Recent evidence suggests that, in women with a history of three or more spontaneous pregnancy losses, a subsequent pregnancy loss has a 58% chance of chromosomal abnormality (15). Among women with recurrent pregnancy loss who are age 35 or older, the aneuploidy rate is much higher (8). The majority of chromosomal abnormalities identified in miscarriages are autosomal trisomies and considered to result from maternal nondisjunction. Maternal age appears as a consistent and important risk factor for trisomy in the majority of studies. There are several options for patients who suffer from recurrent pregnancy loss who have an identified miscarriage due to trisomy. The first is to conceive again without any specific change in medical management, as these abnormalities are sporadic and unlikely to recur. Studies examining patients with recurrent pregnancy loss show that women who miscarry chromosomally abnormal conceptions are more likely to achieve a live birth with subsequent pregnancy than those who miscarry chromosomally normal conceptions (13,346). A second involves preimplantation genetic diagnosis (PGD) or preimplantation screening, and a third involves the use of donor gametes.
Because chromosomal abnormalities are the most commonly identified cause of miscarriage, some have argued that the use of PGD is indicated for patients with recurrent pregnancy loss. PGD involves the removal of a single cell from an in vitro–matured embryo. Genetic testing can be performed on this cell to examine chromosomal composition for the presence of single gene disorders (e.g., cystic fibrosis) or abnormalities in chromosome number and morphology.
Embryos that are diagnosed with genetic abnormalities would be discarded and only those embryos with normal results would be considered appropriate for transfer into the uterus. Use of PGD in patients with known heritable genetic disorders (e.g., cystic fibrosis, X-linked disorders) is presently in widespread use in internationally recognized assisted reproductive technology centers.
The use of PGD has the potential to reduce the incidence of pregnancy loss arising from a genetic etiology. However, definitive studies in this population have not yet been done. The use of PGD requires the patient to go through an IVF cycle to obtain embryos for biopsy, and the impact of the biopsy technique itself on the embryos’ viability is not known at this time. Although there are several retrospective studies showing reduced miscarriage rates with this technique, several prospective trials using the outcome of successful pregnancy per started cycle fail to show any benefit (347–357). IVF is invasive and costly and many patients with recurrent pregnancy loss conceive quickly without intervention and have a high likelihood of live birth with their subsequent pregnancy. Therefore, the optimal control group for a study of IVF PGD in the recurrent pregnancy loss population is debated. Should it be natural conceptions or IVF without PGD? Finally, the prognosis for a patient with recurrent pregnancy loss does seem to be linked to the chromosome analysis of prior miscarriages. Recurrent pregnancy loss patients who miscarry chromosomally abnormal embryos, seem to have better prognosis than those who miscarry chromosomally normal conceptions, again arguing for expectant management for recurrent pregnancy loss patients with a history of aneuploid loss. On the other hand, patients with poorer prognosis are those who miscarry chromosomally normal embryos and therefore would not benefit from PGD. The efficacy of PGD in the treatment of patients with recurrent pregnancy loss continues to be investigated, and the method of embryo biopsy and genetic testing continues to evolve (355,356). As these techniques improve and the understanding of aneuploidy and recurrence improves, there may be a subset of recurrent pregnancy loss patients, such as carriers of parental translocations, who might benefit from this intervention. At this time it cannot be recommended for all patients with a history of recurrent pregnancy loss.