The long-term impact of folic acid in pregnancy on offspring DNA methylation: follow-up of the Aberdeen Folic Acid Supplementation Trial (AFAST).

BACKGROUND: It has been proposed that maternal folic-acid supplement use may alter the DNA-methylation patterns of the offspring during the in-utero period, which could influence development and later-life health outcomes. Evidence from human studies suggests a role for prenatal folate levels in influencing DNA methylation in early life, but this has not been extended to consider persistent effects into adulthood. METHODS: To better elucidate the long-term impact of maternal folic acid in pregnancy on DNA methylation in offspring, we carried out an epigenome-wide association study (EWAS) nested within the Aberdeen Folic Acid Supplementation Trial (AFAST-a trial of two different doses: 0.2 and 5 mg, folic acid vs placebo). Offspring of the AFAST participants were recruited at a mean age of 47 years and saliva samples were profiled on the Illumina Infinium Human Methylation450 array. Both single-site and differentially methylated region analyses were performed. RESULTS: We found an association at cg09112514 (p = 4.03×10-9), a CpG located in the 5' untranslated region of PDGFRA, in the main analysis comparing the intervention arms [low- (0.2 mg) and high-dose (5 mg) folic acid combined (N = 43)] vs placebo (N = 43). Furthermore, a dose-response reduction in methylation at this site was identified in relation to the intervention. In the regional approach, we identified 46 regions of the genome that were differentially methylated in response to the intervention (Sidak p-value <0.05), including HLA-DPB2, HLA-DPB1, PAX8 and VTRNA2-1. Whereas cg09112514 did not replicate in an independent EWAS of maternal plasma folate, there was suggested replication of differential methylation in PAX8. CONCLUSIONS: The results of this study suggest that maternal folic-acid supplement use is associated with changes in the DNA methylation of the offspring that persist for many years after exposure in utero. These methylation changes are located in genes implicated in embryonic development, immune response and cellular proliferation. Further work to investigate whether these epigenetic changes translate into detectable phenotypic differences is required.

Folic acid supplements in pregnancy and birth outcome: re-analysis of a large randomised controlled trial and update of Cochrane review.

Periconceptual folic acid prevents neural tube defects. The effect of folic acid taken throughout pregnancy is unclear, however. We re-analysed data from a large randomised controlled trial performed between 1966 and 1967 and combined the results with those from trials included in a Cochrane review. A total of 2928 women were randomised: 1977 were allocated to placebo, 466 to folic acid 200 microg/day and 485 to folic acid 5 mg/day. Folic acid supplementation was not associated with any difference in mean birthweight, placental weight or gestational age. When combined with trials in the Cochrane review folic acid at high doses was associated with reduced risk of low birthweight (pooled relative risk 0.73 [95% CI 0.53, 0.99]). We found no conclusive evidence of benefit for folic acid supplementation in pregnant women given from time of booking onwards.

Quantifying severe maternal morbidity: a Scottish population study.

OBJECTIVE: To quantify the incidence of severe maternal morbidity in Scotland and determine the feasibility of doing so. DESIGN: Prospective observational study. SETTING: All 22 consultant led maternity units in Scotland, between 1 October 2001 and 30 September 2002. POPULATION: Women during pregnancy and the puerperium. METHODS: Definitions for 13 categories of severe maternal morbidity were developed from published work. Recruitment of maternity units, and training of staff, took place at a national meeting. Each month, every unit reported cases meeting the agreed definitions, the category of incident and date. Data were collated centrally and analysed to determine the frequency of incidents. The number of maternal deaths occurring in Scotland over the same period was obtained from the Confidential Enquiry into Maternal Deaths. MAIN OUTCOME MEASURES: Number and rate of defined events being reported. A subjective view of the feasibility of collecting national data routinely. RESULTS: Severe morbidity was reported in 196 women, out of 51,165 deliveries in Scotland (rate 3.8 per 1000 deliveries). Thirty percent of cases fell into more than one defined category. Major obstetric haemorrhage accounted for 50% of events. Only a third of identified patients were admitted to intensive care units. Four relevant maternal deaths occurred. CONCLUSIONS: Categories of severe maternal morbidity can be defined and may provide a useful measure of the quality of maternity services, particularly in developed countries where maternal mortality is very rare. It appears feasible to set up a national reporting system for maternal morbidity, as well as mortality.