Animal data showing a strong relation between choline status and cognition raised the important questions: is choline related to intelligence in humans, and, if so, could choline supplementation increase intelligence? The relation between gestational choline status and child IQ score has not been addressed previously, possibly because of, in part, the difficulty of collecting samples to measure choline exposure during pregnancy and then following the offspring long enough to get a valid and reliable measure of intelligence.
Our results show no relation between physiologic free and total choline concentrations during pregnancy and children's Full Scale IQ, Verbal and Performance scales, and 2 subscales more specifically related to visuospatial cognition and memory, areas specifically affected by choline in rodents. We were able to analyze multiple samples over the course of pregnancy as well as cord blood. Moreover, data on other influences on child IQ such as maternal scores on the PPVT-R and developmental quality of the home environment were collected to address potential confounding. By measuring maternal choline concentrations at multiple points during pregnancy, we were able to assess choline nutriture at points in human gestation that correspond to times in animal development when choline was shown to affect cognition (13
). We found no correlation between choline concentrations and WPPSI-R IQ scores at any points. Thus, circulating choline over a range of physiologic concentrations in human pregnancy is not an important determinant of child IQ score in this population and does not appear to influence scores on IQ subscales related to visuospatial ability and memory.
Choline plays an important role in brain development (4
). Offspring of rat dams whose diet was supplemented with choline at embryonic days 12–17 (of a 22-d gestation period) show abilities in spatial memory and learning 3 d sooner than offspring of dams fed a control diet (14
). Prenatal choline supplementation also improves memory capacity, precision (34
), and retention (33
) among exposed rats. Similar enhancements in memory are seen when rats are supplemented with choline on postnatal days 16–30 (8
). Conversely, offspring of rats who receive a choline-restricted diet in late pregnancy show hippocampal apoptosis and impaired memory (1
Rat and human brain development proceed at different rates, and the human gestational correlates of specific pre- and postnatal exposure windows in the rat are not known with precision. Nevertheless, in a model of neurodevelopment across species, Clancy et al (32
) have reported that embryonic days 12–17 in the rat correspond to human gestational days 38–81 (first trimester). Similarly, rat postnatal days 16–30 correspond to human gestational days 169 and beyond, or >24 wk gestation. We were able to measure serum free and total choline in human samples broadly corresponding to the perinatal exposure windows in the rat models.
Choline circulates in a free form or bound to phospholipids (primarily as phosphatidylcholine). Concentrations of free and phospholipid bound (total) choline in the current study were similar to those reported previously (12
). There are conflicting data about changes over time of gestational concentrations of free and total choline in maternal serum. As in a previous report (38
), we found that maternal free choline remained stable throughout gestation, although others have reported increasing free choline with gestational age (37
). We observed an increase in maternal concentrations of total choline with gestational age, in contrast to an earlier report (36
). In previous studies (12
), as in ours, free choline was higher and total choline was lower in cord blood than in maternal blood.
Women in the current study consumed their usual diets. They were not eating choline-enriched diets and were not receiving choline supplementation. Therefore, our results indicate that choline concentrations in a physiologic range observed among women consuming a regular diet during pregnancy are not related to IQ in their offspring. We cannot rule out the possibility that choline supplementation could have an IQ effect.
In rodents, choline supplementation affects hippocampal development and improves spatial memory. We examined the relation of choline concentrations with Full Scale IQ and with selected subscores on the WPPSI-R test that depend more specifically on memory and visuospatial abilities and found no choline effect. Nevertheless, it is possible that choline may affect scores on an assessment tool that more directly measures specific components of memory and hippocampal function.
Serum concentrations of free and total choline may be influenced by recent intake of choline-containing foods. However, women who had relatively high or relatively low concentrations of choline early in pregnancy tended to remain relatively high or relatively low as pregnancy progressed, based on the significant correlation between choline concentrations over the course of pregnancy. Certainly, our longitudinal study provides more information on choline status during gestation than cross-sectional studies.
Note that the subjects in this study were from an inner-city population with substantial socioeconomic disadvantages, as evidenced by the high poverty rate, high prevalence of resource-poor environments, and scores on developmental tests well below national norms among both mothers and their children. It is possible that an effect of choline on intelligence was overshadowed by the relatively greater influence of these social and economic factors. However, multiple regression analyses were adjusted for these factors, and our results were strongly negative. Although the study population characteristics are comparable to other low-income, urban, minority populations, our results may not apply to other socioeconomic groups.
Our study has a number of strengths. Our sample size was sufficient to detect small differences in child IQ. Individual serum free and total choline values well above and below previously reported means (12
) were present in our sample. This wide range of choline concentrations should have made it possible to identify a choline effect on IQ had there been one. We were able to examine choline concentrations at multiple time points in pregnancy, allowing us to account for uncertainty in the correlation of developmental time courses between rats and humans. The original study from which this secondary analysis arose was specifically designed to assess relations between gestational exposures and child neurodevelopmental outcomes. As a result, extensive data on factors that may affect child IQ were collected and were included in our multivariate analyses. Child IQ was measured with a reliable and valid instrument.
In conclusion, although animal data strongly suggest that higher choline concentrations are correlated with improved cognitive performance in choline-supplemented rodents, this first human study found no relation between maternal choline concentrations at multiple time points during gestation or cord blood choline on IQ scores at 5 y of age. It is possible that pharmacologic doses of choline could affect intelligence in humans. In the physiologic range of concentrations derived from diet and de novo synthesis, however, choline was not correlated with intelligence in our population.