DISCUSSION
Pregnancy loss (PL) is a common medical problem among reproductive-age women. However, relatively few women having one pregnancy loss experience multiple or recurrent pregnancy loss.(12)Maintaining a normal pregnancy requires a series of differential gene expressions. FVL and MTHFR gene mutations are suggested as being reasons for PL.(13) A study by Rodger et al,(14) addressed the association of inherited thrombophilia with PL in late primigravida, focusing on tests for FVL, and MTHFR.(14) Associations between these heritable thrombophilia variants and other serious pregnancy complications have also been documented. The main underlying mechanisms seem to be inhibition of trophoblast differentiation/invasion, and thrombosis of the maternal side of the placenta resulting in placenta mediated pregnancy complications and fetal loss.(15) However, the relation between thrombophilia associated gene mutations and the adverse obstetric outcome is controversial and data in the literature are inconsistent because of study heterogeneity, potential publication bias, and sequential testing.(16)
The present Cross-sectional study aimed to investigate the prevalence of thrombophilic gene mutations (FVL and MTHFR C 667 T) with miscarriage in primigravida in the late first trimester in an attempt to identify candidates for anticoagulation to improve pregnancy outcome. This study was conducted on 40 primigravida pregnant women with missed abortion in the late first trimester. In the present study, the maternal age was between 18.0 and 34.0years, with a mean of 24.23 ± 3.39 years. While the gestational age was between 8.14 – 13.71 weeks with a mean of 10.91 ± 1.59 weeks. In our study, MTHFR C 667T mutations were present in 21 cases out of 40 participating cases (52.5%). Several studies(17-19) reported increasing evidence for a pathogenetic role of MTHFR gene polymorphism C677T in early PL. On the other hand, other authors(20, 21) found a negative association stating that MTHFR polymorphisms do not carry any risk in pregnancy. The different inclusion criteria and the different ethnic backgrounds of the selected patients may have contributed to the contradictory results. According to FVL gene mutation, it was present in 12 cases out of 40 participating cases (30%). There is a large and contradictory body of literature on the association between maternally inherited thrombophilia and recurrent miscarriage(16, 22, 23). Although most(16, 24, 25) but not all(26, 27) large prospective cohort studies have failed to establish a consistent association between inherited thrombophilia and early or late fetal loss. The case-control and retrospective cohort studies have generally reported a link between FVL heterozygosity and fetal loss after 10 weeks and particularly for nonrecurrent loss after 20 weeks (28-31). This suggests that any association is limited to high-risk populations and is modest. Small case-control or retrospective cohort studies involving heterogeneous populations have frequently reported contradictory results, in part because of the influence of various confounders (e.g. age, obesity) that are often not analyzed appropriately.(29, 31)
In our study, there were 4 cases with combined thrombophilia (10 %). Combined thrombophilia included FVL and MTHFR C677T only. The same results were reported by previous studies(17, 32-34) that identified combined thrombophilic defects in women with recurrent PL, both early and late. The study by Rozano-Gorelick et al,(32) reported that combined thrombophilia exists when inherited and /or acquired prothrombotic factors are pooled and every combination carries a different risk of thrombosis. Furthermore, Sarig et al,(26) proposed a scoring system for women with thrombophilia based on four major categories: obstetric history, previous thromboembolic events, family history of thrombosis or gestational vascular complications, and type of thrombophilia. Combined thrombophilia was given a high score and the total score is calculated by summing up the scores of the four categories. Based upon the score achieved, the pregnancy risk for an individual woman may be stratified into four levels of risk: low ≤5, intermediate (score 6-10), high (score 11-14), and extremely high (score≥ 15). Finally, the number of homozygous and heterozygous individuals were assessed for each of the gene mutations studied. No homozygosity was detected in cases with FVL gene mutation cases. However, 6 cases out of 21 cases of MTHFR gene mutation were homozygous (15 %). A study by Couto et al,(35) reported a low prevalence of homozygotes for FVL and stated that the prothrombotic tendency during pregnancy and the risk of thromboembolic events is increased with antithrombin deficiency and homozygous FVL as single traits. In fact, the reported prevalence in the general population of FVL homozygotes is less than 1% with a 2-4% risk of venous thromboembolism (VTE) per pregnancy increasing to around 17% in women with a previous history of VTE.(36, 37)Hence, our study and other studies reported an association between some types of thrombophilia and early miscarriage, but the absolute risk is small and varies considerably among reports. However, most large prospective cohort studies have failed to establish a consistent association between inherited thrombophilias and adverse pregnancy outcomes. According to recent evidence, screening for inherited thrombophilia in women with a history of recurrent or nonrecurrent fetal loss, abruption, intrauterine growth restriction, or preeclampsia is not recommended.(38) Moreover, there is mounting evidence that the administration of prophylactic anticoagulation during pregnancy for the prevention of placenta- mediated pregnancy complications does not improve pregnancy outcome in affected patients.(39)