**1. Introduction**

Recurrent pregnancy loss (RPL) is defined by two or more losses with gestational age less than 20–24 weeks [1, 2]. Its prevalence varies between 0.8 and 1.4% considering only patients who have had a clinical pregnancy [2]. The pathogenesis is multifactorial, and in only 50% of the cases, the causal factor can be identified: immunological, endocrine, genetic, metabolic, and anatomical, among others [3]. The identification of etiology is not always possible, and recurrence of miscarriage seems to influence negatively the couple's psychological profile [2]. Thus, the understanding of diagnostic methods that can identify etiological factors and treatments that can improve the outcome is fundamental for the follow-up of couples with RPL.

### **2. Risk factors**

Some personal factors such as lifestyle and even environmental exposure may be associated with obstetric complications and gestational loss. Advanced maternal age is one of the best-established risk factors in the literature for RPL [2]. Approximately 50–70% of early gestational losses are associated with chromosomal abnormalities, and their incidence increases with maternal age, reaching 50% in women over 40 years [3]. The European Society of Human Reproduction and Embryology (ESHRE) recommends that women should be informed of the highest risk of miscarriage after age 40 [2].

Obesity also has a major impact on women's reproductive health. High body mass index (BMI) is associated with worse outcomes in infertility treatments and a higher incidence of gestational loss [4]. One study with obese women showed a higher frequency of euploid miscarriages than nonobese women (58% vs. 37%) [5].

**161**

*Recurrent Pregnancy Loss: Investigations and Interventions*

This is probably due to the association of obesity with several endocrine disorders, such as diabetes, hypothyroidism, and polycystic ovary syndrome and possibly endometrial changes [5]. The Royal College of Obstetricians and Gynecologists (RCOG) recommends prepregnancy weight loss due to the associated increased risk of miscarriage, stillbirth, preeclampsia, diabetes, and postpartum hemorrhages [6]. The practice of regular physical activity presents improvement in the obstetric outcome; however, there are no studies investigating the impact of exercise in

Smoking seems to be related to defects in trophoblastic function, thus increasing the risk of gestational loss, in addition to poor obstetric prognosis [2]. Assisted reproduction societies recommend quitting smoking because of the negative impact on the chances of a live birth [2, 3]. Several studies have shown that drinking alcohol during pregnancy also increases the risk of gestational loss [2]. Although further studies are needed to establish if there is any safe dose for drinking in pregnancy, there are recommendations for couples with RPL not to drink alcohol. Caffeine abuse can also affect fertility as well as be a risk factor for gestational losses. Ingestion of high caffeine levels (500 mg per day or > 5 cups per day) is associated with decreased fertility [7]. During pregnancy, drinking between 200 and 300 mg/day (2–3 cups) may increase the risk of miscarriage [3]. Thus, it seems

sensible to guide this population to reduce caffeine consumption.

analysis of products of conception and parental genetic analysis.

**3.1 Genetic analysis of products of conception**

testing in conception products [12].

organochlorine pesticides may be associated with RPL [9].

depression, anxiety, and guilt [3].

**3. Genetic factors**

Few studies assess environmental exposure as a risk factor for RPL, one of which suggests that exposure to heavy metals and lack of micronutrients may cause gestational loss [8]. Another study suggests that ingestion of high concentrations of

It has been suggested in the past that stress could be associated with worsening the reproductive outcomes. There is a higher prevalence of depression in patients with RPL [10], but it is not known if this picture is not the cause or effect of RPL [2]. The American Society for Reproductive Medicine (ASRM) advises psychological support for these women who are more prone to feelings of grief, sadness,

The human conception is a vulnerable event—a large proportion of all conceptions are cytogenetically abnormal, and most of such pregnancies evolve to abortion. In couples with RPL, research can be divided into two main categories: genetic

Studies in which products of conception were analyzed showed that genetic

alterations, mainly aneuploidies, contribute to a significant portion of the causes of gestational losses, accounting for 50% of recurrent losses [11]. Despite the importance of genetic alterations as causes of miscarriage, there is still no consensus as to whether routine evaluation of pregnancy tissue should be performed. ASRM does not recommend genetic evaluation of conception products [3]. ESHRE, in turn, suggests that this analysis should not be done routinely but that it may be promoted for the purpose of clarifying the etiological factor and to assist in deciding whether further investigation or treatment is needed [2]. Other studies and guidelines, however, have proposed new algorithms in which the assessment of gestational repetition losses should be initiated with chromosome

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

patients with RPL [2].

### *Recurrent Pregnancy Loss: Investigations and Interventions DOI: http://dx.doi.org/10.5772/intechopen.89590*

*Innovations in Assisted Reproduction Technology*

be ordered for prognostic purposes, according to ESHRE.,

corrected and prognosis improved is the septate uterus.,

the high prevalence of hypovitaminosis D in this population.,

cerclage between 12 and 16 weeks after first trimester morphological ultrasound.,

**160**

**1. Introduction**

PICSI sperm can be considered.

antibiotics.,

pregnancy.,

couples with RPL.

**2. Risk factors**

risk of miscarriage after age 40 [2].

Recurrent pregnancy loss (RPL) is defined by two or more losses with gestational age less than 20–24 weeks [1, 2]. Its prevalence varies between 0.8 and 1.4% considering only patients who have had a clinical pregnancy [2]. The pathogenesis is multifactorial, and in only 50% of the cases, the causal factor can be identified: immunological, endocrine, genetic, metabolic, and anatomical, among others [3]. The identification of etiology is not always possible, and recurrence of miscarriage seems to influence negatively the couple's psychological profile [2]. Thus, the understanding of diagnostic methods that can identify etiological factors and treatments that can improve the outcome is fundamental for the follow-up of

is the use of low-dose AAS preconception and LMWH in a prophylactic dose initiated when diagnosing

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

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

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 diagnosis of cervical incompetence is based on clinical history. The classic treatment is transvaginal

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

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

Some personal factors such as lifestyle and even environmental exposure may be associated with obstetric complications and gestational loss. Advanced maternal age is one of the best-established risk factors in the literature for RPL [2]. Approximately 50–70% of early gestational losses are associated with chromosomal abnormalities, and their incidence increases with maternal age, reaching 50% in women over 40 years [3]. The European Society of Human Reproduction and Embryology (ESHRE) recommends that women should be informed of the highest

Obesity also has a major impact on women's reproductive health. High body mass index (BMI) is associated with worse outcomes in infertility treatments and a higher incidence of gestational loss [4]. One study with obese women showed a higher frequency of euploid miscarriages than nonobese women (58% vs. 37%) [5]. This is probably due to the association of obesity with several endocrine disorders, such as diabetes, hypothyroidism, and polycystic ovary syndrome and possibly endometrial changes [5]. The Royal College of Obstetricians and Gynecologists (RCOG) recommends prepregnancy weight loss due to the associated increased risk of miscarriage, stillbirth, preeclampsia, diabetes, and postpartum hemorrhages [6]. The practice of regular physical activity presents improvement in the obstetric outcome; however, there are no studies investigating the impact of exercise in patients with RPL [2].

Smoking seems to be related to defects in trophoblastic function, thus increasing the risk of gestational loss, in addition to poor obstetric prognosis [2]. Assisted reproduction societies recommend quitting smoking because of the negative impact on the chances of a live birth [2, 3]. Several studies have shown that drinking alcohol during pregnancy also increases the risk of gestational loss [2]. Although further studies are needed to establish if there is any safe dose for drinking in pregnancy, there are recommendations for couples with RPL not to drink alcohol.

Caffeine abuse can also affect fertility as well as be a risk factor for gestational losses. Ingestion of high caffeine levels (500 mg per day or > 5 cups per day) is associated with decreased fertility [7]. During pregnancy, drinking between 200 and 300 mg/day (2–3 cups) may increase the risk of miscarriage [3]. Thus, it seems sensible to guide this population to reduce caffeine consumption.

Few studies assess environmental exposure as a risk factor for RPL, one of which suggests that exposure to heavy metals and lack of micronutrients may cause gestational loss [8]. Another study suggests that ingestion of high concentrations of organochlorine pesticides may be associated with RPL [9].

It has been suggested in the past that stress could be associated with worsening the reproductive outcomes. There is a higher prevalence of depression in patients with RPL [10], but it is not known if this picture is not the cause or effect of RPL [2]. The American Society for Reproductive Medicine (ASRM) advises psychological support for these women who are more prone to feelings of grief, sadness, depression, anxiety, and guilt [3].
