Monaz: Hello, I'm Monaz Mehta, editor in the Cochrane Editorial and Methods department. Up to one in four couples planning a baby may have difficulty conceiving. Several interventions are available that might help and Cochrane has reviewed many of these. In August 2020, our review of antioxidants for female subfertility was updated and we asked one of the authors, Dr Rebecca Mackenzie-Proctor from the Auckland City Hospital in New Zealand to tell us about the rationale for the review and the latest evidence.

Rebecca: Some causes of subfertility among women are associated with the adverse effects of oxidative stress and antioxidant drugs would be expected to counteract these negative impacts of oxygen free radicals, by acting as free radical scavengers. We did our review to test this idea and found 63 randomised trials in which some women took an oral antioxidant supplement, while others were allocated to either a control group or an alternative antioxidant. We have added 13 studies to the review since the 2017 version, further strengthening the evidence to support the use of these drugs, and now based on data from more than 7500 women.
We were most interested in the effects on live birth but it’s still the case that few trials provide information on this, and we could only use data from just over 1200 women from 13 trials, and increase of five trials since 2017. This evidence shows a significant increase in live birth rates, with nearly twice the likelihood of a live birth for women taking antioxidants, suggesting increases in the chance of a live birth from around one in five women not taking additional antioxidant supplementation, to one in four or three when they took them. 
It was much more common for the trials to investigate outcomes other than live birth and we used these to examine the impact on clinical pregnancy and adverse effects. Clinical pregnancy was higher for women taking antioxidants. Using data from 35 trials, we found a significant difference, with the chances of a clinical pregnancy increasing from around 19% to between 25 and 30%. 
When we looked at specific indications for infertility, live birth and clinical pregnancy rates were higher in women with polycystic ovarian syndrome who took antioxidants. Studies that had mixed indications for infertility also had significantly higher live birth rates. 
However, turning to adverse events, although data on these were reported in 28 trials, there was insufficient evidence to draw conclusions and to determine if there were any differences in miscarriage rate, multiple pregnancies or gastrointestinal disturbances between women taking or not taking antioxidants. 
The next obvious question is which antioxidant is better, but it’s difficult to draw conclusions because too few trials directly tested the same pairs of antioxidants. From the trials against no treatment or placebo, live births were statistically significant increased when women took either combined antioxidants or N-acetyl-cystine. Both these antioxidants, as well as melatonin, Co enzyme Q10, L-carnitine and combined antioxidants all showed an improvement in clinical pregnancy outcomes.
In summary, our updated review suggests that antioxidants may be associated with an increase in live births and clinical pregnancies. We still need more rigorous, high quality trials to allow firmer recommendations regarding the use of these drugs, but subfertile women should consider taking those combination antioxidants that are designed specifically for antenatal and pregnancy care, including folic acid, while any other antioxidants should only be taken on medical advice. This is especially the case for women with polycystic ovarian syndrome.

Monaz: If you’d like to learn more about the overall findings of this updated review and those for the specific antioxidants in the included studies, you can find the review online at Cochrane Library dot com. Just go to the website and search 'antioxidants for female subfertility' to find it.