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.