|04. Micronutrients and Pregnancy Outcome|
Folate is critically important for foetal development. It is a cofactor essential in the nucleotide biosynthesis and in the metabolisation of homocysteine to methionine. Methionine is used in the methylation process of DNA, proteins and lipids with the production of homocysteine as end product (Botto & Yang 2000).
Interference with DNA synthesis gives rise to abnormal cell division. Rapidly dividing cells, such as those in the haematopoetic system, are the most susceptible to irregularities in DNA production. One of the clinical manifestations of folate deficiency is macrocytic anaemia (Scholl & Johnson 2000).
There is no doubt that folic acid deficiency is directly linked to neural tube defects. A recent review studied 35 published studies and found in concordance with a Cochrane review (Lumley et al . 2000) that periconceptual folate supplementation reduced the incidence of neural tube defects by as much as 70% (odds 0.28 C.I. 0.15-0.53). The reduction is similar for occurrent as recurrent defects. The relationship of folate with risk of abortions, preterm delivery and birth weight is not very clear. Many observational studies of folate during pregnancy suggest a potential benefit of good folate status with improvement of birth weight and gestational age. Unlike observational studies, randomised trials of folic acid supplementation have shown less uniform benefit (Scholl & Johnson 2000, Lumley et al . 2000).
Folate deficiency increases homocysteine concentrations. Women with habitual abortions had a higher prevalence of hyperhomocysteinemia as compared to controls (Wouters et al . 1993, Nelen et al . 1998), which is also confirmed by later studies (Scholl & Johnson 2000). Folate supplements reduced significantly the homocysteine concentrations. Homocysteine levels are also higher in women who have given birth to offspring with neural tube defects.
Although dietary intake is directly responsible for folate levels, the interactions with homocysteine are also mediated through a genetic predisposition. A thermolabile reductase has been identified which decreases the metabolisation of folic acid and thus hampers the conversion of homocysteine to methionine. The homozygote frequency ranges from 1% in American blacks to 20% or more among Italians and US Hispanics. Homozygote defects in mothers are associate with a higher risk of neural tube defects. Heterozygote rates range from 5 to more than 40%. It is believed that the both homo- and heterozygotes have increased need of folic acid. The need for a folic acid supplement is thus determined by the prevalence of the genetic defect in the population. We have no information on what this prevalence might be in developing countries. The folic acid supplement needs also to be given in the periconceptual period, which is not a very vulnerable period in operational terms. Improvement in food quality and the use of fortified products seem the only effective strategy.