Study protocol for a randomised controlled trial of a virtual antenatal intervention for improved diet and iron intake in Kapilvastu district, Nepal: VALID.

INTRODUCTION: Despite evidence that iron and folic acid (IFA) supplements can improve anaemia in pregnant women, uptake in Nepal is suboptimal. We hypothesised that providing virtual counselling twice in mid-pregnancy, would increase compliance to IFA tablets during the COVID-19 pandemic compared with antenatal care (ANC alone. METHODS AND ANALYSIS: This non-blinded individually randomised controlled trial in the plains of Nepal has two study arms: (1) control: routine ANC; and (2) 'Virtual' antenatal counselling plus routine ANC. Pregnant women are eligible to enrol if they are married, aged 13-49 years, able to respond to questions, 12-28 weeks' gestation, and plan to reside in Nepal for the next 5 weeks. The intervention comprises two virtual counselling sessions facilitated by auxiliary nurse midwives at least 2 weeks apart in mid-pregnancy. Virtual counselling uses a dialogical problem-solving approach with pregnant women and their families. We randomised 150 pregnant women to each arm, stratifying by primigravida/multigravida and IFA consumption at baseline, providing 80% power to detect a 15% absolute difference in primary outcome assuming 67% prevalence in control arm and 10% loss-to-follow-up. Outcomes are measured 49-70 days after enrolment, or up to delivery otherwise. PRIMARY OUTCOME: consumption of IFA on at least 80% of the previous 14 days. SECONDARY OUTCOMES: dietary diversity, consumption of intervention-promoted foods, practicing ways to enhance bioavailability and knowledge of iron-rich foods. Our mixed-methods process evaluation explores acceptability, fidelity, feasibility, coverage (equity and reach), sustainability and pathways to impact. We estimate costs and cost-effectiveness of the intervention from a provider perspective. Primary analysis is by intention-to-treat, using logistic regression. ETHICS AND DISSEMINATION: We obtained ethical approval from Nepal Health Research Council (570/2021) and UCL ethics committee (14301/001). We will disseminate findings in peer-reviewed journal articles and by engaging policymakers in Nepal. TRIAL REGISTRATION NUMBER: ISRCTN17842200.

Combined action of SAMe, Folate, and Vitamin B12 in the treatment of mood disorders: a review.

Mood disorders affect more than 500 million people around the world. In the last decade, their prevalence has increased, and many people suffer from nervousness, anxiety, and stress at least once in their lives. The incidence of mood disorders and anxiety increases during perimenopause or under stressful conditions. The social restrictions introduced during the COVID-19 pandemic have significantly increased the normal burden of psychological and psychic disorders. In moderate to severe cases, pharmacological treatment is currently recommended, while in mild disorders, especially in the initial phase, psychological therapy is preferable. It is known that several nutrients are crucial for brain function. Among them, folate (vitamin B9), cyanocobalamin (vitamin B12), and S-adenosyl-L-methionine (SAMe) have been shown to influence various neurobiological processes. Overall, the available evidence suggests that dietary supplementation with folic acid, vitamin B12, and SAMe can be beneficial for people with mild mood disorders.

Maternal nutrients and effects of gestational COVID-19 infection on fetal brain development.

BACKGROUND & AIMS: Maternal gestational infection is a well-characterized risk factor for offsprings' development of mental disorders including schizophrenia, autism, and attention deficit disorder. The inflammatory response elicited by the infection is partly directed against the placenta and fetus and is the putative pathogenic mechanism for fetal brain developmental abnormalities. Fetal brain abnormalities are generally irreversible after birth and increase risk for later mental disorders. Maternal immune activation in animals models this pathophysiology. SARS-CoV-2 produces maternal inflammatory responses during pregnancy similar to previously studied common respiratory viruses. METHOD: Choline, folic acid, Vitamin D, and n-3 polyunsaturated fatty acids are among the nutrients that have been studied as possible mitigating factors for effects of maternal infection and inflammation on fetal development. Clinical and animal studies relevant to their use in pregnant women who have been infected are reviewed. RESULTS: Higher maternal choline levels have positive effects on the development of brain function for infants of mothers who experienced viral infections in early pregnancy. No other nutrient has been studied in the context of viral inflammation. Vitamin D reduces pro-inflammatory cytokines in some, but not all, studies. Active folic acid metabolites decrease anti-inflammatory cytokines. N-3 polyunsaturated fatty acids have no effect. CONCLUSIONS: Vitamin D and folic acid are already supplemented in food additives and in prenatal vitamins. Despite recommendations by several public health agencies and medical societies, choline intake is often inadequate in early gestation when the brain is forming. A public health initiative for choline supplements during the pandemic could be helpful for women planning or already pregnant who also become exposed or infected with SARS-CoV-2.

Folic acid as placebo in controlled clinical trials of hydroxychloroquine prophylaxis in COVID-19: Is it scientifically justifiable?

Using folic acid (FA) as placebo complicates the interpretation of the findings of few RCTs evaluating safety and efficacy of hydroxychloroquine prophylaxis in COVID-19. FA is found to bind to furin-protease and spike: ACE2 interface of SARS-CoV-2. In clinical studies, FA level was lowest among severe patients compared to mild and moderate disease. A single controlled study reported the benefit of combination of folic acid with Pyridoxine & cyanocobalamin in terms of clinical and laboratory cure parameters. One hypothesis associates the differences in geographical variation of disease severity with prevalence of methyl tertahydrofolic acid reductase (MTHFR) C677T polymorphism. Other possible domains, where FA is hypothesized to be beneficial are COVID-19 associated pulmonary hypertension and hyper-homocystinemia. So, scientific justification of using folic acid as placebo in COVID-19 trials seems scientifically not credible and this may be one of the major factors for failure of many agents. We need to be more careful in choosing our placebo especially when conducting a placebo controlled trial.

High dose folic acid is a potential treatment for pulmonary hypertension, including when associated with COVID-19 pneumonia.

BACKGROUND: Pulmonary hypertension is a significant complication for some patients with COVID-19 pneumonia, especially those requiring intensive care. Tachyphylaxis to the current therapy, inhaled nitric oxide (iNO), is also common. In vitro, folic acid directly increases nitric oxide (NO) production and extends its duration of action; effects which could be of benefit in reversing pulmonary hypertension and severe hypoxaemia. Our work has shown that, in the systemic circulation, folic acid in high dose rapidly improves nitric oxide mediated vasodilation, by activating endothelial nitric oxide synthase (eNOS). HYPOTHESIS: A similar effect of high dose folic acid on pulmonary endothelial function would be expected from the same mechanism and would lead to improvement in pulmonary perfusion. We therefore hypothesise that folic acid, 5 mg or greater, is a useful therapeutic option for pulmonary hypertension and/or refractory severe hypoxaemia, in patients with severe COVID-19 associated pneumonia in whom NO therapy is considered, with a very low risk of adverse effects.