How does folate fare during a famine?

If folate deficiency causes neural tube defects, a famine should produce an increase.

The case for adding folic acid to flour depends on four linked claims:

1. A shortage of folate in the developing brain causes neural tube defects (strong evidence)

2. Giving pharmaceutical doses of folic acid to high risk women reduces risk of a neural tube defect (strong evidence)

3. A proportion of low risk women have inadequate dietary folate putting them at risk (poor evidence)

4. Giving low doses to low risk women will prevent neural tube defects (only one trial in which there were nine pregnancy losses for every neural tube defect ‘prevented’)

The first two claims are not in dispute here. Most of the trials usually cited for folic acid prevention used high doses in women who had already had an affected pregnancy. Showing a pharmaceutical benefit is not the same as demonstrating that a dietary deficiency was the cause. It is the third claim which is key because the evidence is weakest but it underpins the idea that fortification of food could be justified.

The way to test whether dietary deficiency is the cause is to measure during a famine. A famine sharply reduces food intake including folate across a whole population at once. If a dietary shortage drove these defects they ought to become more common during a famine. Famine is a blunt instrument. It changes calories, many nutrients, infection and fertility. It is not the perfect experiment but if the hypothesis is right, that deficiency causes neural tube defects, then there should be a signal.

How large a signal should a famine produce? The relationship between blood folate and risk rests on a single Irish study, examined in a companion article, in which women in the lowest band of red cell folate carried around eight times the risk of those in the highest. On a gradient that steep, a population whose diet collapses would not show a faint adjustment in risk. It would show a multiple, a doubling at the very least. An effect of that size should be noticeable. Folate stores depend on absorption, on the enzymes that process folate and even on vitamin B12 levels, so diet is one input among several. A famine is the one circumstance in which the impact of diet alone can be properly tested.

Folate is a precious commodity in the body and particularly so for a developing infant. In later pregnancy active transport of folate across the placenta means that the fetal blood level is commonly higher than the mother’s. However, in very early pregnancy, when the placenta is barely formed and when neural tube defects occur the story is different. Folate in the first-trimester sac can sit below the level in maternal blood. This suggests that there is a real risk of low fetal folate during a famine.

Two famines have been examined, the Dutch and the Irish. The largest famine in history, in China between 1959 and 1961, has been studied at length for its effects on those who survived it, but no measurement of neural tube defects has been carried out because no surveillance of birth defects existed at the time.

The Dutch Hunger Winter

In the Dutch Hunger Winter of 1944-45, a German embargo on transport to the occupied western Netherlands drove the daily ration below a thousand calories made up mostly of bread, potatoes and sugar beet. Researchers have dug out historic records to examine the cohort conceived at the peak of the famine. The result, an excess of nervous-system anomalies, has been repeatedly cited as evidence that maternal nutrition drives the risk. There are problems with that conclusion.

The data came from two sources, set out in Susser, Hoek and Brown’s account of the Dutch Famine Study. First, men examined at military induction aged eighteen. They did not just measure neural tube defects but grouped the anomalies to include spina bifida, hydrocephalus and cerebral palsy, only the first of which is a neural tube defect.

A separate look at childhood deaths from birth to seventeen in the same study, hinted at an increase in a similar grouping. The finding describes which affected children died rather than how many were affected. Boys are more likely to die from conception onwards and are more vulnerable to undernutrition in early life. Neural tube defects are more common in girls, with the female excess greatest for anencephaly and the higher lesions. Any measure built on who died would tend to surface boys over girls. During a famine, which kills the vulnerable, more affected boys would die than in ordinary years without any more having been affected. Neural tube defects affect girls and boys alike and if a shortage of folate increased the risk of diagnosis then the number affected should increase in both groups. The only measure is that more boys with this condition died during that time while girls did not. That is more likely to be an indicator of boys’ vulnerability to dying during famine than an indication that more children had been diagnosed.

Despite the weakness of this evidence, the Dutch famine is repeatedly cited as supporting evidence that famine raises neural tube defects.

The Great Irish Famine

Ireland is the sharper test of the two because of what the Irish had been eating. Before the blight the rural poor lived on potatoes, with adult consumption estimated at five pounds a day and often a good deal more. Potatoes carry roughly sixteen micrograms of folate in every hundred grams, and boiling results in loss of a third or more of it, so five pounds a day worked out at around two hundred micrograms, much the same as the current British diet supplies. What the famine subtracted from the Irish diet is comparable to what fortification proposes to add to the British one.

In 1974 a group led by Masterson examined a Dublin maternity hospital’s records from before, during and after the Great Irish Famine of the 1840s, one of the most severe and prolonged famines in modern history. Their main purpose was to test a proposed link with blighted potatoes. They reported that the records “failed to show any appreciable fluctuation in anencephaly/spina bifida incidence during this period”. Through years of starvation this one hospital’s records show no appreciable change. It was a single series rather than national surveillance and it depended on nineteenth-century diagnostics. This is the only direct examination of the famine years and it found no appreciable fluctuation.

What should that have done to the rate? During the famine there were rations: a pound of Indian meal a day, the standard outdoor relief, supplies about seventy micrograms of folate once cooked, half rations gave half of that, the soup was mostly water, and a great many people received nothing at all. Against a pre-famine intake of roughly two hundred micrograms, that is a loss of about two-thirds of dietary folate for those on full rations, more than four-fifths for those on half rations.

This calculation uses entirely mainstream assumptions: the fortification literature’s own dose-response curve and its own recommended intakes. The body’s actual daily loss of folate is nearer fifty micrograms, and the four hundred printed on every supplement bottle was reached from that figure by successive doublings. Furthermore, potato folate is vegetable folate, absorbed at about eighty per cent, where the folic acid going into flour is counted as fully absorbed. Corrected for that, the pre-famine diet delivered about a hundred and ninety micrograms of absorbed folate a day. Someone on full rations had only about sixty. If someone was not given rations then they would lose the whole lot.

The liver holds ten to thirty thousand micrograms of folate and the body loses about fifty a day, so a full ration of Indian meal, at roughly sixty micrograms absorbed, more or less held the line. Half rations did not. At a deficit of twenty micrograms a day the smaller reserve is gone inside eighteen months. With no relief at all the deficit is fifty a day and even the largest reserve empties within two years. The famine continued for seven years. For those on half rations or none, the stores could only last so long.  

Depleted to that degree, those women sit in the lowest of Daly’s own folate bands, where he measured the rate at around three times that of a mid-range population. In a hospital delivering two thousand births a year that is a move from about seven affected babies a year to somewhere between fourteen and twenty-one.

A change on that scale would be clear. These defects arrive in small numbers and yearly counts bounce about, but a doubling sustained across the famine years is a different matter. In a hospital of only a thousand births a year, five famine years would have caught a doubling about nineteen times in twenty and a trebling every time; at two thousand births a year both become near certainties. Masterson’s records show no appreciable change. The chance of a true doubling in risk being unnoticeable carries odds of at least forty to one.

Modern starvation

More recent measurements based on areas with poor diet have not moved the dial. Ethiopia records some of the highest rates of neural tube defects in the world and has done so across decades in which its nutrition has changed beyond recognition, through famine, recovery, aid and war. If diet set the rate, the rate should have moved with it. Across Africa a review of forty-three studies covering more than six million births found the highest rates in Algeria, Ethiopia and Eritrea, that rates have risen over time. Folic acid use in early pregnancy was not among the factors significantly associated with risk.

What the famines show

The government claim that matters here is that a proportion of low risk women have too little folate in their diet and are at risk because of it. That is the link which justifies putting folic acid into everybody’s bread. Even when dietary folate plummets to famine levels there is no evidence of an increase in the incidence of neural tube defects. The excuses used to ignore this finding include saying that a famine could not reveal such an increase anyway, because fewer women conceive and more pregnancies are lost early. Both happen in famines. Both are reasons post rationalised to explain why an expected signal failed to appear. It is clear that other factors are at play.

Finally, a generally well-nourished population, in which most women are not clinically folate deficient, is not a starving one. The case for adding folic acid to the food of a population with good folate stores is not as strong as made out. Famine remains the clearest test we have of the effect of diet on risk. What measurements we have do not show the increased risk that should be present if the conventional hypothesis that diet is to blame is right.

See all other folic acid articles here.