Prevention of covid-19 and other acute respiratory infections with cod liver oil supplementation, a low dose vitamin D supplement: quadruple blinded, randomised placebo controlled trial

The BMJ

Sep 2022

DOI: 10.1136/bmj-2022-071245

Citations:49

Influential Citations:1

Interventional (Human) Studies

Enhanced Details

Methods

Adults aged ≥18 years in Norway; general population; quadruple-masked, randomized, parallel-group two-arm trial; 34,741 randomized; 34,601 analyzed (17,278 cod liver oil, 17,323 placebo); mean age 44.9 years; 64.5% female; mean BMI 26.1; exclusions included renal failure/dialysis, hypercalcaemia, severe liver disease, sarcoidosis or other granulomatous diseases, prior COVID-19, inability to swallow oil, fish/cod liver oil or corn oil allergies, vegan, pregnancy, aged >75, or indications for vitamin D supplements; many participants not on vitamin D supplements before enrollment.

Intervention

Cod liver oil, 5 mL daily for ~6 months during winter 2020-21; lemon-flavoured oil; contains ~10 µg vitamin D3 (400 IU), 1.2 g long-chain omega-3 fatty acids (EPA 0.4 g, DHA 0.5 g), 250 µg vitamin A, 3 mg vitamin E. Placebo: corn oil, 5 mL daily for ~6 months; lemon aroma; contains vitamin A 15.8 µg and vitamin E 3.8 mg.

Results

No protective effect observed for cod liver oil on SARS-CoV-2 infection, serious COVID-19, or other acute respiratory infections versus placebo. SARS-CoV-2 infection: 1.31% vs 1.32% (relative risk 1.00; 97% CI 0.82–1.22). Serious COVID-19: 0.70% vs 0.58% (relative risk 1.20; 98.2% CI 0.87–1.65). Acute respiratory infections: 22.94% vs 22.13% (relative risk 1.04; 99.9% CI 0.97–1.11). A small substudy showed increases in 25(OH)D3 (+15.0 nmol/L) and omega-3 index (+1.9%) with cod liver oil; baseline 25(OH)D3 ≥50 nmol/L was common. Effects were not modified by sex, age, BMI, sun exposure, vitamin D supplement use, fatty fish intake, or strict compliance. Conclusion: Daily cod liver oil containing vitamin D and omega-3 fatty acids did not reduce risk of infection or other respiratory outcomes in a general adult Norwegian winter population.

Limitations

Fewer SARS-CoV-2 infections than expected reduced power to detect a modest effect; trial underpowered for the infection endpoint; biomarker analyses (25(OH)D3 and omega-3 index) were available in a small subset; cannot separate vitamin D effects from omega-3 effects; vaccination during the study could confound results; generalizability to vitamin D-deficient populations is uncertain.

Abstract

Abstract Objective To determine if daily supplementation with cod liver oil, a low dose vitamin D supplement, in winter, prevents SARS-CoV-2 infection, serious covid-19, or other acute respiratory infections in adults in Norway. Design Quadruple blinded, randomised placebo controlled trial. Setting Norway, 10 November 2020 to 2 June 2021. Participants 34 601 adults (aged 18-75 years), not taking daily vitamin D supplements. Intervention 5 mL/day of cod liver oil (10 µg of vitamin D, n=17 278) or placebo (n=17 323) for up to six months. Main outcome measures Four co-primary endpoints were predefined: the first was a positive SARS-CoV-2 test result determined by reverse transcriptase-quantitative polymerase chain reaction and the second was serious covid-19, defined as self-reported dyspnoea, admission to hospital, or death. Other acute respiratory infections were indicated by the third and fourth co-primary endpoints: a negative SARS-CoV-2 test result and self-reported symptoms. Side effects related to the supplementation were self-reported. The fallback method was used to handle multiple comparisons. Results Supplementation with cod liver oil was not associated with a reduced risk of any of the co-primary endpoints. Participants took the supplement (cod liver oil or placebo) for a median of 164 days, and 227 (1.31%) participants in the cod liver oil group and 228 (1.32%) participants in the placebo group had a positive SARS-CoV-2 test result (relative risk 1.00, multiple comparison adjusted confidence interval 0.82 to 1.22). Serious covid-19 was identified in 121 (0.70%) participants in the cod liver oil group and in 101 (0.58%) participants in the placebo group (1.20, 0.87 to 1.65). 8546 (49.46%) and 8565 (49.44%) participants in the cod liver oil and placebo groups, respectively, had ≥1 negative SARS-CoV-2 test results (1.00, 0.97 to 1.04). 3964 (22.94%) and 3834 (22.13%) participants in the cod liver oil and placebo groups, respectively, reported ≥1 acute respiratory infections (1.04, 0.97 to 1.11). Only low grade side effects were reported in the cod liver oil and placebo groups. Conclusion Supplementation with cod liver oil in the winter did not reduce the incidence of SARS-CoV-2 infection, serious covid-19, or other acute respiratory infections compared with placebo. Trial registration ClinicalTrials.gov NCT04609423. show less