What DNA Fragmentation May Tell Us About Recurrent Miscarriage

Sperm DNA Fragmentation in Italian Couples With Recurrent Pregnancy Loss

Carlini T, Paoli D, Faja F, et al
Reprod Biomed Online. 2017;34:58-65

Background

Approximately 20% of clinical pregnancies are lost. Most losses are due to random genetic defects and are not recurrent, but 3%-5% of them are and require an evaluation.^[1,2] Traditionally, the evaluation has focused on the female partner.^[2] Except for a karyotype analysis, the male partner has not been extensively studied despite the fact that the sperm also contributes to the genetic composition of the embryo. In recent years, tests became available that assess the degree of DNA fragmentation in sperm and have been used to study its impact on various aspects of reproduction.^[3,4] Carlini and colleagues' study evaluated the degree of DNA fragmentation in men in couples with recurrent miscarriages, as compared with infertile and fertile men.

Summary

The study included 112 men from couples with recurrent pregnancy loss, defined as two or more losses. For each participant, genetic, immunologic, hematologic, anatomic, and endocrine testing was carried out, with negative results. Two control groups were recruited: 114 men with abnormal semen parameters and 114 fertile men.

The TUNEL assay was used to assess DNA fragmentation. The mean value of DNA fragmentation was 12.8% in fertile men; this was used as a cut-off for low and high values.

The semen volume was lower in recurrent pregnancy loss patients when compared with fertile men, but sperm count, motility, and morphology did not differ. Sperm count, motility, and morphology parameters, however, were significantly lower in infertile men when compared with the other two groups.

The mean DNA fragmentation values were significantly higher in men with recurrent pregnancy loss (18.8%) and infertile men (20.8%) when compared with fertile men (12.8%). Those with more miscarriages (46 vs 2-3) had slightly higher mean DNA fragmentation values (20.3% vs 17.7%,) but the difference did not reach statistical significance.

Over 80% of men affected by recurrent pregnancy loss and infertile men had DNA fragmentation values over 12.8%, while only 44% of healthy controls did.

The authors concluded that the high DNA fragmentation values suggest a potential pathomechanism for recurrent pregnancy loss. They also noted, however, that the test is not predictive of recurrent pregnancy loss, as almost half of the fertile men also had high values.

Viewpoint

Recurrent pregnancy loss is a relatively infrequent clinical problem but when present poses a significant diagnostic and therapeutic dilemma. Even after a thorough evaluation, about half of couples will be left without an explanation and often end up trying experimental treatments. Further research is needed to explore other causes.

Evaluation in men typically is limited to a karyotype analysis. If an abnormal karyotype is found, a clinician may offer IVF using preimplantation genetic diagnosis. A normal karyotype, however, does not exclude problems of genetic origin on the male side. Genetic and epigenetic alterations do have an impact of embryonic development and pregnancy outcome.

Various tests can be used to assess the degree of sperm DNA fragmentation. All tests work slightly differently and their results are hard to compare. This is one of the reasons why the literature on the reproductive impact of DNA fragmentation is controversial.^[4]

A 2008 meta-analysis by Zini and colleagues^[5] reported a 2.5-fold increased risk for pregnancy loss with high DNA fragmentation. According to this study, in couples with recurrent pregnancy loss, additional testing of the semen may prove to be useful. Oxidative stress, older age, varicocele, genital tract infections, toxins, and environmental effects may all be responsible for a higher DNA fragmentation value.^[5] If such values are obtained during the workup, another potential cause could be addressed by lifestyle changes, medical therapy, or surgical therapy and could prove to be useful in the management of unexplained recurrent pregnancy loss.

Abstract

Comments

Commenting is limited to medical professionals. To comment please Log-in.

Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.