Folic Acid Dosage and Malformations Reduction

NCT ID: NCT01244347

Last Updated: 2015-01-14

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

UNKNOWN

Clinical Phase

PHASE3

Total Enrollment

5000 participants

Study Classification

INTERVENTIONAL

Study Start Date

2009-07-31

Study Completion Date

2016-09-30

Brief Summary

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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.

Detailed Description

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Conditions

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Congenital Malformations

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

PREVENTION

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Study Groups

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folic acid 4 mg

Group Type EXPERIMENTAL

folic acid

Intervention Type DRUG

folic acid 0.4 mg

Group Type ACTIVE_COMPARATOR

folic acid

Intervention Type DRUG

Interventions

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folic acid

Intervention Type DRUG

folic acid

Intervention Type DRUG

Eligibility Criteria

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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
Minimum Eligible Age

18 Years

Maximum Eligible Age

44 Years

Eligible Sex

FEMALE

Accepts Healthy Volunteers

No

Sponsors

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International Centre of Birth Defects

OTHER

Sponsor Role collaborator

Azienda Ospedaliera Universitaria Integrata Verona

OTHER

Sponsor Role lead

Principal Investigators

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Renata Bortolus, MD

Role: PRINCIPAL_INVESTIGATOR

Azienda Ospedaliera Universitaria Integrata Verona

Locations

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Ospedale di Adria

Adria, Rovigo, Italy

Site Status

Ospedale San Luca

Trecenta, Rovigo, Italy

Site Status

Ospedale di Conegliano

Conegliano, Treviso, Italy

Site Status

Family Health Centre

Montebelluna, Treviso, Italy

Site Status

Family Health Practice

Oderzo, Treviso, Italy

Site Status

Family Health Practice

Villorba, Treviso, Italy

Site Status

Ospedale Sant'Antonio Abate

Gallarate, Varese, Italy

Site Status

Family Health Practice

Camponogara, Venezia, Italy

Site Status

Family Health Centre

Martellago, Venezia, Italy

Site Status

Family Health Practice

Mira, Venezia, Italy

Site Status

Family Health Centre

Noale, Venezia, Italy

Site Status

Family Health Centre

San Pietro di Stra, Venezia, Italy

Site Status

Family Health Centre

Vogonovo, Venezia, Italy

Site Status

Ospedale di Bussolengo

Bussolengo, Verona, Italy

Site Status

Ospedale di Legnago

Legnago, Verona, Italy

Site Status

Ospedale di San Bonifacio

San Bonifacio, Verona, Italy

Site Status

Family Health Centre

Bassano, Vicenza, Italy

Site Status

Ospedale San Bassiano

Bassano, Vicenza, Italy

Site Status

General Practice

Dueville, Vicenza, Italy

Site Status

General Practice

Malo, Vicenza, Italy

Site Status

General Practice

Schio, Vicenza, Italy

Site Status

General Practice

Sovizzo, Vicenza, Italy

Site Status

Ospedale Boldrini

Thiene, Vicenza, Italy

Site Status

Ospedale di Valdagno

Valdagno, Vicenza, Italy

Site Status

Ospedale di Vicenza

Vicenza, VI, Italy

Site Status

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

Milan, , Italy

Site Status

Azienda Ospedaliera di Padova

Padua, , Italy

Site Status

Family Health Centre

Padua, , Italy

Site Status

Family Health Centre

Verona, , Italy

Site Status

General Practice

Verona, , Italy

Site Status

Ospedale Civile Maggiore

Verona, , Italy

Site Status

General Practice

Verona, , Italy

Site Status

Family Health Centre

Verona, , Italy

Site Status

Policlinico G.B. Rossi

Verona, , Italy

Site Status

Countries

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Italy

References

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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.

Reference Type BACKGROUND
PMID: 17133404 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 10559448 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 14755429 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 17496313 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 1307234 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 17022907 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 1677062 (View on PubMed)

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.

Reference Type DERIVED
PMID: 24884885 (View on PubMed)

Related Links

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Other Identifiers

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2008-004334-25

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

FARM 6KWTCT

Identifier Type: -

Identifier Source: org_study_id

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