A Randomized, Double-Blind, Placebo-controlled Clinical Trial of Choline Supplementation during Pregnancy to Mitigate Adverse Effects of Prenatal Alcohol Exposure on Growth and Cognitive Development

摘要

Abstract Although the adverse effects associated with prenatal alcohol exposure (PAE) are well known, many women continue to drink heavily during pregnancy, putting their infants at risk for fetal alcohol spectrum disorders. Given the limited effectiveness of psychosocial and informational interventions, there is a growing interest in new approaches, such as nutritional interventions, that may be more effective. Animal studies have shown that choline supplementation during the equivalent of the 3rd trimester in humans can mitigate effects of PAE on growth and development. However, findings from studies in humans to date have been inconsistent and difficult to interpret. Choline, an essential nutrient, serves as a methyl-group donor for DNA methylation and is a constituent of the neurotransmitter acetylcholine and a precursor to major components of cell membranes. In an R21 feasibility trial, 70 heavy drinkers were randomly assigned to receive a daily dose of 2g of choline or a placebo from time of enrollment in antenatal care until delivery. Participants were recruited from the Cape Coloured (mixed ancestry) community in Cape Town, South Africa, where the incidence of heavy drinking during pregnancy and fetal alcohol syndrome are among the highest in the world. Infants in the choline-treated arm were more likely to meet criterion for eyeblink conditioning than those in the placebo arm. Infants born to both the choline- and placebo-treated mothers were small at birth, but those in the choline arm showed considerable catch-up growth in weight and head circumference by 6.5 mo, which persisted through 12 mo. At 12 mo, infants in the choline arm showed markedly better recognition memory compared to placebo-treated on the Fagan Test of Infant Intelligence, which is known to have predictive validity for school-age IQ. Key features of this study included the higher choline dose (4.4 times adequate intake (AI), compared to 1.7-2.5 in previous human studies) and initiation of treatment early in pregnancy. We propose to recruit heavy drinking pregnant women from a rural Cape Coloured community to participate in a fully-powered, double-blind, randomized, placebo-controlled choline supplementation trial (1) to assess the effectiveness of maternal choline supplementation during pregnancy to mitigate effects of PAE on three primary outcomes: infant recognition memory and postnatal growth restriction (weight and head circumference); (2) to assess the efficacy of this supplementation for mitigating alcohol effects on the following secondary outcomes: infant eyeblink conditioning, postnatal length, and information processing speed; (3) to use innovative methods from causal inference analysis to examine protocol adherence as an important source of variation in treatment efficacy and to identify socio-demographic factors associated with non-compliance in order to facilitate implementation of the intervention protocol in clinical settings; and (4) in exploratory analyses, to examine whether maternal choline supplementation is particularly effective in women with lower dietary choline intake or poor nutritional status. !