The influence of folic acid supplement on the outcome of pregnancies in the county of Funen in Denmark: Part I

https://doi.org/10.1016/S0301-2115(99)00084-6Get rights and content

Abstract

Objective: To determine whether a supplement of folic acid given preconceptionally or early in pregnancy had any influence on, birth weight, incidence of preterm labour, low birth weight and small for gestational age. Furthermore, the aim was to elucidate, whether the outcome differed following the administration of two different dosages of folic acid, namely 2.5 and 1.0 mg. Material: All women in the childbearing age living on the island of Funen, Denmark (population 500 000) were offered a supplement of folic acid over a period of 3 years and 3 months. 14 021 women, who gave birth to 13 860 single-born and 325 multiborn children, were registered. A total of 8184 women took part in the double-blind randomized trial: 2310 had a supplement of folic acid without being randomized and 2721 women received no folic acid supplement. No information regarding the use of folic acid was available in 806 pregnancies. Abortions (512) were excluded. Results and conclusions: A supplement 1.0 mg folic acid had the same effect as 2.5 mg. The effects of supplementing the diet with folic acid given preconceptionally or in the first half of pregnancy in an affluent Northern country were a slight increase of birth weight and a decrease in the incidence of preterm labour, infants with low birth weight and small for gestational age. The greatest effect was seen in the groups receiving folic acid preconceptionally.

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.

References (22)

  • Prevention of neural tube defects: results of the MRC vitamin study

    Lancet

    (1991)
  • Cited by (52)

    • Impact of Periconceptional Folic Acid Supplementation on Low Birth Weight and Small-for-Gestational-Age Infants in China: A Large Prospective Cohort Study

      2017, Journal of Pediatrics
      Citation Excerpt :

      However, we found no obvious preconception effect. Rolschau et al23 found that periconceptional initiation of folic acid supplementation increased birth weight; however, high doses of folic acid (1 or 2.5 mg) were compared with no supplementation. Czeizel et al24,25 suggested that the excess of LBW singletons among women taking periconceptional folic acid was not statistically significant.

    • The effects of homocysteine and folic acid on angiogenesis and VEGF expression during chicken vascular development

      2012, Microvascular Research
      Citation Excerpt :

      FA is essential in embryonic development. Moreover, maternal periconceptional FA use has been shown to influence placental development, leading to increased placental weight, birth weight and embryonic growth (Rolschau et al., 1979, 1999; Timmermans et al., 2009). The exact mechanisms through which FA exerts these stimulating effects on embryonic development remain unknown.

    • Homocysteine and folate plasma concentrations in mother and baby at delivery after pre-eclamptic or normotensive pregnancy: Influence of parity

      2011, Pregnancy Hypertension
      Citation Excerpt :

      However, this does not mean that hyperhomocysteinaemia is a requirement for the development of pre-eclampsia and the elevated homocysteine concentrations seen in some pre-eclamptic patients may be an associated, or pre-disposing, rather than a causal factor. Folate plays an essential role in the growth of the placenta from early pregnancy; folate deficiency has been linked to placental abruption and thus restricted fetal growth [36]. We observed no significant differences between maternal or fetal samples from normotensive pregnancy or pre-eclampsia.

    • Gestational nutrition improves outcomes of vaginal deliveries in Jordan: an epidemiologic screening

      2010, Nutrition Research
      Citation Excerpt :

      It is widely accepted that deficiencies of specific nutrients during pregnancy may lead to suboptimal embryonic and fetal nutrition, congenital malformations, serious pregnancy complications, and preterm deliveries [9,10]. Micronutrients thought to play essential roles in supporting pregnancy include zinc [11,12], calcium [7,13], vitamin B6 [14], vitamin C [15], vitamin A [16], and folic acid [17]. Marginal depletion of zinc is associated with delivery complications, impaired immune function [18,19], reduced birth weight for gestational age, preterm delivery, and prolonged labor [19,20].

    View all citing articles on Scopus
    1

    Requests for reprints to John Tolschau, Auguststrasse 23 D, 38100 Braunschweig, Germany.

    View full text