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The PONTI study: inositol and prevention of NTDs

The curly tail (Grhl3) mutant mouse whose spina bifida is prevented by inositol

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).

    Mechanism if inositol action in preventing NTDs in mice
  • 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:

  1. to determine the feasibility of recruiting, randomising and following-up women with a history of NTD pregnancy, who are embarking upon a further pregnancy
  2. to gather preliminary data on NTD recurrence frequency in the UK trial setting
  3. to determine the safety of inositol administration during the peri-conceptional period and first trimester of pregnancy
  4. 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:

  1. Women at high risk of NTD recurrence can be recruited to a randomized trial structure, although fewer than half are likely to accept randomization.
  2. Inositol supplementation during pregnancy has proven safe for both mothers and babies in our randomized study group.
  3. No NTDs were encountered amongst 14 randomized and 21 non-randomized pregnancies supplemented with inositol.
  4. 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.
  5. 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

Download the original PONTI clinical trial protocol (PDF)

Media Links:

BBC News report, 2016: Vitamin B8 could prevent spina bifida

Sparks Charity report 2016

Shine Charity report 2016

BBC News report, 2010

BBC News Scotland report, 2010

Interview with Nick Greene and Anne Marie Hodkinson, BBC News, 2010