Die-off ratio correlates with increased TNF-α:IL-10 ratio and decreased IVF success rates correctable with humira

Am J Reprod Immunol. 2012 Nov;68(5):428-37. doi: 10.1111/j.1600-0897.2012.01179.x. Epub 2012 Jul 30.


Background: Human embryos develop at varying rates in culture, with only a fraction of the eggs retrieved developing to 'transfer quality' embryos. We investigated whether the ratios between the number of eggs retrieved or the number of pro-nucleate embryos formed and the number of Day 3 embryos with ≥5 cells [oocyte 'die-off ratios' (DOR)] were correlated with the chance of IVF success, independent of other factors such as embryo grade score and patient's age. We also investigated what factors may be correlated with this ratio.

Methods: 608 IVF fresh cycles in subfertile women were retrospectively evaluated. For each cycle, an oocyte DOR number was calculated as follows: Number of eggs retrieved divided by the number of Day 3 embryos with ≥5 cells. This number was correlated with the subsequent success rates for the index cycles. A 'post-fertilization' or 'embryo' die-off ratio (EDOR; the number of pro-nucleate embryos/the number of day 3 embryos ≥5 cells) was also calculated.

Results: The oocyte DOR showed a reverse linear correlation with IVF live birth rate. Live birth rate = (-5.75; DOR) +71.6 (with DOR > 1; P ≤ 0.005; R = -0.87). In addition, the oocyte DOR continued to show an inverse correlation with success rates even when embryo quality and patient's age were held constant. The post-fertilization or EDOR also continued to show a statistically significant negative correlation with live birth rate (R = -0.91; P ≤ 0.01). The preconception TNF-α:IL-10 ratio, an immmunologic marker (drawn 3.3 ± 2.6 months preconception), was more strongly correlated with high oocyte DOR than either age or number of eggs retrieved (P = 0.04, 0.14, 0.72, respectively). When anti-TNF-α therapy (Humira) was given preconception, the oocyte DOR's negative effect on live birth rate was nearly eliminated (correlation coefficient between oocyte DOR and live birth rate: cycles using no Humira, R = -0.90, P ≤ 0.006; cycles using Humira, R = 0.25, P ≤ 0.55).

Conclusions: In subfertile women undergoing IVF, the oocyte DOR may help predict IVF success rates. This factor may offer an additional tool to help improve implantation rate, clinical pregnancy rate, live birth rate, and live birth rate per embryo transferred for an upcoming IVF cycle. Although many mechanisms may contribute to the oocyte DOR's negative effect on IVF success rates, its correlation with elevated preconception TNF-α:IL-10 ratio and correction with Humira suggests a strong immunologic component that may be treatable.

MeSH terms

  • Adalimumab
  • Adult
  • Antibodies, Monoclonal, Humanized / administration & dosage*
  • Antibodies, Monoclonal, Humanized / therapeutic use
  • Birth Rate
  • Embryo Implantation
  • Embryo Transfer
  • Female
  • Fertilization in Vitro / methods*
  • Humans
  • Interleukin-10 / metabolism*
  • Live Birth
  • Male
  • Oocyte Retrieval
  • Oocytes / physiology*
  • Pregnancy
  • Pregnancy Rate*
  • Tumor Necrosis Factor-alpha / metabolism*


  • Antibodies, Monoclonal, Humanized
  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • Adalimumab