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Effect of folic acid supplementation in pregnancy on preeclampsia: the folic acid clinical trial study.

Wen SW, Champagne J, Rennicks White R, Coyle D, Fraser W, Smith G, Fergusson D, Walker MC - J Pregnancy (2013)

Bottom Line: A web-based randomization system and electronic data collection system provide the platform for participating centers to randomize their eligible participants and enter data in real time.To date we have twenty participating Canadian centers, of which eighteen are actively recruiting, and seven participating Australian centers, of which two are actively recruiting.Recruitment in Argentina, UK, Netherlands, Brazil, West Indies, and United States is expected to begin by the second or third quarter of 2013.

View Article: PubMed Central - PubMed

Affiliation: OMNI Research Group, Department of Obstetrics and Gynecology, Faculty of Medicine, Ottawa Hospital, University of Ottawa, 501 Smyth Road, Ottawa, ON, Canada K1H 8L6 ; Clinical Epidemiology Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON, Canada K1H 8L6 ; Department of Epidemiology, Biostatistics and Occupational Health and Department of Pediatrics, McGill University Faculty of Medicine, 3175 Cote Ste. Catherine, Montreal, QC, Canada H3T 1C5 ; Department of Epidemiology and Community Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, Canada.

ABSTRACT
Preeclampsia (PE) is hypertension with proteinuria that develops during pregnancy and affects at least 5% of pregnancies. The Effect of Folic Acid Supplementation in Pregnancy on Preeclampsia: the Folic Acid Clinical Trial (FACT) aims to recruit 3,656 high risk women to evaluate a new prevention strategy for PE: supplementation of folic acid throughout pregnancy. Pregnant women with increased risk of developing PE presenting to a trial participating center between 8(0/7) and 16(6/7) weeks of gestation are randomized in a 1 : 1 ratio to folic acid 4.0 mg or placebo after written consent is obtained. Intent-to-treat population will be analyzed. The FACT study was funded by the Canadian Institutes of Health Research in 2009, and regulatory approval from Health Canada was obtained in 2010. A web-based randomization system and electronic data collection system provide the platform for participating centers to randomize their eligible participants and enter data in real time. To date we have twenty participating Canadian centers, of which eighteen are actively recruiting, and seven participating Australian centers, of which two are actively recruiting. Recruitment in Argentina, UK, Netherlands, Brazil, West Indies, and United States is expected to begin by the second or third quarter of 2013. This trial is registered with NCT01355159.

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Related in: MedlinePlus

Schematic of different proposed mechanisms of action by which folic acid decreases the risk of developing preeclampsia.
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Related In: Results  -  Collection


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fig1: Schematic of different proposed mechanisms of action by which folic acid decreases the risk of developing preeclampsia.

Mentions: The health benefit of folic acid has so far been focused on its effect on NTDs. Several observations on the association between folic acid and NTDs have been made. Examples include low folate intake levels and risk of NTDs was high in pregnancies from low socio-economic families [41, 42], mean RBC folate concentrations in women with a NTD was lower [43], folic acid metabolism in pregnant women affected by NTD was impaired [44], and the use of aminopterin, a powerful folic acid antagonist, was associated with anencephaly [45]. These observations have led to large scale randomized controlled trials of the effect of periconceptional folic acid supplementation on preventing NTDs. The trials demonstrated a dramatic effect of folic acid on NTDs, at least 70% reduction in the recurrence or first occurrence of NTDs [46, 47]. Based on evidence from the randomized controlled trials, policies and guidelines on periconceptional folic acid supplementation have been implemented since the 1990s in many countries including Canada [37, 38, 48], with high dose folic acid (4.0–5.0 mg) recommended for high risk women and low dose folic acid (0.4–1.1 mg) for low risk women in the prevention of NTDs. High dose folic acid (5 mg per day) during pregnancy to treat anaemia in earlier clinical trials [48, 49] did not show any effect on pregnancy complications, a reassurance of its safety. The hypothesis behind the effect of periconceptional folic acid supplementation on NTDs states that once the chorioallantoic placenta is formed and the fetal heart starts to perfuse it, the requirements for folic acid by the conceptus increase steeply. Based on the fact that folate is required for nucleotide synthesis and cellular methylation potential and therefore modifies DNA synthesis, cell proliferation, and gene regulation, a shortage of folate at this stage might interfere with the orderly closure of the neural tube [50]. While this mechanism may explain the observed effects of folic acid on pregnancy outcomes other than NTDs, a number of other mechanisms have been proposed to explain the observed beneficial effect of folic acid supplementation on PE (Figure 1). The first is related to placental implantation and development. A well implanted and developed placenta is essential for the health and wellbeing of the mother and the fetus. Placental growth/development is a period of increased cell proliferation and differentiation. Therefore, higher folate intakes may be required to support appropriate placental implantation and growth and development in early pregnancy. The second is related to the effect of folic acid on lowering blood homocysteine levels [51, 52], as hyperhomocysteinemia is a risk factor for a number of pregnancy complications including PE [53–55]. The third is related to the effect of folate on improving systemic endothelial function and therefore reducing the risk of such complications as PE [55–58].


Effect of folic acid supplementation in pregnancy on preeclampsia: the folic acid clinical trial study.

Wen SW, Champagne J, Rennicks White R, Coyle D, Fraser W, Smith G, Fergusson D, Walker MC - J Pregnancy (2013)

Schematic of different proposed mechanisms of action by which folic acid decreases the risk of developing preeclampsia.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3852577&req=5

fig1: Schematic of different proposed mechanisms of action by which folic acid decreases the risk of developing preeclampsia.
Mentions: The health benefit of folic acid has so far been focused on its effect on NTDs. Several observations on the association between folic acid and NTDs have been made. Examples include low folate intake levels and risk of NTDs was high in pregnancies from low socio-economic families [41, 42], mean RBC folate concentrations in women with a NTD was lower [43], folic acid metabolism in pregnant women affected by NTD was impaired [44], and the use of aminopterin, a powerful folic acid antagonist, was associated with anencephaly [45]. These observations have led to large scale randomized controlled trials of the effect of periconceptional folic acid supplementation on preventing NTDs. The trials demonstrated a dramatic effect of folic acid on NTDs, at least 70% reduction in the recurrence or first occurrence of NTDs [46, 47]. Based on evidence from the randomized controlled trials, policies and guidelines on periconceptional folic acid supplementation have been implemented since the 1990s in many countries including Canada [37, 38, 48], with high dose folic acid (4.0–5.0 mg) recommended for high risk women and low dose folic acid (0.4–1.1 mg) for low risk women in the prevention of NTDs. High dose folic acid (5 mg per day) during pregnancy to treat anaemia in earlier clinical trials [48, 49] did not show any effect on pregnancy complications, a reassurance of its safety. The hypothesis behind the effect of periconceptional folic acid supplementation on NTDs states that once the chorioallantoic placenta is formed and the fetal heart starts to perfuse it, the requirements for folic acid by the conceptus increase steeply. Based on the fact that folate is required for nucleotide synthesis and cellular methylation potential and therefore modifies DNA synthesis, cell proliferation, and gene regulation, a shortage of folate at this stage might interfere with the orderly closure of the neural tube [50]. While this mechanism may explain the observed effects of folic acid on pregnancy outcomes other than NTDs, a number of other mechanisms have been proposed to explain the observed beneficial effect of folic acid supplementation on PE (Figure 1). The first is related to placental implantation and development. A well implanted and developed placenta is essential for the health and wellbeing of the mother and the fetus. Placental growth/development is a period of increased cell proliferation and differentiation. Therefore, higher folate intakes may be required to support appropriate placental implantation and growth and development in early pregnancy. The second is related to the effect of folic acid on lowering blood homocysteine levels [51, 52], as hyperhomocysteinemia is a risk factor for a number of pregnancy complications including PE [53–55]. The third is related to the effect of folate on improving systemic endothelial function and therefore reducing the risk of such complications as PE [55–58].

Bottom Line: A web-based randomization system and electronic data collection system provide the platform for participating centers to randomize their eligible participants and enter data in real time.To date we have twenty participating Canadian centers, of which eighteen are actively recruiting, and seven participating Australian centers, of which two are actively recruiting.Recruitment in Argentina, UK, Netherlands, Brazil, West Indies, and United States is expected to begin by the second or third quarter of 2013.

View Article: PubMed Central - PubMed

Affiliation: OMNI Research Group, Department of Obstetrics and Gynecology, Faculty of Medicine, Ottawa Hospital, University of Ottawa, 501 Smyth Road, Ottawa, ON, Canada K1H 8L6 ; Clinical Epidemiology Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON, Canada K1H 8L6 ; Department of Epidemiology, Biostatistics and Occupational Health and Department of Pediatrics, McGill University Faculty of Medicine, 3175 Cote Ste. Catherine, Montreal, QC, Canada H3T 1C5 ; Department of Epidemiology and Community Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, Canada.

ABSTRACT
Preeclampsia (PE) is hypertension with proteinuria that develops during pregnancy and affects at least 5% of pregnancies. The Effect of Folic Acid Supplementation in Pregnancy on Preeclampsia: the Folic Acid Clinical Trial (FACT) aims to recruit 3,656 high risk women to evaluate a new prevention strategy for PE: supplementation of folic acid throughout pregnancy. Pregnant women with increased risk of developing PE presenting to a trial participating center between 8(0/7) and 16(6/7) weeks of gestation are randomized in a 1 : 1 ratio to folic acid 4.0 mg or placebo after written consent is obtained. Intent-to-treat population will be analyzed. The FACT study was funded by the Canadian Institutes of Health Research in 2009, and regulatory approval from Health Canada was obtained in 2010. A web-based randomization system and electronic data collection system provide the platform for participating centers to randomize their eligible participants and enter data in real time. To date we have twenty participating Canadian centers, of which eighteen are actively recruiting, and seven participating Australian centers, of which two are actively recruiting. Recruitment in Argentina, UK, Netherlands, Brazil, West Indies, and United States is expected to begin by the second or third quarter of 2013. This trial is registered with NCT01355159.

Show MeSH
Related in: MedlinePlus