Endometriosis and COVID-19: Clinical Presentation and Quality of Life, a Systematic Review

ABSTRACT


Introduction
Endometriosis is the ectopic presence of endometrial glands that causes chronic inflammation, pain, and infertility (1-3).Estimates show that approximately 10% of women of reproductive age have endometriosis, and most of them are symptomatic (4-7).The consequences of the disease can affect the patients' mental health, quality of life and interfere with interpersonal relationships and occupation (6, 8).The standard diagnosis of endometriosis warrants surgical investigation and histopathologic confirmation, while clinical diagnosis is a challenge (3, 8).
After the Coronavirus disease (COVID-19) pandemic, medical care has experienced a dramatic change and reduced patient access on a global scale (9).Endometriosis patients have not been an exception, and the diagnostic or treatment approaches towards them have altered (10).Besides, patients with chronic illnesses like endometriosis are experiencing mental health problems during social isolation (10-12).It is known that the COVID-19 imposes a greater risk of severe outcomes in patients with chronic and inflammatory diseases (12, 13), but it has not been clear whether it has worse outcomes in endometriosis patients or not, nor do we know how the pandemic has affected the mental health and quality of life in endometriosis patients (14).
Therefore, we conducted a systematic review to shed light on the impact of the COVID-19 pandemic on patients with endometriosis.Our objectives were to determine COVID-19 prognosis in endometriosis patients, its influence on diagnosis and treatment, and patients' experience of their disease during the pandemic.

Methods
In accordance with "Preferred Reporting Project for Systematic Evaluation and Meta-Analysis" (PRISMA) guidelines (15), a systematic search on endometriosis and COVID-19 was conducted in different databases: PubMed/Medline, Scopus, and Web of Science on 17 January 2022.The search keywords are brought in the supplementary Table 1.
The inclusion criteria were: 1) articles that their major aim was to evaluate COVID-19 and endometriosis in the following aspects: prognosis, treatment, diagnosis, and quality of life; 2) published articles in English; and 3) peer-reviewed published articles indexed in PubMed/Medline, Scopus and Web of Science.
Preprints, reviews, short communications, editorials, letters to the editor, comments, conference abstracts, conference papers, and articles that did not aim to study COVID-19 and endometriosis were excluded.Also, citations were searched for relevant articles.Finally, 10 articles were recruited and appraised, of them, 9 articles were considered except for one that was not in line with our objectives.
Two independent reviewers collected data from eligible articles, and a third one revised the data.

Search results
A total of 115 articles were evaluated, and following the title screening process and removing duplication, 72 articles were included in this review.Finally, 9 articles met all the criteria.(See Fig. 1).The summary of the articles is provided in two categories: 1.Studies about the COVID-19 effect on diagnosis and treatment of endometriosis patients (see Table 2) and 2. Studies about the mental health and quality of life in these patients (see Table 3).Higher frequency of asymptomatic infection (95.7% vs. 94.5%;P < 0.001) in control group was reported.

Figure. 1. PRISMA guidelines
Higher frequency of fever (1.6% vs. 0%; P = 0.004) in the control was reported.However, no significant difference in the frequency of sore throat, stuffy nose, cough, dyspnea, headache, weakness, and myalgia was reported.
Anosmia and/or ageusia and eye problems did not differ between the two groups (all p > 0.05).
Higher frequency of rare symptoms in the case group (P < 0.001) and no difference in disease period (P = 0.694) was observed.60% overall reported change in healthcare.22% reported no impact on their daily functioning.
76% reported an impact on daily functioning.
12% reported the positive impact of limitation due to COVID-19, while 77% reported no change in their symptoms.
In 23% exacerbating of symptoms, stress, and decreased coping strategies were observed.

Effect of COVID-19 on Endometriosis care
Among Nine studies, four studies evaluated alternations of the care of the endometriosis during social isolation or quarantine due to the COVID-19 pandemic.One online questionnaire-based survey reported a negative impact of the COVID-19 pandemic on the current or planned treatments of 80.7% [95% CI (79.7, 81.6)] among 6729 patients.Regarding the current treatment, difficulty obtaining repeated prescriptions, changing and/or stopping the hormone and painkiller were reported by participants.However, besidesthe impacts on planned care were more remarkable, with gynecologist appointments, primary care appointments, surgeries, and fertility treatment procedures were canceled or postponed (16).One study demonstrated that 60% of participants delineated that pandemic and related restrictions had changed their medical care, a range of unavailable or compromised providers and treatments, including fertility treatments, surgery/laparoscopy, medications, general practitioner and specialist appointment availability, and access to allied health, including pelvic physiotherapists (20).In another study, it has been demonstrated that 70% of patients with endometriosis mentioned that physical appointments were changed to telephone and video consultation appointments (18).Another study showed both the intake of over-the-counter pain medication and prescription-only pain medication was increased by 15.9% of 278 and 276 patients, respectively (p = 0.31 and p = 0.91, respectively) (17).

Impact of COVID-19 pandemic on the pain intensity and cognition of Endometriosis
One of the nine studies assessed the alternations in pain experience and the influence of social isolation or quarantine on endometriosis patients during the COVID-19 pandemic.The study indicated that of 247 participants who answered the questions regarding the pain magnitude (measured by visual analogue scale) of dysmenorrhea, 45.30%, 40.50%, and 14.20% experienced improvement, worsening, and no change in pain, respectively.This result implies that the dysmenorrhea pain intensity decreased significantly during isolation or quarantine of COVID-19 in comparison with the pain intensity before quarantine (P = 0.025<0.05).However, the other pain associated with endometriosis, such as lower back pain, noncyclic pain, dyspareunia, dyschezia, and dysuria did not show a significant change (all P >0.05).Of 280 patients, 43.6% (P<0.001) reported significantly more frequent awareness of pain or more pain hypervigilance, 37.2% (P = 0.09), 29.3% (P = 0.02) and 30.0%(P <0.001) more participants experienced stress due to pain, pain as a disturbing event and pain as a threat, respectively.Nevertheless, the possibility to relax despite the pain was reduced in the 40.0%(P =0.08) of patients, and 43.9% (P = 0.09) of patients reported that the ability of pain management did not change.Verbalization of pain experience was significantly decreased in 36.6% (P = 0.001) of patients (17).

Impact of COVID-19 pandemic on the disability due to Endometriosis
Of Nine studies, two of them aimed to investigate the deterioration of functional disability-induced endometriosis caused by social isolation or quarantine during the COVID-19 pandemic.One study assessed the disability due to endometriosis-induced pain via using Pain Disability Index (PDI) during social isolation in respect of the period prior to isolation.The result of this survey showed a significant enhancement of social, occupational (P <0.001), and sexual (P = 0.001) functioning.However, recreational functioning did not exhibit a significant alternation.Taken together, the sum scores of the mentioned discretionary activities significantly improved (P = 0.001).But, the deterioration of family functioning was observed in the contrary direction (P = 0.026).Basic activity, including self-care and life support, remained unchanged during what (P = 0.218), and also, the global PDI score, which can reflect global physical impairment, demonstrated a significant improvement (improvement of 48.20% vs worsening of 40.90%,P = 0.032) (17).A study showed that 76% of patients reported the impact of the COVID-19 pandemic on daily functioning, most of them felt that life was now harder, including social exclusion, decreased work, and financial challenges.There were some reports indicating that the physiological function of these patients was affected in terms of anxiety and stress.Nevertheless, reduced function was not reported by all.Twenty women (12%) reported the positive outcomes from COVID-19 caused restrictions, including the convenience of telehealth, working from home, more opportunities to rest, and increased opportunities to obtain healthier habits (20).

Impact of COVID-19 pandemic on the social support of patients with Endometriosis
One survey reported that the empathy and social support received from the partner regarding pain experience showed no significant changes (both P >0.05); whereas, the empathy and social support received from family and friends were significantly reduced during the social isolation (all P <0.05) (17).

Impact of COVID-19 pandemic on the endometriosis-related complaints
Two studies investigated COVID-19 impacts on the symptoms of endometriosis.One study indicated that 33.1% of 181 patients (n = 60) reported their endometriosis-related complaints during COVID-19 had changed, in such 81.7% (n = 49) and 26.7% (n = 16) reported increase and decrease in complaints, respectively (18).Another study demonstrated that 77% of 162 participants reported that COVID-19 had not affected their symptoms.Other patients (23%) reported worsening of symptoms such as pain, stress, and decreased withstanding strategies (for instance, sport and less access to healthcare) (20).

Endometriosis and susceptibility to COVID-19 infection
Only one study compared the COVID-19 characteristics between women with (n = 507) and without (n = 520) endometriosis.This manuscript showed there was no significant difference between patients with and without endometriosis with regard to COVID-19 infection (3.2% vs 3%; P = 0.942).Frequency of asymptomatic infection (95.7% vs. 94.5%;P < 0.001) and fever (1.6% vs. 0%; P = 0.004) were higher in the control group, while the frequency of sore throat, nasal congestion, cough, dyspnea, headache, weakness and myalgia, anosmia and/or ageusia and eye problems did not differ between two groups (all P > 0.05).However, other infrequent symptoms were more prevalent in the endometriosis group (P < 0.001).The average disease period was the same (14 days) in both groups (P = 0.694).Frequency of H1N1 vaccination, recent traveling to high-risk regions, social distancing, exposure to infected patients, frequency of implementing screening test, admission, and isolation due to COVID-19 had no significant difference between the two groups (P > 0.05).But the case group significantly had a higher frequency of symptoms (P < 0.05) and H1N1 infection (P < 0.001).Also, this study indicated that close contact is the most significant risk factor for COVID-19 infection in both groups (r = 0.331; P < 0.001 in the case group and r = 0.244; P < 0.001 in the control group).Whereas the association between COVID-19 infection and other variables like social distancing, traveling, underlying diseases, thyroid diseases, and stage of endometriosis was not significant(P > 0.05) (19).

The impact of COVID-19 on endometriosis patients' mental health
There is a growing concern about the effect of the COVID-19 pandemic on the mental state of people worldwide.
A total of 8,032 people were studied in a report, with an average age of 20 to 50 years.All the studies were performed within the first year of the pandemic, ranging from 3 to 10 months after the outbreak.The study surveys were given to women from Puerto Rico, Italy, Turkey, the Netherlands, and Australia.Just one study was performed globally in Europe, Oceania, North America, Latin America, and the Caribbean (16).The disease severity was mostly in mild to moderate stages.Most of the participants were full-time workers, remote workers, students, and self-employed workers.The general effects of COVID-19 on patients with endometriosis are negative and positive effects.Negative effects include increased job affection, peritraumatic stress, job affection, Post-Traumatic Stress Disorder (PTSD), anxiety, depression, worry of having endometriosis-related problems, lack of gynecological help during the pandemic, fear of being vulnerable to COVID-19, and need for mental health support.Other negative effects include postponed elective surgery and appointments and a decrease in quality of sexual activity, quality of life, and coping strategies (such as sport and less access to healthcare).Positive effects include increased relaxing activities, including breathing exercises, relaxing sleep and meditation, and increased attention to hand hygiene (16, 18, 20-23).

The impact of COVID-19 on endometriosis patients' quality of life
According to the Ramos et al. study, many of the patients reported that their job status was affected.17.3% of these patients had lost their jobs.On the other hand, healthy behaviors were also affected.40% of the patients in this study reported a decreasing time in their exercise.29.2% of these patients reported that their alcohol consumption had increased after the start of the pandemic.Fortunately, smoking was not increased.The Peri-traumatic Distress Inventory (PDI) score was increased significantly after the pandemic began (21).Growing concern about access to gynecologic care was reported in women in a study by Arena et al.The older age was demonstrated to be a risk factor for PTSD in this study.Up to 71.8% of the participants were diagnosed with severe anxiety.Although the pandemic affected the job status negatively, the authors declared that women who could leave home from work had beneath levels of PTSD (22).Yalçın Bahat and coworkers also showed that although endometriosis is associated with increased chronic stress, the COVID-19 pandemic clearly leads to psychological problems including PTSD, psychological distress, depression, and anxiety.Most of the patients were concerned about problems that may arise from endometriosis during the pandemic.While other studies showed an increase in postponed elective surgery, in this study, the surgery was mostly not postponed.It was also demonstrated that patients were becoming adapted to social distancing as well as paying more attention to hand hygiene.Eating habits were also reported to be healthier, and the diet became healthier than before the pandemic.Most of the patients believed that their sexual life was not highly affected by the pandemic (23).Demetriou et al. study was the only global study of all included studies.The patients in this study, mostly (over 50%), believed that their disease makes them more susceptible to COVID-19.Mental health was one of the highest priorities among the patients (20% of all) worldwide (16).A study in the Netherlands indicated that 35.9% of the patients with endometriosis experienced an increased stress level since the beginning of the pandemic.35.9% of the patients experienced stress due to the delay in their treatment (21).In a study by Evans et al. it was demonstrated that just a quarter of the patients had no dysfunction in their lives, while the rest experienced harder lives.They reported that the patients missed social communications, their jobs were affected, and they experienced financial problems.Other psychological disorders were discovered in these patients, including stress, fatigue, and other symptoms of anxiety and depression.Although the pandemic affected the endometriosis patients negatively, it had hidden benefits including having more rest, increased opportunities for healthier lifestyle in both nutritional habits and physical activity (20).

Discussion
Our study shows that endometriosis does not raise the risk of SARS-CoV-2 infection; However, Moazzami et al. indicated that endometriosis could increase the chance of symptomatic COVID-19 compared with patients without endometriosis.Of note, quarantine resulting from the COVID-19 pandemic has not induced exacerbation of pain in endometriosis patients (19).Nonsteroidal antiinflammatory drugs play a major role in relieving the pain of the patients.Actually, besides estrogen and progesterone compounds, they are first-line therapies for Endometriosis (24).Thus, providing these agents efficiently and making them available in this condition could be a rational reason for the concept that women with endometriosis could control their symptoms as much as before the pandemic.Furthermore, multiple studies signify the leading cause of painful symptoms in dysphoric mood and even depression of the patients (25, 26).This evidence warrants the meaningful role of symptom control of endometriosis in this situation.In the COVID-19 pandemic, virtual management is one of the alternative ways to manage patients.Particularly, studies show that endometriosis patients do more frequent virtual and telephone management.Although this type of management has general interests and obvious advantages in the pandemic, a reasonable issue of that is the lack of physical examination.As a consequence, we can suggest virtual and telephone visits and consultation for the patients, especially those with severe symptoms, just as a good alternative, not further (18, 27).It is worth noting that the COVID-19 pandemic has provided strategies known as teleworking, in which employees can work from their homes and perform their tasks without attendance at the workplace.A cross-sectional study indicated that women with endometriosis could have more efficient management of their symptoms, as working hours have been decreased, and teleworking and remote work have been prominent (28).
In such wise, one study reported improvement in dysmenorrhea pain intensity, which signifies the favor of teleworking.Despite the prevailing wisdom, Bahat et al. declared that many endometriosis patients do not consider their disease a risk factor for COVID-19.However, this study also showed that most of the patients were concerned about being more symptomatic during the pandemic.While considering this issue besides their lifestyle concerns, including sleep and sexual disturbances, it can be concluded that the pandemic negatively impacted mental health, which adversely affects the patients' peace of mind and quality of life (23).Thus, contrariety between studies about lifestyle changes is prominent, and further evaluation should be considered.
According to a recent study not included in our primary search, women with endometriosis are exposed to an increased risk of psychological and psychiatric disorders, including PTSD (24), which could be related to the fear of access to the health system services.However, medication availability seems to remain intact in the pandemic.However, we cannot deny disorganization and difficulties resulting from the postponement of visits, which make it troublesome for patients to plan (16).A rational factor for challenging the mental health of the patients seems to be thinking of COVID-19 exposure resulting from treatment procedures.Endometriosis patients for many causes, including infertility, may need surgical interventions; as shown in one of the studies, minimally invasive procedures are generally safe and could be performed without concern of increased risk of .This paper has a considerable limitation, mainly related to the narrow populations of the studies.Target populations were from developed and developing countries, where health services are easily accessible, and several strategies are implemented to minimize COVID-19 effects on the health system.On the other hand, undeveloped countries are more vulnerable to and have less compliance against the pandemic troubles because of less developed health care.This consideration highlights the need for further studies, especially in undeveloped countries, where data collection is more difficult.
Another limit to consider is the lack of valid documentation of the patients.Data gathering by online questionnaires has limitations, such as patients' honesty in terms of proven endometriosis and their medical history.Although, this type of survey resulted in the evaluation of more diverse samples around the world.

Conclusion
Our systematic review showed that the COVID-19 pandemic resulted in minor psychological problems for women with endometriosis, although the risk of being infected by COVID-19 was not increased.In addition, strategies obtained in the pandemic, including teleworking, remarkably provide some benefits in their lifestyle.As the effect of COVID-19 upon the severity of endometriosis symptoms remains controversial, further evaluations are needed to draw a definitive conclusion.