title: 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.
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
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Italian trial: ClinicalTrials.gov Identifier: NCT01244347.Dutch trial: Dutch Trial Register ID: NTR3161.
authors.affiliation: Office for Research Promotion, Department of the Hospital Management and Pharmacy, Verona University Hospital, P,le A, Stefani, 1-37126 Verona, Italy. renata.bortolus@ospedaleuniverona.it.
authors.forename: Renata
authors.initials: R
authors.lastname: Bortolus
authors.forename: Fenneke
authors.initials: F
authors.lastname: Blom
authors.forename: Francesca
authors.initials: F
authors.lastname: Filippini
authors.forename: Mireille N M
authors.initials: MN
authors.lastname: van Poppel
authors.forename: Emanuele
authors.initials: E
authors.lastname: Leoncini
authors.forename: Denhard J
authors.initials: DJ
authors.lastname: de Smit
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Benetollo
authors.forename: Martina C
authors.initials: MC
authors.lastname: Cornel
authors.forename: Hermien E K
authors.initials: HE
authors.lastname: de Walle
authors.forename: Pierpaolo
authors.initials: P
authors.lastname: Mastroiacovo
mesh_terms: D000293:Adolescent; D000328:Adult; D003153:Community Health Services; D000013:Congenital Abnormalities / Q000517:prevention & control*; D003376:Counseling; D019587:Dietary Supplements; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D007558:Italy; D008875:Middle Aged; D009426:Netherlands; D016742:Preconception Care; D011247:Pregnancy; D011248:Pregnancy Complications / Q000517:prevention & control*; D011256:Pregnancy Outcome; D011295:Prenatal Care; D012107:Research Design; D012720:Severity of Illness Index; D014803:Vitamin B Complex / Q000008:administration & dosage* / Q000009:adverse effects; D055815:Young Adult
chemical_list: D014803:Vitamin B Complex; D005492:Folic Acid