Descriptive studies have documented poor fetal growth, dysmorphology, and a range of neurobehavioral deficits in infants and children with fetal alcohol spectrum disorder (FASD). Although the adverse effects associated with fetal alcohol exposure are well-known and numerous psychosocial interventions have been attempted, many women continue to drink heavily during pregnancy. Because psychosocial interventions are frequently ineffective, NIAAA has highlighted "the potential of maternal dietary supplementation with choline, folate, and other nutrients to interact with alcohol to reduce the risk of FASD" as a priority research area. This proposal is designed to gather feasibility, adherence, and preliminary data on a promising pharmacological intervention that could prevent or mitigate the severity of fetal alcohol-related impairment. Since 1998, we have conducted research on children born to mothers recruited during pregnancy in the Cape Coloured (mixed ancestry) community in Cape Town, South Africa, where there is an unusually high incidence of alcohol abuse and dependence in women of child-bearing age, very heavy alcohol consumption during pregnancy, and one of the highest rates of fetal alcohol syndrome (FAS) in the world. We have identified a strikingly consistent effect of prenatal alcohol exposure on eyeblink conditioning (EBC), a Pavlovian paradigm that involves contingent temporal pairing of a conditioned stimulus (a tone) with an unconditioned stimulus (an air puff). Not a single child with full FAS met criterin for conditioning, compared with 75% of non-exposed controls. Two-thirds of the other heavily exposed children also failed to meet criterion for conditioning. Because infants reach the same terminal levels of conditioning as adults, EBC can provide an early indicator of alcohol-related impairment and an important tool for evaluating the efficacy of a prenatal intervention. Animal studies have shown that choline supplementation during the equivalent of the 3rd trimester of pregnancy can protect against or mitigate some of the damage incurred by fetal alcohol exposure on EBC and cognitive function. We propose to conduct a randomized, double-blind exploratory trial to examine the feasibility of implementing a choline supplementation intervention in pregnancy, assess acceptability and adherence to the intervention protocol by heavy drinkers, obtain data on plasma choline levels in supplemented mothers and placebo controls and on the prevalence of polymorphisms that substantially alter endogenous choline synthesis in this population, and collect preliminary data regarding the efficacy of the intervention in mitigating fetal alcohol effects on infant EBC and other alcohol- related cognitive deficits. Sixty heavy drinking pregnant women from the Cape Coloured community who initiate prenatal care at or before 20 weeks gestation will receive either choline supplementation (n = 30) or placebo (n = 30) twice daily until delivery. Maternal and infant nutritional intake will be evaluated by dietary history and biological assay. Infants will be assessed for birth size, growth, and EBC and neurocognitive function at 6.5 months postpartum.
Fetal alcohol syndrome (FAS) and other alcohol-related disorders are an important public health problem worldwide. Informational and psychosocial interventions are often ineffective with women who drink heavily during pregnancy. If this exploratory pharmacological trial demonstrates that the proposed intervention is feasible and provides preliminary evidence that choline supplementation during pregnancy can protect against or mitigate adverse effects of fetal alcohol exposure on eyeblink conditioning and other neurobehavioral outcomes, this study will provide the basis for conducting a large, fully powered randomized clinical trial. Development of an effective pharmacological intervention for pregnant women at risk for delivering an infant with fetal alcohol disorder would represent a major breakthrough in prevention of developmental deficits associated with this disorder.
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