title: The effect of high doses of folic acid and iron supplementation in early-to-mid pregnancy on prematurity and fetal growth retardation: the mother-child cohort study in Crete, Greece (Rhea study).
abstract: OBJECTIVE
  We examined whether high doses of folic acid and iron supplementation in early-to-mid pregnancy affect the risk of preterm birth, low birth weight, and small for gestational age neonates, in the mother-child cohort in Crete, Greece (Rhea study).
  
  
  METHODS
  We included 1,279 women with singleton pregnancies with complete data on supplements use in early-to-mid pregnancy and birth outcomes. Anthropometric measurements at birth were obtained from medical records. Red blood cell folate concentrations in cord blood were measured in a subsample of the study population (n = 58).
  
  
  RESULTS
  Sixty-six percent of the study participants reported high doses of supplemental folic acid use (5 mg/day), while 21 % reported excessive doses of folic acid use (>5 mg/day) in early-to-mid pregnancy. Daily intake of 5-mg supplemental folic acid was associated with a 31 % decrease in the risk of preterm birth (RR, 0.69; 95 % CI, 0.44, 0.99), 60 % decrease in the risk of delivering a low birth weight neonate (RR, 0.40; 95 % CI, 0.21, 0.76), and 66 % decrease in the risk of delivering a small for gestational age (SGA) neonate (RR, 0.34; 95 % CI, 0.16, 0.73). Daily doses of iron supplementation more than 100 mg were associated with a twofold increased risk for SGA neonates (RR, 2.14; 95 % CI, 0.99, 5.97).
  
  
  CONCLUSIONS
  These findings suggest that high daily doses of supplementary folic acid in early-to-mid pregnancy may be protective for preterm birth, low birth weight, and small for gestational age neonates, while high daily doses of supplementary iron may be harmful for fetal growth.
authors.affiliation: Centre for Research in Environmental Epidemiology, Barcelona, Spain.
authors.forename: Eleni
authors.initials: E
authors.lastname: Papadopoulou
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Stratakis
authors.forename: Theano
authors.initials: T
authors.lastname: Roumeliotaki
authors.forename: Katerina
authors.initials: K
authors.lastname: Sarri
authors.forename: Domenic F
authors.initials: DF
authors.lastname: Merlo
authors.forename: Manolis
authors.initials: M
authors.lastname: Kogevinas
authors.forename: Leda
authors.initials: L
authors.lastname: Chatzi
mesh_terms: D000328:Adult; D015331:Cohort Studies; D019587:Dietary Supplements; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000737:chemistry / Q000166:cytology; D005260:Female; D047109:Fetal Development; D005317:Fetal Growth Retardation / Q000453:epidemiology*; D005492:Folic Acid / Q000008:administration & dosage*; D006115:Greece / Q000453:epidemiology; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature / Q000254:growth & development; D007235:Infant, Premature, Diseases; D007236:Infant, Small for Gestational Age / Q000254:growth & development; D019266:Iron, Dietary / Q000008:administration & dosage*; D016014:Linear Models; D015999:Multivariate Analysis; D011247:Pregnancy; D047928:Premature Birth / Q000453:epidemiology*; D011446:Prospective Studies; D015203:Reproducibility of Results; D055815:Young Adult
chemical_list: D019266:Iron, Dietary; D005492:Folic Acid