How the Mother Influences the Brain Development of the Fetus

Researchers at Weill Cornell Medicine have discovered in a preclinical model that cytokines – proteins that control immune response – circulating in maternal blood during pregnancy may reduce the offspring’s risk of psychiatric disorders. The results are surprising because circulating maternal cytokines are so low that they have not previously been linked to fetal brain development and offspring behavior.

Brain Development and Maternal Cytokine Levels

The study, published in the journal Brain, Behavior and Immunity, reports that the cytokine XCL1 produced by maternal immune cells may function as a pregnancy hormone and is required for proper placental development and anxiety behavior in male offspring. These findings support epidemiologic studies that have long suggested a link between infections and inflammation in the mother during pregnancy and the development of psychiatric disorders in the offspring later in life.

Using mouse models, the researchers found that circulating XCL1 normally remains at the same low level as before pregnancy throughout gestation, with the exception of a brief rise and fall in mid-pregnancy. This transient increase is essential for the proper development of the placenta and the emotional behavior of the offspring.

When this spike of XCL1 in maternal blood was genetically blocked or neutralized by anti-XCL1 antibodies, the researchers found increased production of factors associated with tissue damage in the fetal placenta, leading to increased innate anxiety and stress responses in male mouse offspring. The researchers also found a neuronal abnormality in the developing brains of these offspring, particularly in the ventral hippocampus, a region that has been associated with fear and anxious behavior.

The immunological and neuronal abnormalities observed when the cytokine spike was blocked normalized in adulthood, suggesting that the anxious behavior of the offspring in adulthood may be related to the proinflammatory state in early life caused by the absence of elevated XCL1. The researchers will investigate other chemokines that regulate placental development and may influence the emotional behavior of the offspring. The team plans to collaborate with researchers who have access to blood samples from pregnant women to see if the profile of XCL1, a protein also found in humans, matches observations in mouse models.

How Choline Supports Fetal Brain Development

Choline, an essential B-vitamin nutrient, may prevent fetal brain development disorders that often occur after prenatal maternal infections such as colds and flu. This research is crucial as viruses, such as influenza, have been linked to fetal brain problems and mental health conditions such as attention deficit disorder and schizophrenia in pregnant women later in life.

Mothers want to give their babies the best possible start in life. Colds and flu are often unavoidable, even if the mother has had a flu vaccination. But colds and flu during pregnancy double the risk of mental illness later in life. More and more information is showing that choline helps the baby’s brain to develop properly. Researchers have found that a high choline content prevents the development of brain problems in the fetus, even if the mother is infected.

The study was conducted at the University of Colorado Prenatal Clinic and Denver Health Medical Center, and maternal infection, C-reactive protein (CRP, a marker of maternal inflammation) and choline levels were assessed before birth. The baby’s brain development before birth was assessed by measuring the baby’s brain waves shortly after birth. The detrimental effects of maternal infections were shown to be a reduction in the normal inhibition of newborns’ brain waves to repetitive sounds, also known as response inhibition. Simply put, response inhibition is the ability to pause or delay an action and be able to reflect rather than engage in impulsive behavior.

• The reaction inhibition of the newborns decreased by 27 percent if the mothers had an infection, such as a cold or flu, in the first 16 weeks of pregnancy; this effect was prevented if the mother had a higher choline level in the first 16 weeks.
• The parents filled out reports on their child’s behavior when the child was one year old.
• Children whose mothers were infected and had lower choline levels were significantly less able to pay attention, play quietly and cuddle with their parents. These effects did not occur when the mother had a higher choline level.
• These characteristics are summarized in a scale of self-regulation, which was reduced by 28 percent in children of women with an infection and lower choline levels. Higher choline levels improved self-regulation to normal levels in the children of women with infections.
• Five of 53 children whose mothers had an infection (9.4 percent) had regulation levels in the lowest fifth percentile of a normal sample, compared with one of 83 children of mothers without infection. This effect did not occur if the mothers had a choline level of more than 7 micromoles during pregnancy. Only 25 percent of the women reached this level, even though they were encouraged to eat choline-containing foods.

The body produces some of the choline itself and it is naturally present in certain foods such as liver, red meat and eggs. However, up to 75 percent of pregnant women consume less choline during pregnancy than recommended (450 mg choline per day). In addition, prenatal vitamins contain little or no choline.