## 4 Discussion
### Folate Transporters SNVs and Pregnancy Failure
In the second study, the rs1131596 (-43T>C) variant of the SLC19A1 gene was significantly associated with a risk of recurrent miscarriage in Iranian women (\(p\) < 0.05). Haplotype frequencies of rs/rs/rs were also found to be significantly different in patients than controls in this research [16]. In our population, we examined only one of these variants (80G>A) and found no association with either miscarriages or IUFD. [PERSON] et al. [42] studied the association between the RFC-1 80G>A polymorphism and placental abruptly and did not find any significant differences between this variant, plasma folate levels and abruption risk. The authors suspected that this was related to the high prevalence of prenatal multivitamin and folate supplementation in this population (over 80%) [42]. In our study, we did not examine the patients' serum folate levels, assuming that it would be unreliable due to the supplementation of folic acid (mainly levomefolic acid) by all participants in this project. Also, the difference in gestational age between the groups at the time of sample collection resulted in our decision not to analyze folate metabolites in the patients' serum. In cases of stillbirth, examining the placenta, which comprises distinct circulatory systems from both the mother and fetus, offers valuable insights into potential causes. Placental pathology has been shown to identify the cause of stillbirth in 64.6% of cases, outperforming other methods such as fetal autopsy (42.4%), genetic testing (11.9%), and antiphospholipid antibody testing (11.1%) [43,44]. [PERSON] et al. [45] conducted an analysis of placental pathology in intrauterine fetal deaths spanning from 13 to 40 weeks of gestation, attributing 32% of stillbirths to placental abnormalities. Similarly, [PERSON] et al. [46] reviewed a clinical database containing 1,256 cases of previously unexplained pregnancy losses between 6 and 43 weeks of gestation. Their examination of placental pathology slides revealed dysmorphic chorionic villi, a feature linked to genetic abnormalities, in 86.2% of unexplained miscarriages (757 cases). For unexplained stillbirths, the most frequent placental anomaly was a small placenta, observed in 33.9% of cases (128 cases) [46]. Given that placental abnormalities and low fetal weight are established risk factors for intrauterine fetal death [47], we restricted our investigation of the relationship between placental and neonatal weights and the studied genetic variants in a control group of healthy mothers. However, our findings revealed no association between the genetic variants implicated in folate transport and distribution and neonatal or placental weights, as assessed in both unadjusted and adjusted models. Folate receptor autoantibodies (FRAbs) can disrupt folate internalization and metabolism by binding to or blocking folate receptors. Experimental studies on pregnant rats have shown that FR\(\alpha\)Ab accumulates rapidly in the placenta, impeding folate transport to the fetus. In such cases, higher concentrations of folate were necessary to overcome receptor blockades and restore transport efficiency [48]. These findings suggest that FR\(\alpha\)Ab could play a significant role in pregnancy complications, warranting careful evaluation when designing therapeutic strategies involving folic acid supplementation for such conditions [49].