Prenatal choline, cannabis, and infection, and their association with offspring development of attention and social problems through 4 years of age.

BACKGROUND: Prenatal choline is a key nutrient, like folic acid and vitamin D, for fetal brain development and subsequent mental function. We sought to determine whether effects of higher maternal plasma choline concentrations on childhood attention and social problems, found in an initial clinical trial of choline supplementation, are observed in a second cohort. METHODS: Of 183 mothers enrolled from an urban safety net hospital clinic, 162 complied with gestational assessments and brought their newborns for study at 1 month of age; 83 continued assessments through 4 years of age. Effects of maternal 16 weeks of gestation plasma choline concentrations ⩾7.07 µM, 1 s.d. below the mean level obtained with supplementation in the previous trial, were compared to lower levels. The Attention Problems and Withdrawn Syndrome scales on Child Behavior Checklist 1½-5 were the principal outcomes. RESULTS: Higher maternal plasma choline was associated with lower mean Attention Problems percentiles in children, and for male children, with lower Withdrawn percentiles. Higher plasma choline concentrations also reduced Attention Problems percentiles for children of mothers who used cannabis during gestation as well as children of mothers who had gestational infection. CONCLUSIONS: Prenatal choline's positive associations with early childhood behaviors are found in a second, more diverse cohort. Increases in attention problems and social withdrawal in early childhood are associated with later mental illnesses including attention deficit disorder and schizophrenia. Choline concentrations in the pregnant women in this study replicate other research findings suggesting that most pregnant women do not have adequate choline in their diets.

Targeting Treatments to Health Disparities.

These initial data suggest that with prenatal vitamins and choline supplements, we might decrease one risk factor associated with poorer health outcomes disproportionally affecting Black families, ie, preterm birth. Dissemination of this research fulfills the principle of Justice in the Belmont Report, to ensure that participants from different racial, ethnic and socioeconomic groups receive benefits from research directed to their specific problems.

Male fetus susceptibility to maternal inflammation: C-reactive protein and brain development.

BACKGROUND: Maternal inflammation in early pregnancy has been identified epidemiologically as a prenatal pathogenic factor for the offspring's later mental illness. Early newborn manifestations of the effects of maternal inflammation on human fetal brain development are largely unknown. METHODS: Maternal infection, depression, obesity, and other factors associated with inflammation were assessed at 16 weeks gestation, along with maternal C-reactive protein (CRP), cytokines, and serum choline. Cerebral inhibition was assessed by inhibitory P50 sensory gating at 1 month of age, and infant behavior was assessed by maternal ratings at 3 months of age. RESULTS: Maternal CRP diminished the development of cerebral inhibition in newborn males but paradoxically increased inhibition in females. Similar sex-dependent effects were seen in mothers' assessment of their infant's self-regulatory behaviors at 3 months of age. Higher maternal choline levels partly mitigated the effect of CRP in male offspring. CONCLUSIONS: The male fetal-placental unit appears to be more sensitive to maternal inflammation than females. Effects are particularly marked on cerebral inhibition. Deficits in cerebral inhibition 1 month after birth, similar to those observed in several mental illnesses, including schizophrenia, indicate fetal developmental pathways that may lead to later mental illness. Deficits in early infant behavior follow. Early intervention before birth, including prenatal vitamins, folate, and choline supplements, may help prevent fetal development of pathophysiological deficits that can have life-long consequences for mental health.

Maternal Prenatal Depression in Pregnancies With Female and Male Fetuses and Developmental Associations With C-reactive Protein and Cortisol.

BACKGROUND: Prenatal depression has lasting effects on development in offspring, including later mental illness risk. Maternal responses to depression include inflammation and hypothalamic-pituitary-adrenal axis stimulation. Effects on development of cerebral inhibitory neurocircuits may differ for female and male fetuses. METHODS: Mothers (N = 181) were assessed periodically, beginning at 16 weeks' gestation, using the Center for Epidemiologic Studies-Depression Scale. Maternal prenatal C-reactive protein and hair cortisol and cortisone levels were determined. Cortisone was determined in neonatal hair. Development of cerebral inhibitory neurocircuits was assessed in 162 1-month-old newborns by inhibition of P50 electrophysiological responses to repeated sounds. RESULTS: Maternal depression was associated with decreased newborn P50 inhibition in both sexes. Maternal C-reactive protein levels were significantly associated with depression only in pregnancies with male fetuses and with decreased newborn P50 inhibition only in male newborns. Maternal cortisol levels were significantly associated with depression only in pregnancies with female fetuses and with decreased newborn P50 inhibition only in female newborns. In pregnancies with male fetuses compared with pregnancies with female fetuses, cortisol was more robustly metabolized to cortisone, which does not activate cortisol receptors. CONCLUSIONS: This study finds sex-specific associations of C-reactive protein and cortisol levels with prenatal depression in women and with decreased development of newborn P50 inhibition. Sex-based differences in maternal response to depression with inflammation or cortisol and their developmental effects may reflect evolutionary influences to promote survival in adversity. Decreased newborn P50 inhibition is associated with later childhood behavioral problems, and decreased P50 inhibition is a pathophysiological feature of several mental illnesses.

Black American Maternal Prenatal Choline, Offspring Gestational Age at Birth, and Developmental Predisposition to Mental Illness.

Black Americans have increased risk for schizophrenia and other mental illnesses with prenatal origins. Prenatal choline promotes infant brain development and behavioral outcomes, but choline has not been specifically assessed in Black Americans. Pregnant women (N = 183, N = 25 Black Americans) enrolled in a study of prenatal stressors and interactions with prenatal choline. Black American women had lower 16-week gestation plasma choline than Whites. Lower choline was not related to obesity, income, or metabolic genotypes. Pregnant women in rural Uganda have higher choline levels than Black American women. Black Americans' lower choline was associated with higher hair cortisol, indicative of higher stress. Lower maternal choline was associated with offsprings' lower gestational age at birth and with decreased auditory P50 inhibition, a marker of inhibitory neuron development. Behavioral development was assessed on the Infant Behavior Questionnaire-R-SF (IBQ-R) at 3 months. Lower Black American maternal gestational choline was associated with lower infant IBQ-R Orienting/Regulation, indicating decreased attention and relation to caregivers. Additional evidence for developmental effects of choline in Black Americans comes from a randomized clinical trial of gestational phosphatidylcholine supplementation versus placebo that included 15 Black Americans. Phosphatidylcholine increased gestational age at birth and newborn P50 inhibition and decreased Social Withdrawn and Attention problems at 40 months of age in Black Americans' offspring compared to placebo. Inhibitory and behavioral deficits associated with lower prenatal choline in offspring of Black American women indicate potential developmental predispositions to later mental illnesses that might be ameliorated by prenatal choline or phosphatidylcholine supplementation.

Maternal choline and respiratory coronavirus effects on fetal brain development.

Prenatal COVID-19 infection is anticipated by the U.S. Centers for Disease Control to affect fetal development similarly to other common respiratory coronaviruses through effects of the maternal inflammatory response on the fetus and placenta. Plasma choline levels were measured at 16 weeks gestation in 43 mothers who had contracted common respiratory viruses during the first 6-16 weeks of pregnancy and 53 mothers who had not. When their infants reached 3 months of age, mothers completed the Infant Behavior Questionnaire-Revised (IBQ-R), which assesses their infants' level of activity (Surgency), their fearfulness and sadness (Negativity), and their ability to maintain attention and bond to their parents and caretakers (Regulation). Infants of mothers who had contracted a moderately severe respiratory virus infection and had higher gestational choline serum levels (≥7.5 mM consistent with U.S. Food and Drug Administration dietary recommendations) had significantly increased development of their ability to maintain attention and to bond with their parents (Regulation), compared to infants whose mothers had contracted an infection but had lower choline levels (<7.5 mM). For infants of mothers with choline levels ≥7.5 µM, there was no effect of viral infection on infant IBQ-R Regulation, compared to infants of mothers who were not infected. Higher choline levels obtained through diet or supplements may protect fetal development and support infant early behavioral development even if the mother contracts a viral infection in early gestation when the brain is first being formed.

Interaction of maternal choline levels and prenatal Marijuana's effects on the offspring.

BACKGROUND: This study investigated whether higher maternal choline levels mitigate effects of marijuana on fetal brain development. Choline transported into the amniotic fluid from the mother activates α7-nicotinic acetylcholine receptors on fetal cerebro-cortical inhibitory neurons, whose development is impeded by cannabis blockade of their cannabinoid-1(CB1) receptors. METHODS: Marijuana use was assessed during pregnancy from women who later brought their newborns for study. Mothers were informed about choline and other nutrients, but not specifically for marijuana use. Maternal serum choline was measured at 16 weeks gestation. RESULTS: Marijuana use for the first 10 weeks gestation or more by 15% of mothers decreased newborns' inhibition of evoked potentials to repeated sounds (d' = 0.55, p < 0.05). This effect was ameliorated if women had higher gestational choline (rs = -0.50, p = 0.011). At 3 months of age, children whose mothers continued marijuana use through their 10th gestational week or more had poorer self-regulation (d' = -0.79, p < 0.05). This effect was also ameliorated if mothers had higher gestational choline (rs = 0.54, p = 0.013). Maternal choline levels correlated with the children's improved duration of attention, cuddliness, and bonding with parents. CONCLUSIONS: Prenatal marijuana use adversely affects fetal brain development and subsequent behavioral self-regulation, a precursor to later, more serious problems in childhood. Stopping marijuana use before 10 weeks gestational age prevented these effects. Many mothers refuse to cease use because of familiarity with marijuana and belief in its safety. Higher maternal choline mitigates some of marijuana's adverse effects on the fetus.

Higher Gestational Choline Levels in Maternal Infection Are Protective for Infant Brain Development.

OBJECTIVE: To assess whether maternal choline decreases effects of mothers' infections on fetal brain circuit development and on expression of infant behavior at 1 year of age. STUDY DESIGN: A cross-sectional study was conducted in a public hospital obstetrics and midwifery service, with prenatal assessments of maternal infection, C-reactive protein, and choline level and postnatal assessments of cerebral neuronal inhibition in 162 newborns. At 1 year, 136 parents completed reports of their child's behavior. RESULTS: Maternal infection at 16 weeks of gestation, experienced by 41% of mothers, raised mean maternal C-reactive protein (d' = 0.47, P = .002) and decreased the development of cerebral inhibition of auditory response at 1 month of age (d' = 0.39, P < .001). Decreased newborn cerebral inhibition manifested as decreased behavioral self-regulation at 1 year. Greater choline levels in mothers with infections were associated with improved newborn inhibition of auditory cerebral response, mitigating the effect of infection (ß = -0.34 [95% CI, -5.35 to -0.14], P = .002). At 1 year of age, children of mothers with infection and greater gestational choline levels had improved development of self-regulation, approaching the level of children of mothers without infection (ß = 0.29 [95% CI 0.05-0.54], P = .03). CONCLUSIONS: Greater maternal choline, recommended by the American Medical Association as a prenatal supplement, is associated with greater self-regulation among infants who experienced common maternal infections during gestation. Behavioral problems with diminished self-regulation often lead to referrals to pediatricians and might lead to later mental illness.