Recurrent pregnancy loss is a complex health challenge with no universally accepted definition. Inconsistency in definitions involves not only the number of spontaneous abortions (two or three) that are accepted for recurrent pregnancy loss but the types of pregnancy and gestational age at miscarriage. Due to the heterogeneity of definitions and criteria applied by international guidelines for recurrent pregnancy loss, the true incidence of recurrent miscarriage, which is reported to range from 1% to 5%, is difficult to estimate. Moreover, the exact etiology of recurrent pregnancy loss remains questionable; thus, it is considered a polyetiological and multifactorial condition with many modifiable and non-modifiable factors involved. Even after thoroughly evaluating recurrent pregnancy loss etiology and risk factors, up to 75% of cases remain unexplained. This review aimed to summarize and critically analyze accumulated knowledge on the etiology, risk factors, relevant diagnostic options, and management approach to recurrent pregnancy loss. The relevance of various factors and their proposed roles in recurrent pregnancy loss pathogenesis remains a matter of discussion. The diagnostic approach and the management largely depend on the etiology and risk factors taken into consideration by a healthcare professional as a cause of recurrent miscarriage for a particular woman or couple. Underestimation of social and health consequences of recurrent pregnancy loss leads to compromised reproductive health and psychological well-being of women after miscarriage. Studies on etiology and risk factors for recurrent pregnancy loss, especially idiopathic, should be continued. The existing international guidelines require updates to assist clinical practice.

The rationale and importance of folic acid supplementation during pregnancy for fetal congenital defect prevention are accepted worldwide. Moreover, a sufficient plasma concentration of folates can reduce the incidence of spontaneous abortions, and support the normal expansion of placental blood vessels, ensuring physiological placental blood flow, thus promoting appropriate fetal growth and development. Furthermore, there is emerging evidence that long-term supplementation with folic acid can effectively prevent preeclampsia. Preeclampsia is unique to the human species in complications during pregnancy, which contributes to maternal and perinatal mortality worldwide. In the pathogenesis of preeclampsia abnormal placental invasion, the excess of antiangiogenic factors and maternal–placental syndrome play a key role. Increased blood levels of homocysteine during pregnancy are associated with the risk of preeclampsia. Moreover, hyperhomocysteinemia has been proposed to be an independent risk factor for preeclampsia. Folate supplementation helps to decrease elevated levels of homocysteine; thus, the role of folic acid supplementation in pregnancy is even more important. Multiple reports suggest that folate administration decreases the level of serum homocysteine and, therefore, reduce the risk and severity of preeclampsia. However, the association between folic acid supplementation and the decreased risk of preeclampsia has been investigated with controversial conclusions. Currently, the optimal dose of folic acid that is effective for preeclampsia prevention remains uncertain. In this review, we aim to summarize the accumulated knowledge on the role of folic acid in the pathogenesis of preeclampsia, and the possible impact of folate supplementation on the decreased risk of preeclampsia.

Background: Recurrent pregnancy loss (RPL) is associated with increased incidence and severity of depression, anxiety, and stress, and screening for these comorbidities following miscarriages is beneficial for women with RPL who are planning future pregnancies. This study aims to investigate depression, anxiety, and stress among Kazakhstani women with RPL. Methods: This was a case–control study involving 70 women with confirmed RPL and 78 ethnically matched control women. Depression, anxiety, and stress were evaluated using the Depression Anxiety Stress Scales (DASS)-21 instrument. Linear regression and correlation analysis were used in assessing the association of RPL with symptoms of depression, and/or anxiety, and/or stress, after adjusting for key covariates. Results: Women with RPL were found to have significantly higher mean scores for depression (p < 0.001), anxiety (p < 0.001), and stress (p < 0.001) symptoms. Mild–moderate stress and mild–moderate and severe–extreme depression and anxiety symptoms were more frequent in the RPL group than in the control group. Regression analysis demonstrated that RPL was the only significant variable associated with anxiety, depression, and stress symptoms. Conclusion: The results of this study suggest that women with RPL are more likely to experience heightened symptoms of depression, anxiety, and stress. Proper psychological counseling is recommended for women with RPL, as well as their spouses.

Introduction: Preeclampsia is a severe multifactorial complication of pregnancy. Studies found associations between folate metabolism genes’ polymorphisms and preeclampsia. However, investigations in this field are limited among Asian populations. Thus, the study’s aim was to evaluate the prevalence of methionine synthase (MTR), methionine synthase reductase (MTRR), and methylenetetrahydrofolate reductase (MTHFR) genes’ polymorphisms among ethnic Kazakh women with preeclampsia. Methods: This was a retrospective study involving 4246 patients’ data for the period of 2018–2022. Identification of MTR, MTRR, and MTHFR genes’ polymorphism was performed via PR-PCR. Peripheral blood samples were obtained for the analyses. In total, 4246 patients’ data of Kazakh ethnicity with preeclampsia at >20 weeks gestational age who had undergone an investigation to identify polymorphisms of the folate metabolism pathway genes for the period of 5 years were included in this study. Results: The most common and prevalent mutation was the MTRR A66G polymorphism: 24.5% of all tested patients with preeclampsia had the MTRR A66G polymorphism. It was highest among the 35–39 age group participants. The second most prevalent was the MTHFR C677T polymorphism: 9% of women with preeclampsia had the MTHFR C677T mutation. It was highest among women aged 30–34. There was a rare association of the MTR A2756G mutation with preeclampsia among the study participants. Conclusions: The identified levels of MTRR A66G and MTHFR C677T polymorphisms among the study participants suggest the importance of evaluating MTRR and MTHFR polymorphisms in women with preeclampsia. The role of the MTR A2756G polymorphism in the development of preeclampsia needs to be further investigated.

Introduction.Preeclampsia remains one of the leading causes of maternal and perinatal morbidity worldwide. Accumulated evidence indicates that disturbances in folate metabolism and elevated homocysteine levels may contribute to the development of hypertensive disorders of pregnancy. This study evaluated the effectiveness of long-term folic acid supplementation for the prevention of preeclampsia in pregnant women with and without polymorphisms in folate cycle genes.Methods.A single-center randomized controlled study included 320 women in the control group (folic acid intake until 12 weeks of gestation) and 894 women in the main group (folic acid intake throughout pregnancy). The main group was stratified by dosage: 400 μg, 800 μg, and 1200 μg. Clinical, biochemical, and genetic assessments were performed, including measurement of homocysteine levels and genotyping of MTHFR, MTR, and MTRR polymorphisms. Pregnancy outcomes and the incidence of hypertensive complications were compared between groups.Results.Long-term folic acid supplementation was associated with a lower overall incidence of hypertensive disorders of pregnancy compared with the control group (RR 1.43; p = 0.038). The incidence of preeclampsia was 1.67 times lower in the main group, indicating a favorable trend. No significant differences in blood pressure dynamics or perinatal outcomes were found among groups receiving different folic acid doses. Homocysteine levels were significantly higher in all women who subsequently developed preeclampsia, regardless of folic acid dosage. Genotype distribution demonstrated population-specific frequencies of MTHFR and MTR polymorphisms; however, no clear dose–response relationship was observed.Conclusion.Long-term folic acid supplementation reduces the risk of hypertensive disorders of pregnancy, including a tendency toward a decreased incidence of preeclampsia, and is safe at all studied doses. The potential benefit is particularly relevant for populations with a high prevalence of genetic variants affecting folate metabolism. Further multicenter randomized studies are required to determine the optimal dosage and duration of supplementation.Keywords:preeclampsia, folate cycle, folic acid.