the full text were excluded. It must be noted that before the exclusion of articles with no access to the full text (n = 1), the corresponding author was reached and she provided us with the full text. Finally, the full text of the remaining articles was reviewed, and those articles that met our inclusion criteria were reviewed in the data extraction process. Two researchers (EI, AY), independently, assessed inclusion and exclusion criteria for each study.

Inclusion criteria

  • Observational studies including cross-sectional, case–control, or cohort studies regarding the mental health of infertile patients facing treatment suspension,

  • Studies published in the English language

  • PECO was as follows:

    • Participants: Infertile patients seeking treatment

    • Exposure: Treatment suspension due to the Covid-19 pandemic

    • Comparator: None

    • Outcomes: Mental health of infertile patients including anxiety, depression, and stress.

Exclusion criteria

  • No access to the full text of the articles

  • Secondary research including systematic reviews, narrative reviews, sco** and rapid reviews as well as other types of articles including qualitative research reports, commentaries and letters to the editor

  • Theses or conference abstracts as well as guidelines

  • Observational studies which did not follow PECO criteria such as studies on infertile couples with ongoing treatment or infertile couples experiencing pregnancy during the Covid-19 pandemic, or studies which assessed outcomes other than those specified in PECO.

  • Languages other than English

Quality assessment

The Newcastle–Ottawa Scale (NOS) was used for the quality assessment of the studies. The scale is consisted of three sections including selection, comparability, and outcome (exposure in case–control studies). The maximum score for the scale is nine stars, and for each sections including selection, comparability, and outcome respectively is four, two, and three stars [36, 59,60,61,62,63,64,65,66,67,68,69,70,71]. Also, 16 studies were included in the meta-analysis [52,53,54,55,56,57,58, 60, 61, 63,64,65,66, 68, 70, 71]. The process of study selection is seen in Fig. 1.

Fig. 1
figure 1

PRISMA Flowchart of study selection

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Study characteristics

There was diversity in the region of the studies. Seven studies were from Europe (France [56], Italy [52, 68, 71], Portugal [25], Serbia [59], and Spain [65]); four were from Asia (China [67, 70] and India [54, 55]); four studies were from the Middle East (Iran [60], Israel [63], and Turkey [61, 64]) and six studies were conducted in Canada and/or USA [53, 57, 58, 62, 66, 69]. Except for the study of Dong et al. (2021) and Rasekh Jahromi et al. (2022), which were case–control studies [60, 70], all of the studies had cross-sectional designs. All the participants (n: 5901) were infertile patients seeking treatment during the covid-19 pandemic and their treatment plans were either halted or postponed; the majority of whom were females (90 Percent, n: 5306); and 8.5 percent (n: 504) of the participants were male. Also, 91 participants (1.5 percent) did not mention their gender (Table 1).

Table 1 Characteristics of published studies included in the systematic review
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Due to the social distancing practice, except for two studies [55, 70], all of the studies were conducted as online surveys [25, 52,53,54, 56,57,58,59,60,61,62,63,64,65,66,67,68,69, 71]. Also, eight studies used Google forms [52, 58, 60, 61, 63, 65, 68, 69], two used REDCap [62, 66], and two used the SurveyMonkey.com platform [57, 71]. Others did not specify the online measures [25, 53,54,55,56, 59, 64, 67, 70]. In terms of data collection tools, except for two studies that used self-structured questionnaires [55, 68], 19 studies used validated instruments [25, 52,53,54, 56, 58,59,60,61,62,63,64,65,66,67, 69,70,71]. Regarding using specific tools for Covid-19, only two studies used covid-19 related questionnaires, including the Fear of Covid-19 Scale (FCV-19S) and the Covid-19 Anxiety Score [63, 64] (Table 1).

Using the Newcastle–Ottawa scale, seven studies were considered of high quality [52, 57, 60, 65, 67, 69, 71], and 14 studies were of moderate quality [25, 53,54,55,56, 58, 59, 61,62,63,64, 66, 68, 70] and In regards to quality assessment of cross-sectional studies, all articles (n = 19) [25, 52,53,54,55,56,57,58,59, 61,62,63,64,65,66,67,68,69, 71] achieved maximum score (three stars) in outcome section. While 74% of articles (n = 14) [52,53,54, 56,57,58, 62, 63, 65,66,67,68,69, 71] achieved maximum score in comparability section and only 10.5% (n = 2) [52, 69] received maximum score in selection section. As for case–control studies (n = 2) [60, 70], only one study achieved maximum score in Comparability and Exposure section (two and three stars respectively) [60], and both [60, 70] achieved three out of four in selection section. (see Additional File 3).

Based on the findings of this review, the rate of anxiety in infertile women whose treatment was suspended or postponed due to the Covid-19 pandemic ranged from 11 to 72 percent. Also, the prevalence of depression varied from 14 to 77 and the prevalence of stress ranged from 38.9 to 64 percent, which is discussed in more detail. Also, it is important to note that, since the majority of the studies under review did not include male patients in their analysis, meta-analysis could not be performed on male anxiety, depression, and stress due to lack of data.

Anxiety

Anxiety was the outcome, which was measured in 15 studies [25, 52, 54,55,56,57,58, 62, 64,65,66,67,68, 70, 71]. Different tools including General Anxiety Disorder (GAD-7), State-Trait Anxiety Inventory (STAI, STAI-5, and STAI-6), Hospital Anxiety and Depression Scale (HADS), Mental Health Inventory (MHI-5), and the Depression, Anxiety, and Stress Scale-21 Items (DASS-21) were used in order to measure infertile patients' anxiety. Although Galhardo et al. (2021) found no significant differences regarding anxiety scores between infertile patients with treatment suspension during the coronavirus pandemic and an infertility reference sample [25], Lablanche et al. (2022) reported that the rate of anxiety was much higher than those expected in the infertile population [56]. Two studies reported an increase in anxiety rate in patients who were in confinement [65, 67]. Fear of covid-19 infection and exposure to covid-19 related news were reported to have a negative effect on patients' anxiousness [52, 54]. Being female [52, 71], having previous IVF cycles [52, 67], and older age [52, 54, 64] were also found to increase the anxiety score.

The pooled prevalence of anxiety in infertile women

Out of the 15 studies mentioned above, twelve studies reported either the number or percentage of women affected with anxiety during the treatment suspension period. The prevalence of anxiety varied from study to study and it was reported from a low percent of 11 to a high percent of 72. The estimated pooled prevalence was 48.4% (95% CI, 34.8–62.3) (Fig. 2). The I2 index was 98.01, which indicated high heterogeneity. Meta-regression was conducted and the sample size was considered as the source of heterogeneity (p < 0.001). Publication bias was not observed (Egger test p-value: 0.30).

Fig. 2
figure 2

The pooled prevalence of anxiety in female patients

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Subgroup analysis of the prevalence of anxiety

The highest pooled prevalence estimate was calculated across the two studies using the STAI (40, 51), which was 72.1% (95% CI, 68.7–75.4). The lowest estimate was calculated for the three studies using the GAD-7 (32, 39, 45), which was 51.3% (95% CI 48.2–54.4). The heterogeneity was not significant between subgroups (P = 0.64) (Table 2).

Table 2 Subgroup analysis of the prevalence of anxiety by tools based on random effect analysis
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Depression

Depression was measured in 10 studies [25, 52, 53, 55, 57, 60, 61, 65, 66, 70]. Different tools including Patient Health Questionnaire (PHQ-8 and PHQ-9), Beck's Depression Inventory (BDI), Hospital Anxiety and Depression Scale (HADS), Mental Health Inventory (MHI-5), and the Depression, Anxiety, and Stress Scale-21 Items (DASS-21) were used in order to measure infertile patients' depression. Although Galhardo et al. (2021) found no significant differences regarding depression scores between infertile patients with treatment suspension during the coronavirus pandemic and an infertility reference sample [25], Dillard et al. (2022) reported that depressive symptoms were greater during the pandemic [69] and Biviá-Roig et al. (2021) reported an increase in depression score in patients who were in confinement [65]. Also, Rasekh Jahromi et al. (2022) reported that infertile women whose treatment was delayed were more depressed than those who were not under treatment[60]. It was reported that women were more depressed than men [52, 71]. Rasekh Jahromi et al. (2022) and Sahin et al. (2021) both reported a positive correlation between depression and hopelessness [60, 61]; in contrast to Sahin et al. (2021) who found that women with secondary infertility had higher mean depression score [61], Rasekh Jahromi et al. (2022) reported that women with primary infertility were more depressed [60].

The pooled prevalence of depression in infertile women

Out of the 10 studies, nine reported either the number or percentage of women affected with depression during the treatment suspension period. The prevalence of depression varied from study to study and it was reported from a low rate of 14 to a high rate of 77 percent. The estimated pooled prevalence was 42% (95% CI, 26.7–59.4) (Fig. 3). The I2 index was 97.70, which indicated high heterogeneity. Meta-regression was conducted and sample size and mean age were considered as the source of heterogeneity (p < 0.001). Publication bias was not observed (Egger test p-value: 0.09).

Fig. 3
figure 3

The pooled prevalence of depression in female patients

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Subgroup analysis of the prevalence of depression

To assess depression, PHQ-9 (32,39,41) with a pooled prevalence of 37.4 (95% CI, 23.8–53.3) was used by three studies. Also, BDI (48, 49) and HADS (34,35) respectively with a pooled prevalence of 62.9 (95% CI, 43.2–79) and 28.2 (95% CI, 14.8–47.2) were used by two studies. Furthermore, PHQ-8 (45) and researcher-made tool (43) each were used in one study. The subgroup analysis suggested evidence of differential prevalence estimates between tools used to assess depression (P = 0.001) (Table 3).

Table 3 Subgroup analysis of the prevalence of depression by tools based on random effect analysis
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Stress

Eleven studies reported stress in infertile patients whose treatments were either suspended or postponed [25, 54, 56,57,58,59, 62, 63, 69,70,71]. Perceived stress scale (PSS-10, PSS-4), Impact of Event Scale-Revised (IES-R), and Depression, Anxiety, and Stress Scale-21 Items (DASS-21) were used to assess stress. Dillard et al. (2022) and Galhardo et al. (2021) reported the mean score of the perceived stress scale-10 in their studies as 19.9 and 20.9 respectively [25, 69]. Three studies reported the prevalence of stress [56, 57, 63]. Higher levels of stress were observed in patients whose treatments were suspended or postponed due to the covid-19 pandemic [69, 70]. Even though two studies reported no significant relationship between demographic characteristics of the patients and stress [58, 69], others reported that age [56, 57, 63], duration of infertility [54, 57], anxiety levels of the patients [56, 58, 62], support system [54, 59], and co** strategies [57, 59] are associated with a higher level of stress.

The pooled prevalence of stress in infertile women

Out of the 11 studies, three reported either the number or percentage of women affected with stress during the treatment suspension period. The prevalence of stress varied from study to study and it was reported from a low rate of 50 to a high rate of 64 percent. The estimated pooled prevalence was 55% (95% CI, 45.4–65) (Fig. 4). The I2 index was 90.99, which indicated high heterogeneity. Publication bias was not observed (Egger test p-value: 0.25). Subgroup analyses and meta-regression were not undertaken because of the small number of studies (n:3) [72].

Fig. 4
figure 4

The pooled prevalence of stress in female patients

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Other findings

The pooled prevalence of patients who wished to resume treatment

Ten studies reported either the number or percentage of patients who wished to resume infertility treatment [52, 54,55,56,57,58, 63, 64, 66, 71]. The prevalence varied from study to study and it was reported from a low rate of 33 to a high rate of 98 percent. The estimated pooled prevalence was 64.4% (95% CI, 50.7–76.1) (Fig. 5). The I2 index was 97.89, which indicated high heterogeneity. Meta-regression was conducted and the sample size was considered as the source of heterogeneity (p < 0.001). Publication bias was not observed (Egger test p-value: 0.21).

Fig. 5
figure 5

The pooled prevalence of patients who wished to resume treatment

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Discussion

The results of this review showed that treatment suspension due to the coronavirus pandemic increased the prevalence of anxiety, depression, and stress in female patients. Based on the findings, the rate of anxiety in infertile women whose treatment was suspended or postponed due to the Covid-19 pandemic ranged from 11 to 72 percent. This wide range may be due to variations in tools and cut-off points that were used to measure infertile women's anxiety. A systematic review on the mental health of the general population during the coronavirus pandemic; reported anxiety rates of 6.33%. This finding in comparison to ours, suggests that infertile patients who faced treatment suspension during the covid-19 pandemic had higher rates of anxiety [59, 64, 66, 68, 69, 75]. In one study a positive relationship was reported between mental distress and the time spent on the coronavirus-related news in infertile patients facing treatment postponement [52]. This positive relationship was also observed in the general population [59, 66, 69, 75]. Many infertile patients felt that treatment suspensions were unfair and made them angry [55, 58, 64]. Closure of fertility treatment centers also decreased the quality of life of patients [53, 65, 68]; this is aligned with the findings of a systematic review on the general population [77]. Delay or suspension of treatment due to the coronavirus pandemic was found to be related to increased levels of mental health problems in other patients too. A systematic review reported an increase in mental disorders in patients with neurocognitive disorders whose treatments were suspended [26]. A negative relationship between mental health and treatment suspension in cancer patients was also reported in another systematic review [27]. Maintaining social relationships, receiving support, kee** fit, and having a daily routine could help infertile patients to cope with this situation better [24, 62, 63].

Based on our results 64.4% percent of infertile patients wished to resume their treatment despite the ongoing Covid-19 pandemic. Reports of one study showed that only 6% of infertile patients agreed with delaying their treatment [74]. A cross-sectional study also reported that only 28% of infertile patients were concerned about maternal–fetal transmission of the virus in case of infection during treatment [78]. Based on these findings and in accordance with studies on providing fertility care during covid-19 pandemic [79, 80], it is important to maintain the continuity of fertility care, with special attention paid to mental health of infertile patients, through all the possible measures including virtual care and telemedicine. To substitute the cancelled appointments and ensure patient satisfaction, fertility treatment centers could arrange virtual appointments.

The main limitation of this study was the significant degree of heterogeneity across the studies, which should be taken into account when interpreting the data. The other limitation was that due to the lack of sufficient quantitative data in the reviewed studies, it was not possible to perform a meta-analysis on the relationship between treatment suspension and mental health of infertile patients. Further research with a larger sample size using validated tools is recommended. Also, the short-term and long-term effects of the coronavirus pandemic and treatment suspension on the mental health of infertile patients need to be investigated further.

One of the strengths of this study was that not only it measured the prevalence of anxiety, depression, and stress in infertile women whose treatment were postponed or suspended, but also compared those results in relation to the pre covid-19 pandemic mental health status of infertile women and those of general public during covid-19 pandemic. Also provided quantitative data on the prevalence of patients who wished to resume their treatment. Another strength of this study was the diversity in the included studies in geographical, and socio-economic terms.

Conclusion

Treatment suspension due to coronavirus pandemic can negatively affect the mental health of infertile patients. Personalized planning could improve infertile patients' mental health. It is important to maintain the continuity of fertility care, with special attention paid to mental health of infertile patients, through all the possible measures including virtual care. Fertility healthcare providers must involve patients in the decision-making process about their treatments even in a public health crisis.