Randomized Trial of Metformin, Ivermectin, and Fluvoxamine for Covid-19.

BACKGROUND: Early treatment to prevent severe coronavirus disease 2019 (Covid-19) is an important component of the comprehensive response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. METHODS: In this phase 3, double-blind, randomized, placebo-controlled trial, we used a 2-by-3 factorial design to test the effectiveness of three repurposed drugs - metformin, ivermectin, and fluvoxamine - in preventing serious SARS-CoV-2 infection in nonhospitalized adults who had been enrolled within 3 days after a confirmed diagnosis of infection and less than 7 days after the onset of symptoms. The patients were between the ages of 30 and 85 years, and all had either overweight or obesity. The primary composite end point was hypoxemia (≤93% oxygen saturation on home oximetry), emergency department visit, hospitalization, or death. All analyses used controls who had undergone concurrent randomization and were adjusted for SARS-CoV-2 vaccination and receipt of other trial medications. RESULTS: A total of 1431 patients underwent randomization; of these patients, 1323 were included in the primary analysis. The median age of the patients was 46 years; 56% were female (6% of whom were pregnant), and 52% had been vaccinated. The adjusted odds ratio for a primary event was 0.84 (95% confidence interval [CI], 0.66 to 1.09; P = 0.19) with metformin, 1.05 (95% CI, 0.76 to 1.45; P = 0.78) with ivermectin, and 0.94 (95% CI, 0.66 to 1.36; P = 0.75) with fluvoxamine. In prespecified secondary analyses, the adjusted odds ratio for emergency department visit, hospitalization, or death was 0.58 (95% CI, 0.35 to 0.94) with metformin, 1.39 (95% CI, 0.72 to 2.69) with ivermectin, and 1.17 (95% CI, 0.57 to 2.40) with fluvoxamine. The adjusted odds ratio for hospitalization or death was 0.47 (95% CI, 0.20 to 1.11) with metformin, 0.73 (95% CI, 0.19 to 2.77) with ivermectin, and 1.11 (95% CI, 0.33 to 3.76) with fluvoxamine. CONCLUSIONS: None of the three medications that were evaluated prevented the occurrence of hypoxemia, an emergency department visit, hospitalization, or death associated with Covid-19. (Funded by the Parsemus Foundation and others; COVID-OUT ClinicalTrials.gov number, NCT04510194.).

Favorable Antiviral Effect of Metformin on Severe Acute Respiratory Syndrome Coronavirus 2 Viral Load in a Randomized, Placebo-Controlled Clinical Trial of Coronavirus Disease 2019.

BACKGROUND: Metformin has antiviral activity against RNA viruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The mechanism appears to be suppression of protein translation via targeting the host mechanistic target of rapamycin pathway. In the COVID-OUT randomized trial for outpatient coronavirus disease 2019 (COVID-19), metformin reduced the odds of hospitalizations/death through 28 days by 58%, of emergency department visits/hospitalizations/death through 14 days by 42%, and of long COVID through 10 months by 42%. METHODS: COVID-OUT was a 2 × 3 randomized, placebo-controlled, double-blind trial that assessed metformin, fluvoxamine, and ivermectin; 999 participants self-collected anterior nasal swabs on day 1 (n = 945), day 5 (n = 871), and day 10 (n = 775). Viral load was quantified using reverse-transcription quantitative polymerase chain reaction. RESULTS: The mean SARS-CoV-2 viral load was reduced 3.6-fold with metformin relative to placebo (-0.56 log10 copies/mL; 95% confidence interval [CI], -1.05 to -.06; P = .027). Those who received metformin were less likely to have a detectable viral load than placebo at day 5 or day 10 (odds ratio [OR], 0.72; 95% CI, .55 to .94). Viral rebound, defined as a higher viral load at day 10 than day 5, was less frequent with metformin (3.28%) than placebo (5.95%; OR, 0.68; 95% CI, .36 to 1.29). The metformin effect was consistent across subgroups and increased over time. Neither ivermectin nor fluvoxamine showed effect over placebo. CONCLUSIONS: In this randomized, placebo-controlled trial of outpatient treatment of SARS-CoV-2, metformin significantly reduced SARS-CoV-2 viral load, which may explain the clinical benefits in this trial. Metformin is pleiotropic with other actions that are relevant to COVID-19 pathophysiology. CLINICAL TRIALS REGISTRATION: NCT04510194.

Examination of eating competence in a geo-diverse sample with metabolic syndrome.

Eating competence (EatC) is an intra-individual approach to eating attitudes and behaviors associated with greater well-being. EatC research has not included persons with confirmed metabolic syndrome (MetS). Therefore, EatC of persons with MetS was explored to identify unique associations and inform implementation of MetS lifestyle interventions using baseline data from a multisite, randomized trial of a 2-year lifestyle intervention with MetS. EatC, measured with the Satter Eating Competence Inventory 2.0 (ecSI 2.0™), was examined for relationships with bioclinical measures (e.g., blood pressure, lipids), medication use, BMI, waist circumference, fruit/vegetable intake, and psychosocial factors, (e.g., stress, mindfulness). Data were collected in person and video call by trained research personnel. EatC was examined as a continuous score and as a categorical variable with ecSI 2.0™ scores ≥ 32 considered eating competent. Participants (n = 618) were predominantly female (76%), White (74%), college educated (60%). Mean age was 55.5 ± 11 y. Mean ecSI 2.0™ was 29.9 ± 7.4 and 42% were eating competent. EatC was greater for males, persons who were older and food secure. Competent eaters (vs. non-eating competent) had lower waist circumference (112.7 ± 12.5 cm vs.116.8 ± 16.0 cm; P < 0.001) and BMI (35.0 ± 6.1 vs. 37.5 ± 7.3; P < 0.001). Serum triglycerides, HDL-cholesterol, fasting blood glucose, HbA1c, and blood pressure did not differ by EatC status. Compared to non-eating competent persons, competent eaters perceived less stress, were more mindful, indicated better physical function, and more habitual vegetable intake (all P < 0.001) and sensory awareness (P < 0.05). EatC in MetS paralleled the non-MetS profile. EatC was associated with a healthier psychosocial profile, waist circumference and BMI. Findings support further research to examine the mediational or moderating influence of EatC in the treatment of MetS.

Impact of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Vaccination and Booster on Coronavirus Disease 2019 (COVID-19) Symptom Severity Over Time in the COVID-OUT Trial.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination has decreasing protection from acquiring any infection with emergence of new variants; however, vaccination continues to protect against progression to severe coronavirus disease 2019 (COVID-19). The impact of vaccination status on symptoms over time is less clear. METHODS: Within a randomized trial on early outpatient COVID-19 therapy testing metformin, ivermectin, and/or fluvoxamine, participants recorded symptoms daily for 14 days. Participants were given a paper symptom diary allowing them to circle the severity of 14 symptoms as none (0), mild (1), moderate (2), or severe (3). This is a secondary analysis of clinical trial data on symptom severity over time using generalized estimating equations comparing those unvaccinated, SARS-CoV-2 vaccinated with primary vaccine series only, or vaccine-boosted. RESULTS: The parent clinical trial prospectively enrolled 1323 participants, of whom 1062 (80%) prospectively recorded some daily symptom data. Of these, 480 (45%) were unvaccinated, 530 (50%) were vaccinated with primary series only, and 52 (5%) vaccine-boosted. Overall symptom severity was least for the vaccine-boosted group and most severe for unvaccinated at baseline and over the 14 days (P < .001). Individual symptoms were least severe in the vaccine-boosted group including cough, chills, fever, nausea, fatigue, myalgia, headache, and diarrhea, as well as smell and taste abnormalities. Results were consistent over Delta and Omicron variant time periods. CONCLUSIONS: SARS-CoV-2 vaccine-boosted participants had the least severe symptoms during COVID-19, which abated the quickest over time. Clinical Trial Registration. NCT04510194.

Obesity Management in Adults: A Review.

Importance: Obesity affects approximately 42% of US adults and is associated with increased rates of type 2 diabetes, hypertension, cardiovascular disease, sleep disorders, osteoarthritis, and premature death. Observations: A body mass index (BMI) of 25 or greater is commonly used to define overweight, and a BMI of 30 or greater to define obesity, with lower thresholds for Asian populations (BMI ≥25-27.5), although use of BMI alone is not recommended to determine individual risk. Individuals with obesity have higher rates of incident cardiovascular disease. In men with a BMI of 30 to 39, cardiovascular event rates are 20.21 per 1000 person-years compared with 13.72 per 1000 person-years in men with a normal BMI. In women with a BMI of 30 to 39.9, cardiovascular event rates are 9.97 per 1000 person-years compared with 6.37 per 1000 person-years in women with a normal BMI. Among people with obesity, 5% to 10% weight loss improves systolic blood pressure by about 3 mm Hg for those with hypertension, and may decrease hemoglobin A1c by 0.6% to 1% for those with type 2 diabetes. Evidence-based obesity treatment includes interventions addressing 5 major categories: behavioral interventions, nutrition, physical activity, pharmacotherapy, and metabolic/bariatric procedures. Comprehensive obesity care plans combine appropriate interventions for individual patients. Multicomponent behavioral interventions, ideally consisting of at least 14 sessions in 6 months to promote lifestyle changes, including components such as weight self-monitoring, dietary and physical activity counseling, and problem solving, often produce 5% to 10% weight loss, although weight regain occurs in 25% or more of participants at 2-year follow-up. Effective nutritional approaches focus on reducing total caloric intake and dietary strategies based on patient preferences. Physical activity without calorie reduction typically causes less weight loss (2-3 kg) but is important for weight-loss maintenance. Commonly prescribed medications such as antidepressants (eg, mirtazapine, amitriptyline) and antihyperglycemics such as glyburide or insulin cause weight gain, and clinicians should review and consider alternatives. Antiobesity medications are recommended for nonpregnant patients with obesity or overweight and weight-related comorbidities in conjunction with lifestyle modifications. Six medications are currently approved by the US Food and Drug Administration for long-term use: glucagon-like peptide receptor 1 (GLP-1) agonists (semaglutide and liraglutide only), tirzepatide (a glucose-dependent insulinotropic polypeptide/GLP-1 agonist), phentermine-topiramate, naltrexone-bupropion, and orlistat. Of these, tirzepatide has the greatest effect, with mean weight loss of 21% at 72 weeks. Endoscopic procedures (ie, intragastric balloon and endoscopic sleeve gastroplasty) can attain 10% to 13% weight loss at 6 months. Weight loss from metabolic and bariatric surgeries (ie, laparoscopic sleeve gastrectomy and Roux-en-Y gastric bypass) ranges from 25% to 30% at 12 months. Maintaining long-term weight loss is difficult, and clinical guidelines support the use of long-term antiobesity medications when weight maintenance is inadequate with lifestyle interventions alone. Conclusion and Relevance: Obesity affects approximately 42% of adults in the US. Behavioral interventions can attain approximately 5% to 10% weight loss, GLP-1 agonists and glucose-dependent insulinotropic polypeptide/GLP-1 receptor agonists can attain approximately 8% to 21% weight loss, and bariatric surgery can attain approximately 25% to 30% weight loss. Comprehensive, evidence-based obesity treatment combines behavioral interventions, nutrition, physical activity, pharmacotherapy, and metabolic/bariatric procedures as appropriate for individual patients.

A WIC-Based Behavior Change Intervention for Postpartum Women With Overweight and Obesity: A Pilot Feasibility Randomized Trial.

Background. Postpartum weight retention is a risk factor for obesity and is particularly important among Hispanic women who have an increased rate of obesity. Given its broad reach, the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) program provides an ideal setting to implement community-based interventions for low-income postpartum women. Purpose. To examine the feasibility, acceptability, and preliminary efficacy of a multicomponent intervention delivered by staff within the WIC program designed to promote behavior changes in urban, postpartum women with overweight/obesity. Method. This was a 12-week pilot trial randomizing participants to a health behavior change (Intervention) or control (Observation) group. The Intervention included monthly visits with trained WIC staff providing patient-centered behavior change counseling, with multiple touchpoints between visits promoting self-monitoring and offering health behavior change support. Results. Participants (n = 41), who were mainly Hispanic (n = 37, 90%) and Spanish-speaking (n = 33, 81%), were randomized to the Intervention (n = 19) or Observation (n = 22) group. In the Intervention group, 79% (n = 15) of eligible participants were retained for the study duration. All Intervention participants endorsed that they would participate again. Regarding physical activity, participant readiness to change and self-efficacy improved for Intervention participants. About one-quarter of women in the Intervention group (27%, n = 4) had a 5% weight loss compared with one woman (5%) in the Observation group; this difference was not statistically significant (p = .10). Conclusions. This pilot demonstrated the feasibility and acceptability of delivering a low-intensity behavior change intervention within the WIC setting for postpartum women with overweight/obesity. Findings support the role of WIC in addressing postpartum obesity.

Breastfeeding Associated with Lower Prevalence of Metabolic Syndrome in Women with Gestational Diabetes in the Very Early Postpartum Period.

OBJECTIVE: The aim of this study is to examine the association of breastfeeding with metabolic syndrome (MetS) in women with recent gestational diabetes mellitus (GDM) in the very early postpartum (PP) period. STUDY DESIGN: We performed a secondary analysis of the Balance After Baby Intervention (BABI) study which enrolled women with recent GDM. Data collected during an early (∼8 weeks) PP visit were used in this analysis. At this visit, weight, height, waist circumference (WC), blood pressure (BP), fasting plasma glucose (FPG), and lipids were obtained. MetS was classified per National Cholesterol Education Program Adult Treatment Program III (NCEP-ATP III) criteria. We defined breastfeeding as currently breastfeeding or not currently breastfeeding for the main analysis. RESULTS: Of 181 women enrolled in BABI, 178 were included in this analysis (3 excluded for missing lipids). Thirty-four percent were Hispanic. Of non-Hispanics, 31.5% were White, 18.5% Asian, and 12.9% Black/African American. The prevalence of MetS was 42.9% in women not breastfeeding versus 17.1% in women breastfeeding (p < 0.001; adjusted odds ratio [aOR] = 0.16 [95% confidence interval (CI): 0.06-0.41]). Breastfeeding women had significantly lower odds of FPG ≥100 mg/dL (aOR = 0.36 [95% CI: 0.14-0.95], p = 0.039), HDL < 50 mg/dL (aOR = 0.19 [95% CI: 0.08-0.46], p < 0.001), and triglycerides (TG) ≥ 150 mg/dL (aOR = 0.26 [95% CI: 0.10-0.66], p = 0.005). When evaluated as continuous variables, WC, FPG, and TG were significantly lower and HDL significantly higher in women breastfeeding in the very early PP period (vs. not breastfeeding). CONCLUSION: In a diverse population of women with recent GDM, there was lower prevalence of MetS in women breastfeeding compared with those not breastfeeding in the very early PP period. This study extends the findings of an association of breastfeeding with MetS previously reported at time points more remote from pregnancy to the very early PP period and to an ethnically and racially diverse population. KEY POINTS: · MetS prevalence in women with recent GDM was lower in breastfeeding than not breastfeeding women.. · FPG, HDL, WC, and TG were improved in the breastfeeding group.. · This study extends prior findings to the very early PP period and to a diverse population..

Association Between Changes in Postpartum Weight and Waist Circumference and Changes in Cardiometabolic Risk Factors Among Women With Recent Gestational Diabetes.

INTRODUCTION: Women with gestational diabetes mellitus (GDM) have a 30% to 70% risk for developing type 2 diabetes and are at increased risk for cardiovascular disease. Little is known about how anthropometric changes in the first postpartum year modify cardiometabolic risk factors. METHODS: We randomly assigned women in the Balance After Baby study to an intervention group consisting of participation in a web-based lifestyle program or to a control group in which no program was offered. We measured weight, height, waist circumference, blood pressure, lipids, insulin, adiponectin, interleukin-6, and high-sensitivity C-reactive protein, and we conducted 2-hour oral glucose tolerance tests at 6 weeks, 6 months, and 12 months postpartum. We evaluated whether women assigned to the intervention had improved cardiometabolic risk markers compared with the control group. We then conducted a post-hoc analysis, pooling the 2 groups to compare changes in weight and waist circumference with changes in cardiometabolic risk factors. RESULTS: Women in the intervention group did not significantly improve cardiometabolic risk markers compared with women in the control group. We noted a large overlap of weight change and change in waist circumference between groups. In our post-hoc analysis pooling groups, changes in diabetes and cardiovascular risk factors were significantly correlated with changes in weight and waist circumference. The strongest associations were observed for fasting insulin, HOMA, and fasting glucose. CONCLUSION: Anthropometric changes in weight and waist circumference in women with recent GDM may affect cardiometabolic risk factors, even in the first postpartum year. Our study demonstrates the importance of the postpartum year as an opportunity to decrease future risk for diabetes and cardiovascular disease in women with a history of GDM.

Patterns of gestational diabetes diagnosis inside and outside of clinical guidelines.

BACKGROUND: Hospital discharge codes are often used to determine the incidence of gestational diabetes mellitus (GDM) at state and national levels. Previous studies demonstrate substantial variability in the accuracy of GDM reporting, and rarely report how the GDM was diagnosed. Our aim was to identify deliveries coded as gestational diabetes, and then to determine how the diagnosis was assigned and whether the diagnosis followed established guidelines. METHODS: We identified which deliveries were coded at discharge as complicated by GDM at the Brigham and Women's Hospital in Boston, MA for the year 2010. We reviewed medical records to determine whether the codes were appropriately assigned. RESULTS: Of 7883 deliveries, coding for GDM was assigned with 98% accuracy. We identified 362 cases assigned GDM delivery codes, of which 210 (58%) had oral glucose tolerance test (OGTT) results available meeting established criteria. We determined that 126 cases (34%) received a GDM delivery code due to a clinician diagnosis documented in the medical record, without an OGTT result meeting established guidelines for GDM diagnosis. We identified only 15 cases (4%) that were coding errors. CONCLUSIONS: Thirty four percent of women assigned GDM delivery codes at discharge had a medical record diagnosis of GDM but did not meet OGTT criteria for GDM by established guidelines. Although many of these patients may have met guidelines if guideline-based testing had been conducted, our findings suggest that clinician diagnosis outside of published guidelines may be common. There are many ramifications of this approach to diagnosis, including affecting population-level statistics of GDM prevalence and the potential impact on some women who may be diagnosed with GDM erroneously.

Employing a Multi-level Approach to Recruit a Representative Sample of Women with Recent Gestational Diabetes Mellitus into a Randomized Lifestyle Intervention Trial.

OBJECTIVE: The postpartum period is a window of opportunity for diabetes prevention in women with recent gestational diabetes (GDM), but recruitment for clinical trials during this period of life is a major challenge. METHODS: We adapted a social-ecologic model to develop a multi-level recruitment strategy at the macro (high or institutional level), meso (mid or provider level), and micro (individual) levels. Our goal was to recruit 100 women with recent GDM into the Balance after Baby randomized controlled trial over a 17-month period. Participants were asked to attend three in-person study visits at 6 weeks, 6, and 12 months postpartum. They were randomized into a control arm or a web-based intervention arm at the end of the baseline visit at six weeks postpartum. At the end of the recruitment period, we compared population characteristics of our enrolled subjects to the entire population of women with GDM delivering at Brigham and Women's Hospital (BWH). RESULTS: We successfully recruited 107 of 156 (69 %) women assessed for eligibility, with the majority (92) recruited during pregnancy at a mean 30 (SD ± 5) weeks of gestation, and 15 recruited postpartum, at a mean 2 (SD ± 3) weeks postpartum. 78 subjects attended the initial baseline visit, and 75 subjects were randomized into the trial at a mean 7 (SD ± 2) weeks postpartum. The recruited subjects were similar in age and race/ethnicity to the total population of 538 GDM deliveries at BWH over the 17-month recruitment period. CONCLUSIONS: Our multilevel approach allowed us to successfully meet our recruitment goal and recruit a representative sample of women with recent GDM. We believe that our most successful strategies included using a dedicated in-person recruiter, integrating recruitment into clinical flow, allowing for flexibility in recruitment, minimizing barriers to participation, and using an opt-out strategy with providers. Although the majority of women were recruited while pregnant, women recruited in the early postpartum period were more likely to present for the first study visit. Given the increased challenges of recruiting postpartum women with GDM into research studies, we believe our findings will be useful to other investigators seeking to study this population.

Identifying postpartum intervention approaches to reduce cardiometabolic risk among American Indian women with prior gestational diabetes, Oklahoma, 2012-2013.

INTRODUCTION: Innovative approaches are needed to reduce cardiometabolic risk among American Indian women with a history of gestational diabetes. We assessed beliefs of Oklahoma American Indian women about preventing type 2 diabetes and cardiovascular disease after having gestational diabetes. We also assessed barriers and facilitators to healthy lifestyle changes postpartum and intervention approaches that facilitate participation in a postpartum lifestyle program. METHODS: In partnership with a tribal health system, we conducted a mixed-method study with American Indian women aged 19 to 45 years who had prior gestational diabetes, using questionnaires, focus groups, and individual interviews. Questionnaires were used to identify women's cardiometabolic risk perceptions and feasibility and acceptability of Internet or mobile phone technology for delivery of a postpartum lifestyle modification program. Focus groups and individual interviews were conducted to identify key perspectives and preferences related to a potential program. RESULTS: Participants were 26 women, all of whom completed surveys; 11 women participated in focus group sessions, and 15 participated in individual interviews. Most women believed they would inevitably develop diabetes, cardiovascular disease, or both; however, they were optimistic that they could delay onset with lifestyle change. Most women expressed enthusiasm for a family focused, technology-based intervention that emphasizes the importance of delaying disease onset, provides motivation, and promotes accountability while accommodating women's competing priorities. CONCLUSIONS: Our findings suggest that an intervention that uses the Internet, text messaging, or both and that emphasizes the benefits of delaying disease onset should be tested as a novel, culturally relevant approach to reducing rates of diabetes and cardiovascular disease in this high-risk population.

The Fit After Baby randomized controlled trial: An mHealth postpartum lifestyle intervention for women with elevated cardiometabolic risk.

BACKGROUND: Postpartum women with overweight/obesity and a history of adverse pregnancy outcomes are at elevated risk for cardiometabolic disease. Postpartum weight loss and lifestyle changes can decrease these risks, yet traditional face-to-face interventions often fail. We adapted the Diabetes Prevention Program into a theory-based mobile health (mHealth) program called Fit After Baby (FAB) and tested FAB in a randomized controlled trial. METHODS: The FAB program provided 12 weeks of daily evidence-based content, facilitated tracking of weight, diet, and activity, and included weekly coaching and gamification with points and rewards. We randomized women at 6 weeks postpartum 2:1 to FAB or to the publicly available Text4baby (T4B) app (active control). We measured weight and administered behavioral questionnaires at 6 weeks, and 6 and 12 months postpartum, and collected app user data. RESULTS: 81 eligible women participated (77% White, 2% Asian, 15% Black, with 23% Hispanic), mean baseline BMI 32±5 kg/m2 and age 31±5 years. FAB participants logged into the app a median of 51/84 (IQR 25,71) days, wore activity trackers 66/84 (IQR 43,84) days, logged weight 17 times (IQR 11,24), and did coach check-ins 5.5/12 (IQR 4,9) weeks. The COVID-19 pandemic interrupted data collection for the primary 12-month endpoint, and impacted diet, physical activity, and body weight for many participants. At 12 months postpartum women in the FAB group lost 2.8 kg [95% CI -4.2,-1.4] from baseline compared to a loss of 1.8 kg [95% CI -3.8,+0.3] in the T4B group (p = 0.42 for the difference between groups). In 60 women who reached 12 months postpartum before the onset of the COVID-19 pandemic, women randomized to FAB lost 4.3 kg [95% CI -6.0,-2.6] compared to loss in the control group of 1.3 kg [95% CI -3.7,+1.1] (p = 0.0451 for the difference between groups). CONCLUSIONS: There were no significant differences between groups for postpartum weight loss for the entire study population. Among those unaffected by the COVID pandemic, women randomized to the FAB program lost significantly more weight than those randomized to the T4B program. The mHealth FAB program demonstrated a substantial level of engagement. Given the scalability and potential public health impact of the FAB program, the efficacy for decreasing cardiometabolic risk by increasing postpartum weight loss should be tested in a larger trial.

Effectiveness of preconception weight loss interventions on fertility in women: a systematic review and meta-analysis.

IMPORTANCE: Weight loss before conception is recommended for women with overweight or obesity to improve fertility outcomes, but evidence supporting this recommendation is mixed. OBJECTIVE: To examine the effectiveness of weight loss interventions using lifestyle modification and/or medication in women with overweight or obesity on pregnancy, live birth, and miscarriage. DATA SOURCES: An electronic search of MEDLINE, Embase, Cochrane Library, including Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials, and Cumulative Index to Nursing and Allied Health Literature was conducted through July 6, 2022, via Wiley. STUDY SELECTION AND SYNTHESIS: Randomized controlled trials examining weight loss interventions through lifestyle and/or medication in women with overweight or obesity planning pregnancy were included. Random-effects meta-analysis was conducted, reporting the risk ratio (RR) for each outcome. Subgroup analyses were conducted by intervention type, type of control group, fertility treatment, intervention length, and body mass index (BMI). MAIN OUTCOME(S): Clinical pregnancy, live birth, and miscarriage events. RESULT(S): A narrative review and meta-analysis were possible for 16 studies for pregnancy (n = 3,588), 13 for live birth (n = 3,329), and 11 for miscarriage (n = 3,248). Women randomized and exposed to a weight loss intervention were more likely to become pregnant (RR = 1.24, 95% CI 1.07-1.44; I2 = 59%) but not to have live birth (RR = 1.19, 95% CI 0.97-1.45; I2 = 69%) or miscarriage (RR = 1.17, 95% CI 0.79-1.74; I2 = 31%) compared with women in control groups. Subgroup analyses revealed women randomized to weight loss interventions lasting 12 weeks or fewer (n = 9, RR = 1.43; 95% CI 1.13-1.83) and women with a BMI ≥ 35 kg/m2 (n = 7, RR = 1.54; 95% CI, 1.18-2.02) were more likely to become pregnant compared with women in the control groups. Miscarriage was higher in intervention groups who underwent fertility treatment (n = 8, RR 1.45; 95% CI 1.07-1.96). CONCLUSION(S): Pregnancy rates were higher in women undergoing preconception weight loss interventions with no impact on live birth or miscarriage rates. Findings do not support one-size-fits-all recommendation for weight loss through lifestyle modification and/or medication in women with overweight or obesity immediately before conception to improve live birth or miscarriage outcomes.

Risk of future cardiovascular disease in women with prior preeclampsia: a focus group study.

BACKGROUND: A history of preeclampsia is a risk factor for the future development of hypertension and cardiovascular disease (CVD). The objective of this study was to assess, in women with prior preeclampsia, the level of knowledge regarding the link between preeclampsia and CVD, motivators for and barriers to lifestyle change and interest in a lifestyle modification program to decrease CVD risk following a pregnancy complicated by preeclampsia. METHODS: Twenty women with a history of preeclampsia participated in 5 phone-based focus groups. Focus groups were recorded, transcribed, and analyzed. Qualitative content analysis was used to identify common themes across focus groups. Consensus was reached on a representative set of themes describing the data. RESULTS: Women with prior preeclampsia were in general unaware of the link between preeclampsia and future CVD but eager to learn about this link and motivated to achieve a healthy lifestyle. Major perceived barriers to lifestyle change were lack of time, cost of healthy foods and family responsibilities. Perceived facilitators included knowledge of the link between preeclampsia and CVD, a desire to stay healthy, and creating a healthy home for their children. Women with prior preeclampsia were interested in the idea of a web-based program focused on lifestyle strategies to decrease CVD risk in women. CONCLUSIONS: Women with prior preeclampsia were eager to learn about the link between preeclampsia and CVD and to take steps to reduce CVD risk. A web-based program to help women with prior preeclampsia adopt a healthy lifestyle may be an appropriate strategy for this population.

Factors associated with depressive symptoms in the early postpartum period among women with recent gestational diabetes mellitus.

Women with gestational diabetes mellitus (GDM) have a substantial risk of subsequently developing type 2 diabetes. This risk may be mitigated by engaging in healthy eating, physical activity, and weight loss when indicated. Since postpartum depressive symptoms may impair a woman's ability to engage in lifestyle changes, we sought to identify factors associated with depressive symptoms in the early postpartum period among women with recent GDM. The participants are part of the baseline cohort of the TEAM GDM (Taking Early Action for Mothers with Gestational Diabetes Mellitus) study, a one-year randomized trial of a lifestyle intervention program for women with a recent history of GDM, conducted in Boston, Massachusetts between June 2010 and September 2012. We administered the Edinburgh Postnatal Depression Scale (EPDS) at 4-15 weeks postpartum to women whose most recent pregnancy was complicated by GDM (confirmed by laboratory data or medical record review). An EPDS score ≥9 indicated depressive symptoms. We measured height and thyroid stimulating hormone, and administered a questionnaire to collect demographic data and information about breastfeeding and sleep. We calculated body mass index (BMI) using self-reported pre-pregnancy weight and measured height. We reviewed medical records to obtain data about medical history, including history of depression, mode of delivery, and insulin use during pregnancy. We conducted bivariable analyses to identify correlates of postpartum depressive symptoms, and then modeled the odds of postpartum depressive symptoms using multivariable logistic regression. Our study included 71 women (mean age 33 years ± 5; 59 % White, 28 % African-American, 13 % Asian, with 21 % identifying as Hispanic; mean pre-pregnancy BMI 30 kg/m(2) ± 6). Thirty-four percent of the women scored ≥9 on the EPDS at the postpartum visit. In the best fit model, factors associated with depressive symptoms at 6 weeks postpartum included cesarean delivery (aOR 4.32, 95 % CI 1.46, 13.99) and gestational weight gain (aOR 1.21 [1.02, 1.46], for each additional 5 lbs gained). Use of insulin during pregnancy, breastfeeding, personal history of depression, and lack of a partner were not retained in the model. Identifying factors associated with postpartum depression in women with GDM is important since depression may interfere with lifestyle change efforts in the postpartum period. In this study, cesarean delivery and greater gestational weight gain were correlated with postpartum depressive symptoms among women with recent GDM (Clinicaltrials.gov NCT01158131).

Effectiveness of the National Diabetes Prevention Program After Gestational Diabetes.

INTRODUCTION: Women with previous gestational diabetes are at high risk of developing Type 2 diabetes. The National Diabetes Prevention Program (NDPP) is a widely disseminated lifestyle intervention to prevent Type 2 diabetes. Although NDPP programs are open to adults of any age, participants are usually older adults. Effectiveness among younger women with previous gestational diabetes is largely unknown. METHODS: The NDPP was delivered by lifestyle coaches in a large network of Federally Qualified Health Centers. Reach, retention, physical activity, and weight loss outcomes were compared between women aged <40 years with previous gestational diabetes and all other participants. Data were collected from 2013 to 2019 and analyzed in 2022. RESULTS: Among 2,865 enrollees who agreed to start the yearlong NDPP, 63.3% were Latinx, 18.8% were non-Latinx Black, and 16.4% were non-Latinx White. Younger women with previous gestational diabetes represented <4% (n=107) of participants. There was no significant difference in the frequency of attending ≥1 NDPP session between these women and all other participants (37.4% vs 44.6%; p=0.146). However, among those attending ≥1 session (n=1,265), younger women with previous gestational diabetes attended more (11.27 ± 1.27 vs 8.50 ± 0.22 sessions, p=0.021) and had greater weight loss (3.04% ± 0.59 vs. 1.49% ± 0.11, p=0.010) in covariate-adjusted models than other participants. CONCLUSIONS: Diverse younger women with previous gestational diabetes attending the NDPP had one third greater attendance and twice as much weight loss as other NDPP participants but represented a much smaller proportion of enrollees. Thus, the NDPP appears to be a beneficial but underutilized resource for this high-risk population.

Postpartum women's experiences in a randomized controlled trial of a web-based lifestyle intervention following Gestational Diabetes: a qualitative study.

INTRODUCTION: Gestational diabetes mellitus (GDM) is associated with an increased maternal risk for the development of type 2 diabetes (T2DM). We previously demonstrated in a randomized trial that a web-based postpartum lifestyle intervention program, Balance After Baby, increased weight loss among postpartum women with recent pregnancies complicated by GDM. The aim of this analysis is to identify the impact of the intervention on study participants as assessed by exit interviews after completion of the 12 month study. METHODS: We conducted structured exit interviews created with a concurrent-contextual design with subjects randomized to the intervention group at the conclusion of their participation (∼12 months) in the Balance After Baby study, with the objectives of 1) understanding the impact of the intervention on participants and their family members, 2) identifying which program components were most and least helpful, and 3) identifying the perceived best timing for diabetes prevention interventions in postpartum women with recent GDM. RESULTS: Seventy-nine percent (26/33) of eligible intervention participants participated in interviews. Participants noted changes in diet and physical activity as a result of the intervention. Several components of the intervention, particularly the online modules and support from the lifestyle coach, were perceived by intervention participants to have had a positive effect on personal and familial lifestyle change, while other components were less utilized, including the community forum, YMCA memberships, and pedometers. Nearly all participants felt that the timing in the intervention study, beginning about 6 weeks postpartum, was ideal. DISCUSSION: Results of this study identify the importance of individualized coaching, impact on family members, and demonstrate that postpartum women feel ready to make changes by 6 weeks postpartum. Findings from this study will help inform the development of future technologically-based lifestyle interventions for postpartum women with recent GDM.

Carbohydrate Intake and Oral Glucose Tolerance Test Results in the Postpartum Period.

CONTEXT: The American Diabetes Association (ADA) recommends a 3-day preparatory diet prior to a diagnostic oral glucose tolerance test (OGTT), a test often recommended in postpartum individuals with a history of gestational diabetes (GDM). OBJECTIVE: Evaluate the relationship between carbohydrate intake and OGTT glucose in 2 cohorts of postpartum individuals. METHODS: We performed analyses of postpartum individuals from 2 prospective studies with recent GDM (Balance after Baby Intervention, BABI, n = 177) or risk factors for GDM (Study of Pregnancy Regulation of INsulin and Glucose, SPRING, n = 104) .We measured carbohydrate intake using 24-hour dietary recalls (SPRING) or Food Frequency Questionnaire (BABI) and performed 2-hour 75-g OGTTs. The main outcome measure was 120-minute post-OGTT glucose. RESULTS: There was no relationship between carbohydrate intake and 120-minute post-OGTT glucose level in either study population (SPRING: ß = 0.03, [-5.5, 5.5] mg/dL, P = .99; BABI: ß = -3.1, [-9.5, 3.4] mg/dL, P = .35). Adding breastfeeding status to the model did not change results (SPRING ß = -0.14, [-5.7, 5.5] mg/dL, P = .95; BABI ß = -3.9, [-10.4, 2.7] mg/dL, P = .25). There was, however, an inverse relationship between glycemic index and 120-minute post OGTT glucose (BABI: ß = -1.1, [-2.2, -0.03] mg/dL, P = .04). CONCLUSION: Carbohydrate intake is not associated with post-OGTT glucose levels among postpartum individuals. Dietary preparation prior to the OGTT may not be necessary in this population.

Strategies used for the COVID-OUT decentralized trial of outpatient treatment of SARS-CoV-2.

The COVID-19 pandemic accelerated the development of decentralized clinical trials (DCT). DCT's are an important and pragmatic method for assessing health outcomes yet comprise only a minority of clinical trials, and few published methodologies exist. In this report, we detail the operational components of COVID-OUT, a decentralized, multicenter, quadruple-blinded, randomized trial that rapidly delivered study drugs nation-wide. The trial examined three medications (metformin, ivermectin, and fluvoxamine) as outpatient treatment of SARS-CoV-2 for their effectiveness in preventing severe or long COVID-19. Decentralized strategies included HIPAA-compliant electronic screening and consenting, prepacking investigational product to accelerate delivery after randomization, and remotely confirming participant-reported outcomes. Of the 1417 individuals with the intention-to-treat sample, the remote nature of the study caused an additional 94 participants to not take any doses of study drug. Therefore, 1323 participants were in the modified intention-to-treat sample, which was the a priori primary study sample. Only 1.4% of participants were lost to follow-up. Decentralized strategies facilitated the successful completion of the COVID-OUT trial without any in-person contact by expediting intervention delivery, expanding trial access geographically, limiting contagion exposure, and making it easy for participants to complete follow-up visits. Remotely completed consent and follow-up facilitated enrollment.

Outpatient treatment of COVID-19 and incidence of post-COVID-19 condition over 10 months (COVID-OUT): a multicentre, randomised, quadruple-blind, parallel-group, phase 3 trial.

BACKGROUND: Post-COVID-19 condition (also known as long COVID) is an emerging chronic illness potentially affecting millions of people. We aimed to evaluate whether outpatient COVID-19 treatment with metformin, ivermectin, or fluvoxamine soon after SARS-CoV-2 infection could reduce the risk of long COVID. METHODS: We conducted a decentralised, randomised, quadruple-blind, parallel-group, phase 3 trial (COVID-OUT) at six sites in the USA. We included adults aged 30-85 years with overweight or obesity who had COVID-19 symptoms for fewer than 7 days and a documented SARS-CoV-2 positive PCR or antigen test within 3 days before enrolment. Participants were randomly assigned via 2 × 3 parallel factorial randomisation (1:1:1:1:1:1) to receive metformin plus ivermectin, metformin plus fluvoxamine, metformin plus placebo, ivermectin plus placebo, fluvoxamine plus placebo, or placebo plus placebo. Participants, investigators, care providers, and outcomes assessors were masked to study group assignment. The primary outcome was severe COVID-19 by day 14, and those data have been published previously. Because the trial was delivered remotely nationwide, the a priori primary sample was a modified intention-to-treat sample, meaning that participants who did not receive any dose of study treatment were excluded. Long COVID diagnosis by a medical provider was a prespecified, long-term secondary outcome. This trial is complete and is registered with ClinicalTrials.gov, NCT04510194. FINDINGS: Between Dec 30, 2020, and Jan 28, 2022, 6602 people were assessed for eligibility and 1431 were enrolled and randomly assigned. Of 1323 participants who received a dose of study treatment and were included in the modified intention-to-treat population, 1126 consented for long-term follow-up and completed at least one survey after the assessment for long COVID at day 180 (564 received metformin and 562 received matched placebo; a subset of participants in the metformin vs placebo trial were also randomly assigned to receive ivermectin or fluvoxamine). 1074 (95%) of 1126 participants completed at least 9 months of follow-up. 632 (56·1%) of 1126 participants were female and 494 (43·9%) were male; 44 (7·0%) of 632 women were pregnant. The median age was 45 years (IQR 37-54) and median BMI was 29·8 kg/m2 (IQR 27·0-34·2). Overall, 93 (8·3%) of 1126 participants reported receipt of a long COVID diagnosis by day 300. The cumulative incidence of long COVID by day 300 was 6·3% (95% CI 4·2-8·2) in participants who received metformin and 10·4% (7·8-12·9) in those who received identical metformin placebo (hazard ratio [HR] 0·59, 95% CI 0·39-0·89; p=0·012). The metformin beneficial effect was consistent across prespecified subgroups. When metformin was started within 3 days of symptom onset, the HR was 0·37 (95% CI 0·15-0·95). There was no effect on cumulative incidence of long COVID with ivermectin (HR 0·99, 95% CI 0·59-1·64) or fluvoxamine (1·36, 0·78-2·34) compared with placebo. INTERPRETATION: Outpatient treatment with metformin reduced long COVID incidence by about 41%, with an absolute reduction of 4·1%, compared with placebo. Metformin has clinical benefits when used as outpatient treatment for COVID-19 and is globally available, low-cost, and safe. FUNDING: Parsemus Foundation; Rainwater Charitable Foundation; Fast Grants; UnitedHealth Group Foundation; National Institute of Diabetes, Digestive and Kidney Diseases; National Institutes of Health; and National Center for Advancing Translational Sciences.