1. Improving Maternal & Child Health in America: A Life-Course Perspective Michael C. Lu, MD, MPH Associate Professor Department of Obstetrics & Gynecology David Geffen School of Medicine at UCLA Department of Community Health Sciences UCLA School of Public Health UCLA OB-GYN Grand Rounds December 4, 2009

2. Acknowledgment  National Institute of Child Health and Development Community Child Health Network National Children’s Study

3. Acknowledgment

4. Maternal Mortality Source: OECD Health Data 2008

5. Infant Mortality Source: United Nations. Table 4. In: United Nations Demographic Yearbook, 2004. New York, NY: United Nations; 2007:73–93.

6. U.S. Rank in OECD  Maternal mortality All races – 25 th Whites only – 19 th  Infant mortality All races – 22 nd Whites only – 22 nd

7. Racial & Ethnic Disparities Pregnancy-Related Mortality Ratio, 1991- 1999 Deaths Per 1,000 Live Births Chang et al MMWR 2003

8. Racial & Ethnic Disparities Infant Mortality, 2005 Deaths Per 1,000 Live Births NCHS 2008

9. How Can This Be?

10. Life-Course Perspective  A way of looking at life not as disconnected stages, but as an integrated continuum

11. Life Course Perspective Lu MC, Halfon N. Racial and ethnic disparities in birth outcomes: a life-course perspective. Matern Child Health J. 2003;7:13-30.

12. Life Course Perspective  Early programming  Cumulative pathways  Implications for research, practice, and policy

13. Early Programming

15. Barker Hypothesis Birth Weight and Coronary Heart Disease Age Adjusted Relative Risk Rich-Edwards JW, Stampfer MJ, Manson JE, Rosner B, Hankinson SE, Colditz GA et al. Birth weight and risk of cardiovascular disease in a cohort of women followed up since 1976. Br Med Jr 1997;315:396-400.

16. Barker Hypothesis Birth Weight and Hypertension Law CM, de Swiet M, Osmond C, Fayers PM, Barker DJP, Cruddas AM, et al. Initiation of hypertension in utero and its amplification throughout life. Br Med J 1993;306:24-27.

17. Barker Hypothesis Birth Weight and Insulin Resistance Syndrome Odds ratio adjusted for BMI Barker DJP, Hales CN, Fall CHD, Osmond C, Phipps K, Clark PMS. Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (Syndrome X): Relation to reduced fetal growth. Diabetologia 1993;36:62-67.

18. Maternal Stress & Fetal Programming

19. 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.

20. Prenatal Programming of the Hypothalamic-Pituitary-Adrenal Axis Welberg LAM, Seckl JR. Prenatal stress, glucocorticoids and the programming of the brain. J Neuroendocrinol 2001;13:113-28.

21. Epigenetics Gibbs WW. The Unseen Genome: Beyond DNA. Scientific American 2003

22. Epigenetics Same Genome, Different Epigenome R.A. Waterland, R.A. Jirtle, "Transposable elements: targets for early nutritional effects on epigenetic gene regulation," Mol Cell Biol, 23:5293-300, 2003. Reprinted in the New Scientist 2004

23. Prenatal Programming of Childhood Obesity

24. Epidemic of Childhood Overweight & Obesity Source: National Center for Health Statistics, National Health and Nutrition Examination Survey Note: Estimate not available for 1976-1980 for Hispanic; overweight defined as BMI at or above the 95 th percentile ofr the CDC BMI-for-age growth charts Children 6-18 Overweight

25. Prenatal Programming of Childhood Overweight & Obesity

26. Maternal Diabetes & Intrauterine Hyperglycemia Intrauterine Hyperinsulinemia (Fetal Pancreatic β Cells) Prenatal& Postnatal Hyperleptinemia Preadipocyte Differentiation Adipocyte Hyperplasia Hypothalamic Leptin Resistance Pancreatic β- Cell Leptin Resistance Hyperphagia Hyperinsulinism Programmed Insulin Resistance Postnatal Hyperinsulinemia Maternal Diabetes & Intrauterine Hyperglycemia Intrauterine Hyperinsulinemia (Fetal Pancreatic β Cells) Prenatal& Postnatal Hyperleptinemia Adipocyte Hyperplasia Hypothalamic Leptin Resistance Pancreatic β- Cell Leptin Resistance Hyperphagia Hyperinsulinism Programmed Insulin Resistance Postnatal Hyperinsulinemia Adipogenesis Dysregulation of the Adipoinsular Feedback System Maternal Diabetes & Intrauterine Hyperglycemia Intrauterine Hyperinsulinemia (Fetal Pancreatic β Cells) Prenatal& Postnatal Hyperleptinemia Preadipocyte Differentiation Adipocyte Hyperplasia Hypothalamic Leptin Resistance Pancreatic β- Cell Leptin Resistance Hyperphagia Hyperinsulinism Programmed Insulin Resistance Postnatal Hyperinsulinemia Adipogenesis Maternal Diabetes & Intrauterine Hyperglycemia Intrauterine Hyperinsulinemia (Fetal Pancreatic β Cells) Prenatal& Postnatal Hyperleptinemia Preadipocyte Differentiation Adipocyte Hyperplasia Hypothalamic Leptin Resistance Pancreatic β - Cell Leptin Resistance Hyperphagia Hyperinsulinism Programmed Insulin Resistance Postnatal Hyperinsulinemia Adipogenesis Prenatal Programming of Childhood Obesity

27. Cumulative Pathways

28. Photo: http://www.lam.mus.ca.us/cats/encyclo/smilodon/

29. Allostasis: Maintain Stability through Change McEwen BS. Protective and damaging effects of stress mediators. N Eng J Med. 1998;338:171-9.

30. Allostastic Load: Wear and Tear from Chronic Stress McEwen BS. Protective and damaging effects of stress mediators. N Eng J Med. 1998;338:171-9.

31. HPA Axis & Immune System Chikanza 2000

32. Stressed vs. Stressed Out  Stressed Increased cardiac output Increased available glucose Enhanced immune functions Growth of neurons in hippocampus & prefrontal cortex  Stressed Out Hypertension & cardiovascular diseases Glucose intolerance & insulin resistance Infection & inflammation Atrophy & death of neurons in hippocampus & prefrontal cortex

33. Allostasis & Allostatic Load McEwen BS, Lasley EN. The end of stress: As we know it. Washington DC: John Henry Press. 2002

34. Rethinking Preterm Birth

35. Sequelae of Preterm Birth 75% PerinatalMortality NeurologicDisabilities 50% 12%

36. Racial & Ethnic Disparities Infant Mortality Deaths Per 1,000 Live Births NCHS 2007 Year 2010 Goal

37. Racial & Ethnic Disparities Preterm Births < 37 Weeks Percent of Live Births NCHS 2007 Year 2010 Goal

38. Racial & Ethnic Disparities Very Preterm Births < 32 Weeks Percent of Live Singleton Births Year 2010 Goal NCHS 2007

39. Rethinking Preterm Birth Vulnerability to preterm delivery may be traced to not only exposure to stress & infection during pregnancy, but host response to stress & infection (e.g. stress reactivity & inflammatory dysregulation) patterned over the life course (early programming & cumulative allostatic load)

40. Preterm Birth & Maternal Ischemic Heart Disease Kaplan-Meier plots of cumulative probability of survival without admission or death from ischemic heart disease after first pregnancy in relation to preterm birth Smith et al Lancet 2001;357:2002-06

41. Improving MCH in America

42. Research

43. Pre-disease Pathways Early and long-term biological, behavioral, psychological and social precursors to disease.

44. Community Child Health Network (CCHN)  Longitudinal study of the causes of disparities in birth and child health outcomes  4,000 families at 5 locations (LA, Baltimore, DC, NC, Chicago) recruited at birth of index child  One of the richest databases to study developmental origins of child health disparities  Community Based Participatory Research (CBPR) A collaborative process that equitably involves all partners in the research process and recognizes the unique strengths that each brings. CBPR begins with a research topic of importance to the community with the aim of combining knowledge and action for social change to improve community health and eliminate health disparities (Minkler & Wallerstein 2003)

45. National Children’s Study  Longitudinal study – from before birth to 21 years of age  Cohort of 100,000 children from 100 Study Locations  Study how children’s genes and their environments interact to affect their health and development  In Los Angeles, 4,000 children 56 neighborhoods 67 birth hospitals Followed for 21+ years

46. Practice

47. Prenatal Care 1.0 Receptionist Medical Assistant Ultrasound Tech Nurse Manager

48. Prenatal Care 2.0 Oral Health Teratogen Information Services Primary & Specialty Care Social Services Mental Health Nutritional Counseling Receptionist Medical Assistant Ultrasound Tech Nurse Manager High Risk OB Family Support

49. 010203040Years Prenatal Care 3.0 NHVFRC PED Prenatal Care Family Planning Primary Care Reproductive Potential Optimal Health Development Lower Health Development Trajectory Medical Home for Women’s Health Medical Home for Adolescent Health Pediatric Medical Home

50. Healthcare Education Community Development Environment MCH

51. NMPP MCH Life- Course Organization

52. Policy

53. Closing the Black-White Gap in Birth Outcomes: A 12-Point Plan 1. Provide interconception care to women with prior adverse pregnancy outcomes 2. Increase access to preconception care for African American women 3. Improve the quality of prenatal care 4. Expand healthcare access over the life course 5. Strengthen father involvement in African American families 6. Enhance service coordination and systems integration 7. Create reproductive social capital in African American communities 8. Invest in community building and urban renewal 9. Close the education gap 10. Reduce poverty among Black families 11. Support working mothers and families 12. Undo racism Lu MC, Kotelchuck M, Hogan V, Jones L, Jones C, Halfon N. Closing the Black-White gap in birth outcomes: A life-course approach. Ethnicity and Disease Forthcoming in 2009.

54. All this will not be finished in the first 100 days. Nor will it be finished in the first 1,000 days, nor in the life of this Administration, nor even perhaps in our lifetime on this planet. But let us begin. John F Kennedy (1961)