Maternal choline and respiratory coronavirus effects on fetal brain development
Abstract: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.
The Centers for Disease Control (CDC) anticipate that maternal COVID-19 infection will affect fetal development like other respiratory coronaviruses (Centers for Disease Control and Prevention, 2020). COVID-19 is not usually transmitted directly to the fetus (Kimberlin and Stagno, 2020). Instead, the maternal inflammatory response to the virus is thought to be the pathogenic mechanism underlying effects on the fetus and its support by the placenta (Brown and Meyer, 2018). Common respiratory infections increase the risk for attention deficit disorder, autism spectrum disorder, and schizophrenia, with relative risks ranging from 1.6 to 2.2 (Mednick et al., 1988; Hornig et al., 2018; Dreier et al., 2016). Higher maternal C-reactive protein (CRP) at the beginning of the second trimester is associated with increased risk of schizophrenia in the offspring (Canetta et al., 2014).
We reported that common bacterial and viral infections from 10 to 16 weeks gestation increase maternal inflammation as assessed by elevated maternal CRP levels. Higher maternal choline levels at 16 weeks gestation consistent with U.S. Food and Drug Administration (FDA) dietary recommendations for pregnant women appear to mitigate the adverse effects of the inflammation on the offspring's behavior at 3 months of age (Freedman et al., 2019). We analyzed a subset of the data from that study to examine the effects on infant behavior if the mother had contracted a respiratory virus. The new analysis may provide information relevant to potential COVID-19 effects on fetal brain development and their interaction with higher prenatal maternal choline levels.
At 16 weeks gestation, mothers were asked if they had experienced illnesses in the preceding 6 weeks including infections. Most of the 43 mothers with viral respiratory infections rated their symptoms as moderate to severe (N = 36, 84%). These self-ratings of symptom severity correlated with the clinical assessment of infection severity in the prenatal clinic medical record (rho = 0.95, P < 0.001). A comparison group of mothers (N = 53) reported no infections. Maternal CRP and choline levels were determined at 16 weeks in both groups. CRP levels remain elevated for up to 10 days after onset of a viral respiratory infection (Melbye et al., 2004). Infection reports at 22, 28, 34, and 40 weeks had no significant effects on infant outcomes (Freedman et al., 2019). Choline levels ≥7.5 μM are consistent with diets that meet or exceed the FDA minimum daily requirement for pregnant women, 550 mg (Wu et al., 2012).
When the infant reached 3 months of age, mothers completed the Infant Behavior Questionnaire-Revised Short Form (IBQ-R; Gartstein and Rothbart, 2004), a parent-report measure of infant behaviors indicative of temperamental reactivity and self-regulation. Mothers rated 91 infant behaviors on Likert scales ranging from 1 (never) to 7 (always). The ratings were then averaged into 14 scales of infant temperament and behavior. Factor weightings from Gartstein and Rothbart (2004) original report grouped these 14 scales into 3 dimensions: Orienting/Regulation (Regulation), Negative Affectivity (Negativity), and Surgency/Extraversion (Surgency). Regulation includes duration of attention, enjoyment of quiet play, cuddliness and engagement with parents, and soothability; Surgency includes general level of activity and perceptual sensitivity, pleasure in high-intensity activities, vocal reactivity, and smiling and laughter; Negativity includes fearfulness, sadness, and recovery after exposure to a stressor.
This research was approved by the Colorado Multi-Institutional Review Board and conducted in accordance with the Helsinki Declaration as revised 1989. Detailed methods have been previously reported (Freedman et al., 2019). Full statistical analyses are in the Supplement (Tables S1–S6).
Mothers with respiratory viral infections in early gestation were younger and more likely to be depressed and anxious (Table 1 ). Viral infection was associated with increased CRP, 11.0 mg/L (SEM 1.4) in infected women versus 7.5 mg/L (SEM 1.2) in uninfected women, Fdf1,82 = 4.06, P = 0.047. The range in infected women in our sample was 0.6–38.8 mg/L. In a case series of 9 COVID-19 infected mothers from Wuhan, China, CRP levels ranged from 3.3 to 33.4 mg/L (Chen et al., 2020).