Introduction
Gestational hypertension and preeclampsia are common hypertensive disorders during pregnancy [
1,
2]. Preeclampsia is a devastating complication of pregnancy responsible for maternal mortality and morbidity [
3,
4]. Mothers with preeclampsia during pregnancy may result in neurocognitive dysregulation and suboptimal infant development in offspring [
5]. During pregnancy, hypertension is a risk factor for diabetes and cardiovascular disease in later life [
6,
7]. Preeclampsia is always caused by impaired placental perfusion, nevertheless, but other risk factors for preeclampsia remain unclear [
8].
Accumulating evidences have suggested that elevated levels of blood homocysteine are a cause of gestational hypertension and preeclampsia [
9,
10]. In addition, more and more studies confirm that folic acid supplementation can reduce blood homocysteine levels [
11,
12]. Furthermore, the relationship between folic acid supplementation and preeclampsia risk has been investigated by several epidemiological studies, but their results are inconsistent. Some studies showed that the supplementation of folic acid is beneficial in decreasing the incidence of preeclampsia and gestational hypertension during pregnancy [
13‐
15]. However, Li et al. demonstrated that there was no association between the occurrence of preeclampsia or gestational hypertension and the consumption of folic acid alone during early pregnancy [
16].
In light of these inconsistent results, we conducted this meta-analysis to systematically analyze exploration of the relationship between folic acid supplementation in pregnancy and the risk of preeclampsia or gestational hypertension. This meta-analysis will provide significant clues for further clinical studies.
Discussion
In this meta-analysis, 14 studies were included and pooled results showed that the supplementation of folic acid during pregnancy significantly reduced preeclampsia risk, but had no effects on gestational hypertension risk. Moreover, the decreased preeclampsia risk was associated with supplementation of multivitamins containing folic acid rather than folic acid alone. These results merit further discussion.
Supplementation of folic acid has been found to decrease preeclampsia risk. The possibility is that folic acid can affect the levels of hyperhomocysteinemia, which is suggested to damage the vascular endothelium of the developing placenta [
33]. Moreover, a folate deficiency may induce the apoptosis of human cytotrophoblast cells, thus possibly affecting trophoblast invasion and placental development [
34,
35]. Therefore, the supplementation of folic acid may improve placental implantation and subsequently affect the incidence of hypertensive pregnancy disorders. In this study, our results are consistent with the findings of a previous study reported by Catov et al. [
36] that a decreased preeclampsia risk is related to multivitamin use, but there is no association between the risk of preeclampsia and folic acid supplement alone. Given the biologic rationale of folic acid in reducing the risk of developing preeclampsia, we speculate that folic acid may play a more important role in preeclampsia than other vitamins because the biologic mechanisms of other vitamins in reducing the risk of developing preeclampsia have not been fully explored. Moreover, previous RCTs have found that supplementation with vitamins C and E (without folic acid) during pregnancy has no protective effect on preeclampsia [
37,
38]. Lv et al. also demonstrated that the risk for lower clinical pregnancy rate was not significantly correlated with deficient serum vitamin D level in infertile woman undergoing in vitro fertilization [
39]. In addition to several studies that have confirmed a relationship between decreased preeclampsia risk and the supplementation of multivitamins containing folic acid [
13,
14], we speculate that other vitamins may also play some roles in the prevention of preeclampsia, and the key roles of folic acid in preventing the risk of preeclampsia may be enhanced by other nutrients present in multivitamins. However, the ingredients of multivitamins in different included studies are largely unknown, hindering us to further explore the key other vitamins in preventing the risk of preeclampsia. More studies are still needed to confirm our observation.
Furthermore, strengths and limitations should be considered. Strengths of our study were that a total of 14 articles containing a larger number of patients were included in this study. The larger sample size increased the reliability of our results. In addition, this meta-analysis was conducted on a basis of good quality studies. Although publication bias existed among our included studies, the results of trim and fill method and a sensitivity analysis also confirmed that the pool results had no significant changes. Despite these, our results should be considered in light of limitations. First, a high heterogeneity existed in this study. One possibility for this was that the sample size differed among different studies, which may result in inconsistent 95% CI. Second, among all included studies, 13 were cohort studies and one was a RCT study. Third, we did not collect baseline nutritional data on the cohorts, especially the data on folic acid intake from food. In consideration of the findings of Ray and Mamdani [
40] that folic acid from food intake was very low to make any impact on the risk of preeclampsia, we believe that supplementation of multivitamins containing folic acid during pregnancy may be beneficial. Fourth, the dosage of folic acid is largely unknown due to lack of related information in included studies and the period in which the women received folic acid was insistent, which may influence the effects of folic acid on the prevention of preeclampsia. Notably, previous findings showed that there was no significant association between dosage of folic acid supplementation and the strength of its effect [
41,
42], but an inverse relationship exists between the duration of folic acid supplementation and the risk of stroke [
42], suggesting that the supplementation duration of folic acid is more important than its dosage. A further analysis on exploring key period of folic acid supplementation may have important clinical significance. Considering the different study design among studies, our results are still needed to be further verified by more high-quality clinical studies.
In conclusion, the findings of this meta-analysis indicate that the supplementation of multivitamins containing folic acid during pregnancy may reduce preeclampsia risk. Multivitamin supplementation may be considered as a promising prevention strategy for preeclampsia.