Some cases of NTD can be prevented by supplementation with folic acid before and during early pregnancy, but it is increasingly apparent that a significant proportion of NTDs fail to respond to FA. Most programmes of voluntary supplementation and folic acid food-fortification have observed a reduction in NTD prevalence of less than 50%.
As a result, NTDs continue to occur at an average frequency of 0.5-1.0 per 1000 established pregnancies, worldwide. We have explored the possibility that inositol, a vitamin-like molecule with a key role in cellular metabolism, has a NTD-preventive action that is independent of folic acid. If confirmed, this could lead to a combined approach to primary prevention of NTDs, involving both folic acid and inositol supplements.
IN PREVIOUS WORK, THE NEURAL TUBE GROUP HAS:
Established that both myo- and D-chiro-inositol can significantly reduce the frequency of spinal NTDs in curly tail (Grhl3 gene) mice, both by dosing the pregnant female, and by direct treatment of embryos in culture (Greene & Copp, 1997; Cogram et al, 2002).
- Shown inositol therapy to be safe in mouse pregnancy, with no adverse effects noted in either mothers or fetuses (Cogram et al, 2002).
- Demonstrated that inositol acts via activation of protein kinase C, with a specific requirement for PKC isoforms beta and gamma (Cogram et al, 2004).
- Developed a mass-spectrometry-based assay for inositol in biological samples (Leung et al, 2011).
The PONTI pilot study
PONTI: Prevention of Neural Tube Defects by Inositol
UK women with a history of NTD pregnancy were recruited into a double-blind, randomised controlled trial of myo-inositol supplementation before and during early pregnancy. The pilot study was designed to provide information on the following primary outcomes:
- to determine the feasibility of recruiting,
randomising and following-up women with a history of NTD pregnancy, who
are embarking upon a further pregnancy
- to gather preliminary data on NTD recurrence frequency in the UK trial setting
- to determine the safety of inositol administration during the peri-conceptional period and first trimester of pregnancy
- to assess compliance with supplementation using the mass spectrometry-based assay for inositol
The PONTI study was published in February 2016 (Greene et al, Br J Nutr). Its results are:
- Women at high risk of NTD recurrence can be recruited to a randomized trial structure, although fewer than half are likely to accept randomization.
- Inositol supplementation during pregnancy has proven safe for both mothers and babies in our randomized study group.
- No NTDs were encountered amongst 14 randomized and 21 non-randomized pregnancies supplemented with inositol.
- In contrast, one NTD recurred amongst 19 randomized and two NTDs recurred amongst three non-randomized pregnancies that were supplemented with FA but not inositol.
- This study provides an impetus to further evaluate inositol for primary prevention of NTDs.
For details of trial registration go to https://clinicaltrials.gov/ct2/show/NCT00452829?term=ponti&rank=1