Homocysteine Is Lower in the Third Trimester of Pregnancy in Women with Enhanced Folate Status from Continued Folic Acid Supplementation Valerie A. Holmes, 1,2 Julie M.W. Wallace, 1* H. Denis Alexander, 2 William S. Gilmore, 1 Ian Bradbury, 1 Mary Ward, 1 John M. Scott, 3 Peter McFaul, 4 and Helene McNulty 1 Background: In many countries, current recommenda- tions are that women take a daily 400-g folic acid supplement from before conception until the end of the 12th week of gestation for the prevention of neural tube defects. Low folate status is associated with an increased concentration of plasma total homocysteine (tHcy), a risk factor associated with pregnancy complications such as preeclampsia. Methods: In a longitudinal study, we determined tHcy and corresponding folate status in 101 pregnant women at 12, 20, and 35 weeks of gestation, in 35 nonpregnant controls sampled concurrently, and in a subgroup (n  21 pregnant women and 19 nonpregnant controls) at 3 days postpartum. Results: Plasma tHcy was significantly lower through- out pregnancy compared with nonpregnant controls, with values lowest in the second trimester before in- creasing toward nonpregnant values in the third trimes- ter. Importantly, mean tHcy concentrations were lower in pregnant women taking folic acid supplements than in those not, an effect that reached significance in the third trimester (5.45 vs 7.40 mol/L; P <0.05). During the third trimester, tHcy concentrations were significantly higher in pregnant women with a history of miscarriage than in women with no previous history (8.15 vs 6.38 mol/L; P <0.01). Conclusions: This is the first longitudinal study to show that homocysteine concentrations increase in late pregnancy toward nonpregnant values; an increase that can be limited by enhancing folate status through con- tinued folic acid supplementation. These results indi- cate a potential role for continued folic acid supplemen- tation in reducing pregnancy complications associated with hyperhomocysteinemia. © 2005 American Association for Clinical Chemistry As a result of unambiguous evidence published over 10 years ago showing that folic acid protects against both the first occurrence and recurrence of neural tube defects (NTDs) 5 (1, 2), expert committees worldwide issued folic acid recommendations. In essence, these guidelines rec- ommend that women of child-bearing age, capable of becoming pregnant, take 400 g/day folic acid (3–5 ). In general, the recommended timing of folic acid adminis- tration is from before conception until the end of the first trimester. Although the prevention of NTDs (which are malformations occurring in very early pregnancy) is clearly the focus of current policy, the importance of folate status in later pregnancy is much less clear, despite well-established evidence that maternal folate status is compromised throughout pregnancy. The issue of whether women should be supplemented with folic acid in later pregnancy is not covered by any official recom- mendations; therefore, practice is likely to be very vari- able among healthcare professionals caring for women during pregnancy. Folate is essential for DNA and RNA biosynthesis and is required for homocysteine metabolism. Hyperhomo- cysteinemia is not only considered to be a strong inde- 1 Northern Ireland Centre for Food and Health (NICHE), School of Biomedical Sciences, University of Ulster, Coleraine, UK. Departments of 2 Haematology and 4 Obstetrics and Gynaecology, Belfast City Hospital, Belfast, UK. 3 Department of Biochemistry, Trinity College Dublin, Dublin, Republic of Ireland. *Address correspondence to this author at: Northern Ireland Centre for Food and Health (NICHE), School of Biomedical Sciences, University of Ulster, Coleraine, Co Londonderry BT52 1SA, UK. Fax 44-028-7032-3023; e-mail j.wallace@ulster.ac.uk. Received February 11, 2004; accepted December 3, 2004. Previously published online at DOI: 10.1373/clinchem.2004.032698 5 NTD, neural tube defect; tHcy, total homocysteine; RCF, red cell folate; MTHFR, 5,10-methylenetetrahydrofolate reductase; BMI, body mass index; and CI, confidence interval. Clinical Chemistry 51:3 629 – 634 (2005) Nutrition 629