Miscarriage and Its Associations

Stephen Brown, M.D.


Semin Reprod Med. 2008;26(5):391-400. 

In This Article

Chromosome Abnormality

Studies performed on spontaneous losses have consistently shown that ∼50% are associated with fetal chromosome abnormalities. Table 1 provides a summary of one large study of the cytogenetics of miscarriage. Several other studies have shown remarkably similar results, making it safe to say that the discovery of aneuploidy as a root cause of miscarriage represents the biggest single leap in the history of endeavors to understand this problem.

The likelihood that a miscarriage is due to chromosome abnormality is a function of gestational age, with earlier gestations being more likely to be affected.[2] The true proportion of conceptions affected with aneuploidy is likely to be larger when one considers other data. For instance, studies of preimplantation embryos suggest that 30 to 65% of normally developing, good-quality embryos have an aneuploidy in at least one cell.[4,5,6]

As indicated in Table 1 , autosomal trisomy is the single largest category of abnormality, and molecular studies have proved that ∼90% of trisomies are the result of errors in maternal meiosis.[2] Interestingly, the relative proportions of maternal versus paternal meiotic error varies substantially among the different chromosomes with nearly 50% of XXY pregnancies being the result of paternal nondisjunction whereas less than 10% of other trisomies arise by paternal meiotic error. Monosomy X, another large category (∼7% of spontaneous abortions), is generally caused by loss of the paternal sex chromosome,[7] which is consistent with the lack of a maternal age effect on the incidence of 45X. Polyploidy (mostly triploidy), which is found in ∼8 to 9% of spontaneous abortions (SABs), is not the result of maternal nondisjunction. Rather, it is the consequence of either dispermy or failure of extrusion of the second polar body, with the clinical manifestations being different depending on the origin of the extra set of chromosomes. As in 45X, no maternal age effect has been described.[8]

Recurrent Aneuploidy

The question of whether a history of a trisomic miscarriage confers an increased risk of a subsequent aneuploidy pregnancy loss has been debated for years. A recent comprehensive analysis of this issue has shown that the history of a trisomic miscarriage does increase the chances of recurrence; however, this effect is most pronounced in young women when the overall incidence of aneuploidy is low.[9] For women under age 30 with a history of a trisomic pregnancy, the chances of recurrence are estimated to be about eightfold higher than their age-related risk. For women above 35 years with such a history, their age-related risk overwhelms any increase conferred by their history and can be taken to be approximately correct. This effect may be even more pronounced if one considers preimplantation studies. In one such study, patients with a history of recurrent miscarriage had a much higher incidence of aneuploid embryos than did patients who underwent preimplantation diagnosis for Mendelian genetic conditions.[10]

Inherited Aneuploidy

Although inherited chromosome abnormalities are an uncommon cause of sporadic miscarriage, they contribute significantly to recurrent miscarriage. This is evidenced by the fact that 4 to 5% of couples with two or more miscarriages are found to have a balanced chromosome abnormality.[11] In the past, the main importance of making this diagnosis was that such couples may also have viable but severely abnormal pregnancies. In the modern world, couples with balanced translocations may also benefit from preimplantation diagnosis.


The discovery that miscarriage is often caused by de novo abnormalities in chromosome number has many consequences. On the clinical side, it has led to a general understanding that first-trimester loss is often an untreatable and unavoidable part of life that one must accept. It is generally very comforting for patients to know that a miscarriage was caused by a chromosome abnormality. They need not have guilt or lingering worry that something could have prevented it, and the risk of recurrence is low.

From the biological perspective, investigations into human aneuploidy have led to fundamental discoveries in the biology of meiosis and recombination. The discovery that aneuploidy causes most miscarriages has also been critical for refining research to find causes for other, non-aneuploid miscarriages.


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