Choline chloride

Endpoint summary

Description of key information

- scientific review evaluating available data on the relationship of choline supplementation or choline levels during pregnancy and fetal brain development (Freedman and Ross, 2015)

Additional information

In the publication of Freedman and Ross (2015) the relationship of choline supplementation (done often either as choline chloride or phosphadidylcholine) on the relationship of choline supplementation or choline levels during pregnancy and fetal brain development has been evaluated. In fetal life the concentration of choline does affect the activation of alpha-7 nicotinic receptors. The necessary millimolar concentrations of choline are normally found in the amniotic fluid. Choline deficiency does not occur in non-pregnant adult women, however, it is estimated that approximately 30 % of women are choline deficient during pregnancy because of the extraordinary requirements for choline by the fetus. About one third the necessary choline can by synthesized by the woman herself; the remainder requires dietary intake. Choline is found in significant amounts in animal cell membranes, so meat or eggs are the most concentrated sources. Among non-animal sources, soybeans have the highest levels. During stress, the woman preferentially holds choline in her own liver, which lowers the levels observed in the serum that is available to the fetus. Newborn inhibition of P50 response reflects the pathophysiological effect of in utero exposure to factors that increase the offspring’s later risk for schizophrenia. The thesis was formulated that perinatal choline might overcome the genetic deficiency in alpha-7 nicotinic receptors and produce mice offspring with a permanent enhancement in cerebral inhibition. Experiment raised the possibility that perinatal choline might overcome the genetic deficiency in alpha-7 nicotinic receptors and produce mice offspring with a permanent enhancement in cerebral inhibition. To determine if the effect was due to specific interaction with alpha-7 nicotinic receptors, the experiment was repeated in mice of the same strain whose alpha-7 nicotinic receptors were entirely removed by a CHRNA7 null mutation. These animals failed to show the enhancement of cerebral inhibition after perinatal choline supplementation, which indicates that the choline needs to interact with alpha-7 nicotinic receptors.

Based on these animal model experiments, the permission from United States Food and Drug Administration (U.S. FDA) to conduct a placebocontrolled trial of choline supplementation in pregnant women was secured. The women were selected to have normal pregnancies with no history of fetal defects or known genetic abnormalities such as Down’s syndrome. Choline was administered as 7 capsules, 4 in the morning and 3 at night, each containing 900 mg of phosphatidylcholine. The total daily choline supplement was 900 mg, approximately twice the recommended dietary intake. There were no serious side effects that were observed in greater frequency in choline-treated pregnancies for either mother or baby. Babies regardless of treatment had a normal range of weight, head circumference, length, gestational age, and Apgar scores at birth and were normal for overall developmental assessment at 6 months. Recordings of P50 evoked potentials were performed at one and three months after birth. Inhibition of the P50 potential in the paired stimulus paradigm by at least 50 % was the pre-determined criterion for normal development of cerebral inhibition. Significantly more of the choline-treated newborns at one month achieved that criterion than the placebo-treated infants. The catch-up by the placebo-treated infants is typical of early developmental abnormalities, which, regardless of later significance, often disappear in early childhood. What is more concerning is that 20 % of infants in both groups continued to have abnormal cerebral inhibition. These tended to be lower birth weight males, who are generally susceptible to an increase in developmental issues. It is not known if higher doses of choline would have increased their cerebral inhibition. It remains to be seen whether or not the choline-treated babies will have fewer attention deficit symptoms than the placebo-treated babies–as predicted from their one month P50 evoked potential. Of course, the long-term outcome in adulthood, including the risk for schizophrenia, will not be known for over two decades. In the placebo-treated babies, a CHRNA7 polymorphism in the gene’s promoter that is associated with schizophrenia was also associated with decreased P50 inhibition, consistent with the hypothesis that the pathophysiological effect of the gene manifests early in development. In the choline-treated babies, this effect was not observed; the infants had normal cerebral inhibition regardless of genotype, consistent with the hypothesis that dietary choline can overcome the genetic effect, as was previously seen in the animal model experiments.