Postscript to ‘Folic acid and neural tube defects: Discovery,debate and the need for policy change’

This postscript clarifies and explains the previously described approach proposed to achieve fully effective fortification in the prevention of neural tube defects (NTDs). ¹

Estimating the level of folic acid fortification required to achieve fully effective prevention of NTDs is essential in determining fortification policy. ¹ There are two ways of estimating the fortification level to achieve this objective using results from the UK Medical Research Council (MRC) funded randomised trial, ² one based on the supplement dose and the other on achieving the serum folate concentration in folic acid supplement users.

Using the NTD rates in women in the MRC trial who took a daily folic acid supplement and in those who did not

The NTD rate was 83% lower among women who took a daily 4mg folic acid supplement before becoming pregnant compared with the rate in women who did not. ² It might therefore be thought reasonable that an extra 4mg/day from folic acid fortification would achieve the same risk reduction, provided the background serum folate concentration was similar to that in the MRC funded trial (5ng/ml).

• 2.

   Using the median serum folate concentrations in women in the MRC trial who took a folic acid supplement and in those who did not

The median serum folate level in the women in the MRC trial who took a folic acid supplement was 44ng/ml. This concentration sets a target to achieve the estimated 83% NTD prevention observed in the MRC trial. Given a pre-fortification median serum folate concentration of about 5ng/ml, ³ an average wheat flour consumption of 160g/day ⁴ and a fortification level of 1mg/100g flour, ¹ folic acid intake from folic acid fortification of 1.6mg/day is estimated to achieve the 44ng/ml serum folate concentration target (see Box 5 in reference 1).

A serum folate concentration of 44ng/ml can therefore be achieved either by fortification using 1mg folic acid per 100g flour at a consumption of 160g flour a day (i.e. 1.6mg/day folic acid intake), or by using a 4mg once-daily folic acid supplement, both from a starting concentration of about 5ng/ml. One can only speculate on the explanation for the difference (1.6 v 4.0mg/day); a once-a-day supplement delivered as a “bolus” may be less effective in raising serum folate than the same amount of folic acid consumed throughout the day from fortification. Whatever the explanation for the difference, the appropriate method of determining the fortification level is one based directly on the concentration of serum or plasma folate, ⁵ because that is what influences how much folate is transferred from mother to fetus.

A practical approach would be to select an initial fortification level of 1mg/100g flour and grains, then measure serum folate in a sample of the population, including women of childbearing age, and then adjust the fortification level up or down to achieve a serum folate concentration of 44ng/ml plus or minus, say, 4ng/ml. Serum folate concentrations could be monitored periodically and, if necessary, the fortification level adjusted. Such a serum folate determined fortification level would be evidence-based and flexible – tailored to the requirements of different countries. Together with fortification beyond wheat flour, it would realise the fully effective folic acid fortification desired without having to make assumptions or requiring modelling to estimate flour and grain consumption in populations. It would intrinsically link fully effective fortification with population monitoring, which is sound public health practice.