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. 2015 Apr 11;21:1051–1056. doi: 10.12659/MSM.892898

Meta-Analysis of the Association between Plasminogen Activator Inhibitor-1 4G/5G Polymorphism and Recurrent Pregnancy Loss

Xuejiao Li 1,B,C,D,E,F, Yukun Liu 1,B,C,D, Rui Zhang 1,C,D, Jianping Tan 1,C,D, Libin Chen 1,F, Yinglin Liu 1,A,B,C,D,E,F,✉
PMCID: PMC4403499  PMID: 25862335

Abstract

Background

The association between plasminogen activator inhibitor-1 (PAI-1) 4G/5G polymorphism and recurrent pregnancy loss (RPL) risk is still contradictory. We thus performed a meta-analysis.

Material/Methods

Relevant studies were searched for in PubMed, Web of Science, Embase, and Cochrane Library. An odds ratio (OR) with a 95% confidence interval (CI) was used to assess the association between PAI-1 4G/5G polymorphism and RPL risk.

Results

A total of 22 studies with 4306 cases and 3076 controls were included in this meta-analysis. We found that PAI-1 4G/5G polymorphism was significantly associated with an increased RPL risk (OR=1.89; 95% CI 1.34–2.67; P=0.0003). In the subgroup analysis by race, PAI-1 4G/5G polymorphism was significantly associated with an increased RPL risk in Caucasians (OR=2.23; 95% CI 1.44–3.46; P=0.0003). However, no significant association was observed in Asians (OR=1.47; 95% CI 0.84–2.59; P=0.18).

Conclusions

In conclusion, this meta-analysis suggests that PAI-1 4G/5G polymorphism might be associated with RPL development in Caucasians.

Keywords: Abortion, Habitual; Plasminogen Activator Inhibitor 1; Polymorphism, Genetic

Background

Recurrent pregnancy loss (RPL) is a common clinical problem that may occur during pregnancy. About 15% of clinically recognized pregnancies could suffer from RPL before the 20th week of gestation, with no known cause [1]. The pathogenesis of RPL remains unknown in many patients, and approximately 55% of patients are suspected to have thrombophilic defects [2].

Thrombophilia is a common cause of RPL and is found in 40–50% of cases [3]. Laude et al. found that levels of circulating procoagulant microparticles were higher in women with RPL when compared with controls [4]. Thrombophilia might cause a syncytiotrophoblast invasion of the maternal blood vessels, which could lead to the formation of microthrombosis at the site of implantation and result in RPL and implantation failure [5].

Plasminogen activator inhibitor-1 (PAI-1) is the urinary plasminogen activator and principal inhibitor of tissue. The main function of PAI-1 is converting plasminogen to the proteolytic enzyme plasmin [6]. Sun and colleagues found that PAI-1 4G/5G polymorphism was significant positive explanatory variable for polycystic ovary syndrome (PCOS) patients with spontaneous abortions [7]. In addition, PAI-1 4G/5G polymorphism was associated with increased PAI-1 concentrations and hypofibrinolysis and contributed to early pregnancy loss [7]. Many studies assessed the association between PAI-1 4G/5G polymorphism and RPL risk [8–29]. However, the result was still uncertain. A meta-analysis found that PAI-1 4G/5G polymorphism did not increase the risk of RPL. However, recent studies did not confirm this result [24,25,27]. Therefore, we conducted this meta-analysis to investigate the association between PAI-1 4G/5G polymorphism and RPL risk.

Material and Methods

Publication search

Relevant studies were searched for in PubMed, Web of Science, Embase, and Cochrane Library. The following terms and strategies were used for the search: (“Plasminogen activator inhibitor-1” OR “PAI-1”) AND (“single nucleotide polymorphism” OR “SNP” OR “genetic variation” OR “genetic polymorphism”) AND (“Recurrent pregnancy loss” OR “RPL”). To avoid possible missing of qualified trails, introduction and reference list of eligible trails identified through primary search were screened manually. No language restriction was applied when searching.

Inclusion and exclusion criteria

The following criteria were used to screen eligible studies for this meta-analysis: (1) a case–control study or cohort study that studied the association between PAI-1 4G/5G polymorphism and RPL risk; and (2) sufficient data were available for calculation of allele/genotype frequency. Only studies meeting both these criteria were included for analysis.

Data extraction

Two authors extracted the data independently. These data included: the first author, year, ethnicity, genotype distribution, and sample size. Disagreement in data extraction was resolved by group discussion by referring to original studies with a third reviewer.

Statistical analysis

The odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated to assess the association between PAI-1 4G/5G polymorphism and RPL risk. The recessive genetic model (4G/4G vs. 4G/5G+5G/5G) was chosen, because PAI-1 4G/4G genotype was significantly associated with increased PAI-1 production. The significance of pooled estimates was assessed with Z test. Hardy-Weinberg equilibrium (HWE) of genotype frequency in the control group was assessed by chi-square test. Between-studies heterogeneity was assessed by the chi-square-based Q test and I2. P<0.1 or I2>50% was considered as significant heterogeneity. If no significant heterogeneity was observed, fixed-effects model with Mantel-Haenszel method was used to make estimates. However, if significant heterogeneity observed, the sources of heterogeneity would be further analyzed by Galbraith plots. If there were no significant clinical or methodological differences in trails, the random effects model based on DerSimonian-Laird method was be used. Subgroup analysis was performed based on ethnicity of participants recruited in each study. A cumulative meta-analysis was conducted. Sensitivity analysis by another model, HWE, and sample size were also conducted. Publication bias was tested using Begg’s test and funnel plot (P<0.05 was considered as significant). Statistical analysis was conducted using Stata software 11.0 (StataCorp, College Station, Texas, USA).

Results

Study characteristics

After searching and screening with preset criteria, a total of 22 studies with 4306 cases and 3076 controls were included for this meta-analysis. Four studies were conducted in Asians and 18 in Caucasians. The characteristics and the HWE results of the included studies are listed in Table 1. Four studies were not in HWE.

Table 1.

Characteristics of the studies included in this meta-analysis.

Year Ethnicity Case Control Case Control HWE
Study 4G/4G 4G/5G 5G/5G 4G/4G 4G/5G 5G/5G
Wolf 2003 Caucasian 49 102 17 25 7 32 50 20 Yes
Buchholz 2003 Caucasian 184 127 72 75 37 41 58 28 Yes
Dossenbach-Glaninger 2003 Caucasian 49 48 12 28 9 8 25 16 Yes
Guan 2005 Asian 127 117 58 52 17 20 59 38 Yes
Coulam 2006 Caucasian 150 20 11 117 22 2 13 5 Yes
Coulam 2008 Caucasian 550 41 39 396 115 6 22 13 Yes
Goodman 2009 Caucasian 120 84 38 57 25 23 48 13 Yes
Al Sallout 2010 Caucasian 100 100 16 44 40 16 48 36 Yes
Ivanov 2010 Caucasian 110 97 46 44 20 26 45 26 Yes
Ivanov 2011 Caucasian 52 125 14 23 15 26 45 26 Yes
Aarabi 2011 Caucasian 63 114 19 30 14 25 47 22 Yes
Jeddi-Tehrani 2011 Caucasian 100 100 9 31 60 1 27 72 Yes
Idali 2012 Caucasian 106 100 17 53 35 1 27 72 Yes
Torabi 2012 Caucasian 100 100 9 31 60 1 27 72 Yes
Ozdemir 2012 Caucasian 543 327 121 331 91 10 62 34 No
Parveen 2013 Asian 200 300 45 100 55 74 131 95 No
Magdoud 2013 Caucasian 304 371 37 128 139 10 104 257 Yes
Subrt 2013 Caucasian 157 74 59 75 23 10 54 10 No
Jeon 2014 Asian 308 227 129 132 47 71 117 39 Yes
Khosravi 2014 Caucasian 595 100 122 288 184 1 27 72 Yes
Kim 2014 Asian 227 304 73 123 31 102 154 48 Yes
Lino 2014 Caucasian 112 98 12 57 37 16 40 42 Yes
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HWE – Hardy-Weinberg equilibrium.

Meta-analysis results

As shown in Figure 1, we found that PAI-1 4G/5G polymorphism was significantly associated with an increased RPL risk (OR=1.89; 95% CI 1.34–2.67; P=0.0003). In the subgroup analysis by race, PAI-1 4G/5G polymorphism was significantly associated with an increased RPL risk in Caucasians (OR=2.23; 95% CI 1.44–3.46; P=0.0003). However, no significant association was observed in Asians (OR=1.47; 95% CI 0.84–2.59; P=0.18). Results of the meta-analysis are listed in Table 2. In the sensitivity analysis, when the fixed-effects model was used, the result was still positive (OR=1.87; 95% CI 1.64–2.13; P<0.00001). When the studies without HWE were excluded, the result was not changed (OR=1.56; 95% CI 1.12–2.19; P=0.009). Furthermore, when the studies with small sample size were excluded, the result was also not changed (OR=1.98; 95% CI 1.25–3.13; P=0.004). The results of sensitivity analysis are listed in Table 3.

Figure 1.

Figure 1

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Forest plot of RPL risk associated with PAI-1 4G/5G polymorphism.

Table 2.

Results of meta-analysis.

Comparison Subgroup No. studies OR (95% CI) P Value I2 (%)
4G/4G vs. 4G/5G+5G/5G Overall 22 1.89 (1.34–2.67) 0.0003 81
4G/4G vs. 4G/5G+5G/5G Asian 4 1.47 (0.84–2.59) 0.18 86
4G/4G vs. 4G/5G+5G/5G Caucasian 18 2.23 (1.44–3.46) 0.0003 79
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Table 3.

Results of sensitivity analyses.

Comparison Subgroup No. studies OR (95% CI) P Value I2 (%)
4G/4G vs. 4G/5G+5G/5G Fixed-effect model 22 1.84 (1.61–2.09) <0.00001 81
4G/4G vs. 4G/5G+5G/5G HWE 19 1.56 (1.12–2.19) 0.009 67
4G/4G vs. 4G/5G+5G/5G n<200 16 1.98 (1.25–3.13) 0.004 84
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Results from the cumulative meta-analysis suggest that the evidence was consistent over time (Figure 2), indicating that the results of this meta-analysis are robust. Significant heterogeneity (I2=81%) was detected in the recessive genetic model. Thus, we used the Galbraith plot to explore the source of the heterogeneity. As shown in Figure 3, 10 studies were considered as outliers. When these studies were excluded, the heterogeneity was decreased. No obvious heterogeneity among the remaining studies could be found (I2=0%). Furthermore, the result was significant (OR=1.48, 95% CI 1.22–1.79, P<0.0001). No significant publication bias was found by Begg’s funnel plot (Figure 4) and Egger’s test (P=0.313).

Figure 2.

Figure 2

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Cumulative meta-analysis of the association between PAI-1 4G/5G polymorphism and RPL risk.

Figure 3.

Figure 3

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Galbraith plot of the association between PAI-1 4G/5G polymorphism and RPL risk.

Figure 4.

Figure 4

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Funnel plot analysis to detect publication bias for PAI-1 4G/5G polymorphism and RPL risk.

Discussion

Our previous meta-analysis investigated the association between PAI-1 4G/5G polymorphism and RPL risk [30]. However, that meta-analysis did not find a positive association between PAI-1 4G/5G polymorphism and risk of RPL. Several new studies have been published since then. Thus, we did a new meta-analysis. When these new studies were included, we found that PAI-1 4G/5G polymorphism was significantly associated with risk of RPL, indicating that PAI-1 4G/5G polymorphism carriers might have increased RPL risk. In the subgroup analysis based on race, PAI-1 4G/5G polymorphism showed increased RPL risk in Caucasians. However, no positive association was found in Asians. Ethnic differences can occur in genotype frequencies, which might account for the different results. In addition, there were only four studies with Asians. More studies with Asian populations are needed to validate this result. We then did cumulative meta-analysis. We found that the result from our meta-analysis was stable. In the sensitivity analyses, we also found the results were not altered, indicating this meta-analysis was robust.

In human and animal models, PAI-1 was involved not only in fibrinolysis regulation, but also in extracellular proteolytic processes during ovulation, ovarian follicle growth, and embryo implantation [31,32]. Much evidence has suggested that abnormal levels of PAI-1 significantly increase miscarriage and complicated pregnancy rates [33]. Additionally, Glueck et al. suggested that PAI activity was a significant positive explanatory variable for the number of miscarriages [34]. Furthermore, Glueck et al. found that administration of metformin throughout pregnancy in women with PCOS reduced the risk of first-trimester spontaneous abortion [35]. Palomba and coworkers also confirmed that metformin reduced PAI-1 activity in women with PCOS and abortion risk [36]. Therefore, it might be possible that increased PAI-1 associated with high RPL risk and PAI-1 4G/5G polymorphism might influence RPL risk.

There were some limitations in this meta-analysis. First, lack of the original data limited the evaluation of gene-gene and gene-environment interactions. Second, Dawson et al. indicated that PAI-1 level was not only changed by PAI- 1 4G/5G polymorphism, but also by concentration of blood sugar, insulin, and triglycerides [37]. However, we did not adjust these factors in this meta-analysis due to lack of original data. Third, the studies included in our meta-analysis were small. Thus our meta-analysis had little statistical power to assess the association between the PAI-1 4G/5G polymorphism and RPL risk.

Conclusions

The results of this meta-analysis suggest that PAI-1 4G/5G polymorphism might be associated with RPL development in Caucasians. Large-scale studies are necessary to validate this result.

Footnotes

Source of support: Departmental sources

Conflict of interest

The authors declare no conflict of interest.

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