HLA-G as a marker for embryo selection in assisted reproductive technology

LETTER TO THE EDITOR HLA-G as a marker for embryo selection in assisted reproductive technology REPLY OF THE AUTHORS: We agree with the statements in the letter. We use this opportunity to highlight a few problem areas regarding the sHLA-G assay. It has been postulated by Hviid et al. (1) that sHLA-G plays a pivotal role during the implantation process. The presence of sHLA-G in spent media of individually cultured embryos and its influence on assisted reproductive technology outcomes have been reported by Sher et al. (2) and in a meta-analysis by Vercammen et al. in 2008 (3). The results of a prospective randomized trial (4) followed by a multicenter (5) approach confirmed our previous findings. Lately, the quest to find the best way to identify an embryo with the highest potential to develop into a live baby has been an issue of active debate. Notwithstanding the patient population that undoubtedly needs preimplantation genetic screening/preimplantation genetic diagnosis, there is a desperate need to establish criteria for a noninvasive method to be implemented to achieve the goal of identifying such embryos for transfer. We have shown that embryos transferred on day 3 (with good morphology) that have a positive expression of sHLA-G had superior outcome compared with embryos that were transferred based on morphology only. That said, we further suggest that transferring blastocysts with a positive sHLA-G expression might be even more superior. We highlighted shortfalls in the current publication. To apply this assay effectively, all embryos have to be cultured and tracked individually to specifically identify the ‘‘correct’’ embryo(s) for transfer. A positive aspect of applying this assay is the potential to transfer fewer embryos (even a single blastocyst) without compromising pregnancy outcome and simultaneously to reduce the risk of multiple pregnancies.

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Owing to the lack of standardization, it is our belief that a standardized sHLA-G assay with a specifically defined range (for positive sHLA-G expression) and standard ‘‘measuring units’’ should be established through international collaboration. This relatively inexpensive noninvasive approach could shift the paradigm for identifying the most competent embryos for transfer and to achieve the abovementioned goal. Dirk Kotze, Ph.D.a Thinus F. Kruger, M.D., Ph.D., D.Sc.b a Jones Institute, Norfolk, Virginia; and b Tygerberg Hospital and Stellenbosch University, Tygerberg, South Africa October 8, 2013 http://dx.doi.org/10.1016/j.fertnstert.2013.10.014

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Hviid TV, Hylenius S, Lindhard A, Christiansen OB. Association between human leukocyte antigen-G genotype and success of in vitro fertilization and pregnancy outcome. Tissue Antigens 2004;64:66–9. Sher G, Keskintepe L, Nouriani M, Roussev R, Batzofin J. Expression of sHLA-G in supernatants of individually cultured 46-h embryos: a potentially valuable indicator of ‘‘embryo competency' and IVF outcome. Reprod Biomed Online 2004;9:74–8. Vercammen MJ, Verloes A, van de Velde H, Haentjens P. Accuracy of soluble human leukocyte antigen-G for predicting pregnancy among women undergoing infertility treatment: meta-analysis. Hum Reprod Update 2008; 14:209–18. Kotze DJ, Hansen P, Keskintepe L, Snowden E, Sher G, Kruger T. Embryo selection criteria based on morphology versus the expression of a biochemical marker (sHLA-G) and a graduated embryo score: prediction of pregnancy outcome. J Assist Reprod Genet 2010;27:309–16. Kotze D, Kruger TF, Lombrd C, Padayachee T, Keskintepe L, Sher G. The effect of the biochemical marker soluble human leukocyte antigen G on pregnancy outcome in assisted reproductive technology—a multicenter study. Fertil Steril 2013;100:1303–9.

VOL. 100 NO. 6 / DECEMBER 2013