Thrombophilia Polymorphisms in Indian Women with Unexplained Recurrent Pregnancy Loss: A Population-Specific Case–Control Study and Observational Data on Genotype-Guided Management

Abstract

Background: Inherited thrombophilia has been implicated in recurrent pregnancy loss (RPL), but its clinical relevance remains controversial. Current international guidelines mainly emphasize Factor V Leiden (FVL) and Prothrombin G20210A, although these variants are uncommon in South Asian populations. This study evaluated thrombophilia-associated polymorphisms in Indian women with unexplained RPL, with particular attention to PAI-1 4G/5G and MTHFR C677T. Methods: This retrospective case–control study included 451 women with unexplained primary RPL and 198 fertile controls. Women with anatomical, endocrine, chromosomal, autoimmune, infectious, or male-factor causes of pregnancy loss were excluded. Genotyping for FVL G1691A, Prothrombin G20210A, PAI-1 4G/5G, MTHFR C677T, and MTHFR A1298C was performed using multiplex allele-specific PCR followed by capillary electrophoresis. Associations with RPL were evaluated using carrier-based analyses and logistic regression. Pregnancy outcomes among women carrying combined PAI-1 and MTHFR C677T variants who received individualized genotype-guided management were retrospectively described without inference of treatment efficacy. Results: Among 451 women with unexplained RPL, a total of 1527 pregnancy losses were recorded. PAI-1 4G/5G was the most prevalent thrombophilia-associated polymorphism, detected in 70.1% of women with RPL compared with 47.2% of fertile controls (p < 0.001). MTHFR C677T variants were also significantly more frequent among women with RPL (27.7% vs. 9.1%; p < 0.001). In contrast, Factor V Leiden and Prothrombin G20210A polymorphisms were uncommon, occurring in only 3.1% and 0.4% of women with RPL, respectively. Combined carriage of PAI-1 and MTHFR C677T variants was observed in 19.1% of women with RPL and identified the subgroup with the highest observed odds of recurrent pregnancy loss. Pregnancy outcomes in this subgroup are summarized descriptively to provide observational context. Conclusions: This study demonstrates a distinct Indian thrombophilia profile in unexplained RPL, where PAI-1 4G/5G and MTHFR C677T appear more clinically relevant than FVL and Prothrombin G20210A. These findings provide descriptive, population-specific observational data and underscore the need for larger prospective multicenter studies to clarify their relevance for future screening strategies.