Abstract
BackgroundThe origins of adverse reproductive outcome can be multifactorial, but the contribution of the maternal immune system is considered debatable. Elevated intracellular cytokine ratios have been proposed, although not universally supported, as a marker for immunological dysfunction in implantation and early pregnancy. Poor patient selection or inadequate treatment or testing may be confounding factors. Specific immunomodulation, in carefully selected sub-populations of ART patients with poor reproductive history, despite transfer of good quality blastocysts, may potentially improve clinical outcomes.MethodsIntracellular cytokine ratios (CKR) were prospectively assessed in 337 patients presenting with a history of implantation failure and/or pregnancy loss, prior to further treatment, and were found to be elevated in 150 (44.5%). Of this group, 134 agreed to initiate a standardised immunotherapy regime (nutraceuticals, prednisolone & intralipids) to evaluate the efficacy of this proposed therapy. Of the intervention population, a small cohort (n = 70) delayed commencing ART for ~ 10 weeks to assess if extended pre-treatment nutraceutical supplementation could normalise CKRs prior to starting ART, and if this conferred additional benefit.ResultsBaseline assessment in the intervention population (n = 134) identified 160 miscarriages from 180 total pregnancies (89% miscarriage rate, MR), conceived both spontaneously and by assisted reproduction. Post-treatment analysis of subsequent ART cycles revealed a significant improvement in both implantation (OR 3.0, 2.0–4.5) and miscarriage rates (41/97, 42.2% MR, P < 0.001). Interestingly, pre-treatment normalisation of CKRs appeared to impart marginal extra benefit prior to subsequent fertility treatment with immunotherapy.ConclusionsFollowing immunomodulation, significant improvements in both implantation rate and miscarriage rate were seen in this poor prognosis population. This suggests a possible role for both detailed immuno-evaluation of patients with poor reproductive history with good embryo quality, and application of personalised immunotherapy regimes alongside ART in selected cases. Future randomised controlled trials are needed to definitively evaluate this potentially promising therapeutic approach.
Highlights
The origins of adverse reproductive outcome can be multifactorial, but the contribution of the maternal immune system is considered debatable
Patients presenting with a history of early pregnancy losses or failed embryo transfers were offered an initial assessment of their CD4+ intracellular cytokine ratios (CKR) prior to their assisted reproductive technology (ART) cycle using the investigative technique as previously described [38]
Monoclonal antibodies to TNF-α, IFN-γ and Interleukin 10 (IL-10) were employed, phycoerythrin (PE)-anti-human TNF-α clone IPM2, Fluorescein isothiocynate (FITC)- anti- human IFN-γ clone 45.15 and allophycocyanin (APC)-anti human IL-10 clone JES3-19F1 (BD Pharmingen)
Summary
The origins of adverse reproductive outcome can be multifactorial, but the contribution of the maternal immune system is considered debatable. Intralipid has been proposed to exert a modulating effect on certain immune cellular mechanisms, potentially down-regulating cytotoxic or activated natural killer cells (NKa) [24]. This effect may act synergistically with the concomitant administration of corticosteroids, such as dexamethasone or prednisolone, to suppress cytotoxic/activated T-lymphocytes. In-vitro testing has shown that Intravenous Intralipid administration can successfully downregulate natural killer cell activation (NKa) within 2–3 weeks in up to 78% of women experiencing suspected immunologic implantation dysfunction [25,26,27]
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