From Preconception to Infancy: Environmental and Nutritional Strategies to Lowering The Risk of Autism and other Chronic Conditions David Berger, MD, FAAP Tampa, FL Medical Director – Wholistic Pediatrics Assistant Professor – University of South Florida College of Nursing

What’s Going On? An Autism Epidemic? - Cumulative incidence to 5 years of age per 10,000 births rose consistently from 6.2 for 1990 births to 42.5 for 2001 Hertz-Picciotto et al. Epidemiology. 2009 Jan;20(1):84-90. The CDC now estimates that an average of 1 in 88 children in the U.S have a diagnosis of Autism (110 per 10000) Prevalence of Autism Spectrum Disorders — Autism and Developmental Disabilities Monitoring Network, 14 Sites, United States, 2008. Surveillance Summaries, March 30, 2012 / 61(SS03);1-19

Questions that have been raised Does toxic exposures, abnormal metabolism and insufficient nutrition during fetal development and infancy contribute to the development of Autism and other chronic medical conditions? If so, what measures can be taken to try and reduce this risk? How can these treatments and recommendations be studied to drive change on a national and international level?

Can Prevalence of ASD in Future Siblings Be Reduced? Many families of ASD children have asked me through the years if there are things that they could do even prior to conception, and/or during pregnancy, to decrease the likelihood of having another child develop an ASD. Few formal studies have looked into this issue, and with so many different variables in play it is challenging to perform good research on this. The research must be done correctly in order to effect real change in the lives of many.

Is This Just About ASD? Some of the recommendations discussed today are not specific to and may have never been studied in relation to ASD. However, strategies intended to decrease toxic expsosure and improve nutritional status ,which can reduce antibiotic exposure, candida development, and the prevalence of allergies, asthma, and autoimmune diseases likely are relevant to lowering the prevalence of autism and increase cognitive development.

How Successful Can These Strategies Be? Since I began implementing these strategies 14 years ago with families, to the best of my knowledge , not a single child born into my medical practice has gone on to develop autism. None have developed diabetes, just one has developed asthma, and only one family (of 3 kids) has developed recurring ear infections.   I have not had any subsequent siblings of children with autism go on to develop the disorder, even though the incidence in siblings has otherwise been documented to be high (close to 1 in 5)1 1) Ozonoff S, Young GS, Carter A, Messinger D, Yirmiya N, Zwaigenbaum L, et al. Recurrence risk for autism spectrum disorders: a Baby Siblings Research Consortium study. Pediatrics. 2011 Sep;128(3):e488-95.

How can ASD incidence rise so fast? Some people feel this is due to more lax criteria or greater awareness of this condition. Genetic variation can not change this fast. How much does environmental exposure and lower quality nutrition play a role?

It Can’t Just Be the Genes Many documented cases of identical twins with only one child affected, or one much more severely affected. I have seen identical twins where: The twin who was sick and did not receive vaccines at 2 and 4 months did not develop autism, but the one who was vaccinated did develop autism. A twin who was exposed to many antibiotics for ear infections developed autism, but the one not exposed did not develop autism (both vaccinated).

Genetic Factors Although there are genetic abnormalities that have been associated with ASD, no genes have been identified that are present in even close to a majority of children with ASD (and many of these gene tests are not commercially available).

(Image by S. Jill James used with permission)

An Example of how Genes can effect nutritional status MTHFR (methylenetetrahydrofolate reductase), the enzyme that converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate (a substrate in the homocysteine-to-methionine methylation reaction.) In simplest terms, this enzyme is needed to help activate folic acid. This is essential for the body to efficiently carry out a process called methylation. Abnormalities is the gene that codes for MTHFR have been associated with fetal miscarriage7,8 and cardiovascular disease.9,10 7. Li XM, et al. [Study on the relationship of MTHFR polymorphisms with unexplained recurrent spontaneous abortion]. [Article in Chinese]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2004 Feb;21(1):39-42. 8. Rodríguez-Guillén M del R, et al. Maternal MTHFR polymorphisms and risk of spontaneous abortion. Salud Publica Mex. 2009 Jan- Feb;51(1):19-25. 9. Klerk M, et al. MTHFR 677C→T polymorphism and risk of coronary heart disease: a meta-analysis. JAMA. 2002 Oct;288(16):2023-31. 10. Cortese C, Motti C. MTHFR gene polymorphism, homocysteine and cardiovascular disease. Public Health Nutr. 2001 Apr;4(2B):493-7.

Why Is It Important To Support the Methylation/Transulferation enzymes? The biochemical abnormalities that can occur due to atypical MTHFR genes may be at least partially overcome with the use of methylcobalamin (MB-12) and activated folate (folinic acid or L-methylfolate).11 Supporting the methylation/transsulfuration pathway with proper B vitamin supplementation may be particularly important for a mother of a child with ASD as parents of children with autism have been found to have similar abnormal biochemical markers of the methylation pathway as their children.12 11. James SJ, et al. Efficacy of methylcobalamin and folinic acid treatment on glutathione redox status in children with autism. Am J Clin Nutr. 2009 Jan;89(1):425-30. 12. James SJ, et al. Abnormal transmethylation/ transsulfuration metabolism and DNA hypomethylation among parents of children with autism. J Autism Dev Disord. 2008 Nov;38(10):1966-75.

Why Is It Important To Support the Methylation/Transulferation enzymes? A study found that mothers of children with autism were less likely than those of typically developing children to report having taken prenatal vitamins during the 3 months before pregnancy or the first month of pregnancy.13 Children were 4.5 times more likely to be diagnosed with autism if their mothers had the homozygous MTHFR C677T single nucleotide polymorphism (SNP) (SNPs are DNA sequence variations) .13 Because of the greater risk for autism when mothers did not report taking prenatal vitamins, it was suggested that the B vitamin component of prenatal vitamins may protect against fetal brain development deficits. 13. Schmidt RJ, et al. Prenatal vitamins, one-carbon metabolism gene variants, and risk for autism. Epidemiology. 2011 Jul;22(4):476-85.

Epigenetics and the cellular environment An epigenetic trait is a stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence.16 I expect that in coming years, research will reveal specific alterations in the cellular environment that lead to these epigenetic changes. Ultimately, epigenetics may be the map that explains how the body and it’s environment interact in a manner that prevents or causes disease. While this is being figured out, we already know enough to minimize toxic exposure and enhance maternal nutrition to give cells a better environment in which to develop and reproduce. 16. Berger SL, et al. An operational definition of epigenetics. Genes Dev. 2009 Apr;23(7):781-3.

Preconception/Prenatal Vitamins Although vitamins for pregnancy are referred to as “prenatal,” for an optimal pregnancy I proposed the use of “preconception” vitamins Most women wait until they find out they are pregnant to start taking vitamins, after critical cell divisions and differentiations have taken place There are some nutritional needs that are different once a woman gets pregnant, but by promoting the idea of a preconception vitamin, it drives home the need to be nutritionally optimized BEFORE getting pregnant.

Multivitamins - Concerns A recently identified concern about multivitamins, in general, however, is the possibility that chromium, an essential mineral, could be present in its carcinogenic chromium VI (hexavalent chromium) form.15 Unfortunately, most manufacturers do not test for the different forms of chromium to make sure that the hexavalent form is not present. We should demand of the companies that we suggest to our patients that they do purity testing of all raw ingredients that are used in their products. 15. Martone N, et al. Determination of chromium species and mass balance in food supplements using speciated isotope dilution mass spectrometry. Pittsburgh, PA: Department of Environmental Science and Management, Duquesne University, unpublished study.

A word about Calcium supplements If a woman is avoiding dairy, this may be difficult to accomplish though the diet, and calcium supplementation may be needed. As lead (Pb) has been found to be present in some calcium supplements86, it is essential to use supplements from manufacturers who are testing for lead and rejecting calcium raw materials that have increased amounts of lead. (This means verifying that the manufacturer is screening for lead in the raw material or in each batch produced.) 86. Ross EA, et al.Lead content of calcium supplements.JAMA. 2000 Sep 20;284(11):1425-9.

Lower birth weight indicates higher risk of autistic traits in discordant twin pairs. METHOD: They studied a population-based sample of 3715 same-sex twin pairs ASD was assessed using a structured parent interview for screening of ASD and related developmental disorders.Birth weight was obtained from medical birth records maintained by the Swedish Medical Birth Registry. RESULTS: Twins lower in birth weight in ASD-discordant twin pairs (n=34) were more than three times more likely to meet criteria for ASD than heavier twins. Analyses of birth weight as a continuous risk factor showed a 13% reduction in risk of ASD for every 100 g increase in birth weight (n=78). for every 100 g increase in birth weight, a 2% decrease in severity of ASD CONCLUSIONS: The data were consistent with the hypothesis that low birth weight confers risk to ASD. Thus, although genetic effects are of major importance, a non-genetic influence associated with birth weight may contribute to the development of ASD. Psychol Med. Losh M et al. 2012 May;42(5):1091-102. Epub 2011 Dec 2.

Folate and Low Birth Weight Periconception folic acid supplementation, fetal growth and the risks of low birth weight and preterm birth: the Generation R Study. They examined whether periconception folic acid supplementation affects fetal growth and the risks of low birth weight, small for gestational age (SGA) and preterm birth, in the Generation R Study in Rotterdam, the Netherlands…… Data on 6353 pregnancies were available. Periconception folic acid supplementation was positively associated with fetal growth. In conclusion, periconception folic acid supplementation is associated with increased fetal growth resulting in higher placental and birth weight, and decreased risks of low birth weight and SGA. Timmerman et al . Br J Nutr. 2009 Sep;102(5):777-85.

Folate Folate is known to be essential for fetal brain development. Folate deficiency has been associated with spina bifida and other neural tube defects. However, because women who have the abnormal MTHFR gene sequence may not be able to efficiently complete the conversion of folic acid to methylfolate, they may have issues if taking only folic acid. In such cases, I recommend that women take folic acid as L-methylfolate or folinic acid or possibly a combination of both. These two forms bypass the faulty MTHFR enzyme and provide the fetus with activated folate.

Iron and Low Birth Weight Iron supplementation during pregnancy, anemia, and birth weight: a randomized controlled trial. They tested the hypothesis that administration of a daily iron supplement from enrollment to 28 wk of gestation to initially iron-replete, nonanemic pregnant women would reduce the prevalence of anemia at 28 wk and increase birth weight. Compared with placebo, iron supplementation from enrollment to 28 wk of gestation did not significantly affect the overall prevalence of anemia or the incidence of preterm births but led to a significantly higher mean birth weight a significantly lower incidence of low-birth-weight infants (4% compared with 17%; P = 0.003), and a significantly lower incidence of preterm low-birth-weight infants (3% compared with 10%; P = 0.017). Cogswell ME et al. Am J Clin Nutr 2003;78:773–81.

Iron Iron is an essential mineral, not only for the production of hemoglobin; it also may affect a person’s cognitive function. Iron deficiency without anemia has been associated with autism,41 attention-deficit/hyperactivity disorder (ADHD),42 and lower math scores in children.43 Correcting non-anemic iron deficiency has been shown to correct verbal learning and memory and ADHD.44 41. Latif A, et al. Iron deficiency in autism and Asperger syndrome. Autism. 2002 Mar;6(1):103-14. 42. Konofal E, et al. Iron deficiency in children with attention-deficit/ hyperactivity disorder. Arch Pediatr Adolesc Med. 2004 Dec;158(12):1113-5. 43. Halterma JS, et al. Iron deficiency and cognitive achievement among school-aged children and adolescents in the United States. Pediatrics. 2001 Jun;107(6):1381-6. 44. Bruner AB, et al. Randomised study of cognitive effects of iron supplementation in non-anaemic iron-deficient adolescent girls. Lancet. 1996 Oct;348(9033):992-6.

Prenatal Zinc Levels A positive association between maternal serum zinc concentration and birth weight. For all subjects maternal serum zinc was significantly related to birth weight after various independent determinants of birth weight were controlled for. ….maternal serum zinc concentration measured early in pregnancy could be used to identify those women at higher risk of giving birth to a low-birth-weight infant. Neggers YA et al. Am J Clin Nutr April 1990 vol. 51 no. 4 678-684. Relationship between Low Birth Weight Neonate and Maternal Serum Zinc Concentration. Maternal zinc concentration was shown to affect birth weight and prematurity. Khadem et al. Iran Red Crescent Med J. 2012 Apr;14(4):240-4. Epub 2012 Apr 1.

Vitamin D Vitamin D has long been established to be essential for bone health, and emerging evidence is showing its importance for proper immune development. Children born to women who are low in vitamin D have an increased incidence of allergies and severity of asthma36 and a greater incidence of type I diabetes.37 The Vitamin D Council has hypothesized that vitamin D deficiency may be contributing to the increased incidence of autism.38 36. Brehm JM, et al. Serum vitamin D levels and markers of severity of childhood asthma in Costa Rica. Am J Respir Crit Care Med. 2009 May;179(9):765-71. 37. Sorensen IM, et al. Maternal serum levels of 25-hydroxy-vitamin D during pregnancy and risk of type 1 diabetes in the offspring. Diabetes. 2012 Jan;61(1):175-8. 38. Vitamin D Council. Autism: introduction. Revised 2011 May 17. Available online at: http://www.vitamindcouncil.org/health-conditions/

The Role of Food Reactions Circulating maternally derived antibodies may have a negative impact on the future health of children. The intake of foods that a woman is allergic to during pregnancy may increase the risk of allergy in the offspring. Sausenthaler S, et al. Am J Clin Nutr. 2007 Feb;85(2):530-7. High levels of anti-gliadin IgG in the maternal circulation are associated with an elevated risk for the development of a nonaffective psychosis in offspring. Karlsson H et al. Am J Psychiatry. 2012 Jun 1;169(6):625-32.

Hypothyroidism Hypothyroidism is a known cause of developmental delay in children,33 and thyroid hormone is also a growth factor for fetuses and young children.34 The prevalence of hypothyroidism in pregnant women has been estimated at 5%, and thyroid autoantibodies can be seen in 12% of pregnant women.35 My personal observation is that the actual percentages are higher. 33. Sutandar M, et al. Hypothyroidism in pregnancy. J Obstet Gynaecol Can. 2007;29(4):354-6. 34. Fisher DA, et al. The thyroid hormone effects on growth and development may be mediated by growth factors. Endocrinol Exp. 1982 Nov;16(3-4):259-71. 35. Nambiar V, et al. Prevalence and impact of thyroid disorders on maternal outcome in Asian- Indian pregnant women. J Thyroid Res. 2011 Jul;2011:article ID 429097.

Omega3 fatty acids - Benefits Children of mothers who took 3.3 grams of combined EPA and DHA during pregnancy demonstrated greater hand-eye coordination,49 and children of mothers who took about 2 grams of combined EPA/DHA (as 2 teaspoons of cod liver oil) had increased mental processing.50 Fish oil supplementation during pregnancy has also been associated with lower potential for allergies and possibly other immune-mediated diseases.51,52 49. Dunstan JA, et al. Cognitive assessment of children at age 2(1/2) years after maternal fish oil supplementation in pregnancy: a randomised controlled trial. Arch Dis Child Fetal Neonatal Ed. 2008 Jan;93(1):F45-50. 50. Helland IB, et al. Maternal supplementation with very-long-chain n-3 fatty acids during pregnancy and lactation augments children’s IQ at 4 years of age. Pediatrics. 2003 Jan;111(1):e39-e44. 51. Dunstan JA, Prescott SL. Does fish oil supplementation in pregnancy reduce the risk of allergic disease in infants? Curr Opin Allergy Clin Immunol. 2005 Jun;5(3):215-21. 52. Dunstan JA, et al. Fish oil supplementation in pregnancy modifies neonatal allergen-specific immune responses and clinical outcomes in infants at high risk of atopy: a randomized, controlled trial. J Allergy Clin Immunol. 2003 Dec;112(6):1178-84.

Toxins For consideration: for a developing fetus, what is actually circulating in the blood of the mother at time of gestation and lactation more important than chronic exposure and tissue levels of the mother. Testing of toxins will be covered by Skip Kingston.

Continuing Optimal Health: The Birth Process

Birth: C-sections An increased incidence of autism has been identified in children born by both emergency as well as elective Cesarean section.53 all efforts should be made to avoid C-sections whenever possible. 53. Glasson EJ, et al. Perinatal factors and the development of autism: a population study. Arch Gen Psychiatry. 2004 Jun;61(6):618-27.

Reducing C-sections The American Congress of Obstetricians and Gynecologists (ACOG) recently declared, “Attempting a vaginal birth after cesarean (VBAC) is a safe and appropriate choice for most women who have had a prior cesarean delivery, including for some women who have had two previous cesareans.”54 There are techniques such as Hypnobirthing and Perineal stretching/massage that can be done during 3rd trimester to help promote a vaginal birth. 54. American College of Obstetricians and Gynecologists. ACOG practice bulletin #115: vaginal birth after previous Cesarean delivery. Obstet Gynecol. 2010 Aug;116(2 Pt 1):450-63.

Birth Induction vs. Delivering after the Due Date Induction of pregnancy itself may have a negative role on a child’s development. In one study, there was almost a 2-fold increase in ADHD diagnosis in children born to mothers who were induced.55 I instruct parents that a baby is not considered past due until after 42 weeks. There is no reason to artificially rush the delivery. If there is any concern, an ultrasound can be performed to ensure that the baby is healthy and not under stress. 55. Kurth L, Haussmann R. Perinatal pitocin as an early ADHD biomarker: neurodevelopmental risk? J Atten Disord. 2011 Jul;15(5):423-31.

Prevention strategies in the infant

Discharge From Hospital After Birth After birth, I advocate for discharging the mother and baby as soon as possible. Hospitals are known to harbor higher levels of certain infections (such as candida, methicillin-resistant Staphylococcus aureus [MRSA], and clostridia) than most of the outside world, including people’s homes.

Breastfeeding: The Benefits The importance of breastfeeding is now universally accepted. Babies who are breastfed have been suggested to have higher IQs and cognitive development60,61and a lower incidence of Type I diabetes,62 allergies (when compared with cow’s milk and soy formulas),63 asthma,64 and ear infections.65 60. Kramer MS, et al. Breastfeeding and child cognitive development: new evidence from a large randomized trial. Arch Gen Psychiatry. 2008 May; 65(5):578-84. 61. Isaacs EB, et al. Impact of breast milk on intelligence quotient, brain size, and white matter development. Pediatr Res. 2010 Apr;67(4):357-62. 62. Majeed AA, et al. Risk factors for type 1 diabetes mellitus among children and adolescents in Basrah. Oman Med J. 2011 May;26(3):189-95. 63. Gruskay FL. Comparison of breast, cow, and soy feedings in the prevention of onset of allergic disease: a 15-year prospective study. Clin Pediatr (Phila). 1982 Aug;21(8):486-91. 64. Oddy WH, et al. Association between breast feeding and asthma in 6 year old children: findings of a prospective birth cohort study. BMJ. 1999 Sep;319(7213):815-9. 65. Duncan B, et al. Exclusive breast-feeding for at least 4 months protects against otitis media. Pediatrics. 1993 May;91(5):867-72.

Breastfeeding: The Benefits (cont) The American Academy of Pediatrics (AAP) recommends that babies be exclusively breastfed for 6 months, continue breastfeeding for at least the first year of life, and longer if desired by the mother and baby.59 Babies who receive cow’s milk-based formula may have increased intestinal permeability (leaky gut) compared with babies who receive breast milk,66 especially if they were born prematurely.67 59. American Academy of Pediatrics. Breastfeeding and the use of human milk. Pediatrics. 2005 Feb;115(2):496-506. 66. Weaver LT, et al. Milk feeding and changes in intestinal permeability and morphology in the newborn. J Pediatr Gastroenterol Nutr. 1987 May-Jun;6(3):351-8. 67. Taylor SN, et al. Intestinal permeability in preterm infants by feeding type: mother’s milk versus formula. Breastfeed Med. 2009 Mar;4(1):11-5.

Breastfeeding: The Benefits (continued) Babies who are breastfed are provided with antibodies through the milk to fight off infection within hours of a mother being exposed to a virus or bacteria. This can protect the baby against a host of different pathogens that could otherwise lead to the baby being exposed to antibiotics. Another advantage of breastfeeding is that a mother who continues to optimize her nutrition (as already discussed with regard to pregnancy) provides the nutrients to her baby through the breast milk.

Introduction of solid foods Available information suggests that early introduction can increase the risk of food allergy and that avoidance of solids can prevent the development of specific food allergies69. 69. Fiocchi A, et al. Food allergy and the introduction of solid foods to infants: a consensus document. Adverse Reactions to Foods Committee, American College of Allergy, Asthma and Immunology. Ann Allergy Asthma Immunol. 2006 Jul;97(1):10-20.

Avoiding Antiboitics Even if serving just as a consultant, we must give parents the information they need to make wise health choices, especially since they have to work with their local doctor. I find that with breast feeding and optimized nutrition, infants and toddlers rarely get sick. On The First Signs of Illness: protocols for use of vitamin A, vitamin C, zinc and ecchinacea/larix If truly needing antibiotics, need to make sure well covered with probiotics

Avoiding Antibiotics Ear infections / sinus infections ¾ clear without antibiotics…..“Watchful waiting” is acceptable per AAP Bronchitis In pediatrics – by definition a viral infection. No role for antibiotics . Pharyngitis 70% viral. Most not Strep Skin infections Can use topical antibiotics most of time, especially if small or not extensive face involvement

Vaccines A lecture unto itself. For further consideration, see the video or slide presentation entitles "The Biological Plausibility of a Relationship Between Vaccines and Autism", which I first presented to the Florida Governor’s Autism Task Force, September 2008. Found on the “Lectures” section at www.wholisticpeds.com Consider alternative vaccine schedules, including delay or avoidance for children who may be high risk. Those with significant personal family history of: Neurological disorders Developmental disorders Psychiatric disorders Mitochondrial disorders Atopic conditions Hyper-inflammatory conditions Autoimmune disorders

In Practice: Advance My Baby Each chapter covers developmental areas of gross motor, fine motor, cognitive, language, self-care, and emotional social skills — the building blocks to academic achievement, athletic prowess and social and emotional balance.

Red boxes provide activities and exercises to do with the child to promote the various developmental skills for optimal overall growth and development. The manual is structured in various monthly development stages so that the parent learns as they go. This information is powerful. It is everything a parent needs to have the knowledge and skills to make the most of their time with their child. Hundreds of photos visually stimulate what a parent can do to help your toddler reach their full potential. Blue boxes share pertinent information of key points that helps parents grasp core developmental concepts.

Where do we go from here? Agree on defined tests and treatment protocols Set up clinics in different environmental and demographic regions to collect data. Train other clinicians on the protocols

Where do we go from here? Set up a usable, searchable database using new technologies. Be able to compare prevalence of disease against national norms, and those in database not ding intervention Be able to study the “breakthrough” kids to see if any areas of deficiency or toxicity were not addressed.