Associations of maternal folic acid supplementation and folate concentrations during pregnancy with foetal and child head growth: the Generation R Study.
OBJECTIVE
Folic acid supplementation during pregnancy has been associated with a reduced risk of common neurodevelopmental delays in the offspring. However, it is unclear whether low folate status has effects on the developing brain. We evaluated the associations of maternal folic acid supplementation and folate concentrations during pregnancy with repeatedly measured prenatal and postnatal head circumference in the offspring.


METHODS
Within a population-based prospective cohort, we measured maternal plasma folate concentrations at approximately 13 weeks of gestation (90 % range 10.5-17.2) and assessed folic acid supplementation by questionnaire (2001-2005). Up to 11 repeated measures of head circumference were obtained during foetal life (20 and 30 weeks of gestation) and childhood (between birth and age 6 years) in 5866 children (2002-2012).


RESULTS
In unadjusted models, foetal head growth was 0.006 SD (95 % CI 0.003; 0.009, P < 0.001) faster per week per 1-SD higher maternal folate concentration. After adjustment for confounders, this association was attenuated to 0.004 SD per week (95 % CI 0.000; 0.007, P = 0.02; estimated absolute difference at birth of 2.7 mm). The association was independent of overall foetal growth. No associations were found between maternal folate concentrations and child postnatal head growth. Preconceptional start of folic acid supplementation was associated with larger prenatal head size, but not with prenatal or postnatal head growth.


CONCLUSIONS
Our results suggest an independent, modest association between maternal folate concentrations in early pregnancy and foetal head growth. More research is needed to identify whether specific brain regions are affected and whether effects of folate on foetal head growth influence children's long-term functioning.
The Generation R Study Group, Erasmus Medical Centre, Rotterdam, The Netherlands.|Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC-Sophia, P.O. Box 2060, 3000 CB, Rotterdam, The Netherlands.
Jolien
J
Steenweg-de Graaff
Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC-Sophia, P.O. Box 2060, 3000 CB, Rotterdam, The Netherlands.|Department of Psychiatry, Erasmus Medical Centre, Rotterdam, The Netherlands.
Sabine J
SJ
Roza
The Generation R Study Group, Erasmus Medical Centre, Rotterdam, The Netherlands.|Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC-Sophia, P.O. Box 2060, 3000 CB, Rotterdam, The Netherlands.|Department of Psychiatry, Leiden University Medical Centre, Leiden, The Netherlands.
Alette N
AN
Walstra
The Generation R Study Group, Erasmus Medical Centre, Rotterdam, The Netherlands.|Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC-Sophia, P.O. Box 2060, 3000 CB, Rotterdam, The Netherlands.
Hanan
H
El Marroun
Department of Obstetrics and Gynaecology, Erasmus Medical Centre, Rotterdam, The Netherlands.
Eric A P
EAP
Steegers
The Generation R Study Group, Erasmus Medical Centre, Rotterdam, The Netherlands.|Department of Paediatrics, Erasmus Medical Centre, Rotterdam, The Netherlands.|Department of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands.
Vincent W V
VWV
Jaddoe
Department of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands.
Albert
A
Hofman
Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC-Sophia, P.O. Box 2060, 3000 CB, Rotterdam, The Netherlands.
Frank C
FC
Verhulst
Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC-Sophia, P.O. Box 2060, 3000 CB, Rotterdam, The Netherlands.|Department of Psychiatry, Erasmus Medical Centre, Rotterdam, The Netherlands.|Department of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands.
Henning
H
Tiemeier
Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC-Sophia, P.O. Box 2060, 3000 CB, Rotterdam, The Netherlands. t.white@erasmusmc.nl.|Department of Radiology, Erasmus Medical Centre, Rotterdam, The Netherlands. t.white@erasmusmc.nl.
Tonya
T
White
D000328:Adult; D002657:Child Development / Q000187:drug effects; D019587:Dietary Supplements; D005260:Female; D047109:Fetal Development / Q000187:drug effects*; D005333:Fetus / Q000187:drug effects / Q000378:metabolism; D005492:Folic Acid / Q000008:administration & dosage / Q000097:blood*; D005865:Gestational Age; D006257:Head / Q000254:growth & development*; D006801:Humans; D007223:Infant; D008137:Longitudinal Studies; D008297:Male; D039382:Maternal Nutritional Physiological Phenomena; D011247:Pregnancy; D011446:Prospective Studies; D012959:Socioeconomic Factors; D055815:Young Adult
D005492:Folic Acid
Foetal neurodevelopment; Folate; Folic acid supplementation; Head growth; Head size; Pregnancy