Association of sex hormone receptor gene polymorphisms with recurrent pregnancy loss: A systematic review and meta-analysis

Objective: To investigate the genetic association between estrogen and progesterone receptor polymorphisms (ER, PR) and skewed X chromosome inactivation (XCI) and idiopathic recurrent pregnancy loss (RPL). Design: A systematic review and meta-analysis using electronic database (MEDLINE and EMBASE) up to April 2011. Setting: 24 eligible studies from 14 countries. Patient(s): 2,750 RPL patients and 3,123 controls were included. Intervention(s): Meta-analyses by means of random-effects models. Main Outcome Measurement(s): Common polymorphisms of ER and PR and skewed XCI. Result(s): Of 221 potentially relevant studies, 24 case-control studies were included: 6 reports of PR polymorphisms (PROGINS), 6 reports of ER-α (3 each of rs2234693 [PvuII], rs9340799 [XbaI], and B domain) and 12 reports of skewed XCI. The integrated result showed that women with skewed XCI (>90%) had a higher risk for RPL (the summary OR [95% CI]: 2.43 [1.34-4.43]), and the subgroup analysis of those studies that included more than three consecutive miscarriages (5 studies), also showed a significant association with RPL (2.52 [1.16-5.44]). Among studies of PR (PROGINS) and ER (PuvII, XbaI, B domain) polymorphisms in RPL, the summary ORs were 1.46 (0.56-3.79), 0.90 (0.47-1.75), 0.83 (0.53-1.29), and 1.07 (0.43-2.63), respectively. Conclusion(s): Meta-analyses of the available data showed a significant association between skewed XCI and idiopathic RPL. More data on the associations between ER and PR polymorphisms and RPL would be helpful to elucidate their roles in RPL.