Skewed X-chromosome inactivation is associated with trisomy in women ascertained on the basis of recurrent spontaneous abortion or chromosomally abnormal pregnancies.

An increase in extremely skewed X-chromosome inactivation (XCI) (> or = 90%) among women who experienced recurrent spontaneous abortion (RSA) has been previously reported. To further delineate the etiology of this association, we have evaluated XCI status in 207 women who experience RSA. A significant excess of trisomic losses was observed among the women who had RSA with skewed XCI versus those without skewed XCI (P=.02). There was also a significant excess of boys among live births in this group (P=.04), which is contrary to expectations if the cause of skewed XCI was only that these women carried X-linked lethal mutations. To confirm the association between skewed XCI and the risk of trisomy, an independent group of 53 women, ascertained on the basis of a prenatal diagnosis of trisomy mosaicism, were investigated. Only cases for which the trisomy was shown to be of maternal meiotic origin were included. The results show a significantly higher level of extreme skewing (> or = 90%) in women whose pregnancies involved placental trisomy mosaicism (17%) than in either of two separate control populations (n=102 and 99) (P=.02 compared with total control subjects). An additional 11 cases were ascertained on the basis of one or more trisomic-pregnancy losses. When all women in the present study with a trisomic pregnancy (n=103) were considered together, skewed XCI was identified in 18%, as compared with 7% in all controls (n=201) (P=.005). This difference was more pronounced when a cutoff of extreme skewing of 95% was used (10% vs. 1.5% skewed; P=.002). Maternal age was not associated with skewing in either the patient or control populations and therefore cannot account for the association with trisomy. Previous studies have shown that a reduced ovarian reserve is associated with increased risk of trisomic pregnancies. We hypothesize that the association between skewed XCI and trisomic pregnancies is produced by a common mechanism that underlies both and that involves a reduction of the size of the follicular pool.

Skewed X inactivation and recurrent spontaneous abortion.

Recent studies show that women experiencing recurrent spontaneous abortion exhibit nonrandom X-chromosome inactivation (XCI) more often than in controls. This suggests that genetic factors may be important in explaining the losses in this subset of women. Nonetheless there are a number of possible explanations for this finding and the underlying causes may be heterogeneous. One hypothesis commonly cited is that a mutation on the X chromosome results in both preferential inactivation of the mutated X as well as lethality of male embryos inheriting this mutated X. However, this hypothesis does not explain the increase in chromosome abnormalities observed in the karyotyped losses from women with recurrent pregnancy loss and skewed XCI. This finding leads us to suggest that the mechanism involved may be associated with a reduction in number of ovarian follicles, either due to X mutations affecting oocyte atresia or a restriction in precursor pool size during development.

Resectoscopic management of müllerian fusion defects.

Of the 103 patients taken to the operating room for hysteroscopic resection of a septum, 72 underwent successful resection of the septum. The initial hysterogram can identify those patients who may benefit from the procedure but cannot discriminate between bicornuate and septate uteri. Knowledge of the size and contour of the uterus is essential to the final decision to proceed transcervically, opposed to transabdominally. In the transcervical repair group, at the time this article was written, there were 58 term deliveries and 5 ongoing pregnancies greater than 30 weeks (1 had a spontaneous abortion after surgery and subsequently conceived a term pregnancy), for a successful pregnancy rate of 86%. This correlated well with the pregnancy rates observed after metroplasty. Therefore, hysteroscopic resection constitutes a valuable alternative to the classical transabdominal approach.

Embryonic development in consecutive specimens from recurrent spontaneous abortions.

Although habitual abortion occurs in a relatively small number of patients, its successful management is often difficult. Etiologic factors may be either maternal or embryonic or both; there is much information available on maternal factors but little is known of factors related to the embryo. Information obtained from examining and karyotyping the aborted embryo or fetus may be of considerable importance in determining the possible cause of the abortion and subsequent investigation and counseling of the patient. At least two specimens from over 50 women who have had two or more consecutive spontaneous abortions have been examined and the results show that: (1) Patients aborted conceptuses of the same developmental stage, i.e., embryo or fetus, in consecutive pregnancies. This suggests that investigation should be directed to factors which may be important in the stage of pregnancy indicated. (2) Late abortions were associated with normal fetal development and factors related to the uterine environment. (3) The conceptus in an early abortion was significantly more likely to have a cytogenetic abnormality, suggesting a problem at, or prior to, conception/fertilization. A case study is also included.