TNFα and MFG-E8: Novel Biomarkers to Predict Implantation Failure
Condition: Infertility; Recurrent Pregnancy Loss
MeSH terms: Infertility
Study type: Observational

Summary: 
      Question: Can implantation failure (IF) be predicted prior to in vitro fertilization (IVF)? A
      pilot, non-interventional, clinical study Prospective, controlled, cohort study
    

Detailed description: 
      The investigators hypothesize that TNFα and MFG-E8 cooperatively maintain the integrity of
      the normal endometrium, and that in patients with IF or with recurrent pregnancy loss (RPL)
      of unexplained origin, excessive TNFα increases the maternal shedding of MFG-E8, disrupting
      the normal protective effect of this protein, resulting in damage of the endometrial
      epithelium and impairing trophoblast invasion. The investigators propose that these molecules
      can be measured in local tissue (endometrium) as well as in serum as a reflection of
      increased inflammation and can therefore be used as markers of implantation and its failure.
      The investigators hypothesis is that TNFα is up-regulated in serum of women with implantation
      defects (IF and RM of unexplained origin) and this causes perturbation of MFG-E8 secretion.
      These results will provide first evidence demonstrating endometrial dysfunctions resulting
      from over-expression of pro-inflammatory molecules. The release of significant quantities of
      these molecules into serum broadens the maternal-fetal interface beyond the uterus and into
      the maternal circulation. The characterization of these molecules is essential to better
      understand, not only their biological effects, but also their potential as prognostic and
      diagnostic biomarkers for detection of IF. More importantly, these molecules could be
      potential therapeutic targets (perhaps intrauterine infusion of MFG-E8 for tissue repair,
      and/or oral administration of TNFα antagonists) to improve implantation outcomes. Two recent
      studies have reported the successful therapeutic use of recombinant human MFG-E8 (rhMFG-E8)
      in animals: one was used to decrease intestinal injury after whole body radiation (Ajakaiye
      et al, 2012), and the other was to mitigate inflammation and tissue injury after hemorrhagic
      stroke (Wang et al, 2012). Also, TNFα inhibitors have been shown to significantly increase
      IVF outcome in infertile patients (Winger et al, 2009 and 2008). In summary, these two
      pivotal studies show promising clinical uses of rhMFG-E8 in tissue repair/remodeling by
      decreasing apoptosis, and provide basis for their use as candidates for further clinical
      development in reproductive health.

      Objectives: Here, the investigators seek to delineate novel diagnostic methods with the
      ultimate long term goal of designing directed therapies to improve embryo implantation
      competence.

        -  The specific aim is to quantify and correlate MFG-E8 and TNFα in serum and in
           endometrial biopsies of women in 3 groups: controls, IF and RM.

        -  The ultimate goal of this study is to provide data leading to a simple and quick test to
           measure soluble serum markers of IF/RM in order to discriminate prospectively between
           these groups of patients.

        -  To translate these findings into the use of modulators of these inflammatory molecules
           to improve pregnancy rates in patients with predicted implantation defects. It is widely
           known that "classic" markers of endometrial receptivity such as those provided by an
           invasive endometrial biopsy (with Hematoxilin-Eosin staining, or immuhistochemistry, or
           even with microarray technology) are not reliable to establish clear-cut diagnosis due
           to cycle-to-cycle variations and overlap of results.
    

Observational model: Case-Control
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        women 21-35 years old attending an infertility clinic in an academic center
      
Keywords: pregnancy failure