FACT Biomarker Subgroup Analysis

Completed

Conditions: Pre-Eclampsia

Interventions: Other: 4.0mg Folic Acid received through participation in FACT (NCT01355159)
Other: Placebo received through participation in FACT

Registration Number: NCT03981029

Lead Sponsor: Ottawa Hospital Research Institute

Brief Summary: The FACT Biomarker Subgroup Analysis is a pilot study of mothers who participated in the Folic Acid Clinical Trial (FACT, NCT01355159). This subgroup analysis aims to determine the effect of high-dose folic acid supplementation in pregnancy on maternal folate status and subsequent impact on risk for pre-eclampsia.

Detailed Description: The Folic Acid Clinical Trial (FACT) was developed to conclusively determine the effect of high dose folic acid supplementation in pregnancy on the prevention of preeclampsia (PE) in a randomized controlled trial (RCT) design.

The primary objective of the FACT Biomarker Subgroup Analysis is to determine the folate status and its impact on risk for PE in a subgroup of women participating in FACT. Our secondary objectives are to:

i) To determine serum vitamin B6 and B12 status, modifiers of folate metabolism, and their impact on risk for PE in women participating in the FACT

ii) To determine plasma homocysteine status, a folate-responsive biomarker for PE risk, and its relationship with risk for PE in women participating in the FACT

iii) To determine the modifying effect of single nucleotide polymorphisms (SNPs) in key folate metabolic enzymes (MTHFR, MTHFD1, MTR) on PE risk in women participating in the FACT

iv) To determine the effect of folic acid supplementation and folate status on biomarkers of PE (sFLT, sENG, PlGF) and their association with PE risk in women participating in the FACT

Folate biomarker analyses will provide key information to identify modifiers of the response to folic acid treatment and elucidate the mechanism(s) underlying the relationship between folic acid treatment and PE risk. Folate status will vary in response to folic acid treatment depending on a number of factors including compliance in taking the study supplement, folate intake from the diet (natural folate and folic acid used for enrichment), vitamin B12 status, and genetic polymorphisms in enzymes involved in folate metabolism that have been shown to effect placental development/function. As such, variation in the response to folic acid treatment may account for differences in observed PE risk.

Folic acid supplementation may also reduce homocysteine, its related endothelial dysfunction and consequently reduce PE risk. In addition, homocysteine metabolism is dependent on vitamins B12 and B6, the deficiency of which can result in hyperhomocysteinemia. Thus, homocysteine, B12 and B6 will each be evaluated.

Lastly, it will be useful to assess biomarkers of placental health and PE risk (sFlt-1, sEng, PlGF) that are found in maternal circulation and determine their association with folate intake and status.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 51

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: OBSERVATIONAL

Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
FACT High-dose folic acid treatment group	4.0mg Folic Acid received through participation in FACT (NCT01355159)	Consenting study participants who, through their participation in FACT (NCT01355159) are randomized to receive daily high-dose folic acid supplementation during pregnancy.
FACT Placebo treatment group	Placebo received through participation in FACT	Consenting study participants who, through their participation in FACT (NCT01355159) are randomized to receive daily placebo supplementation during pregnancy.

Primary Outcome Measures

Name	Time	Method
Folate Status	From FACT randomization at 8-16 weeks gestation to date of sample collection taken at one time point between 24 and 26 completed weeks gestation.	The primary outcome measure is maternal folate status. Folate status will be determined by: 1. Red blood cell (RBC) folate concentrations. 2. Total serum folate concentrations. 3. The relative contribution of folate vitamers to total serum folate concentrations (unmetabolized folic acid, tetrahydrofolic acid, 5,10-methenylTHF, 5-formylTHF, 5-methylTHF and MeFox).

Secondary Outcome Measures

Name	Time	Method
Status of Modifiers of Folate metabolism_ Vitamin B6 (Pyridoxal 5-phosphate)	Taken at one time point between 24 and 26 completed weeks gestation.	Status of modifiers of folate metabolism will be determined by Vitamin B6 and B12 concentrations
Homocysteine Status	From FACT randomization at 8-16 weeks gestation to date of sample collection taken at one time point between 24 and 26 completed weeks gestation.	Maternal homocysteine concentrations will be determined.
Status of Modifiers of Folate metabolism_vitamin B-12	Taken at one time point between 24 and 26 completed weeks gestation.	Status of modifiers of folate metabolism will be determined by Vitamin B6 and B12 concentrations
Angiogenic Potential	From FACT randomization at 8-16 weeks gestation to date of sample collection taken at one time point between 24 and 26 completed weeks gestation.	Angiogenic potential will be determined from measurement of maternal circulating s-FLT-1, s-ENG-1 and placental growth factor concentrations.
Status of Modifiers of Folate metabolism_MTHFR Genotype (C677T)	Taken at one time point between 24 and 26 completed weeks gestation.	Status of modifiers of folate metabolism will be determined by frequency of single nucleotide polymorphisms (SNPs) in the key folate metabolic enzyme MTHFR

Trial Locations

Locations (4): The Moncton Hospital
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Moncton, New Brunswick, Canada
The Ottawa Hospital
🇨🇦
Ottawa, Ontario, Canada
Kingston General Hospital
🇨🇦
Kingston, Ontario, Canada
Health Canada
🇨🇦
Ottawa, Ontario, Canada