This trial is active, not recruiting.

Condition congenital malformations
Treatments folic acid
Phase phase 3
Sponsor Azienda Ospedaliera Universitaria Integrata Verona
Collaborator International Centre of Birth Defects
Start date July 2009
End date September 2015
Trial size 5000 participants
Trial identifier NCT01244347, 2008-004334-25, FARM 6KWTCT


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.

United States No locations recruiting
Other countries No locations recruiting

Study Design

Allocation randomized
Endpoint classification efficacy study
Intervention model parallel assignment
Masking double blind (subject, caregiver, investigator, outcomes assessor)
Primary purpose prevention
folic acid
(Active Comparator)
folic acid

Primary Outcomes

number of congenital malformations
time frame: 112 weeks

Secondary Outcomes

rate of selected congenital malformations
time frame: 112 weeks
Miscarriages and recurrent abortions
time frame: 47 weeks
time frame: 60 weeks
abruptio placentae
time frame: 34 weeks
intrauterine growth restriction
time frame: 31 weeks
pre-term delivery
time frame: 30 weeks
multiple births
time frame: 24 weeks

Eligibility Criteria

Female participants from 18 years up to 44 years old.

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

Additional Information

Official title Randomized Clinical Trial to Evaluate the Efficacy of High Dose of Folic Acid to Prevent the Occurrence of Congenital Malformations
Principal investigator Renata Bortolus, MD
Trial information was received from ClinicalTrials.gov and was last updated in January 2015.
Information provided to ClinicalTrials.gov by Azienda Ospedaliera Universitaria Integrata Verona.