Birth weight is one of the most important pregnancy outcome parameters; it is strongly associated with infant mortality during the first year of life and influences later developmental processes as well
. Folate required for growth reaches the maximal level in the last trimester
, because of rapid growth of the fetus and the uteroplacental system and fetal accumulation of folate stores. Without sufficient folate intake, maternal plasma and red blood cell (RBC) folate decreases from the fifth month of pregnancy until several weeks after delivery
. A recent prospective study has also shown that low folate intake (< 187 μg/day) and low RBC folate status in the late pregnancy increase the risk of small for gestational age (SGA) birth in an adolescent population
. Other studies reported positive association between birth weight and maternal RBC folate status
The present systematic review was aimed to summarize available data on the role of folate status in basic aspects of pregnancy outcome. Moreover, we included 10 studies (from 8 published papers) into a meta-analysis in order to assess whether there is any dose–response relationship between folate intake and birth weight, placental weight and length of gestation.
We applied base-e logarithmic transformation on folate intake and on the aforementioned pregnancy outcome parameters. These transformations make it possible to pool
values and report them as dose–response relationship between intake and health. The overall
represents the difference in the loge-transformed predicted value of the given health outcome for each one-unit difference in the loge-transformed value in folate intake. The intervention was started from the second trimester in all the included studies; therefore our results allow inferences about supplementation during pregnancy which differ substantially from periconceptional folate supplementation.
Our results support the hypothesis that increased folate intake after the first trimester is associated with higher birth weight. The overall
was found to be 0.03 indicating that a two-fold increase in folate intake corresponds to a 2% higher birth weight, which is a slight but significant increase. Or to put it in another way, a neonate whose mother has a folate intake of 500 μg per day is predicted to have a birth weight that is 2% higher than a neonate whose mother has a folate intake of 250 μg per day.
Placental weight is an important determinant of fetal weight. It has been also demonstrated that placental weight was significantly lower in SGA neonates compared to appropriate for gestational age neonates of the same birth weight
. Placental uptake of folate from the maternal circulation is critical for adequate folate supply to the developing fetus. Maternal folate is transferred against a concentration gradient to the fetus, the net effect is a two-fold higher plasma folate level of the neonates compared to the maternal plasma level at delivery
. Inadequate folate status during pregnancy may be a risk factor of several adverse health outcomes, such as fetal malformations and various placenta-related diseases
. Moreover, low folate status results in elevated plasma homocysteine level, which may increase the risk of placental damage and dysfunction, disturbing thereby oxygen and nutrient transport to the fetus
In the present study we failed to detect any dose response relationship between folate intake and placental weight; our data did not show significantly elevated placental weight in treatment groups compared to placebo groups (P=0.08). In contrast to the growth of the fetus, the placenta grows rapidly in the first trimester and reaches its full size during the second trimester
, therefore folate supplementation may have no further effect on placental weight in the later period of pregnancy.
A prospective study conducted on more than 2000 pregnant women demonstrated that low serum folate is associated with nearly a double risk of preterm delivery
. Scholl and colleagues have found similar degree of risk for preterm delivery in women with low folate intake (≤ 240 μg per day)
. Still, like in the case of placental weight, we did not find significant effect of folate supplementation on the length of gestation in the intervention groups compared to placebo groups (P=0.77).
The strength of our meta-analysis is the inclusion of RCTs. Ideally, RCTs should provide reliable data about the effect of an intervention. Randomization allows us to assume that changes in birth weight, placental weight or length of gestation are definitely due to folate intervention. Other factors that might affect these pregnancy outcomes would be expected to be distributed randomly between the intervention and control groups.
The findings of this meta-analysis must be interpreted in the light of certain limitations. First of all, the majority of studies were conducted at least 30 years ago and, according to our current standards, all of them had high risk of bias. These uncertainties originate mainly from the lack of methodological information in studies published several decades ago: e.g. the laboratory parameters of the included pregnant women and other potential confounders, like smoking, alcohol consumption, maternal BMI or sex of the infant were usually poorly described. The substantial risk of bias increases the uncertainty of our results and may lead to overestimation or underestimation of the true treatment effect. Differences in supplement form, gestational age, dose or duration may explain the observed heterogeneity of intervention effect; however, the low number of studies included did not allow us to divide them into groups and perform further subgroup analysis. Furthermore, it must be taken into account that the potential reason of the non-significant results of placental weight and length of gestation analysis may be explained by the effect of inadequate sample size. In addition, the studies included in this meta-analysis evaluated approximately 700 birth weights and 400 durations of pregnancy, which would correspond to about 70 SGA birth weights and 40 preterm births in both interventional groups together. Thus this study may be underpowered to make inferences about those most important outcomes.