Key messages

• Compared to a dummy pill (placebo), zinc and N-acetylcysteine (NAC; 1200 mg) may not reduce the frequency of painful episodes (crises) that people with sickle cell disease (SCD) experience.

• Zinc may improve haemoglobin status (number of red blood cells) slightly, but L-arginine may not. L-arginine also probably reduces the severity of pain, but may not reduce the frequency of hospitalization.

• Larger studies to assess the effects of vitamin C plus vitamin E, zinc, NAC, L-arginine, and omega-3 are needed. Future studies should assess the number and severity of painful episodes that people with SCD experience, their quality of life, harmful effects of treatment, and frequency of hospitalization.

What is sickle cell disease (SCD) and how is it treated?

Sickle cell disease is an inherited condition affecting blood cells that carry oxygen through the body. Red blood cells in people with this condition become sickle-shaped (almost like the letter C) when oxygen levels are low. Sickle-shaped red cells lead to the production of harmful substances called free radicals.

'Antioxidant' is a general term used to describe any substance that can protect the cells of our body against chemicals called free radicals, which are capable of damaging the cells.

Antioxidants may help reduce the sickling process and improve recovery from sickle cell complications known as sickle cell crisis. A sickle cell crisis is the pain that occurs when the red cells become sickle-shaped due to low oxygen in the blood.

What did we want to find out?

We wanted to find out whether giving antioxidant supplements to people with SCD reduced the frequency of crises, reduced pain, and improved their quality of life. We also wanted to find out if there were harms associated with antioxidant supplements for people with SCD.

What did we do?

We searched for studies that compared antioxidants to placebo or other antioxidants, or compared two different doses of the same antioxidant. We compared and summarised their findings and rated our confidence in the evidence, based on factors such as study methods and sizes.

What did we find?

We included 26 studies that looked at 11 antioxidants, involving 1609 children and adults with SCD. The studies took place in Belgium, Brazil, India, Jamaica, the Netherlands, Nigeria, Sudan, UK, and the USA. Thirteen studies were publicly funded, three studies were funded by pharmaceutical companies, and four studies were funded by a mixture of both. One study received no funding and five studies provided no information on their funding sources.

Only eight studies reported on our important outcomes at six months after treatment:

• frequency of crisis (four studies);
• pain severity (three studies);
• quality of life (one study);
• adverse effects (that is, unwanted effects; two studies);
• frequency of hospitalization (two studies);
• frequency of SCD-related complications (three studies);
• change in haemoglobin status (five studies).

The eight studies investigated different antioxidants: vitamin C plus E, zinc, N-acetylcysteine (NAC), L-arginine, and omega-3.

Main findings

We are very uncertain whether vitamin C (1400 mg) plus vitamin E (800 mg) are better than placebo at reducing the frequency of crises or pain severity, or if they cause more unwanted effects (1 study, 83 participants). We are also uncertain whether vitamin C plus vitamin E are better than placebo at reducing SCD-related health problems and increasing blood levels in people with SCD.

Zinc may not be better than placebo at reducing the frequency of crises but may result in a slight increase in blood level (1 study, 36 people). We are very uncertain about zinc's effects on SCD-related complications such as leg ulcers (1 study, 34 participants).

NAC (1200 mg) may not be better than placebo at reducing the frequency of crises, severity of pain, and blood levels. We are very uncertain about its effect on quality of life, unwanted effects, frequency of hospitalization, and SCD-related complications (1 study, 96 participants).

L-arginine may not be better than placebo at reducing the frequency of crises (monthly pain) (1 study, 50 participants). However, L-arginine may be better than placebo at reducing the severity of pain (2 studies, 125 participants). Also, the rate of unwanted events was similar in both treatment groups. L-arginine may not be better than placebo at shortening hospital stay (2 studies, 125 participants) or increasing blood levels (2 studies, 106 participants).

We are uncertain whether omega-3 causes more unwanted effects in people with SCD than placebo, or if it is better at increasing blood levels (1 study, 67 participants).

What are the limitations of the evidence?

Overall, we are not very confident about the effects of antioxidants in treating sickle cell disease because there were too few studies for each comparison to be certain about the results. We also had concerns about how some of the studies were conducted. Further research is likely to change these results.

How up to date is this evidence?

The evidence is current to 15 August 2023.