Does folic acid cause as well as complicate formula feeding?
Dr Clare Craig
The measurement of the effect of folic acid in pregnancy has been confined to neural tube defects but the effects are far wider. There are adverse effects in the mother with multiple births and with gestational diabetes, which tripled across the introduction of fortification in Australia and rose stepwise with folate level, along with all the complications that both of those bring. It also has effects on the fetus and the impact of that can determine whether that baby ends up fed formula milk. Some of the highest folic acid exposures per kilogram in the population are in formula fed premature babies. So does folic acid in pregnancy increase the risk of formula exposure and further folic acid exposure?
Overview
● Tongue tie, prematurity, twinning and the delivery complications of gestational diabetes, have all been suggested as being associated with maternal folic acid. The evidence differs enormously in quality and some of it is contradictory.
● All these are risk factors for formula feeding.
● Formula must by law contain more folate per calorie than breast milk and it almost always uses folic acid.
● Premature babies receive far more folic acid per kilogram via formula than term babies.
● No tolerable upper level exists for infants under four months.
● Formula containing natural folate has been trialled and made lawful in Britain but only one mainstream British brand uses it.
Babies get the biggest dose
The European Food Safety Authority is the body that sets nutrient limits for the European Union and its limits have been carried into British law after Brexit. Its tolerable upper level for adults is 1,000 micrograms of folic acid a day based on an average male of 70 kilograms with a mature liver. That works out at 14 micrograms per kg per day. A term newborn on formula takes in 12 to 17 micrograms of folic acid per kilogram per day depending on volume eaten. A 1.5 kilogram premature baby on hospital preterm formula takes in about 52 micrograms per kilogram per day, three to four times the term rate.
There is no safety limit. EFSA has set no tolerable upper level for any infant under four months. For 4 month olds right up to 3 year olds the limit is set at 200 micrograms a day, which is the same as the entire recommended daily folate intake for an adult.
A British cohort published in 2024 tested premature infants across several neonatal units. None showed evidence of deficiency. However, it found concentrations above the study’s reference threshold in 31 percent of infants at the first measurement and 42 percent at the second. The worst affected were receiving fortifier, parenteral nutrition or supplements. The authors called for research into the consequences of exceeding the threshold but nobody has done that research.
How much is in there?
Aptamil says it contains folate at 13 micrograms per 100 millilitres. SMA contains folic acid at 11 micrograms. A parent would read those as nearly the same quantity of the same thing. Unless she knows the regulatory conversion, she has no way to see that one figure is folic acid by weight and the other is folate equivalents, a unit that counts folic acid at 1.7 times its mass. Both declarations are lawful.
The conversion sits in a footnote to the law that governs formula composition, assimilated Commission Delegated Regulation 2016/127: one microgram of dietary folate equivalents equals 0.6 micrograms of folic acid from formula. The convention comes from the American Institute of Medicine, which in 1998 judged synthetic folic acid taken with food to be 1.7 times as available to the body as the folate in food itself. Cow & Gate is the one brand that declares both figures, 10 micrograms of folic acid and 17 of folate per 100 millilitres, and there is the 1.7 ratio, printed on the tin for anyone who looks.
The same footnote mentions the legal range of 15 to 47.6 micrograms of dietary folate equivalents (DFE) per 100 kcal, which is 9 to 28.6 micrograms of actual folic acid.
| Product | Folic acid per 100 kcal | Folate as DFE per 100 kcal |
| Aptamil First Infant milk | 11.8 µg | 19.7 |
| SMA PRO First Infant Milk | 13.7 µg | 22.9 |
| Cow & Gate First Infant milk | 15.2 µg | 25.8 |
| SMA First Infant Milk | 16.4 µg | 27.4 |
| Legal range | 9.0 to 28.6 µg | 15 to 47.6 |
| Breast milk | approximately 12.7 |
Table 1: The four leading British first infant milks, the range the law permits and breast milk itself, in both units the labels use.
On the regulatory conversion the legal minimum for formula is 15 micrograms of folate equivalents per 100 kcal compared to the approximately 12.7 in breast milk. No formula may lawfully be sold containing as little folate per calorie as the actual breast milk it is meant to replicate.
The 1.7 multiplier exists because folate is poorly recovered from vegetable sources, so more of it is needed for the same effect. Breast milk folate is bound to folate binding protein, which protects it through the gut and delivers it efficiently. The conversion therefore makes little sense in this context.
The smallest babies get the most
The milk given to premature babies has no upper limit for folic acid because neonatal products are foods for special medical purposes and the limits for formula composition therefore do not apply.
Aptamil Nutriprem 1, given to babies of 1 to 1.8 kilograms and supplied to hospitals only, declares 34.8 micrograms of folic acid per 100 millilitres at 80 kcal. That is 43.5 micrograms per 100 kcal, half as much again as the 28.6 the law permits for a healthy full-term baby. A 1.5 kilogram baby fed at the usual 150 millilitres per kilogram takes 180 kcal a day and with it 78 micrograms of folic acid. Using the EFSA adult upper limit and scaling down for weight would suggest an upper limit for a 1.5 kilogram baby of 56 micrograms a day. The sickest and smallest patients receive the most concentrated product.
A premature baby that is managing to breast feed is still given human milk fortifier, which in a recent British cohort added 30 micrograms of folic acid per 100 millilitres. Since 2018 UK guidance has even added a 50 microgram daily oral supplement for exclusively breastfed preterm infants. Those babies on intravenous nutrition are given 10 to 40 micrograms per kilogram per day. The European Society for Paediatric Gastroenterology, Hepatology and Nutrition, which writes the feeding guidelines used across British neonatal units, recommends a range running from 23 to 100 micrograms per kilogram per day of folate rather than folic acid. The studies underlying it measured the correction of deficiency based on blood tests. None of these studies was designed to detect harm from excess.
That 56 microgram upper limit is not a safety limit because the research required to ensure safety has never been done. The number is instead a result of scaling the adult limit, which itself is based only on masking of B12 deficiency, to a smaller body. By contrast to the 56 microgram upper limit, a 1.5 kilogram baby on Nutriprem 1 at ordinary feed volumes takes in 78 micrograms a day and on fortified breast milk 68.
The same scaling method gives 106 micrograms a day as an upper limit for a term baby at 3.5 kilograms and the leading products deliver 41 to 58. It is clear that preterm babies are exposed far more than term babies.
Does the mother’s dose fill the bottle?
Folic acid in pregnancy may even increase the risk that a baby is exposed to the folic acid in formula. Babies with tongue ties, prematurity, twins or triplets or a delivery complicated by gestational diabetes or pre-eclampsia all have a higher risk of formula exposure. There is evidence for each of these that exposure to folic acid in pregnancy increases the risk, though it varies in strength from a randomised trial for twinning to a single case-control study for tongue tie.
In 2020 an Israeli group compared 85 infants who had undergone frenotomy for a tongue tie in Jerusalem with 148 controls. Regular pre-conceptional folic acid use was reported by 54.1 percent of case mothers against 25.7 percent of controls, an odds ratio of 3.41, with weaker results in the looser exposure categories, 1.45 for any use and 1.67 for most days. The effect size is large, but the study was small and retrospective and exposure depended on maternal recall. A separate group in Palembang measured maternal serum folate rather than asking about tablets and found an association in the same direction, an odds ratio for tongue tie of 2.13 among 144 mothers, though that work remains an unreviewed preprint.
On prematurity the evidence is contradictory. A 2019 meta-analysis of thirteen cohorts found supplement users had 10 percent less preterm birth. But supplement users are older, richer, better educated, non-smoking planners of their pregnancies and every one of those lowers preterm birth by itself, so residual healthy-user confounding could plausibly account for a modest protective association of that size. The Norwegian Mother and Child Cohort set out to minimise that problem, excluding every known risk pregnancy and adjusting for eleven maternal variables across 66,014 singleton pregnancies. It found folic acid begun more than eight weeks before conception carried an 18 percent increase in spontaneous preterm delivery, with confidence intervals suggesting the true rise was between 5 to 32 percent. The association strengthened when the analysis was restricted to first pregnancies and to women who conceived within a month.
The only randomised trial that could address the question is not clear because of how it was analysed. Czeizel randomised 5,502 confirmed pregnancies to a multivitamin containing 0.8 mg of folic acid or to a control group given trace elements. It reported a significant increase in multiple births in the supplemented arm and also reported no significant change in risk of preterm birth in the singletons. Multiple pregnancies carry a substantially higher risk of preterm delivery, so by restricting the prematurity analysis to singletons the analysis of prematurity risk may have been biased. The overall rate of preterm delivery across all the randomised pregnancies including twins and triplets has never been reported.
The randomised evidence on twinning is stronger than it is usually reported to be. When the rate is calculated per pregnancy rather than per baby, which is the correct unit, Czeizel’s trial gives a rate ratio of 1.49 with a confidence interval from 0.94 to 2.38. That figure comes from the authors of the study most often cited against him. A 49 percent increase that just fails to reach significance in a trial of this size is an underpowered result, not a negative one. A study of Swedish registry data found more twin deliveries in folic acid users after adjusting for fertility history, Czeizel found the same in the Hungarian case-control surveillance data, and American studies agreed.
The one large study that did not is treated as the refutation. Li and colleagues followed 242,015 Chinese women taking 400 micrograms of folic acid a day and found multiple births in 0.59 percent of users against 0.65 percent of non-users, a rate ratio of 0.91. The direction is the first difficulty. No proposed mechanism has folic acid reducing twinning, so a 9 percent reduction points to differences between the two groups rather than to an effect of the pill.
Also, the two groups differed. Women who took folic acid were 16 months younger and far more likely to be first-time mothers, 92.3 percent against 72.2 percent. Maternal age and parity are two of the strongest determinants of dizygotic twinning and both were higher in the unexposed group, which inflates the unexposed rate and would hide any impact from folic acid. No adjustment was made for parity, and the adjustment that was made for education had a disproportionate impact, moving the rate ratio from 0.91 to 0.98, suggesting the two groups were poorly matched from the outset.
The second difficulty is precision where it matters. The mechanism at issue is dizygotic twinning, which requires two eggs. In this cohort dizygotic twinning ran at 2.5 per 1000 pregnancies, against 10 to 20 per 1000 in Europe and North America. The cleanest marker for it is the opposite sex twin pair, and the study found 304 of them. The rate ratio for opposite sex twins was 0.95 with a confidence interval from 0.76 to 1.19, so the study is compatible with a 19 percent increase in dizygotic twinning. The authors’ power calculation is for a 40 percent increase in all multiple births, which is not the quantity in dispute. They also record that the MTHFR 677C to T variant is common in Chinese populations and that this variant reduces dichorionic twin pregnancy. The population was, on their own account, genetically selected against the outcome being measured.
This does not mean the Chinese study is wrong. It tested a different dose of a different preparation in a population with among the lowest dizygotic twinning rates in the world, and it reported a null whose confidence interval does not exclude a modest increase. It is a genuine null. It is not a refutation.
Gestational diabetes and pre-eclampsia both delay milk coming in which increases the likelihood of formula feeding. Australian data show gestational diabetes tripling across the introduction of mandatory fortification, rising stepwise with red cell folate, and in 3,196 Adelaide pregnancies pre-eclampsia was more common in women taking under 800 micrograms of folic acid daily, 10.3 percent, than in women taking none, 6.1 percent.
What is the alternative?
Formula does not have to contain folic acid. Folic acid is the synthetic oxidised form. Formula can instead be made with the reduced folate L-5-methyltetrahydrofolate, the form the body actually uses. A trial has been run on 240 term infants randomised to one or the other. They showed identical growth and the methylfolate babies had markedly less unmetabolised folic acid circulating. EFSA assessed the ingredient and found it safe and it has been lawful in British formula since 2023.
HiPP, one of Europe’s largest formula manufacturers, already uses calcium L-methylfolate in its infant formulas, listed on the tin as Metafolin. Three years after Britain made it lawful, this is the only mainstream British formula which contains it. Even there the label has to read folic acid, with the actual substance in brackets after it, because folic acid is the nutrient name the law recognises. Folic acid is preferred by manufacturers because it is cheap and exceptionally stable on the shelf, which methylfolate is not, so switching means more careful dosing and ensuring stock is fresh.
It is shocking that the highest folic acid exposures are seen in babies for whom there is no upper safety limit. When reduced folates are available in formula, why does folic acid remain the default.
