Maternal Immune Activation and Autism Spectrum Disorders

There has been a recent surge of research on the topic of inflammation during pregnancy and how that impacts the neurological development of children. Scientists have been exploring this with great interest. Inflammation brought on by the immune system during pregnancy appears to be a massive, critical puzzle piece as to why autism spectrum disorders and other neurodevelopmental disorders develop. This is incredibly important for all involved with family planning.

Gut Flora Helps Neurodevelopment

Research on the gut microbiome tells us that the gut flora plays an enormous role with the nervous system in health of adults and children affecting cognition, mood, and function, but it goes even further. The gut microbiome is also involved in the very young with fundamental neurological development.

This amazing gut microbiome sends molecular cues from the gut to the nervous system which impacts growth and development. For instance, the gut microbiome is involved with the formation of the blood brain barrier, myelination or the development of the protective, fatty sheath that wraps around certain nerves, the birth of new nerves/neurogenesis, and maturation of microglial cells. 

This entwined influence of the gut flora and brain is vital to proper development, but when it goes awry, it may lead to a damaging cascade of inflammation. Science shows us that when the brain-gut-immune system within the mother becomes upset by a trigger, it can affect the fetus, and even provoke a long-lasting effect in the function of nervous system of the offspring. The activation of the immune system in the expectant mother is known as maternal immune activation (MIA) which is linked with the development of autism spectrum disorders.

Maternal Immune Activation Triggers

Maternal immune activation may be triggered by a few different things, such as gut bacterial imbalances, lipopolysaccharide or LPS toxins, bacterial or viral infections, autoimmune disorders, and significant prenatal stress. LPS refers to an endotoxin shed by bacteria or another germ that induces inflammation. When the infection occurs during pregnancy, it plays a powerful role in its systemic effects.

Viral infections in the first trimester and bacterial infections during the second trimester are related with increased risk of autism development and maternal immune activation. Influenza virus in the third trimester may also lead to autism development. The challenge to the unborn is due to toxins and inflammation created by the germs in the mother, not the germ itself infecting the fetus.

Research published September 2017 in the journal Nature suggests that the viral infections and autoimmune disorders can activate gut bacteria in pregnant mothers which induces and stimulates TH17 immune cells in the offspring. Activation of TH17 immune cells in the fetus or newborn creates inflammation and increases the risk of neurological developmental disorders like autism. 

The Journal of NeuroInflammation September 2017 shows that lipopolysaccharide (LPS) exposure in the uterus activated microglial cells in the offspring during pregnancy and persisted for weeks after birth. Elevated levels of glutamate levels, changes in nerve synapse function, and microglial cell activation occurred.

The hippocampus, which is the memory and learning center of the brain, was found to also be affected in the offspring. Glutamate is needed by the brain in small amounts at select times, but excess amounts or chronic exposure is problematic as it becomes an excitotoxin. Microglial cells are the primary immune cells, or macrophages, that are the first and main form of active defense found within the brain. They manage inflammation, nerve damage and infections within the brain.

Maternal Immune Activation Creates Long-Term Effects

Earlier this year, scientists published a study that evaluated long-term effects of viral-induced maternal immune activation in offspring. Scientists studied a small group of non-human primates to best evaluate outcomes compared to human studies. Rhesus macaque monkeys were given a viral mimic near the end of the first trimester or near the end of the second trimester versus while controls received saline. The offspring were then followed until four years of age.

At one year of the age, the offspring exposed to the virus and MIA showed elevation of several immune cytokines, i.e. IL-1beta, IL-6, IL-12p40 and TNFa. At four years of age the offspring continued to show IL-1beta and increased production of TH2 cytokines, IL-4 and IL-13. Behavioral changes were common as seen with autism spectrum disorder or other neurodevelopmental disorders. For those who are familiar with TH2, you might recognize that TH2 production or dominance in adults is seen with various autoimmune disorders like allergies, asthma, inflammatory bowel disease, lupus, cancer, sinusitis, scleroderma, and multiple chemical sensitivity.

An October 2017 study expanded on the findings with IL-6 and maternal immune inflammation. In this publication, the animals used in the study were exposed to high stress states during pregnancy which triggered maternal immune inflammation and produced high levels of the immune cytokine IL-6. Microglial cells were stimulated as a result in the offspring.

The puzzle piece identified here showed that GABA function was disrupted. GABA is the dominant inhibitory neurotransmitter that helps buffer stimulus, stress, and excitotoxins like glutamate. The behaviors seen with this shift in brain chemistry included increased anxiety, decreased sociability, and movement disorders seen with developmental neurological challenges. The effects of the microglial cell inflammation and changes in the nerve structure persisted long-term.

These studies point to mounting evidence that maternal infection and high stress during pregnancy may increase the risk of autism spectrum disorder by triggering maternal immune activation. Genetic susceptibility, intensity and timing of the infection during pregnancy, and other stressors are under investigation to understand the progression. Infection and maternal inflammation provoke microglial cell activation, increased glutamate, TH17, TH2, etc, and decreased GABA which may lead to problematic neuro-immune inflammation in the fetus. This can set the stage for autism spectrum disorder and other neurodevelopmental concerns affecting later life.

Key Nutrients Needed to Prevent or Inhibit Maternal Immune Activation

Pregnancy is a time of preparation and self-care, and naturally there is a bit of worry for many. Information like this isn’t meant to heighten fears and encourage one to become germ phobic. Rather, the intent is to help those trying to conceive to make sure they have some fundamental basics covered. Information about maternal immune activation is still new and developing, but there have been some key points that research identifies which helps prevent and manage MIA and neurological deterioration from occurring.

Iron, Vitamin D, and Zinc Deficiency

Iron deficiency during pregnancy increases the risk for maternal immune activation. Animal studies show that when pregnant female rats were iron deficient and had exposure to LPS toxins or other bacterial toxins during early pregnancy, higher levels of the inflammatory cytokines IL-6 and TNF-a occurred compared to the study group that had sufficient iron.

The combination of iron deficiency and exposure to toxins produced higher amounts of brain-immune inflammation that led to negative neurodevelopmental changes in behavior in the offspring. The first stage of iron deficiency is seen with low serum ferritin levels.

Get your serum ferritin checked at least a couple of times per year if you are trying to conceive or have a history of iron deficiency anemia. Women of reproductive age should be at least 50 or ideally at 100 ng/mL for serum ferritin. Iron bysglycinate, a gentle, easily absorbable form of iron works great for those in need of iron. It does not cause digestive upset like ferrous sulfate does.

Zinc deficiency has been found to increase the toxic effects of LPS to the fetus and increase maternal immune activation. LPS toxins are known to cause zinc deficiency. Researchers found that prenatal zinc prevented impairments with reproduction, improved social behavior and modulated BDNF (brain derived neurotrophic factor). 

Omega-3 essential fatty acids (EPA/DHA) and probiotics are also highly beneficial for maternal immune activation. Omega-3 fish oils (EPA and DHA) are vital for prenatal and postnatal neurological development and inflammation management. Studies show that EPA/DHA deficiency and high omega-6 (vegetable oil) intake induces dysbiosis or gut flora imbalances and germ overgrowth. When enough EPA/DHA is present, beneficial bacteria Lactobacillus and Bifidobacterium are supported and enriched.

Gut flora is largely imbalanced in the offspring exposed to maternal immune activation. High levels of Clostridia toxins and Bacteroides and Firmicutes have been found. Restoration of beneficial bacteria like Bacteroides fragilis has been helpful for health.

Other Immune Support

We provide a number of resources for immune support. These may be utilized by women and children to help support healthy immune function and reduce the inflammation caused by germs. Favorite nutritional support includes colostrum or lactoferrin, vitamin C, zinc, beta carotene and vitamin A, grape seed extract, arabinogalactan, and NAC. 

We have previously discussed other concerns with autism disorders like glyphosate/Roundup gut-immune alterations, vaccine injuries, plastics, heavy metal toxins, antidepressant use during pregnancy, and obesity and leptin problems which provoke additional layers of inflammation. It is likely that if the mother is already struggling with any or all of these concerns prior to conception and then gets a mild infection at the wrong time during pregnancy, the unborn will be exposed to very challenging amounts of inflammation that may affect the rest of their life.

Focus on nutritional support like iron, zinc, omega-3 fish oil, probiotics, and vitamin D with a diet rich in antioxidants from several servings of colorful fruits and vegetables and fiber every day. These may be taken along with a high quality prenatal multiple vitamin. It may be easy to say, “My diet is healthy. I get enough nutrients to supply my needs”, but the reality is twenty-first century life demands bring significant nutritional challenges. Health is about being proactive rather than “If only I had…..”