Psychological domain of quality of life, depression and anxiety levels in in vitro fertilization

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Psychological domain of quality of life, depression and anxiety levels in in vitro fertilization/intracytoplasmic sperm injection cycles of women with endometriosis: a prospective study

Assoc.Prof.Dr.Mehmet Ufuk Ceran 1, N Yilmaz 2, E N Ugurlu 3, N Erkal 4, A S Ozgu-Erdinc 2, Y Tasci 2, H C Gulerman 2, Y Engin-Ustun 5

Abstract

Objective

To evaluate the psychological domain of quality of life (PDQoL), anxiety and depression levels of infertile women with endometriosis versus non endometriosis who applied for Assisted Reproductive Technologies (ART).

Method

This prospective case–control study compromised a total of 105 women who applied for IVF/ICSI program. Ninety-three women were divided into two groups as endometriosis (n = 37) and non-endometriosis (n = 56) after 12 patients who refused to participate in the study were excluded. The WHOQOL-BREF questionnaire, Beck Depression and Anxiety Inventory scales were used to determine the psychological stress levels.

Results

A significant difference was found between the endometriosis and non-endometriosis groups regarding depression scores, while no significant difference was reported with respect to PDQoL and anxiety (p < 0.01, p = 0.897 and p = 0.058, respectively). A weak but significant correlation was observed between depression and endometriosis (CC: 0.435, p < 0.01). Though anxiety scores were found to be higher in endometriosis group this can not reach statistical significance (p = 0.058). Impact of PDQoL, depression and anxiety scores on pregnancy outcomes were found to be insignificant.

Conclusion

Women with endometriosis seem to be more susceptible to depression and anxiety than women without endometriosis. Although infertility treatment outcomes are not found to be significantly affected, the impact of depression and anxiety over ART treatment success merit further research.

Introduction

Endometriosis is an estrogen-dependent, chronic inflammatory and generally progressive disease that occurs in 10–15% of the reproductive age group. It is considered to be one of the main causes of female infertility . The pathogenesis of the disease remains elusive despite many theories proposed. Endometriosis can present with a wide range of symptoms such as menstrual irregularities, dysmenorrhea, chronic pelvic pain, dyspareunia, subfertility and infertility.

Many studies had reported decreased quality of life domains including all aspects, mainly psychological domain (PDQoL) and higher depression and anxiety scores. Depression and anxiety may occur more frequently in women with endometriosis by virtue of the possible consequences of the disease, especially chronic pelvic pain and infertility .When chronic pelvic pain complicated the disease, the depression and anxiety were found to be amplified and significant reduction in the quality of life indexmainly physical domain and PDQoL was observed. Neuroinflammation and autoimmunity dysregulation may account for the depression and anxiety as well. Physical and psychological suffering from these adverse effects may lead to deterioration of all aspects of life including personal, professional and sexual life. There could also be some shared familial risk factors that make these women more prone to both endometriosis and mood disorders. Another possible cause of anxiety and depression may be medications used in the treatment of endometriosis. Gonadotropin-releasing hormone (GnRH) agonists emotional lability and depression possibly due to estrogen withdrawal effects which could trigger mood disorders via reduced neurotransmitter activity. Oral contraceptives and progestational medications are also reported to be associated with depression, but evidence is limited. Since the diagnosis of endometriosis is challenging, delays occur in diagnosisand treatment possibly contributing to disease progression and emotional impairment.

There is a well-known association between infertility and endometriosis. Adverse effects of endometriosis on fertility may disrupt women’s emotional well-being leading to depression, anxiety, sense of inadequacy and consequently reduced quality of life. Considering that 50% of infertile women have endometriosis, it may be surprising the studies investigating the psychological experience of these women are so few. It has to be emphasized that besides from endometriosis presence, infertility per se has great adverse effects on couples’ psychological well-being. Women face additional psychological pressure when confronted with infertility treatments. Exposure to stress and anxiety is inevitable due to the invasive procedures such as oocyte retrieval, as well as prolonged use of specific medications along with their adverse effects. Imprecise results, recurrent failed IVF cycles and prolongation of infertility may exacerbate anxiety and stress symtoms preparing the ground for depression. Moreover, emotional impairment has adverse effects on IVF treatment outcomes forming a vicious circle.

The primary aim of this study was to assess whether endometriosis in IVF patients had any adverse impact on psychological wellbeing (PDQoL, depression and anxiety levels). The secondary aim was to examine if PDQoL, depression and anxiety had any effect upon IVF outcome.

Material and methods

Study design

The study was designed prospectively and conducted at Dr. Zekai Tahir Burak Education and Research Hospital. Local Ethics Committee approved the study, and written informed consents were obtained from the participants. A two-tails power analysis of two independent groups using the G Power computer program was performed and a total sample number of 70 was obtained to be necessary to detect large effects using chi-square with % 90 power. Although previously agreed to participate, after completing questionnares, 12 women gave up participitating without any excuse. Ninety-three participants of 105 women applied for between September 2017 and June 2018 were included.

Inclusion and exclusion criterias

Women between the ages of 21–45 were included. IVF indications were male factor, reduced ovarian reserve, tubal factor and unexplained infertility. Before beginning treatment, all women were evaluated thorougly by Health Council comprising of gynecologist, internal medicine specialist and psychiatrist. Exlusion criteria were; women with uncontrolled hypertension and diabetes, thyroid disorders, neurological disorders, malignancy, major psychiatric disturbaces; including major depression, bipolar disease and psychotic abnormalities.

Diagnosis of endometriosis was done eitherwith laparoscopy, MRI or USG. Endometrioma was detected in 19 patients by transvaginal ultrasound and MRI. In addition, 18 endometriosis patients were diagnosed with laparoscopy. Women with endometriosis of all stages were included. There were 37 women in study (endometriosis) group and 56 women in control (non-endometriosis) group. In addition to the absence of symptoms of endometriosis (dysmenorrhea, pelvic pain, dyspareunia), patients with normal pelvic examination and ultrasound findings were included in the control group.

Data collection

Women’ age, body mass index (BMI), the presence of endometriosis, baseline characteristics including follicle-stimulating hormone (FSH), antral follicle count (AFC), and estradiol (E2) levels were recorded. Women were monitored and gonadotropin doses were adjusted according to serially performed transvaginal ultrasonography (USG) and E2 measurements. Antagonist protocol was applied to all women along with fresh embryo transfer. Stimulation parameters, follicle count before oocyte pick-up (OPU) and MII oocyte after OPU, numbers of obtained embryos, and clinical pregnancy results were recorded. Clinical pregnancy was determined by the presence of at least one gestational sac, documented with transvaginal USG two weeks after a positive pregnancy test. All data were analyzed and compared between two groups.

Questionnaires

At beginning IVF treatment (first day of controlled ovarian hyperstimulation, generally on second or third day of menstruation), women were requested to fill three different questionnaires in a quiet room in the clinic.

Beck Depression Inventory-Turkish (BDI-II-TR)

The BDI-II is a self-report inventory consisting of 21 items, designed to assess depressive symptomsas specified in the DSM-IV. Each item is rated on a 4-point scale ranging from 0 to 3. The total score ranges from 0 to 63, with higher scores indicating more severe depressive symptoms. According to our country-specific cut off values, a total score of 0–12 is considered as minimal level of depression, 13–18 as mild, 19–28 as moderate and 29–63 as severe depression.

Beck Anxiety Inventory (BAI)

BAI is a self report inventory consisting of 21 items, designed to assess level of anxiety symptoms. It measures physical, emotional and cognitive aspects of anxiety and fear of losing control. It was shown to be applicable for Turkish population by Ulusoy et al. Each item is rated on a 4-point scale ranging from 0 (not at all) to 3 (severely bothered). The total score ranges from 0 to 63. Higher scores represent a higher intensity level of anxiousness. A total score of 0–7 is interpreted as a minimal level of anxiety, 8–15 as mild, 16–25 as moderate and 26–63 as severe level of anxiety.

The World Health Organization Quality of Life Short Form Turkish version (WHOQOL-BREF-TR) questionnaire

The World Health Organization Quality of Life (WHOQOL) is a scale composed of different domains to assess quality of life. This instrument is adapted for different cultures. WHOQOL-BREF is shorter version of original instrument. We used the WHOQOL-BREF-TR specific for Turkey, which was validated by studies . WHOQOL-BREF-TR is composed of 26 items about different aspects of life. These items are related with the following domains; physical (7 items), psychological (6 itemes), environment (8 items), social relationships (3 items) and overall (2 items). The quality of life score cannot be defined by adding up the scores of all domains. All domains are assessed seperately and they reflect different aspects of quality of life independently. Scores range from 1 to 5 for each question. The raw score calculated for each domain is converted into computerized scores ranging from 0 to 100. Higher scores indicate better quality of life. There is no cut off value. Instrument is designed to make comparisons.

Due to its relevance, psychological domain of quality of life (PDQoL) was used in this study. This domain is related with negative and positive feelings, self esteem, personel beliefs as well as beliefs about religion and spirituality, thinking-learning-memory and concentration. PDQoL scores were calculated according to answers to questions 5, 6, 7, 11, 19 and 26.

PDQoL scores were calculated as percentiles. Depression and anxiety scales were categorized through the scores (minimal, mild, moderate-severe).

Statistical analysis

The Statistical Package for the Social Sciences software package (SPSS version 25.0, IBM, United States, licensed by Baskent University) was used. Lilliefords corrected Kolmogorov–Smirnov test and Shapiro–Wilk tests were used to determine whether the data matched normal distribution. To compare continuous variables of two independent groups, The Mann–Whitney U-test was used. In comparing the categorical variables, Pearson’s Chi-square test (with Fisher exact results) was used. Cramer’s V value for Pearson’s Chi square test was calculated to assess effect size. The Kruskal–Wallis H test was used to compare three independent groups. Correlation measurements were tested using Spearman’s Rho test. Quantitative data are expressed as median (minimum–maximum), categorical data are expressed as number (n) and percentages (%). Data were analyzed at 95% confidence intervals (CI), and a p value of <0.05 was considered statistically significant.

Results

The median age of the women was 32 and 30 years in the endometriosis and non-endometriosis groups, respectively (p = 0.501). No statistically significant differences were observed between the both groups in terms of BMI, duration of infertility, FSH, E2 levels, and ovulation induction parameters. Total dose of gonadotropin used was significantly higher in the endometriosis group than control group (p < 0.05). Number of oocytes retrieved, MII oocyte counts, numbers of embryos obtained, and grade of embryos were found to be comparible between endometriosis and non-endometriosis groups. Number of positive pregnancy test was 26. There was no statistical difference in clinical pregnancy rates between two groups (p = 0.21).

The PDQoL (Cronbach a coefficients = 0.81) computerized domain scores were 75% and 77% for the endometriosis group and non-endometriosis group, respectively; there was no statistical difference (p = 0.897) In addition, there was no significant relationship between PDQoL and age, BMI, duration of infertility, number of IVF/ICSI cylesand clinical pregnancy rates.

In this study, BDI-II-TR questionnaires showed high consistency with Cronbach coefficients (0,84). In terms of depression scores, moderate–severe depression scores were observed in 19 of 93 women (20%) included in the study. Moderate–severe depression scores were found to be statistically higher in endometriosis group than non-endometriosis group (37.8%, 8.9%, respectively, p < 0.01, Cramer’s V = 0,436). A weak but significant positive correlation was observed between depression scores and endometriosis (CC: 0.435, p < 0.01). Gonadotropin dose was higher in endometriosis group, but there was no significant correlation between depression scores.

When the anxiety scores are examined according to BAI questionnaires (Cronbach a coefficients = 0.77) 23 of 93 women (24%) had moderate–severe anxiety scores. Although the result of the endometriosis group was more than twice the non-endometriosis group, it was not statistically significant (37.6%, 16.1%, respectively, p = 0.058).

There was no significant relationship between depression and anxiety scores and other parameters (age, BMI, duration of infertility, number of cycles, clinical pregnancy) (Table 2).

Discussion

The primary objective of this research was to evaluate the effects of endometriosis on PDQoL, depressive and anxiety symptoms in women undergoing IVF treatments. The secondary objective was to determine if PDQoL scores, depression and anxiety had any impact upon IVF treatment and pregnancy rates.

To our knowledge, this is the first prospective study which evaluated anxiety, depression and PDQoL scales in infertile women with endometriosis receiving IVF treatment.

In this study, depression scores in women with endometriosis were found to be significantly higher than non-endometriosis group, while PDQoL scores and anxiety scores were found to be comparable. We also observed that this relationship was not particularly influenced by variables such as age, duration of infertility and number of cycles. Although statistically insignificant, it has to be highlighted that anxiety scores in women with endometriosis were found to be more than twice the women with non-endometriosis. There is a clear tendency for women with endometriosis to have anxiety and this finding may have clinical importance. Anxiety levelsdid not seem to be associated with age, BMI, duration of infertility, and number of cycles. PDQoL, depression and anxiety scores were shown to have no significant effect on duration of infertility, number of ART cycles, GND doses as well as pregnancy rates. Nonetheless, we have to emphasize that despite being statistically insignificant, number of positive clinical pregnancies in group with minimal depression was 4 times more than severe depression group and nearly three times more than mild depression group. Meanwhile, number of positive clinical pregnancies was four times more in minimal anxiety group than mild anxiety group and nearly three times more than severe anxiety group.

Consistent with our results, in many studies, higher prevalance of depression and anxiety scores were reported among women with endometriosis than non-endometriosis. Gao et al evaluated 854, 361 women with endometriosis regarding psychological disturbances and concluded that these women were more prone to be have depressive, anxiety and stress related disorders than women without endometriosis. In a review, it was stated that women with endometriosis experienced higher rates of depression and anxiety compared with women without endometriosis. They also emphasized that despite lack of firm evidence, chronic pelvic pain seemed to be at the center of emotional impairment, namely feelings of anxiety, hopelessness and depression. They concluded by adding that the mechanisms underlying this association needs to be clarified. In a metatalaysis, it was demonstrated that women with endometriosis and associated pain experienced significantly higher depressive symptoms than women with endometriosis but without pelvic pain. It was also underlined that the rate of depressive symptoms among pain-free women with endometriosis was comparable to women without endometriosis. The association between endometriosis and depression may also be explained partly by dysregulated immunological and inflamatory reactions. It was suggested that over secretion of inflammatory cytokines might impair some brain areas including cingulate cortex bringing about emotional disturbances, mainly anxiety and depression.

Facchin et al. showed that women with endometriosis accompanied by pelvic pain reported higher levels of anxiety and depression as well as decreased quality of life than women without pelvic pain, suggesting that pain was the determinant of psychological well-being. Lack of awereness, the absence of non-invasive diagnostic methods along with uncertainty regarding diagnosis, pathogenesis and treatment lead to diagnostic delays and eventually depression and anxiety. Consequences of endometriosis, especially chronic pelvic pain, infertility/subfertility and dyspareunia may cause physical and emotional suffering and disturbances of personel and intimate relationships inevitably ending up with depression and anxiety. Lack of definitive treatment, along with side effects of medications used for treatment may intensify these symptoms.

Regarding impact of endometriosis on psychological aspect of quality of life, data in literature are conflicting. In a recent study that searched for endometriosis effect over quality of life via WHOQOL scale, the authors demonstrated that all aspects of life including psychological aspect were adversely affected and they recommended holistic treatment approach including psychological support. In another study that assessed effects of endometriosis over quality of life showed that consequences of endometriosis, especially chronic pelvic pain and infertility, induced significant adverse effects over psychological and physical aspects of QoL. In a study that compares women with endometriosis and non-endometriosis controls in terms of psychological symptoms, it was noted that women in endometriosis group had reduced mental health along with increased anxiety and depressive symptoms. Tripoli et al compared three groups of women regarding quality of life and emotional impairment. Group 1; women with pain and endometriosis, group 2; women with non-endometriosis related pelvic pain, group 3; healthy controls without disease. WHOQOL-BREF was used and scores of all subscales especially psychological and physical domains were found to be significantly decreased in groups 1 and 2 compared with group 3, whereas no remarkable difference was noted between group 1 and 2, suggesting that pain was the determinant of QoL. In accordance with our results, Lagana et al. demonstrated that while depression, anxiety and sensitivity are higher in women with endometriosis than controls, no significant difference was observedwith regard to psychological outlook subscale of QoL index.

In our current study, even though women with endometriosis had been shown to experience more depressive symtoms than women with nonendometriosis, the impact on PDQoL had been found to be insignificant. This is in contrast with above-mentioned studies. This may be due to differences between social and cultural status of the populations studied as well as differences between patients’ adaptive mechanisms and coping strategies. Data in literature regarding effects of depression and anxiety over IVF treatment outcomes are scarce and inconsistent. Our findings are congruent with the results of a metaanalysis consisting of 14 prospective studies which showed that emotional distress, namely feeling of depression, tension and anxiety before IVF treatment did not seem to affect pregnancy rates after a single cycle of treatment. They claimed that IVF specialists may reassure patients that emotional distress did not have significant impact over IVF success. Inconsistent with our findings, some studies also reported no association between depression and anxiety levels and pregnancy rates. As opposed to our findings, in a study done among infertile women undergoing their first IVF cycle, it was stated that women with depression or anxiety were 40% less likely to conceive when compared to women without anxiety or depression. In a large study done in Denmark including 42,880 women, it was reported that women with a diagnosis of depression before ART treatments had decreased pregnancy rates than healthy controls. More extensive researches should be carried out to draw firm conclusions regarding effects of depression and anxiety over IVF treatment outcomes. But based on our findings, we may speculate that these emotional impairments do not have significant impact over IVF success.

We have some limitations of our study. The distinction between primary and secondary infertility could be made and prior obstetric hystory could be recorded. Pain is the most debilitating consequence of this disorder but we did not perform pain scoring and other current endometriosis sympytoms. Previous medical and surgical treatments for endometriosis, duration of endometriıosis, stage of endometriosis were not recorded. All women in our study received fresh antagonist IVF/ICSI cycles. In this respect, future studies that include freeze-thaw cycles and GnRH agonist cycles, which have been applied more frequently in recent years, will provide more comprehensive results

Conclusion

Women with endometriosis seem to be susceptible to emotional impairments, mainly depressive and anxiety symptoms. The pathophysiology behind this association needs to be clarified and psychological support should be implemented as a part of integrative treatment approach. The potential effects of endometriosis on fertility brings about feelings of desperation and inadequacy. Infertility per se and infertility treatments may place a heavy psychological stress upon people. Although infertility treatment outcomes are not demonstrated to be adversely affected, the impact of depression and anxiety over IVF treatment success merit further research and understanding. Before initiating IVF treatments, open discussion about emotional stress, anxiety and depressive symtoms will help identify women suffering from these disorders and alleviate their symptoms via different strategies and regain their psycological health.

There was no significant relationship between depression and anxiety scores and other parameters (age, BMI, duration of infertility, number of cycles, clinical pregnancy).

Discussion

To our knowledge, this is the first prospective study which evaluated anxiety, depression and PDQoL scales in infertile women with endometriosis receiving IVF treatment.

In our current study, even though women with endometriosis had been shown to experience more depressive symtoms than women with nonendometriosis, the impact on PDQoL had been found to be insignificant. This is in contrast with above-mentioned studies. This may be due to differences between social and cultural status of the populations studied as well as differences between patients’ adaptive mechanisms and coping strategies. Data in literature regarding effects of depression and anxiety over IVF treatment outcomes are scarce and inconsistent. Our findings are congruent with the results of a metaanalysis consisting of 14 prospective studies which showed that emotional distress, namely feeling of depression, tension and anxiety before IVF treatment did not seem to affect pregnancy rates after a single cycle of treatment. They claimed that IVF specialists may reassure patients that emotional distress did not have significant impact over IVF success.Inconsistent with our findings, some studies also reported no association between depression and anxiety levels and pregnancy rates. As opposed to our findings, in a study done among infertile women undergoing their first IVF cycle, it was stated that women with depression or anxiety were 40% less likely to conceive when compared to women without anxiety or depression. In a large study done in Denmark including 42,880 women, it was reported that women with a diagnosis of depression before ART treatments had decreased pregnancy rates than healthy controls.More extensive researches should be carried out to draw firm conclusions regarding effects of depression and anxiety over IVF treatment outcomes. But based on our findings, we may speculate that these emotional impairments do not have significant impact over IVF success.

Conclusion

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