Sperm DNA fragmentation and idiopathic recurrent pregnancy loss: Results from a multicenter case-control study

Background: Sperm DNA fragmentation was hypothesized to have a role in the pathogenesis of recurrent pregnancy loss. Unfortunately, the quality of already published evidence is low.

Objectives: To investigate the association between sperm DNA fragmentation and idiopathic recurrent pregnancy loss by limiting, as much as possible, the interference of confounding factors.

Materials and methods: This was a retrospective multicenter case-control study conducted in two Italian University Hospitals (i.e., Policlinico Gemelli, Rome and Humanitas S. Pio X, Milan) from July 2020 to March 2022. Cases were men belonging to couples affected by first trimester idiopathic recurrent pregnancy loss, defined as the previous loss of two or more pregnancies. Two control groups were selected: (i) men belonging to couples with proven fertility (i.e., at least two previous full-term pregnancies) (control group A); (ii) men belonging to couples with proven infertility (i.e., the failure to achieve a pregnancy after 12 months or more of regular unprotected sexual intercourse) (control group B). The sperm DNA fragmentation index was measured by the terminal deoxynucleotidyl transferase dUTP nick end labeling assay.

Results: We included 74 cases, 37 men with proven fertility (control group A) and 100 men belonging to infertile couples (control group B). The median sperm DNA fragmentation index was significantly lower in control group A (17%, interquartile range: 14.3%-20.6%) compared to both case group (24.5%, interquartile range: 17%-32%; p < 0.0001) and control group B (24%, interquartile range: 18.9%-30%; p = 0.001). The rate of subjects with sperm DNA fragmentation index greater than 30% was significantly higher in both case groups (28%, 95% confidence interval [18%-40%]) and control group B (26%, 95% confidence interval [18%, 36%]) compared to control group A (0%, 95% confidence interval [0%-10%]) (p < 0.001). Multivariate regression models yielded a significant association between sperm DNA fragmentation index and recurrent pregnancy loss (adjusted odds ratio 1.13, 95% confidence interval [1.04-1.23], p = 0.006), but failed to show an association between sperm DNA fragmentation index and infertility (adjusted odds ratio 1.13, 95% CI [1-1.29], p = 0.05).

Conclusions: Men within couples affected by recurrent pregnancy loss or infertility had a significantly higher rate of sperm DNA fragmentation compared to fertile controls. However, after adjusting for covariates, sperm DNA fragmentation index was associated only with recurrent pregnancy loss.