Abstract
Research questionDoes periconceptional maternal folate status influence the size of human embryonic head and brain structures? DesignThe study population was selected from the Rotterdam Periconceptional Cohort conducted at the Erasmus MC. Three-dimensional (3D) ultrasound scans were performed at 9 and 11 weeks of gestational age. Using 3D ultrasound datasets, head volume, head circumference, diencephalon (DTD), mesencephalon (MTD) and left/right telencephalon (TTL/TTR) measurements were performed offline using a virtual reality technique and specialized 3D software. Maternal venous blood samples were taken at study entry to determine red blood cell (RBC) folate. Linear regression models were applied to investigate associations between RBC folate status and embryonic head and brain structures adjusted for gestational age, alcohol use, smoking, maternal age and mode of conception. ResultsRBC folate measurements were available for 144 of the 166 singleton pregnancies eligible for analysis. RBC folate quartiles were defined: 466–1078 nmol/l (Q1), 1079–1342 nmol/l (Q2), 1343–1594 nmol/l (Q3), 1595–2919 nmol/l (Q4), with Q3 being used as reference. At 11 weeks of gestational age, head volume was largest in Q1 (β = 0.866; P = 0.004) and Q4 (β = 0.764; P = 0.007). In addition, head circumference at 11 weeks of gestational age was significantly larger in Q4 (β = 2.745; P = 0.03). There were no statistical significantly associations between the RBC folate quartiles and the sizes of the DTD, MTD, TTL and TTR. ConclusionsU-shaped associations were shown between the periconceptional maternal RBC folate status and embryonic head volume and head circumference. The clinical implication of these findings needs further investigation.
Highlights
P regnancy is defined as a period of rapid growth and cell development, during which major changes take place to create a safe environment for the unborn child
red blood cell (RBC) folate quartiles were defined: 466–1078 nmol/l (Q1), 1079–1342 nmol/l (Q2), 1343–1594 nmol/l (Q3), 1595–2919 nmol/l (Q4), with quartile 3 (Q3) being used as reference
At 11 weeks of gestational age, head volume was largest in quartile 1 (Q1) (β = 0.866; P = 0.004) and quartile 4 (Q4) (β = 0.764; P = 0.007)
Summary
P regnancy is defined as a period of rapid growth and cell development, during which major changes take place to create a safe environment for the unborn child. Fetal growth and development are susceptible to multiple environmental factors, for example maternal factors such as smoking, alcohol use, mode of conception and natural food folate and synthetic folic acid intake (Koning et al, 2016; Mook-Kanamori et al, 2010; Van Dijk et al, 2018; van Uitert et al, 2013). From that moment on the brain undergoes major structural changes This complex process is highly dependent on the expression of specific combinations of Hox genes and other transcription factors, and very susceptible to changes in DNA methylation patterns (epigenetics), possibly leading to permanent modifications in gene expression and postnatal phenotypes (Carlson, 2004). DNA methylation and synthesis of RNA, lipids and proteins is highly dependent on one-carbon metabolism, an essential metabolism throughout human life for cellular growth and differentiation in general, and in particular highly important for the development of the growing fetus (Steegers-Theunissen et al, 2013). Studies have shown that adequate maternal folate status is associated with multiple beneficial pregnancy outcomes; it is associated with a reduction of neural tube defects and fetal growth restriction (van Uitert and Steegers-Theunissen, 2013; van Uitert et al, 2014), and neurodevelopmental outcome in later life (Julvez et al, 2009; Roza et al, 2010; Veena et al, 2010)
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