A systematic review and meta-analysis of the Endometriosis and Mental-Health Sequelae; The ELEMI Project

Gayathri Delanerolle, Rema Ramakrishnan, Dharani K. Hapangama, Dharani Hapangama, Hapangama D, Yutian Zeng, Zeng Y, Ashish Shetty, Sohier Elneil, Chong S, Sam Chong, Hirsch M, Martin Hirsch, Oyewole M, Molola Oyewole, Peter Phiri, Kathryn Elliot, Elliot K, Trusha Kothari, Kothari T, Bryony Rogers, Rogers B, Sandle N, Natasha Sandle, Nyla Haque, Haque N, Nicola Pluchino, Silem M, Martin Silem, Rebecca O'Hara, Rebecca O’Hara, M Louise Hull, Majumder K, Kingshuk Majumder, Jian Shi, Shi JQ, Jian Qing Shi, Vanessa Raymont
Women's health (London, England) · 2021 · vol. 17 , pp. 17455065211019717 · doi:10.1177/17455065211019717 · PMID:34053382 · PMC8182632 · W3164259130
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This systematic review and meta-analysis identified anxiety and depression as the most commonly reported mental health outcomes associated with endometriosis among 34 included studies.

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This ELEMI systematic review and meta-analysis evaluated evidence on the prevalence of mental-health sequelae (symptoms and/or psychiatric disorders) in women with endometriosis, using a predefined PROSPERO-registered protocol and literature searches across multiple databases and citation snowballing up to November 2020. The authors pooled outcomes from 12 included cross-sectional studies (from 34 total reviewed) using random-effects models, extracting prevalence or converting symptom scale scores (with Monte Carlo simulations when needed), and assessed study quality and risk of bias with modified Newcastle–Ottawa approaches. They reported pooled prevalence estimates for anxiety symptoms of 31.8% (95% CI 26.5–37.1%) and planned additional pooled analyses for depression and pelvic pain outcomes, while explicitly noting that all included studies were cross-sectional, limiting causal inference. This paper is centrally about endometriosis—specifically the prevalence of mental-health sequelae (e.g., anxiety and depression) in endometriosis patients.

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Abstract

BACKGROUND: It is important to evaluate sequalae for complex chronic health conditions such as endometriosis and mental health disorders. Endometriosis impacts 1 in 10 women. Mental health outcomes can be a primary determinant in many physical health conditions although this is an area not well researched particularly in women's health. This has been problematic for endometriosis patients in particular, who report mental health issues as well as other key comorbidities such as chronic pelvic pain and infertility. This could be partly due to the complexities associated with comprehensively exploring overlaps between physical and mental health disorders in the presence of multiple comorbidities and their potential mechanistic relationship. METHODS: In this evidence synthesis, a systematic methodology and mixed-methods approaches were used to synthesize both qualitative and quantitative data to examine the prevalence of the overlapping sequalae between endometriosis and psychiatric symptoms and disorders. As part of this, an evidence synthesis protocol was developed which included a systematic review protocol that was published on PROSPERO (CRD42020181495). The aim was to identify and evaluate mental health reported outcomes and prevalence of symptoms and psychiatric disorders associated with endometriosis. FINDINGS: A total of 34 papers were included in the systematic review and 15 were included in the meta-analysis. Anxiety and depression symptoms were the most commonly reported mental health outcomes while a pooled analysis also revealed high prevalence of chronic pelvic pain and dyspareunia. INTERPRETATION: It is evident that small-scale cross-sectional studies have been conducted in a variety of settings to determine mental health outcomes among endometriosis patients. Further research is required to comprehensively evaluate the mental health sequalae with endometriosis.
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Data

For prevalence estimation, summary statistics were extracted from studies that reported MH outcomes in women with endometriosis or chronic pain or CPP. These statistics were either prevalence or mean (standard deviation (SD) or median and interquartile range (IQR). Estimates for studies that reported median and IQR were converted to mean and SD. For studies that did not report prevalence rates but reported only mean (SD) or median (IQR) we employed Monte Carlo simulations to estimate the proportion of the outcome based on appropriate cut-off points for the tool used to measure the outcome (a score of 19 for BDI and 8 for HADS). 13 – 15 We assumed normality of the distribution when mean (SD) were reported or the data were symmetrical. Estimate pooled prevalence were calculated for anxiety and depression, CPP, and dyspareunia for which purpose we used a random-effects model. We also used a random effect model to compute pooled estimate of mean score of CPP measured using SF-MPQ and compute prevalence ratios of anxiety and depression. We used the I 2 statistic to assess heterogeneity between the studies for which the cut-off values for degree of heterogeneity were – 25% for low, 50% for moderate, and 75% for high. 16 To investigate sources of heterogeneity we conducted sensitivity analyses for outcomes that had sufficient sample size for these analyses. These included estimate of prevalence of depression by excluding a lone study where participants were enrolled from primary care and another analysis that included only cross-sectional studies. We were able to assess potential publication bias through visualization of funnel plot and Egger’s test for only depression since it was the only outcome with ⩾ 10 studies. Analysis was conducted using STATA 14.0. A total of 34 cross-sectional studies were finalized for the systematic review, although 12 were included into the meta-analysis. The 12 studies reported depression, anxiety, CPP, dyspareunia and dysmenorrhea. The remaining studies were reviewed as part of the thematic and narrative analysis. The prevalence for anxiety symptoms was found to be 31.8% (95% CI: 26.5% - 37.1%) ( Figure 2(a) ). We were able to pool five studies to compute prevalence ratios. The prevalence of anxiety symptoms was 2.8 times higher among women who had endometriosis compared to women without endometriosis ( Figure 3(a) ). A prospective cohort study that was not included in the meta-analysis 17 reported 44% increased risk for anxiety for women with endometriosis compared to women without endometriosis. The same study reported a hazard ratio of 1.39 (95%CI: 1.14, 1.71) for anxiety among women with endometriosis who were < 40 years of age and 1.53 (95%CI: 1.15, 2.04) for women who were ⩾ 40 years of age. PRISMA chart. Forest plot of pooled prevalence of (a) anxiety among women with endometriosis, (b) depression among women with endometriosis. Forest plot of prevalence odds ratio of (a) anxiety among women with endometriosis compared to women without endometriosis, (b) depression among women with endometriosis compared to women without endometriosis. We found the prevalence of depressive symptoms among women with endometriosis to be 28.9% (95% CI: 8.6%–49.2%) ( Figure 2(b) ). When we included only the studies that used the Beck Depression Inventory (BDI) to assess depressive symptoms we did not find the results to be materially different from the overall estimate (prevalence: 24.8%, 95% CI: 10.1%–39.4%) ( Supplemental Figure 1 ). Analysis conducted after excluding a study that enrolled patients from primary care instead of tertiary care/women’s clinics/university hospital/gynaecological clinics resulted in little change to the prevalence estimate ( Supplemental Figure 2 ). However, meta-analysis of only cross-sectional studies resulted in a lower prevalence compared to the overall estimate (22.0% vs 28.9%) ( Supplemental Figure 3 ). Meta-analysis of three studies did not reveal strong evidence of higher prevalence of depression among women with endometriosis compared to women without endometriosis ( Figure 3(b) ). The pooled prevalence for CPP was high at 57.2% (95% CI: 7.0%–107.4%) ( Figure 4(a) ). We found the pooled estimate of mean SF-MPQ for chronic pain to be 13.09 (95% CI: 7.13–19.05) ( Supplemental Figure 4 ). The other outcome for which we were able to compute prevalence was dyspareunia which was found to be high too at 54.9% (95% CI: 43.9%–65.9%) ( Figure 4(b) ). Six studies that reported anxiety among BAME women with endometriosis were identified, therefore it was not possible to complete a meta-analysis. Forest plot of pooled prevalence of (a) chronic pelvic pain among women with endometriosis, (b) dyspareunia among women with endometriosis. Studies that were excluded from the meta-analysis were still part of the systematic review and therefore were used as part of the thematic and narrative analysis included within the discussion. Funnel plot suggested evidence for publication bias with a tendency for studies with low prevalence rates for depression to be not published ( Supplemental Figure 5 ). However, the p-value for Egger’s test for funnel asymmetry was found to be 0.50 suggesting insufficient evidence to test for publication bias, probably due to low power (only 11 studies included) to detect such a bias.

Intro

Endometriosis is defined by the presence of endometrium-like tissue outside the uterine cavity and can lead to complex outcomes such as dysmenorrhea, chronic pelvic pain (CPP), sexual dysfunction and subfertility. Women with endometriosis suffer from a range of symptoms although the most complex of these are frequently associated with mental health (MH)-related distress and psychiatric comorbidities. Consequential psychosocial factors and a range of pelvic pain disorders frequently exacerbate the patient’s experience of endometriosis and associated MH symptoms. Cross-sectional studies have shown exacerbated MH distress due to alterations of body image, loss, hopelessness, alexithymia and worthlessness as a result of endometriosis. 1 Aerts et al. 1 summarized the detrimental psychological impact and adjustments made by women with endometriosis, including heightened pain–related experiences and levels of distress. One of the theories of the pathogenesis in endometriosis is Sampson’s transplantation theory, 2 , 3 where retrograde motion of endometrial cells via the fallopian tubes into the pelvic cavity during menstruation. During this process, endometrial tissue implants on the peritoneal surface. This theory is further evidenced where increases in endometriosis incidence among women with Mullerian Duct anomalies indicate an obstructed flow increases the possibility of retrograde menstruation. This is also supported by the frequent, lengthy and heavy menstruation common in endometriosis, which further increases the exposure of the pelvic cavity to develop endometriosis. However, contradictions to this theory have been published, as some epidemiological data indicate that only 0.5%–5% of women with retrograde menstruation appear to develop endometriosis. 4 The diagnosis and management of endometriosis is complicated by multiple factors, including issues around the pathophysiology of the disease, staging, severity and treatment responses, as well as limitations in current clinical and surgical management. However, the most severe and common comorbidities are pelvic pain, infertility and MH issues. As a result of this, further complications may arise in its long-term management as a result of MH symptomatologies and psychiatric comorbidities that may compromise the social relationships of these patients. CPP is a key clinical feature of endometriosis which may exacerbate depression and anxiety, and these, in turn, may exacerbate CPP. In addition to these complex symptoms, these patients are also at high risk of comorbidities such as inflammatory bowel disease, adenomyosis, fibromyalgia and autoimmune diseases. 5 Endometriosis is further influenced by ovarian hormone fluctuations and dynamic inflammatory changes in the ‘ectopically’ located endometriotic tissues, that can lead to changes in the temporal pattern of any pain and a wide range of symptoms that can be challenging to manage. As a result, these issues can have a negative impact on all aspects of a woman’s life and her wellbeing and may have wider implications for ongoing management. The latest epidemiological data from the UK suggest 1 in 10 women may have endometriosis although the international prevalence remains unclear 6 as comprehensive global endometriosis and mental health research is lacking. Although, even with further epidemiological study, given endometriosis comprises of subclinical courses and is frequently subject to misdiagnoses and delayed diagnosis, affirming prevalence with ‘real-world’ data could be challenging. The relationship between endometriosis and MH issues have been reported differently across a variety of studies. In addition, the perception of CPP or pain disorders such as dyspareunia, their reporting and impact on MH symptoms remain complex to evaluate, although there is some evidence to suggest they could lead to the development of mood disorders. 7 , 8 Laganà et al. 7 demonstrated an association between psychiatric disorders such as depression, somatization and anxiety among endometriosis patients. Given the presentation of endometriosis, it is very likely to adversely affect women’s MH, although theories around the pathophysiology and mechanism remain under-researched and unclear. 9 The long-term consequences of restricted preoperative psychosocial evaluations and the lack of ongoing psychological support after surgery could be far reaching. Similarly, delayed or under diagnosed endometriosis could cause MH issues. Therefore, the overall quality of life of women with endometriosis is at risk and it has been reported that the potential for increased incidence in depression may be significant. 10 Current published research indicates a strong link between mental and physical health, 11 although most chronic conditions are not well evaluated holistically. As per guidelines from the American Society for Reproductive Medicine, it is argued that women with endometriosis require lifelong personalized management plans. 12 However, similar guidelines are not available globally. In order to achieve such recommendations, further knowledge of the prevalence of the MH sequalae would be required.

Methods

An evidence synthesis protocol was developed as part of a systematic methodology. As part of this evidence synthesis, a systematic review was conducted to evaluate the current knowledge gap around MH outcomes within endometriosis patients, to help develop evidence based clinical guidelines and inform the design and conduct of future research. There are many different types of evidence synthesis methodologies that could be used, although these are mostly non-standardized and non-specific to research associated with sequalae where a primary and secondary health condition is evaluated. Therefore, we developed a multi-analysis method. The systematic review protocol was developed in accordance with the International Prospective Register of Systematic Reviews (PROSPERO) on the 15 July 2020 (CRD42020181495) with an eligibility criteria that is relevant to the clinical research question.

Research

The primary aim was to determine the prevalence of the MH sequalae in endometriosis (symptoms and/or psychiatric disorders), including any indirect covariates.

Narrative

The translation of analytical and descriptive themes are important to facilitate transparency of reporting qualitative and quantitative data. Based on all 34 papers identified systematically, anxiety, depression, CPP and dyspareunia were identified as recurring themes reported by all the studies. In addition, a range of other non-standardized variables were identified as demonstrated in Table 3 . However, the data were unclear regarding the prevalence of symptoms versus clinical diagnoses, which hinders a full assessment of the short, medium and long-term implications for patients and healthcare systems. The identification of CPP and dyspareunia in particular purports further impact on patients’ MH, as highlighted by Till et al. 18 Women with CPP are reported to have significant rates of psychological disorders in comparison to those without CPP. 18 Bryant et al. 19 further reported that in their outpatient clinics for CPP, over 50% of patients had moderate to severe anxiety while over 25% had moderate to severe depression. Symptoms such as anxiety and depression may share a symbiotic relationship which may be exacerbated among endometriosis women that use opioids due to CPP. Generalized anxiety disorder (GAD) has been found to be more common in patients with CPP or any type of pain disorder or symptomatology associated with a primary condition such as endometriosis. Bryant et al. 19 reported patients with CPP demonstrate 30%–73% with anxiety which is 3 to 7 times higher in comparison to the general population which is around 12%. 20 Demonstration of mental health themes identified within the systematically identified dataset. GAD causes pervasive worries which can be coupled with muscle tension or fatigue that impact other endometriosis symptoms. Dyspareunia is a key feature of sexual pain disorders and CPP. It is also a cardinal feature of endometriosis, 21 and is connected with various other gynaecological conditions such as infertility. However, this meta-analysis has demonstrated that despite a high prevalence of CPP, the assessment tools used in most trials are inadequate and its association with dyspareunia is unclear. Furthermore, while it is agreed most endometriosis patients may have ‘deep dyspareunia’, it is challenging to confirm this clinically. Self-administered measures of pain (e.g. the McGill Pain Questionnaire 22 ) and its impact on sexual function (e.g. Female Sexual Function Index, 23 Female Sexual Distress Scale 24 ), and psychological (e.g. Beck Depression Inventory-II, 25 Beck Anxiety Inventory 26 ) and relationship adjustment (e.g. Dyadic Adjustment Scale, 27 the Locke-Wallace Marital Adjustment Test 28 ) are some of the tools that have been used. These assessment questionnaires are often nonspecific for CPP. There is scant evidence that the current assessment tools provide meaningful clinical results in patients suffering from CPP as a consequence of endometriosis. The pain assessment tools are not universally used for CPP suffers and this can be attributed to lack of evidence and a clear guidance for its use. Surgically diagnosed endometriosis patients may have a better probability of confirming symptomatologies of dyspareunia. Inadequate assessments could be one reason for the current difficulties in identifying and managing these symptoms, that could lead to psychological distress which could further impact physical and mental wellbeing. This in turn could make the provision of the clinical care of CPP cumbersome. The EUA guidelines on management of persistent CPP after appropriate medical treatment recommends an approach focussed on managing pain, via integrated medical and psychological care. Patients with pelvic pain differ substantially in the extent they will volunteer information about emotional and behavioural aspects of pain. 29 One way to address this would be to introduce a tool for early assessment of pain and any associated psychosocial impact, that incorporates long-term monitoring that could support clinical management. A total of 17 papers reported the impact of endometriosis on generalized quality of life (QoL) using the Short Form Health Survey-36 and 12 (SF36 and SF 12) and also using assessments specific to endometriosis (Endometriosis Health Profile-30 and EHP-30 and EHP-5). These studies (which were not included in the meta-analysis) demonstrated a reduction in QoL, 29 – 34 with a few patients reporting their experience to be ‘worse than death’. 35 However, these QoL assessments were not conducted in conjunction with any MH assessments.

Discussion

This paper highlights the prevalence of MH sequalae in endometriosis. But a key finding of the review is that the pain and MH assessments used have considerable variability, and lack specificity. As a result, this could contribute to a significant knowledge and practice gap. Most studies describe stress-related disorders, eating disorders, attention deficit hyperactivity disorders and personality disorders as being common among women with endometriosis and some even suggest familial liability, although the mechanistic causation requires to be investigated further as the generalizability of this data remains poor. Overall, psychiatric comorbidities remain unreported and unsubstantiated with the exception of a study reporting reduced psychological functioning and QoL as a result of MH difficulties, 41 when the authors reported that 56.4% of women with endometriosis fulfilled the clinical criteria for psychiatric disorders. While we acknowledge pain and MH disorders are complex conditions independently, they appear to share an overlapping sequalae with endometriosis. However, the pathophysiology of this construct remains to be seen. It is important that future research conducted should comprise of larger sample sizes that could be generalisable to the wider population, as well as psychiatric diagnostic assessments. In order to evaluate, diagnose and treat endometriosis in a holistic manner, it is vital to understand the applicability of existing instruments and whether these could be harmonized even when varied methods and settings use these. Finally, the MH burden associated with endometriosis and its associated pain disorders should be determined to improve clinical practices.

Conclusions

This SR demonstrated that the most common type of MH symptoms and psychiatric comorbidities reported in patients with endometriosis are anxiety and depression. However, there were a large proportion of studies with poor study designs and small sample sizes, therefore, these outcomes may not be reflective of the wider population. These studies also failed to differentiate MH symptoms from psychiatric disorders. Overall, the prevalence of psychiatric comorbidities among the endometriosis populations remains significantly unresearched. Interim clinical plans to address these disturbances remain inconclusive due to the lack of association data from epidemiological studies between CPP, endometriosis and MH issues. This paper also demonstrates that the current literature is insufficient to establish either a unidirectional and/or a bidirectional causality between endometriosis and MH problems. It is vital to acknowledge the importance of conducting comprehensive and statistically significant research to further the understanding of the association of endometriosis and MH issues. This would further the management of this complex, and life long, multifaceted condition.

Limitations

The primary limitations of this review is the small number of studies included in the meta-analysis. This evidence synthesis is based on cross-sectional studies only. Cross-sectional data often lacks directionality and provides no insight into mechanistic associations or causal effects between endometriosis and MH issues. Furthermore, poor quality data was a concern, as was the lack of psychiatric diagnostic data, and some studies were excluded on this basis. There was moderate-to-high heterogeneity for the studies included in the overall prevalence estimates of anxiety (I 2  = 73%) and depression (I 2  = 99%). We could not, however, thoroughly investigate sources of heterogeneity due the limited number of studies included in the analysis (especially for CPP and dyspareunia prevalence estimate). Another limitation is that, the results of the meta-analysis should be interpreted with caution given that it is based on small number of studies for each outcome, but this also throws light on the fact that there is a gap in the literature on MH disorders in women with endometriosis.

Supplementary Material

Click here for additional data file. Supplemental material, sj-pdf-1-whe-10.1177_17455065211019717 for A systematic review and meta-analysis of the Endometriosis and Mental-Health Sequelae; The ELEMI Project by Gayathri Delanerolle, Rema Ramakrishnan, Dharani Hapangama, Yutian Zeng, Ashish Shetty, Sohier Elneil, Sam Chong, Martin Hirsch, Molola Oyewole, Peter Phiri, Kathryn Elliot, Trusha Kothari, Bryony Rogers, Natasha Sandle, Nyla Haque, Nicola Pluchino, Martin Silem, Rebecca O’Hara, M Louise Hull, Kingshuk Majumder, Jian Qing Shi and Vanessa Raymont in Women’s Health Click here for additional data file. Supplemental material, sj-pdf-2-whe-10.1177_17455065211019717 for A systematic review and meta-analysis of the Endometriosis and Mental-Health Sequelae; The ELEMI Project by Gayathri Delanerolle, Rema Ramakrishnan, Dharani Hapangama, Yutian Zeng, Ashish Shetty, Sohier Elneil, Sam Chong, Martin Hirsch, Molola Oyewole, Peter Phiri, Kathryn Elliot, Trusha Kothari, Bryony Rogers, Natasha Sandle, Nyla Haque, Nicola Pluchino, Martin Silem, Rebecca O’Hara, M Louise Hull, Kingshuk Majumder, Jian Qing Shi and Vanessa Raymont in Women’s Health Click here for additional data file. Supplemental material, sj-pdf-3-whe-10.1177_17455065211019717 for A systematic review and meta-analysis of the Endometriosis and Mental-Health Sequelae; The ELEMI Project by Gayathri Delanerolle, Rema Ramakrishnan, Dharani Hapangama, Yutian Zeng, Ashish Shetty, Sohier Elneil, Sam Chong, Martin Hirsch, Molola Oyewole, Peter Phiri, Kathryn Elliot, Trusha Kothari, Bryony Rogers, Natasha Sandle, Nyla Haque, Nicola Pluchino, Martin Silem, Rebecca O’Hara, M Louise Hull, Kingshuk Majumder, Jian Qing Shi and Vanessa Raymont in Women’s Health

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Condition tags

dysmenorrheadyspareuniaendometriosischronic_pelvic_paininfertility

MeSH descriptors

Dyspareunia Endometriosis Endometriosis Endometriosis Cross-Sectional Studies Dysmenorrhea Female Humans Mental Health Pelvic Pain Pelvic Pain

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