Folic acid supplementation in children with sickle cell disease: study protocol for a double-blind randomized cross-over trial

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Abstract

Background

Sickle cell disease (SCD) is a genetic disorder which causes dysfunctional red blood cells (RBC) and is thought to increase requirements for folate, an essential B vitamin, due to increased RBC production and turnover in the disease. High-dose supplementation with 1–5 mg/d folic acid, synthetic folate, has been the standard recommendation for children with SCD. There is concern about whether children with SCD need such high doses of folic acid, following mandatory folic acid fortification of enriched grains in Canada, and advancements in medical therapies which extend the average lifespan of RBCs. In animal and human studies, high folic acid intakes (1 mg/d) have been associated with accelerated growth of some cancers, and the biological effects of circulating unmetabolized folic acid (UMFA), which can occur with doses of folic acid ≥ 0.2 mg/d, are not fully understood. The objective of this study is to determine efficacy of, and alterations in folate metabolism from high-dose folic acid in children with SCD during periods of folic acid supplementation versus no supplementation.

Methods

In this double-blind randomized controlled cross-over trial, children with SCD ( n = 36, aged 2–19 years) will be randomized to either receive 1 mg/d folic acid, the current standard of care, or a placebo for 12 weeks. After a 12-week washout period, treatments will be reversed. Total folate concentrations (serum and RBC), different folate forms (including UMFA), folate-related metabolites, and clinical outcomes will be measured at baseline and after treatment periods. The sum of the values measured in the two periods will be calculated for each subject and compared across the two sequence groups by means of a test for independent samples for the primary (RBC folate concentrations) and secondary (UMFA) outcomes. Dietary intake will be measured at the beginning of each study period.

Discussion

As the first rigorously designed clinical trial in children with SCD, this trial will inform and assess current clinical practice, with the ultimate goal of improving nutritional status of children with SCD.

Trial registration

ClinicalTrials.gov NCT04011345. Registered on July 8, 2019

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Most cited references 40

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Folic acid for the prevention of colorectal adenomas: a randomized clinical trial.

Bernard F Cole, John A. Baron, Robert Sandler … (2007)

Laboratory and epidemiological data suggest that folic acid may have an antineoplastic effect in the large intestine. To assess the safety and efficacy of folic acid supplementation for preventing colorectal adenomas. A double-blind, placebo-controlled, 2-factor, phase 3, randomized clinical trial conducted at 9 clinical centers between July 6, 1994, and October 1, 2004. Participants included 1021 men and women with a recent history of colorectal adenomas and no previous invasive large intestine carcinoma. Participants were randomly assigned in a 1:1 ratio to receive 1 mg/d of folic acid (n = 516) or placebo (n = 505), and were separately randomized to receive aspirin (81 or 325 mg/d) or placebo. Follow-up consisted of 2 colonoscopic surveillance cycles (the first interval was at 3 years and the second at 3 or 5 years later). The primary outcome measure was occurrence of at least 1 colorectal adenoma. Secondary outcomes were the occurrence of advanced lesions (> or =25% villous features, high-grade dysplasia, size > or =1 cm, or invasive cancer) and adenoma multiplicity (0, 1-2, or > or =3 adenomas). During the first 3 years, 987 participants (96.7%) underwent colonoscopic follow-up, and the incidence of at least 1 colorectal adenoma was 44.1% for folic acid (n = 221) and 42.4% for placebo (n = 206) (unadjusted risk ratio [RR], 1.04; 95% confidence interval [CI], 0.90-1.20; P = .58). Incidence of at least 1 advanced lesion was 11.4% for folic acid (n = 57) and 8.6% for placebo (n = 42) (unadjusted RR, 1.32; 95% CI, 0.90-1.92; P = .15). A total of 607 participants (59.5%) underwent a second follow-up, and the incidence of at least 1 colorectal adenoma was 41.9% for folic acid (n = 127) and 37.2% for placebo (n = 113) (unadjusted RR, 1.13; 95% CI, 0.93-1.37; P = .23); and incidence of at least 1 advanced lesion was 11.6% for folic acid (n = 35) and 6.9% for placebo (n = 21) (unadjusted RR, 1.67; 95% CI, 1.00-2.80; P = .05). Folic acid was associated with higher risks of having 3 or more adenomas and of noncolorectal cancers. There was no significant effect modification by sex, age, smoking, alcohol use, body mass index, baseline plasma folate, or aspirin allocation. Folic acid at 1 mg/d does not reduce colorectal adenoma risk. Further research is needed to investigate the possibility that folic acid supplementation might increase the risk of colorectal neoplasia. clinicaltrials.gov Identifier: NCT00272324.

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The metabolism of homocysteine: pathways and regulation.

Marsha Finkelstein (1998)

Two pathways, the methionine cycle and transsulfuration, account for virtually all methionine metabolism in mammals. Every tissue possesses the methionine cycle. Therefore, each can synthesize AdoMet, employ it for transmethylation, hydrolyze AdoHcy, and remethylate homocysteine. Transsulfuration, which occurs only in liver, kidney, small intestine and pancreas, is the means for catabolizing homocysteine. Liver has a unique isoenzyme of MAT that allows the utilization of excess methionine for the continued synthesis of AdoMet. Metabolic regulation is based on the distribution of available homocysteine between remethylation and conversion to cystathionine. The tissue content of the enzymes and their inherent kinetic properties provide the basis for the regulatory mechanism. The effector properties of the metabolites AdoMet, AdoHcy and methylTHF are of particular relevance.

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Fetal hemoglobin in sickle cell anemia: a glass half full?

Martin Steinberg, David Chui, George J Dover … (2014)

Fetal hemoglobin (HbF) modulates the phenotype of sickle cell anemia by inhibiting deoxy sickle hemoglobin (HbS) polymerization. The blood concentration of HbF, or the number of cells with detectable HbF (F-cells), does not measure the amount of HbF/F-cell. Even patients with high HbF can have severe disease because HbF is unevenly distributed among F-cells, and some cells might have insufficient concentrations to inhibit HbS polymerization. With mean HbF levels of 5%, 10%, 20%, and 30%, the distribution of HbF/F-cell can greatly vary, even if the mean is constant. For example, with 20% HbF, as few as 1% and as many as 24% of cells can have polymer-inhibiting, or protective, levels of HbF of ∼10 pg; with lower HbF, few or no protected cells can be present. Only when the total HbF concentration is near 30% is it possible for the number of protected cells to approach 70%. Rather than the total number of F-cells or the concentration of HbF in the hemolysate, HbF/F-cell and the proportion of F-cells that have enough HbF to thwart HbS polymerization is the most critical predictor of the likelihood of severe sickle cell disease.

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Author and article information

Contributors

Crystal D. Karakochuk:

ORCID: http://orcid.org/0000-0002-1025-2194

crystal.karakochuk@ubc.ca

Journal

Journal ID (nlm-ta): Trials

Journal ID (iso-abbrev): Trials

Title: Trials

Publisher: BioMed Central (London )

ISSN (Electronic): 1745-6215

Publication date (Electronic): 29 June 2020

Publication date PMC-release: 29 June 2020

Publication date Collection: 2020

Volume: 21

Electronic Location Identifier: 593

Affiliations

[1 ]GRID grid.17091.3e, ISNI 0000 0001 2288 9830, Food, Nutrition, and Health, Faculty of Land and Food Systems, , The University of British Columbia, ; 2205 East Mall, Vancouver, British Columbia V6T 1Z4 Canada

[2 ]GRID grid.414137.4, ISNI 0000 0001 0684 7788, BC Children’s Hospital Research Institute, ; 950 W 28th Avenue, Vancouver, British Columbia V5Z 4H4 Canada

[3 ]GRID grid.17091.3e, ISNI 0000 0001 2288 9830, Department of Pediatrics, Faculty of Medicine, , The University of British Columbia, ; 4480 Oak Street, Vancouver, British Columbia V6H 3V4 Canada

[4 ]GRID grid.414137.4, ISNI 0000 0001 0684 7788, Department of Pharmacy, , BC Children’s Hospital, ; 4480 Oak Street, Vancouver, British Columbia V6H 3V4 Canada

[5 ]GRID grid.17091.3e, ISNI 0000 0001 2288 9830, School of Population and Public Health, , The University of British Columbia, ; 2206 East Mall, Vancouver, British Columbia V6T 1Z3 Canada

[6 ]GRID grid.416553.0, ISNI 0000 0000 8589 2327, The Centre for Health Evaluation and Outcome Science, , St. Paul’s Hospital, ; 588 – 1081 Burrard Street, Vancouver, British Columbia V6Z 1Y6 Canada

[7 ]GRID grid.414137.4, ISNI 0000 0001 0684 7788, Department of Pathology and Laboratory Medicine, , BC Children’s Hospital, ; 4480 Oak Street, Vancouver, British Columbia V6H 3V4 Canada

Author information

Crystal D. Karakochuk http://orcid.org/0000-0002-1025-2194

Article

Publisher ID: 4540

DOI: 10.1186/s13063-020-04540-7

PMC ID: 7325072

PubMed ID: 32600389

SO-VID: ac104aba-b0fd-4c79-9b47-27c88ca832a1

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 19 May 2020

Date accepted : 19 June 2020

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100000024, Canadian Institutes of Health Research;

Award ID: 419565

Award Recipient : Crystal D. Karakochuk

Funded by: FundRef http://dx.doi.org/10.13039/100005627, Thrasher Research Fund;

Award ID: 14798

Award Recipient : Crystal D. Karakochuk

Custom metadata

ScienceOpen disciplines: Medicine

Keywords: sickle cell disease,pediatrics,nutrition,folic acid,micronutrient supplementation,randomized control trial

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ScienceOpen disciplines: Medicine

Keywords: sickle cell disease, pediatrics, nutrition, folic acid, micronutrient supplementation, randomized control trial

Folic acid supplementation in children with sickle cell disease: study protocol for a double-blind randomized cross-over trial

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Abstract

Background

Methods

Discussion

Trial registration

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CHAIN Network Collection

Most cited references 40

Folic acid for the prevention of colorectal adenomas: a randomized clinical trial.

The metabolism of homocysteine: pathways and regulation.

Fetal hemoglobin in sickle cell anemia: a glass half full?

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