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Blastocysts with disproportionally high mtDNA copy number can result in healthy babies

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      Introduction

      Mitochondrial DNA (mtDNA) copy number has been proposed as a biomarker of implantation in IVF embryos. Some studies suggest that blastocysts containing disproportionately elevated levels of mtDNA per cell always fail to implant, and blastocysts implanting successfully have lower mtDNA levels on average (
      • Fragouli E.
      • Spath K.
      • Alfarawati S.
      • et al.
      Altered levels of mitochondrial DNA are associated with female age, aneuploidy, and provide an independent measure of embryonic implantation potential.
      ,
      • Diez-Juan A.
      • Rubio C.
      • Marin
      • et al.
      Mitochondrial DNA content as a viability score in human euploid embryos: less is better.
      ). Other studies do not report such a trend, including one from our group (
      • Treff N.R.
      • Zhan Y.
      • Tao X.
      • et al.
      Levels of trophectoderm mitochondrial DNA do not predict the reproductive potential of sibling embryos.
      ,
      • Victor A.R.
      • Brake A.J.
      • Tyndall
      • et al.
      Accurate quantitation of mitochondrial DNA reveals uniform levels in human blastocysts irrespective of ploidy, age, or implantation potential.
      ). An explanation for the conflicting reports couldbe that the method for quantitation of mtDNA copy number varies across studies. As a result, technicalguidelines have been proposed to increase uniformity of mtDNA quantitation (
      • Wells D.
      Mitochondrial DNA quantity as a biomarker for blastocyst implantation potential.
      ). Here, weadhere to those guidelines in analyzing mtDNA copy number in a large number of blastocysts used fortransfer, to determine whether it is a valid predictor of implantation.

      Materials & Methods

      We quantified mtDNA levels in surplus product of the PGT-A process from blastocysts used in IVF withknown outcomes. In order to satisfy the suggested guidelines for mtDNA quantitation, we used qPCRmeasuring a locus in the mtDNA sequence and a multicopy locus in the nuclear DNA sequence, andcomputed the ratio between the two values. All molecular material was fresh and devoid of degradation.

      Results

      In our hands, unlike in previous reports, blastocysts with extremely high mtDNA levels successfully implanted and led to healthy births. If using mtDNA copy number to deselect embryos, these samples would not have been chosen for transfer. In addition, analysis of >100 blastocysts showed a statistically insignificant difference between mtDNA levels in implanted versus non-implanted blastocysts.

      Conclusions

      These findings suggest that in a single-clinic setting, measurement of mtDNA copy number might not provide any advantage to embryo ranking, and might even lead to de-selection of blastocysts that result to healthy pregnancies. The validity of measurement of mtDNA copy number requires further investigation, given different findings in individual centers.

      Keywords

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      References

        • Diez-Juan A.
        • Rubio C.
        • Marin
        • et al.
        Mitochondrial DNA content as a viability score in human euploid embryos: less is better.
        Fertil Steril. 2015; 104: 534-541
        • Fragouli E.
        • Spath K.
        • Alfarawati S.
        • et al.
        Altered levels of mitochondrial DNA are associated with female age, aneuploidy, and provide an independent measure of embryonic implantation potential.
        PLoS Genet. 2015; 11e1005241
        • Treff N.R.
        • Zhan Y.
        • Tao X.
        • et al.
        Levels of trophectoderm mitochondrial DNA do not predict the reproductive potential of sibling embryos.
        Hum Reprod. 2017; 32: 954-962
        • Victor A.R.
        • Brake A.J.
        • Tyndall
        • et al.
        Accurate quantitation of mitochondrial DNA reveals uniform levels in human blastocysts irrespective of ploidy, age, or implantation potential.
        Fertil Steril. 2017; 107: 34-42
        • Wells D.
        Mitochondrial DNA quantity as a biomarker for blastocyst implantation potential.
        Fertil Steril. 2017 Nov; 108: 742-747