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

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.

Neural tube defects (NTDs) are common birth defects with a high prevalence in many low and middle income countries. NTDs can be lethal at birth (anencephaly) or cause severe disability (spina bifida). Primary NTD prevention is based on peri-conceptional supplementation with folic acid (FA), but considerable numbers of NTDs still occur, indicating frequent FA-resistance. Research in mice, and a pilot clinical trial in high-risk women, both show a potential preventive effect of inositol (vitamin B8) for FA-resistant NTDs. Vitamin B12 supplements could also enhance FA prevention of NTDs, although this is untested. This Trial Development grant will prepare for a future large scale, randomised controlled trial of inositol and B12, as a means of preventing a greater proportion of NTDs than with FA alone. China offers a unique opportunity for the study, given the large size of the reproductive population, high NTD rate, and well organised birth defects surveillance. Study particpantswill be women with a history of NTD-affected pregnancy who wish to become pregnant again. They will be randomised to four intervention arms: (i) inositol, (ii) vitamin B12, (iii) inositol + vitamin B12, (iv) no treatment. All women will receive FA (5 mg/day). We aim to identify ~ 460 women with a previous NTD-affected pregnancy, of whom we predict that ~320 will satisfy eligibility criteria. We aim to consent 200 women to trial entry in order to follow 140 pregnancies with a measurable fetal outcome (NTD or non-NTD). We will test key requirements for a subsequent, fully-powered phase III trial in China: effectiveness of the NTD surveillance mechanisms, proportions of potential subjects who are eligible to enter the study, consent to randomisation, comply with the study protocol, and have an informative pregnancy outcome. This study will be a vital step towards providing an evidence base for enhancing pregnancy supplementation worldwide, to further reduce the global burden of NTDs.

The PONTib-Development study represents a step towards implementation of research findings with clear impact for human health. This includes:

1. Enhanced primary prevention of neural tube defects (NTDs) beyond that achieved by folic acid (FA) alone. As neonatal care has improved over the decades, birth defects have increased as a proportional cause of morbidity and mortality in young children. Hence, the primary prevention of NTDs by FA was a major step towards reversing this trend. However, compared with the prevention of rubella-mediated congenital defects by immunisation of school-age girls, which is virtually complete in many populations (e.g. UK), the prevention of NTDs is far from complete. Further progress will undoubtedly be made as FA usage is introduced more widely. Nevertheless, only a proportion of NTDs are preventable by FA, and so the remaining 30-50% of NTD cases need alternative preventive strategies. A positive result in the PONTib-Development study, and subsequent Phase III efficacy trial, would represent the first major advance in NTD prevention since the 1991 MRC Vitamin trial. It would enable a further step-change in public health measures aimed at eradicating congenital defects as a cause of infant death.

2. Implementation of enhanced pregnancy supplementation in China, as an extension of the findings in the study population. The first public health opportunity may be to introduce inositol and/or vitamin B12 supplements, alongside FA, in the Chinese population. The Investigator team on PONTib ensures high-level access to the governmental National Health and Family Planning Commission (which includes the former Ministry of Health), so that a positive finding in the trial can be rapidly transmitted to policy makers. FA is already provided free of charge to women in rural communities (where NTD rates are especially high). Addition of inositol and/or vitamin B12 would represent a modest additional provision, not needing extra infrastructure. Hence, China is likely be the first country to benefit on a large scale from this extended NTD prevention strategy.

3. Implementation in other low and middle income countries and in the developed world. The 1990s saw widespread introduction of FA supplements for NTD prevention, following publication of the MRC Vitamin trial conducted in the UK and Hungary. Given that interest in and priority for birth defects prevention has increased over the intervening decades, it can be anticipated that there would be considerable pressure on governments globally to make inositol and/or vitamin B12 available in combination with FA, and to publicise the need for its use when planning a pregnancy.

4. Engagement with pharmaceutical companies. Currently, inositol is not formulated specifically as a pregnancy supplement, although it is available as a vitamin supplement in many countries (e.g. Europe and North America) and in a product in combination with folic acid. Vitamin B12 (6 micrograms) is included in an over-the-counter supplement, Pregnacare, along with 400 micrograms of FA. If the PONTib-Development study provides an indication for a combined inositol + B12+FA supplement to use for NTD prevention, it would appear that there are no barriers to engaging with nutritional supplement companies to ensure a suitable combined supplement is manufactured.

5. Effect on medical management of NTDs. Clinical geneticists, genetic counsellors and GPs advise families on the likelihood of congenital defect recurrence in future pregnancies, and strategies to avoid this outcome. Their clinical practice will be directly impacted by evidence from the PONTib-Development study.

6. Impact on the public. Many support groups provide expertise, information and funding to patients and families with NTDs: through our existing links (detailed in Pathways to Impact), we will ensure that findings are made known to their members.