**9. Male factors**

There is a growing acceptance of male etiological factors for RPL. Its screening consists of detailed sperm analysis. Excessive sperm DNA fragmentation is an important constraint to conception. Two meta-analyses have shown the association of gestational losses with high rates of sperm DNA fragmentation [63, 64]. The available tests for sperm DNA fragmentation index are the sperm chromatin structure assay (SCSA), the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL), the Sperm Chromatin Dispersion test, and the comet assay.

Some clinical conditions are related to increased fragmentation of sperm DNA. High seminal plasma leukocyte concentration, systemic infections, varicocele, and smoking, among others, were related to spermatic DNA damage [65]. A Cochrane meta-analysis suggests that the use of antioxidants, including vitamins C and E, may have benefits for subfertile men with no apparent cause, improving sperm DNA fragmentation [66]. The generally recommended dose is 1 gram of vitamin C and 1000 IU of vitamin E per day for at least 2 months [67]. However, this effect is not yet established in patients with RPL. ESHRE determines that sperm DNA fragmentation research should be considered for explanatory purposes for RPL [2].

For intracytoplasmic sperm injection (ICSI)-indicated couples, laboratory techniques may be performed to select sperm with lower DNA fragmentation rate, such as physiological intracytoplasmic sperm injection (PICSI) and intracytoplasmic morphologically selected injection (IMSI). However, the use of testicular sperm seems to improve fertilization, pregnancy, and live birth rates when compared to PICS and IMSI techniques [68]. Nevertheless, further studies are needed to identify the best method for selecting sperm to reduce abortion rates.

The morphological analysis of sperm is another point to consider in cases of RPL. The presence of spermatozoa with structural anomalies may be associated with aneuploidy, resulting in aneuploid embryos that usually do not implant or are aborted. This is especially true in cases of globozoospermia and macrospermia, forms of monomorphic teratospermia—when all sperms have the same anomaly [69]. Infertility is generally associated with these cases, and the prognosis of IVF is reserved. Thus, when associated with abortion, IVF followed by embryonic biopsy for preimplantation genetic testing for aneuploidies (PGT-A) may be an option.

### **10. Conclusion**

Recurrent spontaneous abortion is an entity with a multifactorial etiology, and in approximately 50% of cases, we did not identify the cause of the loss. This explains the large number of controversies regarding the investigation and treatment of the pathologies that lead to repeated losses.

Despite so much controversy, there are some points on which experts agree. Psychological support for couples is essential and is associated with a better prognosis in subsequent pregnancy. Undergoing through periodic consultations and ultrasounds especially during the period of previous losses reduces the stress of these couples. The woman's age and number of previous losses are the most important factors in predicting the couple's chance of having a live baby in the next pregnancy.

There is a need for consensus among human reproduction societies on the tests that must be ordered and diagnostic criteria for all specialists to evaluate couples evenly. In this way, we will be able to evaluate the effectiveness of each available treatment, avoiding further financial burns, emotional disorders, and iatrogenesis for these couples.

### **Conflict of interest**

The authors have no conflicts of interest that are relevant to this report.

## **Author details**

Vinicius M. Lopes\*, Murilo C. Souza-Oliveira, Amanda Evelyn C. Goulart, Eduardo S. Pimentel, Natalia I. Zavattiero Tierno, Tatianna Q. F. Ribeiro, Cristina T. Medina, Valéria L. Mathias Castro, Leilane G. Noleto Lima, Anna Luiza M. Souza and Jean Pierre B. Brasileiro VERHUM Institute, Brasilia-DF, Brazil

\*Address all correspondence to: vinicius@verhum.com.br

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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