A novel X chromosome–linked genetic cause of recurrent spontaneous abortion

Objective: Unexplained recurrent spontaneous abortion is a common women’s health problem that affects approximately 1 of every 200 women who wish to have children. It has long been assumed that a large proportion of recurrent spontaneous abortion results from genetic problems, but no causative genes have been identified to date. Here, we tested the hypothesis that a subset of women with recurrent spontaneous abortion are carriers of X-linked recessive disorders that result in the loss of male pregnancies. Study Design: X chromosome inactivation patterns, an assay used to detect women who are likely to be carriers of X-linked recessive cell-lethal traits, were compared between 105 female patients with idiopathic recurrent pregnancy loss and 101 women (control subjects) with a single successful pregnancy and no history of pregnancy loss. Inheritance patterns and gender of offspring were studied in relevant subsets of participants. Results: Female patients showed a highly statistically significant increase in the frequency of skewed X chromosome inactivation (90%; P< .0005). Female patients with highly skewed X chromosome inactivation showed a significant decrease in male children. Four of 6 families that were studied showed maternal inheritance of the skewed inactivation trait. Conclusion: We found the 14% of women with unexplained recurrent pregnancy loss show highly skewed X inactivation, which suggests that they are carriers of X-linked recessive lethal traits. Furthermore, the observed gender bias among women with highly skewed X inactivation suggests selective loss of male conceptions, which is consistent with an X chromosome–linked genetic defect that leads to cell death or growth disadvantage. Identification of such female carriers is important for the reproductive counseling and treatment of these women. (Am J Obstet Gynecol 2001;185: 563-68.)