Is National Institute of Clinical Excellence (NICE) guideline a nice guideline?

We read with interest the well written commentary by Dr. Potdar (1) in response to the practice recommendations by Agarwal et al. (2). Dr. Potdar correctly pointed out the limitations of semen analysis in predicting outcome of assisted reproductive technologies (ART) and the role of sperm DNA fragmentation (SDF) tests in guiding treatment decision. The author highlighted a list of important clinical questions concerning the clinical application of SDF and agreed that the practice recommendations have successfully addressed all of them (1). Here, we would like to respond with further discussion on: (I) recommendation against varicocele repair for infertility from National Institute of Clinical Excellence (NICE) guideline; (II) treatment strategies for high SDF; (III) concerns about risk of aneuploidy from testicular sperm; and (IV) aim of the practice recommendations.

Clinical practice varies among clinicians and localities. It is also true that management should be individualized for each infertile couple according to the unique scenario. However, guidelines are proposed to summarize the best scientific evidence available at a time spot in answering an important and well defined clinical question. The primary aim is to set a basic standard care deliverable to patients and discourage potentially ineffective interventions (3). When the clinical question of ‘does correction of varicocele improve pregnancy outcome?’ is put up and analyzed by using the same body of evidence, it is hard to believe that completely opposing opinions come out from different professional societies. The value of varicocelectomy in the management of subfertile male is endorsed by American Urological Association (AUA) (4), American Society of Reproductive Medicine (ASRM) (5) and European Association of Urology (EAU) (6). In addition, AUA also suggested clear-cut criteria for varicocele repair in the Best Practice Statement (4). The suggestion from the various authorities is based on meta-analyses by Ficarra et al. (7) and Marmar et al. (8). Both meta-analyses reported improvement in natural pregnancy after varicocelectomy by only including patients with clinical varicocele and abnormal semen parameters. The meta-analyses specifically addressed the pitfall of the systematic review by Evers et al. (9) by inclusion of subclinical varicocele and normal semen parameters leading to heterogeneity of studies included. In a subgroup analyses of five randomized controlled trials in the latest Cochrane Review comparing treatment to observation in men with clinical varicocele and abnormal semen parameter, repair of varicocele result in favourable outcome with a combined odds ratio of 2.39 (95% confidence interval, 1.56 to 3.66) (10). Unfortunately, NICE guideline based its recommendation largely on the systematic review by Evers et al. (9) published in 2001 without considering more recent and larger body of evidence supporting varicocelectomy as treatment for male subfertility. The systematic review by Evers et al. (9) was regarded as level 1a evidence without recognizing its methodological flaw. Meta-analysis and systematic review is merely an analytic tool to summarize the vast quantity of clinical data. Selection of good-quality data is of paramount importance to ensure generation of a reliable result. The inclusion of unfiltered heterogenous data will mask a significant outcome of a potentially beneficial treatment. It is the responsibility of fertility specialists in United Kingdom and worldwide to urge for a timely update on guidelines. The delivery of the best treatment to our patients should not be prohibited by an outdated guideline.

In addition to the use of antioxidants and testicular sperm in the treatment of high SDF, varicocele repair and sperm selection techniques represent the other major treatment strategies. A meta-analysis of six studies demonstrated a mean reduction of 3.37% in SDF after varicocelectomy (11). Sperm preparation technique including density gradient centrifugation has been attempted to isolate sperm populations with less SDF (12). However, there is concern that sperm from infertile patients with high SDF are more susceptible to further damage after processing (13). Hyaluronic acid binding method, sperm magnetic sorting and high magnification microscopy are among other proposed sperm selection techniques (14-16). Although the current techniques are still limited by the fact that none of them completely deselect sperm with DNA damage (17), the treatment effect of sperm selection based on motility and morphology with physiological intracytoplasmic injection and intracytoplasmic morphologically selected sperm injection has been revealed by a recent study (18).

The concern about risk of aneuploidy from testicular sperm is a valid one. In the study cited by Dr. Potdar, the incidence of mosaicism in embryo derived from testicular sperm extraction in men with non-obstructive azoospermia or oligozoospermia was significantly higher compared to embryos from intracytoplasmic sperm injection (ICSI) with ejaculated sperm (19). Another study that specifically addressed the aneuploidy rates in patients with high SDF may provide more relevant information to the concern: the aneuploidy rates between ejaculated and testicular spermatozoa in the same individual with persistently high SDF were reported. Although the aneuploidy rates is doubled in testicular sperm compared to ejaculated sperm (12.41% vs. 5.77%), SDF is reduced threefold (14.9% vs. 40.6%) (20). It is argued that the uncorrected high SDF would render natural pregnancy and intrauterine insemination unsuccessful. High SDF also negatively impacts pregnancy outcome after in vitro fertilization and ICSI with higher rates of pregnancy loss (21). The risk of genetic and birth defects of offsprings in ICSI candidates with high SDF cannot be eliminated without reducing level of SDF (21). A relatively small risk of aneuploidy by using testicular sperm in this group of patients may be justified by the substantial benefit offered by significant decrease in SDF, i.e., higher live birth rate (22).

Lastly, the practice recommendations proposed by Agarwal et al. (2) aim at transferring SDF test from laboratory bench to clinical practice. Cumulative experience and evidence from the last three decades on SDF tests were critically analyzed. The scenarios in the practice recommendations are considered appropriate to start the application of SDF testing clinically based on current best evidence. The practice recommendations serve as a kick-off and we contemplate wider clinical utilization of SDF testing with rapidly emerging data. We believe that the practice recommendations give food for thought not only for translational research, but also to clinicians alike. The panel brought together both researchers and clinicians and bridged the gap between laboratory and clinic. Nonetheless, research data must be translated to clinical practice before they will benefit patients. It is the high time to call for collaboration and effort among clinicians and researchers to further explore the potential of SDF testing.

Acknowledgements

None.

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

References

1. Potdar N. Application of sperm DNA fragmentation test in clinical setting. Transl Androl Urol 2017;6:S613-4.
2. Agarwal A, Majzoub A, Esteves SC, et al. Clinical utility of sperm DNA fragmentation testing: practice recommendations based on clinical scenarios. Transl Androl Urol 2016;5:935-50. [Crossref] [PubMed]
3. Esteves SC, Chan P. A systematic review of recent clinical practice guidelines and best practice statements for the evaluation of the infertile male. Int Urol Nephrol 2015;47:1441-56. [Crossref] [PubMed]
4. Jarow J, Sigman M, Kolettis PN, et al. The optimal evaluation of the infertile male: best practice statement reviewed and validity confirmed 2011. Available online: https://www.auanet.org/education/guidelines/male-infertility-d.cfm
5. Practice Committee of American Society for Reproductive Medicine. Diagnostic evaluation of the infertile male: a committee opinion. Fertil Steril 2015;103:e18-25. [Crossref] [PubMed]
6. Jungwirth A, Diemer T, Dohle GR, et al. EAU Guidelines of Male Infertility; 2015. Available online: http://uroweb.org/guideline/male-infertility/#5
7. Ficarra V, Cerruto MA, Liguori G, et al. Treatment of varicocele in subfertile men: The Cochrane review—a contrary opinion. Eur Urol 2006;49:258-63. [Crossref] [PubMed]
8. Marmar JL, Agarwal A, Prabakaran S, et al. Reassessing the value of varicocelectomy as a treatment for male subfertility with a new metaanalysis. Fertil Steril 2007;88:639-48. [Crossref] [PubMed]
9. Evers JL, Collins JA, Vandekerckhove P. Surgery or embolisation for varicocele in subfertile men. Cochrance Database Syst Rev 2001;(1):CD000479.
10. Kroese AC, de Lange NM, Collins J, et al. Surgery or embolization for varicoceles in subfertile men. Cochrane Database Syst Rev 2012;10:CD000479. [PubMed]
11. Wang YJ, Zhang RQ, Lin YJ, et al. Relationship between varicocele and sperm DNA damage and the effect of varicocele repair: a meta-analysis. Reprod Biomed Online 2012;25:307-14. [Crossref] [PubMed]
12. Sakkas D, Manicardi GC, Tomlinson M, et al. The use of two density gradient centrifugation techniques and the swim-up method to separate spermatozoa with chromatin and nuclear DNA anomalies. Hum Reprod 2000;15:1112-6. [Crossref] [PubMed]
13. Zini A, Nam RK, Mak V, et al. Influence of initial semen quality on the integrity of human sperm DNA following semen processing. Fertil Steril 2000;74:824-7. [Crossref] [PubMed]
14. Jakab A, Sakkas D, Delpiano E, et al. Intracytoplasmic sperm injection: a novel selection method for sperm with normal frequency of chromosomal aneuploidies. Fertil Steril 2005;84:1665-73. [Crossref] [PubMed]
15. Bucar S, Goncalves A, Rocha E, et al. DNA fragmentation in human sperm after magnetic-activated cell sorting. J Assist Reprod Genet 2015;32:147-54. [Crossref] [PubMed]
16. Berkovitz A, Eltes F, Yaari S, et al. The morphological normalcy of the sperm nucleus and pregnancy rate of intracytoplasmic injection with morphologically selected sperm. Hum Reprod 2005;20:185-90. [Crossref] [PubMed]
17. Celik-Ozenci C, Jakab A, Kovacs T, et al. Sperm selection for ICSI: shape properties do not predict the absence or presence of numerical chromosomal aberrations. Hum Reprod 2004;19:2052-9. [Crossref] [PubMed]
18. Bradley CK, McArthur SJ, Gee AJ, et al. Intervention improves assisted conception intracytoplasmic sperm injection outcomes for patients with high levels of sperm DNA fragmentation: a retrospective analysis. Andrology 2016;4:903-10. [Crossref] [PubMed]
19. Silber S, Escudero T, Lenahan K, et al. Chromosomal abnormalities in embryos derived from testicular sperm extraction. Fertil Steril 2003;79:30-8. [Crossref] [PubMed]
20. Moskovtsev SI, Alladin N, Lo KC, et al. A comparison of ejaculated and testicular spermatozoa aneuploidy rates in patients with high sperm DNA damage. Syst Biol Reprod Med 2012;58:142-8. [Crossref] [PubMed]
21. Agarwal A, Cho CL, Esteves SC. Should we evaluate and treat sperm DNA fragmentation? Curr Opin Obstet Gynecol 2016;28:164-71. [Crossref] [PubMed]
22. Esteves SC, Sánchez-Martín F, Sánchez-Martín P, et al. Comparison of reproductive outcome in oligozoospermic men with high sperm DNA fragmentation undergoing intracytoplasmic sperm injection with ejaculated and testicular sperm. Fertil Steril 2015;104:1398-405. [Crossref] [PubMed]