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2.1. Study Design
aggression, irritability, DSM-5
This 12-week open-label pilot study was conducted to investigate the efficacy of glutathione use as a supplement for the symptomatic treatment of irritability and aggression in children with ASD, as defined by criteria set forth in the DSM-5. Trials were conducted in the outpatient setting at the University of Chicago. Institutional review board proposal was submitted and approved for the intent and purpose of this experimental study. The study is registered under NCT05954052 with clincialtrials.gov. All studied subjects agree to this voluntary study without financial incentives or otherwise. After obtaining informed consent from parents, subjects are screened for inclusion and exclusion criteria as highlighted below. For the purpose of this study, oral glutathione refers to oral supplementation with Opitac
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2.2. Inclusion and Exclusion Criteria
myocardial infarction, seizures, neoplasia, anemia, hematological disorders, milk thistle, asthma, unstable medical illness, DSM-5
MYOCARDIAL INFARCTION, COAGULOPATHIES, NEOPLASIA, ANEMIA, HEMATOLOGICAL DISORDERS, ASTHMA
Inclusion criteria included the following: (a) children and adolescents of both sexes between ages 4–17; (b) diagnosis of ASD as determined by criteria set forth in DSM-5 (Exclusion criteria included the following: (a) unstable medical illness or clinically significant abnormalities on physical examination; (b) history of seizures; (c) history of hematological disorders such as anemia, coagulopathies, neoplasia; (d) history of myocardial infarction within the last 6 months; (e) current pregnancy, lactation, or inadequate contraception in females of childbearing potential; (f) current or recent (past 3 months) substance use or dependence; (g) illegal substance use within 2 weeks of study initiation; (h) previous treatment with glutathione; (i) current treatment with supplements that interfere with glutathione levels including NAC, milk thistle, vitamin C, vitamin B, grape seed extract, amino acids, or zinc; (j) current treatment with medications with known glutamatergic properties such as dextromethorphan, d-cyloserine, amantadine, memantine, lamotrigine, or riluzole; (k) underlying asthma that may potentiate worsening of respiratory symptoms due to glutathione use.
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2.3. Interventions
SRS
Subjects were followed over a 12-week course with an initial intake appointment for baseline screening of vital signs, oxidative laboratory work, Social Responsiveness Scale, Aberrant Behavior Checklist, and Clinical Global Impression scale. The use of oral glutathione was discussed with subjects and their parents who provided signed consent for this trial.OpitacSubjects were followed up using several qualitative measures including the Aberrant Behavior Checklist (ABC), Social Responsiveness Scale (SRS), Clinical Global Impression Scale—Severity (CGI-S), and Side Effects Checklist (SEC) (
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2.4. Outcome Measures
SECONDARY
Our primary outcome was to monitor therapeutic efficacy of glutathione in treating symptoms of ASD in children. Our secondary outcome was to evaluate the tolerability of oral glutathione in children with ASD. The following scales and checklists were used for the goals of the study.
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2.4.1. Oxidative Labs
OXIDATIVE STRESS, OXIDATIVE STRESS
Subjects underwent laboratory studies to assess oxidative burden pre- and post-treatment during the study period. Oxidative Stress Analysis 2.0 was performed by Geneva Diagnostics and included a battery of tests to quantify oxidative stress. Specifically, this panel looks at (I) reduction–oxidation reserve including glutathione, total antioxidant capacity, cysteine, cystine, cysteine/cystine ratio, sulphate, cysteine/sulphate ratio; (II) protective enzymes including superoxide dismutase and glutathione peroxidase; (III) cellular damage as measured by lipid peroxides.
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2.4.2. Aberrant Behavior Checklist (ABC)
lethargy, epilepsy, hyperactivity, agitation, irritability, ASD, intellectual disability, developmental disabilities
SECONDARY, EPILEPSY
This is 58-item symptom checklist that assesses behavioral problems in adults and children with developmental disabilities including ASD, intellectual disability, epilepsy, etc. The checklist is a versatile assessment tool that can be used in a variety of settings including home, community settings, educational settings, and in developmental centers. The checklist can also be administered by various direct caregivers including but not limited to parents, healthcare workers, and educators. Items are divided into 5 domains or subscales that assess (I) irritability and agitation; (II) lethargy and social withdrawal; (III) stereotypic behavior; (IV) hyperactivity and non-compliance; (V) inappropriate speech. Subscale scores at baseline are compared to post-treatment scores to assess primary and secondary outcomes.
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2.4.3. Social Responsiveness Scale (SRS)
autism mannerisms, deficit in social interaction, SRS
This scale is a respondent-based outcome measure used to assess deficits and symptoms related to ASD. The scale comes in two forms differentiated by gender and age. The scale can be administered by parents/caregivers and consists of subscales that assess (I) social awareness; (II) social cognition; (III) social communication; (IV) social motivation; (V) autism mannerisms. The raw subtotal of each domain is converted to a standardized score (T-score) and summed to calculate a total SRS score. All T-scores have a mean of 50 points and a standard deviation of 10 points. Clinical severity of ASD as determined by SRS total t-score is as follows: (I) less than or equal to 59 represents low-to-no symptom impact (normal); (II) between 60–65 represents mild-to-moderate deficits in social interaction; (III) between 66–75 represents moderate deficit in social interaction; (IV) greater than or equal to 76 represents severe (strongly associated with a clinical diagnosis of ASD). Repeated SRS assessments are compared and monitored to track progress toward achieving treatment plan goals.
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2.4.4. Clinical Global Impressions (CGI) Scale
ill
ADVERSE EVENTS
This brief, 3-item assessment tool provides a global rating of illness severity (CGI-S), global improvement or change (CGI-I), and therapeutic efficacy (CGI-E). CGI-S is measured on a 7-point scale ranging from 1 (normal, not at all ill) to 7 (among the most extremely ill patients). CGI-I is measured on a 7-point scale as well, ranging from 1 (very much improved) to 7 (very much worse). CGI-E takes into account both the therapeutic effect and adverse events, ranging from 1 (marked therapeutic effect) to 04 (unchanged or worse). Our study utilizes a CGI-E final index score ranging from 0–16 which depends on separate subscale ratings of therapeutic benefits versus side effects.
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2.4.5. Side Effect Checklist (SEC)
SIDE EFFECT
This in-house glutathione side effect questionnaire (
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2.5. Statistical Analyses
The CGI severity scale was used to assess clinically significant change after treatment. For someone to have a clinically significant change, her or his final CGI severity score had to be less than the cutoff score, and his or her change from baseline had to be greater than the reliable change index. The statistical significance of pre- and post-treatment ABC scores were determined via paired
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3. Results
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3.1. Study Population
autism spectrum disorder, DSM-5
After screening the potential subjects for the inclusion and exclusion criteria, this pilot study recruited a total of six subjects, all of whom met DSM-5 criteria for a diagnosis of autism spectrum disorder. Parental consent was obtained for each participant during enrollment prior to the study. The demographics of the study group are outlined in
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3.2. Oxidative Stress Analysis
OXIDATIVE STRESS, STD
The participants all underwent baseline oxidative stress screening prior to glutathione treatment and post-glutathione treatment upon completion of the study where appropriate. One patient was unable to complete the full study and did not undergo the post-treatment oxidative stress screen. The results of the oxidative stress testing are outlined in Three subjects’ baseline glutathione levels were below the normal ranges during the pre-treatment assessment. Two of these three subjects’ below normal glutathione levels improved to normal ranges with oral glutathione supplementation. The total antioxidant capacity did not improve in one subject, and even worsened in another subject. Cysteine is the rate-limiting amino acid for glutathione production. There were no pre- and post-treatment differences in the cysteine levels in all patients supplemented with oral glutathione. Sulfate is produced from cysteine via sulfoxidation. Sulfate is important in detoxification reactions, and is essential for GI function and joint health. A high cysteine/sulfate ratio or low sulfate level may indicate oxidative stress. Two subjects showed greater than one standard deviation improvement in sulfate levels after treatment, and three subjects showed at least one standard deviation decrease in their cysteine/sulfate ratio after treatment. Cystine is the oxidized product of cysteine and is the predominant form in blood due to its greater relative stability. Both the cystine and cysteine/cystine ratios were within the normal ranges for all patients. The oxidative panel looked at two protective enzymes, namely, superoxide dismutase and glutathione peroxidase. The function of these enzymes is to protect against oxidative stress by reducing superoxide anions to hydrogen peroxide and from hydrogen peroxide to water, respectively. Four of the six subjects experienced >1 std deviation increase in glutathione peroxidase from baseline, and two of the six patients experienced >1 std deviation increase in superoxide dismutase from baseline. One patient with baseline >2 standard deviations below the normal ranges of glutathione peroxidase and superoxide dismutase did not experience any significant enzyme level changes with glutathione supplementation. Lipid peroxides are a direct indicator of oxidative damage to polyunsaturated fatty acids, suggesting an imbalance of redox reactions favoring oxidation. Lipid peroxides were unremarkable for most subjects. Of note, the patient who dropped out had low baseline levels of glutathione and an elevated baseline level of the cysteine/sulfate ratio, superoxide dismutase, and lipid peroxides.
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3.3. Behavioral Outcomes
SRS
The ASD severity was measured using SRS. All subjects underwent SRS screening during the initial enrollment, with the results outlined in ABC was another scale used to track the ASD treatment progress with oral glutathione supplementation. The pre- and post-treatment subscores in five different domains are outlined in
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3.4. Safety Evaluation
ADVERSE EFFECTS
Oral glutathione supplementation was generally well-tolerated throughout the course of the study. There were minimal adverse effects reported, as summarized in The CGI scale was also used as a tool to measure the improvement with oral glutathione supplementation; the results are summarized in
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4. Discussion
ASD and gastrointestinal abnormalities, mitochondrial dysfunction, irritability, psychiatric
SIDE EFFECT, STOMACH, CYSTIC FIBROSIS, MITOCHONDRIAL DYSFUNCTION, OXIDATIVE STRESS
Our pilot investigation examined the utility and tolerability of oral supplementation with glutathione as a treatment for patients with ASD. A similar study by Kern et al. looked at glutathione supplementation for the treatment of ASD. Kern et al. demonstrated the safety profile of oral glutathione supplementation and significant increases in plasma reduced glutathione using glutathione dosages significantly lower (ranging from 50–200 mg/30 lbs or 3.67–14.7 mg/kg) than those used in this pilot study; however, they did not demonstrate a statistically significant difference in the increased whole blood glutathione. As previously mentioned in the study design, patients with cystic fibrosis require ~65 mg/kg of glutathione for adequate absorption. Our study utilizes a more conservative approach of ~32.5 mg/kg of glutathione, which is still well above the range used by Kern et al. Even at higher glutathione doses, our study once again demonstrates a good safety profile for glutathione use.The study by Kern et al. also showed statistically significant increases in plasma transsulfuration metabolites including sulfate, cysteine, and taurine following glutathione supplementation, but they were unable to delineate whether the increased metabolites were truly due to glutathione’s effect on the transsulfuration pathway or whether the increases in transsfulfuration metabolites were due to the increased breakdown of glutathione [Glutathione was generally well-tolerated except in the case of one subject, who experienced a significant increase in irritability and ultimately discontinued their participation in the study. Stomach upset was reported in four of the six subjects in the study as a side effect with oral glutathione treatment. Stomach upset and GI side effects may not necessarily be attributed to oral glutathione alone. With the exception of irritability, all other reported side effects with oral glutathione (The baseline oxidative stress analysis was crucial in understanding the redox imbalance in the patients with ASD. In the case of the subject that dropped out of the study, the pre-treatment laboratory work shows a baseline depletion of the glutathione reserve, high levels of superoxide dismutase despite normal glutathione peroxidase, and elevated lipid peroxides. Another subject shows baseline low levels of antioxidant capacity, significantly elevated glutathione peroxidase, and significantly elevated superoxide dismutase. Both subjects had high oxidative burdens prior to treatment and did not seem to experience any clinical or redox benefit with oral glutathione supplementation. A possible explanation for this phenomenon is that these subjects are at maximum physiologic compensation with a high baseline oxidative burden. The further addition of glutathione is unable to surpass the physiologic cap on the redox balance. The results may indicate that subjects with high baseline oxidative burden may be poor responders to oral glutathione supplementation. All other subjects showed improved total antioxidant capacity, increased sulfate levels, and significant increases in glutathione peroxidase and superoxide dismutase. Another observation is that oxidative burden does not necessarily translate to clinical severity, as indicated via the CGI scores.The clinical progress in this study was monitored via ABC. There were decreases in the post-treatment mean scores across all ABC domains as compared to the pre-treatment scores, but the mean differences were not statistically significant. However, it is important to note that despite the lack of statistical significance, there was a mild improvement in the severity of ASD symptoms in 66.7% of the patients, according to the CGI-I. This translates to an observable clinical significance and improvement in the quality of life of some patients with ASD.As referenced, an imbalance in redox reactions is only one of the many factors that contribute to ASD. Impaired neurotransmission, immune dysregulation in the brain, mitochondrial dysfunction, and a mix of environmental factors may also contribute to treatment response. A recent study by Huang et al. demonstrates the critical role of glutathione in astrocytes to help maintain blood–brain barrier stability by suppressing endothelial cell tight junction phosphorylation and delocalization [Given the association between ASD and gastrointestinal abnormalities, food picking, and food aversion, many individuals with ASD have concurrent deficiencies in macro and micronutrients. The most well-studied agents are vitamin A, vitamin BAnother key component in the baseline redox balance involves genetics. Glutathione S-transferases (GST) are a family of enzymes that aid in the conjugation of reduced GSH to xenobiotics for detoxification and also helps reduce endogenous oxidative species. All four major classes of GST have been shown to exhibit genetic polymorphisms reducing their antioxidative ability and are associated with psychiatric pathologies such as ASD [The method of delivery is an important consideration in this study. Opitac
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Author Contributions
Conceptualization: K.R. and K.B.-W.; methodology: K.R. and K.B.-W., software: G.W.; formal analysis: G.W.; investigation: K.R., K.B.-W. and R.R., resources, K.R.; data curation: G.W.; writing: K.R. and G.W.; writing—review and editing: K.R. and K.B.-W., visualization: G.W. and K.R., supervision: K.R., project administration: K.R.; funding acquisition: K.R. All authors have read and agreed to the published version of the manuscript.
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Institutional Review Board Statement
The study was approved by the University of Chicago BSD IRB # IRB 19-0017.
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Informed Consent Statement
Informed written consent was obtained from all subjects involved in the study.
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Data Availability Statement
The study is registered with the clincialtrials.gov.
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Conflicts of Interest
The authors declare no conflict of interest.
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Appendix A. Diagnostic Criteria
intellectual developmental disorder, verbal nonverbal behavior, repetitive motor movements, Intellectual disability, Asperger’s disorder, autistic disorder, communication disorder, intellectual disability, catatonia, hyporeactivity, autism spectrum disorder, deficits in social communication, DSM-5
DISORDER, GENETIC CONDITION, DISORDERS
The following diagnostic criteria for ASD will be utilized. The criteria are defined by the Diagnostic and Statistical Manual for Mental Disorders (DSM-5) for a diagnosis of autism spectrum disorder:Persistent deficits in social communication and social interaction across multiple contexts, as manifested by the following, currently or by history (examples are illustrative, not exhaustive, see text): Deficits in social-emotional reciprocity, ranging, for example, from abnormal social approach and failure of normal back-and-forth conversation; to reduced sharing of interests, emotions, or affect; to failure to initiate or respond to social interactions.Deficits in nonverbal communicative behaviors used for social interaction, ranging, for example, from poorly integrated verbal and nonverbal communication; to abnormalities in eye contact and body language or deficits in understanding and use of gestures; to a total lack of facial expressions and nonverbal communication.Deficits in developing, maintaining, and understanding relationships, ranging, for example, from difficulties adjusting behavior to suit various social contexts; to difficulties in sharing imaginative play or in making friends; to absence of interest in peers.Specify current severity: Severity is based on social communication impairments and restricted repetitive patterns of behavior. Restricted, repetitive patterns of behavior, interests, or activities, as manifested by at least two of the following, currently or by history (examples are illustrative, not exhaustive; see text): Stereotyped or repetitive motor movements, use of objects, or speech (e.g., simple motor stereotypies, lining up toys or flipping objects, echolalia, idiosyncratic phrases).Insistence on sameness, inflexible adherence to routines, or ritualized patterns or verbal nonverbal behavior (e.g., extreme distress at small changes, difficulties with transitions, rigid thinking patterns, greeting rituals, need to take same route or eat food every day).Highly restricted, fixated interests that are abnormal in intensity or focus (e.g., strong attachment to or preoccupation with unusual objects, excessively circumscribed or perseverative interest).Hyper- or hyporeactivity to sensory input or unusual interests in sensory aspects of the environment (e.g., apparent indifference to pain/temperature, adverse response to specific sounds or textures, excessive smelling or touching of objects, visual fascination with lights or movement).Specify current severity: Severity is based on social communication impairments and restricted, repetitive patterns of behavior. Symptoms must be present in the early developmental period (but may not become fully manifest until social demands exceed limited capacities or may be masked by learned strategies in later life).Symptoms cause clinically significant impairment in social, occupational, or other important areas of current functioning.These disturbances are not better explained by intellectual disability (intellectual developmental disorder) or global developmental delay. Intellectual disability and autism spectrum disorder frequently co-occur; to make comorbid diagnoses of autism spectrum disorder and intellectual disability, social communication should be below that expected for general developmental level.Note: Individuals with a well-established DSM-IV diagnosis of autistic disorder, Asperger’s disorder, or pervasive developmental disorder not otherwise specified should be given the diagnosis of autism spectrum disorder. Individuals who have marked deficits in social communication, but whose symptoms do not otherwise meet criteria for autism spectrum disorder, should be evaluated for social (pragmatic) communication disorder.Specify if:With or without accompanying intellectual impairmentWith or without accompanying language impairmentAssociated with a known medical or genetic condition or environmental factorAssociated with another neurodevelopmental, mental, or behavioral disorderWith catatonia
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Appendix B
SIDE EFFECT
Glutathione Side Effect Questionnaire.
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References
SE, GS, SAH
SIDE EFFECTS
Glutathione redox cycle. Glutathione is primarily synthesized in the liver. Oxidized glutathione (GSSG) is then reduced via glutathione reductase and nicotinamide adenine dinucleotide phosphate (NADPH) into reduced glutathione (GSH). GSH is a major antioxidant in the body that primarily acts to eliminate reactive oxygen species (ROS). A major source of ROS is from oxidative phosphorylation in mitochondria. Mitochondrial GSH (mGSH) plays an important role in maintaining the redox balance in the body.Methionine cycle, transsulfuration pathway, and production of glutathione. The top portion of the figure depicts the methionine pathway, in which methionine is catalyzed by methionine adenosyltransferase (MAT) to form S-adenosyl-methionine (SAM), which is a primary methyl donor in the body. SAM is converted to S-adenosylhomocysteine (SAH) after donating its methyl group, and later hydrolyzed to form homocysteine. Homocysteine can be remethylated to form methionine using betaine-homocysteine methyltransferase (BHMT), thus closing the methionine cycle. The transsulfuration pathway depicted starts with the condensation of homocysteine and serine using cystathionine-β-synthase (rate-limiting step) to form cystathionine. Cystathionine is further hydrolyzed by cystathionine-γ-lyase to produce cysteine, which is further used to produce taurine and pyruvate. Glutathione production starts with cysteine, which is combined with glutamate via the enzyme glutamate cysteine ligase (GCL). The resulting γ-glutamylcysteine is then converted to reduced glutathione (GSH) via glutathione synthetase (GS). GSH is used for the reduction of ROS via glutathione peroxidase (GPX) and the resulting glutathione disulfide (GSSG) can be converted back to GSH via glutathione reductase (GR).Patient demographics for study sample.Comparison of baseline (pre) and post-treatment (post) oxidative lab values.Baseline Social Responsive Scale (SRS).Comparison of Aberrant Behavior Checklist (ABC) at baseline and post-treatment.Mean difference and clinical significance of Aberrant Behavior Checklist (ABC) pre- and post-treatment scores.Side effects of glutathione during course of treatment.Comparison of pre- and post-treatment CGI scores. Note: TE, therapeutic effect; SE, side effects.
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INTRODUCTION:
IBS
IRRITABLE BOWEL SYNDROME (IBS)
Delivered in person, yoga is effective in managing irritable bowel syndrome (IBS) symptoms. The evidence for efficacy, feasibility, and safety of virtually delivered yoga for patients with IBS is unknown.
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METHODS:
IBS, depression, fatigue, anxiety
ADVERSE EVENTS, SECONDARY, RECRUITMENT
Adults diagnosed with IBS were randomized to either Hatha yoga intervention of 8 weekly online classes delivered virtually or an advice-only control group and assessed at baseline and postintervention. We used an unadjusted ANOVA to determine differences between and within groups on the primary outcome (decrease of ≥50 points in IBS Symptom Severity Scale [IBS-SSS]) and secondary outcomes (quality of life, anxiety and depression, fatigue, somatic symptoms, perceived stress, COVID-19 stress, and self-compassion). We assessed feasibility through recruitment and attrition rates, adherence, participant satisfaction, and safety (i.e., adverse events).
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RESULTS:
Seventy-nine people participated (mean age 45.4 years [SD = 14.0], 92% women, 20% attrition rate). IBS-SSS decreased significantly in the treatment group (Δ
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DISCUSSION:
IBS
Virtually delivered yoga is safe and feasible, and effective in reducing IBS symptoms. Based on the primary end point, the intervention was not superior to an advice-only control group.
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INTRODUCTION
MY-IBS, IBS, psychiatric, fatigue
IRRITABLE BOWEL SYNDROME, IRRITABLE BOWEL SYNDROME
Irritable bowel syndrome (IBS) is a common chronic condition frequently involving alterations of the gut-brain axis. IBS is associated with psychiatric comorbidities, incomplete symptom control, and impaired quality of life (QOL) (Yoga is a mind-body therapy that includes physical postures (asanas), breathing exercises (pranayama), and meditation (The primary objective of the Meditation and Yoga for Irritable Bowel Syndrome (MY-IBS) study was to examine the efficacy and feasibility of a virtual 8-week yoga program on IBS symptom severity compared with an advice-only control group. Secondary objectives were to determine (i) whether a virtual yoga program improves the QOL, mental health outcomes, perceived stress, fatigue, COVID-19–related stress, and self-compassion, and (ii) the level of intention to practice yoga at baseline and whether intention correlated with practice minutes.
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METHODS
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Study design overview
IBS
INFLAMMATION
MY-IBS was a randomized 2-group controlled trial conducted at the University of Calgary in Alberta, Canada, from March 2021 to December 2022. Participants were not blinded to trial arms. Eligible participants diagnosed with IBS based on Rome IV (Individuals across Canada were eligible to participate. Participants were recruited between March and October 2021 and identified through (i) gastroenterology clinics across Calgary, Alberta, (ii) a previous survey where participants indicated an interest in this study and provided consent to be contacted, (iii) social media, (iv) self-referrals, (v) Canadian Association of Gastroenterologists monthly newsletter, and (vi) the IMAGINE (Inflammation, Microbiome and Alimentation Gastrointestinal and Neuropsychiatric Effects) cohort study at the University of Calgary. The University of Calgary Conjoint Health Research Ethics Board approved this study (ID: REB20-0084).
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Interventions
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Yoga intervention group.
The details of the yoga program have been published elsewhere (
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Advice-only control group.
IBS
Control participants received a 10-minute video including general education on IBS, the mind-gut connection in IBS, and the role of mind-body therapies in the management of IBS. These participants also received a list of IBS-related resources from the Canadian Digestive Health Foundation, a link to an IBS patient support group (
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Outcome measures
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Efficacy outcomes.
IBS, cancer
CANCER, DISEASE
The intervention and control groups were assessed on efficacy outcomes at baseline and 8 weeks. The primary end point measure was at least a 50-point difference on the IBS Symptom Severity Scale (IBS-SSS) between the groups postintervention (Secondary outcomes (and their measures) include QOL (IBS-QOL) (The Theory of Planned Behavior (TPB) was applied to determine whether the intention to practice yoga at baseline correlated with practice minutes. The TPB is a widely used social-cognitive theory to understand health behaviors in various disease and nondisease populations, including cancer (
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Sample size
Symptom reduction of at least 50 points on the IBS-SSS is considered clinically meaningful (
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Randomization, treatment allocation, and blinding
Participants were randomized after baseline assessment to either the yoga intervention or the advice-only control group. A statistician blinded to the randomization key created a computer-generated REDCap randomized sequence to allocate participants. Participants were aware of the group to which they were allocated. The principal investigator and data analyst remained blinded to the randomization process.
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Data analysis
REGRESSION, SECONDARY
Participant characteristics and feasibility metrics for both treatment and control groups as well as program adherence for the treatment group only were summarized using descriptive statistics. Fisher exact tests examined baseline differences between groups for categorical variables. Percentages were calculated to determine the proportion of participants in each group who reached clinical significance.Both intent-to-treat and per-protocol analysis were conducted. Adjusted ANOVA was used to determine the differences between and within groups in the primary and secondary outcomes at 4 weeks and after the intervention. Multiple comparisons (i.e., post hoc) were adjusted using Bonferonni corrections. Multiple multivariate logistic regression was used to examine determinants of response to intervention. Responders were defined as individuals with a reduction of 80 points or more on the IBS-SSS (Fisher exact tests were used to determine whether the proportion of individuals falling in each intention category differed between treatment and control groups at baseline and postintervention separately and if any changes in proportions of intentions between baseline and postintervention. In the treatment group alone, regression analysis was used to determine whether intention predicts total yoga practice in minutes and whether there was a relationship between total practice minutes and change (baseline to week 8) in IBS-SSS. All analysis was conducted using RStudio version 1.4.1717 using R version 4.1.1.This study has been approved by the Conjoint Health Research Ethics Board (REB ID 20-0084).
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RESULTS
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Participant characteristics
A total of 142 patients expressed interest in participating and 63 were excluded (see Figure Participant flowchart based on the CONSORT guidelines.Participant baseline sociodemographic characteristics by group (N = 79)
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Primary outcome.
SECONDARY
The sample mean IBS-SSS was moderate at 245.3 (196.5–317.0, SD = 86.6) points at baseline and 207.9 (117.0–270.0, SD = 100.2) at week 8. The percentage of patients meeting the ≥50-point decrease in IBS-SSS postintervention (8 weeks) was 37% (n = 14) in the yoga group compared with 20% (n = 8) in the control group (Within-group and between-group differences in primary and secondary effectiveness outcomes (N = 79)
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Subgroup exploratory analysis of responders.
Twenty-two patients were included in the responder analysis (14 [51.8%] and 8 [22.2%]) (i.e., responders in the treatment and control groups). The difference between the groups was nonsignificant (Changes in outcome measures for treatment and control groups among responders (n = 22)Determinants of response (variables with <0.2
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Secondary outcomes.
fatigue
Using intent-to-treat analysis, we observed between-group differences postintervention favoring the treatment group for QOL, fatigue, and perceived stress (Table
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Previous yoga experience and intention to do yoga
Most participants had tried yoga in the past. Intention to do yoga was 6.5 (SD = 0.7) at baseline and 4.0 (SD = 1.8) at 8 weeks for the treatment group and 6.5 (SD = 0.6) at baseline and 5.2 (SD = 1.7) at 8 weeks for the control group. There was a significant change in proportions of intention to do yoga from baseline to postintervention for both groups (treatment
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Feasibility outcomes
IBS
EVENTS
The attrition rate was 20% (29% and 12% in the treatment and control groups, respectively). In the treatment group, 7 of 11 participants were randomized to the intervention but did not start the program, 2 participants withdrew because of changing work schedules, 1 participant was hospitalized for a non–IBS-related concern, and 1 participant did not provide a reason. Average class attendance was 79% (SD = 20%). Treatment participants accumulated an average of 1,220.9 (SD = 513.7) minutes doing yoga. No adverse or safety events were reported. Forty-one percent of participants rated the program as excellent, 30% as great, and 29% as good. All participants strongly agreed that the practice videos and feedback on their practices were helpful and the yoga facilitator was knowledgeable and approachable. Fifty-two percent strongly agreed they would recommend the program to other patients with IBS.
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DISCUSSION
IBS, depression, fatigue, anxiety
The MY-IBS study is the first to demonstrate the feasibility and safety of an 8-week virtual yoga program combined with the home-based practice for patients with IBS compared with an advice-only control group. The sample had moderate IBS symptom severity at baseline. Significant within-group improvements in IBS symptoms were observed in the treatment group alone at both 4 and 8 weeks after baseline. We did not find significant differences in IBS symptoms between groups postintervention as measured by the IBS-SSS. The response seen in both groups could be explained by the high placebo effect in IBS. Based on a previous meta-analysis of 19 studies examining the placebo response in complementary and alternative medicine trials of IBS, the rate of placebo response was 42.6% (We determined predictors of yoga response using a reduction of 80 points on the IBS-SSS. Fifty-two percent of the treatment participants and 22% of the control participants were classified as responders. One other study (We used a 50-point drop in the IBS-SSS as our primary outcome rather than using the composite outcome mandated by the US Food and Drug Administration for drug trials in IBS (Our study demonstrates beneficial effects of yoga for QOL, fatigue, somatic symptoms, perceived stress, COVID-19–related stress, and self-compassion among patients with IBS. These outcomes were not frequently assessed in the other RCTs. Stress and somatic symptom improvements have been found only in the yoga group in 3 separate RCTs (We did not observe any within-group or between-group differences for anxiety and depression, especially considering the evidence base for yoga for each condition (The yoga intervention in this study was feasible for adherence (79%), attrition rate (20%), and high program satisfaction. Adherence was reported in 3 of the previously described RCTs, varying from 62% to 90% (
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Strengths and limitations
IBS, depression
ADVERSE EVENTS, RECRUITMENT
This study is the first to evaluate the efficacy and feasibility of a virtual yoga intervention. The yoga intervention was developed based on IBS mechanistic rationale supported by an international yoga foundation and delivered by an experienced yoga instructor and at-home practice was supported by videos. We recruited patients from across Canada, using heterogeneous recruitment methods including gastroenterologist offices, primary care physician clinics, and social media. These results may not be generalizable as our sample is largely composed of educated White women with a high family income. Our data are also limited by the lack of data capture on the frequency of yoga practice, if any, in the control group, and lack of information as to the time that had passed between previous yoga practice and the current study. Our sample did not include patients with severe depression. Finally, 7 of 11 treatment participants did not start the intervention.Future studies should consider including objective measures of autonomic function testing (e.g., electrocardiogram), sympathetic reactivity tests (e.g., mental arithmetic test), and parasympathetic reactivity tests (e.g., heart rate variability in deep breathing) to determine physiological mechanisms of yoga response. Future studies with a larger sample size should also investigate the effects of yoga on IBS subgroups (IBS-diarrhea-predominant, constipation-predominant, or mixed) individually and the long-term effects of yoga.Our study results suggest that virtually delivered yoga is safe and feasible. Yoga improved IBS symptoms and a breadth of other psychological and physiological outcomes that are understudied but frequently affect patients with IBS. The intervention was also found to be safe without any adverse events. The virtual delivery of yoga represents an opportunity to increase access to effective management therapies for patients with IBS. Combining the convenience and flexibility of virtual programs and the social benefits of in-person interactions into hybrid programming may improve program efficacy, intervention adherence, and patient outcomes.
PMC9889201
Study Highlights
PMC9889201
REFERENCES
PMC9889201
ABSTRACT
PMC10539208
Background
fracture
LOW BONE MINERAL DENSITY, VITAMIN K DEFICIENCY
Vitamin K deficiency is highly prevalent in patients on dialysis and may contribute to their low bone mineral density (BMD) and increased risk of fracture. This study investigated the effect of menaquinone-7 (MK-7) supplementation on BMD in patients on chronic dialysis.
PMC10539208
Methods
In a multicentre, double-blind, placebo-controlled intervention trial, 123 patients on chronic dialysis were randomised to a daily oral supplement of either MK-7 360 µg or placebo for 2 years. BMD of the distal radius (1/3, mid, ultradistal and total), femoral neck, lumbar spine (L1–L4) and whole body was assessed by dual-energy X-ray absorptiometry. Serum levels of vitamin K1 and MK-7 and plasma levels of total osteocalcin, dephosphorylated-uncarboxylated matrix Gla protein and protein induced by vitamin K absence II were measured to assess vitamin K status.
PMC10539208
Results
BMD loss of the 1/3 distal radius
After 2 years, an accelerated BMD loss of the 1/3 distal radius was found with MK-7 supplementation {mean difference of changes relative to placebo −0.023 g/cm
PMC10539208
Conclusion
BMD loss of the 1/3 distal radius
Compared with placebo, an accelerated BMD loss of the 1/3 distal radius was found after 2 years of MK-7 supplementation, whereas a decline in lumbar spine BMD was prevented. As such, MK-7 supplementation might modify BMD site-specifically in patients on dialysis. In aggregate, our findings do not support MK-7 supplementation to preserve bone in patients on dialysis.
PMC10539208
Graphical Abstract
fracture, chronic kidney disease, BMD loss of the 1/3 distal radius
LOW BONE MINERAL DENSITY, VITAMIN K DEFICIENCY
In patients with chronic kidney disease on dialysis treatment, low bone mineral density (BMD) is prevalent.Low BMD is associated with an increased risk of bone fracture and mortality.Vitamin K deficiency may contribute to low BMD. In a 2-year randomised, double-blind, placebo-controlled study of patients on chronic dialysis treatment, an accelerated BMD loss of the 1/3 distal radius but preserved BMD of the lumbar spine were seen with 2 years of MK-7 supplementation compared with the changes in BMD with placebo in an intention-to-treat analysis. BMD at the other sites measured was unaffected.Vitamin K supplementation improved the vitamin K status compared with placebo. The results of the present study indicate that MK-7 supplementation might modify BMD site-specifically in patients receiving dialysis treatment but, in aggregate, do not support MK-7 supplementation to preserve bone.
PMC10539208
INTRODUCTION
chronic kidney disease, CKD-MBD, bone loss, bone disorder, soft-tissue calcification
BONE LOSS, MINERALIZATION, BONE DISORDER
As kidney function declines, disturbances in the mineral metabolism cause abnormalities in bone turnover, mineralization and bone loss, as well as increased vascular and other soft-tissue calcification, the so-called chronic kidney disease–mineral and bone disorder (CKD-MBD) [BMD may be affected by vitamin K status. In observational studies, vitamin K levels were positively associated with BMD in the elderly general population [Patients treated with dialysis are very often vitamin K deficient, with highly elevated levels of vitamin K–dependent proteins. Vitamin K supplementation has been demonstrated to improve vitamin K status, as systemic levels of osteocalcin [OC; as undercarboxylated osteocalcin (ucOC)], matrix Gla protein [MGP; as dephosphorylated-uncarboxylated matrix Gla protein (dp-ucMGP)] and protein induced by vitamin K absence II (PIVKA-II) significantly decreased during supplementation [The aim of this randomised, double-blind, placebo-controlled, study was to investigate the effect of vitamin K supplementation on BMD in patients on dialysis treatment.
PMC10539208
MATERIALS AND METHODS
PMC10539208
Study design
vascular calcification
VASCULAR CALCIFICATION
The RenaKvit trial was a 2-year randomised, multicentre, double-blind, placebo-controlled study examining the effects of vitamin K supplementation as menaquinone-7 (MK-7) on bone and vascular calcification in patients on dialysis treatment. The study design and the effects on vascular calcification have been described previously [The study was approved by the Scientific Ethics Committee for the Region of Zealand (SJ-511) and the Danish Data Protection Agency and was registered at ClinicalTrial.gov (NCT02976246). The supporting CONSORT checklist can be found in
PMC10539208
Study population and intervention
ADVERSE EVENT
In brief, eligible participants were adult patients on chronic dialysis treatment not treated with vitamin K antagonists, recombinant parathyroid hormones, anti-osteoporotic drugs or vitamin K supplements. Participants were excluded during follow-up if they initiated vitamin K antagonist treatment, were <50% adherent to or had non-acceptable side effects from the study tablets or received a kidney transplant. Informed consent was obtained from all participants included in the study.Participants were randomised to receive one daily tablet containing 360 µg MK-7 or a visually identical placebo tablet using concealed block randomisation with blocks of four (2:2). Each block consisted of patients treated with the same dialysis modality at the same dialysis centre. Double blinding was maintained until the last patient's last visit.Kappa Bioscience AS, Oslo, Norway, produced the synthetic MK-7 (K2VITAL Delta), according to the Hazard Analysis Critical Control Point principles, and Orkla Care AS, Ishøj, Denmark, produced all tablets used in the study.Adverse events (AEs) and serious AEs (SAEs) were monitored according to the procedure described in Supplementary Table 2S.
PMC10539208
Outcomes
fractures
The primary outcome was changes in BMD of the 1/3 distal radius, since BMD of the 1/3 distal radius predicts fractures in patients on dialysis treatment [
PMC10539208
Measurements
PMC10539208
Dual-energy X-ray absorptiometry (DXA)
BMD of the distal half of the left radius [divided into the 1/3 (most proximal 20 mm), mid and ultradistal radius (most distal 15 mm)], lumbar spine (L1–L4), left femoral neck and whole body were assessed by DXA. DXA procedures are described in detail in Supplementary Material 4S.
PMC10539208
Biochemical measurements
Serum vitamin K1 and MK-7 were analysed by mass spectrometry according to Boegh
PMC10539208
Conventional X-ray of the lumbar spine
AAC scores were quantified as per Kauppila
PMC10539208
Statistical methods
SECONDARY
No data on changes in BMD over time of the 1/3 distal radius were available in patients on dialysis when the study was planned. The sample size calculation was therefore based on cross-sectional data in which a difference in BMD of the 1/3 distal radius of 0.26 g/cmDue to severe heteroscedasticity in the MK-7 group, the variance of residuals at follow-up measurements was allowed to differ from residual variances at baseline. All analyses were repeated with adjustments for age and sex (partly adjusted) and adjustments for sex, age and baseline measures of 25-hydroxyvitamin D and dp-ucMGP (fully adjusted). The testing of secondary endpoints was not hierarchical. Mixed effects models were implemented in Stata version 16 (StataCorp, College Station, TX, USA) and other data processing and analyses using SPSS version 26 (IBM, Armonk, NY, USA).
PMC10539208
RESULTS
±, fracture, SD
ACUTE MYOCARDIAL INFARCTION
A total of 689 patients on dialysis were screened for eligibility (Fig. CONSORT flow diagram. GI, gastro intestinal; PTH, parathyroid hormone. Baseline characteristics of participants.B: blood; P: plasma; S: serum; FGF-23: fibroblast growth factor 23; BSAP: bone-specific alkaline phosphatase; CTX-1: type I collagen cross-linked C-telopeptide; P1NP, total procollagen type 1 N-terminal propeptide.Previous fracture of the vertebra, upper- or forearm and/or upper or lower leg within the last 5 years and verified by X-ray. Former medically and biochemically verified acute myocardial infarction, percutaneous coronary intervention or coronary artery bypass graft. Baseline bone characteristics of participants assessed by DXA.Data presented as mean ± SD unless stated otherwise.
PMC10539208
DXA
DXA scans were performed in 92 of the 97 participants at year 1 and in 62 of the 65 participants completing the study at year 2 (Fig. 
PMC10539208
Distal radius BMD
After 1 year, BMD of the 1/3 distal radius decreased significantly in both the group treated with MK-7 {−0.015 g/cmEffects of 2-years of supplementation with vitamin K2 (MK-7, 360 μg daily) or placebo: Bone mineral density of the distal radius. Mixed effect model analysis of changes in bone mineral density of the distal radius. (Effects of 2 years of supplementation with vitamin K2 (MK-7, 360 µg/day) or placebo: Significant changes in bone mineral density.Mixed effects model analysis of changes in BMD. Partly adjusted for gender and age; fully adjusted for baseline vitamin D and dp-ucMGP levels.After both 1 and 2 years of intervention, BMD of the mid, ultradistal and total distal radius decreased significantly in both the MK-7 and placebo groups, but without significant differences in mean changes or absolute BMD levels between groups (all Adjustments for gender and age, and additionally baseline vitamin D and vitamin K levels, did not modify the results of MK-7 supplementation on BMD in a stepwise model of any of the regions of the distal radius (Table 3 and Supplementary Table 7S).
PMC10539208
Lumbar spine, femoral neck and whole body BMD
After 1 year, BMD of the lumbar spine did not change significantly in either the MK-7 or placebo groups and the mean changes from baseline or absolute BMD levels did not differ between study groups (Effects of 2-years of supplementation with vitamin K2 (MK-7, 360 μg daily) or placebo: Bone mineral density. Mixed effect model analysis of changes in bone mineral density. (There were no significant differences between the study groups in BMD changes of the femoral neck or whole body (all Adjustment for gender and age and baseline vitamin K and D levels did not significantly modify the results of MK-7 on BMD of the lumbar spine, femoral neck or whole body (Table 3 and Supplementary Table 7S).
PMC10539208
Biochemical outcomes
PMC10539208
Markers of vitamin K
At baseline, participants were highly vitamin K deficient, as demonstrated by the elevated levels of plasma dp-uc-MGP (P-dp-uc-MGP) and PIVKA-II.Serum MK-7 (S-MK-7) increased significantly in the MK-7 group but remained stable in the placebo group. The mean changes from baseline and the absolute MK-7 levels differed highly significantly between study groups (all Effects of 2-year supplementation with vitamin K2 (MK-7, 360 μg daily) or placebo: Biochemical markers of vitamin K status. Mixed effect model analysis of changes in biochemical markers of vitamin K status. (Plasma total osteocalcin (tOC) levels were unchanged in the MK-7 group but increased significantly in the placebo group after 1 year. Over the 2-year study period, levels increased significantly in both study groups, yet to a larger extent with placebo (P-dp-ucMGP and PIVKA-II levels decreased significantly in the MK-7 group and increased significantly in the placebo group, with significant differences in changes and absolute levels between groups (all
PMC10539208
Markers of mineral and bone turnover
There were no significant differences between the study groups in the markers of mineral metabolism or bone turnover at any time (all
PMC10539208
Conventional X-ray of the lumbar spine
fractures, lumbar vertebral compression
After 1 and 2 years, AAC scores increased in both study groups, but the changes from baseline (The number and extent of lumbar vertebral compression fractures did not differ between the study groups at baseline (
PMC10539208
Clinical outcomes
death, bone fracture
THROMBOEMBOLIC EVENT
The number of participants who experienced bone fracture, parathyroidectomy, a thromboembolic event or death during the study did not differ between study groups (ITT analyses; all
PMC10539208
Adherence and AEs
SAEs
The mean adherence to study tablets was >90% after year 1 and 2 in both study groups. A total of 110 participants experienced 968 AEs during the trial and 481 SAEs occurred in 90 participants.The number of participants who experienced an AE or SAE did not differ between groups (all
PMC10539208
DISCUSSION
uraemia, ESKD, BMD loss of the 1/3 distal radius, osteoarthritis, kidney impairment, fractures, arteriovenous fistula
URAEMIA, STILL, OSTEOARTHRITIS, RECRUITMENT, AORTIC CALCIFICATION
In the present randomised, double-blind, placebo-controlled trial, the effects on bone of daily supplementation with 360 µg vitamin K2 (MK-7) were compared with placebo in 123 patients receiving chronic dialysis treatment. In the ITT analysis, an accelerated BMD loss of the 1/3 distal radius was observed with MK-7 supplementation compared with placebo, whereas the decrease in lumbar spine BMD observed in the placebo-supplemented participants was prevented with MK-7. The RenaKvit trial is the first to investigate the effect of vitamin K supplementation on BMD in patients on dialysis treatment.Surprisingly, we found the primary outcome, BMD of the 1/3 distal radius, to decrease ≈3% after 2 years of MK-7 supplementation compared with placebo, whereas BMD of the remaining distal radius sites was unaffected. However, these findings could not be confirmed in per protocol analysis. This may be because the participants able to complete the study represent only a subgroup of participants not randomly distributed between the groups. It may also be due to a type 1 statistical error in the ITT analysis. Four randomised studies, all in postmenopausal women with no kidney impairment, have examined the 2-year effect of vitamin K supplementation on distal radius BMD. One open-labelled study in 396 Japanese women examined the 1/3 distal radius and found a reduced BMD loss with supplements of vitamin K2 (MK-4) compared with no treatment [BMD of the lumbar spine decreased in the placebo group to a similar extent as reported in a previous 2-year observational study in patients on dialysis [In postmenopausal women without kidney impairment, the influence of vitamin K on lumbar spine BMD varies. Whereas three neither blinded nor placebo-controlled Japanese randomised 2-year studies [BMD of the femoral neck decreased in both study groups after 2 years, although to a lesser extent with MK-7 supplementation and with borderline significance between treatments groups. Four randomised, controlled trials in elderly Caucasian populations without kidney impairment investigated the 3-year effect of vitamin K supplementation on BMD of the femoral neck. Two studies observed increased BMD with supplements of MK-7 [In ESKD, low BMD predicts fractures [Similar to our findings, MK-7 supplementation had contrasting effects on trabecular and cortical bone as assessed by high-resolution peripheral quantitative computed tomography in a 3-year study of Caucasian postmenopausal women [Vitamin D regulates the expression of OC and appropriate vitamin D status may therefore be of importance for the effects of vitamin K supplementation on bone [In accordance with other studies [Even though markers of bone turnover may be affected by ESKD [In uraemia, this absence of convincing beneficial effects of MK-7 supplementation on bone might be explained by the profound disturbances in vitamin K lipoprotein distribution and metabolism as recently discussed by Kaesler This study has strengths and limitations. Being a randomised, placebo-controlled, double-blind study, important biases were eliminated. Also, the high adherence to study supplementation demonstrated both by tablet counting and blood concentrations of MK-7 and PIVKA-II was an important strength.According to our power calculation, we aimed at including 2 × 70 participants. Due to challenged recruitment, unfortunately we ended up with only 61 + 62 participants. Furthermore, the dropout rate in year 2 was higher than anticipated. For these reasons, only 30 + 32 patients contributed with 2-year primary outcome data, a number somewhat lower than required according to the power calculations (2 × 49). Nonetheless, we managed to detect significant changes in the primary outcome variable. It is possible that a larger sample size and a longer trial duration would have demonstrated more convincing differences in the response between treatment groups, and even other significant differences in outcomes as well.Previous studies have reported worsening of BMD on the arteriovenous fistula arm [Lumbar spine BMD may be increased by osteoarthritis, compression fractures, severe aortic calcification, which is common in the dialysis population, and intestinal deposition of phosphate binders [Finally, we cannot exclude a more pronounced effect if a higher dosage of MK-7 had been used, if vitamin K1 had been supplemented [In conclusion, 2 years of vitamin K (MK-7) supplementation may modify BMD site-specifically in patients receiving dialysis treatment, in addition to improvement in functional vitamin K status. Still, our findings do not support MK-7 supplementation to preserve bone in patients with ESKD receiving dialysis treatment.
PMC10539208
Supplementary Material
Click here for additional data file.
PMC10539208
ACKNOWLEDGEMENTS
RENAL
The authors wish to express their gratitude to the lab technicians and staff at the Departments of Clinical Biochemistry and Immunology at Lillebælt Hospital, Vejle, and Zealand University Hospital, Denmark, and to the study nurses and lab technicians at the Department of Renal Medicine, Aarhus University Hospital, Department of Nephrology, Aalborg University Hospital, and the Department of Endocrinology at Zealand University Hospital, Aarhus University Hospital and Aalborg University Hospital. The authors are grateful to the nurses and the administrative staff of the involved dialysis departments. Finally, we would like to acknowledge the willingness of the many patients on dialysis who participated in this demanding study.
PMC10539208
FUNDING
KIDNEY
The study was funded by the Danish Society of Nephrology, Danish Kidney Association, Region Zealand Research Foundation, Kappa Bioscience AS, Aase and Ejnar Danielsens Foundation, Helen and Ejnar Bjørnows Foundation, Beckett Foundation and Karen Elise Jensens Foundation. Kappa Bioscience AS and Orkla Care AS donated study tablets and DiaSorin donated the CLIA FGF-23 assay, but neither had further involvement in the study or any part in interpreting the data or acceptance of the results.
PMC10539208
AUTHORS’ CONTRIBUTIONS
M.F.H.
K.L.-S., D.H., M.F.-M., N.E.F. and P.M. designed the study. K.L.-S., C.D.P., K.D.K., C.S. and J.D.J. collected the clinical data. A.S., C.L.B., J.S.M. and N.R.J. were responsible for the specialized biochemical analyses. M.F.H., B.L. and P.V. conducted the DXA scans. H.S. and J.B.F. led and analysed the radiological investigations. K.L.-S. and I.P. did the statistical analyses and drafted the tables and figures. K.L.-S. and D.H. drafted the manuscript. All authors revised the article and approved the final version for publication.
PMC10539208
DATA AVAILABILITY STATEMENT
Our data sharing statement is available as Supplementary Table 13S.
PMC10539208
CONFLICT OF INTEREST STATEMENT
JENSEN
K.L.-S.’s salary was partially funded by Kappa Bioscience AS, the Danish Society of Nephrology and the Karen Elise Jensen Foundation during the RenaKvit trial. M.F.H. has received a research grant from Orkla Care AS. B.L. has received research grants from Amgen and honoraria for academic services from Amgen, UCB, Gilead, Astellas, AstraZeneca and Gedeon-Richter, unrelated to the RenaKvit trial. The remaining authors have nothing to declare.
PMC10539208
REFERENCES
PMC10539208
Background
Urinary incontinence
URINARY INCONTINENCE
Urinary incontinence (UI) is a highly prevalent health concern commonly observed during and after pregnancy that can substantially impact women’s physical and psychological well-being and quality of life. Owing to its numerous advantages, mobile health may be a promising solution; however, it is unclear whether the app-based intervention can effectively improve UI symptoms during and after pregnancy.
PMC10337423
Objective
URINARY INCONTINENCE
This study aimed to evaluate the effectiveness of the Urinary Incontinence for Women (UIW) app–based intervention for UI symptom improvement among pregnant women in China.
PMC10337423
Methods
incontinence
SECONDARY, INCONTINENCE
Singleton pregnant women without incontinence before pregnancy who were aged ≥18 years and between 24 and 28 weeks of gestation were recruited from a tertiary public hospital in China and were randomly allocated (1:1) to either an experimental group (n=63) or a control group (n=63). The experimental group received the UIW app intervention and oral pelvic floor muscle training (PFMT) instructions, whereas the control group received oral PFMT instructions alone. Neither the participants nor the researchers were blinded to the intervention. The primary outcome was UI severity. The secondary outcomes included quality of life, self-efficacy with PFMT, and knowledge of UI. All data were collected at baseline, 2 months after randomization, and 6 weeks post partum through electronic questionnaires or by checking the electronic medical record system. Data analysis followed the intention-to-treat principle. A linear mixed model was used to examine the intervention effect on primary and secondary outcomes.
PMC10337423
Results
Participants in the experimental and control groups were comparable at baseline. Of the 126 overall participants, 117 (92.9%) and 103 (81.7%) women completed follow-up visits at 2 months after randomization and 6 weeks after delivery, respectively. A statistically significant difference in UI symptom severity was observed between the experimental group and control group (2 months after randomization: mean difference −2.86, 95% CI −4.09 to −1.64,
PMC10337423
Conclusions
LATE PREGNANCY
The app-based UI self-management intervention (UIW) effectively improved UI symptom severity, quality of life, self-efficacy with PFMT, and knowledge of UI during the late pregnancy and early postnatal periods. Larger multicenter studies with a longer postpartum follow-up are required to further extend these findings.
PMC10337423
Trial Registration
Chinese Clinical Trial Registry ChiCTR1800016171; http://www.chictr.org.cn/showproj.aspx?proj=27455
PMC10337423
International Registered Report Identifier (IRRID)
RR2-10.2196/22771
PMC10337423
Introduction
chronic illness, Urinary incontinence
URINARY INCONTINENCE, CHRONIC ILLNESS, URINARY INCONTINENCE, LEAKAGE
Urinary incontinence (UI), defined as the involuntary leakage of urine [Pelvic floor muscle training (PFMT) is the first-line conservative treatment for UI [In recent years, an increasing body of research has demonstrated that mobile health (mHealth) interventions may benefit health promotion, especially in chronic illness management areas [Herein, we developed a Urinary Incontinence for Women (UIW) mobile app for maternal UI self-management [
PMC10337423
Methods
PMC10337423
Study Design
This was a single-center, 2-arm, unblinded pragmatic randomized controlled trial with 1:1 intervention allocation that was reported in line with the CONSORT-eHEALTH (Consolidated Standards of Reporting Trials of Electronic and Mobile Health Applications and Online Telehealth) guidelines (
PMC10337423
Ethics Approval
The study was registered in the Chinese Clinical Trial Registry (ChiCTR1800016171), and the ethical approval was obtained from the Ethics Committees of Shenzhen Hospital, Southern Medical University (NYSZYYEC20190012). The trial protocol has been published, and the findings from an embedded process evaluation will be presented elsewhere [
PMC10337423
Participants
heart disease, cognitive impairment, pain, psychiatric, pelvic floor muscle contraction, pelvic organ prolapse
PREGNANCY-INDUCED HYPERTENSION, HEART DISEASE, DIABETES MELLITUS, PLACENTA PREVIA, PLACENTAL ABRUPTION, FETAL GROWTH RESTRICTION, THREATENED ABORTION
A trained graduate nurse sequentially recruited participants during routine obstetrics clinic visits at Shenzhen Hospital, Southern Medical University, a tertiary level A public hospital in China, between June and October 2020. Eligibility was first assessed by checking the medical records from the obstetrics clinic, after which those who met the eligibility criteria (see the following paragraph) were provided with an information letter describing the study and invited to participate in the study. After providing written informed consent, eligible participants completed a baseline electronic survey at the same time. They were told to contact the researchers via telephone if they experienced any discomfort or pain associated with the PFMT. After completing all follow-ups, participants received compensation with a gift worth RMB ¥100 (equal to US $14.44).The inclusion criteria were as follows: (1) age ≥18 years, (2) having a singleton pregnancy, (3) being at 24 to 28 gestational weeks, (4) being continent before pregnancy, and (5) having a mobile phone with internet access. The exclusion criteria were (1) cognitive impairment and psychiatric conditions, (2) a history of pelvic organ prolapse or pelvic surgery, (3) severe comorbidities found in prenatal examinations that were not suitable for PFMT in pregnancy (such as heart disease, pregnancy-induced hypertension, diabetes mellitus, threatened abortion, placenta previa, placental abruption, and fetal growth restriction), and (4) pain during pelvic floor muscle contraction.
PMC10337423
Randomization and Masking
The trial used a simple randomization approach. A 1:1 random assignment sequence was generated via a table of random numbers by a research assistant who was not involved in the study and was placed into sequentially numbered, opaque, and sealed envelopes. When each participant was enrolled, the intervention manager opened the envelope in sequence, and the participant was assigned to the experimental group, which received oral PFMT instructions and the UIW app intervention, or the control group, which received oral PFMT instructions. Owing to the nature of the app-based intervention and self-reported outcomes, neither the participants nor the research staff were blinded to the intervention.
PMC10337423
Interventions
PMC10337423
UIW App
The participants allocated to the experimental group were granted access to the UIW app, which is a mobile app for Chinese pregnant women developed by our research team with technical assistance from the Guangdong Zhuoshang Network Technology Company (registration number: 2019SR1342273). The introduction of the UIW app, including its content and function, can be found in previously published papers [
PMC10337423
Contents of staged pelvic floor muscle training program in the Urinary Incontinence for Women app (test contraction: 2-second contraction and 2-second relaxation; strong contraction: 6-second contraction and 6-second relaxation; and rapid contraction: 3-second contraction and 3-second relaxation).
CONTRACTION, CONTRACTIONS
Stage 1: eight test contractions for 1 set of exercises, 3 sets per dayStage 2: eight test contractions+2 strong contractions for 1 set of exercises, 3 sets per day Stage 1: eight strong contractions+1 endurance contraction for 1 set of exercises, 3 sets per day; endurance contraction at this stage was 15-second contraction and 5-second relaxationStage 2: ten strong contractions+1 endurance contraction for 1 set of exercises, 3 sets per day; endurance contraction at this stage was 25-second contraction and 5-second relaxation (if pregnant women cannot reach this training stage as assessed, stay in the previous stage)Stage 3: ten strong contractions+1 endurance contraction+5 rapid contractions for 1 set of exercises, 3 sets per day, endurance contraction at this stage was 35-second contraction and 35-second relaxation (if pregnant women cannot reach this training stage as assessed, stay in the previous stage)Stage 4: ten strong contractions+1 endurance contraction+10 strong contraction+5 rapid contractions for 1 set of exercises, 3 sets per day; endurance contraction at this stage was 35-second contraction and 35-second relaxation (if pregnant women cannot reach this training stage as assessed, stay in the previous stage)
PMC10337423