Choline Supplementation as an Intervention for Fetal Alcohol Spectrum Disorders: A commentary

It is estimated that in the U.S. alone, somewhere between 1–5% of births are affected by prenatal alcohol exposure. Prevalence estimates are even higher in other regions of the world, including South Africa. Prenatal alcohol exposure can disrupt development, leading to a range of effects referred to as fetal alcohol spectrum disorders (FASD). Of particular concern are alterations in brain development, which lead to lifelong challenges in motor, emotional, social, and cognitive domains. There is an urgent need to identify treatments that can reduce neuropathology and consequent behavioral alterations to improve quality of life in individuals exposed to alcohol prenatally.

In this issue, Warton et al (2021) provide the first clinical evidence that prenatal supplementation with choline is associated with increased volumes of some brain structures in infants exposed to prenatal alcohol. Importantly, enhanced brain volumes were not only correlated with adherence to maternal choline intake, but were also associated with improved behavioral outcome. These important data support the ability of choline supplementation during prenatal development to reduce FASD and further illustrate that maternal nutritional status can modify the effects of prenatal alcohol exposure on brain development.

Choline is an essential nutrient, critical for healthy brain development, and animal studies have shown that perinatal choline supplementation can reduce vulnerability to a number of brain insults, including prenatal alcohol (Blusztajn et al., 2017). The present report was generated from one of only two clinical studies examining the effects of maternal choline supplementation in pregnant women who consumed alcohol. Led by Sandra and Joe Jacobson, Ernesta Meintjes, and colleagues at the University of Cape Town, data were collected from individuals who participated in a randomized, double-blind placebo-controlled study of maternal choline supplementation, with choline treatment initiated during the 2^nd trimester and continued through pregnancy. Magnetic resonance imaging was used to examine brain development in neonates born to participants. Neonates with choline supplementation exhibited significantly increased volumes of the corpus callosum and several subcortical brain regions, including the thalamus, caudate, and putamen, areas known to be affected in individuals with FASD.

Previous data from this same cohort illustrated that prenatal choline enhances postnatal body growth and improves classical delay eyeblink conditioning and recognition memory in infants exposed to prenatal alcohol (Jacobson et al., 2018). The current study demonstrates that enhanced volumes of some brain regions (corpus callosum and right putamen) were associated with performance on the Fagan Test of Infant Intelligence at 12 months, with a trend toward partial mediation of recognition memory. The finding that improved behavioral function relates to changes in brain development is not surprising, but the increases in gross regional brain volumes shown in the Warton study are striking, even with a relatively small sample size. Moreover, the significant relationship between brain volumetric changes and adherence to choline supplementation provides further confidence that choline mitigates ethanol’s adverse effects on neurodevelopment. These data are consistent with some animal studies showing that prenatal choline supplementation can attenuate prenatal alcohol-related reductions in brain weight (Thomas et al., 2009, Bottom et al., 2020) and brain size (Sawant et al., 2019).

Data from the Warton study contribute to accumulating evidence that choline supplementation may serve as an effective intervention for FASD, although clinical data have been mixed. Chambers, Coles and colleagues examined the effects of maternal micronutrient supplementation, with and without added choline (750 mg/day), on infants of women who consumed alcohol during pregnancy. Infants whose mothers received choline supplementation during pregnancy did exhibit enhanced habituation of the cardiac orienting response (Kable et al., 2015), an indication of improved attention and/or learning. However, the study did not find any benefit of choline on newborn growth or performance on the Bayley Scale of Infant Development (BSID-II) at six months (Coles et al., 2015); only maternal micronutrient supplementation improved the Mental Development Index on the BSID-II (Coles et al., 2015). That clinical study differs from Warton et al (2021), as it examined a population in Ukraine, utilized a lower maternal choline dose, only provided choline to pregnant women receiving a multivitamin/mineral supplementation, and relied on adherence through maternal report with no significant increases in measured plasma choline levels. Thus, any of these factors could impact differences in the outcome.

There are a few notable limitations of the Warton study. First, women who did not drink during pregnancy were not included. Without examining the effect of choline in a typically developing comparison group, one cannot determine whether choline-related increases in brain volumes are specific to individuals exposed to prenatal alcohol. Secondly, it is possible that the association between choline adherence and cognitive outcome could be influenced by other confounding factors, such as level of maternal functioning. Finally, this study was conducted in a high-risk socioeconomically disadvantaged population in South Africa, with insufficient intake of many nutrients (Carter et al., 2017). For example, more than 70% of women in this sample had inadequate choline intake. Importantly, dietary choline intake was similar between choline and placebo groups; however, it is not clear how the levels of choline supplementation (2 g/day) would translate to populations with more secure nutrition.

Unfortunately, inadequate choline intake is a challenge for pregnant women across the globe, including the U.S. (Wallace and Fulgoni, 2016). Interestingly, the levels of dietary choline intake in the South African population were not that different from other populations. Individuals who are consuming low levels of dietary choline may be placing their fetus at greater risk for FASD if they also drink during pregnancy. In fact, animal studies have shown that even moderate reductions in maternal dietary choline exacerbates ethanol’s effects on fetal development (Idrus et al., 2017). In addition, there are a number of genetic polymorphisms that influence dietary choline need (Ganz et al., 2017) and these variations may also contribute to risk for FASD, as well as the efficacy of choline treatment (Smith et al., 2021).

Importantly, choline may also be effective when administered postnatally, although it may be most effective when administered during early childhood. One randomized, double-blind placebo-controlled clinical study, led by Jeffrey Wozniak and colleagues at the University of Minnesota, demonstrated that 9 months of choline supplementation administered to children with FASD (aged 2–5) leads to long-lasting improvements in cognitive functioning four years later (Wozniak et al., 2020). These findings indicate that choline can effectively improve the trajectory of cognitive development when administered early in postnatal life. Specifically, they found that children with FASD who received choline had improved verbal and working memory, visual-spatial reasoning, memory for faces, and reduced symptoms of attention deficit disorder. These clinical data are consistent with findings from animal studies showing that postnatal choline administration mitigates ethanol’s adverse effects on a number of behavioral outcomes, particularly behaviors that depend on the functional integrity of the hippocampus and prefrontal cortex (Thomas and Tran, 2012, Akison et al., 2018). In contrast, choline supplementation in school-aged children with FASD (5–10) did not effectively improve cognitive functioning (Nguyen et al., 2016), differing from animal studies that find enhanced working memory when choline is administered during a period equivalent to adolescence (Schneider and Thomas, 2016). However, the duration of choline supplementation in school-aged children was notably short. Thus, it is not clear whether differences in outcome following later postnatal choline supplementation is due to the developmental timing or duration of treatment. Not surprisingly, animal studies do not find gross increases in regional brain volumes when choline is administered later in postnatal development. Thus, although evidence supports beneficial effects of postnatal choline administration on cognitive functioning, prenatal supplementation, as administered in the Warton study, likely produces the greatest impact on both physical and behavioral outcome.

Notably, choline’s beneficial effects are evident long after choline supplementation has ceased. Choline exerts many actions that can influence brain and behavioral development (Zeisel and Niculescu, 2006). Not only is choline a precursor to the neurotransmitter acetylcholine, which influences brain development and function, it is also a methyl donor, acting as an epigenetic factor and influencing gene expression. Choline also plays a role in lipid metabolism, and as a precursor to phosphatidylcholine and sphingomyelin, influences cell membranes, signaling and myelination. Choline likely acts through many of these actions to alter brain development and function in individuals exposed to prenatal alcohol. For example, recent clinical data show that choline supplementation during early childhood modifies DNA methylation and consequent overexpression of stress genes in children with FASD (Sarkar et al., 2019), consistent with choline modification of ethanol-related hypermethylation in animal studies (Otero et al., 2012, Bekdash et al., 2013). Further, preclinical data illustrate that perinatal choline can modify ethanol’s effects on microRNA expression, L1 cell adhesion molecules, neurite outgrowth, and cholinergic development. Increases in brain volumes associated with prenatal choline supplementation may be related to many of these actions. In fact, perinatal choline supplementation in otherwise typically developing animals reduces apoptosis, enhances neuronal proliferation, increases dendritic arborization, and enhances neural plasticity (Zeisel and Niculescu, 2006, Derbyshire and Obeid, 2020), all developmental processes adversely affected by prenatal alcohol exposure. Recent data also indicate that prenatal choline may increase placental efficiency (Steane et al., 2021), which could further influence fetal development.

Importantly, improving maternal nutritional status, particularly with essential nutrients such as choline, may protect against some of ethanol’s teratogenic effects. It will be critical to follow the neural and behavioral development of children from the Warton study cohort to determine how the developmental trajectory is altered. We also need to continue investigating specific changes in neural structure/function that underlie behavioral improvement associated with choline loading, the mechanisms by which choline exerts these effects, and the most effective parameters of supplementation that improve clinical outcome, particularly with individual variation in choline need. Studies such as Warton et al (2021) illustrate that nutritional interventions offer a promising and accessible approach for improving outcome in individuals with prenatal alcohol exposure.