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

神经管缺陷（NTDs）是危及生命的出生缺陷，其中脊柱裂最为人所知。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。被忽视热带病是常见的缺陷，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病率更高。在怀孕前和怀孕前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，尽管服用了FA补充剂，许多妇女仍然生下了患有NTDs的婴儿。这一经验表明，30-50%的被忽视热症具有“抗fa性”，因此需要一种不同的补充剂来有效预防。我们之前对小鼠和人类的研究发现，肌醇（维生素B8）可能是预防对FA没有反应的NTDs的一种新方法。其他研究表明，维生素B12可能是一种有效的补充。在实际应用肌醇或B12补充剂之前，有必要在临床试验中确认其有效性。本研究建议在热带病高发的中国开展肌醇的临床试验。这项相对较小的研究将为大规模的、统计上可靠的临床试验铺平道路，这将告诉我们肌醇、维生素B12或两者是否应该在临床实践中使用。中国是开展这项工作的理想地点，因为它有良好的基础设施，可以找到以前受热带病影响的怀孕妇女，而且人口众多，可以招募足够的女性受试者。该研究的参与者将是以前受ntd影响的怀孕并希望再次怀孕的妇女。那些同意参与的人将被随机分配服用肌醇、B12、肌醇+ B12，或者两者都不服用。根据对被忽视热带病高风险妇女的标准护理，所有妇女受试者每天将接受5毫克FA。补充将从受孕前开始，一直持续到怀孕第12周。这项工作将由伦敦大学学院的科学家——包括被忽视热带病和临床试验方面的专家——和北京大学的科学家合作完成。中国研究人员有多年在当地人群中开展孕期研究的经验，例如近年来招募了10万多名妇女进行孕期营养研究。这项试点研究将测试是否有强有力和可靠的过程来识别、招募、随机分配和跟踪女性受试者的怀孕情况。然后，我们计划进行大规模的试验，其中积极的结果将表明肌醇和/或维生素B12应该与FA一起用于计划怀孕的妇女的联合补充。肌醇或维生素B12的使用可以在中国迅速推广，因为女性在计划怀孕时已经获得了免费的FA片。含有肌醇/B12和FA的联合片剂可以以较低的额外成本提供。此后，其他国家可能会引入类似的联合补充剂，以改善非传染性疾病的预防。这不仅将使个人和家庭受益，避免因被热带病影响而怀孕的影响，而且还将在经济上使卫生保健系统受益：脊柱裂患者一生的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的使用已经扩展到世界上大多数国家，我们预计我们目前提出的研究将对全球儿童的未来健康产生类似的有益影响。

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.