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 Bortolus, Fenneke Blom, Francesca Filippini, Mireille N M van Poppel, Emanuele Leoncini, Denhard J de Smit, Pier Paolo Benetollo, Martina C Cornel, Hermien E K de Walle, Pierpaolo Mastroiacovo, Italian and Dutch folic acid trial study groups, Renata Bortolus, Francesca Filippini, Alessandra Compagni, Erika Rigotti, Antonella Noya di Lannoy, Pierpaolo Mastroiacovo, Emanuele Leoncini, Marilisa Coati, Silvia Manfrè, Roberto Barbazza, Giovanni Zanconato, Maria Teresa Zenorini, Vittorio Travagliati, Elena Mantovani, Anna Angeli, Elena Cavaliere, Greta Cherubini, Alice Negretto, Elena Lavarini, Milena Ozzi, Nikolaos Papadopoulos, Enrico Di Mambro, Maddalena Vessella, Giuseppe Ettore, Sebastiano Bianca, Chiara Barone, Garibaldi Nesima, Erich Cosmi, Silvia Visentin, Martina Camerin, Paola Lanza, Simonetta Marinangeli, Giorgia Negrini, Alberto Ottaviani, Laura Zivelonghi, Andrea Baffoni, Michaela Bertezzolo, Mara Pistolato, Enrico Ioverno, Edgardo Somigliana, Claudia Scarduelli, Federica Alagna, Giulia Santi, Elena Cesari, Paola Zanini, Achille Morandini, Irene Cetin, Arianna Laoreti, Chiara Tresso, Maria Grazia Salviato, Marina Matterazzo, Carlo Failli, Maurizia Marzolini, Anna Casaro, Debora Balestreri, Elena Benassi, Elisa Caloi, Francesco Libero Giorgino, Alessandra Schiavo, Gian Pietro Piazza, Renato Ruffini, Gianfranco Jorizzo, Gaetana Cirelli, Francesca Arcidiacono, Anna De Toni, Silvia Rusconi, Claudia Guaraldi, Laura Valotto, Angelo Guido, Giuliano Zanni, Chiara Vernier, Anna Sandri, Nedelia Minisci, Martina Cornel, Mireille van Poppel, Fenneke Blom, Tamar Kruit, Denhard de Smit, Hermien de Walle, Renata Bortolus, Fenneke Blom, Francesca Filippini, Mireille N M van Poppel, Emanuele Leoncini, Denhard J de Smit, Pier Paolo Benetollo, Martina C Cornel, Hermien E K de Walle, Pierpaolo Mastroiacovo, Italian and Dutch folic acid trial study groups, Renata Bortolus, Francesca Filippini, Alessandra Compagni, Erika Rigotti, Antonella Noya di Lannoy, Pierpaolo Mastroiacovo, Emanuele Leoncini, Marilisa Coati, Silvia Manfrè, Roberto Barbazza, Giovanni Zanconato, Maria Teresa Zenorini, Vittorio Travagliati, Elena Mantovani, Anna Angeli, Elena Cavaliere, Greta Cherubini, Alice Negretto, Elena Lavarini, Milena Ozzi, Nikolaos Papadopoulos, Enrico Di Mambro, Maddalena Vessella, Giuseppe Ettore, Sebastiano Bianca, Chiara Barone, Garibaldi Nesima, Erich Cosmi, Silvia Visentin, Martina Camerin, Paola Lanza, Simonetta Marinangeli, Giorgia Negrini, Alberto Ottaviani, Laura Zivelonghi, Andrea Baffoni, Michaela Bertezzolo, Mara Pistolato, Enrico Ioverno, Edgardo Somigliana, Claudia Scarduelli, Federica Alagna, Giulia Santi, Elena Cesari, Paola Zanini, Achille Morandini, Irene Cetin, Arianna Laoreti, Chiara Tresso, Maria Grazia Salviato, Marina Matterazzo, Carlo Failli, Maurizia Marzolini, Anna Casaro, Debora Balestreri, Elena Benassi, Elisa Caloi, Francesco Libero Giorgino, Alessandra Schiavo, Gian Pietro Piazza, Renato Ruffini, Gianfranco Jorizzo, Gaetana Cirelli, Francesca Arcidiacono, Anna De Toni, Silvia Rusconi, Claudia Guaraldi, Laura Valotto, Angelo Guido, Giuliano Zanni, Chiara Vernier, Anna Sandri, Nedelia Minisci, Martina Cornel, Mireille van Poppel, Fenneke Blom, Tamar Kruit, Denhard de Smit, Hermien de Walle

Abstract

Background: 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.

Methods/design: 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.

Discussion: 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: ClinicalTrials.gov Identifier: NCT01244347.Dutch trial: Dutch Trial Register ID: NTR3161.

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