There are a variety of genetic factors that may result in failure of a pregnancy to develop. These include aneuploidy (the gain or loss of a chromosome), chromosomal imbalances as a result of parentally harbored translocations or inversions, deletions or duplications of genetic information within chromosomes, and single-gene mutations. Broadly, genetic factors may be divided into embryonic errors derived from known parental chromosomal abnormalities and embryonic errors that arise de novo in apparently chromosomally normal parents.



Parental chromosomal disorders

Parental chromosome anomalies occur in 3-5% of couples with RPL as opposed to 0.7% in the general population. These include translocations, inversions, and the relatively rare ring chromosomes. Balanced translocations are the most common chromosomal abnormalities contributing to recurrent pregnancy loss. In couples with RPL, this abnormality is found more frequently in the female partner at a ratio of 2:1 up to 3:1 (female:male). In addition to genetic errors resulting from the parental balanced translocation, recent data from preimplantation genetic testing has shown that embryos resulting from parents harboring a balanced reciprocal translocation also have rates of unrelated chromosomal aneuploidy at rates exceeding 35%.

Translocations are where chromosome segments are exchanged between nonhomologous chromosomes.  There are two main types of balanced translocation: reciprocal and Robertsonian. Robertsonian translocations involve two acrocentric chromosomes (numbers 13,14,15,21,22) that fuse near the centromere region with loss of the short arms.  Studies indicate that when the Robertsonian translocation is maternal, there is a greater risk that the fetus will exhibit an unbalanced phenotype. In reciprocal translocations, the type of rearrangement results from breakage of nonhomologous chromosomes, with reciprocal exchange of the broken-off segments [64]. Balanced reciprocal translocations are thought to directly contribute to both infertility and recurrent pregnancy loss (RPL).

Parental balanced chromosomal errors such as translocations or inversions are diagnosed through karyotyping of couples. Chromosomal abnormality in one of the parents can be found in up to 3-5% of couples that experience multiple spontaneous miscarriages. If no miscarriage chromosome results are available and the couple has a history of at least 2 early losses, we recommend obtaining parental karyotypes.


Genetic causes3


Recurrent Aneuploidy

The first chromosomally abnormal miscarriage was documented in 1961, and since then a large body of data on the chromosomal status of miscarriages has accumulated. The overall frequency of chromosome abnormalities in spontaneous miscarriages is at least 50%. Of these abnormalities, most are numerical: 52% are trisomies, 29% are monosomy 45,X, 16% are triploidies, 6% are tetraploidies, and 4% are structural rearrangements. In the largest study of miscarriage chromosome results in a recurrent pregnancy loss cohort, the risk of aneuploidy in women <35 yrs of age was less in RPL compared to the general reproductive population.  These data suggest that there are factors, other than genetic, that contribute to miscarriages in many women with RPL. No evidence of recurrent aneuploidy was found; as in the general reproductive population, the risk of trisomy increased with advancing maternal age. The vast majority of embryonic aneuploidy is thought to be a result of maternal meiotic nondisjunction during oocyte development though abnormalities arising from the sperm component are possible, especially in couples with male factor infertility.

There is significant debate in the professional community as to how prevalent aneuploidy is among RPL embryos. Emerging data suggest that RPL patients may have lower rates of embryonic aneuploidy in first trimester miscarriages as compared to all women. For example, a study evaluating 4,873 embryos via single nucleotide polymorphism (SNP) microarray showed the rate of aneuploidy found using trophectoderm biopsy at the blastocyst stage in RPL was significantly lower (32%) than the rate of aneuploidy found with cleavage stage biopsy (61%). This lower aneuploidy rate in preimplantation embryos from women with RPL is reflected in the lower aneuploidy frequency detected in miscarriage chromosome analysis. Other data from small studies suggest that the rate of aneuploidy in embryos in RPL is higher than 65% . The true rate of embryonic aneuploidy in couples with a diagnosis of RPL is currently a topic of great debate among reproductive endocrinologists.


Chromosomal Deletions and Duplications

In contrast to aneuploidy, which is the gain or loss of an entire chromosome, chromosomal deletions and duplications of discrete regions of chromosomes in euploid embryos is also possible. The impact of these regions of deletions and duplications is still unclear. Certain deletions and duplications in which a critical area of a chromosome is significantly altered may certainly lead to significant medical disorders or arrest of a developing embryo.