Immune modulation treatments—where is the evidence?

Abstract

While advances in assisted reproductive techniques have been substantial, failure of the apparently viable embryo to implant remains a source of distress and frustration to patients and specialists alike. The unique maternal immunological response to the embryo and the notion that defects in early placentation underlie the great complications of pregnancy have focused attention on the therapeutic potential of peri-implantation immunomodulation. On the face of it, the rationale for this approach is very attractive. However, as will be argued in this review, the clinical evidence base supporting the use of immunosuppressive treatments is weak and difficult to apply in practice and fails the needs of both doctors and their patients. This evidence gap is filled by justifications that are based largely on meeting patient expectations and commercial imperatives. However, this does not mean that immunomodulation treatments should be written off as ineffective. The literature in this field, while suffering the same challenges of heterogeneity, small studies, and publication bias as other areas of medicine, does hint at the way forward. Recurrent implantation failure and pregnancy loss are not diagnoses but clinical presentations that require appropriate phenotyping and etiological investigation. We are increasingly gaining the tools to make an "endometrial diagnosis," and these will allow us to design clinical studies of interventions that treat the underlying cause rather than the symptoms of implantation failure. The current evidence base does not support the clinical use of immunomodulation therapies in patients undergoing IVF. However, more discerning phenotyping may identify groups who could benefit.

Epigenomics and genotype-phenotype association analyses reveal conserved genetic architecture of complex traits in cattle and human

“…3b). This is in agreement with previous findings in human that reproduction traits have been linked with immunological processes such as allergic response to sperm and immunological tolerance of the embryo [39]. We observed that mammary is the top significant tissue for somatic cell score (SCS, an indicator of mastitis), consistent with prior knowledge that an infection of the udder is the main cause for increased somatic cell counts in milk [40].…”

Detailed endometrial immune assessment of both normal and adverse reproductive outcome populations

“…Immunotherapy for implantation failure or miscarriage is a controversial strategy, with a lack of strong evidence to support its routine use [45]. A common theme to many of these investigations is poor study design and patient selection which perhaps underpowers the work to show a significant impact of therapy on outcomes such as live birth [46] or adds potential bias during patient selection.…”

ART implantation failure and miscarriage in patients with elevated intracellular cytokine ratios: response to immune support therapy

“…The ability to determine the relative effect of each component would allow a more personalised protocol for each individual patient. Studies assessing the individual relative benefits of the empiric treatments described here have previously been conducted with variable findings both advocating and not advocating their use [ 21 , 48 , 49 ]. The success of the regimen employed here as evidenced by improved implantation, successful pregnancies and a dramatic reduction in the overall miscarriage rate demonstrates both the combined beneficial effect of these agents as well as the potential importance of specific immunological testing in selected cases.…”