Our study results indicated that folic acid supplementation was associated with a reduced risk of LBW, term-LBW, and multiparous-LBW, those risk decreasing with increasing duration of folic acid supplementation. After stratifying by time periods of folic acid supplementation, similar patterns were observed for those who took supplements before conception and during pregnancy or during pregnancy only. And there was not interaction of folic acid supplement and dietary folate intake on LBW.
Occurrence of LBW are exceedingly complex biologic processes, the exact protective mechanism of folic acid has yet to be elucidated. The epigenome is particularly susceptible during early stages of embryogenesis (31), folate may cause epigenetic modifications resulting in increased placental and fetal growth patterns (32; 33). In addition, folate may indirectly influence fetal growth by modulating placental growth and development (34; 35), and folate plays a critical role in protein and DNA synthesis (36; 37).
Earlier epidemiological researches investigating the associations between folic acid supplements and the risk of LBW have provided ambiguous results. In Europe, five studies (10–14) based on cohort studies indicated that folic acid supplementation was associated with birth weight and one cohort study (15) indicated that the effects of supplementing the diet with folic acid given preconceptionally or in the first half of pregnancy were a slight increase of birth weight. Timmermans et al found that preconception start of folic acid was associated with a decreased risk of low birth weight, and start of folic acid supplementation after pregnancy recognition was also associated with a decrease of having a child with low birth weight (10), Pastor-Valero et al thought periconceptional use of folic acid supplements greater than 1 mg/d may entail a risk of decreased birth weight (13), and Papadopoulou et al indicated that high daily doses of supplementary folic acid in early-to-mid pregnancy may be protective for low birth weight (12). In addition, Bergen et al found that low folate concentrations and erythrocyte folic acid were associated with birthweight (23). But one case control study indicated that there was no significant reduction in the rate of low birthweight in pregnant women with early or late onset pre-eclampsia after folic acid supplementation (20). In Japan, only one study indicated that lower dietary intake of protein, iron and folic acid are known risk factors for low birth weight (21). In USA, Martinussen et al. found that there were no significant associations between folic acid supplementation and low birth weight (19), but Scholl et al indicated that lower concentrations of serum folate at week 28 were also associated with a greater risk of preterm delivery and low birth weight (22). In China, Li et al indicated that statistically significant reductions in risk were evident in women who used folic acid peri or postconception, but not in those who took folic acid preconception (16), Liu et al found that The risk of LBW among pregnant women who did not take folic acid during periconception was 1.30 times higher than those who took folic acid (17), but Yang et al found folic acid supplementation was not associated with birth weight (18).
The different recommendations about folic acid supplements and dietary pattern between international entities maybe contribute to the conflicting results. In order to prevent neural tube defects and other congenital anomalies, more than forty seven countries have recommended to take folic acid supplement in the periconceptional period (38) based on two randomized trials by the British Medical Research Council in 1991 and Hungarian National Institute of Hygiene in 1992 (39; 40). In Europe, none has mandatory fortification folic acid and the voluntary fortification was permitted (41). In North America, folic acid fortification were mandatory in grain products. In china, women were recommend to supplement folic acid at least 4 weeks before conception and throughout the pregnancy. other countries/regions, Singapore and Taiwan emphasize the importance of a healthy diet with no need for supplementation, Slovenia, Sweden and Hong Kong published e-leaflets for the general public with detailed information about folate healthy diet during pregnancy (38). In addition to folate, variations in study populations, the time for initiating supplementation of folic acid, and the dosing of use of folic acid maybe also contribute to the conflicting results.
Our study found that the significant dose-response for duration of supplemented was observed for those who took supplements before conception and during pregnancy or during pregnancy only, indicating that risk of LBW, term-LBW, and multiparous-LBW decreased with increasing duration of folic acid supplementation. In China, Li et al (16) found that the trend relative risks significantly decreased as compliance with folic acid use increased. However, the significant dose-response for duration of supplemented was not shown, and other previous studies also did not explore this association. This result was important for preventing LBW, and suggested that starting folic acid supplementation should be earlier pregnancy and continuous at least 12 weeks.
To our knowledge, this is the first study investigating the associations of term-LBW and preterm-LBW with folic acid supplementation, and the associations of nulliparous-LBW and multiparous-LBW with folic acid supplementation. Significant associations were observed for term-LBW and multiparous-LBW but not for preterm-LBW or nulliparous-LBW, which indicated that may have different etiological profiles, and the biologic processes should be further studied.
Actually, there are some limitations in current study. Firstly, the study participants were predominantly from Lanzhou, so generalizability of our results to other populations with quite different demographic characteristics may not be appropriate. Secondly, dietary folate in a combination with other micronutrients could potentially confound our results. And in model b c and d, we have adjusted for total energy, which could control this problem effectively. Thirdly, although we have adjusted many important confounding factors, we cannot rule out the potential for residual confounding. Because information on folic acid supplementation and dietary folate intake was based on self-reported, it existed recall bias. But during the period of questionnaire design, field investigation and information input, there were enough professionals undertook the quality control ensuring the accuracy of information. In addition, one study have already suggested that a strong correlation between self-reported folate intake and serum folate concentrations during pregnancy (22).