Steps to Take Before, During, and After Pregnancy to Help Assure the Child’s Mental Health

M. Camille Hoffman, M.D., MSCS, completed medical school at the Medical University of South Carolina, OBGYN residency at University of Miami, and her maternal fetal medicine fellowship at University of Colorado Anschutz Medical Campus. Dr. Hoffman directs a clinical and translational perinatal mental health research program that she established to investigate maternal-child mental and physical health relationships and to promote maternal-child wellness.

Dr. Hoffman, you are a “high-risk” obstetrician who takes care of women and their babies in the period surrounding birth, both before and after. But you’re also a researcher who looks at the 9-month period of fetal life. What happens during fetal development that can affect the baby’s mental health after birth?

A lot of research emphasis has been put on early childhood development and how that shapes a person’s health over the lifespan. However, in more recent years, researchers have backed that up into prenatal life. The second and third trimesters of pregnancy are critical periods for the wiring of brain pathways that lead to an overall well-functioning brain. Once the scaffolding for the brain is set in early fetal life, then different layers of brain development occur on top. If the scaffolding setup is off, you can end up with a brain that doesn’t come together as it should or is dysfunctional in some way.

How fast is the brain growing during the second and third trimesters?

Extremely rapidly. Between the second and third trimester it physically increases in size by 10-fold, with the formation and wiring together of billions of neurons. The brain triples in size during the last trimester alone.

What are possible events that may happen during a pregnancy that could affect a child’s brain development, and subsequently, his or her mental health?

One of the more common things to be aware of is infection of the mother with something such as the flu or a urinary tract infection early in pregnancy, and especially during the second trimester. Another thing to be aware of is extreme maternal stress, which can have a harmful impact. So can high levels of alcohol or marijuana use throughout pregnancy.

The more we look at the exposures that are detrimental to fetal brain development, the more we see the second trimester as a critical period for establishing the brain’s scaffolding. I’m not saying, by the way, that fetal brain damage only happens during the first or second trimester. It can be affected at any stage by something like heavy alcohol consumption by the mother. However, in the case of other risks like marijuana use or infection, earlier pregnancy exposures also matter more than we thought they did.

In general, we consider the fetal period, and indeed, the entire perinatal period, before and after birth, to be the main window for preventing illness later on, including mental illnesses.

This brings to mind a classic preventive measure, now universally recommended: taking folate supplements.

Yes, it’s one of medicine’s great prevention success stories. Folic acid is a vital dietary nutrient for both the mother and the fetus. Inadequate folate levels in the mother are linked with a very serious birth defect called an open neural tube defect (ONTD). The neural tube is a structure that forms in the first few weeks after conception. It is the basis for the entire brain and nervous system. Severe neural tube defects can result in miscarriage earlier in pregnancy, and later, when the tube fails to close somewhere along the developing spinal cord, it can cause an ONTD. This type of birth defect can be life-altering for infants who survive and sadly can also be life-limiting.

For decades we’ve known that by simply adding folic acid to the diet, the risk of open neural tube defect is diminished tenfold—if the supplements are started before conception or at least early in pregnancy, which is the time just before the neural tube normally closes.

All women are advised to take folate supplements, beginning 3 months prior to conception, if possible. It’s not hard to get adequate folate through the diet, but decades of research shows that women who get additional supplementation have far less chance of having a fetus with neural tube defects.

In your own research, you have identified another way of potentially preventing serious brain-related disorders by supplementing the mother’s diet. I refer to your recent work on choline supplementation. Tell us about this very important discovery.

Just as a deficiency of folic acid in the mother can perturb the fetus’ development, and specifically nervous system development (which includes the brain), so too can a deficiency of another essential nutrient called choline. I and others have come to this problem through research on factors involved in the causation of schizophrenia and psychosis. Genetic factors can predispose an individual to developing schizophrenia, but in those who eventually develop the illness it’s usually a combination of genetics and other exposures—in fetal life and environmental exposures after birth—that can come together and make a perfect storm that results in illness.

What does the level of choline in the mother’s diet during pregnancy have to do with the risk that a fetus will develop, perhaps 20 years after birth, a serious illness like schizophrenia?

This is what our team at the University of Colorado, under the leadership of Dr. Robert Freedman (a BBRF Scientific Council Member, 2015 Lieber Prizewinner for Outstanding Achievement in Schizophrenia Research, and 2006 and 1999 Distinguished Investigator) and the late Dr. Randall Ross, has been studying. In broad terms, it has to do with what neuroscientists call neural inhibition. Early in development, there is a tremendous amount of excitation in and among brain cells as they develop, grow, and communicate. One of the final steps in fetal brain development has to do with the emergence of inhibitory mechanisms that enable brain circuits to modulate their output. If brain cells are constantly “on”—in excitatory mode, rather than be capable of exciting and inhibiting, as needed—then mental illness can result.

How does the brain do this?

There is a type of receptor on the surface of brain cells that becomes vital at the very end of gestation, when neural inhibition is emerging. This receptor is called the alpha-7 nicotinic receptor, and during fetal life it is stimulated by choline. In the fetus, it is choline coming from the mother, via the placenta, that activates these receptors and stimulates their development. Choline is needed throughout pregnancy for various purposes and at the end of pregnancy it’s needed by the fetal brain to promote the emergence of inhibition which leads to proper brain function for the remainder of that individual’s life.

What’s the connection between emergence of normal neural inhibition and the risk of schizophrenia?

It’s thought that people with schizophrenia have an insufficiency in inhibition which leads to over-activity in brain areas involved in cognition and emotional processing. There’s also evidence that in infants who go on to develop schizophrenia in later years, the brain’s inhibitory system doesn’t establish itself as robustly as it should.

Surveys have revealed that one pregnant woman in five does not receive adequate choline from her diet. This provides a rationale for choline supplementation during pregnancy, and is the purpose of our current and past research.

We conduct clinical research studies aimed at assessing the impact of choline supplementation—when started early in the second trimester and continued through pregnancy—compared to a placebo, in pregnant women and their fetuses. We also study the comparative impact on these fetuses as they grow into infants and toddlers. We measured impact through multiple maternal, fetal, and child measures. Among these are measures that we devised specifically to assess inhibition in newborns.

What did your research reveal about choline supplementation?

In our pilot trial, we found that moms who received choline during pregnancy had infants with better “auditory gating” very early in life, at about one month of age, compared to children of moms who received the placebo.

Auditory gating is a type of EEG measure that parallels an assessment of adults with schizophrenia. Infants are exposed to two virtually identical sounds, 50 milliseconds apart. In normal gating, we would suppress our brain’s response to the second sound because it’s similar to the first. Our brain perceives it as background noise. But in some babies, and in individuals with schizophrenia, there is a failure to inhibit the brain’s response to the second sound. Most people’s brains help filter out distractions. Otherwise, you would hear everything all the time, which is commonplace in people with schizophrenia.

So, you’re measuring this response in the babies after they’re born, comparing those whose moms took choline supplements with those whose moms got a placebo.

Right. We measured it at one month of age, and saw a difference in choline-exposed versus non-choline-exposed babies. That effect was no longer evident at one year of life. But when we assessed the choline-exposed babies at age 4, we found that they performed better on the child behavioral checklist: they were more attentive, more interactive, and less withdrawn than the non-choline-exposed babies.

If I understand correctly, then, choline supplementation has proven itself well enough to be a recommendation at this point. It’s not strictly experimental.

To us, it’s not experimental anymore. Additional studies are in progress and their results will be important in the issuance of general recommendations. That being said, the American Medical Association has already endorsed choline at 450 mg a day to be included in a prenatal vitamin regimen, because of evidence on how choline can buffer the impact of fetal alcohol exposure.

When should an expecting mother start this choline regimen?

Ideally she would start it before conception, just like supplementation of that other essential nutrient, folate, and in combination with a healthy diet. At the latest, it needs to be started in the early- to mid-second trimester to have the most potent impact.

Where can women find choline? How much should they take?

The highest dietary sources of choline are eggs, salmon, and animal livers. And then there are different choline supplements commercially available. For vegetarian moms, there are lecithin granules, typically from soy, that contain choline in vegetarian form. A lot of prenatal vitamins will also contain choline, but usually it’s around 40 mg, which is a drop in the bucket as far as our recommendation goes. We advise our patients to take 900 mg per day

Should women without any of the obvious family risk factors for schizophrenia or psychosis still take choline?

Think about what happened with folate. The risk of an open neural tube defect in the general population is one in 1,000. Folate supplementation reduces that risk to about one in 10,000. The rate of mental illnesses alone that we were talking about is one in 100 for schizophrenia, two in 100 for bipolar disorder, about three or four in 100 for autism spectrum disorder—which also has some potential preventive benefits from choline.

So, if we could reduce the risk of these conditions with choline supplementation, why wouldn’t we do it? The population impact could be huge.

Which brings us back to something you mentioned earlier. You noted the importance of maternal infection and severe stress during pregnancy.

Yes, a mother should do whatever possible to minimize her risk of infection. However, many infections are not avoidable. So now, based on the research we’ve performed, I have started to recommend that women who develop an infection during pregnancy consider increasing their choline intake during pregnancy, either via diet or supplements or a combination of the two. I recommend choline also when a pregnant woman has other risk factors such as heavy alcohol or marijuana consumption, particularly if she has used these substances early in pregnancy.

What kind of interventions are possible for reducing maternal stress?

There are positive data on mindfulness-based cognitive therapy interventions, interpersonal therapy interventions and other psychotherapy modalities, and women should consult with their physician or midwife about these options. Also, there are several meditation apps that can be downloaded onto phones and a whole body of literature on how mindfulness practices are stress-reducing. We are doing a study on an app designed for the period prior to conception, as well as pregnant and post-partum women. It’s a daily mindfulness meditation that’s 15 to 20 minutes.

More generally, Dr. Hoffman, what are some things within the mother’s power that could minimize the risks of a negative mental health outcome for the child?

First, planning pregnancy: planning your family size and spacing, and then achieving the best health possible before you get pregnant. Second, having a healthy diet that includes folate and choline, both in dietary and supplement form. Feed yourself the best nutrients and you’ll grow your fetus from the healthiest building blocks. Third, avoiding infections as best as possible with hand-washing, and early prenatal care to identify any risk factors for infection. Also, avoiding alcohol consumption, marijuana, and other illicit substances throughout pregnancy. Lastly, incorporating movement and physical activity into your daily routine. Regular physical activity improves mood, helps moderate stress, and decreases anxiety—all of which can be detrimental to pregnant women and their developing fetuses (and all of us, really).

— Written By Peter Tarr

M. Camille Hoffman, M.D., MSCS

Associate Professor, Maternal & Fetal Medicine

University of Colorado School of Medicine

2015 Baer Prize for Innovative &  Promising Schizophrenia Research

Click here to read the Brain & Behavior Magazine's March 2019 issue