*4.2. Recurrent Pregnancy Loss*

Approximately 5% of all couples undergoing IVF treatment are affected by recurrent pregnancy loss (RPL), defined as two or more consecutive miscarriages at a gestational age up to 20 weeks. It can be explained by genetic, anatomic, endocrinologic, and immunologic abnormalities [81]. However, in more than 50% of cases, the current diagnostic procedures are not able to identify etiologic factors [82–84]. Unexplained RPL is a distressing condition for the affected couple, and a frustrating problem for the clinician since no effective therapy exists.

A retrospective cohort study including 46,939 women who underwent fetal karyotype analysis through amniocentesis or chorionic villus sampling, documented that women with no prior spontaneous abortions had a risk for aneuploidy of 1.3%. In women with one, two, or three previous spontaneous abortion this risk increased significantly to 1.6%, 1.8% and 2.1%, respectively [85]. A higher aneuploidy rate in RPL patients has also been confirmed by other authors [83–87].

PGT-A could be helpful in the treatment of couples with unexplained RPL, when considering that embryo aneuploidies could be the cause of miscarriages. Several studies using genetic testing in couples with this indication have shown a decrease in miscarriage rate [88]. Earlier studies were typically performed with the use of FISH on cleavage-stage embryos and typically tested only 7–12 chromosomes. In one meta-analysis [89], four observational studies [70,90,91] evaluated patients with RPL undergoing cleavage-stage biopsy and compared them to patients looking for a natural-conception. The spontaneous abortion rate of 9% in the first group was significantly lower than in the controls (28%).

The incidence of aneuploidies in blastocysts from patients with idiopathic RPL undergoing PGT-A and PGT for monogenic diseases (PGT-M) resulted to be increased in women aged ≤35 years (48.9% vs. 36.9%), whereas no significant increase was found in group aged >35 years (66.9% vs. 61.4%). However, despite euploid embryo transfer, young patients had a higher miscarriage rate (26.1% vs. 3.1%) suggesting that in these group of patients RPL may derived not only from genetic reasons [92].

A literature review searching for available evidences on LB and miscarriage rates after PGT-A, compared to natural conception in couples with unexplained RPL suggested that PGT-A application, might reduce the miscarriage rate when compared to natural conception (9% vs. 28%) [89]. Hodez-Wertz et al. [93] documented that, in a total of 2282 embryos analyzed, 60% were aneuploid. Euploid embryo transfers performed were 181, with an implantation rate of 45% and ongoing pregnancy rate of 92%. The miscarriage rate was found to be only 6.9%, as compared with the expected rate of 33.5% in a RPL control and 23.7% in infertile control population. Therefore, the authors concluded that PGT-A by aCGH decreases miscarriage rate in idiopathic RPL, providing, at the same time, diagnosis and treatment for these patients.

No significant differences in LB and miscarriage rates per patient given or not given PGT-A were evidenced by Sato et al. [94]: 26.8 versus 21.1% and 14.3% versus 20.0%, respectively. Live birth rate per embryo transfer was improved by the application of PGT-A (52.4 vs. 21.6%), which also had the advantage of reducing the number of embryo transfers that are required to achieve a similar number of live births as compared with cycles in which PGT was not performed.

In the study by Murugappan et al. [95], PGT-A in patients with RPL resulted in a LB rate of 53% and a clinical miscarriage rate of 7%. Expectant management had a LB rate of 67% and clinical miscarriage rate of 24%. However, the IVF/PGT-A strategy was 100-fold more expensive, costing \$45,300 per live birth when compared with \$418 per live birth with expectant management. According to current literature, IVF/PGT-A is a very expensive way to reduce miscarriage, without increasing the chance of achieving a live birth; further study should be conducted before recommending it as standard treatment for RPL.

Katz-Jaffe et al. [96] showed a higher incidence of aneuploid blastocysts in patients with diminished ovarian reserve (DOR), whereas Trout et al. [97] evidenced a higher incidence of DOR in RPL patients. Shahine et al. [98] examined the role PGT-A in patients with RPL and DOR, being defined as a cycle day 3 FSH > 10 IU/mL and/or antimüllerian hormone <1 ng/mL. Patients with DOR had a higher percentage of aneuploid blastocysts (57% vs. 49%) when compared to controls. In all patients aged <38 years, a higher aneuploidy rate of was observed in embryos from DOR patients, when compared to patients with normal ovarian reserve (67% vs. 53%, *p* = 0.04). In the two groups, the implantation and the live birth rates after transfer of euploid blastocysts were similar (61% vs. 59% and 54% vs. 47%, respectively), despite the difference in ovarian reserve testing. The miscarriage rate was slightly higher in the DOR group, but it was not statistically significant (14% vs. 10%). It can be affirmed that patients with RPL and DOR, transferring euploid embryos, may benefit from PGT-A, as demonstrated by outcomes that are comparable with those of patients with RPL and normal ovarian reserve testing.
