**Abstract**

Recurrent pregnancy loss (RPL) affects 0.8–1.4% of couples, and this prevalence increases with aging. However, etiology is commonly unknown, and most therapies are not supported by strong evidence. There are many examinations that investigate causes of RPL: hormonal status, spermatozoa morphology and DNA fragmentation, immunologic status, uterine assessment, thrombophilia, and others. Recently different types of treatment have emerged, most lacking good evidence. As for example, we may mention the use of anticoagulants, aspirin, corticosteroids, progesterone, and antioxidants and psychological support. It is argued that some procedures such as preimplantation genetic testing for aneuploidy and intracytoplasmic morphologically selected sperm injection would impact on the outcomes and help RPL management. This chapter will discuss the current evidence concerning examinations and treatments that would improve the outcomes in patients with RPL, with recommended practice.

**Keywords:** recurrent pregnancy loss, recurrent miscarriage, in vitro fertilization, infertility, preimplantation *genetic* testing for aneuploidy, thrombophilia, sperm DNA fragmentation, natural killer cells, reproductive techniques, maternal KIR, paternal HLA-C

### **Keypoints**

The practice of physical activity, healthy eating, quitting smoking, and reduction of alcohol consumption are factors that interfere in the reproductive outcomes. Medical understanding and ability to listen to patients about their obstetric past are fundamentally important for the treatment.

The genetic investigation is controversial and consists of chromosomal evaluation of the conception products and the couple's karyotype. The goal is to identify the etiology of the loss and may be useful for future guidance of the couple. There is no consensus on performing IVF-PGT, and this option should be discussed case by case. In extreme cases IVF using donated gametes may be the last option.,

Patients with RPL without other risk factors for thrombosis should not be screened for inherited thrombophilias, and those with positive screening have no benefit from available treatment. The only thrombophilia that should be routinely investigated for early miscarriage is APS. The recommended treatment is the use of low-dose AAS preconception and LMWH in a prophylactic dose initiated when diagnosing pregnancy.,

Screening immunological factors for patients with RPL is not recommended. There is also no recommendation to use venous immunoglobulin or corticosteroids empirically. Only antinuclear antibody can be ordered for prognostic purposes, according to ESHRE.,

Screening for congenital uterine anomalies is part of the investigation of women with a history of RPL. Nuclear magnetic resonance is the gold standard for diagnosis. The only finding that can be surgically corrected and prognosis improved is the septate uterus.,

The diagnosis of cervical incompetence is based on clinical history. The classic treatment is transvaginal cerclage between 12 and 16 weeks after first trimester morphological ultrasound.,

Patients with RPL should undergo through endometrial cavity evaluation. The gold standard is hysteroscopy. Although there is limited evidence linking submucosal fibroids, endometrial polyps, and synechiae with RPL, surgical correction in patients with RPL without other identifiable factors is suggested.,

There are no research and treatment benefits for PCOS patients and their associated endocrine disorders. Thyroid evaluation should be performed with serum TSH and anti-TPO, and clinical hypothyroidism should be treated. For prolactin, the test is not indicated in the absence of signs of hyperprolactinemia, but if this condition is diagnosed, treatment is indicated. Vitamin D test is not routinely recommended, but the preconception counseling in women with RPL may include prophylactic vitamin D supplementation due to the high prevalence of hypovitaminosis D in this population.,

The relationship of chronic endometritis with RPL is unclear. The current gold standard for the diagnosis of chronic endometritis is the pathological anatomy of immunohistochemically endometrial biopsy for the CD138 marker. A therapeutic option would be the use of doxycycline alone or in combination with other antibiotics.,

For male factor, measurement of spermatic DNA fragmentation index and Kruger morphology would be indicated. The use of antioxidants is a clinical treatment that can improve DNA fragmentation. In the presence of ICSI indication associated with increased spermatic DNA fragmentation, the use of testicular, IMSI, or PICSI sperm can be considered.
