Perinatal Phosphatidylcholine Supplementation and Early Childhood Behavior Problems: Evidence for CHRNA7 Moderation

Abstract

Objective: α7-Nicotinic receptors are involved in the final maturation of GABA inhibitory synapses before birth. Choline at levels found in the amniotic fluid is an agonist at α7-nicotinic receptors. The authors conducted a double-blind placebo-controlled trial to assess whether high-dose oral phosphatidylcholine supplementation during pregnancy to increase maternal amniotic fluid choline levels would enhance fetal development of cerebral inhibition and, as a result, decrease childhood behavior problems associated with later mental illness.

Method: The authors previously reported that newborns in the phosphatidylcholine treatment group have increased suppression of the cerebral evoked response to repeated auditory stimuli. In this follow-up, they report parental assessments of the children's behavior at 40 months of age, using the Child Behavior Checklist.

Results: At 40 months, parent ratings of children in the phosphatidylcholine group (N=23) indicated fewer attention problems and less social withdrawal compared with the placebo group (N=26). The improvement is comparable in magnitude to similar deficits at this age associated with later schizophrenia. The children's behavior is moderated by CHRNA7 variants associated with later mental illness and is related to their enhanced cerebral inhibition as newborns.

Conclusions: CHRNA7, the α7-nicotinic acetylcholine receptor gene, has been associated with schizophrenia, autism, and attention deficit hyperactivity disorder. Maternal phosphatidylcholine treatment may, by increasing activation of the α7-nicotinic acetylcholine receptor, alter the development of behavior problems in early childhood that can presage later mental illness.

Trial registration: ClinicalTrials.gov NCT00332124.

FIGURE 1. Parent Ratings on the Subscales of the Child Behavior Checklist at 40 Months of Age After Perinatal Choline Supplementation or Placebo^a

^aIn panel A, parent ratings of children at 40 months on the Child Behavior Checklist attention subscale showed a significant main effect of perinatal choline treatment (F=4.56, df=1, 46, p=0.038) and no significant effect of gender. In panel B, rating on the withdrawn subscale showed a main effect of choline (F=9.61, df=1, 46, p=0.003) and a main effect of gender (F=7.60, df=1, 46, p=0.008). Panel C shows results with 10 subscales of the Child Behavior Checklist shown as differences from placebo using ranked scores. For all comparisons, 49 children were included, 23 whose mothers were treated with choline and 26 with placebo.

FIGURE 2. Regression of Rank Scores on the Withdrawn Subscale of the Parent-Rated Child Behavior Checklist at 40 Months of Age With CHRNA7 rs3087454 Alleles, by Treatment^a

^aThe choline-by-genotype interaction was significant (gender-adjusted F=4.41, df=1, 39, p=0.042). For placebo, the slope is positive (r=0.46, N=24, p=0.024), and for choline, the slope is negative (r=−0.41, N=20, p=0.072).

FIGURE 3. Parent Ratings on the Subscales of the Child Behavior Checklist at 40 Months of Age and P50 S2/S1 Amplitude Ratios^a

^aPanel A shows the effect of P50 S2/S1 amplitude ratios <0.5 or ≥0.5 a 1 month of age on parent ratings on the withdrawn and attention subscales and total problems on the Child Behavior Checklist at 40 months of age. P50 recordings were available for 46 newborns (the others did not sleep long enough during the recording session for adequate data to be obtained). For the withdrawn subscale, t=2.48, df 45, p=0.017; for the total problems subscale, t=2.09, df 45, p=0.042. Panel B shows examples of P50 auditory evoked potentials recorded in newborns in the placebo and choline groups, at ages 29 and 30 days, respectively, adjusted for gestational age at birth. Recordings are the average response to 96 pairs of stimuli delivered with a 0.5-second intrapair interval during active sleep. Amplitudes of response to the first (S1) and second (S2) stimuli were measured from P50 peak amplitude (tick above wave) to the preceding negativity (tick below wave); these amplitudes are used to calculate P50 S2/S1 ratio. The vertical axis is amplitude in microvolts, and the horizontal axis is time from the stimulus in milliseconds. *p<0.05.