Projects / Programmes
New frontiers in folate supplementation in obstetrics and gynaecology (NFFS OB-GYN)
| Code |
Science |
Field |
Subfield |
| 3.05.00 |
Medical sciences |
Human reproduction |
|
| Code |
Science |
Field |
| B570 |
Biomedical sciences |
Obstetrics, gynaecology, andrology, reproduction, sexuality |
| Code |
Science |
Field |
| 3.02 |
Medical and Health Sciences |
Clinical medicine |
birth defects, folic acid metabolism, polymorphisms, cell lines, preeclampsia, preventative folic acid intake
Researchers (18)
Organisations (2)
Abstract
Congenital birth defects and adverse pregnancy outcomes represent a great public-health problem, as they have a long-term impact on health and quality of life of affected children and their families. Disruptions and perturbations in folate metabolism are one of the most important potential risk factors for the most frequent congenital birth defects, such as neural tube defects (NTD), orofacial clefts (OFC) and congenital heart defects (CHD), as well as adverse pregnancy outcomes such as pre-eclampsia. In the aetiology of these conditions can be increased levels of homocysteine and disrupted methylation (especially the methylation of DNA in the context of epigenetic regulation of gene expression).
Polymorphisms in the genes of folate pathway enzymes have a major impact on folate metabolism and the concentration of biologically active form of folate, which is 5-Me-THF. These polymorphisms affect the remethylation cycle, synthesis of DNA and amino acids metabolism. Common genetic polymorphisms are present in all enzymes in the folate and methionine cycle. The average enzymatic activity in subjects with one mutated allele is between 50 and 60%; but it can be decreased to 30% of wild type activity.
Since 1997, gynaecologists and obstetricians in Slovenia recommend folic acid supplementation to all women in the first trimester of pregnancy. At the same time, we know, that in Slovenia only 19 % of pregnant women were taking folic acid properly.
The key aim of this research proposal is to introduce individualized treatment of women during pregnancy and those who are planning a pregnancy with the goal of improving maternal health and pregnancy outcomes. The overall objective of the project is to evaluate efficacy of different derivatives and formulations of folic acid in individuals with different genetic backgrounds of folate-methionine pathway on folate status, pregnancy outcomes and the efficacy of the prevention of anti-folate effects of certain drugs. To achieve the objectives we will use several different research approaches (family based and retrospective studies) and study models (cell lines, healthy individuals, OFC, CHD, pre-eclampsia patients and in silico models).
AIM 1: Study of influence of different folate forms on folate status according to the genetically determined variants of enzymes of the folate-methionine cycle.
Work package (WP) 1. In silico study model – Estonian genome centre cohort
WP 2. In vitro study - lymphoblastoid cell lines
WP 3: In vivo study – healthy individuals
AIM 2: Impact of genetic variants in genes of folate-methionine cycle on pregnancy outcomes
WP 1: Comparison of healthy and affected pregnancy in mothers of children with CHD or OFC
WP 2: Family studies of CHD and OFC
WP3: Retrospective study of the impact of genetic variants in genes of folate-methionine cycle on the incidence of PE and the associated consequences for the child
AIM 3: A study of interactions between drugs prescribed in pregnancy and in childbearing age and folate supplements
WP 1: Study of the impact of different folate forms on the anti-folate effect of the selected drug models
WP 2: Study of the impact of different folate forms on the anti-folate effects of the selected model drugs, according to the genotype of the relevant enzymes of the folate cycle
The advantage of the proposed project is in translational approach to research: we follow the principle of transfer of new findings from laboratory to the patients and vice versa transfer of clinical problems to basic research.
The project represents the real issues of identification and prevention of developmental abnormalities and diseases, formation of (new) scientific approaches to solving problems and returning the results and findings back in the medical practice.
The interdisciplinary team includes cooperation of experts from University Medical Center Ljubljana and Faculty of Pharmacy, Univ
Significance for science
Despite relatively high frequency and extensive research of developmental defects associated with folate metabolism their aetiology remains unclear. Consequently, their adequate prevention is impaired.
In many cases the research is fragmented and there is limited connection between basic and clinical researchers. The advantage of the proposed project is in translational approach to research: we follow the principle of transfer of new findings from laboratory to the patients and vice versa transfer of clinical problems to basic research.
The closer integration between basic researchers in laboratories and clinicians will result in increased understanding of the challenges everyone involved in the translation chain - from the patient's needs to the complexity of the cell models in vitro in basic research laboratory. The consistent introduction of the principles of translational research will increase the capacity of personnel in research and development and their innovation.
In vitro studies in cell lines with different combinations of genotypes in genes of the folate cycle will enable basic research of the biological mechanisms that lead to the occurrence of certain developmental abnormalities and diseases.
The project represents a continuation of already established research program group with a strong emphasis on mutual cooperation and exchange of information/experience between basic researchers and clinicians in the development and use of new "state-of-the-art" designs. By cooperation of different research groups we achieve growing scientific power due to the synergistic effect and the simultaneous complementary expertise in research and professional fields.
The project represents the real issues of identification and prevention of developmental abnormalities and diseases, formation of (new) scientific approaches to solving problems and returning the results and findings back in the medical practice.
The project is important for the development of medicine and pharmacy (perinatology, embryology, drug development, pharmaceutical care), education of professionals and to improve the health care in Slovenia.
The research project will be carried out by an interdisciplinary team, which is already successfully participated in previous completed projects. The interdisciplinary team includes cooperation of experts from University Medical Center Ljubljana and Faculty of Pharmacy, University of Ljubljana, which ensures high scientific relevance and completion of ambitiously set goals.
Significance for the country
Perinatal mortality rates are an indicator of the health status of a given population and reflect country’s economic development and standard of living. Congenital developmental anomalies represent a leading cause of death of children in their first year of life. Among them, those associated with folate metabolism (congenital heart defects, neural tube defects and orofacial clefts) are the most common. Studies indicate that aforementioned disorders occur more frequently in lower socioeconomic strata. Heart defects and neural tube defects strongly influence the survival of neonates whereas orofacial clefts primarily affect the quality of the children life.
At the same time, we know, that in Slovenia only 19 % of pregnant women are taking folic acid properly.
Identification of potential genetic biomarkers associated with decreased folate status would allow prediction of the birth defects associated with folate metabolism. Consequently, this could lead to the reduction of incidence of birth defects and improvement of pregnancy outcomes. Our results might improve the detection of women at higher risk of birth defects associated with folate metabolism; they would be recommended for higher daily doses of folic acid or methyl-tetrahydrofolate before and during pregnancy.
The treatment of affected children represents economic burden that can be reduced by prevention of developmental defects and their early detection. The results of international economic evaluations demonstrate that the costs of comprehensive health care in a first year of life are up to 30,000 euro higher for a child suffering from a neural tube defect compared with the expenses for a healthy child.
Most important scientific results
Interim report,
final report
Most important socioeconomically and culturally relevant results
Interim report,
final report
