Sperm DNA fragmentation to predict embryo development, implantation and miscarriage: still an open question


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Volume 112, Issue 3, Page 466


Laura Rienzi, B.Sc., M.Sc.a, Rossella Mazzilli, M.D.a,b, Filippo Maria Ubaldi, MDa


Reflections on "Sperm DNA fragmentation is correlated with poor embryo development, lower implantation rate and higher miscarriage rate in reproductive cycles of non-male factor infertility" by Borges et al.

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Fertility and Sterility

Editorial Office, American Society for Reproductive Medicine

Fertility and Sterility® is an international journal for obstetricians, gynecologists, reproductive endocrinologists, urologists, basic scientists and others who treat and investigate problems of infertility and human reproductive disorders. The journal publishes juried original scientific articles in clinical and laboratory research relevant to reproductive endocrinology, urology, andrology, physiology, immunology, genetics, contraception, and menopause. Fertility and Sterility® encourages and supports meaningful basic and clinical research, and facilitates and promotes excellence in professional education, in the field of reproductive medicine.


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EDSON BORGES JR about 1 year ago

Re: Sperm DNA fragmentation to predict embryo development, implantation and miscarriage: still an open question


Edson Borges Jr., Ph.D1, Daniela Paes de Almeida Ferreira Braga, Ph.D1, Amanda Souza Setti, M.Sc1.

1Fertility Medical Group, Sao Paulo – SP, Brazil.


Because basic semen analysis isn’t enough to predict male fertility potential, focus has long shifted toward studying the molecular aspects of spermatozoa. The sperm chromatin structure is now being intensively analyzed since it is essential for the outcomes of fertilization, embryo development, and pregnancy (1).
Of many points highlighted by Prof. Rienzi, we want to expand the discussion on some topics:
-         SCD inter-observer variability - Despite the SCD (Halo test) is subject to inter-observer variability that might interfere with the results, it is important to highlight that, when the analysis is performed by a single operator, inter-observer variability is ruled-out. Additionally, and intra-observer variability is drastically reduced by operator expertise. In our study, there was a single operator analyzing SCD samples, who is a highly trained and experienced andrologist. In addition, a meta-analysis demonstrated that sperm DNA damage compromises pregnancy rates regardless of the assay used (TUNEL, Comet, or SCD) (2).
-         Sperm DNA fragmentation index (DFI) threshold – To date, the threshold value for DFI and its clinical significance is not clear. In fact, the lack of a cut-off value for SDF assays is the main factor hindering the wider clinical application of the test. In our study, we applied the clinically established Sperm Chromatin Structure Assay (SCSA) threshold value. However, as (3) previously stated “a single magic test with a clear cut-off in the context of the complex human reproductive system is probably an oversimplification”. Infertility is a multifactorial illness that enrolls both male and female factors and, therefore, cannot be precisely evaluated by a single laboratory test on one of the partners. It is also important to realize the predictive value of SDF testing on reproductive outcomes regardless of the inconsistency in reported cut-off values. For that reasons, the prerogative to discourage SDF testing clinical application seems unconvincing.
-         Prolonged oocyte incubation - Oocyte developmental competence relies on the achievement of both nuclear and cytoplasmatic maturation. Cytoplasmatic maturation involves an extensive reorganization of organelles, and, to date, is impossible to assess non-invasively. Most articles are concordant that a pre-incubation time before ICSI is beneficial on ICSI outcomes; however, the data regarding the extension of the pre-incubation time are not concordant (4). Previous studies demonstrated that performing ICSI 6 h after oocyte retrieval may have positive effects on the rates of embryo quality and clinical pregnancy (5). Nevertheless, regardless of the interval between hCG trigger and oocyte retrieval, and the interval between oocyte retrieval and ICSI, we always respect an interval of 40h between hCG trigger and ICSI.  Shorter intervals have been related to poorer outcomes, compared with 38– 42 h (6).
-         Further prospective investigations to outline the predictivity of SDF tests - We are in agreement that further prospective investigations are still needed to outline the predictive value of SDF tests in the absence of male factor infertility. We also follow the guidelines of the Practice Committee of the American Society for Reproductive Medicine. However, there is evidence supporting the use of SDF testing in specific clinical scenarios, including varicocelectomy, couples with recurrent pregnancy loss, unexplained infertility, previous IVF failure, and infertile men exposed to lifestyle risk factors (7). Results from well-designed meta-analysis confirm that sperm DNA damage is negatively associated with pregnancy outcomes. Simonet al. (2) showed a strong detrimental effect of sperm DNA damage on clinical pregnancy outcome. Robinson et al. (8) observed that miscarriage rates are positively correlated with sperm DNA damage levels. Finally, Osman et al. (9) demonstrated that high sperm DNA fragmentation is associated with lower live birth rates in couples undergoing assisted reproduction techniques.
In view of the facts here presented, we believe that assays for the detection of sperm DNA damage could be considered in the aforementioned specific clinical scenarios. Moreover, we suggest (i) the use of methods which select sperm without DNA damage such as density gradient centrifugation, electrophoretic sperm isolation, hyaluronic acid-binding method, sperm magnetic sorting, and high-magnification microscopy (10), (ii) oral antioxidant therapy in men presenting with high reactive oxygen species levels (11), (iii) lower ejaculatory abstinence lengths (12), and (iv) abstinence from cigarette smoking and alcohol consumption (13), in order to decrease DNA damage in sperm for use in IVF treatment.



1.            Ward WS. Function of sperm chromatin structural elements in fertilization and development. Mol Hum Reprod 2010;16:30-6.

2.            Simon L, Zini A, Dyachenko A, Ciampi A, Carrell DT. A systematic review and meta-analysis to determine the effect of sperm DNA damage on in vitro fertilization and intracytoplasmic sperm injection outcome. Asian journal of andrology 2017;19:80-90.

3.            Cho CL, Agarwal A, Majzoub A, Esteves SC. A single cut-off value of sperm DNA fragmentation testing does not fit all. Transl Androl Urol 2017;6:S501-S3.

4.            Rubino P, Vigano P, Luddi A, Piomboni P. The ICSI procedure from past to future: a systematic review of the more controversial aspects. Hum Reprod Update 2016;22:194-227.

5.            Falcone P, Gambera L, Pisoni M, Lofiego V, De Leo V, Mencaglia L, et al. Correlation between oocyte preincubation time and pregnancy rate after intracytoplasmic sperm injection. Gynecol Endocrinol 2008;24:295-9.

6.            Cohen Y, Malcov M, Schwartz T, Mey-Raz N, Carmon A, Cohen T, et al. Spindle imaging: a new marker for optimal timing of ICSI? Hum Reprod 2004;19:649-54.

7.            Agarwal A, Majzoub A, Esteves SC, Ko E, Ramasamy R, Zini A. Clinical utility of sperm DNA fragmentation testing: practice recommendations based on clinical scenarios. Transl Androl Urol 2016;5:935-50.

8.            Robinson L, Gallos Id Fau - Conner SJ, Conner Sj Fau - Rajkhowa M, Rajkhowa M Fau - Miller D, Miller D Fau - Lewis S, Lewis S Fau - Kirkman-Brown J, et al. The effect of sperm DNA fragmentation on miscarriage rates: a systematic review and meta-analysis. Hum Reprod 2012;27:2908-17.

9.            Osman A, Alsomait H, Seshadri S, El-Toukhy T, Khalaf Y. The effect of sperm DNA fragmentation on live birth rate after IVF or ICSI: a systematic review and meta-analysis. Reproductive BioMedicine Online 2015;30:120-7.

10.          Sakkas D. Novel technologies for selecting the best sperm for in vitro fertilization and intracytoplasmic sperm injection. Fertility and Sterility 2013;99:1023-9.

11.          Imamovic Kumalic S, Pinter B. Review of clinical trials on effects of oral antioxidants on basic semen and other parameters in idiopathic oligoasthenoteratozoospermia. BioMed research international 2014;2014:426951-.

12.          Borges E, Jr., Braga D, Zanetti BF, Iaconelli A, Jr., Setti AS. Revisiting the impact of ejaculatory abstinence on semen quality and intracytoplasmic sperm injection outcomes. Andrology 2019;7:213-9.

13.          Borges E, Jr., Braga D, Provenza RR, Figueira RCS, Iaconelli A, Jr., Setti AS. Paternal lifestyle factors in relation to semen quality and in vitro reproductive outcomes. Andrologia 2018;50:e13090.