**3. Genetic factors**

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 analysis of products of conception and parental genetic analysis.

### **3.1 Genetic analysis of products of conception**

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 testing in conception products [12].

New chromosomal tests such as the chromosomal microarray analysis (CMA) have the potential to reduce costs since, in the presence of altered examination, costly and unnecessary evaluations will not be employed [13]. In addition, when a cause is identified, the tendency is to reduce the use of empirical treatments that have no scientific evidence [13]. Research has shown that in couples with previous embryonic aneuploidy, the likelihood of a child's birth during subsequent pregnancies was higher than patients with prior normal karyotype of conception products (71% vs. 44%) [14].

The suffering that the couple goes through experiencing abortion episodes without knowing the etiological factor can by itself justify the investigation of the existence of genetic alterations as a cause of the events.

### **3.2 Parental genetic analysis**

In about 5% of all couples suffering two or more fetal losses, one partner carries a balanced chromosomal rearrangement, which represents approximately eightfold increase compared to the general population [15]. Guiding this couple for genetic counseling is important, as the likelihood of a healthy child born will depend on the type of rearrangement found and the chromosomes involved—for example, gestational losses are more present in carriers of balanced translocations and inversions than in carriers of Robertsonian translocations [16]. Even with one spouse carrying a chromosomal rearrangement, the cumulative rate of live birth, even in natural conception, is significant—63.4% despite the increased risk for miscarriage [17].

As for the existing guidelines regarding parental cytogenetic investigation, ESHRE determines that such assessment should not be performed routinely, but in specific cases after individual risk assessment [2]. ASRM, however, recommends routine parental karyotyping as information obtained may assist in counseling on the prognosis of future pregnancies, including guidance for performing preimplantation genetic testing (PGT), amniocentesis, or chorionic villus analysis [3].

Couples with structural cytogenetic changes have an increased number of gametes with chromosomal imbalances, so it would be expected that the implantation of embryos selected by PGT increases the rate of live births. However, in spouses carrying chromosomal rearrangement with RPL, the rate of live births, time to subsequent conception, and miscarriage rates were similar in both naturally conceived and in vitro fertilization associated with preimplantation diagnosis (IVF-PGT) [18]. Other papers showed discordant results. Similar live birth rate and time to new pregnancy were reported; however, the miscarriage rate was significantly lower in the IVF-PGT group [19]. Thus, there is no consensus showing the benefit of such strategy in this population, and no randomized controlled trials have been conducted to this date to validate possible benefits.

### **4. Thrombophilias**

Thrombophilias are inherited and/or acquired conditions that predispose individuals to thrombosis, with varied prevalence in the general population [20]. The most common hereditary thrombophilias are methylenetetrahydrofolate reductase (MTHFR) gene polymorphism 4–16%, factor V Leiden mutation 1691G → A (heterozygote, 1–15%; homozygote, <1%), prothrombin mutation 20210G → A (heterozygote, 2–5%; homozygote, <1%), antithrombin deficiency (0.02%), protein C deficiency (0.2–0.4%), protein S deficiency (0.03–0.13%) [21], and serpin gene polymorphism. On the other hand, acquired thrombophilia is mainly represented

**163**

*Recurrent Pregnancy Loss: Investigations and Interventions*

by the antiphospholipid antibody syndrome (APS) 2% [20]. Successful pregnancy requires an adequate endovascular implantation and remodeling measured by trophoblast, and these prothrombotic conditions would be the target of investigation and intervention with anticoagulant therapy to prevent miscarriage [21].

The screening of inherited thrombophilias even in patients with a thrombosis context is still questioned [2]. The factor V Leiden mutation (1691G→ A) and the prothrombin mutation (20210G→ A) were related to recurrent miscarriage [22]; however, the lack of evidence that the treatment changes the gestational outcome leads to questioning the relevance of investigating such mutations. Other thrombophilias, such as protein C deficiency, protein S deficiency, and antithrombin deficiency, although associated with thromboembolic event, were not associated with RPL [2, 3, 20, 22]. MTHFR gene polymorphisms are no longer considered risk

The association between RPL and inherited thrombophilias is weak or absent [2]. Thus, thrombophilic screening should be restricted to patients with family history of thrombophilias or previous thrombotic event [1, 2]. There is no recommendation to screen inherited thrombophilias in patients with RPL without other risk factors [1, 2, 21, 23]. Screening tests may be influenced by physiological/ pathophysiological changes in the pregnancy-puerperal period, thrombotic event, or use of anticoagulants [21]. It should be performed within 6 weeks or more after

The use of anticoagulant therapy with low-molecular-weight heparin and/or aspirin has no benefit in preventing early (<10 weeks) or late (≥10 weeks) RPL [24]. Thus, ineffectiveness of the treatment, the risk exposure, and the increased cost do not justify treatment with anticoagulants in patients with inherited throm-

APS is indicated in patients with RPL, as well as in patients with adverse gestational outcome or episode of thrombosis without apparent cause [25]. The diagnosis of APS is based on the combination of at least one clinical criterion, which includes thrombotic events and/or gestational morbidity, and a laboratory criterion, which includes three antibodies: lupus anticoagulant, anticardiolipin, and anti-β2 glyco-

In the cases of late gestational loss, lupus anticoagulant was more closely related to RPL than any of the other antibodies [26, 27]. Anticardiolipin (IgG and IgM) has been associated with early and late gestational loss [26, 27]. The relationship between anti-β2GP1 and late gestational loss seems to be controversial [26, 27]. ESHRE recommends for patients with two losses, consecutive or not, to conduct a research for lupus anticoagulant antibodies and anticardiolipin, and the research

The use of combined therapy, low-molecular-weight heparin at prophylactic dose, and low aspirin dose (75–100 mg/day) increases the live birth rate in patients with APS and RPL from 10% to 70–80% [28]. In treatment failure, the use of heparin in therapeutic dose may be used, although there is no benefit evidence [28]. Other treatment regimens with limited evidence are the use of hydroxychloroquine or low dose of prednisolone in the first trimester [28]. The use of immunoglobulin is questioned because studies are limited and show no

delivery, miscarriage, or thrombotic event or early if necessary [2, 21].

bophilias and RPL without other risk factors for thrombosis [2, 20].

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

**4.1 Inherited thrombophilias**

factors for thrombophilias [2].

**4.2 Acquired thrombophilias**

protein 1 (anti-β2GP1) [25].

should consider anti-β2GP1.

increase in live birth rate [28].

by the antiphospholipid antibody syndrome (APS) 2% [20]. Successful pregnancy requires an adequate endovascular implantation and remodeling measured by trophoblast, and these prothrombotic conditions would be the target of investigation and intervention with anticoagulant therapy to prevent miscarriage [21].
