Researchers have obtained further evidence that during pregnancy, the presence of adequate levels of choline, an essential nutrient, in the mother’s system has a protective role in the development of the fetal brain and on behavior in children following birth.

The new evidence, published in the Journal of Pediatrics, bolsters the case for choline supplementation during pregnancy, a measure now advised by the American Medical Association but which is not yet common practice in this country or worldwide.

A team led by Robert Freedman, M.D., and M. Camille Hoffman, M.D., both of the University of Colorado Denver School of Medicine, enrolled 201 pregnant women in a study, 82 of whom (41%) developed an infection by the 16th week of gestation. Prior research has established that the mother’s immune response to infection affects the placenta and compromises its support of the fetus, although in ways that are not yet fully understood.

The question in this study was: did levels of choline in the plasma of mothers with second- trimester infections affect brain development and early postnatal indicators of brain function in their newborns? The working hypothesis was that infected women with higher levels of choline in the plasma—which supplies choline to the fetus via the placenta—would have babies that performed better in two key areas of brain function compared with babies of infected mothers whose choline levels were lower during pregnancy.

That is exactly what the data revealed, after 136 of the participating moms stayed in the trial and brought their babies in for key tests at 1 and 3 months after birth and submitted a detailed questionnaire about their newborns’ behavior at 3 months of age.

The test given to the newborns in the months after birth is a well-established measure of the response to repetitive sounds. It is used by neuroscientists to test a property of the brain called cerebral inhibition. Dr. Freedman, a member of the BBRF Scientific Council, winner of the 2015 Lieber Prize and 2006 and 1999 BBRF Distinguished Investigator, has used the test over the last two decades in pioneering studies helping to explain implications of a major transition in the fetal brain that occurs just before birth.

This transition, which marks the emergence of the maturing brain’s capacity to modulate, or dial down, the activity of excitatory neural communication, is an essential step if the newborn brain is not to be overexcited or hyperactive. Hyperactivity is one of the suspected aspects of brain dysfunction that can contribute to a number of mental illnesses, including schizophrenia and attention-deficit disorder.

The brain’s emerging inhibitory capacity, Dr. Freedman and colleagues have discovered, is partly dependent upon the action of choline during the fetal period. In addition to its role in enabling brain cells to build cell walls, choline is the substance that engages receptors which are abundant in the placenta and fetal brain. They are called alpha-7 nicotinic cholinergic receptors.

A deficiency of choline, Drs. Freedman, Hoffman and colleagues have proposed, prevents or impairs the maturation of neurocircuits, including inhibitory circuits, possibly contributing to pathology seen in schizophrenia and other disorders.

As they have pointed out, levels of maternal choline dip naturally during the second trimester of pregnancy, making it a particular period of vulnerability for the fetus. Many pregnant women have choline deficiencies—54% from the blood levels found in the current study and an estimated 20-50% in the general population, according to dietary reports. For these reasons, it is especially important, the researchers suggest, for pregnant women to take dietary supplements.

In two past studies, Drs. Freedman and Hoffman have demonstrated a correlation between maternal choline supplementation and improved outcomes in newborns on the test that measures the brain’s inhibitory function. At 40 months of age, the same infants had fewer behavioral problems than children in a group whose mothers took a placebo pill instead of choline during pregnancy and in the month after giving birth.

In the current study, which did not involve supplementation of choline, similar results were noted based on levels of choline that occur naturally in the mother’s diet. Mothers whose natural choline levels during pregnancy were higher gave birth to children who performed “significantly” better in the inhibition test than children of mothers whose choline levels were lower during pregnancy. And at the 3-month follow-up, a feature of behavior called behavioral regulation was also superior in the children of mothers with higher choline levels during pregnancy.

Decreased cerebral inhibition is associated with poor attention and executive function in people with schizophrenia. Genetic variations affecting the gene that encodes the alpha-7 receptor that choline engages prenatally are also seen in people with schizophrenia, autism, and ADHD.

“In this study,” the researchers noted, “decreased inhibition presaged poorer self-regulation at 3 months of age,” and this, in turn, “is associated with decreased reading readiness at age 4 years, and decreased conscientiousness, organization, and increased distractibility at age 9 years.”

Noting that their study supported the case for prenatal maternal choline supplementation, the team pointed out that prenatal vitamins currently contain as little as 10mg—a small fraction of the 900mg they suggest in addition to the recommended dietary intake of 550mg—meaning “additional supplementation would be needed” to reach their target.

Dr. Freedman also noted: infections during pregnancy, including the flu and respiratory illness, can happen to any woman, and these infections predispose the offspring to future mental illness, as established by research conducted by Dr. Alan Brown, BBRF’s 2019 Lieber Prize winner. Choline supplementation offers a way for mothers to protect their unborn children from this unforeseeable and often unpreventable risk, he said.

Dr. Hoffman is a winner of the BBRF’s 2015 Baer Prize. Team members also included Amanda Law, Ph.D., a member of the BBRF Scientific Council, winner of the 2011 Baer Prize, 2009 BBRF Distinguished Investigator and 2006 Young Investigator; and Sharon Hunter, Ph.D., a 2003 BBRF Young Investigator.