PMID- 31408467 OWN - NLM STAT- MEDLINE DCOM- 20200109 LR - 20210110 IS - 1549-1676 (Electronic) IS - 1549-1277 (Print) IS - 1549-1277 (Linking) VI - 16 IP - 8 DP - 2019 Aug TI - A novel nutritional supplement to reduce plasma homocysteine in nonpregnant women: A randomised controlled trial in The Gambia. PG - e1002870 LID - 10.1371/journal.pmed.1002870 [doi] LID - e1002870 AB - BACKGROUND: Infant DNA methylation profiles are associated with their mother's periconceptional nutritional status. DNA methylation relies on nutritional inputs for one-carbon metabolic pathways, including the efficient recycling of homocysteine. This randomised controlled trial in nonpregnant women in rural Gambia tests the efficacy of a novel nutritional supplement designed to improve one-carbon-related nutrient status by reducing plasma homocysteine, and assesses its potential future use in preconception trials. METHODS AND FINDINGS: We designed a novel drink powder based on determinants of plasma homocysteine in the target population and tested it in a three-arm, randomised, controlled trial. Nonpregnant women aged between 18 and 45 from the West Kiang region of The Gambia were randomised in a 1:1:1 allocation to 12 weeks daily supplementation of either (a) a novel drink powder (4 g betaine, 800 mug folic acid, 5.2 mug vitamin B12, and 2.8 mg vitamin B2), (b) a widely used multiple micronutrient tablet (United Nations Multiple Micronutrient Preparation [UNIMMAP]) containing 15 micronutrients, or (c) no intervention. The trial was conducted between March and July 2018. Supplementation was observed daily. Fasted venepuncture samples were collected at baseline, midline (week 5), and endline (week 12) to measure plasma homocysteine. We used linear regression models to determine the difference in homocysteine between pairs of trial arms at midline and endline, adjusted for baseline homocysteine, age, and body mass index (BMI). Blood pressure and pulse were measured as secondary outcomes. Two hundred and ninety-eight eligible women were enrolled and randomised. Compliance was >97.8% for both interventions. At endline (our primary endpoint), the drink powder and UNIMMAP reduced mean plasma homocysteine by 23.6% (-29.5 to -17.1) and 15.5% (-21.2 to -9.4), respectively (both p < 0.001), compared with the controls. Compared with UNIMMAP, the drink powder reduced mean homocysteine by 8.8% (-15.8 to -1.2; p = 0.025). The effects were stronger at midline. There was no effect of either intervention on blood pressure or pulse compared with the control at endline. Self-reported adverse events (AEs) were similar in both intervention arms. There were two serious AEs reported over the trial duration, both in the drink powder arm, but judged to be unrelated to the intervention. Limitations of the study include the use of a single targeted metabolic outcome, homocysteine. CONCLUSIONS: The trial confirms that dietary supplements can influence metabolic pathways that we have shown in previous studies to predict offspring DNA methylation. Both supplements reduced homocysteine effectively and remain potential candidates for future epigenetic trials in pregnancy in rural Gambia. TRIAL REGISTRATION: Clinicaltrials.gov Reference NCT03431597. FAU - James, Philip T AU - James PT AUID- ORCID: 0000-0001-5448-8193 AD - Medical Research Council Unit The Gambia at the London School of Hygiene and Tropical Medicine, London, United Kingdom. FAU - Jawla, Ousubie AU - Jawla O AD - Medical Research Council Unit The Gambia at the London School of Hygiene and Tropical Medicine, London, United Kingdom. FAU - Mohammed, Nuredin I AU - Mohammed NI AUID- ORCID: 0000-0002-4067-1103 AD - Medical Research Council Unit The Gambia at the London School of Hygiene and Tropical Medicine, London, United Kingdom. FAU - Ceesay, Kabiru AU - Ceesay K AD - Medical Research Council Unit The Gambia at the London School of Hygiene and Tropical Medicine, London, United Kingdom. FAU - Akemokwe, Fatai M AU - Akemokwe FM AD - Medical Research Council Unit The Gambia at the London School of Hygiene and Tropical Medicine, London, United Kingdom. FAU - Sonko, Bakary AU - Sonko B AUID- ORCID: 0000-0003-3822-2680 AD - Medical Research Council Unit The Gambia at the London School of Hygiene and Tropical Medicine, London, United Kingdom. FAU - Sise, Ebrima A AU - Sise EA AD - Medical Research Council Unit The Gambia at the London School of Hygiene and Tropical Medicine, London, United Kingdom. FAU - Prentice, Andrew M AU - Prentice AM AUID- ORCID: 0000-0001-5389-451X AD - Medical Research Council Unit The Gambia at the London School of Hygiene and Tropical Medicine, London, United Kingdom. FAU - Silver, Matt J AU - Silver MJ AUID- ORCID: 0000-0002-3852-9677 AD - Medical Research Council Unit The Gambia at the London School of Hygiene and Tropical Medicine, London, United Kingdom. LA - eng SI - ClinicalTrials.gov/NCT03431597 GR - MC_U123292700/MRC_/Medical Research Council/United Kingdom GR - MC-A760-5QX00/MRC_/Medical Research Council/United Kingdom GR - MC_EX_MR/M01424X/1/MRC_/Medical Research Council/United Kingdom GR - MR/R010161/1/MRC_/Medical Research Council/United Kingdom GR - MC_UU_00026/3/MRC_/Medical Research Council/United Kingdom PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20190813 PL - United States TA - PLoS Med JT - PLoS medicine JID - 101231360 RN - 0LVT1QZ0BA (Homocysteine) RN - 3SCV180C9W (Betaine) RN - 935E97BOY8 (Folic Acid) RN - P6YC3EG204 (Vitamin B 12) RN - TLM2976OFR (Riboflavin) SB - IM MH - Adolescent MH - Adult MH - Betaine/administration & dosage/therapeutic use MH - *Dietary Supplements MH - Female MH - Folic Acid/administration & dosage/therapeutic use MH - Gambia MH - Homocysteine/antagonists & inhibitors/*blood MH - Humans MH - Middle Aged MH - Nutritional Status MH - Riboflavin/administration & dosage/therapeutic use MH - Vitamin B 12/administration & dosage/therapeutic use MH - Young Adult PMC - PMC6691988 COIS- The authors have declared that no competing interests exist. EDAT- 2019/08/14 06:00 MHDA- 2020/01/10 06:00 PMCR- 2019/08/13 CRDT- 2019/08/14 06:00 PHST- 2019/02/27 00:00 [received] PHST- 2019/07/08 00:00 [accepted] PHST- 2019/08/14 06:00 [entrez] PHST- 2019/08/14 06:00 [pubmed] PHST- 2020/01/10 06:00 [medline] PHST- 2019/08/13 00:00 [pmc-release] AID - PMEDICINE-D-19-00740 [pii] AID - 10.1371/journal.pmed.1002870 [doi] PST - epublish SO - PLoS Med. 2019 Aug 13;16(8):e1002870. doi: 10.1371/journal.pmed.1002870. eCollection 2019 Aug.