**7. Endocrine factors**

Hormones play a key role in placentation, and their changes may result in the risk of miscarriage [2].

## **7.1 Luteal phase insufficiency**

It is a condition of insufficient exposure to progesterone to maintain a secretory endometrium that will lead to normal embryo implantation and growth [50]. The

diagnostic criteria for luteal insufficiency are not well established which makes it difficult to conduct studies that can demonstrate the causal link between luteal phase insufficiency and RPL. Thus, luteal phase failure testing is not recommended for patients with RPL [2, 3]. The use of progesterone or human chorionic gonadotropin (hCG) for its treatment is divergent in the literature [2, 3].

### **7.2 Thyroid disorders**

Studies relating subclinical hypothyroidism, defined as thyroid-stimulating hormone (TSH) > 2.5 mU/L and normal free thyroxine, and increased risk of RPL, have low levels of evidence [2]. The anti-thyroid peroxidase antibodies' (anti-TPO) presence in patients with RPL, even euthyroid, is an important gestational prognostic factor [51]. Thus, a TSH and anti-TPO dosage is recommended for women with RPL. And, in detecting abnormal levels of the above exams, it recommends that T4 levels should be evaluated [2].

Patients with clinical hypothyroidism should be treated with levothyroxine [2, 3]. In women with RPL and subclinical hypothyroidism, the benefit of treatment should be evaluated as the evidences are conflicting [2, 3]. In addition, euthyroid women with positive anti-TPO should not be treated with levothyroxine [2, 52].

### **7.3 Polycystic ovary syndrome and disorders of insulin metabolism**

Several abnormalities observed in patients with polycystic ovary syndrome (PCOS) have been independently associated with RPL, including insulin resistance, hyperinsulinemia, hyperandrogenemia, hyperprolactinemia, and obesity.

There is a higher prevalence of insulin resistance among women with RPL than controls [53]. However, no study has confirmed the cause-effect relationship between insulin resistance and RPL. Thus, there is insufficient evidence to recommend assessment of PCOS, fast insulin and fast glucose, and insulin and glycemia nor the use of metformin in pregnancy to prevent gestational loss in women with RPL and defects in glucose metabolism [2].

The presence of an independent link between hyperandrogenemia and RPL remains controversial. Therefore, researching androgen levels is not recommended in women with RPL [2].

### **7.4 Prolactin disorders**

Most studies fail to establish a direct link between RPL and serum prolactin concentration. Thus, prolactin test is not routinely recommended in the absence of clinical signs of hyperprolactinemia [2]. But if hyperprolactinemia is detected, treatment with dopaminergic agonists may be considered in women to increase live birth rates [2, 3].Since hyperprolactinemia is an easily treatable cause, most centers routinely test serum prolactin levels.

### **7.5 Vitamin D**

There are few studies evaluating the association between vitamin D deficiency and RPL [2]. One of them showed increased prevalence of hypovitaminosis D in women with RPL, but it was unable to demonstrate cause-effect relationship [2, 54]. Thus, based on the significant prevalence of hypovitaminosis D in women with RPL and possible association with obstetric and fetal complications, the preconception counseling in these women may include prophylactic vitamin D supplementation [2].

**169**

**9. Male factors**

*Recurrent Pregnancy Loss: Investigations and Interventions*

Chronic endometritis (CE) is defined as a persistent inflammation of the endometrial mucosa caused by the presence of bacterial pathogens in the uterine cavity [55]. Its prevalence in patients with RPL is approximately 12–13% [56]. The influence of CE on reproductive capacity is controversial, but many authors suggest that CE may negatively affect embryonic implantation [56]. Some studies suggest an infectious etiology with positive cultures in 75% of women with histologically confirmed CE, with the most common bacteria being *Escherichia coli*, *Enterococcus faecalis*, and *Streptococcus agalactiae* (77.5%) [57]. Most patients are asymptomatic, with pain on uterine or cervical mobilization being the most common clinical presentation [58, 59]. CE is histopathologically diagnosed as a lymphoplasmacytic infiltrate in the endometrial stroma [58, 59]. Immunohistochemistry for the marker present in CD138 plasma cells is used to improve diagnostic accuracy [60]. A diagnostic video hysteroscopy can help identify CE, with direct visualization of the endometrial cavity, which usually presents with mucosal edema, focal or diffuse endometrial hyperemia, or micropolyps. The sensitivity, specificity, and positive and negative predictive values of hysteroscopy in diagnosing CE were 86.36, 87.30, 70.37, and 94.82%, respectively [61]. Up to a few years ago, the uterine cavity was thought of as a sterile environment. Recently, there has been discussed that an imbalance of the uterine microbiota might compromise embryonic implantation or induce an abortion. Endometrial biopsy for next-generation sequencing (NGS) microbiota evaluation and etiological agent research can now be done through commercial kits [55]. However, further studies are needed to evaluate diagnostic efficacy and therapy on the reproductive outcomes. Some studies suggest that treatment is related to increased live birth rates and reduced abortion rates [62]. There are several therapeutic options; the main ones mentioned in the literature refer to the use of doxycycline alone (100 mg, 12/12 hours orally, for 14 days) or the combination of metronidazole (250 mg, 12/12 hours orally,

for 14 days) and ciprofloxacin (250 mg orally 12/12 hours for 14 days) [59].

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

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

*DOI: http://dx.doi.org/10.5772/intechopen.89590*

**8. Chronic endometritis**
