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 P. Benetollo, Martina C. Cornel, Hermien E K de Walle, Pierpaolo Mastroiacovo, Alessandra Compagni, Erika Rigotti, Antonella Noya di Lannoy, Marilisa Coati, Silvia Manfrè, Roberto Barbazza, Giovanni Zanconato, Maria Teresa Zenorini, Vittorio Travagliati, Elena MantovaniAnna Angeli, Elena Cavaliere, Greta Cherubini, Alice Negretto, Elena Lavarini, Milena Ozzi, Nikolaos Papadopoulos, Enrico Di Mambro, Maddalena Vessella, Giuseppe Ettore, Sebastiano Bianca, Chiara Barone, 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, Patrizia Rosi, Graziella Mortaro, Laura Valotto, Angelo Guido, Giuliano Zanni, Chiara Vernier, Anna Sandri, Nedelia Minisci

Research output: Contribution to journalArticle

22 Citations (Scopus)

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.

Original languageEnglish
Article number166
JournalBMC Pregnancy and Childbirth
Volume14
Issue number1
DOIs
Publication statusPublished - May 13 2014

Fingerprint

Pregnancy Outcome
Folic Acid
Netherlands
Italy
Randomized Controlled Trials
Pre-Eclampsia
Neural Tube Defects
Premature Birth
Spontaneous Abortion
Gestational Age
Hope
Women Physicians
Abruptio Placentae
Fetal Growth Retardation
Risk Reduction Behavior
Sample Size
Observational Studies
Meta-Analysis
Counseling
Mothers

Keywords

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

ASJC Scopus subject areas

  • Obstetrics and Gynaecology
  • Medicine(all)

Cite this

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

In: BMC Pregnancy and Childbirth, Vol. 14, No. 1, 166, 13.05.2014.

Research output: Contribution to journalArticle

Bortolus, R, Blom, F, Filippini, F, van Poppel, MNM, Leoncini, E, de Smit, DJ, Benetollo, PP, Cornel, MC, de Walle, HEK, Mastroiacovo, P, Compagni, A, Rigotti, E, di Lannoy, AN, Coati, M, Manfrè, S, Barbazza, R, Zanconato, G, Zenorini, MT, Travagliati, V, Mantovani, E, Angeli, A, Cavaliere, E, Cherubini, G, Negretto, A, Lavarini, E, Ozzi, M, Papadopoulos, N, Di Mambro, E, Vessella, M, Ettore, G, Bianca, S, Barone, C, Cosmi, E, Visentin, S, Camerin, M, Lanza, P, Marinangeli, S, Negrini, G, Ottaviani, A, Zivelonghi, L, Baffoni, A, Bertezzolo, M, Pistolato, M, Ioverno, E, Somigliana, E, Scarduelli, C, Alagna, F, Santi, G, Cesari, E, Zanini, P, Morandini, A, Cetin, I, Laoreti, A, Tresso, C, Grazia Salviato, M, Matterazzo, M, Failli, C, Marzolini, M, Casaro, A, Balestreri, D, Benassi, E, Caloi, E, Libero Giorgino, F, Schiavo, A, Pietro Piazza, G, Ruffini, R, Jorizzo, G, Cirelli, G, Arcidiacono, F, De Toni, A, Rusconi, S, Guaraldi, C, Rosi, P, Mortaro, G, Valotto, L, Guido, A, Zanni, G, Vernier, C, Sandri, A & Minisci, N 2014, '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 and Childbirth, vol. 14, no. 1, 166. https://doi.org/10.1186/1471-2393-14-166
Bortolus, Renata ; Blom, Fenneke ; Filippini, Francesca ; van Poppel, Mireille N M ; Leoncini, Emanuele ; de Smit, Denhard J. ; Benetollo, Pier P. ; Cornel, Martina C. ; de Walle, Hermien E K ; Mastroiacovo, Pierpaolo ; Compagni, Alessandra ; Rigotti, Erika ; di Lannoy, Antonella Noya ; Coati, Marilisa ; Manfrè, Silvia ; Barbazza, Roberto ; Zanconato, Giovanni ; Zenorini, Maria Teresa ; Travagliati, Vittorio ; Mantovani, Elena ; Angeli, Anna ; Cavaliere, Elena ; Cherubini, Greta ; Negretto, Alice ; Lavarini, Elena ; Ozzi, Milena ; Papadopoulos, Nikolaos ; Di Mambro, Enrico ; Vessella, Maddalena ; Ettore, Giuseppe ; Bianca, Sebastiano ; Barone, Chiara ; Cosmi, Erich ; Visentin, Silvia ; Camerin, Martina ; Lanza, Paola ; Marinangeli, Simonetta ; Negrini, Giorgia ; Ottaviani, Alberto ; Zivelonghi, Laura ; Baffoni, Andrea ; Bertezzolo, Michaela ; Pistolato, Mara ; Ioverno, Enrico ; Somigliana, Edgardo ; Scarduelli, Claudia ; Alagna, Federica ; Santi, Giulia ; Cesari, Elena ; Zanini, Paola ; Morandini, Achille ; Cetin, Irene ; Laoreti, Arianna ; Tresso, Chiara ; Grazia Salviato, Maria ; Matterazzo, Marina ; Failli, Carlo ; Marzolini, Maurizia ; Casaro, Anna ; Balestreri, Debora ; Benassi, Elena ; Caloi, Elisa ; Libero Giorgino, Francesco ; Schiavo, Alessandra ; Pietro Piazza, Gian ; Ruffini, Renato ; Jorizzo, Gianfranco ; Cirelli, Gaetana ; Arcidiacono, Francesca ; De Toni, Anna ; Rusconi, Silvia ; Guaraldi, Claudia ; Rosi, Patrizia ; Mortaro, Graziella ; Valotto, Laura ; Guido, Angelo ; Zanni, Giuliano ; Vernier, Chiara ; Sandri, Anna ; Minisci, Nedelia. / 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. In: BMC Pregnancy and Childbirth. 2014 ; Vol. 14, No. 1.
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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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month = "5",
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TY - JOUR

T1 - Prevention of congenital malformations and other adverse pregnancy outcomes with 4.0 mg of folic acid

T2 - Community-based randomized clinical trial in Italy and the Netherlands

AU - Bortolus, Renata

AU - Blom, Fenneke

AU - Filippini, Francesca

AU - van Poppel, Mireille N M

AU - Leoncini, Emanuele

AU - de Smit, Denhard J.

AU - Benetollo, Pier P.

AU - Cornel, Martina C.

AU - de Walle, Hermien E K

AU - Mastroiacovo, Pierpaolo

AU - Compagni, Alessandra

AU - Rigotti, Erika

AU - di Lannoy, Antonella Noya

AU - Coati, Marilisa

AU - Manfrè, Silvia

AU - Barbazza, Roberto

AU - Zanconato, Giovanni

AU - Zenorini, Maria Teresa

AU - Travagliati, Vittorio

AU - Mantovani, Elena

AU - Angeli, Anna

AU - Cavaliere, Elena

AU - Cherubini, Greta

AU - Negretto, Alice

AU - Lavarini, Elena

AU - Ozzi, Milena

AU - Papadopoulos, Nikolaos

AU - Di Mambro, Enrico

AU - Vessella, Maddalena

AU - Ettore, Giuseppe

AU - Bianca, Sebastiano

AU - Barone, Chiara

AU - Cosmi, Erich

AU - Visentin, Silvia

AU - Camerin, Martina

AU - Lanza, Paola

AU - Marinangeli, Simonetta

AU - Negrini, Giorgia

AU - Ottaviani, Alberto

AU - Zivelonghi, Laura

AU - Baffoni, Andrea

AU - Bertezzolo, Michaela

AU - Pistolato, Mara

AU - Ioverno, Enrico

AU - Somigliana, Edgardo

AU - Scarduelli, Claudia

AU - Alagna, Federica

AU - Santi, Giulia

AU - Cesari, Elena

AU - Zanini, Paola

AU - Morandini, Achille

AU - Cetin, Irene

AU - Laoreti, Arianna

AU - Tresso, Chiara

AU - Grazia Salviato, Maria

AU - Matterazzo, Marina

AU - Failli, Carlo

AU - Marzolini, Maurizia

AU - Casaro, Anna

AU - Balestreri, Debora

AU - Benassi, Elena

AU - Caloi, Elisa

AU - Libero Giorgino, Francesco

AU - Schiavo, Alessandra

AU - Pietro Piazza, Gian

AU - Ruffini, Renato

AU - Jorizzo, Gianfranco

AU - Cirelli, Gaetana

AU - Arcidiacono, Francesca

AU - De Toni, Anna

AU - Rusconi, Silvia

AU - Guaraldi, Claudia

AU - Rosi, Patrizia

AU - Mortaro, Graziella

AU - Valotto, Laura

AU - Guido, Angelo

AU - Zanni, Giuliano

AU - Vernier, Chiara

AU - Sandri, Anna

AU - Minisci, Nedelia

PY - 2014/5/13

Y1 - 2014/5/13

N2 - 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.

AB - 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.

KW - Birth defects

KW - Birth weight

KW - Congenital malformations

KW - Folic acid

KW - Meta-analysis

KW - Pre-eclampsia

KW - Prematurity

KW - Prevention

KW - Vitamins

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U2 - 10.1186/1471-2393-14-166

DO - 10.1186/1471-2393-14-166

M3 - Article

C2 - 24884885

AN - SCOPUS:84902075676

VL - 14

JO - BMC Pregnancy and Childbirth

JF - BMC Pregnancy and Childbirth

SN - 1471-2393

IS - 1

M1 - 166

ER -