First Trimester Miscarriage Evaluation

Ruth B. Lathi, M.D.; Florette K. Gray Hazard, M.D.; Amy Heerema-McKenney, M.D.; Joanne Taylor, M.S., C.G.C.; Jane Tsung Chueh, M.D.


Semin Reprod Med. 2011;29(6):463-469. 

In This Article

Genetic Evaluation of the Miscarriage

Ultrasound and pathologic evaluation are the most common tests done in a miscarriage, but neither can confirm the chromosomal status of the developing embryo. In every case of miscarriage, especially when there are developmental anomalies, chromosomal analysis of the miscarriage should be performed. Although the most common cause of first trimester miscarriage is a numeric chromosome error, it fortunately does not confer an increased risk of miscarriage in subsequent pregnancies. If chromosome testing is done on the second miscarriage and the result is aneuploid or polyploidy, it can eliminate the need for a costly and time-consuming evaluation. Additionally, patients will have an explanation that may help lessen anxiety about causes associated with recurrent pregnancy loss. Studies have suggested a 75% success rate in future pregnancies after a documented numeric chromosome error.[46] Therefore, knowing the chromosome results of the miscarried embryo/fetus is important, particularly for parents struggling with fertility or recurrent miscarriage.

The most common numeric chromosome errors identified in first trimester miscarriages are monosomy X, followed by trisomy 16. Numeric errors of all chromosomes have been reported for all 24 chromosomes. The most frequent reason for such errors is meiotic nondisjunction, which is most commonly a random event occurring in the fertilized oocyte and therefore not a reflection of an abnormal oocyte pool. The rate of trisomies increases with maternal age; thus the proportion of miscarriages with numeric chromosome errors increases with maternal age. Other chromosome errors, such as triploidy and tetraploidy, account for ~8% of miscarriages with numeric chromosome errors.[47] Maternal age is the major risk factor for trisomic pregnancies. Other factors, such as diminished ovarian reserve, premature ovarian insufficiency, and recurrent miscarriage, have been proposed, but further study is needed.

Most cytogenetic laboratories use metaphase karyotyping as their primary method of testing. This testing gives a clear view of both chromosome number and arrangement, and it is available in most hospital settings. Although this is the gold standard for evaluating chromosomal abnormalities, it has several limitations, including requirements for tissue culture and the possibility of maternal cell contamination. To ensure the highest yield, tissue from the miscarriage needs to be gathered and sent to the cytogenetics laboratory as quickly as possible in either culture media or saline to ensure adequate cell growth. Tissue from either a spontaneous miscarriage or following surgical evacuation of the uterus can be used. However, if tissue is exposed to formalin, it cannot be used.

Maternal cell contamination is a concern with conventional cytogenetic analysis because maternal and pregnancy cells are both expelled or collected together. The risk of maternal cell contamination of tissue culture can be reduced if the chorionic villi are carefully dissected from the maternal decidua. Unfortunately, because the chromosomes are analyzed with G-banding only, differentiating maternal 46, XX from pregnancy 46, XX cannot be accomplished. Studies examining the rate of maternal cell contamination with metaphase karyotypes have reported that a third to half of reported 46, XX results are false negatives due to maternal cell contamination.[48,49]

Other methods of analyzing miscarriage tissue include array comparative genomic hybridization (CGH), single nucleotide polymorphism (SNP) microarrays, and florescence in situ hybridization. These techniques can be performed either on fresh tissue or preserved (formalin-fixed or paraffin-embedded) tissue. CGH detects aneuploidy or an unbalanced structural chromosome rearrangement but cannot detect balanced translocations, triploidy, or tetraploidy. Although CGH is more expensive than conventional cytogenetics and not readily available in all settings, it could be considered when conventional cytogenetic analysis fails. CGH has the same limitation of cytogenetics in that maternal cells cannot be differentiated from pregnancy. SNP microarrays can differentiate maternal and paternal SNPs from maternal SNPs and therefore readily identify maternal contamination and triploidy. Similar to CGH, SNP microarrays cannot detect balanced structural chromosome rearrangements or tetraploidy.

The one exception to the low recurrence risk of chromosome errors is the discovery of an unbalanced structural chromosome rearrangement in the miscarriage. Although some translocations found in miscarriages are sporadic, ~77% are inherited from one of the parents who carries a balanced form of the rearrangement.[50] If a structural chromosome rearrangement is found in the miscarriage tissue, the partners should have their peripheral blood karyotyped. If a partner is found to have a balanced structural chromosome rearrangement, then genetic counseling is indicated because these couples are at increased risk of miscarriage[51,52] There is also an increased risk of an unbalanced structural chromosome rearrangement that could result in miscarriage or an ongoing pregnancy with major congenital anomalies. This risk depends on mode of ascertainment, the sex of the transmitting parent, and the size of the unbalanced segments. The chance of having an abnormal liveborn ranges from 0% to 30%.[51] Following two or three pregnancy losses, there is a 3 to 5% chance that one member of the couple carries a chromosome rearrangement.[53] Approximately 50% of these rearrangements are balanced reciprocal translocations, 24% are Robertsonian translocations, and the remainder are inversions, mosaicism, and other sporadic abnormalities. Females are twice as likely as males to have a structural rearrangement.[54,55] Carriers of balanced translocations should be offered preconception genetic counseling and prenatal diagnosis through chorionic villus sampling (CVS) or amniocentesis.

If miscarriage chromosome testing is not available, parental karyotypes are indicated after two or more first trimester miscarriages. Conversely, parental karyotypes are not indicated when sporadic numeric chromosome errors are found in the miscarriage. Likewise, such errors are not an indication for diagnostic testing through CVS or amniocentesis in future pregnancies.


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