Prevention of Neural Tube Defects by Inositol and Vitamin B12 (PONTib) - Development Trial

通过肌醇和维生素 B12 (PONTib) 预防神经管缺陷 - 开发试验

• 批准号: MR/T003847/1
• 负责人: Nicholas Greene
• 金额: $ 38.56万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT003847%2F1
• 关键词: Prevention; Neural; Tube; Defects; Inositol

Neural tube defects (NTDs) are life-threatening birth defects, of which spina bifida is best known. It causes paralysis of the lower body, incontinence of urine and faeces, hydrocephalus ('water on the brain') and other serious health problems. NTDs are common defects, affecting 1 in every 500-2000 pregnancies and with higher frequencies in many low and middle income countries. Supplements containing folic acid (FA), when taken before conception and for the first 3 months of pregnancy, can reduce the risk of a fetus being affected by NTD. However, many women still have babies with NTDs despite taking FA supplements. This experience has shown that 30-50% of NTDs are 'FA-resistant', and for this reason a different supplement is needed to prevent them effectively. Our previous research in mice and humans identified inositol (vitamin B8) as a possible new way to prevent NTDs that do not respond to FA. Other research suggests that vitamin B12 may be an effective additional supplement. Before either inositol or B12 supplementation can be implemented in practice, it is essential to confirm their effectiveness in a clinical trial.This research proposes a pilot clinical trial of inositol in China where there is a high rate of NTDs. This relatively small study will 'pave the way' towards a large-scale, statistically robust clinical trial that will tell us whether inositol, vitamin B12 or both should be used in clinical practice. China is an ideal location for the work as it has an excellent infrastructure for locating women with previous NTD-affected pregnancies, and a very large population to enable sufficient women subjects to be recruited. The study participants will be women with a previous NTD-affected pregnancy who wish to become pregnant again. Those who consent to participate will be randomly assigned to take either inositol, B12, inositol + B12, or neither. In line with the standard care for women at high risk of NTDs, all women subjects will receive 5 mg FA daily. Supplementation will begin before conception and continue until the 12th week of pregnancy. The work will be a collaboration between scientists at University College London - including experts in NTDs and clinical trials - and scientists at Peking University in Beijing. The Chinese investigators have many years' experience of conducting studies during pregnancy in their local populations, for example having recruited over 100,000 women for a study of nutrients in pregnancy in recent years.This pilot study will test whether robust and reliable processes are in place to identify, recruit, randomise and follow up the pregnancies of the women subjects. Then, we plan to progress on to the large-scale trial, where a positive outcome would indicate that inositol and/or vitamin B12 should be taken together with FA in a combined supplement for women planning a pregnancy. The use of inositol or B12 could be rapidly implemented in China, as women already receive free FA tablets when planning a pregnancy. A combined tablet containing inositol/B12 and FA could be provided at a low additional cost. Thereafter, other countries are likely to introduce similar combined supplements to improve NTD prevention. This will not only benefit individuals and families by avoiding the impact of an NTD-affected pregnancy, but will also benefit health care systems economically: the life-time medical and social care costs of a person with spina bifida are more than $0.5M. When the preventive effect of FA was discovered in 1991, this was based on a very similar clinical trial to the one we propose. FA usage has spread to most countries in the world, and we anticipate a similar beneficial effect of our currently proposed research on the future health of children worldwide.

神经管缺陷（NTD）是威胁生命的出生缺陷，其中脊柱裂是最有名的。它会导致下半身瘫痪、大小便失禁、脑积水（"脑积水“）和其他严重的健康问题。NTD是常见的缺陷，每500-2000例妊娠中就有1例受到影响，在许多低收入和中等收入国家发生率更高。在怀孕前和怀孕的前3个月服用含有叶酸（FA）的补充剂，可以降低胎儿受NTD影响的风险。然而，许多妇女仍然有NTD的婴儿，尽管服用FA补充剂。这一经验表明，30-50%的NTD是“抗FA”的，因此需要不同的补充剂来有效预防它们。我们之前在小鼠和人类中的研究确定肌醇（维生素B8）是预防对FA无反应的NTD的可能新方法。其他研究表明，维生素B12可能是一种有效的补充剂。在肌醇或B12补充剂可以在实践中实施之前，必须在临床试验中确认它们的有效性。本研究建议在NTDs发生率较高的中国进行肌醇的试点临床试验。这项相对较小的研究将为大规模的，统计学上可靠的临床试验铺平道路，该试验将告诉我们是否应该在临床实践中使用肌醇，维生素B12或两者。中国是开展这项工作的理想地点，因为它拥有良好的基础设施，可以找到以前受NTD影响的孕妇，而且人口众多，能够招募足够的女性受试者。研究受试者将是既往妊娠受NTD影响并希望再次妊娠的女性。同意参与的患者将被随机分配服用肌醇、B12、肌醇+ B12或两者都不服用。根据NTD高风险女性的标准治疗，所有女性受试者将每日接受5 mg FA。补充将在受孕前开始，并持续到怀孕的第12周。这项工作将是伦敦大学学院的科学家--包括NTD和临床试验的专家--和北京大学的科学家之间的合作。中国研究人员在当地人群中开展妊娠期研究已有多年经验，例如，近年来招募了10万多名女性进行妊娠期营养素研究。这项试点研究将测试是否有健全可靠的流程来识别、招募、随机分配和随访女性受试者的妊娠情况。然后，我们计划进行大规模试验，积极的结果表明，肌醇和/或维生素B12应该与FA一起服用，作为计划怀孕的女性的联合补充剂。肌醇或维生素B12的使用可以在中国迅速实施，因为妇女在计划怀孕时已经获得免费的FA片剂。可以以低的附加成本提供含有肌醇/B12和FA的组合片剂。此后，其他国家可能会引入类似的联合补充剂，以改善NTD的预防。这不仅有利于个人和家庭避免NTD影响怀孕的影响，而且还将使医疗保健系统在经济上受益：脊柱裂患者的终身医疗和社会护理费用超过50万美元。当FA的预防作用在1991年被发现时，这是基于一个与我们提出的非常相似的临床试验。FA的使用已蔓延到世界上大多数国家，我们预计我们目前提出的研究对全球儿童未来健康的有益影响类似。

项目成果

Maternal Inositol Status and Neural Tube Defects: A Role for the Human Yolk Sac in Embryonic Inositol Delivery?

• DOI: 10.1093/advances/nmaa100
• 发表时间: 2021-02-01
• 期刊: Advances in nutrition (Bethesda, Md.)
• 作者: D'Souza SW;Copp AJ;Greene NDE;Glazier JD
• 通讯作者: Glazier JD

Inositols: From Established Knowledge to Novel Approaches.

• DOI: 10.3390/ijms221910575
• 发表时间: 2021-09-30
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Dinicola S;Unfer V;Facchinetti F;Soulage CO;Greene ND;Bizzarri M;Laganà AS;Chan SY;Bevilacqua A;Pkhaladze L;Benvenga S;Stringaro A;Barbaro D;Appetecchia M;Aragona C;Bezerra Espinola MS;Cantelmi T;Cavalli P;Chiu TT;Copp AJ;D'Anna R;Dewailly D;Di Lorenzo C;Diamanti-Kandarakis E;Hernández Marín I;Hod M;Kamenov Z;Kandaraki E;Monastra G;Montanino Oliva M;Nestler JE;Nordio M;Ozay AC;Papalou O;Porcaro G;Prapas N;Roseff S;Vazquez-Levin M;Vucenik I;Wdowiak A
• 通讯作者: Wdowiak A

Passive Smoking During the Periconceptional Period and Risk for Neural Tube Defects in Offspring - Five Counties, Shanxi Province, China, 2010-2016.

• DOI: 10.46234/ccdcw2021.193
• 发表时间: 2021-09-10
• 期刊: China CDC weekly
• 影响因子: 4.7
• 作者: Zhang Y;Liu J;Zhang L;Jin L;Greene NDE;Li Z;Ren A
• 通讯作者: Ren A