Early second trimester maternal plasma choline and betaine are related to measures of early cognitive development in term infants

Abstract

Background: The importance of maternal dietary choline for fetal neural development and later cognitive function has been well-documented in experimental studies. Although choline is an essential dietary nutrient for humans, evidence that low maternal choline in pregnancy impacts neurodevelopment in human infants is lacking. We determined potential associations between maternal plasma free choline and its metabolites betaine and dimethylglycine in pregnancy and infant neurodevelopment at 18 months of age.

Methodology: This was a prospective study of healthy pregnant women and their full-term, single birth infants. Maternal blood was collected at 16 and 36 weeks of gestation and infant neurodevelopment was assessed at 18 months of age for 154 mother-infant pairs. Maternal plasma choline, betaine, dimethylglycine, methionine, homocysteine, cysteine, total B12, holotranscobalamin and folate were quantified. Infant neurodevelopment was evaluated using the Bayley Scales of Infant Development-III. Multivariate regression, adjusting for covariates that impact development, was used to determine the associations between maternal plasma choline, betaine and dimethylglycine and infant neurodevelopment.

Results: The maternal plasma free choline at 16 and 36 weeks gestation was median (interquartile range) 6.70 (5.78-8.03) and 9.40 (8.10-11.3) µmol/L, respectively. Estimated choline intakes were (mean ± SD) 383 ± 98.6 mg/day, and lower than the recommended 450 mg/day. Betaine intakes were 142 ± 70.2 mg/day. Significant positive associations were found between infant cognitive test scores and maternal plasma free choline (B=6.054, SE=2.283, p=0.009) and betaine (B=7.350, SE=1.933, p=0.0002) at 16 weeks of gestation. Maternal folate, total B12, or holotranscobalamin were not related to infant development.

Conclusion: We show that choline status in the first half of pregnancy is associated with cognitive development among healthy term gestation infants. More work is needed on the potential limitation of choline or betaine in the diets of pregnant women.

Figure 1. Simplified scheme to show the roles of choline and its metabolites.

BHMT: betaine-homocysteine S-methyltransferase.

Figure 2. Schematic to show the role of choline in one-carbon metabolism intersecting with the methionine-homocysteine cycle.

Measured metabolites are shown in orange boxes; enzymes are shown in bolded alphabets. 10-Formyl-THF: 10-formyl-tetrahydrofolate; 5,10-CH = THF: 5,10-methenyltetrahydrofolate; 5,10-CH2-THF: 5,10-methylenetetrahydrofolate; 5-CH3-THF: 5-methyltetrahydrofolate; BADH: betaine aldehyde dehydrogenase; BHMT: betaine-homocysteine S-methyltransferase; CBS: cystathionine beta synthase; CHDH: choline dehydrogenase; Cys: cysteine; cSHMT: cytoplasmic serine hydroxymethyltransferase; DD: dimethylglycine dehydrogenase; DHF: dihydrofolate; DHFR: dihydrofolatereductase; DMG: dimethylglycine; dUMP: 2′-deoxyuridine 5′-monophosphate; FTD: 10-formyl-tetrahydrofolate dehydrogenase; FTS: 10-formyl-tetrahydrofolate synthase; GDC: glycine decarboxylase; Gly: glycine; GNMT: glycine N-methyltransferase; Hcy: homocysteine; MAT, methionine adenosyltransferase; Met: methionine; MS: methionine synthase; mSHMT: mitochondrial serine hydroxymethyltransferase; MTCH: 5,10-methylenetetrahydrofolate cyclohydrolase; MTHFD: 5,10-methylenetetrahydrofolate dehydrogenase; MTHFR: 5,10-methylenetetrahydrofolate reductase; MTs, S-adenosyl methionine-dependent methyltransferases; SAH, S-adenosyl homocysteine; SAHH: S-adenosyl homocysteine hydrolase; SAM: S-adenosyl methionine; Sarc: sarcosine; SDH: sarcosine dehydrogenase; Ser: serine; THF: tetrahydrofolate; TS: thymidylate synthase. Not all enzymes and intermediates are shown in this pathway.

Figure 3. Scatter plot to show the correlation between estimated maternal choline intake and plasma free choline.

The results for plasma free choline were skewed and transformed to natural log values for analysis, r = 0.200, p = 0.013.

Figure 4. Scatter plots to show the relationship between infant cognitive scores and maternal plasma choline metabolites.

Plasma metabolite concentrations were normalized by a single natural log transformation (A, B and C). Infant cognitive development was assessed using the Bayley Scales of Infant Development III. The antilog of the natural log is equivalent to the exponential of the natural log value, that is 2.718 to the exponential of the value plotted on the x axis or e^x. The results were analysed for 154 mother-infant pairs using Pearson correlation analysis, A. choline r = 0.190, p = 0.019, B. betaine r = 0.288, p = 0.0003, C. dimethylglycine, r = 0.157, p = 0.053.