The Principles of Clinical Cytogenetics - Extra Materials - Springer

Cytogenetics of Spontaneous Abortion 337
Structural rearrangements appear to occur with greater frequency in females than in males.
Braekeleer and Dao found translocations or inversions in 2.6% of females with a history of reproductive
failure compared with 1.4% in males, and Gadow and colleagues found that 3.5% of women and
1.7% of men with recurrent loss had balanced translocations (77,78). Both reports suggest increased
risk for sterility in male carriers as a possible explanation. Chromosomal rearrangement appears to be
associated with increased risk for infertility as well as for pregnancy loss.
The risk for poor pregnancy outcome when one member of a couple carries a structural rearrangement
varies considerably depending on the particular type of rearrangement and the chromosome(s)
involved. Counseling must be individualized for each family, with attention given to potential viability
of any unbalanced meiotic products.
The risk figures that are used in counseling are often based on pooled data from translocations
involving various chromosomes and breakpoints. Generally, it has been suggested that a male carrier
is at lower risk for abnormal offspring than a female carrier. However, such generalizations might not
be applicable in all cases and more specific risks figures based on the particular chromosomes
involved might be beneficial in evaluating reproductive options for a family in which a balanced
translocation has been identified (79).
The cause of reproductive failure in patients with balanced translocations is most likely the production
of unbalanced gametes as a result of abnormal segregation during meiosis. Inversions can
also lead to unbalanced gametes through crossover events involving the inverted segment. A discussion
of the implications of specific rearrangements with regard to abnormal segregation products can
be found in Chapter 9; see also ref. 25.
Chromosomally Normal Pregnancy Loss
Identification of the cytogenetically normal spontaneous abortion might be more important clinically
than identification of the aberrant gestation. The risk of repeat miscarriage is higher when the
prior loss is chromosomally normal (80). Boué and colleagues found a risk of repeat loss of 23% after
a chromosomally normal miscarriage compared with 16.5% following a chromosomally abnormal
loss (14). Morton and colleagues found that in women under 30, the risk for miscarriage was 22.7%
following a chromosomally normal loss, 15.4% following a trisomy, and 17% following other chromosome
abnormalities. In women over 30, these risks were 25.1%, 24.7%, and 20.3%, respectively
(81). Cytogenetic study of repeated spontaneous abortions suggests that those patients who experience
a chromosomally normal pregnancy loss are more likely to show normal karyotypes in subsequent
losses (82,83).
Women with recurrent pregnancy losses and normal fetal karyotypes might be more likely to have
underlying uterine abnormalities or endocrine dysfunction (see Chapter 11). Menstrual irregularities
and elevated luteinizing hormone levels are more common in women with normal fetal karyotypes
than in women with abnormal fetal karyotypes (84).
Immunological disorders have also been linked with recurrent normal pregnancy loss (85). Systemic
lupus erythematosus is perhaps the best known, but other autoimmune conditions have also
been implicated (86). Because patients with antiphospholipid antibodies and pregnancy failure frequently
respond to treatment with prednisone and low-dose aspirin or heparin, it is important to
recognize autoimmune disease as a frequent cause of recurrent chromosomally normal pregnancy
losses (87–89). Alloimmune disorders are less well understood but also appear to play a role in
recurrent pregnancy failure. Several therapies including immunization with paternal white cells (90)
and administration of intravenous immunoglobulin, have been suggested (91).
Mutations that are lethal in the embryo are known from animal models and could also be a factor
in recurrent euploid abortion in man (92). Mutations in genes responsible for early organization of
the embryo can have devastating effects on embryogenesis, with resultant pregnancy failure. Parental
sharing of human leukocyte antigens (HLAs) might also increase risk for spontaneous abortion,
although the mechanism is not yet clearly understood (93). More study of such genes and their effects