PAI-1, MTHFR, and FVL Thrombophilic Polymorphisms as Risk Factors for Fetal Growth Restriction: A Case–Control Study from a Tertiary Care Center

Abstract

Background/Objectives: Fetal growth restriction (FGR) is one of the main causes of perinatal morbidity and mortality, and in most cases the mechanism is placental dysfunction of vascular origin. Hereditary thrombophilias have been evaluated as factors that favor maternal vascular malperfusion, but the data in the literature remain contradictory. The objective of the study was to evaluate the association between the PAI-1 4G/5G, MTHFR C677T and factor V Leiden G1691A polymorphisms and fetal growth restriction, as well as to analyze the dose–effect relationship between the number of thrombophilic variants and the severity of restriction. Methods: This was a retrospective case–control study including 480 singleton pregnancies: 240 cases with fetal growth restriction and 240 pregnant women with eutrophic fetuses, followed up for a period of five years. Cases were defined biometrically as an estimated fetal weight below the 10th centile, without Doppler confirmation, and the phenotype therefore corresponds to small-for-gestational-age rather than to the full consensus definition of fetal growth restriction; a secondary analysis restricted to cases below the 5th centile, performed in response to review, is reported. Maternal characteristics, genotypes, perinatal outcomes, and cumulative pattern of thrombophilic variants were analyzed. Results: PAI-1 4G allele carriers were significantly more frequent in the growth restriction group compared to the control group (70.8% vs. 44.6%; OR 3.02; 95% CI 2.07–4.40; p < 0.001), as were MTHFR C677T allele carriers (57.1% vs. 39.2%; OR 2.07; 95% CI 1.44–2.97; p < 0.001) and factor V Leiden carriers (33.3% vs. 12.1%; OR 3.64; 95% CI 2.27–5.83; p < 0.001). Carrier prevalence increased progressively with severity of restriction for the PAI-1 4G allele and, most steeply, for factor V Leiden (from 12.1% in controls to 75.0% below the 3rd centile; trend test p < 0.001); for the MTHFR 677T allele the increase was confined in the two case strata above the 3rd centile, and the estimate in the smallest subgroup was uninformative. The risk of growth restriction increased with the number of coexisting thrombophilic variants: OR 2.12 (95% CI 1.24–3.64) for one variant, OR 5.60 (95% CI 3.21–9.78) for two, and OR 24.42 (95% CI 7.87–75.78) for all three, compared with the absence of any variant. In multivariable analysis, the three polymorphisms remained independent predictors, with the strongest adjusted association being that of factor V Leiden (adjusted OR 3.33; 95% CI 2.03–5.47). Carriage of each variant was associated with a lower birth-weight centile: −12.3 points for PAI-1 4G, −10.2 for factor V Leiden and −8.0 for MTHFR C677T (all p < 0.001). Conclusions: In this study, PAI-1 4G/5G, MTHFR C677T, and factor V Leiden polymorphisms were independently associated with fetal growth restriction. The results are compatible with a contribution of hypofibrinolysis and inherited thrombophilia to the placental insufficiency phenotype, most clearly in the more severe strata, but they are associative and require confirmation in prospective cohorts incorporating Doppler assessment and placental histopathology.