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）是威胁生命的先天缺陷，脊柱裂是最著名的。它导致下半身瘫痪，尿液和粪便的尿失禁，脑积水（“大脑的水”）以及其他严重的健康问题。 NTD是常见的缺陷，每500-2000次怀孕中有1个缺陷，许多低收入和中等收入国家的频率更高。在受孕之前和怀孕的前三个月之前，含有叶酸（FA）的补充剂可以降低受NTD影响的胎儿的风险。但是，尽管服用了足总补充剂，但许多妇女仍然有NTD的婴儿。这种经验表明，30-50％的NTD是“耐FA的”，因此，需要采取不同的补充来有效防止它们。我们以前在小鼠和人类的研究确定肌醇（维生素B8）是预防对FA反应的NTD的可能新方法。其他研究表明，维生素B12可能是有效的补充。在实践中可以实施肌醇或B12补充之前，必须在临床试验中确认其有效性。这项研究提议在中国进行肌醇的试验临床试验，其中NTD率高。这项相对较小的研究将“铺平道路”，朝着一项大规模，统计上强大的临床试验，这将告诉我们肌醇，维生素B12还是应在临床实践中使用。中国是这项工作的理想场所，因为它具有出色的基础设施，可以找到以前受NTD影响怀孕的妇女，并且人口很大，可以招募足够的妇女受试者。研究参与者将是以前受NTD影响怀孕的女性，希望再次怀孕。那些同意参加的人将被随机分配给肌醇，B12，肌醇 + B12或两者。根据针对NTD高风险的妇女的标准护理，所有女性受试者每天将获得5 mg FA。补充剂将在受孕之前开始，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之间的合作 - 包括NTD和临床试验的专家 - 北京北京大学的科学家。中国研究者在怀孕期间对当地人群进行研究的经验多年，例如，近年来招募了100,000多名妇女进行妊娠的养分研究。这项试验研究将测试是否存在稳健和可靠的过程来识别，招募，随机，随机，随机及其妇女受试者的妊娠。然后，我们计划继续进行大规模试验，在该试验中，积极的结果表明肌醇和/或维生素B12应与FA一起在计划怀孕的妇女的合并补充剂中与FA一起进行。在中国可以迅速实施肌醇或B12，因为在计划怀孕时妇女已经免费获得FA片。可以以较低的额外成本提供包含肌醇/B12和FA的组合片剂。此后，其他国家可能会引入类似的组合补充剂以改善NTD预防。这不仅将通过避免受NTD影响的怀孕的影响来使个人和家庭受益，而且还将从经济上受益：脊柱裂的人的终身医疗和社会护理费用超过550万美元。当1991年发现FA的预防作用时，这是基于与我们提出的临床试验非常相似的临床试验。 FA使用已扩散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的未来健康有类似的有益作用。

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