Neurodegeneration before birth: can inositol increase prevention of neural tube defects in conjunction with folic acid?
Lead Research Organisation:
University College London
Department Name: Unlisted
Abstract
Neural tube defects (NTDs) are serious birth defects that affect up to 1 in every 500 pregnancies in all countries. Around 120,000 pregnancies are affected in the world each year. The best known NTD malformation is spina bifida, in which children are often paralysed from the waist down. They need frequent operations to treat the many associated medical conditions, including incontinence of urine and faeces and deformities of the vertebral column. Over the past 15 years, it has emerged that folic acid, a B-group vitamin, if taken in the first few weeks of pregnancy, can prevent the onset of spina bifida and other NTDs, ensuring the birth of a normal baby. However, it is clear that not all cases of NTD are preventable by folic acid. NTDs come in different ?types?, with only certain types being responsive to folic acid. Work in the mouse has shown that another vitamin-like molecule, inositol, can prevent NTDs where folic acid is ineffective. Evidence has now accumulated, in mice and humans, to suggest that inositol would be a safe and possibly effective ?extra? therapy to use in conjunction with folic acid, to protect against more types of NTD than with either agent alone. Here, we propose to carry out a pilot study in which we will randomly assign women, contemplating a pregnancy, to supplementation with folic acid alone (the control group) or folic acid plus inositol (the study group). Women who have had a previous NTD pregnancy will be invited to enter the trial, as they are at high risk of a further NTD pregnancy. The treatment group will not be known either to the mother or to the physician treating her, until the pilot study is completed and the data are analysed. Statistical analysis will be used to compare the frequency of further NTD pregnancies in the study and control groups, to determine whether addition of inositol to the standard folic acid therapy lowers the frequency of NTDs. If a positive result emerges, this study could pave the way for a new, improved method of preventing NTDs in human pregnancy. The findings of the study will be published, presented at conferences, disseminated via the Institute of Child Health/Great Ormond Street website and communicated to patient groups (e.g. the Association for Spina Bifida and Hydrocephalus). Future intensive public campaigns will be necessary if inositol proves effective in this clinical trial.
Technical Summary
Neural tube defects (NTDs) are severe malformations of the CNS, occurring in 0.5 to 2 per 1000 pregnancies, and resulting when the embryonic neural tube fails to close. Exposure to the amniotic fluid environment leads to neurodegeneration during pregnancy and, by birth, the exposed brain and/or spinal cord are totally degenerate. Fetuses with brain NTDs (e.g. anencephaly) are stillborn and those with spinal NTDs (e.g. myelomeningocele) are neurologically impaired below the lesion.
Folic acid (FA), administered early in pregnancy, can prevent up to 70% of NTDs (Lancet, 1991, 338, 131-7). However, a proportion of NTDs do not respond to FA and currently cannot be prevented. Some mouse models of NTD show prevention by FA whereas others are resistant. We found that inositol (both myo- and D-chiro- forms), prevents NTDs in a FA-resistant mouse model. Moreover, serum inositol is lower in mothers and children with NTDs. Pre-clinical animal testing, and limited testing in humans, suggest that inositol therapy is safe in pregnancy.
We propose to develop a randomised, double blind clinical trial protocol to compare (i) FA alone with (ii) FA plus D-chiro-inositol, for prevention of NTD recurrence. In this project, we will: (a) establish a network of collaborators in UK and Europe who can recruit trial subjects with a previous NTD pregnancy; (b) develop laboratory assays for inositol to monitor compliance and investigate levels in trial subjects; (c) conduct a pilot trial in the UK to determine feasibility and enable accurate power analysis for a larger scale trial.
Folic acid (FA), administered early in pregnancy, can prevent up to 70% of NTDs (Lancet, 1991, 338, 131-7). However, a proportion of NTDs do not respond to FA and currently cannot be prevented. Some mouse models of NTD show prevention by FA whereas others are resistant. We found that inositol (both myo- and D-chiro- forms), prevents NTDs in a FA-resistant mouse model. Moreover, serum inositol is lower in mothers and children with NTDs. Pre-clinical animal testing, and limited testing in humans, suggest that inositol therapy is safe in pregnancy.
We propose to develop a randomised, double blind clinical trial protocol to compare (i) FA alone with (ii) FA plus D-chiro-inositol, for prevention of NTD recurrence. In this project, we will: (a) establish a network of collaborators in UK and Europe who can recruit trial subjects with a previous NTD pregnancy; (b) develop laboratory assays for inositol to monitor compliance and investigate levels in trial subjects; (c) conduct a pilot trial in the UK to determine feasibility and enable accurate power analysis for a larger scale trial.
Organisations
- University College London, United Kingdom (Collaboration, Lead Research Organisation)
- University of Rome I (La Sapienza), Italy (Collaboration)
- University of Toronto (Collaboration)
- University of Leuven (Collaboration)
- Great Ormond Street Hospital (GOSH) (Collaboration)
- Peking University, China (Collaboration)
- University College Hospital Ibadan (Collaboration)
Publications

Burren KA
(2010)
The genetic background of the curly tail strain confers susceptibility to folate-deficiency-induced exencephaly.
in Birth defects research. Part A, Clinical and molecular teratology

Burren KA
(2006)
Quantitative analysis of s-adenosylmethionine and s-adenosylhomocysteine in neurulation-stage mouse embryos by liquid chromatography tandem mass spectrometry.
in Journal of chromatography. B, Analytical technologies in the biomedical and life sciences

Burren KA
(2008)
Gene-environment interactions in the causation of neural tube defects: folate deficiency increases susceptibility conferred by loss of Pax3 function.
in Human molecular genetics

Copp AJ
(2010)
Genetics and development of neural tube defects.
in The Journal of pathology

Copp, A.J.
(2022)
Fetal and Neonatal Physiology

D'Souza SW
(2021)
Maternal Inositol Status and Neural Tube Defects: A Role for the Human Yolk Sac in Embryonic Inositol Delivery?
in Advances in nutrition (Bethesda, Md.)

De Castro SC
(2010)
Neural tube defects induced by folate deficiency in mutant curly tail (Grhl3) embryos are associated with alteration in folate one-carbon metabolism but are unlikely to result from diminished methylation.
in Birth defects research. Part A, Clinical and molecular teratology

Dinicola S
(2021)
Inositols: From Established Knowledge to Novel Approaches.
in International journal of molecular sciences

Doudney K
(2009)
Evaluation of folate metabolism gene polymorphisms as risk factors for open and closed neural tube defects.
in American journal of medical genetics. Part A

Dunlevy LP
(2007)
Abnormal folate metabolism in foetuses affected by neural tube defects.
in Brain : a journal of neurology
Description | Increased uptake of inositol during pregnancy to prevent recurrence of neural tube defects (NTDs) |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Citation in clinical reviews |
Description | Inositol supplementation advice to doctors |
Geographic Reach | National |
Policy Influence Type | Influenced training of practitioners or researchers |
Impact | Occurrence of neural tube defects (NTDs: spina bifida, anencephaly) in families where women have taken folic acid (FA) at the recommended level, often leads to requests for 'genetic counselling' to avoid recurrence of this adverse outcome. Our introduction of inositol as a possible adjunct preventive supplement, for NTD cases that do not respond to FA, has become widely known in the UK and beyond. I regularly receive requests for information and guidance from medical doctors who are looking after families with previously affected pregnancies. This is often prior to a planned consultation with the patients, and sometimes results in the family electing to use inositol in the next pregnancy. Hence, inositol supplementation is already making a significant difference to the medical supervision of pregnancies in women at high risk of spina bifida. |
Description | Inositol supplementation advice to patients and families |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Implementation circular/rapid advice/letter to e.g. Ministry of Health |
Impact | Occurrence of neural tube defects (NTDs: spina bifida, anencephaly) in families where women have taken folic acid (FA) at the recommended level, often leaves these families confused and worried about the future, and their ability to have a normal child. They expect that folic acid will protect them in pregnancy, and are shocked when it sometimes does not. Our introduction of inositol as a possible adjunct preventive supplement, for NTD cases that do not respond to FA, has become widely known in the UK and beyond, and is easy to find using Google. I regularly receive requests for information and guidance from families with recently affected pregnancies who are in despair after being offered essentially no helpful advice by medical practitioners. I provide information on FA action and resistance, and options involving inositol. This has led many families to use inositol in their next pregnancy, so far always with a normal outcome. Hence, inositol supplementation is already making a significant difference to the medical supervision of pregnancies in women at high risk of spina bifida. |
Description | CLRN PONTI trial support costs |
Amount | £34,353 (GBP) |
Organisation | National Institute for Health Research |
Sector | Public |
Country | United Kingdom |
Start | 01/2010 |
End | 01/2012 |
Description | Inositol and birth defects |
Amount | £189,516 (GBP) |
Funding ID | GN2656 |
Organisation | Sparks Charity |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 05/2018 |
End | 09/2020 |
Description | Joint Global Health Trials |
Amount | £302,630 (GBP) |
Funding ID | MR/T003847/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 08/2020 |
End | 12/2022 |
Description | Prevention of Neural Tube Defects by Inositol and Vitamin B12 (PONTib) - Development Trial |
Amount | £302,630 (GBP) |
Funding ID | T003847 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2021 |
End | 02/2023 |
Description | SPARKS PONTI trial grant |
Amount | £67,111 (GBP) |
Funding ID | 09ICH01 |
Organisation | Sparks Charity |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 02/2011 |
End | 08/2013 |
Description | Spina bifida research support |
Amount | € 100,000 (EUR) |
Organisation | Hjelt Foundations |
Department | Bo Hjelt Foundation for Spina Bifida |
Sector | Charity/Non Profit |
Country | Switzerland |
Start | 08/2020 |
End | 12/2022 |
Title | Inositol assay |
Description | An HPLC-MS/MS method was developed allowing separation and selective detection of myo-inositol from other inositol stereoisomers. Inositol was also separated from contaminating hexose monosaccharides of the same molecular weight, including glucose, galactose, mannose and fructose. This method can be used on both blood and urine samples to accurately estimate inositol concentration |
Type Of Material | Technology assay or reagent |
Year Produced | 2011 |
Provided To Others? | Yes |
Impact | Method has been published and so available to all interested parties. Technique is in active use in our ongoing clinical trial of inositol supplementation in human pregnancy to prevent neural tube defects |
URL | http://www.ncbi.nlm.nih.gov/pubmed/21856255?dopt=Citation |
Description | CCTU NTD clinical trial partnership |
Organisation | University College London |
Department | Comprehensive Clinical Trials Unit |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We developed the concept of inositol as a means to prevent NTDs that are resistant to folic acid, and proposed a large-scale clinical trial. |
Collaborator Contribution | The Comprehensive Clinical Trials Unit (CCTU) at UCL provided resources and expertise to develop the large-scale clinical trial concept to enable funding applications. This was successful in 2019, with award of a pilot clinical trial grant by the MRC NIHR DfID Wellcome Global Health Trials Call 8. |
Impact | Pilot study funded (£300K) by the MRC NIHR DfID Wellcome Global Health Trials Call 8 to support the start of a large-scale clinical trial of inositol for prevention of folic acid-resistant NTDs. |
Start Year | 2015 |
Description | Dolutegravir effects on development: association with folate status |
Organisation | University of Toronto |
Country | Canada |
Sector | Academic/University |
PI Contribution | Advisory, planning and data analysis in relation to the study of dolutegravir on the developing mouse embryo. Effects of folate and inositol on the dolutegravir phenotype. Use of whole embryo culture to enhance the in vivo studies conducted in Toronto. |
Collaborator Contribution | Conduct of the studies in the mouse in vivo model, using previously determined dolutegravir administration protocol. |
Impact | None yet. |
Start Year | 2018 |
Description | Experts' Group on Inositol (EGOI) |
Organisation | Sapienza University of Rome |
Country | Italy |
Sector | Academic/University |
PI Contribution | The Experts' Group on Inositol in preclinical and clinical research was created in 2020 to bring together workers in Italy and other countries who are working on inositol in various contexts. It is an electronic communications group, but with plans to meet in person once the pandemic allows travel. |
Collaborator Contribution | The Sapienza University of Rome has organised this partnership. |
Impact | Facchinetti F, Cavalli P, Copp AJ, D'Anna R, Kandaraki E, Greene NDE, Unfer VfTEGoIiB, Clinical R. (2020). An update on the use of inositols in preventing gestational diabetes mellitus (GDM) and neural tube defects (NTDs). Expert Opin Drug Metab Toxicol 16: 1187-1198. |
Start Year | 2020 |
Description | PONTI collaborations |
Organisation | Great Ormond Street Hospital (GOSH) |
Country | United Kingdom |
Sector | Hospitals |
PI Contribution | Conducting the PONTI clinical trial. |
Collaborator Contribution | The manufacture (UCLH) and dispensing (GOSH) of inositol tablets for the PONTI clinical trial. |
Impact | Outputs of the PONTI clinical trial. Increasing dissemination and uptake of inositol for families experiencing neural tube defects in pregnancy, and wishing to embark on a new pregnancy. |
Start Year | 2008 |
Description | PONTI collaborations |
Organisation | University College Hospital |
Department | Pharmacy |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Conducting the PONTI clinical trial. |
Collaborator Contribution | The manufacture (UCLH) and dispensing (GOSH) of inositol tablets for the PONTI clinical trial. |
Impact | Outputs of the PONTI clinical trial. Increasing dissemination and uptake of inositol for families experiencing neural tube defects in pregnancy, and wishing to embark on a new pregnancy. |
Start Year | 2008 |
Description | Peking University NTD collaboration |
Organisation | Peking University |
Country | China |
Sector | Academic/University |
PI Contribution | Our work with inositol supplementation in mice, and our PONTI pilot clinical trial in the UK, posed the hypothesis that inositol can increase the prevention of neural tube defects, alongside folic acid. |
Collaborator Contribution | Collaborators at PKU are providing access to women at high risk of neural tube defects in China, to allow a large-scale clinical trial to follow up from the PONTI pilot study in the UK. |
Impact | Pilot study funded (£300K) by the MRC NIHR DfID Wellcome Global Health Trials Call 8 to support the start of a large-scale clinical trial of inositol for prevention of folic acid-resistant NTDs. |
Start Year | 2016 |
Description | Tet-1 collaboration |
Organisation | University of Leuven |
Country | Belgium |
Sector | Academic/University |
PI Contribution | Advice on use of folic acid and inositol, and dietary deficiency for these nutrients, in modulating NTD frequencies. |
Collaborator Contribution | The Tet-1 knockout mouse model of NTDs, for analysis in relation to small molecule deficiency or supplementation. |
Impact | None |
Start Year | 2017 |
Title | PONTI - Inositol for prevention of folic acid-resistant neural tube defects |
Description | A proportion of neural tube defects (NTDs; e.g. spina bifida) are resistant to folic acid supplementation, whereas animal model research, in our laboratory, has indicated a preventive action of inositol in cases where folic acid is ineffective. The PONTI pilot randomized clinical trial has been completed having been started with funding from this MRC Trial Platform Grant. It sought to determine whether inositol treatment, in conjunction with folic acid, may lead to a reduction in the frequency of neural tube defects compared with use of folic acid alone. While the study was small, and not fully powered to detect a statistical effect of inositol, nevertheless we found 3 recurrences of NTD in patients taking folic acid alone, but zero recurrences in a larger group of patients who took inositol plus folic acid. This is encouraging for a further, more statistically powered clinical trial in the coming years. The paper on the pilot study was published in the British Journal of Nutrition, Feb 2016. |
Type | Preventative Intervention - Nutrition and Chemoprevention |
Current Stage Of Development | Refinement. Clinical |
Year Development Stage Completed | 2016 |
Development Status | Actively seeking support |
Clinical Trial? | Yes |
Impact | Knowledge of the suspected beneficial effects of inositol in pregnancies at high risk of neural tube defect is now widespread, following our animal model studies. A number of high risk pregnancies have been supplemented with inositol, so far with no recurrences. Hence, beneficial effects of inositol usage may be occurring already. Formal clinical trial evidence of inositol efficacy will be required from a future larger-scale study, which is now beginning with a MRC/NIHR/DFID/Wellcome Global Health Trials grant, beginning in 2020. |
URL | https://clinicaltrials.gov/ct2/show/NCT00452829?term=inositol&rank=28 |
Description | BBC Horizon, Spina Bifida & Me |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | BBC Horizon programme on Spina Bifida. Prof Copp was featured in the programme. |
Year(s) Of Engagement Activity | 2018 |
URL | https://www.bbc.co.uk/programmes/b0bcmjht |
Description | Links to patient group web sites |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | Yes |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Articles were written and posted on the web sites of the Association for Spina Bifida and Hydrocephalus, and other charities. Following publication of the PONTI pilot study in Feb 2016, various articles appeared including one on the SHINE web site - see URL below. Improved visibility of the clinical trial and increased interest from potential trial subjects |
Year(s) Of Engagement Activity | 2006,2007,2008,2009,2010,2011,2012 |
URL | http://www.shinecharity.org.uk/mediaccentre/news/2016/02/10/new-research-findings-bring-prevention-h... |
Description | PONTI trial media publicity |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Interview with BBC health correspondent led to a piece published on the BBC News Scotland website (http://www.bbc.co.uk/news/uk-scotland-11230642). This prompted several interviews on BBC Breakfast TV, Radio Ulster, Radio 5 Live. Following publication of the PONTI paper (Feb 2016), there was further media attention: BBC News Scotland website (http://www.bbc.co.uk/news/uk-scotland-35503529), and the London Evening Standard. Increased recruitment into the clinical trial, from women who had encountered the publicity. |
Year(s) Of Engagement Activity | 2010,2016 |
URL | http://www.bbc.co.uk/news/uk-scotland-35503529 |
Description | PONTI trial web site |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | Yes |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | The clinical trial is named PONTI: Prevention of Neural Tube Defects by Inositol. The original web site (2006-12) provided information for prospective trial subjects, encouraging them to enroll in the clinical trial. Since the trial has finished, this web page is no longer displayed. In 2016, following the publication of the PONTI study in the British Journal of Nutrition, we have dedicated a page of the NTD Group web site (UCL Institute of Child Health) to the PONTI study - see URL below. Significant interest in the clinical trial has arisen in part from the web site, and has led to continuing recruitment of patients into the trial |
Year(s) Of Engagement Activity | 2006,2007,2008,2009,2010,2011,2012 |
URL | http://www.ucl.ac.uk/ich/research/developmental-biology-cancer/developmental-biology-birth-defects/c... |