Evidence from a Cochrane review by Lumley et al. 2001 showed that peri-conceptional folic acid supplementation has a significant protective effect on occurrence of neural tube defects [RR 0.28, 95% CI 0.13–0.58], particularly in women who had a previous pregnancy affected by it (recurrent neural tube defects) [RR 0.31, 95% CI 0.14–0.66] [10
]. A review by Blencowe et al. for Lives Saved Tool has shown that folic acid supplementation can reduce the primary incidence of NTDs by 62 % [RR 0.38; 95 % CI 0.29-0.51] and recurrence of NTDs by 70 %. [RR 0.30; 0.14-0.65] [21
]. They also pooled data for fortification studies and showed a reduction of 46 % in primary incidence of NTDs. Our pooled estimates for primary prevention of neural tube defects by folic acid supplementation/fortification are similar to these reviews. The pooled estimate for folic acid fortification showed a reduction of 41 % (95 % CI 32 % to 48 %) in the occurrence NTDs. The small difference in effect size compared to previous LiST review was because we added three more studies to the previous met-analysis [28
There was no convincing evidence from the current published literature in favor or against of peri-conceptional folic acid supplementation/fortification for prevention of stillbirths due to NTDs. Although it can be argued that a reduction in NTDs should be associated with a reduction in stillbirths, most of the studies did not report disaggregated data on proportion of stillbirths due to NTDs. Only one supplementation study [24
] and one fortification study [31
] reported direct data on NTD related stillbirths. We know from the previous literature that a major proportion of anencephalic babies and those with spina bifida cystica result in stillbirths [75
]. Given the strong biological plausibility in favor of the intervention based on results of supplementation and fortification studies, we assumed that reduction in NTD incidence would be equal to reduction in NTDs related stillbirths with equal rates of incidence and fatalities of Anencephaly and Spina Bifida. It is important to mention that this estimate is applied to NTD related stillbirths only and the absolute effect of folic acid fortification for all-cause stillbirths will depend on the coverage of intervention and baseline incidence of NTDs in any given population.
We based our recommendations on folic acid fortification studies rather that of synthetic supplementation. This is based on the observation that widespread adoption of policies of folic acid supplementation in many developed countries have yielded disappointing results at a public health level [81
]. The main contributing factors to this could be a relatively high proportion of unplanned pregnancies [82
] and lack of easy access to a functioning health system and effective local social marketing interventions [23
]. A policy of folic acid supplementation would be even more difficult to implement in low-income countries with high levels of poverty, poor health-care infrastructure and more number of unplanned pregnancies compared to developed countries [23
]. Folic acid fortification seems a more suitable option for developing countries but it requires careful considerations including level of folic acid fortification and selection of suitable food vehicle. For example in certain population use of rice may be more common than flour or maize.
It is important to note that the effect of folic acid on incidence of NTDs and related stillbirths will be different in different countries. The amount of protective effect will depend on baseline NTDs incidence rate, folate deficiency in child bearing women, genetic susceptibility and existing system for screening and termination of affected pregnancies [75
]. For example in one part of China, incidence of NTDs is much higher than other regions in the country and folic acid supplementation was more effective in reducing NTDs in this area compared to others [25
]. The estimate in our meta-analysis of folic acid-fortification effect is based primarily on white populations and the effect may differ in different races. A before and after study from USA reported not only lower background NTD rates amongst black Americans compared to Hispanic or white groups, but also a reduced effect of folic acid fortification in the black American group [38
]. This indicates that a policy of folic acid fortification may yield different results in different populations across the developing and developed countries.
The beneficial effects of folic acid may extend beyond NTDs and related stillbirths. A recent review by Blencowe et al. for Live Saved Tool has shown that folic acid fortification can reduce congenital anomalies related neonatal mortality by 13 % [21
]. A study from Canada has shown that folic acid fortification reduced incidence of severe congenital heart diseases [79
]. Another study has reported that folic acid supplementation can reduce spontaneous preterm delivery [80
Balance protein energy supplementation has been shown to have a significant reduction on incidence of intrauterine growth restriction [2
]. The current analysis suggests that it could also reduce occurrence of stillbirths [RR 0.55, 95 % CI 0.31-0.97]. There was no significant statistical heterogeneity in the pooled estimate (I2
=20%) (Figure ). The overall grade quality evidence for the pooled estimate was that of ‘low’ level due to inadequate method of sequence generation and allocation concealment of the two of the included studies. The total numbers of stillbirhs in all the three included studies was less than 50. According to CHERG rules, it is a pre-requisite for an estimate to be considered for inclusion in the LiST model that the total number of events is at least greater than 50 [16
]. It should also be noted that all three included studies used different formulas to deliver the intervention. There is no single proven formula to recommend on large scale. Thus the value of protein supplementation is uncertain.
There was no effect of multiple micronutrient supplements on incidence of stillbirths compared to iron-folate supplementation alone. The Cochrane review on the subject by us in 2006 [7
], however, did not have any meta-analysis on stillbirths as outcome. Most of the studies in the current analysis were representative of low- or middle-income populations. As the results were not statistically significant, we do not recommend MMN supplementation during pregnancy for inclusion in the LiST for reduction of stillbirths. A recently published review on MMN showed similar results [84
In conclusion, folic acid fortification reduces incidence of neural tube defects and may also have an effect on stillbirths. This estimate of 41% reduction has been recommended as a proxy for reduction in stillbirths due to NTDs, for inclusion in the LiST model. Based on 3 studies balanced protein energy supplementation during pregnancy may reduce all-cause stillbirths by 45%. While promising, there is need of more operations research before we can recommend this intervention on large scale for reducing stillbirths. There is no evidence of effect of multiple micronutrients supplementation on reducing stillbirths.