How to make a smart healthy baby

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

Acknowledgment o Support for this work was provided by n National Institute of Health Women’s Reproductive Health Career Development Fellowship #HD 01281 -03 n Federal Maternal and Child Health Bureau for the National Center for Infant and Early Childhood Health Policy #5 U 93 MC 00099.

Programming o 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.

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

o o o Brain development Immune development Metabolic development

Brain Development

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

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

2. Migration Peaks at 9 and 12 weeks

3. Differentiation

4. Aggregation Completed before 22 weeks

Development of the cerebral cortex

5. Synaptogenesis Begins about 22 weeks

6. Neuron Death

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

7. Synapse Rearrangement

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

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

Fetal Enrichment

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

Fetal Enrichment o Music n Does music during pregnancy promote brain development? o o Chen DG, Huang YF, Zhang JY Qi GP. Influence of prenatal music- and touchenrichment 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.

Thyroid Hormones

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

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.

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.

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.

Maternal Hypothyroidism & Child IQ 19% P < 0. 08 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.

Fetal Brain Foods

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

DHA (docosahexanenoic acid) o Omega-3 long-chain polyunsaturated fatty acids (LCPUFA) n n n n o 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)

Omega 3 & Child Development At 4 years of age 106 P = 0. 049 102 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: e 39 -e 44

Infections & Cytokines

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

Chorioamnionitis & Cerebral Palsy o Meta-analysis n n Preterm RR = 1. 9 (95% CI, 1. 4 -2. 5) Term RR, 4. 7 (95% CI, 1. 3 -16. 2 ) o Wu YW et al. Chorioamnionitis as a risk factor for cerebral palsy: A meta-analysis. JAMA. 2000; 284: 1417 -24. o Mechanisms n Inflammatory cytokines (e. g. TNF, IL) o o Direct injuries Interferes with placental exchange causing hypoxic-ischemic injuries to the brain

Prenatal respiratory infections & schizophrenia o Second-trimester respiratory infections is associated with a twofold increased risk of schizophrenia (RR = 2. 3, 95% CI 1. 05 -4. 35) n o 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) n Buka SL. Maternal cytokine levels during pregnancy and adult psychosis. Brain, Behavior, and Immunity. 2001; 15: 411 -20.

Stress & Cortisol

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

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

Prenatal Stress & Programming of the Brain o Prenatal stress (animal model) n Hippocampus o Site of learning & memory formation o Stress down-regulates glucocorticoid receptors o Loss of negative feedback; overactive HPA axis n Amygdala o Site of anxiety and fear o Stress up-regulates glucocorticoid receptors o 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.

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

Prenatal Stress & Programming of the Brain o Prenatal steroid use (human studies) n No long-term neurodevelopmental effects o o o United States Antenatal Steroid Trial, Collaborative Group on Antenatal Steroid Therapy. Effects of antenatal dexamethasone administration in the infant: longterm follow-up. J Pediatr 1984; 104: 259 -267. Mac. Arthur 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.

Nutritional Neurotoxins

Environmental Neurotoxins

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

Lead o Sources n n n o o o 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 n Schetter T et al. Generations at risk: Reproductive health and the environment. Boston, MA: MIT Press. 2000.

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

Mercury o Methylmercury interferes with mitosis & migration of neurons o Two birth cohorts studied prospectively n Seychellois Islands: no effect o n 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 o cord blood levels associated with deficits in language, attention, and memory n o 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 n Murata K et al. Delayed brainstem auditory evoked potential latencies in 14 year-old children exposed to methylmercury. J Pediatr. 2004; 144: 177 -83.

What You Need to Know about Mercury in Fish & Shellfish o 2004 EPA/FDA Joint Advisory for n n o o 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 n n o 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 n www. epa. gov/ost/fish www. epa. gov/mercury

Summary: Fetal Brain Development o o o “Should I play Mozart to my baby? ” “Should I have my thyroid checked? ” “Are there foods I can eat to make my baby smarter? ” “Should I get a flu shot? ” “Can you check my cervix? “Can you strip my membranes? ” “Can you induce my labor? ” “Does my stress level affect my baby? ” “Will the steroid shot affect my baby? ” “Will the lead paint in my old house hurt my baby? ” “What fish can I eat? What should I avoid? ” “Is there prenatal programming of school readiness? ”

Immune Development

Critical Windows of Immune Development o 8 -10 wks n o 10 -16 wks n o Colonization of bone marrow & thymus First year n o Migration of stem cells & expansion of progenitor cells 16 wks- birth n o Initiation of hematopoiesis Maturation to immune competence 1 -18 years n Establishment of immune memory Dietert RR et al. Workshop to identify critical windows of exposure for children’s health: Immune and respiratory systems work group summary. Environ Health Perspect 2000; 108: 483 -490 S

Fetal Immune Development o Potential Immunoenhancers n o o o n n Selenium Iron Copper Zinc Calcium Folate o o o n o o Vitamin A Vitamin E Vitamin C Arginine o o n Deficiencies Tobacco Alcohol Drugs Environmental o Amnio acids o Nutritional o Probiotics Antioxidants o n Potential Immunotoxins Micronutrients o n o Polycyclic halogenated hydrocarbons Polycyclic aromatic hydrocarbons Pesticides Fungicides Heavy metals Hormonal substances Therapeutic agents Mycotoxins Irradiation Infections

Functional Foods

Fetal Immune Development o Functional Foods n Micronutrients o o o n n Probiotics Antioxidants o o o n Selenium Iron Copper Zinc Calcium Folate Vitamin A Vitamin E Vitamin C Amnio acids o Arginine Dietert RR et al. Workshop to identify critical windows of exposure for children’s health: Immune and respiratory systems work group summary. Environ Health Perspect 2000; 108: 483 -490 S

Functional Foods & Fetal Immune Development o No long-term follow-up studies on immune functions n Zinc supplementation – 7 trials o n Iron supplementation – 20 trials o n Mahomed K. Zinc supplementation in pregnancy. Cochrane Database Syst Rev. 2000; (2): CD 000230. Mahomed K. Iron and folate supplementation in pregnancy. Cochrane Database Syst Rev. 2000; (2): CD 001135. Vitamin A supplementation – 5 trials o Van DE. et al. Vitamin A supplementation during pregnancy. Cochrane Database Syst Rev. 2002; (4): CD 001996

Prenatal Undernutrition & Immune Development 0. 70 P = 0. 023 0. 32 Mc. Dade TW et al. Prenatal undernutrition, postnatal environments, and antibody response to Vaccination in adolescence. Am J Clin Nutr 2001; 74: 543 -8.

Nutritional Immunotoxicants

Environmental Immunotoxicants

Environmental Immunotoxicants o Polycyclic halogenated hydrocarbons n o Polycyclic aromatic hydrocarbons n o Acyclovir, buslfan, cyclophosphamide, cyclosporin A Mycotoxins n o Estrogen/DES, testosterone, cortisone Therapeutic n o Methyl mercury, lead, cadmium Hormonal n o hexachlorbenzene Heavy metals n o Hexachlorocyclohexane, chlordane, diainon, DDT, carbofuran Fungicides n o B[a]p; methylcholanthrene, 7, 20 -dimethyl-benz[a]anthracene Pesticides n o TCDD, PCBs, PBBs T-2 toxin Irradiation n X-ray Holladay SD. Development of the murine and human immune system: Differential effects of Immunotoxicants depend on time of exposure. Environ Health Perspect 2000; 108: 463 -73.

Dioxins o o o Endocrine disruptor Developmental neurotoxicant Developmental immunotoxicant n o o Disrupt thymocyte maturation & T-lymphyocyte functions Bioaccumulate in animal fat Long half life: 7 years Crosses the placenta easily Prevention n n Low animal fat diet for children & young women Quit feeding animal fat to animals

Inflammation o Is there a fetal origin to childhood or adult chronic diseases mediated by inflammation?

Inflammation TH-1 IFN-γ and IL-2 Thymus Eliminates intracellular Pathogens TH-0 IL-4, IL-5, and IL-10 Activates B cells Involved in atopy & asthma TH-2

Summary: Fetal Immune Development o o o Should I take zinc to boost my baby’s immune system? Are there things in the environment that could weaken my baby’s immune system? Do inflammatory-mediated chronic adult diseases have a fetal origin?

Metabolic Development

Is there prenatal programming of obesity?

Maternal Diabetes

Maternal Diabetes & Obesity in the Offspring Age at assessment Population Exposure Result/Strength of Association Germany GDM, IDDM 5 -9 yrs 20. 0% of offspring of GDM, 25. 8% of offspring of IDDM had BMI ≥ 95 th percentile Chicago, IL IDDM, NIDDM 14 -17 yrs ODM had BMI of 24. 6 ± 5. 8 kg/m 2, controls had BMI of 20. 9 ± 3. 4 kg/m 2 Pima Indians, AZ NIDDM mean 13 yrs ODM BMI 2. 6 kg/m 2 greater (95% CI: 0. 9 -4. 3), P=. 003 compared to their siblings of nondiabetic pregnancies United States GDM 9 -14 yrs OR=1. 4 (95% CI: 1. 2 -1. 6)† Pima Indians, AZ NIDDM, GDM 15 -19 yrs OR=6. 85 (95% CI: 2. 61 -18. 19)‡ Chicago, IL GDM 8 yrs More than 50% ODM had weight >90 th percentile Lu et al, manuscript in preparation

Maternal Diabetes & Childhood Obesity Maternal Diabetes & Intrauterine Hyperglycemia Intrauterine Hyperinsulinemia (Fetal Pancreatic β Cells) Preadipocyte Differentiation Adipocyte Hyperplasia Prenatal& Postnatal Hyperleptinemia Programmed Insulin Resistance Postnatal Hyperinsulinemia Hypothalamic Leptin Resistance Pancreatic βCell Leptin Resistance Hyperphagia Hyperinsulinism Adipogenesis Lu et al, manuscript in preparation

Maternal Malnutrition

Maternal Malnutrition & Obesity in the Offspring Aut hor Rave lli Stan ner Y ea r Intrauteri ne Exposure Outcome in Offspring & Strength of Association 19 76 Maternal undernutrit ion during World War II Dutch Famine in western Netherland s At age 19 years, significantly higher obesity rates (p<0. 0005, OR=1. 94) after exposure during first 2 trimesters of pregnancy; significantly lower obesity rates (p<0. 005, OR=0. 62) after exposure during last trimester of pregnancy and first 3 -5 months of life 19 99 Maternal undernutrit ion during World War II Dutch Famine in western Netherland s At age 50 years, only women exposed to famine during early gestation had significantly higher BMI; adjusted difference was +8. 8% (2%-16%) 19 97 Maternal undernutrit ion during Siege of Leningrad At age 53 years, no difference in BMI from Lu nonexposed group born in the province of Leningrad but outside siege limits et al, manuscript in preparation

Maternal Malnutrition & Obesity in the Offspring

Maternal Smoking

Maternal Smoking & Obesity in the Offspring Author Year Intrauterine Exposure Outcome in Offspring Strength of Association Bergmann 2003 Maternal smoking during pregnancy Increased risk of overweight/obesity at age 6 years p=0. 0073; calculated OR for obesity=1. 84; calculated OR for overweight=1. 5 Blake 2000 Maternal smoking during pregnancy as reported at 18 weeks GA Significantly higher BMI at age 6 years p<0. 01 Montgomery 2002 Maternal smoking after the 4 th month of pregnancy Increased risk of obesity at age 33 years Adjusted OR for obesity=1. 24 (1. 07 -1. 69), 1. 35 (0. 95 -1. 92), and 1. 38 (1. 06 -1. 79) for medium, variable, and heavy smokers, respectively Power 2002 Maternal smoking after the 4 th month of pregnancy Increased risk of obesity at age 33 years Adjusted OR for obesity=1. 56 (1. 22 -2. 00) for males and 1. 41 (1. 12 -1. 79) for females Toschke 2003 Maternal smoking during the 1 st trimester of pregnancy only or throughout pregnancy Increased risk of overweight/obesity at age 5 -6 years Adjusted OR for obesity for 1 st trimester exposure=1. 22 (1. 33 -3. 69); adjusted OR for obesity for full GA exposure=1. 70 (1. 02 -2. 87); analagous ORs for overweight=1. 52 (1. 14 -2. 01) and 1. 23 (0. 89 -1. 70), respectively Toschke 2002 Maternal smoking during pregnancy Increased risk of obesity at age 5 -6. 99 years Adjusted OR for obesity=1. 92 (1. 29%-2. 86%) Vik 1996 Maternal smoking of 1 -25 cigg/day during pregnancy Increased mean subscapular skinfold thickness (SST), triceps skinfold thickness (TST), and ponderal index (PI) at age 5 years p<0. 01 for SST; p<0. 05 for TST; p<0. 01 for PI von Kries 2002 Maternal smoking during pregnancy Increased risk of overweight/obesity at age 5 -6 years Adjusted OR for overweight=1. 43 (1. 07 -1. 90); adjusted OR for obesity=2. 06 (1. 31 -3. 23) von Kries 1999 Maternal smoking during pregnancy Increased risk of overweight/obesity at age 5 -6 years OR for obesity=1. 5 (1. 20 -1. 89); OR for overweight =1. 82 (1. 28 -2. 58) 2003 Maternal smoking during week 17 of pregnancy Increased risk of overweight at age 5 years ORs for overweight=2. 9 (1. 3 -6. 6) for BMI, 2. 4 (1. 0 -5. 5) for skinfold thickness 1999 Maternal smoking during pregnancy Statistically significant association b/t maternal smoking and BMI of offspring at age 9 years but not at age 18 years Regression coefficient b/t maternal smoking and BMI of offspring was 0. 05 at age 9 years Wilderoe Williams Lu et al, manuscript in preparation

Summary: Fetal Metabolic Development o How to prevent childhood and adult obesity n n n Control maternal diabetes Reduce maternal poor nutrition Stop maternal smoking

Conclusion

Implications o Need more longitudinal studies

Implications o Need more integrated studies

Genetics

Epigenetics

Scientific American 2003

Implications for Practice o o Preconceptional or prenatal screening for maternal hypothyroidism? Reduce infection risks n n n o Reduce maternal stress n n o n n n o o o Screen for maternal depression Screen for intimate partner violence Partner involvement Social support Provide warnings about environmental exposures n o Screen & treat periodontal infections, RTIs, UTIs, STIs, GBS Avoid unnecessary inductions, cervical exams, stripping of membranes, internal monitors, PROM Provide flu vaccination Lead Fish & mercury Dioxin & animal fat Pesticides Optimal glycemic control for pregestational & gestational diabetes Promote healthy nutrition during pregnancy Promote smoking cessation during pregnancy Encourage breastfeeding

Implication for Policy o Social investment in life course health development