{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T21:30:28Z","timestamp":1778707828154,"version":"3.51.4"},"reference-count":46,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,12,20]],"date-time":"2022-12-20T00:00:00Z","timestamp":1671494400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fonds voor Wetenschappelijk Onderzoek (FWO), Research Foundation Flanders","award":["TBMT007016N"],"award-info":[{"award-number":["TBMT007016N"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Background: Sperm DNA fragmentation has been proposed as a candidate test for the assessment of sperm function on the premise that damage to the sperm chromatin is associated with a detrimental reproductive outcome. The objective of our study was to investigate whether sperm DNA fragmentation testing has a prognostic value, and thus can play a pivotal role in selecting future patients for intra-uterine insemination (IUI) therapy. Methods: This was a prospective cohort study conducted in a University Hospital setting. SDF was measured through TUNEL assay on the fresh semen sample presented at diagnosis and at insemination in couples with idiopathic\/mild male infertility undergoing natural cycle IUI treatment. The generalized estimating equation (GEE)-model and multivariable model were used to analyze the probability of live birth and clinical pregnancy, respectively. ROC analysis was carried out to determine an SDF cut-off. Results: There was an inverse relationship between SDF in the ejaculate of the diagnostic semen sample and CP (p = 0.02; OR 0.94 95% CI (0.90, 0.989)) as well as LB (p = 0.04; OR 0.95 95% CI (0.90, 0.9985)). No significant association was found between SDF after gradient and IUI outcome in the diagnostic sample nor between SDF (ejaculate\/after gradient) in the IUI samples. The ROC analysis proposed a cutoff of 17.5% as the best compromise between sensitivity and specificity in the diagnostic SDF for live birth; however, the test diagnostics are low, with an AUC of 0.576. Conclusions: Overall, this study strengthens the hypothesis of an inverse relationship between SDF and CP\/LB. Furthermore, SDF taken together with other clinical characteristics might provide more insight into male reproductive potential and predicting IUI outcome. Couples with SDF \u2265 17.5% in the diagnostic semen sample did not reach live birth. Further research is necessary to establish the diagnostic and prognostic potential of SDF as an add-on test.<\/jats:p>","DOI":"10.3390\/life13010011","type":"journal-article","created":{"date-parts":[[2022,12,21]],"date-time":"2022-12-21T01:32:53Z","timestamp":1671586373000},"page":"11","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Is There a Relationship between Sperm DNA Fragmentation and Intra-Uterine Insemination Outcome in Couples with Unexplained or Mild Male Infertility? Results from the ID-Trial"],"prefix":"10.3390","volume":"13","author":[{"given":"Alessa","family":"Sugihara","sequence":"first","affiliation":[{"name":"Centre for Reproductive Medicine, Algemeen Ziekenhuis Klina, 2930 Brasschaat, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9675-2511","authenticated-orcid":false,"given":"Usha","family":"Punjabi","sequence":"additional","affiliation":[{"name":"Centre for Reproductive Medicine, Antwerp University Hospital, 2650 Edegem, Belgium"},{"name":"Department of Reproductive Medicine, Antwerp Surgical Training, Anatomy and Research Centre (ASTARC), Faculty of Medicine and Health Sciences, University of Antwerp, 2000 Antwerp, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ella","family":"Roelant","sequence":"additional","affiliation":[{"name":"Clinical Trial Centre (CTC), CRC Antwerp, Antwerp University Hospital, University of Antwerp, Drie Eikenstraat 655, 2650 Edegem, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9159-5083","authenticated-orcid":false,"given":"Diane","family":"De Neubourg","sequence":"additional","affiliation":[{"name":"Centre for Reproductive Medicine, Antwerp University Hospital, 2650 Edegem, Belgium"},{"name":"Department of Reproductive Medicine, Antwerp Surgical Training, Anatomy and Research Centre (ASTARC), Faculty of Medicine and Health Sciences, University of Antwerp, 2000 Antwerp, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1016\/j.fertnstert.2010.02.024","article-title":"Role of semen analysis in subfertile couples","volume":"95","author":"Steures","year":"2011","journal-title":"Fertil. Steril."},{"key":"ref_2","unstructured":"World Health Organization (2010). WHO Laboratory Manual for the Examination and Processing of Human Semen, WHO."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.urology.2011.08.003","article-title":"Critical appraisal of World Health Organization\u2019s new reference values for human semen characteristics and effect on diagnosis and treatment of subfertile men","volume":"79","author":"Esteves","year":"2012","journal-title":"Urology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/S0015-0282(99)00462-8","article-title":"Sperm chromatin damage impairs human fertility. The Danish First Pregnancy Planner Study Team","volume":"73","author":"Bonde","year":"2000","journal-title":"Fertil. Steril."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"S761","DOI":"10.21037\/tau.2017.09.13","article-title":"DNA damage in human spermatozoa; Important contributor to mutagenesis in the offspring","volume":"6","author":"Aitken","year":"2017","journal-title":"Transl. Androl. Urol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e221","DOI":"10.1111\/j.1365-2605.2009.00995.x","article-title":"Sperm chromatin structure assay as an independent predictor of fertility in vivo: A case\u2013control study","volume":"33","author":"Giwercman","year":"2010","journal-title":"Int. J. Androl."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2908","DOI":"10.1093\/humrep\/des261","article-title":"The effect of sperm DNA fragmentation on miscarriage rates: A systematic review and meta-analysis","volume":"27","author":"Robinson","year":"2012","journal-title":"Hum. Reprod."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.ejogrb.2019.10.005","article-title":"The role of sperm DNA fragmentation testing in predicting intra-uterine insemination outcome: A systematic review and meta-analysis","volume":"244","author":"Sugihara","year":"2020","journal-title":"Eur. J. Obs. Gynecol. Reprod. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1093\/humrep\/14.4.1039","article-title":"Utility of the sperm chromatin structure assay as a diagnostic and prognostic tool in the human fertility clinic","volume":"14","author":"Evenson","year":"1999","journal-title":"Hum. Reprod."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1016\/j.fertnstert.2015.11.037","article-title":"Sperm DNA fragmentation and mitochondrial membrane potential combined are better for predicting natural conception than standard sperm parameters","volume":"105","author":"Golob","year":"2016","journal-title":"Fertil. Steril."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.clinbiochem.2018.05.011","article-title":"Sperm DNA fragmentation in the total and vital fractions before and after density gradient centrifugation: Significance in male fertility diagnosis","volume":"62","author":"Punjabi","year":"2018","journal-title":"Clin. Biochem."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Cissen, M., Wely, M.V., Scholten, I., Mansell, S., Bruin, J.P., Mol, B.W., Braat, D., Repping, S., and Hamer, G. (2016). Measuring Sperm DNA Fragmentation and Clinical Outcomes of Medically Assisted Reproduction: A Systematic Review and Meta-Analysis. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0165125"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"80","DOI":"10.4103\/1008-682X.182822","article-title":"A systematic review and meta-analysis to determine the effect of sperm DNA damage on in vitro fertilization and intracytoplasmic sperm injection outcome","volume":"19","author":"Simon","year":"2017","journal-title":"Asian J. Androl."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"998","DOI":"10.1016\/j.fertnstert.2014.06.033","article-title":"Whether sperm deoxyribonucleic acid fragmentation has an effect on pregnancy and miscarriage after in vitro fertilization\/intracytoplasmic sperm injection: A systematic review and meta-analysis","volume":"102","author":"Zhao","year":"2014","journal-title":"Fertil. Steril."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2663","DOI":"10.1093\/humrep\/den321","article-title":"Sperm DNA damage is associated with an increased risk of pregnancy loss after IVF and ICSI: Systematic review and meta-analysis","volume":"23","author":"Zini","year":"2008","journal-title":"Hum. Reprod."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1007\/s10815-006-9066-9","article-title":"Correlation of sperm DNA damage with IVF and ICSI outcomes: A systematic review and meta-analysis","volume":"23","author":"Li","year":"2006","journal-title":"J. Assist. Reprod. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1915","DOI":"10.1093\/humrep\/dez151","article-title":"Novel use of COMET parameters of sperm DNA damage may increase its utility to diagnose male infertility and predict live births following both IVF and ICSI","volume":"34","author":"Nicopoullos","year":"2019","journal-title":"Hum. Reprod."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1398","DOI":"10.1016\/j.fertnstert.2015.08.028","article-title":"Comparison of reproductive outcome in oligozoospermic men with high sperm DNA fragmentation undergoing intracytoplasmic sperm injection with ejaculated and testicular sperm","volume":"104","author":"Esteves","year":"2015","journal-title":"Fertil. Steril."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1093\/humrep\/deh590","article-title":"Efficient treatment of infertility due to sperm DNA damage by ICSI with testicular spermatozoa","volume":"20","author":"Greco","year":"2005","journal-title":"Hum. Reprod."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Arafa, M., AlMalki, A., AlBadr, M., Burjaq, H., Majzoub, A., AlSaid, S., and Elbardisi, H. (2018). ICSI outcome in patients with high DNA fragmentation: Testicular versus ejaculated spermatozoa. Andrologia, 50.","DOI":"10.1111\/and.12835"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"412","DOI":"10.5534\/wjmh.200128","article-title":"Sperm DNA Fragmentation: A New Guideline for Clinicians","volume":"38","author":"Agarwal","year":"2020","journal-title":"World J. Men\u2019s Health"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1093\/humupd\/dmx041","article-title":"IUI: Review and systematic assessment of the evidence that supports global recommendations","volume":"24","author":"Cohlen","year":"2018","journal-title":"Hum. Reprod. Update"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Ayeleke, R.O., Asseler, J.D., Cohlen, B.J., and Veltman-Verhulst, S.M. (2020). Intra-uterine insemination for unexplained subfertility. Cochrane Database Syst. Rev., 3.","DOI":"10.1002\/14651858.CD001838.pub6"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"78","DOI":"10.3109\/19396368.2010.515704","article-title":"Are sperm chromatin and DNA defects relevant in the clinic?","volume":"57","author":"Zini","year":"2011","journal-title":"Syst. Biol. Reprod. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1093\/humrep\/del326","article-title":"Sperm DNA integrity assessment in prediction of assisted reproduction technology outcome","volume":"22","author":"Bungum","year":"2007","journal-title":"Hum. Reprod."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3122","DOI":"10.1093\/humrep\/17.12.3122","article-title":"Sperm DNA quality predicts intrauterine insemination outcome: A prospective cohort study","volume":"17","author":"Duran","year":"2002","journal-title":"Hum. Reprod."},{"key":"ref_27","first-page":"977","article-title":"[Sperm chromatin structure assay predicts the outcome of intrauterine insemination]","volume":"17","author":"Yang","year":"2011","journal-title":"Zhonghua Nan Ke Xue"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1093\/humrep\/dei403","article-title":"Value of the sperm chromatin dispersion test in predicting pregnancy outcome in intrauterine insemination: A blind prospective study","volume":"21","author":"Muriel","year":"2005","journal-title":"Hum. Reprod."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1093\/humupd\/dms031","article-title":"Why do patients discontinue fertility treatment? A systematic review of reasons and predictors of discontinuation in fertility treatment","volume":"18","author":"Gameiro","year":"2012","journal-title":"Hum. Reprod. Update"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1016\/j.fertnstert.2010.11.026","article-title":"Costs of infertility treatment: Results from an 18-month prospective cohort study","volume":"95","author":"Katz","year":"2011","journal-title":"Fertil. Steril."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1055\/s-0031-1287662","article-title":"The FIGO recommendations on terminologies and definitions for normal and abnormal uterine bleeding","volume":"29","author":"Fraser","year":"2011","journal-title":"Semin. Reprod. Med."},{"key":"ref_32","unstructured":"(2022, November 20). Belgian Register for Assisted Procreation (BELRAP). Available online: www.belrap.be."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1136\/bmj.39335.541782.AD","article-title":"Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: Guidelines for reporting observational studies","volume":"335","author":"Altman","year":"2007","journal-title":"BMJ"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Punjabi, U., De Neubourg, D., Van Mulders, H., Cassauwers, W., and Peeters, K. (2018). Validating semen processing for an intrauterine program should take into consideration the inputs, actions and the outputs of the process. Andrologia, 50.","DOI":"10.1111\/and.12977"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/j.fertnstert.2017.06.005","article-title":"The International Glossary on Infertility and Fertility Care, 2017","volume":"108","author":"Adamson","year":"2017","journal-title":"Fertil. Steril."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1007\/s10815-019-01476-z","article-title":"DNA fragmentation in concert with the simultaneous assessment of cell viability in a subfertile population: Establishing thresholds of normality both before and after density gradient centrifugation","volume":"36","author":"Punjabi","year":"2019","journal-title":"J. Assist. Reprod. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1016\/j.fertnstert.2010.08.019","article-title":"Sperm DNA damage measured by the alkaline Comet assay as an independent predictor of male infertility and in vitro fertilization success","volume":"95","author":"Simon","year":"2011","journal-title":"Fertil. Steril."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.fertnstert.2008.09.038","article-title":"Effects of cryopreservation on human sperm deoxyribonucleic acid integrity","volume":"93","author":"Zribi","year":"2010","journal-title":"Fertil. Steril."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/j.fertnstert.2006.01.047","article-title":"Effect of cryopreservation on sperm apoptotic deoxyribonucleic acid fragmentation in patients with oligozoospermia","volume":"86","author":"Bertolla","year":"2006","journal-title":"Fertil. Steril."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/j.rbmo.2017.01.016","article-title":"Predictive value of different covariates influencing pregnancy rate following intrauterine insemination with homologous semen: A prospective cohort study","volume":"34","author":"Thijssen","year":"2017","journal-title":"Reprod. Biomed. Online"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Rex, A.S., Wu, C., Aagaard, J., and Fedder, J. (2021). DNA Fragmentation in Human Spermatozoa and Pregnancy Rates after Intrauterine Insemination. Should the DFI Threshold Be Lowered?. J. Clin. Med., 10.","DOI":"10.3390\/jcm10061310"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Zhu, C., Zhang, S., Chen, F., She, H., Ju, Y., Wen, X., Ji, Y., Pan, Y., Yang, C., and Sun, Y. (2022). Correlations between elevated basal sperm DNA fragmentation and the clinical outcomes in women undergoing IUI. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.987812"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1016\/S1472-6483(10)62000-7","article-title":"Meta-analysis of sperm DNA fragmentation using the sperm chromatin structure assay","volume":"12","author":"Evenson","year":"2006","journal-title":"Reprod. Biomed. Online"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1016\/j.fertnstert.2007.04.055","article-title":"Do sperm DNA integrity tests predict pregnancy with in vitro fertilization?","volume":"89","author":"Collins","year":"2008","journal-title":"Fertil. Steril."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Punjabi, U., Roelant, E., Peeters, K., Goovaerts, I., Van Mulders, H., and De Neubourg, D. (2022). Variability in Sperm DNA Fragmentation in Men with Mild\/Unexplained Subfertility in a Prospective Longitudinal Intrauterine Insemination Trial. Life, 12.","DOI":"10.3390\/life12111826"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1111\/j.1365-2605.2006.00710.x","article-title":"Clinical correlates of the biological variation of sperm DNA fragmentation in infertile men attending an andrology outpatient clinic","volume":"30","author":"Smit","year":"2007","journal-title":"Int. J. Androl."}],"container-title":["Life"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-1729\/13\/1\/11\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:45:00Z","timestamp":1760147100000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-1729\/13\/1\/11"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,20]]},"references-count":46,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,1]]}},"alternative-id":["life13010011"],"URL":"https:\/\/doi.org\/10.3390\/life13010011","relation":{},"ISSN":["2075-1729"],"issn-type":[{"value":"2075-1729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,20]]}}}