Greater Maternal Weight and the Ongoing Risk of Neural Tube Defects After Folic Acid Flour Fortification Joel G. Ray, MD, MSc, Philip R. Wyatt, MD, PhD, Marian J. Vermeulen, BScN, MHSc, Chris Meier, BSc, and David E. C. Cole, MD, PhD OBJECTIVE: Maternal obesity is likely a risk factor for neu- ral tube defects (NTDs). By late 1997, it became mandatory in Canada that all refined wheat flour be fortified with folic acid. Because overweight women may consume greater quantities of refined wheat flour, we questioned whether their risk of NTD changed after flour fortification. METHODS: A retrospective population-based study was con- ducted between 1994 and late 2000. We included all On- tarian women who underwent antenatal maternal screen- ing at 15 to 20 weeks of gestation. Self-declared maternal date of birth, ethnicity, current weight, and the presence of pregestational diabetes mellitus were recorded in a stan- dardized fashion on the maternal screening requisition sheet. The presence of NTDs was systematically detected both antenatally and postnatally. The risk of open NTD was evaluated across maternal weight quartiles and de- ciles, and an interaction between greater maternal weight and the presence of flour fortification was tested using multiple logistic regression analysis. RESULTS: A total of 292 open NTDs were detected among 420,362 women. The adjusted odds ratio (OR) for NTD was 1.2 (95% confidence interval CI 1.1–1.3) per 10-kg incremental rise in maternal weight. Comparing the high- est with the lowest quartile of maternal weight, the adjusted OR for NTD was 2.6 (95% CI 1.8 – 4.0). A similar finding was observed for the highest compared with lowest weight deciles (adjusted OR 3.3, 95% CI 1.7– 6.2). The interaction between elevated maternal weight and the presence of folic acid flour fortification was of borderline significance (P  .09). Before fortification, greater maternal weight was asso- ciated with a modestly increased risk of NTD (adjusted OR 1.4, 95% CI 1.0–1.8); after flour fortification, this effect was more pronounced (adjusted OR 2.8, 95% CI 1.2– 6.6). CONCLUSION: These data emphasize the higher risk of NTD associated with increased maternal weight, even after univer- sal folic acid flour fortification. Beyond periconceptional folic acid use, consideration should be given to testing whether prepregnancy weight reduction is an independent means of preventing NTD. (Obstet Gynecol 2005;105:261–5. © 2005 by The American College of Obstetricians and Gynecologists.) LEVEL OF EVIDENCE: II-2 Maternal obesity is likely one of several risk factors for neural tube defects (NTDs) 1–3. Greater mean daily con- sumption of sucrose-containing and high-glycemic index foods was recently shown to be associated with an in- creased risk of NTD, especially among obese women. 4 At the same time, greater physical activity was associated with a lower risk of NTD. 5 Commercially available white–wheat-flour breads and cereals have a high glyce- mic index, a standardized measure of the postprandial rise in serum glucose concentrations per 50 g of carbo- hydrate, 6 and are associated with a higher risk of obesi- ty 7 and non–insulin-dependent diabetes mellitus. 8 Randomized clinical trials have demonstrated at least a 50% reduction in the relative risk of NTD with pericon- ceptional folic acid supplement use. 9 Moreover, after the introduction of mandatory folic acid fortification of all refined wheat flour milled in the United States and Canada in late 1997, an impressive decline was observed in the prevalence of open NTDs, 10 –12 along with a significant rise in blood folate concentrations. 13 Women who ingest greater quantities of white–wheat- flour foods before conception are at increased risk for obesity 14 and, perhaps, fetal NTD. 4 At the same time, these individuals would be expected to ingest greater quantities of folic acid than nonobese women in the From the Department of Medicine, St. Michael’s Hospital, University of Toronto; Department of Genetics, North York General Hospital; Institute for Clinical Evaluative Sciences, Sunnybrook and Women’s College Health Sciences Centre, University of Toronto; Ontario Maternal Serum Screening Database Department, Genetics Programme, North York General Hospital; and Departments of Labo- ratory Medicine and Pathobiology, Medicine and Paediatrics (Genetics), University of Toronto, Toronto, Ontario, Canada. Supported by the Spina Bifida and Hydrocephalus Association of Canada and the physicians of Ontario, through the Physicians’ Services Incorporated Foundation. The authors thank both the Ontario provincial laboratories and genetics clinics for contributing data to the Ontario MSS Database. VOL. 105, NO. 2, FEBRUARY 2005 261 © 2005 by The American College of Obstetricians and Gynecologists. 0029-7844/05/$30.00 Published by Lippincott Williams & Wilkins. doi:10.1097/01.AOG.0000151988.84346.3e