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Fertil Res Pract. 2018 Mar 2;4:1. doi: 10.1186/s40738-018-0046-4. eCollection 2018.

Anti-oxidant mediated normalisation of raised intracellular cytokines in patients with reproductive failure.

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Sims IVF Clinic, Clonskeagh Road, Clonskeagh, Dublin 14, Ireland.
2Royal College of Surgeons Ireland, 123 St Stephen's Green, Dublin 2, Ireland.



Raised intracellular cytokine ratios (CKR) are proposed as a significant risk factor for adverse reproductive outcome. An elevated cytokine ratio, such as between TNFa and/or IFNg to IL-10 is associated with recurrent miscarriage (RM). The use of pharmacological immunomodulators such as TNFα inhibitors in these patients is controversial and not generally recommended due to a lack of conclusive data supporting their use. We evaluated whether the use of anti-oxidants/dietary supplements as an alternative could positively influence CKR's in ART patients.


A prospective non-placebo control trial of antioxidant treatment for abnormal peripheral inflammatory cytokine ratios was performed. CKRs were assessed using flow cytometry in stimulated versus unstimulated whole blood samples in 337 IVF patients presenting with a previous history of poor outcome (RM or implantation failure). CKR's were found to be elevated in 150/337. 70/150 patients in this elevated group agreed to a 10 week regime of Omega 3, vitamin D3, and B complex, followed by retesting to evaluate effect.


Mean cytokine ratios significantly improved between tests. Pre-treatment TNFa:IL-10 ratio improved from 71.6 to 21.0 (p < 0.0001) and IFNg:IL-10 ratio dropped from 24.5 to 12.5 (p < 0.0001). The improved ratios were achieved primarily by an increase in IL-10 expression (P = 0.0007), but also by a moderate decrease in stimulated TNFa expression (p = 0.008). Mean IFNg expression was unchanged (p = 0.42). On an individual basis CKR levels were normalised in 43 patients, improved in 12 and remained unchanged in 15. No significant differences in improvement were found between RM and IF subgroups.


Intracellular cytokine expression levels and ratios were modifiable by the supplement regime employed. Elevated cytokine ratios have been linked with adverse reproductive outcomes, and proposed treatments have included biological immunomodulators which antagonise TNFa, but come with significant associated cost implications and more importantly, cytotoxic side-effects. A dietary regime is more patient friendly and lower risk, while still achieving a similar effect in many patients.


Cytokines; Immunomodulation; Implantation; Miscarriage

Conflict of interest statement

Kevin Marron is Clinical laboratory manager at one of Ireland largest IVF Clinics. He gained his PhD in human cardiac immunocytochemistry from imperial College London in 1996 and has developed a strong research interest in reproductive immunology.Informed consent was obtained from patients for the analysis and approval was obtained from the Clinic’s research and quality management department. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.N/AThe authors declare that they have no competing interests. No conflict of interest is declared by any of the authors. Patients all gave informed consent for their data to be used in this study. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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