Association between Plasminogen Activator Inhibitor‐1 Gene Polymorphisms and Recurrent Pregnancy Loss: A Systematic Review and Meta‐Analysis

Abstract

Human plasminogen activator inhibitor-1 (PAI-1) is closely related to embryonic development and pregnancy success. The association between PAI-1 gene polymorphisms (PAI-1-844G/A and PAI-1-675G/A) and the risk of recurrent pregnancy loss (RPL) is controversial. Therefore, we perform this review to clarify the association between PAI-1 gene polymorphisms and RPL risk. We performed a systematic search for studies that described the effect of PAI-1 polymorphisms on RPL risk. The odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were considered under recessive genetic models. Furthermore, we conducted a subgroup analysis based on the studies' geographic regions of origin. Data were analyzed using Stata 11.2 software. Eighteen studies were included, and a high degree of statistical heterogeneity existed among the studies. In this study, we found a significant association between the PAI-1-675G/A polymorphism and the risk of RPL under the recessive model (OR = 1.70, 95% CI = 1.21-2.38). However, no significant association between the PAI-1-844G/A polymorphism and RPL was noted. PAI-1-675G/A (4G/5G) polymorphisms play a potential role in RPL. The screening of PAI-1 (4G/5G) gene mutations should be included during an RPL diagnostic workup, and patients should be treated using anticoagulant therapy during pregnancy if necessary.

Association of Plasminogen Activator Inhibitor-1 Gene Polymorphisms and Methylene Tetrahydrofolate Reductase Polymorphisms with Spontaneous Miscarriages

“…We found that the PAI-1 4G/5G genotype was more frequent in the group of women with 1 SM (56%) versus the control group (42%). Our results are similar to the results of a meta-analysis by Chen et al [16] which confirmed that PAI-1 4G/5G polymorphisms play a potential role in SMs, indicating that the PAI-1 4G/5G polymorphism is significantly associated with a risk of SM (OR = 1.70, 95% CI 1.21-2.38). Results of another meta-analysis conducted by Xuejiao et al [17] suggest that the PAI-1 4G/5G polymorphism might be associated with SM development specifically in Caucasians (OR = 2.23, 95% CI 1.44-3.46).…”

Enoxaparin Effect on Pregnancy Outcomes in a Patient with Elevated Plasminogen Activator Inhibitor-1

“…In 1984, Wiman et al was the first to characterize the association between increased PAI-1 levels and preeclampsia [8]. A meta-analysis of 6 case control studies investigating the 4G/5G polymorphism found no significant difference in the frequency of the 4G allele in patients with and without preeclampsia; however, patients with the 4G allele had a 1.27-fold increased risk of preeclampsia [7,8]. Similarly, a meta-analysis of 18 case control studies found that the 4G/5G polymorphism is associated with an increased risk of RPL (OR = 1:7, 95%CI = 1:21 − 2:38), and advocated for PAI-1 screening and treatment with anticoagulation [7].…”

“…The PAI-1 gene promoter region has well-characterized polymorphisms, specifically the 4G insertion/5G deletion polymorphism, which enhances transcription of PAI-1 [7,8]. The expression of PAI-1 is modified by atherosclerotic risk factors that induce endothelial damage, including diabetes, insulin resistance, and hypertriglyceridemia [8].…”

Plasminogen Activator Inhibitor‐1 4G/5G Polymorphism is Associated with Reproductive Failure: Metabolic, Hormonal, and Immune Profiles

“…These findings are consistent with the previous reports, which demonstrated an increased incidence of the 4G allele and/or 4G/4G genotype among the patients with RPL, although contradictory results were reported . Recently, two meta‐analysis of PAI‐1 gene mutation in women with RPL have published, which demonstrated an association between PAI‐1 4G/5G polymorphism and RPL . However, another meta‐analysis failed to demonstrate an association, possibly due to the high heterogeneity among the study population, such as ethnicity, number of abortions considered as RPL, and the exclusion criteria of study population with known causes of RPL.…”

“…Previous studies have found an association between PAI‐1 ‐675 4G/5G polymorphism and RPL and to a lesser extent, RIF . In this study, we aim to investigate the association between PAI‐1 4G/5G polymorphism with various types of reproductive failures and compare the metabolic, hormonal, and immune profiles of these patients in association with PAI‐1 genotypes.…”