Clinical trial NCT01244347: Folic Acid Dosage and Malformations Reduction
Official title: Randomized Clinical Trial to Evaluate the Efficacy of High Dose of Folic Acid to Prevent the Occurrence of Congenital Malformations
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Congenital Malformations
Keywords: folic acid
malformations
prevention
Lead sponsor: Azienda Ospedaliera Universitaria Integrata Verona
Sponsor class: OTHER
Collaborators: name: International Centre of Birth Defects
First posted: 2010-11-19
Enrollment: 5000
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 44
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.


Eligibility criteria: Inclusion Criteria:

* age between 18 and 44 years
* women who intend to become pregnant (not excluded women

Exclusion Criteria:

* 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
* women allergic to folic acid
* women presenting contraindications to folic acid
* women affected by megaloblastic anaemia
* assuming folic acid at defined doses for conditions other than those already mentioned

Primary outcomes:
measure: number of congenital malformations
timeFrame: 112 weeks
Secondary outcomes:
measure: rate of selected congenital malformations
timeFrame: 112 weeks
measure: Miscarriages and recurrent abortions
timeFrame: 47 weeks
measure: pre-eclampsia
timeFrame: 60 weeks
measure: abruptio placentae
timeFrame: 34 weeks
measure: intrauterine growth restriction
timeFrame: 31 weeks
measure: pre-term delivery
timeFrame: 30 weeks
measure: multiple births
timeFrame: 24 weeks
Other outcomes:
Locations:
city: Adria
country: Italy
facility: Ospedale di Adria
state: Rovigo
city: Trecenta
country: Italy
facility: Ospedale San Luca
state: Rovigo
city: Conegliano
country: Italy
facility: Ospedale di Conegliano
state: Treviso
city: Montebelluna
country: Italy
facility: Family Health Centre
state: Treviso
city: Oderzo
country: Italy
facility: Family Health Practice
state: Treviso
city: Villorba
country: Italy
facility: Family Health Practice
state: Treviso
city: Gallarate
country: Italy
facility: Ospedale Sant'Antonio Abate
state: Varese
city: Camponogara
country: Italy
facility: Family Health Practice
state: Venezia
city: Martellago
country: Italy
facility: Family Health Centre
state: Venezia
city: Mira
country: Italy
facility: Family Health Practice
state: Venezia
city: Noale
country: Italy
facility: Family Health Centre
state: Venezia
city: San Pietro di Stra
country: Italy
facility: Family Health Centre
state: Venezia
city: Vogonovo
country: Italy
facility: Family Health Centre
state: Venezia
city: Bussolengo
country: Italy
facility: Ospedale di Bussolengo
state: Verona
city: Legnago
country: Italy
facility: Ospedale di Legnago
state: Verona
city: San Bonifacio
country: Italy
facility: Ospedale di San Bonifacio
state: Verona
city: Bassano
country: Italy
facility: Family Health Centre
state: Vicenza
city: Bassano
country: Italy
facility: Ospedale San Bassiano
state: Vicenza
city: Dueville
country: Italy
facility: General Practice
state: Vicenza
city: Malo
country: Italy
facility: General Practice
state: Vicenza
city: Schio
country: Italy
facility: General Practice
state: Vicenza
city: Sovizzo
country: Italy
facility: General Practice
state: Vicenza
city: Thiene
country: Italy
facility: Ospedale Boldrini
state: Vicenza
city: Valdagno
country: Italy
facility: Ospedale di Valdagno
state: Vicenza
city: Vicenza
country: Italy
facility: Ospedale di Vicenza
state: VI
city: Milan
country: Italy
facility: Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
city: Padova
country: Italy
facility: Azienda Ospedaliera di Padova
city: Padova
country: Italy
facility: Family Health Centre
city: Verona
country: Italy
facility: Family Health Centre
city: Verona
country: Italy
facility: General Practice
city: Verona
country: Italy
facility: Ospedale Civile Maggiore
city: Verona
country: Italy
facility: General Practice
city: Verona
country: Italy
facility: Family Health Centre
city: Verona
country: Italy
facility: Policlinico G.B. Rossi
Study officials:
affiliation: Azienda Ospedaliera Universitaria Integrata Verona
name: Renata Bortolus, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: Berry 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.
citation: Botto 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.
citation: Catov 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.
citation: Czeizel 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.
citation: Ingrid 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.
citation: Prevention 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.
citation: Bortolus 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.