How to make a smart & healthy baby for life : What we know & what we don’t

1. How to make a smart & healthy baby for life:What we know & what we don’t Michael C. Lu, MD, MPH Assistant Professor Department of Obstetrics & Gynecology David Geffen School of Medicine at UCLA Department of Community Health Sciences UCLA School of Public Health

2. Acknowledgment • Support for this work was provided by • National Institute of Health Women’s Reproductive Health Career Development Fellowship #HD01281-03 • Federal Maternal and Child Health Bureau for the National Center for Infant and Early Childhood Health Policy #5U93MC00099.

4. Programming • The process whereby a stimulus or insult, at a sensitive or ‘critical’ period, has lasting or lifelong impact on health or function. Barker DJP. Mothers, babies and health in later life. Edinburgh: Churchill Livingstone. 1998.

5. Prenatal Period is a “Sensitive Period” Health or Function Birth

6. Brain development • Immune development • Metabolic development

7. Brain Development

8. Eight Stages in Embryonic and Fetal Brain Development at a Cellular Level 1. Mitosis 2. Migration 3. Aggregation and 4. Differentiation 5. Synaptogenesis 6. Death 7. Rearrangement 8. Myelination

9. 1. Mitosis/Proliferation Begins at about 5 weeks after conception

10. 2. Migration Peaks at 9 and 12 weeks

11. 3. Differentiation

12. 4. Aggregation Completed before 22 weeks

13. Development of the cerebral cortex

14. 5. Synaptogenesis Begins about 22 weeks

15. 6. Neuron Death

16. Neuron Death Leads to Synapse Rearrangement Release and uptake of neurotrophic factors Neurons receiving insufficient neurotropic factor die Axonal processes complete for limited neurotrophic factor

17. 7. Synapse Rearrangement

18. 8. Myelination Begins in the 3rd trimester & lasts up to 30 years

19. Potential Neuroenhancers Fetal enrichment Oxygen Thyroid hormones Functional foods DHA Folate Iron Balanced energy/protein Potential Neurotoxins Infections & cytokines Stress & cortisol Nutritional toxins Tobacco Alcohol Drugs Environmental toxins Heavy metals Mercury Lead Endocrine disruptors PCB Dioxins Some pesticides Fetal Brain Development

20. Fetal Enrichment

22. Fetal Enrichment • Music • Can the fetus hear the music? • Can the fetus form memories? • Mames DK, Spencer CJ, Stepsis BW. Fetal learning: A prospective randomized controlled study. Ultrasound Obstet Gynecol 2002;431-8.

23. Fetal Enrichment • Music • Does music during pregnancy promote brain development? • Chen DG, Huang YF, Zhang JY Qi GP. Influence of prenatal music- and touch-enrichment on the IQ, motor development and behavior of infants. Chinese J Psychol 1994;8:148-51. • Manrique B, Contasi M, Avarado MA et al. Nurturing parents to stimulate their children from prenatal stage to three years of age. In Blum T, ed. Prenatal perception, learning and bonding. Berlin: Leonardo Publishers, 1993;153-86. • Lamont A, Dibben N. Motivic structure and the perception of similarity. Music Perception 2001;18:245-74. • Panthuraamphorn C, Dookchitra D, Sanmaneechai M. The effects of prenatal tactile and vestibular enrichment on human development. Int J Prenatal Pernatal Psychol Med 1998;10:181-8.

24. Thyroid Hormones

25. Maternal Hypothyroidism & Fetal Brain Development • Fetal thyroid active by 12 weeks • Before 12 weeks the mother is the sole source of thyroid hormones • Maternal hypothyroidism disrupts neuron migration • Lavado-Autric R, et al. Early maternal hypothyroxinemia alters histogenesis and cerebralCortex cytoarchitecture of the progeny. J Clin Invest 2003;111:1073-82. • Maternal hypothyroidism alters expression of reelin-dab signaling system • Alverez-Dolado M et al. Thyroid hormone regulates reelin and dab 1 expression during brain development. J Neurosci 1999;19:6979-93.

26. Maternal Hypothyroidism & Fetal Brain Development Lavado-Autric R, et al. Early maternal hypothyroxinemia alters histogenesis and cerebral Cortex cytoarchitecture of the progeny. J Clin Invest 2003;111:1073-82.

27. Maternal Hypothyroidism & Child Development At 2 years of age P = 0.02 106 98 Pop VJ et al. Maernal hypothyroxinaemia during early pregnancy and subsequent child development: a 3-year follow-up study. Clin Endocrinol 2003;59:282-8.

28. Maternal Hypothyroidism & Child Development At 2 years of age P = 0.005 102 92 Pop VJ et al. Maernal hypothyroxinaemia during early pregnancy and subsequent child development: a 3-year follow-up study. Clin Endocrinol 2003;59:282-8.

29. Maternal Hypothyroidism & Child IQ P < 0.08 19% 5% Haddow JE, Palomaki GE, Allan WC, et al. Maternal thyroid deficiency during pregnancy and Subsequent neuropsychological development of the child. N Engl J Med 1999;341:549-55.

30. Fetal Brain Foods

31. Brain Foods • Long-chain polyunsaturated fatty acids (LCPUFA) • Folate • Iron • Balanced protein/energy

32. DHA(docosahexanenoic acid) • Omega-3 long-chain polyunsaturated fatty acids (LCPUFA) • Fish oil • Flaxseed oil • Flax seeds • Herring • Mackerel • Purslane • Salmon • Sardines • Soybean oil • Soybeans • Walnut oil • Walnuts • Breastmilk • Integral component of cell membrane & influences synaptic signaling and neurotransmitter systems (e.g. dopamine in frontal cortex)

33. Omega 3 & Child Development At 4 years of age P = 0.049 106 102 Helland IB. 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;111:e39-e44

34. Infections & Cytokines

35. Chorioamnionitis& Cerebral Palsy P = 0.001 14% 4% Wu YW et al. Chorioamnionitis and cerebral palsy in term and near-term infants. JAMA 2003;290:2677-84

36. Chorioamnionitis & Cerebral Palsy • Meta-analysis • Preterm RR = 1.9 (95% CI, 1.4-2.5) • Term RR, 4.7 (95% CI, 1.3-16.2 ) • Wu YW et al. Chorioamnionitis as a risk factor for cerebral palsy: A meta-analysis.JAMA. 2000;284:1417-24. • Mechanisms • Inflammatory cytokines (e.g. TNF, IL) • Direct injuries • Interferes with placental exchange causing hypoxic-ischemic injuries to the brain

37. Prenatal respiratory infections & schizophrenia • Second-trimester respiratory infections is associated with a twofold increased risk of schizophrenia (RR = 2.3, 95% CI 1.05-4.35) • Brown AS. Maternal exposure to respiratory infections and adult schizophrenia spectrum disorders: A prospective birth cohort study. Schizophr Bull 2000;26:287095. • Maternal TNF-α at the time of birth was increased for offspring with schizophrenia (p = .04) • Buka SL. Maternal cytokine levels during pregnancy and adult psychosis. Brain, Behavior, and Immunity. 2001;15:411-20.

38. Stress & Cortisol

39. Does Maternal StressCross the Placenta? • Incomplete inactivation of maternal cortisol by placental 11β-hydroxysteroid dehydrogenase type 2 • Activation of corticotropin-releasing hormone (CRH) gene expression in the placenta

40. CRH: “The Coordinator of the Stress Response” Hobel CJ 2004

41. Prenatal Stress & Programming of the Brain • Prenatal stress (animal model) • Hippocampus • Site of learning & memory formation • Stress down-regulates glucocorticoid receptors • Loss of negative feedback; overactive HPA axis • Amygdala • Site of anxiety and fear • Stress up-regulates glucocorticoid receptors • Accentuated positive feedback; overactive HPA axis Welberg LAM, Seckl JR. Prenatal stress, glucocorticoids and the programming of the brain. J Neuroendocrinol 2001;13:113-28.

42. Welberg LAM, Seckl JR. Prenatal stress, glucocorticoids and the programming of the brain. J Neuroendocrinol 2001;13:113-28.

43. Prenatal Stress & Programming of the Brain • Prenatal steroid use (human studies) • No long-term neurodevelopmental effects • United States Antenatal Steroid Trial, Collaborative Group on Antenatal Steroid Therapy. Effects of antenatal dexamethasone administration in the infant: long-term follow-up. J Pediatr 1984;104:259-267. • MacArthur BA, Howie RN, Dezoete JA, Elkins J. School progress and cognitive development of 6-year-old children whose mothers were treated antenatally with betamethasone. Pediatrics 1982;70:99-105. • Smolders-de Haas H, Neuvel J, Schmand B, Treffers PE, Koppe JG, Hoeks J. Physical development and medical history of children who were treated antenatally with corticosteroids to prevent respiratory distress syndrome: a 10- to 12-year follow-up. Pediatrics 1990;86:65-70.

44. Nutritional Neurotoxins

45. Environmental Neurotoxins

46. Potential Environmental Neurotoxins • Heavy metals • Lead • Mercury • Arsenic • Cadmium • Manganese • Endocrine disruptors • Dioxin • Polycholorinated biphenyls (PCB) • Pesticides • Organochlorines (dicofol, pentachlorophenol, dinoseb, bromoxynil) Schetter T et al. Generations at risk: Reproductive health and the environment. Boston, MA: MIT Press. 2000

47. Lead • Sources • Lead paint (houses built before 1950) • Drinking water • Lead-glazed potteries • Causes neurodevelopmental delay in children • Crosses the placenta easily • Prenatal lead exposure associated with modest decrement in child IQ • Schetter T et al. Generations at risk: Reproductive health and the environment. Boston, MA: MIT Press. 2000.

48. Mercury Schetter T et al. Generations at risk: Reproductive health and the environment. Boston, MA: MIT Press. 2000.

49. Mercury • Methylmercury interferes with mitosis & migration of neurons • Two birth cohorts studied prospectively • Seychellois Islands: no effect • Myers GJ et al. Main neurodevelopmental study of Seychellois children following in utero exposure to methylmercury from a maternal fish diet: Outcome at six months. Neurotoxicology 1995;16:653-64. • Faroe Islands • cord blood levels associated with deficits in language, attention, and memory • Grandjean P et al. Cognitive deficit in 7-year-old children with prenatal exposure to methylmercury. Neurotoxicol Teratol. 1997 Nov-Dec;19(6):417-28. • 14-year follow-up showed delayed brainstem auditory evoked potential latencies • Murata K et al. Delayed brainstem auditory evoked potential latencies in 14-year-old children exposed to methylmercury.J Pediatr. 2004;144:177-83.

50. What You Need to Know about Mercuryin Fish & Shellfish • 2004 EPA/FDA Joint Advisory for • Women who might become pregnant • Women who are pregnant • Nursing mothers • Young children • Do not eat Shark, Swordfish, King Mackerel, or Tilefish • Eat up to 12 ounces (2 average meals) a week • Shrimp, canned light tuna, salmon, pollock, catfish are low in mercury • Albacore (“white”) tuna has more mercury than canned light tuna • Check local advisories about locally caught fish • www.epa.gov/ost/fish www.epa.gov/mercury