Identifying, synthesising and appraising existing evidence relating to myalgic encephalomyelitis/chronic fatigue syndrome and pregnancy: a mixed-methods systematic review

Abstract

Objectives: To identify, synthesise and appraise evidence relating to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and pregnancy.

Design: Mixed-methods systematic review, using convergent segregated design.

Data sources: MEDLINE, EMBASE, Scopus, PsycINFO, CINAHL, MedRxiv, PROSPERO and grey literature sources through 6 August 2023.

Eligibility criteria: We included original research studies, expert opinion and grey literature reporting on ME/CFS and pregnancy/post partum (up to 2 years), risk of pregnancy outcomes with ME/CFS or experiences during pregnancy for mother, partner or health and social care professionals following ME/CFS during pregnancy, all where the evidence was relevant to a confirmed ME/CFS diagnosis prior to pregnancy.

Data extraction and synthesis: Three independent reviewers completed all screening, data extraction and quality assessment. Risk of bias was assessed using the mixed-methods appraisal tool V.2018. Qualitative and quantitative literature was analysed separately using thematic and descriptive syntheses. Findings were integrated through configuration.

Results: Searches identified 3675 articles, 16 met the inclusion criteria: 4 quantitative (1 grey), 11 qualitative (9 grey) and 1 grey mixed-methods study. Of the four quantitative studies that reported on ME/CFS severity during pregnancy, two suggested pregnancy negatively impacted on ME/CFS, one found most women had no change in ME/CFS symptoms and one found ME/CFS improved; this difference in symptom severity across studies was supported by the qualitative evidence. The qualitative literature also highlighted the importance of individualised care throughout pregnancy and birth, and the need for additional support during family planning, pregnancy and with childcare. Only one quantitative study reported on pregnancy outcomes, finding decreased vaginal births and higher rates of spontaneous abortions and developmental and learning delays associated with pregnancies in those with ME/CFS.

Conclusions: Current evidence on ME/CFS in pregnancy is limited and findings inconclusive. More high-quality research is urgently needed to support the development of evidence-based guidelines on ME/CFS and pregnancy.

Source: Slack E, Pears KA, Rankin J, Newton JL, Pearce M. Identifying, synthesising and appraising existing evidence relating to myalgic encephalomyelitis/chronic fatigue syndrome and pregnancy: a mixed-methods systematic review. BMJ Open. 2023 Oct 5;13(10):e070366. doi: 10.1136/bmjopen-2022-070366. PMID: 37798026. https://bmjopen.bmj.com/content/13/10/e070366 (Full text)

Association Between Chronic Fatigue Syndrome/Myalgic Encephalomyelitis and Cardiovascular Disease

Abstract:

Background: Chronic Fatigue Syndrome or Myalgic Encephalomyelitis (CFS/ME) is a medical condition characterized by severe and prolonged fatigue that is not relieved by rest or attributed to any underlying medical or psychological condition. Individuals with CFS/ME are considered to have an increased risk of a wide range of comorbid conditions, including cardiovascular disease (CVD). The association between CFS/ME and CVD is not fully understood.

Objective: To determine the prevalence of CFS/ME in a sample population and examine its association with CVD.

Methods: Data was analyzed from the 2021 National Health Interview Survey (NHIS). Information on sociodemographic factors, CVD risk factors, and history of CFS/ME and CVD were collected. Multivariate logistic regression model was used to determine the association between CFS/ME and CVD, adjusting for traditional CVD risk factors (age, sex, race, hypertension, diabetes, dyslipidemia, smoking, and body mass index (BMI).

Results: Median age of participants was 53 years, and majority of participants were female (53.9%). Prevalence of CFS/ME was 1.4%. A history of CFS/ME was significantly associated with CVD (aOR: 3.13, 95%CI: 2.37, 4.15, p-value: <0.001) after adjusting for traditional CVD risk factors.

Conclusion: A history of CFS/ME was independently associated with CVD after adjusting for traditional CVD risk factors. Patients with CFS/ME need close evaluation for CVD. Further studies are needed to better understand the relationship between CFS/ME and CVD.

Source: Mawulorm KI Denu, Ritika Revoori, Cherita Eghan, Fredrick Larbi Kwapong, Andrew Hillman, Cornelius A Normeshie, Kofi Poku Berko, Emily L. Aidoo. Association Between Chronic Fatigue Syndrome/Myalgic Encephalomyelitis and Cardiovascular Disease. BMC Archives of Publis Health. https://doi.org/10.21203/rs.3.rs-3332913/v1 (Full text)

Fatigue, chronic fatigue syndrome and migraine: Intersecting the lines through a cross-sectional study in patients with episodic and chronic migraine

Abstract:

Objectives: Fatigue is a common symptom occurring in a variety of disorders. Chronic fatigue syndrome (CFS) is characterized by debilitating fatigue as the core symptom. The risk of CFS is nearly 1.5 times higher in migraine while headaches have been reported in 59% of cases with CFS. However, details of its occurrence and severity remain largely unexplored.

The primary objective of our study was to determine the occurrence and severity of fatigue and CFS in patients with episodic and chronic migraine. The secondary objectives were to define their relationship with other common comorbidities.

Materials and methods: 60 migraine patients (30 each, episodic [EM] and chronic migraine [CM]) were recruited from Neurology Outpatient Department, GIPMER a tertiary referral center in New Delhi, India. Patients’ headache severity was analyzed using the Headache impact test-6 (HIT-6) score while fatigue and other migraine accompaniments were assessed using Fatigue severity scale (FSS), Chalder fatigue scale, CDC diagnostic criteria for CFS, American College of Rheumatology Diagnostic Criteria for fibromyalgia, Hamilton Depression Scale, the Generalized Anxiety Disorder 7-Item Scale, and Epworth sleepiness Scale (ESS). Comparative analysis was further done among migraine patients with and without fatigue and CFS.

Results: The mean HIT-6 score was significantly higher in CM versus EM. The CM group had a higher mean FSS score (47.87 vs. 37.3 in EM; P = 0.004), a percentage of patients with severe fatigue (60% vs. 20% in EM; P = 0.004), and a higher percentage of patients with pathological fatigue (83.3% vs. 63.3% in EM; P = 0.04). Around 23.33% of CM patients fulfilled the criteria of CFS. Fatigue correlated positively with severity, frequency, attack duration and chronicity of the migraine episodes, along with depression, anxiety, and excessive daytime sleepiness.

Conclusion: Fatigue and related comorbid disorders are significantly more common in CM than in EM, expanding the morbidity of the condition and underscores the need to address these accompanying symptoms for devising a holistic treatment plan.

Source: Kumar H, Dhamija K, Duggal A, Khwaja GA, Roshan S. Fatigue, chronic fatigue syndrome and migraine: Intersecting the lines through a cross-sectional study in patients with episodic and chronic migraine. J Neurosci Rural Pract. 2023 Jul-Sep;14(3):424-431. doi: 10.25259/JNRP_63_2022. Epub 2023 Apr 20. PMID: 37692810; PMCID: PMC10483198. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10483198/ (Full text)

A population-based investigation into the prevalence of chronic fatigue syndrome in United States military Veterans with chronic pain

Abstract:

Objective: Chronic fatigue syndrome (CFS) is a debilitating illness characterized by persistent fatigue among other symptoms. Pain symptoms are common and included in the diagnostic criteria for CFS but are not required for diagnosis. Despite the association between CFS and pain, few studies have examined CFS in the context of chronic pain (CP) conditions. The current study estimates the period prevalence of comorbid CFS among military Veterans with CP and compares sociodemographic characteristics and CP conditions of Veterans with CP + CFS to those with CP without CFS.

Methods: This study included Veterans Health Administration (VHA) data on 2,261,030 patients with chronic pain in 2018. Sociodemographic characteristics included age, sex, race, ethnicity, and rurality. Descriptive statistics were used to describe the sample and between-group comparisons included independent samples t-tests and chi-square tests of independence. Effect sizes were also examined.

Results: A total of 15,248 (0.67%) of Veterans with CP also had a diagnosis of CFS. Veterans diagnosed with CP + CFS were younger and were more likely to be female, White, non-Hispanic, and rural-dwelling. However, small and weak effect sizes were observed for these differences. The majority of Veterans with CP + CFS had limb/extremity (69.20%) back pain (53.44%), or abdominal/bowel pain (24.11%).

Conclusion: CDC treatment recommendations for CFS include treating pain first, studying CFS in the context of CP is critically important. Veterans diagnosed with CP + CFS appear demographically similar, compared to Veterans with CP without CFS. Examining the utilization of pain-related healthcare services among this group would be a useful next step.

Source: Jenna L. Adamowicz, Emily B. K. Thomas, Brian C. Lund, Mary A. Driscoll, Mark Vander Weg & Katherine Hadlandsmyth (2023) A population-based investigation into the prevalence of chronic fatigue syndrome in United States military Veterans with chronic pain, Fatigue: Biomedicine, Health & Behavior, DOI: 10.1080/21641846.2023.2239977

Hypothesis: Symptomatic myodesopsia/vitreous floaters may constitute a risk factor for Long COVID and ME/CFS

Abstract:

The ophthalmological condition known as myodesopsia or vitreous floaters results from aggregates of proteins or cellular debris in the vitreous body casting shadows onto the retina that are perceived as objects moving through the visual field. While this is commonly viewed as a benign condition associated with aging, a growing body of research suggests that for some patients it can severely impact visual function and quality of life. Myodesopsia is often caused by posterior vitreous detachment, but can also result from other conditions such as asteroid hyalosis, uveitis, or myopic vitreopathy.

There are strong reasons to suspect that its presence may be indicative of a susceptibility to collagen degradation in response to inflammatory triggers, which may represent a risk factor for the development of Long COVID, ME/CFS, or related chronic illnesses. Evidence for such susceptibility includes the presence of collagen-degrading enzymes in the vitreous, associations with other connective tissue disorders, and links between myodesopsia and infections with various pathogens.

Source: Mazewski, M. (2023). Hypothesis: Symptomatic myodesopsia/vitreous floaters may constitute a risk factor for Long COVID and ME/CFS. Patient-Generated Hypotheses Journal for Long COVID & Associated Conditions, Vol. 1, 13-20 https://patientresearchcovid19.com/hypothesis-symptomatic-myodesopsia-vitreous-floaters-may-constitute-a-risk-factor-for-long-covid-and-me-cfs-pghj-issue1-may2023/ (Full text)

Causal Effects between Gut Microbiome and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Two-Sample Mendelian Randomization Study

Abstract:

Background: Evidence from previous studies have implicated an important association between gut microbiota (GM) and Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS), but whether there is a definite causal relationship between GM and ME/CFS has not been elucidated.

Method: This study obtained instrumental variables of 211 GM taxa from the Genome Wide Association Study (GWAS), and mendelian randomization (MR) study was carried out to assess the effect of gut microbiota on ME/CFS risk from UK Biobank GWAS (2076 ME/CFS cases and 460857 controls). Inverse variance weighted (IVW) was the primary method to analyze causality in this study, and a series of sensitivity analyses was performed to validate the robustness of the results.

The inverse variance weighted (IVW) method indicated that genus Paraprevotella (OR:1.001, 95%CI:1.000-1.003, p-value<0.05) and Ruminococca-ceae_UCG_014(OR 1.003, 95% CI 1.000 to 1.005, p-value < 0.05) were positively associated with ME/CFS risk. Results from the weighted median method supported genus Paraprevotella (OR 1.003, 95% CI 1.000 to 1.005, p-value < 0.05) as a risk factor for ME/CFS.

Conclusions: This study reveals a causal relationship between genus.paraprevotella, genus.Ruminococcaceae_UCG_014 and ME/CFS, and our findings provide novel insights for further elucidating the developmental mechanisms mediated by the gut microbiota of ME/CFS.

Source: Gang He, Yu Cao, Wangzi Xu and Houzhao Wang. Causal Effects between Gut Microbiome and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Two-Sample Mendelian Randomization Study. Front. Microbiol. Volume 14 – 2023 | doi: 10.3389/fmicb.2023.1190894 https://www.frontiersin.org/articles/10.3389/fmicb.2023.1190894/abstract

Socioeconomic determinants of myalgic encephalomyelitis/chronic fatigue syndrome in Norway: a registry study

Abstract:

Background:

Previous research has shown that socioeconomic status (SES) is a strong predictor of chronic disease. However, to the best of our knowledge, there has been no studies of how SES affects the risk of Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) that has not been based upon self-reporting or retrospectively screening of symptoms. As far as we know, this is therefore the first study that isolate and describe socioeconomic determinants of ME/CFS and calculate how these factors relate to the risk of ME/CFS diagnosis by utilizing individual level registry data, which allows for objective operationalization of the ME/CFS population, and the utilization of different control groups.

Data and methods: We utilize health registry data from all adult patients diagnosed with ME/CFS from 2016-2018 in Norway, coupled with socioeconomic data from statistics Norway from 2009-2018. We operationalize SES as household income and educational attainment fixed at the beginning of the study period. We compare the effects of SES on the risk of ME/CFS diagnosis to a population of patients with hospital diagnoses that share clinical characteristics of ME/CFS and a healthy random sample of the Norwegian population. Our models are estimated by logistic regression analyses.Results: When comparing the risk of ME/CFS diagnosis with a population consisting of people with four specific chronic diseases, we find that high educational attainment is associated with a 19% increase (OR: 1.19) in the risk of ME/CFS and that high household income is associated with a 18% increase (OR:0.82) in risk of ME/CFS. In model 2, when comparing with a healthy population sample, we find that low educational attainment is associated with 69% decrease (OR:0.31) in the risk of ME/CFS and that low household income is associated with a 53% increase (OR: 1.53).

Conclusion: We find statistically significant associations between SES and the risk of ME/CFS. However, our more detailed analyses shows that our findings vary according to which population we compare the ME/CFS patients with, and that the effect of SES is larger when comparing with a healthy population sample, as opposed to controls with selected hospital diagnoses.

Source: Hilland GH, Anthun KS. Socioeconomic determinants of myalgic encephalomyelitis/chronic fatigue syndrome in Norway: a registry study. Research Square; 2023. DOI: 10.21203/rs.3.rs-2755999/v1. https://europepmc.org/article/ppr/ppr646979 (Full text available as PDF file)

Natural killer cytotoxicity in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): a multi-site clinical assessment of ME/CFS (MCAM) sub-study

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multisystem illness characterized by substantial reduction in function accompanied by profound unexplained fatigue not significantly relieved by rest, post-exertional malaise, and other symptoms. Reduced natural killer (NK) cell count and cytotoxicity has been investigated as a biomarker for ME/CFS, but few clinical laboratories offer the test and multi-site verification studies have not been conducted.

Methods: We determined NK cell counts and cytotoxicity in 174 (65%) ME/CFS, 86 (32%) healthy control (HC) and 10 (3.7%) participants with other fatigue associated conditions (ill control [IC]) from the Multi-Site Clinical Assessment of ME/CFS (MCAM) study using an assay validated for samples shipped overnight instead of testing on day of venipuncture.

Results: We found a large variation in percent cytotoxicity [mean and (IQR) for ME/CFS and HC respectively, 34.1% (IQR 22.4-44.3%) and 33.6% (IQR 22.9-43.7%)] and no statistically significant differences between patients with ME/CFS and HC (p-value = 0.79). Analysis stratified on illness domain measured with standardized questionnaires did not identify an association of NK cytotoxicity with domain scores. Among all participants, NK cytotoxicity was not associated with survey results of physical and mental well-being, or health factors such as history of infection, obesity, smoking, and co-morbid conditions.

Conclusion: These results indicate this assay is not ready for clinical implementation and studies are needed to further explore immune parameters that may be involved in the pathophysiology of ME/CFS.

Source: Querec TD, Lin JS, Chen Y, Helton B, Kogelnik AM, Klimas NG, Peterson DL, Bateman L, Lapp C, Podell RN, Natelson BH, Unger ER; MCAM Study Group. Natural killer cytotoxicity in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): a multi-site clinical assessment of ME/CFS (MCAM) sub-study. J Transl Med. 2023 Apr 3;21(1):242. doi: 10.1186/s12967-023-03958-2. PMID: 37013608. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-03958-2 (Full text)

Towards a Better Understanding of the Complexities of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex condition arising in susceptible people, predominantly following viral infection, but also other stressful events. The susceptibility factors discussed here are both genetic and environmental although not well understood.

While the dysfunctional physiology in ME/CFS is becoming clearer, understanding has been hampered by different combinations of symptoms in each affected person.

A common core set of mainly neurological symptoms forms the modern clinical case definition, in the absence of an accessible molecular diagnostic test. This landscape has prompted interest in whether ME/CFS patients can be classified into a particular phenotype/subtype that might assist better management of their illness and suggest preferred therapeutic options.

Currently, the same promising drugs, nutraceuticals, or behavioral therapies available can be beneficial, have no effect, or be detrimental to each individual patient. We have shown that individuals with the same disease profile exhibit unique molecular changes and physiological responses to stress, exercise and even vaccination.

Key features of ME/CFS discussed here are the possible mechanisms determining the shift of an immune/inflammatory response from transient to chronic in ME/CFS, and how the brain and CNS manifests the neurological symptoms, likely with activation of its specific immune system and resulting neuroinflammation.

The many cases of the post viral ME/CFS-like condition, Long COVID, following SARS-CoV-2 infection, and the intense research interest and investment in understanding this condition, provide exciting opportunities for the development of new therapeutics that will benefit ME/CFS patients.

Source: Tate WP, Walker MOM, Peppercorn K, Blair ALH, Edgar CD. Towards a Better Understanding of the Complexities of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID. International Journal of Molecular Sciences. 2023; 24(6):5124. https://doi.org/10.3390/ijms24065124 (Full text)

Presence of depression and anxiety with distinct patterns of pharmacological treatments before the diagnosis of chronic fatigue syndrome: a population-based study in Taiwan

Abstract:

Objective: An increased prevalence of psychiatric comorbidities (including depression and anxiety disorder) has been observed among patients with chronic fatigue syndrome (CFS). However, few studies have examined the presence of depression and anxiety disorder before the diagnosis of CFS. This study aimed to clarify the preexisting comorbidities and treatments associated with patients with subsequent CFS diagnosis in a population-based cohort in Taiwan.

Methods: An analysis utilizing the National Health Insurance Research Database of Taiwan was conducted. Participants included were 6303 patients with CFS newly diagnosed between 2000 and 2010 and 6303 age-/sex-matched controls.

Results: Compared with the control group, the CFS group had a higher prevalence of depression and anxiety disorder before the diagnosis of CFS. Sampled patients who took specific types of antidepressants, namely, selective serotonin reuptake inhibitors (adjusted odds ratio [aOR] = 1.21, 95% confidence interval [CI] 1.04-1.39), serotonin antagonists and reuptake inhibitors (SARI; aOR = 1.87, 95% CI 1.59-2.19), and tricyclic antidepressants (aOR = 1.46, 95% CI 1.09-1.95), had an increased risk of CFS. CFS risk was also higher among participants taking benzodiazepine, muscle relaxants, and analgesic drugs.

A sub-group analysis revealed that SARI use was related to an increased risk of CFS in the depression, anxiety disorder, male, and female groups. In the depression and anxiety disorder groups, analgesic drug use was associated with an increased CFS risk. Nonpharmacological treatment administration differed between men and women.

Conclusion: This population-based retrospective cohort study revealed an increased risk of CFS among populations with preexisting depression and anxiety disorder, especially those taking SARI and analgesic drugs.

Source: Chen C, Yip HT, Leong KH, Yao WC, Hung CL, Su CH, Kuo CF, Tsai SY. Presence of depression and anxiety with distinct patterns of pharmacological treatments before the diagnosis of chronic fatigue syndrome: a population-based study in Taiwan. J Transl Med. 2023 Feb 8;21(1):98. doi: 10.1186/s12967-023-03886-1. PMID: 36755267; PMCID: PMC9907887. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9907887/ (Full text)