European Journal of Obstetrics & Gynecology and Reproductive Biology
The influence of folic acid supplement on the outcome of pregnancies in the county of Funen in Denmark: Part I
Introduction
The folic acid (FA) metabolite tetrahydrofolate is a coenzyme in the formation of RNA and DNA and is necessary for cell division in the placenta and the foetus. As a part of this mechanism folic acid prevents the possible embryopathic effect of increased homocystein formation [1]. Hibbard and Smithells [2] found that a deficiency in FA could produce neural tube defects in the foetus. Later, others [3], [4], [5] confirmed that FA could prevent neural tube defects (NTD). The placenta grows rapidly due to cell multiplication in the early part of pregnancy, whereas during the late part of pregnancy hypertrophy prevails [6], [7]. In contrast to the growth of the placenta the growth of the foetus takes place quantitatively late in pregnancy.
A lack of folic acid early in pregnancy causing low nucleic acid synthesis may impair the growth of the placenta leading to a lower birth weight [7], [8]. The main sources of folic acid in a Northern country such as Denmark are vegetables, citrus fruit and, to some extent, meat products. Consequently, there is a pronounced seasonal variation in the intake of folic acid. Rolschau [7] demonstrated a clear variation in placental weight, placental RNA and DNA with the lowest values occurring in May–June and the highest values in August–September. As these variations could be related to a variation in folic acid intake, women expected to deliver in May–June took part in a single-blind intervention trial in which the effect of a supplement of 5 mg folic acid daily was elucidated [9]. The results showed a significantly higher birth weight, placental weight and placental DNA in the group given a supplement of folic acid. Other investigators [10], [11] were unable to demonstrate this effect in similar trials. At the time, when the present trial was planned, the evidence of the beneficial effect on the prevalence of neural tube defects (NTD) was so strong [3] that the use of placebo was considered unethical, and the protocol was unacceptable to the local Ethical Committee. We, therefore, chose two intervention doses of folic acid of 2.5 and 1.0 mg the object being to give women with a pregnancy wish and pregnant women on the island (population 500 000) a supplement of folic acid.
The variables in the present study were birth weight, incidence of preterm, low birth weight and small for gestational age, the results of this section of the study are presented as Part I. The prevalence of congenital anomalies are reported in Parts II and III [12], [13]
The aims were to elucidate the effect of a supplement of 2.5 or 1.0 mg folic acid on these variables; further, to determine whether the time at which the supplement was commenced would have any influence on the results.
Section snippets
Material and methods
During the period 1 January 1983 to 15 March 1986 all Danish female citizens resident in the county of Funen were offered a free supplement of folic acid, when pregnancy was planned, possible or already established. Information was given by health personnel, by advertisements in the press and by mailed folder to the age group 18–35 years. Midwives, obstetricians, paediatricians, departments of obstetrics and most general practitioners cooperated in order to ensure that information was available
Birth weight and gestational age
Curves for birth weight have been constructed for the various randomized folic acid dose groups in order to demonstrate the effect of folic acid dose 2.5 vs. 1.0 mg on birth weight in preconceptional groups as compared to group 10 (no folic acid supplement) (Fig. 1). Birth weights showed no difference between these three groups, except for a higher birth weight in the supplemented groups in gestational week 43, where 2.5 mg folic acid supplement gave a higher birth weight than no supplement of
Discussion
The effect of a folic acid supplementation on gestational age can be expected to influence birth weight, the number of preterm, low birth weight children, but not the number of small for gestational age children, due to the fact that the latter were defined statistically according to individual gestational weeks.
Scholl et al. [15], found a correlation between low daily intake of FA (=240 μg/day) and the number of pre-term infants. In another trial, Scholl et al. [16] also found that a
Conclusion
It is concluded that folic acid supplementation given preconceptionally is able to increase birth weight, and that also given preconceptionally or in the first half of pregnancy can reduce the incidence of preterm labour, low birth weight and small for gestational age infants.
We have found that a supplement of 1.0 mg folic acid is sufficient, but are unable to demonstrate that a lower dose may also be effective. We will recommend women to take a supplement folic acid as early as possible in
Acknowledgments
Thanks to cand. scient. Lise Hansen, Electronic Data Processing Department, Odense University Hospital, for having done the electronic programming work. To A/S Ferrosan, Sydmarken 5, 2860 Søborg, for having supplied us with folic acid tablets for randomization. To Fyns amts` forebyggelsesråd for financial support.
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Requests for reprints to John Tolschau, Auguststrasse 23 D, 38100 Braunschweig, Germany.