PROFILAXY OF CONGENITAL ABNORMALITIES IN FETUS

ABSTRACT

This article analyzes current literature on the prevention of fetal congenital malformations. Serum folate deficiency in pregnant women is discussed as a factor influencing the incidence of neural tube defects. The biochemical mechanisms of folic acid action are described. Evidence supporting the use of folic acid (FA) in women at high risk (obesity, history of birth defects, etc.) for the prevention of fetal defects is presented. Data on the potential negative impact of elevated folate levels is presented. The importance of further research in the prevention of fetal congenital malformations is emphasized.

АННОТАЦИЯ

В данной статье проведен анализ современной литературы по профилактике врожденных пороков развития плода. Рассматривается дефицит фолиевой кислоты в сыворотке крови у беременных женщин как фактор, влияющий на частоту дефектов нервной трубки. Описываются биохимические механизмы действия фолиевой кислоты. Представлены данные, подтверждающие целесообразность применения фолиевой кислоты у женщин с высоким риском (ожирение, наличие врожденных дефектов в анамнезе и т. д.) для профилактики пороков развития плода. Приведены данные о потенциально негативном влиянии повышенного уровня фолиевой кислоты. Подчеркивается важность дальнейших исследований в области профилактики врожденных пороков развития плода.

Keywords: fetus, congenital malformations, prevention, mother.

Ключевые слова: врожденные аномалии плода, профилактика, мать.

Introduction:

The importance of implementing preventive medicine methods for congenital malformations (CM) and hereditary diseases is driven by the increasing role of hereditary diseases in childhood disability and morbidity. Currently, the prevention of fetal congenital diseases is divided into primary and secondary. Primary prevention is aimed at improving the environment and taking a number of measures to improve the health of parents before and during the upcoming pregnancy in order to

The incidence of severe malformations is 2-3 per 1000 births [13]. Genetic and non-genetic factors are distinguished. According to studies, neural tube defects (NTDs) can develop as a result of vitamin deficiency, while exogenous or periconceptional folic acid (FA) intake reduces the risk of NTDs in the unborn child [17].

Methods of researches

According to large studies including tens of thousands of people, most adults consume less folate than established standards[56]. In particular, a study of folate consumption in the German population from 1997 to 2000 showed that, on average, folate consumption by adults was less than 80% of the recommended daily intake for folate in Germany. Moreover, 25% of women of childbearing age had reduced folate levels in their red blood cells and blood plasma[57]. Research by the Institute of Nutrition of the Russian Academy of Medical Sciences indicates a widespread prevalence of vitamin deficiency among pregnant women in all regions of our country. Deficiency of B vitamins was detected in 20-100% of those examined, ascorbic acid in 13-50%, and carotenoids in 25-94%, with a relatively good supply of vitamins A and E[58][59]. The most common deficiencies are iron, iodine, calcium, zinc, chromium, folate, biotin, and vitamins A, D, B1, and B6.[60]

Combination of vitamins for the prevention of congenital malformations

An analysis of data from the National Birth Defects Prevention Study (NBDPS, USA, 1997-2003) showed that higher intakes of B vitamins (folate, vitamins B1, B2, B6, and B12), minerals (calcium, iron, magnesium, and zinc), and vitamin E reduced the risk of congenital malformations by 30-70%[27]. A Norwegian study of 280,127 pregnant women showed that folic acid supplementation reduced the risk of placental abruption by 26%. However, the greatest preventive efficacy was observed with folic acid taken as part of a multivitamin: the risk was reduced by 32% (OR 0.68, 95% CI 0.56-0.83)[61][62].

A study of over 5,000 pregnancies conducted in Hungary showed that the use of multivitamins for the prevention of neural tube defects and other developmental anomalies resulted in a 92% reduction in the incidence of NTDs, a 42% reduction in cardiovascular malformations, and a significant reduction in other developmental defects. Multivitamins containing 0.4–0.8 mg/day of folic acid were more effective in preventing neural tube defects than high doses of folic acid alone [118][52].

Primary prevention of congenital malformations (CM) is a set of measures taken during preconception and pregnancy to eliminate or at least significantly reduce the risk of developing CM in the fetus. According to the WHO, in many countries, congenital malformations are one of the most important causes of childhood mortality, chronic diseases, and disability. As of October 2012, 1 in 33 newborns (approximately 3.2 million annually) have a congenital malformation. 270,000 children die from congenital malformations annually within the first 28 days of life. However, primary prevention is possible. Key methods include nutritional interventions (supplementation with physiological doses of folate, iodine, and other micronutrients), vaccination, and appropriate prenatal care.[1]

According to recommendations in the WHO information letter, primary prevention of congenital malformations should include the following measures[1]:

Improving women's nutrition throughout their reproductive years by ensuring adequate intake of vitamins and minerals (most notably folate and iodine).

Limiting exposure to alcohol and tobacco byproducts.

Eliminating exposure to teratogenic substances (heavy metals, pesticides, and certain medications).

Improving women's physical health (combatting insulin resistance, preventing gestational diabetes, reducing excess body weight, etc.).

Eliminating intrauterine infections (including vaccination against rubella).

Improving training for healthcare workers and other personnel involved in strengthening preventive measures against congenital malformations. The basis for the primary prevention of congenital malformations in the majority of women (more than 60%) is ensuring the woman's nutrition during pregnancy in accordance with the recommended intake of macro- and micronutrients [2]. The study [3] systematized the available scientific information on the relationship between vitamins and birth defects (analysis of more than 1000 articles in PUBMED, www.ncbi.nlm.nih.gov/pubmed). Based on a combined analysis of clinical and experimental data, it was shown that deficiencies of vitamins A, E, D, C, and B vitamins (including folates, pyridoxine, and cyanocobalamin) during pregnancy significantly increase the risk of pregnancy pathologies and fetal malformations.

According to various authors, folate deficiency is associated with multiple disorders, including fetal malformations (including NTDs) [4-6]. Biochemical intracellular reactions: DNA methylation plays an important role in the formation of embryogenesis [1-3]. FA plays a crucial role in the methylation process. The normal range of folate levels is 2.7-17 ng/ml [7]. Of course, it is important to assess the daily dose of folate consumed by a woman during pregnancy. Considering that women consume 400 mcg/day of folate from food and also take prenatal supplements containing FA, this may lead to elevated serum folate levels in pregnant women.[8,9]

Neural tube defects (NTDs) are common, complex, multifactorial disorders of neurulation during the development of the brain and spinal cord in the human embryo between 21 and 28 days after conception [11]. Folate deficiency is a risk factor for NTDs, while the entire methylation process can lead to these defects [12-14]. Studies have been published assessing serum folate levels in women whose fetuses were diagnosed with NTDs during pregnancy. However, studies in cultured rat or mouse embryos with FA deficiency have shown the absence of NTDs in FA deficiency (15-20).

Clinical observations have revealed altered formiminoglutamic acid levels in women who gave birth to children with developmental defects (anencephaly, spina bifida), compared to women who gave birth to healthy children [21].

Analysis of studies conducted worldwide has shown that folate levels may be an important factor in the development of NTDs, based on clinical observations. Thus, the study included the use of a multivitamin-enriched diet (FC 0.36 mg/day) during the periconceptional period in women who had previously given birth to children with NTDs. The control

Scientific and Practical Peer-Reviewed Journal "Current Problems of Health Care and Medical Statistics" 2018, No. 2 _ISSN 2312-2935_

group consisted of women who became pregnant without taking vitamins. The results of the multicenter study showed an 83-91% reduction in the incidence of NTDs in the fetus in women taking vitamins compared to the control group [22-25]. These results indicate the important role of vitamin or FC intake in reducing the incidence of NTDs in newborns.

In the 1990s, a randomized controlled trial conducted at 33 centers (7 countries) by the British Medical Research Council suggested that in women with a history of NTDs in the fetus, daily 400 mcg FA intake was effective in reducing NTDs in repeat pregnancies by 70% [26]. A similar study conducted in Hungary confirmed the need for 0.8 mg/day FA intake during the periconceptional period to reduce primary NTDs (26).

In 2007, Canada proposed including obesity (BMI over 35) as a risk factor, recommending FA intake in doses of 5 mg for patients with a history of poor medication compliance, as well as those with dietary disorders, alcohol consumption, smoking, over-the-counter medication use, and maternal epilepsy and diabetes [27-29].

FA is essential for one-carbon metabolism, which plays an important role in various cellular reactions (amino acid metabolism, purine and pyrimidine biosynthesis) [10]. Transmembrane transport and transport of folate are carried out through receptors and specific transporters. The entire metabolism of FA is modulated by several folate coenzymes. The main function of such a coenzyme is to modulate the metabolic pathway by accepting or donating a one-carbon group [30]. The key genes of this metabolic pathway, involved in the process of transferring a methyl group to the homocysteine ​​molecule, are methylenetetrahydrofolate reductase (MTHFR), methionine synthase reductase (MTRR), reduced folate transporter (RFC), and cobalamin-dependent methionine synthase (MTR) [31]. According to the literature, the etiology of NTDs is associated with dysregulation of genes involved in the major folate or methionine synthase metabolic pathway, as well as with single-nucleotide polymorphisms, such as 677C>T in the MTHFR gene [32].

According to international literature, nutritional epigenetic factors, such as FC (a cofactor in one-carbon metabolism during gestation), can influence fetal cell programming, modulate DNA methylation patterns throughout the genome, and

Scientific and practical peer-reviewed journal "Current problems of health care and medical statistics" 2018, No. 2 _ISSN 2312-2935_

ause dysregulation of gene expression [33]. In an analysis of a study conducted in young children whose mothers took 400 μg of folate during the periconceptional period, improved methylation of the insulin-like growth factor II imprinting gene was noted compared to women who did not take folate during the periconceptional period [34].

To understand the folate-induced epigenetic mechanism regulating neural tube closure, a recent study was conducted on Splotch (Sp-/-) embryos. It showed that maternal folate intake during the periconceptional period reduces the number of H3K27 methylation markers and remodels chromatin in the promoters of Hesl and Neurog2—genes necessary for neural tube development [35].

Results and discussions

To date, the clinical significance of chronic or excessive folate intake remains controversial. A study in mice showed that increasing maternal FA intake during gestation altered the expression of several genes in the frontal cortex of day-old pups by 10-fold [36]. FA intake may prevent the onset of neoplasms at an early stage or potentially cause harm by stimulating the progression of existing preneoplastic lesions [37]. However, a meta-analysis of 50,000 cases evaluating the effect of FA showed that FA intake did not cause a significant increase or decrease in the incidence of cancer at a specific site during the first 5 years of treatment (RR = 1.06, 95% CI, 0.99-1.13) compared with placebo (38). To date, the question of dosage and potential side effects of FA remains controversial [39].

Conclusion

Despite the lack of a trend toward a reduction in the incidence of congenital pathologies in the fetus, issues of prevention and the causes of congenital malformations have not been adequately addressed. It is necessary to continue the search for ways to improve the effectiveness of prenatal diagnosis, as well as new research methods, including Non-invasive methods that allow for the diagnosis of fetal congenital malformations early in pregnancy. Numerous adverse environmental factors have terato- and mutagenic activity. Affecting the body at various stages of development, they lead to disruption of morphogenesis, resulting in congenital malformations. Therefore, preventing congenital pathologies at all stages of development will significantly reduce the incidence of congenital malformations and improve the health of both modern humans and future generations.

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