NTDs remain an important yet potentially preventable cause of neonatal mortality. Dietary change and selective termination of affected pregnancies has resulted in severe NTDs rarely being seen in high-income countries. Data from three randomized trials indicate that periconceptional folic acid supplementation has a large effect on the recurrence of NTDs (70% reduction; 95% CI: 35–86). Four prevention-of-first-occurrence studies indicate a reduction in incidence of 62% (95% CI: 49–71). These two meta-analyses are the first to separate the effects of folic acid supplementation on NTD incidence from the effect on NTD recurrence.
In addition, there is increasing, although lower quality evidence regarding folic acid fortification of food. Our systematic review identified 10 before-and-after population-based studies of the effect of folic acid food fortification on the occurrence of NTDs. These large-scale studies consistently report substantial reductions in the incidence of NTDs or in perinatal or neonatal mortality due to NTDs. A meta-analysis of the eight included studies suggests that food fortification can reduce the incidence of NTDs by 46% (37–54%). This is the first meta-analysis that we are aware of for folic acid fortification and NTDs and shows a substantial and consistent effect even in large-scale programmes. Assuming that folic acid affects NTD occurrence but not severity or case-fatality rate, we assume that folic fortification will reduce NTD-specific neonatal mortality by 46%. There is emerging evidence that folic acid fortification reduces both the incidence and the severity of NTDs,49–50
which would make this assumption conservative.
The effect of folic acid on incidence and mortality may be different in countries with higher baseline rate of NTDs, poorer diets (with higher levels of folate deficiency in women of child-bearing age) and without screening for, or termination of, affected pregnancies.
There is evidence of a complex dose–response relationship with different fortification regimes, depending on the initial average birth prevalence of NTDs and the additional intake of folic acid.51
The estimate in this meta-analysis of folic acid-fortification effect is based primarily on white populations. A study from the USA reported lower background NTDs rates amongst black Americans compared to Hispanic or white groups, but also a reduced effect of folic acid fortification in the black American group.52
In Australia, the 30% reduction in the incidence of NTDs seen following the introduction of the folic acid-supplementation recommendation and voluntary food fortification was limited to the white population, with no changes in the NTD rates amongst the aboriginal populations seen across this time period.53
However, one large study in China found very high rates of NTDs, which were substantially reduced by periconceptional folic acid.34
Prevalence studies in South Asia report very high rates.54–56
We based our estimate on fortification rather than supplementation. Although efficacy studies of supplementation have shown a large potential biological impact, the widespread adoption of policies of folic supplementation in many high- and middle-income countries have generally produced disappointing results at a public health level. The barriers to supplementation are likely to be even greater in low-income countries and those with high levels of poverty and poor health-care infrastructure. However, maximizing effectiveness of fortification in low-income countries may also present challenges. What level of folic fortification should be adopted? What vehicle should be used? This is likely to be country/region specific, dependent on the proportion of the population who buy particular food staples, such as flour, maize or rice. Despite intense efforts, folic acid fortification may not reach the poorest, as was seen in Guatemala.57
The main limitation of this review and the resulting effect estimate is the lack of high-quality studies reporting the impact of folic acid supplementation or fortification on neonatal mortality. Our estimate for folic fortification is based on low-quality before-and-after population studies from Canada, the USA and three middle-income countries to determine the impact on incidence. Given the consistency of the effect size across studies, the quality can be upgraded to moderate, but once assumptions are applied to ‘translate’ this to mortality effect, the quality of the estimate is again downgraded to low. Further, possible sources of bias are that the review retrieved only published articles and that a single person was responsible for the screening and abstraction of the articles.
The proportion of neonatal deaths due to congenital abnormalities is problematic. Congenital abnormalities are under-reported in Verbal Autopsy and, indeed, also in hospital-based data since only obvious external abnormalities such as NTDs are detected yet the most common lethal congenital abnormalities are congenital heart disease, which are most likely to be misclassified as pneumonia. Hence the proportion of neonatal deaths attributed to congenital abnormalities is underestimated and reflects only those deaths due to clearly visible abnormalities. In addition, there may be systematic, selective misclassification of live-born babies with congenital abnormalities who die shortly after birth as stillbirths ‘to protect the mother’. These global estimates () are particularly uncertain for South Asia where both the prevalence of NTDs appears to be especially high, based on four studies, and yet the proportion of neonatal death attributed to congenital conditions is based on verbal autopsy and is low and very uncertain.48
The effects of folic acid on pregnancy outcome may extend beyond NTDs. Recent studies have suggested a possible effect on reducing spontaneous preterm delivery58
and severe congenital heart disease.59
Any benefit of universal folic acid food fortification on pregnancy outcome needs to be balanced against potential, but as yet unclear, adverse effects. There is very limited evidence that the amount of folic acid consumed from fortified foods has any adverse effects. Even in the USA amongst those who consume daily supplements with folic acid of 400 µg, the likelihood is low of exceeding a total intake of 1000 µg/day.60–61
Very high serum folate levels, higher than those usually associated with fortification have been associated with potential adverse effects, but strong evidence of causation is lacking, e.g. masking of vitamin B12 deficiency amongst individuals with pernicious anaemia in the population and promoting progression of already existing pre-neoplasms.62–65