Folic Acid Dosage and Malformations Reduction

Congenital Malformations Clinical Trial

Official title:

Randomized Clinical Trial to Evaluate the Efficacy of High Dose of Folic Acid to Prevent the Occurrence of Congenital Malformations

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01244347
• Other study ID #: FARM 6KWTCT
• Secondary ID: 2008-004334-25
• Status: Active, not recruiting
• Phase: Phase 3
• First received: October 11, 2010
• Last updated: January 13, 2015
• Start date: July 2009
• Est. completion date: September 2016

Study information

• Verified date: January 2015
• Source: Azienda Ospedaliera Universitaria Integrata Verona
• Contact: n/a
• Is FDA regulated: No
• Health authority: Italy: The Italian Medicines Agency
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 5000
• Est. completion date: September 2016
• Est. primary completion date: September 2015
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 44 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention

Related Conditions & MeSH terms

• Congenital Abnormalities
• Congenital Malformations

Intervention

Drug:
• folic acid

• folic acid

Locations

Country	Name	City	State
Italy	Ospedale di Adria	Adria	Rovigo
Italy	Family Health Centre	Bassano	Vicenza
Italy	Ospedale San Bassiano	Bassano	Vicenza
Italy	Ospedale di Bussolengo	Bussolengo	Verona
Italy	Family Health Practice	Camponogara	Venezia
Italy	Ospedale di Conegliano	Conegliano	Treviso
Italy	General Practice	Dueville	Vicenza
Italy	Ospedale Sant'Antonio Abate	Gallarate	Varese
Italy	Ospedale di Legnago	Legnago	Verona
Italy	General Practice	Malo	Vicenza
Italy	Family Health Centre	Martellago	Venezia
Italy	Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico	Milan
Italy	Family Health Practice	Mira	Venezia
Italy	Family Health Centre	Montebelluna	Treviso
Italy	Family Health Centre	Noale	Venezia
Italy	Family Health Practice	Oderzo	Treviso
Italy	Azienda Ospedaliera di Padova	Padova
Italy	Family Health Centre	Padova
Italy	Ospedale di San Bonifacio	San Bonifacio	Verona
Italy	Family Health Centre	San Pietro di Stra	Venezia
Italy	General Practice	Schio	Vicenza
Italy	General Practice	Sovizzo	Vicenza
Italy	Ospedale Boldrini	Thiene	Vicenza
Italy	Ospedale San Luca	Trecenta	Rovigo
Italy	Ospedale di Valdagno	Valdagno	Vicenza
Italy	Family Health Centre	Verona
Italy	Family Health Centre	Verona
Italy	General Practice	Verona
Italy	General Practice	Verona
Italy	Ospedale Civile Maggiore	Verona
Italy	Policlinico G.B. Rossi	Verona
Italy	Ospedale di Vicenza	Vicenza	VI
Italy	Family Health Practice	Villorba	Treviso
Italy	Family Health Centre	Vogonovo	Venezia

Sponsors (2)

Lead Sponsor	Collaborator
Azienda Ospedaliera Universitaria Integrata Verona	International Centre of Birth Defects

Country where clinical trial is conducted

Italy, 

References & Publications (7)

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. — View 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. Erratum in: N Engl J Med. 1999 Dec 9;341(24):1864. — View 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. Review. — View 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. Epub 2007 May 11. — View Citation

Czeizel AE, Dudás 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. — View Citation

Goh YI, 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):680-9. Review. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	rate of selected 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	No
Secondary	Miscarriages and recurrent abortions	The time frame was computed as an average of 32 weeks before conception, plus an average of 15 weeks as a mean of time from conception to different clinical conditions related to miscarriage.	47 weeks	No
Secondary	pre-eclampsia	The time frame was computed as an average of 32 weeks before conception, plus an average of 28 weeks to the occurrence of pre-eclampsia.	60 weeks	No
Secondary	abruptio placentae	The time frame was computed as an average of 32 weeks before conception, plus an average of 34 weeks to the occurrence of abruptio placentae.	34 weeks	No
Secondary	intrauterine growth restriction	The time frame was computed as an average of 32 weeks before conception, plus an average of 31 weeks to the occurrence of intrauterine growth restriction.	31 weeks	No
Secondary	pre-term delivery	The time frame was computed as an average of 32 weeks before conception, plus an average of 30 weeks to the occurrence of pre-term delivery.	30 weeks	No
Secondary	multiple births	The time frame was computed as an average of 32 weeks before conception, plus an average of 24 weeks to the possible diagnosis of twinnings or delivery.	24 weeks	Yes

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