How to make a smart

1
How to make a smart healthy baby for
lifeWhat we know what we dont

• 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 Womens 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.

3
(No Transcript)
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
Fetal Brain Development

• 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

20

• Fetal Enrichment

21
(No Transcript)
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 2002431-8.

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 19948148-51.
• 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,
  1993153-86.
• Lamont A, Dibben N. Motivic structure and the
  perception of similarity. Music Perception
  200118245-74.
• Panthuraamphorn C, Dookchitra D, Sanmaneechai M.
  The effects of prenatal tactile and vestibular
  enrichment on human development. Int J Prenatal
  Pernatal Psychol Med 199810181-8.

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 20031111073-82.
• 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 1999196979-93.

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 20031111073-82.
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
200359282-8.
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
200359282-8.
29
Maternal Hypothyroidism Child IQ
P lt 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 1999341549-55.
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 childrens IQ at 4 years of
age. Pediatrics 2003111e39-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
20032902677-84
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.
  20002841417-24.
• 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 200026287095.
• Maternal TNF-a 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. 200115411-20.

38

• Stress
• Cortisol

39
Does Maternal StressCross the Placenta?

• Incomplete inactivation of maternal cortisol by
  placental 11ß-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 200113113-28.
42
Welberg LAM, Seckl JR. Prenatal stress,
glucocorticoids and the programming of the
brain. J Neuroendocrinol 200113113-28.
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
  1984104259-267.
• 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
  19827099-105.
• 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 19908665-70.

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
  199516653-64.
• 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-Dec19(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.
  2004144177-83.

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
51
SummaryFetal Brain Development

• 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?

52
(No Transcript)
53

• Immune
• Development

54
Critical Windows of Immune Development

• 8-10 wks
• Initiation of hematopoiesis
• 10-16 wks
• Migration of stem cells expansion of progenitor
  cells
• 16 wks- birth
• Colonization of bone marrow thymus
• First year
• Maturation to immune competence
• 1-18 years
• Establishment of immune memory

Dietert RR et al. Workshop to identify critical
windows of exposure for childrens health
Immune and respiratory systems work group
summary. Environ Health Perspect 2000108483-490S
55
Fetal Immune Development

• Potential Immunoenhancers
• Micronutrients
• Selenium
• Iron
• Copper
• Zinc
• Calcium
• Folate
• Probiotics
• Antioxidants
• Vitamin A
• Vitamin E
• Vitamin C
• Amnio acids
• Arginine

• Potential Immunotoxins
• Nutritional
• Deficiencies
• Tobacco
• Alcohol
• Drugs
• Environmental
• Polycyclic halogenated hydrocarbons
• Polycyclic aromatic hydrocarbons
• Pesticides
• Fungicides
• Heavy metals
• Hormonal substances
• Therapeutic agents
• Mycotoxins
• Irradiation
• Infections

56

• Functional Foods

57
Fetal Immune Development

• Functional Foods
• Micronutrients
• Selenium
• Iron
• Copper
• Zinc
• Calcium
• Folate
• Probiotics
• Antioxidants
• Vitamin A
• Vitamin E
• Vitamin C
• Amnio acids
• Arginine

Dietert RR et al. Workshop to identify critical
windows of exposure for childrens health
Immune and respiratory systems work group
summary. Environ Health Perspect 2000108483-490S
58
Functional Foods Fetal Immune Development

• No long-term follow-up studies on immune
  functions
• Zinc supplementation 7 trials
• Mahomed K. Zinc supplementation in pregnancy.
  Cochrane Database Syst Rev. 2000(2)CD000230.
• Iron supplementation 20 trials
• Mahomed K. Iron and folate supplementation in
  pregnancy. Cochrane Database Syst Rev.
  2000(2)CD001135.
• Vitamin A supplementation 5 trials
• Van DE. et al. Vitamin A supplementation during
  pregnancy. Cochrane Database Syst Rev.
  2002(4)CD001996

59
Prenatal Undernutrition Immune Development
P 0.023
0.70
0.32
McDade TW et al. Prenatal undernutrition,
postnatal environments, and antibody response to
Vaccination in adolescence. Am J Clin Nutr
200174543-8.
60

• Nutritional
• Immunotoxicants

61

• Environmental
• Immunotoxicants

62
Environmental Immunotoxicants

• Polycyclic halogenated hydrocarbons
• TCDD, PCBs, PBBs
• Polycyclic aromatic hydrocarbons
• Bap methylcholanthrene, 7,20-dimethyl-benzaan
  thracene
• Pesticides
• Hexachlorocyclohexane, chlordane, diainon, DDT,
  carbofuran
• Fungicides
• hexachlorbenzene
• Heavy metals
• Methyl mercury, lead, cadmium
• Hormonal
• Estrogen/DES, testosterone, cortisone
• Therapeutic
• Acyclovir, buslfan, cyclophosphamide, cyclosporin
  A
• Mycotoxins
• T-2 toxin
• Irradiation
• X-ray

Holladay SD. Development of the murine and human
immune system Differential effects
of Immunotoxicants depend on time of exposure.
Environ Health Perspect 2000108463-73.
63
Dioxins

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

64
(No Transcript)
65
Inflammation

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

66
Inflammation
TH-1
IFN-? and IL-2
Eliminates intracellular Pathogens
Thymus
TH-0
Activates B cells Involved in atopy asthma
IL-4, IL-5, and IL-10
TH-2
67
Summary Fetal Immune Development

• Should I take zinc to boost my babys immune
  system?
• Are there things in the environment that could
  weaken my babys immune system?
• Do inflammatory-mediated chronic adult diseases
  have a fetal origin?

68
(No Transcript)
69

• Metabolic
• Development

70

• Is there prenatal programming of obesity?

71

• Maternal Diabetes

72
Maternal Diabetes Obesity in the Offspring
Lu et al, manuscript in preparation
73
Maternal Diabetes Childhood Obesity
Lu et al, manuscript in preparation
Dysregulation of the Adipoinsular Feedback System
Maternal Diabetes Intrauterine Hyperglycemia
Maternal Diabetes Intrauterine Hyperglycemia
Maternal Diabetes Intrauterine Hyperglycemia
Intrauterine Hyperinsulinemia (Fetal Pancreatic ß
Cells)
Intrauterine Hyperinsulinemia (Fetal Pancreatic ß
Cells)
Intrauterine Hyperinsulinemia (Fetal Pancreatic ß
Cells)
Prenatal Postnatal Hyperleptinemia
Prenatal Postnatal Hyperleptinemia
Preadipocyte Differentiation
Programmed Insulin Resistance
Programmed Insulin Resistance
Prenatal Postnatal Hyperleptinemia
Preadipocyte Differentiation
Programmed Insulin Resistance
Adipocyte Hyperplasia
Adipocyte Hyperplasia
Adipocyte Hyperplasia
Postnatal Hyperinsulinemia
Postnatal Hyperinsulinemia
Postnatal Hyperinsulinemia
Hypothalamic Leptin Resistance
Hypothalamic Leptin Resistance
Pancreatic ß- Cell Leptin Resistance
Pancreatic ß- Cell Leptin Resistance
Hypothalamic Leptin Resistance
Pancreatic ß- Cell Leptin Resistance
Hyperphagia
Hyperphagia
Hyperphagia
Hyperinsulinism
Hyperinsulinism
Hyperinsulinism
Adipogenesis
Adipogenesis
74

• Maternal
• Malnutrition

75
Maternal Malnutrition Obesity in the Offspring
Lu et al, manuscript in preparation
76
Maternal Malnutrition Obesity in the Offspring
77

• Maternal
• Smoking

78
Maternal Smoking Obesity in the Offspring
Lu et al, manuscript in preparation
79
Summary Fetal Metabolic Development

• How to prevent childhood and adult obesity
• Control maternal diabetes
• Reduce maternal poor nutrition
• Stop maternal smoking

80

• Conclusion

81
Implications

• Need more longitudinal studies

82
Implications

• Need more integrated studies

83

• Genetics

84

• Epigenetics

85
Scientific American 2003
86
Implications for Practice

• Preconceptional or prenatal screening for
  maternal hypothyroidism?
• Reduce infection risks
• Screen treat periodontal infections, RTIs,
  UTIs, STIs, GBS
• Avoid unnecessary inductions, cervical exams,
  stripping of membranes, internal monitors, PROM
• Provide flu vaccination
• Reduce maternal stress
• Screen for maternal depression
• Screen for intimate partner violence
• Partner involvement
• Social support
• Provide warnings about environmental exposures
• 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

87
Implication for Policy

• Social investment in life course health
  development