Abstract
Although peri-conceptional folic acid (FA) supplementation can prevent a proportion of neural tube defects (NTD), there is increasing evidence that many NTD are FA non-responsive. The vitamin-like molecule inositol may offer a novel approach to preventing FA-non-responsive NTD. Inositol prevented NTD in a genetic mouse model, and was well tolerated by women in a small study of NTD recurrence. In the present study, we report the Prevention of Neural Tube Defects by Inositol (PONTI) pilot study designed to gain further experience of inositol usage in human pregnancy as a preliminary trial to a future large-scale controlled trial to evaluate efficacy of inositol in NTD prevention. Study subjects were UK women with a previous NTD pregnancy who planned to become pregnant again. Of 117 women who made contact, ninety-nine proved eligible and forty-seven agreed to be randomised (double-blind) to peri-conceptional supplementation with inositol plus FA or placebo plus FA. In total, thirty-three randomised pregnancies produced one NTD recurrence in the placebo plus FA group (n 19) and no recurrences in the inositol plus FA group (n 14). Of fifty-two women who declined randomisation, the peri-conceptional supplementation regimen and outcomes of twenty-two further pregnancies were documented. Two NTD recurred, both in women who took only FA in their next pregnancy. No adverse pregnancy events were associated with inositol supplementation. The findings of the PONTI pilot study encourage a large-scale controlled trial of inositol for NTD prevention, but indicate the need for a careful study design in view of the unwillingness of many high-risk women to be randomised.
Highlights
Neural tube defects (NTD) are severe congenital malformations, affecting 0·5–2/1000 pregnancies[1]
A proportion of NTD cases can be prevented by peri-conceptional folic acid (FA) supplementation, as demonstrated in the 1991 Medical Research Council (MRC) Vitamin Study[2]
We describe the findings of the Prevention of Neural Tube Defects by Inositol (PONTI) pilot study
Summary
Neural tube defects (NTD) are severe congenital malformations, affecting 0·5–2/1000 pregnancies[1]. Food fortification programmes have generally resulted in a reduction in NTD prevalence, compared with historical pre-fortification frequencies, a proportion of NTD persists[3]. In part, this may be due to a group of women who have erythrocyte folate concentrations that are ‘suboptimal’ for NTD prevention. A mechanism of action of inositol was identified, in which diacylglycerol is generated by the action of phospholipase C on phosphatidylinositol, activating protein kinase C isoforms β1 and γ(12) This normalises neural tube closure by correcting a Grhl3-dependent cell proliferation defect in the ventral tissues underlying the closing neural tube[13,14]. Peri-conceptional supplementation with inositol and FA was studied in a cohort of twelve Caucasian mothers
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