Association of skewed X chromosome inactivation and idiopathic recurrent spontaneous abortion: a systematic review and meta-analysis.

Evidence of an association between skewed X chromosome inactivation (SXCI) and idiopathic recurrent spontaneous abortion (RSA) is conflicting. No consensus has been reached on the degree of SXCI and the number of pregnancy losses in patients who have experienced RSA. In this systematic review and meta-analysis, different degrees of skewing and definitions of RSA are used to establish an association between SXCI and idiopathic RSA. Twelve studies comprising 1594 women who had experienced RSA and 1924 controls were included. No significant association was found between SXCI and RSA when 80 or 90% was used as cut-off value of skewing; more stringent 95% or greater SXCI was significantly higher in women who had experienced RSA than in controls (odds ratio [OR] = 4.27, 95% confidence interval [CI] 1.46 to 12.46). A significantly higher incidence of SXCI when defined as greater than 90% (or ≥90%) was found in women who had experienced RSA with three or more pregnancy losses (OR = 2.31, 95% CI 1.41, 3.78); significance diminished when RSA was defined as two or more losses. Extreme skewing of SXCI is associated with idiopathic RSA with three or more losses. More studies are needed to validate the potential genetic mechanism.