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High Dosage Folic Acid Supplementation, Oral Cleft Recurrence and Fetal Growth
Department of Health Management and Policy, University of Iowa, Iowa City, IA 52242, USA
Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul 90035-903, Brazil
RTI International, Research Triangle Park, NC 27709, USA
Hospital de Reabilitação de Anomalias Craniofaciais, Bauru, Sao Paulo 17.043-900, Brazil
Department of Epidemiology and Biostatistics, University of South Carolina, Columbia, SC 29208, USA
Centro de Atendimento Integral ao Fissurado Lábio Palatal, Curitiba, Paraná 81.050-000, Brazil
Instituto Materno Infantil Prof. Fernando Figueira-CADEFI/IMIP, Recife, Pernambuco 50070-550, Brazil
Hospital Santo Antônio: Obras Sociais Irmã Dulce, Salvador, Bahia 40.415-000, Brazil
Genetic Counseling Service, São Paulo State University, Botucatu, Sao Paulo 18618-000, Brazil
Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA
* Author to whom correspondence should be addressed.
Received: 8 October 2012; in revised form: 25 January 2013 / Accepted: 25 January 2013 / Published: 4 February 2013
Abstract: Objectives: To evaluate the effects of folic acid supplementation on isolated oral cleft recurrence and fetal growth. Patients and Methods: The study included 2,508 women who were at-risk for oral cleft recurrence and randomized into two folic acid supplementation groups: 0.4 and 4 mg per day before pregnancy and throughout the first trimester. The infant outcome data were based on 234 live births. In addition to oral cleft recurrence, several secondary outcomes were compared between the two folic acid groups. Cleft recurrence rates were also compared to historic recurrence rates. Results: The oral cleft recurrence rates were 2.9% and 2.5% in the 0.4 and 4 mg groups, respectively. The recurrence rates in the two folic acid groups both separately and combined were significantly different from the 6.3% historic recurrence rate post the folic acid fortification program for this population (p = 0.0009 when combining the two folic acid groups). The rate of cleft lip with palate recurrence was 2.9% in the 0.4 mg group and 0.8% in the 4 mg group. There were no elevated fetal growth complications in the 4 mg group compared to the 0.4 mg group. Conclusions: The study is the first double-blinded randomized clinical trial (RCT) to study the effect of high dosage folic acid supplementation on isolated oral cleft recurrence. The recurrence rates were similar between the two folic acid groups. However, the results are suggestive of a decrease in oral cleft recurrence compared to the historic recurrence rate. A RCT is still needed to identify the effect of folic acid on oral cleft recurrence given these suggestive results and the supportive results from previous interventional and observational studies, and the study offers suggestions for such future studies. The results also suggest that high dosage folic acid does not compromise fetal growth.
Keywords: oral clefts; cleft lip; cleft palate; birth defects; folic acid; vitamins; prevention; pregnancy; nutrition; Brazil
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Wehby, G.L.; Félix, T.M.; Goco, N.; Richieri-Costa, A.; Chakraborty, H.; Souza, J.; Pereira, R.; Padovani, C.; Moretti-Ferreira, D.; Murray, J.C. High Dosage Folic Acid Supplementation, Oral Cleft Recurrence and Fetal Growth. Int. J. Environ. Res. Public Health 2013, 10, 590-605.
Wehby GL, Félix TM, Goco N, Richieri-Costa A, Chakraborty H, Souza J, Pereira R, Padovani C, Moretti-Ferreira D, Murray JC. High Dosage Folic Acid Supplementation, Oral Cleft Recurrence and Fetal Growth. International Journal of Environmental Research and Public Health. 2013; 10(2):590-605.
Wehby, George L.; Félix, Têmis M.; Goco, Norman; Richieri-Costa, Antonio; Chakraborty, Hrishikesh; Souza, Josiane; Pereira, Rui; Padovani, Carla; Moretti-Ferreira, Danilo; Murray, Jeffrey C. 2013. "High Dosage Folic Acid Supplementation, Oral Cleft Recurrence and Fetal Growth." Int. J. Environ. Res. Public Health 10, no. 2: 590-605.