Dr. Judy Van de Water, Ph.D., explores the role of gestational factors in the development of autism. She explains how maternal immune activation, antibody patterns, and immune markers play significant roles in neurodevelopment and may contribute to the etiology and phenotypic variation of autism. The speaker presents various investigations and critical findings. She asserts the need for further research on the interaction of these gestational influences with other genetic and environmental factors. Van de Water provides thanks and acknowledgments before the Q&A.

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In this webinar:

1:02 – Potential etiologies of autism
3:03 – Maternal Immune Activation Model
5:30 – Research sample characteristics
7:40 – Study: Maternal prenatal cytokines
11:05 – Study: Newborn immune markers
15:06 – Study: Effect of sex on newborn immune system profile
17:30 – Maternal autoantibody related autism subtype (MARA)
19:25 – Target proteins and brain development
20:46 – Study: MAR antibody test
24:26 – Study: Early markers of autism – prenatal validation
27:40 – MAR antibody patterns phenotypes
29:30 – Summary of clinical findings
31:03 – Study: Translational animal model
34:15 – Rodent model findings
38:40 – Conclusions
41:55 – Q & A

Introduction

Van de Water lists potential etiologies for autism, including genetic predisposition, immune dysregulation, and infections during gestation. She explains that maternal infection, specifically inflammation resulting from infection, has been implicated as a risk factor for autism and schizophrenia (1:02). The speaker introduces the Maternal Immune Activation Model, which proposes that when an inflammatory event occurs during pregnancy, the mother’s immune response may be more active, leading to the transfer of different factors to the fetal compartment (e.g., cytokines) Such immune dysregulation can increase the risk of altered fetal neurodevelopment (3:03). Van de Water notes that genetic susceptibility, gestational timing, intensity of immune response and other postnatal events all play a role in autism etiology (5:00). 

Inflammatory response during pregnancy

The presenter describes recent investigations into risk factors for autism and developmental delays (5:30). She summarizes sample collection and research methods for a study that assessed maternal prenatal cytokines in mothers of autistic children with intellectual delays (ID), mothers of autistic children without ID, and mothers of children with ID but not autism (7:40). Researchers found that mothers of autistic children with ID had the highest levels of inflammatory cytokines and chemokines compared to all other groups. This suggests, Van de Water continues, a lack of selective immune regulation in these women and a potential link between immune activation and ID in autistic individuals (10:08). A second study found that newborns diagnosed with autism and delayed development (DD) had lower levels of specific cytokines and chemokines at birth compared to those with typical development or DD without autism (11:05). Van de Water discusses particular chemokines and cytokines that may impact autism etiology (13:30). 

The speaker details another study investigating the effect of offspring sex on immune profiles at birth (15:06). Researchers found that neonatal immune signatures differ by sex regardless of the neurodevelopmental outcome. However, control males had higher levels of certain immune markers than females, and autistic females with DD had higher levels than males with autism (17:20). The speaker asserts that such sex-specific differences in immune markers may contribute to the variability in autism phenotypes, highlighting the need for individualized treatments (16:15). 

Maternal autoantibody-related autism

Van de Water discusses the maternal autoantibody-related autism subtype (MAR) (around 20% of cases), where mothers have antibodies that are reactive against proteins in the developing brain (17:30). She explains that during fetal development, the mother’s antibodies cross the placenta to provide immune protection for the fetus. In the case of MAR, some antibodies can bind to pre-neuronal cells, which leads to different brain development. The speaker presents a MAR antibody test designed by her team (20:46). Initial findings revealed antibody patterns specific to autism in 20% of the sample and that mothers with these antibodies were 31 times more likely to have a child with autism (22:30). 

The presenter outlines a second study that validated the MAR antibody test with prenatal data (24:26). They also found that specific MAR antibody patterns were associated with phenotypic differences in autism. Van de Water therefore asserts that these patterns could not only serve as autism biomarkers but could also inform more specific and individualized interventions (27:40). She summarizes clinical findings from the previous studies and notes that as autism incidence increases, they see an increase in MAR as well (29:30). 

Translational animal models 

The speaker details translational animal models and why they are essential in preclinical trials. She explains how they used animal models to determine whether MAR autoantibodies are related to etiology or are just biomarkers (31:03). Animal studies generally include measures of behavior, brain scans, and cell cultures (32:15). Van de Water outlines an antibody study that found both mice and rats showed altered social behavior, self-grooming, and increased repetitive behaviors and produced the same antibodies found in humans with autism (34:15). These data, she continues, also exhibit differences in brain volume, with males and females displaying distinct patterns of brain development (37:30). 

Van de Water summarizes the main conclusions from the animal models. She highlights that gestational immune dysregulation may contribute to altered neurodevelopment and that antibodies localize to developing animals’ brains. The speaker emphasizes that we see enlarged brains in humans, mice, monkeys, and rats with gestational exposure to MAR autoantibodies and underscores the structural effects of MAR antibodies and the usefulness of animal models (38:40). She provides acknowledgments and thanks to collaborators before the Q & A (41:55). 

Vicki Kobliner, MS RDN, CD-N, discusses steps for optimizing preconception health through good nutrition and healthy environments. She discusses the US healthcare systems and statistics and asserts that, although the numbers can be scary, taking preventive action is often simple. The speaker outlines steps for personal health risk assessment and self-advocacy with family and healthcare providers. Kobliner discusses aspects of a nutritious diet and best practices for protein and produce consumption. She considers environmental exposure to chemicals and pesticides and provides alternatives for household products and foods. The presenter highlights the need to “keep it simple” and summarizes the healthy baby road map before the Q & A. 

In this webinar: 

1:10 – Introduction and disclaimer
2:16 – Healthy Baby Roadmap and presentation goals
4:04 – US health statistics
7:00 – Study – Folate deficiencies and risk of autism
8:08 – Study – Maternal diet and fetal microbiome
8:45 – Placental microbiome
9:22 – Study – Toxins and chemical and umbilical blood
10:45 – Study – Body burden of chemical exposure
11:35 – State of women’s health care in the US
13:22 – Assessment and action steps for a healthy baby road map
16:40 – Health history and clues to look for
20:00 – Medications and supplements
21:50 – Study – Acid-suppressive drugs and childhood asthma
22:37 – Gut health during pregnancy
23:59 – MTHFR gene (Methylenetetrahydrofolate reductase)
25:35 – Genotypes for CT variant of MTHFR
26:38 – Testing
27:30 – What matters for nutrition
28:10 – Proteins, produce, and fats
32:11 – Dirty Dozen and Clean Fifteen
32:58 – Water
33:34 – Priority preconception nutrients
34:26 – Omega 3s, Vitamin D, and Choline
38:07 – Inflammatory triggers
38:41 – Study – Maternal inflammation and chronic illness risk
39:29 – Pitch the parabens, toxic bedding, and kitchen storage
42:11 – Cleaning supplies and air filters
43:40 – Reducing stress
44:37 – Steps for advocacy
45:40 – How to keep it simple
46:23 – Q & A

Background and introduction

Kobliner defines the healthy baby road map (2:16) with reference to preconception planning for chronic illness risk reduction (1:10). She explains that 38% of children in the US have one or more chronic illnesses and that more than one in five kids have a mental, emotional, developmental, or behavioral problem (4:04). The presenter outlines studies investigating folate deficiencies and risk of autism (7:00), maternal diets and infant gut microbiota (8:08), and the levels of toxins and chemicals present in umbilical cord blood after birth (9:22). Kobliner discusses body burden and explains the different effects of chemical exposure on a mother (150 – 200 pounds) and a fetus (one pound) (10:45). The presenter details how women are treated within current US medical systems (11:35) and asserts that “women need facts so they can be empowered to make the choices that align with their pregnancy goals” (13:00). This knowledge, she continues, must be acquired via personal research (13:22) and discussions with family and health care providers (16:05).

Assessing and planning for risks

Health history information, like genetics, supplements, and family and personal medical history, is vital for understanding what risks to consider (16:40). The speaker discusses critical factors and clues in medical histories (17:50) and suggests investigating the sources and intake amount of essential vitamins and nutrients in one’s diet (20:00). Kobliner discusses birth control and vitamin B (21:40) and summarizes the first study that significantly associated acid-suppressive drugs and the risk of childhood asthma (21:50). The speaker demonstrates how changes to gut microbiota during pregnancy often lead to increased lactic acid and have been linked to an elevated risk of gestational diabetes, autoimmune diseases, and preterm pregnancy (22:37). 

The MTHFR gene (Methylenetetrahydrofolate reductase) is integral to the body’s ability to process folate, which is necessary for producing DNA and modifying proteins (basis of fetal development) (23:59). Kobliner details the difference between active folate and folic acid (synthetic), noting that children may inherit folate mutations (24:45). She outlines potential genotype mapping for the MTHFR CT variants and underscores that such mutations do not indicate disease but mean that the body needs support for normal folate processing (25:35). To investigate potential risks further, the speaker advises asking one’s doctor to test levels of various vitamins and thyroid panels and conduct a comprehensive digestive stool analysis before conception (26:38). 

What matters for nutrition

Kobliner dives into aspects of a quality diet (27:30) and discusses differences in protein sourced conventionally, organically, and pasture-fed (28:10), noting that truly grass-fed animals are the most nourishing. She considers pesticides in produce and stresses their correlation with developmental disabilities (30:06). The Environmental Working Group’s annual Dirty Dozen and Clean Fifteen is a good reference for understanding which produce is safe to purchase conventionally and which is not, based on known pesticide levels (32:11). Kobliner provides sources and ideas for buying affordable pasture-fed protein and clean produce. The speaker gives examples of inflammatory and anti-inflammatory fats and highlights the need to consume the correct type (not avoiding fats) and add lacto-fermented foods to one’s diet (31:18). She also suggests using a good water filter as water generally lacks minerals and contains chlorine, fluoride, pesticides, antibiotics, and BPA which seeps from plastic bottles as well (32:58). 

The speaker lists priority preconception nutrients (33:34), underscoring Omega 3s as “hands down the most important thing to do to support preconception and periconception health” (34:26). Kobliner explains that up to 60% of the US population is vitamin D deficient as the recommended levels, between 30 and 70, are insufficient to support optimal health and should be between 50 and 75 (35:30). Choline, she continues, is under-appreciated for its effect on neurological health and is often chronically deficient in women (37:06). The presenter reminds viewers that such deficiencies are generally an easy fix as long as one is aware of one’s risks and needs. 

Lifestyle and body burdens

Maternal inflammation has been linked to autism, asthma, obesity, tics/OCD, gestational and childhood diabetes (38:41). Kobliner notes that common inflammatory triggers include sugar, processed foods, and stress (38:07). To reduce bodily stress and burden, it is vital to account for toxins present in one’s environment and lifestyle (38:52). The speaker advises viewers to “pitch the parabens” as they can disrupt hormones and interfere with fertility and reproductive health and increase cancer risk (39:29). She lists bedding and furniture labels that indicate they are free of toxins associated with neurobehavior, reproductive health, and cancer (40:29). The speaker suggests using steel or glass containers, parchment paper, and silicone bags for kitchen storage, instead of plastics (and soft plastics) which are known endocrine disruptors with links to cancer, diabetes, and fertility issues (41:30). Household cleaning supplies are high in chemicals and toxins, but most can be replaced with a mix of vinegar, lemon juice, baking soda, and water (42:11). Kobliner suggests indoor plants and filters for cleaner air (42:55) and highlights reducing stress as a necessity that should be done however and whenever one can (43:40). 

Advocacy and moving forward

Kobliner lays out four steps to successful self-advocacy in conversations with family and healthcare providers (44:37): 

1. Do your research
2. Ask a lot of questions
3. Use a decision tree
   1. H: Healthiest option for me and my baby
   2. B: Best choice and possible alternatives
   3. R: Risk involved in my choice
4. Show evidence

The speaker gives examples for each step and reminds viewers to keep it simple. She suggests starting with the “low-hanging fruit” (easiest thing to accomplish) and asserts that progress will grow from there, one day at a time. Kobliner reviews the health baby road map before opening the Q & A. 

Dr. Beversdorf discusses prenatal stress and its implication in autism etiology. He provides a brief history of autism heredity, epigenetics, and the role of serotonin. The speaker details current understandings of the association between prenatal stress and autism. Beversdorf discusses recent research on the impact of SERT, prenatal stress, and other epigenetic factors. Clinical studies are provided alongside rodent models. The speaker highlights options for future research before the Q&A.

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In this webinar: 

2:00 – Overview of autism and epigenetics
4:30 – Previous data on prenatal stress
6:30 – Serotonin transporter (SERT)
8:00 – Study: Effect of prenatal stress and SERT on sociability
10:15 – Studies: Clinical support for rodent models
13:20 – Other contributing factors
15:00 – Study: Effect of DHA diet and stress
17:30 – Study: DHA before gestation
20:10 – DHA and anti-inflammatory and anti-oxidative pathways
22:10 – Study: Epigenetics mechanisms
27:10 – Study: Clinical epigenetics mechanisms
30:25 – Future directions
31:50 – Thanks and acknowledgements
34:15 – Q&A

Introduction

Beversdorf briefly reviews hereditary and epigenetic aspects of autism etiology and lists common environmental factors associated with autism (2:00). Prenatal stress, he continues, could be an identifying characteristic for those at higher risk of adverse environmental factors (3:54). The speaker outlines previous research on prenatal stress revealing that mothers of autistic children have significantly higher stress during pregnancy compared to controls. Another study found the prevalence of autistic births increased after a tropical storm or hurricane (4:40). Beversdorf outlines the serotonin transporter (SERT) and notes that increased blood serotonin and altered serotonin processing in the brain are associated with autism. He explains that variations in the serotonin transport proteins are associated with increased stress reactivity linked to depression (6:30). 

Recent studies

Beversdorf and his colleagues studied the impact of prenatal stress and maternal SERT variations on mouse offspring. The study used a sociability assay to test autism behavior (8:00). Results showed that mice with no stress or SERT genotypes preferred social interaction, as did those with only SERT or stress components. However, offspring with both SERT and maternal stress scored significantly lower on sociability (9:43). These findings were demonstrated in a clinical study where mothers with SERT had a history of prenatal stress (10:15). A converging line of clinical evidence based on a slightly larger study also assessed typical siblings of autistic kids and found no association to stress or SERT genes. These findings, Beversdorf asserts, show that these stressors (SERT and prenatal stress) are specific to autism (12:02). 

Diet is also a factor in overall health and neurodevelopment. Specifically, changes in diet affect the Omega 6: Omega 3 ratio, which is essential in stress reactivity and inflammation. Contemporary North American diets generally have an O6:O3 ratio of 15:1 – 17:1 – compared to the 2:1 – 3:1 ratios of hunter-gatherers (13:20). Beversdorf outlines a study that found that diets with large O6:O3 ratios impact offspring social habits more than maternal stress (15:00). Researchers then combined two extensive studies on diet, SERT, and stress to see if changes in diet could mitigate some effects. They found that offspring of mothers with both SERT and a regular diet had decreased sociability and that a DHA (Omega 3) diet slightly increased sociability but not significantly (16:20). The speaker details a rodent study that implemented a DHA diet before gestation to the end of pregnancy, and then to the offspring (17:30). They found that offspring of mothers who experienced stress and were on the DHA diet were more social than those who experienced stress but had no diet (19:00). Beversdorf asserts that although this is only a mouse model, it provides compelling evidence for the effectiveness of simple diet changes. 

The speaker details methods for a rodent model study on how epigenetic mechanisms affect gene expression. The study assessed DNA methylation, gene transcription, and microRNA expression (22:10). Researchers found significantly more methylated areas in mice with SERT and stress factors. They also revealed an overlap in genes where transcription was affected by stress or SERT (24:10). MicroRNA had the same pattern, and the presence of maternal SERT diminished gene expression in response to stress exposure. Beversdorf posits that these responses are adapted to help offset the effects of stress but that this cannot be accomplished with SERT (26:00). 

A clinical investigation of these findings showed distinct blood patterns between stress versus no stress groups. The presenter discusses the overlap of what’s happening in the blood of mothers of autistic children and what was found in rodent models. He concludes that genes are significantly affected by both stress and maternal genotype and wonders at how they are involved in both pathways (27:10). Beversdorf highlights that microRNA are heavily regulated by dopamine, which should be a focus of future research (29:29). Future directions for research should also include maternal antibodies and the intersection of stress and immunity. The presenter gives thanks and acknowledgments before the Q&A (34:15). 

Published: 06/06/2018

Dr. Beversdorf graduated from Indiana University and completed Neurology residency at Dartmouth. After his fellowship in Behavioral Neurology at University of Florida, he joined the Ohio State University faculty. He has published on memory disorders, autism, cognitive neuroscience, fMRI, neurpsychopharmacology and drug addiction. He joined the University of Missouri (Radiology, Neurology, Psychology and the Thompson Center) to focus on autism, with particular interest in pharmacofMRI as a potential treatment marker, and gene/stress interactions in autism.