Open Access Study protocol

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

Renata Bortolus1*, Fenneke Blom2, Francesca Filippini1, Mireille NM van Poppel3, Emanuele Leoncini4, Denhard J de Smit5, Pier Paolo Benetollo6, Martina C Cornel2, Hermien EK de Walle7, Pierpaolo Mastroiacovo4 and on behalf of the Italian and Dutch folic acid trial study groups

Author Affiliations

1 Office for Research Promotion, Department of the Hospital Management and Pharmacy, Verona University Hospital, P.le A. Stefani, 1-37126 Verona, Italy

2 Community Genetics, Department of Clinical Genetics, EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, the Netherlands

3 Department of Public and Occupational Health, EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, the Netherlands

4 Alessandra Lisi International Centre on Birth Defects and Prematurity-ICBD, WHO Collaborating Centre, Rome, Italy

5 MediClara Projects BV, Abcoude, the Netherlands

6 Healthcare Directorate, Verona University Hospital, Verona, Italy

7 Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands

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BMC Pregnancy and Childbirth 2014, 14:166  doi:10.1186/1471-2393-14-166

Published: 13 May 2014



In 2010 a Cochrane review confirmed that folic acid (FA) supplementation prevents the first- and second-time occurrence of neural tube defects (NTDs). At present some evidence from observational studies supports the hypothesis that FA supplementation can reduce the risk of all congenital malformations (CMs) or the risk of a specific and selected group of them, namely cardiac defects and oral clefts. Furthermore, the effects on the prevention of prematurity, foetal growth retardation and pre-eclampsia are unclear.

Although the most common recommendation is to take 0.4 mg/day, the problem of the most appropriate dose of FA is still open.

The aim of this project is to assess the effect a higher dose of peri-conceptional FA supplementation on reducing the occurrence of all CMs. Other aims include the promotion of pre-conceptional counselling, comparing rates of selected CMs, miscarriage, pre-eclampsia, preterm birth, small for gestational age, abruptio placentae.


This project is a joint effort by research groups in Italy and the Netherlands. Women of childbearing age, who intend to become pregnant within 12 months are eligible for the studies. Women are randomly assigned to receive 4 mg of FA (treatment in study) or 0.4 mg of FA (referent treatment) daily. Information on pregnancy outcomes are derived from women-and-physician information.

We foresee to analyze the data considering all the adverse outcomes of pregnancy taken together in a global end point (e.g.: CMs, miscarriage, pre-eclampsia, preterm birth, small for gestational age). A total of about 1,000 pregnancies need to be evaluated to detect an absolute reduction of the frequency of 8%. Since the sample size needed for studying outcomes separately is large, this project also promotes an international prospective meta-analysis.


The rationale of these randomized clinical trials (RCTs) is the hypothesis that a higher intake of FA is related to a higher risk reduction of NTDs, other CMs and other adverse pregnancy outcomes. Our hope is that these trials will act as catalysers, and lead to other large RCTs studying the effects of this supplementation on CMs and other infant and maternal outcomes.

Trial registration

Italian trial: Identifier: NCT01244347.

Dutch trial: Dutch Trial Register ID: NTR3161.

Congenital malformations; Birth defects; Folic acid; Vitamins; Prevention; Prematurity; Birth weight; Pre-eclampsia; Meta-analysis