Abstract: No studies of vitamin A or other retinoid supplementation were eligible for inclusion. However, one randomised study of beta (β)-carotene supplementation involving 24 people with CF who were receiving pancreatic enzyme substitution was included. The study compared successive β-carotene supplementation periods (high dose followed by low dose) compared to placebo. The results for the low-dose supplementation period should be interpreted with caution, due to the lack of a wash-out period after the high-dose supplementation. The included study did not report on two of the review's primary outcomes (vitamin A deficiency disorders and mortality); results for our third primary outcome of growth and nutritional status (reported as z score for height) showed no difference between supplementation and placebo, mean difference (MD) -0.23 (95% confidence interval (CI) -0.89 to 0.43) (low-quality evidence). With regards to secondary outcomes, supplementation with high-dose β-carotene for three months led to significantly fewer days of systemic antibiotics required to treat pulmonary exacerbations, compared to controls, MD -15 days (95% CI -27.60 to -2.40); however, this was not maintained in the second three-month section of the study when the level of β-carotene supplementation was reduced, MD -8 days (95% CI -18.80 to 2.80) (low-quality evidence). There were no statistically significant effects between groups in lung function (low-quality evidence) and no adverse events were observed (low-quality evidence). Supplementation affected levels of β-carotene in plasma, but not vitamin A levels. The study did not report on quality of life or toxicity. Since no randomised or quasi-randomised controlled studies on retinoid supplementation were identified, no conclusion on the supplementation of vitamin A in people with CF can be drawn. Additionally, due to methodological limitations in the included study, also reflected in the low-quality evidence judged following the specific evidence grading system (GRADE), no clear conclusions on β-carotene supplementation can be drawn. Until further data are available, country- or region-specific guidelines regarding these practices should be followed.

Plain-language summary: No studies comparing vitamin A or other retinoid supplements to placebo (dummy drug containing no vitamin A) were included, but we did find one study comparing beta-carotene supplementation (a precursor of vitamin A) to placebo. A total of 24 people with cystic fibrosis (aged 6.7 to 27.7 years) were put into groups at random and treated either with β-carotene capsules (at a high dose for three months followed by a low dose for a further three months) or with placebo (for six months). No studies on vitamin A supplementation were included in this review. The single included study revealed that high-dose beta-carotene supplementation for three months led to fewer days on which people with CF required antibiotics compared to placebo, but this was not the case in the following three-month section of the study when low-dose beta-carotene supplementation was compared to placebo. Other clinical outcome measures (growth, nutritional status and lung function) showed no statistical significant differences between treatment and placebo groups. No side effects were observed. The other outcomes in this review, such as vitamin A deficiency symptoms, mortality, toxicity and quality of life, were not reported. We could only include one study in this review and that study had several limitations. This is reflected in the assessment of low-quality evidence, judged using the specific evidence grading system (GRADE). So, we feel that the strength of evidence is low. Not all outcome measures were reported after each supplementation dose and results should be viewed with some caution as some beta-carotene from the high-dose period was probably still present in the blood during the low-dose supplementation period. Since no studies on vitamin A supplementation were included in the review, no conclusions can be drawn regarding the routine use of vitamin A supplements. Due to limitations of the included study of beta-carotene supplementation, no definitive conclusions regarding its use can be drawn either. Until further evidence is available, local guidelines should be followed regarding supplementation.