**4.1 Inherited thrombophilias**

*Innovations in Assisted Reproduction Technology*

(71% vs. 44%) [14].

miscarriage [17].

**4. Thrombophilias**

**3.2 Parental genetic analysis**

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

The suffering that the couple goes through experiencing abortion episodes without knowing the etiological factor can by itself justify the investigation of the

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

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 preimplan-

tation 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

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

conducted to this date to validate possible benefits.

existence of genetic alterations as a cause of the events.

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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 factors for thrombophilias [2].

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

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