Inositol for the prevention of neural tube defects: a pilot randomised controlled trial

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.

Keywords: FA folic acid; Folic acid supplementation; Inositol; MRC Medical Research Council; NTD neural tube defects; Neural tube defects; PONTI Prevention of Neural Tube Defects by Inositol; Pregnancy supplements.

Fig. 1

Flow of women subjects through the Prevention of Neural Tube Defects by Inositol study. Number of subjects are shown at each stage of the study. For outcome of randomisations and pregnancies, see Table 1. FA, folic acid.

Fig. 2

Inositol concentration in the urine of the Prevention of Neural Tube Defects by Inositol pilot study subjects. Inositol was quantified by MS^{( 18 )} in urine samples collected before the beginning of supplementation (pre-suppl) or 6 weeks after the subjects had received their first batch of supplements (6 weeks suppl). Box and whisker plots define the median flanked by (bottom to top) the 10th, 25th, 75th and 90th percentile values. Outlying values are represented by dots. Sample numbers: study group, eleven (pre-suppl), eleven (6 weeks); control group, seventeen (pre-suppl), sixteen (6 weeks). For statistical analysis, see Table 2. , Study group (inositol+folic acid (FA)); , control group (placebo+FA).

Fig. 3

Inositol concentration in urine and blood of research staff volunteers. Inositol was quantified by MS^{( 18 )} in urine (, inositol concentration µm/mm creatinine) and venous blood plasma (, inositol concentration in blood (µm)) samples obtained from a group of ten volunteer subjects (Subj 1–10) who took daily inositol supplements (1·3 g) on days 1–7 of the experiment (). Urine was obtained on the day preceding the start of dosing (day 0), on days 1 and 5 of dosing (in each case 3–8 h after taking inositol) and on day 8 when 24 h had elapsed since the final dose. Blood samples were obtained at these same times on days 0, 5 and 8. Note the relatively uniform blood inositol concentration response of subjects to the dosing, whereas urinary excretion of inositol is highly variable between individuals. For example, Subj 1, 3 and 8 show marked (3–5-fold) increases in urinary inositol after dosing, whereas Subj 5, 6, 7, 9 and 10 show almost no increase in inositol excretion.