Influence of genotype on optimal folate and vitamin B12 intake during pregnancy (N05040)

Study Duration: January 2003 to January 2006

Contractor: Rowett Research Institute

Epidemiological studies have shown a relationship between maternal folic acid status and the birth weight of the newborn, the health of the neonate and the health of the mother. Women with a low mean daily folate intake have a greater risk of preterm delivery and infant low birth weight even after controlling for factors such as maternal characteristics, energy intake, and other correlated nutrients. Both birth weight and length are reported to correlate with maternal and neonatal folate levels. Clinical studies have confirmed an association between marginal folate status and the occurence of recurrent spontaneous abortions, abruptio placentae and neural tube defects. Folic acid supplementation has favorable effects on birth weight and Apgar scores of newborns, and reduces prevalence of low birth weight, very low birth weight and maternal infections. Many of these effects are relatively small when assessed in whole populations but there is reason to believe that a significant proportion of the population would benefit significantly from targeted nutritional advice in relation to folate and B vitamin intake. This is the case in relation to susceptibility to neural tube defect but may also apply to all the other processes listed above which are affected by folate status. With the advent of universal fortification of flour with folate and the widespread use of folate/multivitamin supplements in pregnancy some women may achieve very high intakes of folate. This may also result in adverse outcomes such as an increase in spontaneous abortion, multiple births and the masking of certain kinds of anaemia. Thus the definition of optimal intakes of folate and B vitamins for pregnancy is important.

Folate-requiring metabolic processes are influenced by both the dietary intake and a number of genetic polymorphisms in enzymes involved in the methylation cycle. The most common of these occur in the enzyme 5,10-methylenetetrahydrofolate reductase (C677T & A1298C) which generates the active form of folate required for re-methylation of homocysteine to methionine. The presence of 5,10-methylenetetrahydrofolate reductase polymorphisms is associated with an increase in plasma homocysteine and plasma homocysteine levels have been used as an indicator of the balance of folate intake and the presence of the above polymorphisms. These polymorphisms are found with a relatively high frequency in the UK population (e.g. 37% for C677T; 10% homozygous) although the risk of a functional folate deficiency associated with homozygosity also depends on nutrient intake and may be modulated by the genotype of other folate-related genes.

The ultimate aim of this project is to determine the importance of the prior identification of folate genotype when providing dietary advice to women before and during pregnancy for optimum health and pregnancy outcome. The project is designed to determine how folate cycle genotype (in both mother and baby) modulates the effect of folate/B vitamin intake on the health of the mother and baby. In order to address these issues we will determine in 1000 pregnancies the dietary intake of folate and B12, the maternal and fetal folate/B12 status and the presence of 4 polymorphisms for the folate cycle, on maternal health and birth outcome.

Advice on folic acid supplement use was introduced in the UK in 1992. The mothers in this study were born before the introduction of this advice (1970-1980) and their babies after (2001-2003). The recommendation is that women intending to become pregnant in the UK have been recommended to take 400µg/day of supplementary folic acid prior to conception and up to 12 weeks’ gestation to reduce the risk of having a baby with neural tube defect.

Main findings from the study:

• The previously reported genotype frequency changes associated with folic acid use related to the MTHFR 677 TT and MTHFR 1298 CC mutant genotypes. The frequency of these polymorphisms was essentially the same in the babies and their mothers.
• In the study group seven pregnancies (0.5%) resulted in loss of the baby either before birth or in the first week of post-natal life. The overwhelming majority of recognised pregnancies (95.5%) resulted in a surviving baby and this is generally the case in developed countries. Because non-survivors accounted for such a small proportion of all pregnancies, even if all of these had mutant genotypes it would make no significant difference to the genotype frequencies in the whole birth cohort or the maternal nutrient exposure groups they came from.
• Peri-conceptual use of folic acid was reported in 42% of women with 39% taking at least the recommended 400 µg/day. The mean intake from normal foods was 353 (SD 78) µg/day for folate and 6.3 (SD 2.8) µg/day for vitamin B12. These values were similar to those measured in non-pregnant women of similar age and from the same geographical area. Confirmation of the intake data was provided by blood folate status at 19 weeks gestation.
• There was no evidence of an effect of maternal folate/folic acid or B12 intake (from foods or supplements or foods and supplements combined) or status on the frequency of the mutant genotypes in the offspring.

In conclusion, this study did not find any adverse effects of folic acid fortification or supplement use in pregnancy.

The final report is available from the Agency’s Information Centre.
To obtain a copy, please contact the Enquiry Desk, Information Services, Food Standards Agency (tel: 020 7276 8181/8182 or email: infocentre@foodstandards.gsi.gov.uk)

For any enquiries concerning this research project, please contact the relevant Programme contact or email: science@foodstandards.gsi.gov.uk

www.eatwell.gov.uk/agesandstages

www.eatwell.gov.uk/healthydiet