Folic Acid Dosage and Malformations Reduction
Randomized Clinical Trial to Evaluate the Efficacy of High Dose of Folic Acid to Prevent the Occurrence of Congenital Malformations
2 other identifiers
interventional
5,000
1 country
34
Brief Summary
In 1991 the Medical Research Council Vitamin Study Group and in 1992 the Hungarian randomised clinical trial have shown conclusively that the risk of neural tube defects can be reduced substantially by taking folic acid during the peri-conceptional period. At present there is enough evidence to support the hypothesis that folic acid supplementation can reduce the risk of all congenital malformations or of a specific and selected group of them, namely: neural tube defects, oral clefts, cardiac defects, urinary tract anomalies except hypospadias, limb reduction defects, omphalocele, anal atresia and trisomy 21. The hypothesis that a higher intake of folic acid is related to an higher risk reduction of neural tube defects and of other congenital malformations is the main rationale for the present study. The present study is a randomized, double-blind, controlled trial evaluating whether supplementation with folic acid at high dose (4 mg/day) reduces the overall risk of major congenital malformations in the population more than the standard recommended dose (0.4 mg/day). At the enrolment visit all the eligible women will be interviewed to assess sociodemographic, life style and health status. After randomization, women will be interviewed every 4 months to evaluate pregnancy status. Women who have a pregnancy diagnosis during the study period will be interviewed by telephone at the expected 16, 24 and 40 weeks of gestation to evaluate the pregnancy outcome. The health status of live births will be evaluated at the child's age of 1 month, 3 months and 1 year. The primary aim of this project is conducting a study to assess the effect of folic acid periconceptional supplementation of 4 mg/day compared to the 0.4 mg/day standard dose on reducing the occurrence of all congenital malformations. Secondary aims of this study include comparing severity of CMs in offspring of trial mothers, rates of "selected congenital malformations", rates of twinning, miscarriages, recurrent abortions, small-for-gestational age, preeclampsia and abruptio placentae. The sample size is not easy to be computed because lacking robust estimate of the size effect of the treatment. Three hypotheses of a size effect of 45%, 26% and 13% were considered. A sample size of outcomes (and women) respectively of 2,006 (5,015), 8,510 (21,275) and 30,126 (75,315) is needed. Since the sample size needed to evaluate different scenarios is large, the present study is also the pilot study to promote an international prospective meta-analysis.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_3
Started Jul 2009
Longer than P75 for phase_3
34 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
Study Start
First participant enrolled
July 1, 2009
CompletedFirst Submitted
Initial submission to the registry
October 11, 2010
CompletedFirst Posted
Study publicly available on registry
November 19, 2010
CompletedPrimary Completion
Last participant's last visit for primary outcome
September 1, 2015
CompletedStudy Completion
Last participant's last visit for all outcomes
September 1, 2016
CompletedJanuary 14, 2015
January 1, 2015
6.2 years
October 11, 2010
January 13, 2015
Conditions
Keywords
Outcome Measures
Primary Outcomes (1)
number of congenital malformations
The time frame was computed as an average of 32 weeks before conception, plus an average of 28 weeks to all possible outcomes, plus 52 weeks of baby observation.
112 weeks
Secondary Outcomes (7)
rate of selected congenital malformations
112 weeks
Miscarriages and recurrent abortions
47 weeks
pre-eclampsia
60 weeks
abruptio placentae
34 weeks
intrauterine growth restriction
31 weeks
- +2 more secondary outcomes
Study Arms (2)
folic acid 4 mg
EXPERIMENTALfolic acid 0.4 mg
ACTIVE COMPARATORInterventions
Eligibility Criteria
You may qualify if:
- age between 18 and 44 years
- women who intend to become pregnant (not excluded women
You may not qualify if:
- pregnant women
- women planning to move to an area where the study is not ongoing
- women who do not understand and speak Italian
- women who do not have a phone
- women affected by epilepsy, even not assuming anticonvulsivant drugs
- women affected by diabetes
- women who previously had a tumour or a disease relevant for the study (Crohn disease, rheumatoid arthritis, ulcerative colitis)
- women who recently assumed antifolates, like methotrexate
- women who currently abuse or previously abused alcohol
- obese women
- vegetarian women
- women who had a previous pregnancy with neural tube defect (NTD) or any other congenital structural defect
- women or partners with NTD, or one of their relatives with an NTD
- women with positive family history for breast or colorectal cancer
- women with positive family or personal history of hereditary syndrome like adenomatous polyposis, or hereditary nonpolyposis colorectal cancer
- +4 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (34)
Ospedale di Adria
Adria, Rovigo, 45011, Italy
Ospedale San Luca
Trecenta, Rovigo, 45027, Italy
Ospedale di Conegliano
Conegliano, Treviso, 31015, Italy
Family Health Centre
Montebelluna, Treviso, 31044, Italy
Family Health Practice
Oderzo, Treviso, 31046, Italy
Family Health Practice
Villorba, Treviso, 31020, Italy
Ospedale Sant'Antonio Abate
Gallarate, Varese, 21013, Italy
Family Health Practice
Camponogara, Venezia, 30010, Italy
Family Health Centre
Martellago, Venezia, 30030, Italy
Family Health Practice
Mira, Venezia, 30034, Italy
Family Health Centre
Noale, Venezia, 30033, Italy
Family Health Centre
San Pietro di Stra, Venezia, 30031, Italy
Family Health Centre
Vogonovo, Venezia, 30030, Italy
Ospedale di Bussolengo
Bussolengo, Verona, 37012, Italy
Ospedale di Legnago
Legnago, Verona, 37045, Italy
Ospedale di San Bonifacio
San Bonifacio, Verona, 37047, Italy
Family Health Centre
Bassano, Vicenza, 36061, Italy
Ospedale San Bassiano
Bassano, Vicenza, 36061, Italy
General Practice
Dueville, Vicenza, 36031, Italy
General Practice
Malo, Vicenza, 36034, Italy
General Practice
Schio, Vicenza, 36014, Italy
General Practice
Sovizzo, Vicenza, 36050, Italy
Ospedale Boldrini
Thiene, Vicenza, 36016, Italy
Ospedale di Valdagno
Valdagno, Vicenza, 36078, Italy
Ospedale di Vicenza
Vicenza, VI, 36100, Italy
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
Milan, 20100, Italy
Azienda Ospedaliera di Padova
Padua, 35100, Italy
Family Health Centre
Padua, 35132, Italy
Family Health Centre
Verona, 37122, Italy
General Practice
Verona, 37126, Italy
Ospedale Civile Maggiore
Verona, 37126, Italy
General Practice
Verona, 37129, Italy
Family Health Centre
Verona, 37131, Italy
Policlinico G.B. Rossi
Verona, 37134, Italy
Related Publications (8)
Badovinac RL, Werler MM, Williams PL, Kelsey KT, Hayes C. Folic acid-containing supplement consumption during pregnancy and risk for oral clefts: a meta-analysis. Birth Defects Res A Clin Mol Teratol. 2007 Jan;79(1):8-15. doi: 10.1002/bdra.20315.
PMID: 17133404BACKGROUNDBerry RJ, Li Z, Erickson JD, Li S, Moore CA, Wang H, Mulinare J, Zhao P, Wong LY, Gindler J, Hong SX, Correa A. Prevention of neural-tube defects with folic acid in China. China-U.S. Collaborative Project for Neural Tube Defect Prevention. N Engl J Med. 1999 Nov 11;341(20):1485-90. doi: 10.1056/NEJM199911113412001.
PMID: 10559448BACKGROUNDBotto LD, Olney RS, Erickson JD. Vitamin supplements and the risk for congenital anomalies other than neural tube defects. Am J Med Genet C Semin Med Genet. 2004 Feb 15;125C(1):12-21. doi: 10.1002/ajmg.c.30004.
PMID: 14755429BACKGROUNDCatov JM, Bodnar LM, Ness RB, Markovic N, Roberts JM. Association of periconceptional multivitamin use and risk of preterm or small-for-gestational-age births. Am J Epidemiol. 2007 Aug 1;166(3):296-303. doi: 10.1093/aje/kwm071. Epub 2007 May 11.
PMID: 17496313BACKGROUNDCzeizel AE, Dudas I. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med. 1992 Dec 24;327(26):1832-5. doi: 10.1056/NEJM199212243272602.
PMID: 1307234BACKGROUNDIngrid Goh Y, Bollano E, Einarson TR, Koren G. Prenatal multivitamin supplementation and rates of congenital anomalies: a meta-analysis. J Obstet Gynaecol Can. 2006 Aug;28(8):680-689. doi: 10.1016/S1701-2163(16)32227-7.
PMID: 17022907BACKGROUNDPrevention of neural tube defects: results of the Medical Research Council Vitamin Study. MRC Vitamin Study Research Group. Lancet. 1991 Jul 20;338(8760):131-7.
PMID: 1677062BACKGROUNDBortolus R, Blom F, Filippini F, van Poppel MN, Leoncini E, de Smit DJ, Benetollo PP, Cornel MC, de Walle HE, Mastroiacovo P; Italian and Dutch folic acid trial study groups. Prevention of congenital malformations and other adverse pregnancy outcomes with 4.0 mg of folic acid: community-based randomized clinical trial in Italy and the Netherlands. BMC Pregnancy Childbirth. 2014 May 13;14:166. doi: 10.1186/1471-2393-14-166.
PMID: 24884885DERIVED
Related Links
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Renata Bortolus, MD
Azienda Ospedaliera Universitaria Integrata Verona
Study Design
- Study Type
- interventional
- Phase
- phase 3
- Allocation
- RANDOMIZED
- Masking
- QUADRUPLE
- Who Masked
- PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
- Purpose
- PREVENTION
- Intervention Model
- PARALLEL
- Sponsor Type
- OTHER
Study Record Dates
First Submitted
October 11, 2010
First Posted
November 19, 2010
Study Start
July 1, 2009
Primary Completion
September 1, 2015
Study Completion
September 1, 2016
Last Updated
January 14, 2015
Record last verified: 2015-01