1. The Life Course Perspective: CuttingEdge Science for Urban MCH
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
I was asked to talk about the life course perspective. Over the past few years, many of you have heard me talk about disparities in birth outcomes from the life course perspective.

2. Life Course Perspective
Reproductive Potential
For those of you who haven’t, it’s a simple message. Birth outcome is the product of not only exposures over the nine months of pregnancy, but also experiences over the entire life course of the woman.
Age
Pregnancy

3. Life Course Perspective
White
Reproductive Potential
African
American
Disparities in birth outcomes, therefore, are the consequences of not only differential exposures during pregnancy, but also differential developmental trajectories over the life course. It is the consequences of having different slopes on these developmental trajectories.
Pregnancy
Age

4. Life Course Perspective
Early programming
Cumulative pathways
There are two main components to the life course perspective – an early programming component and a cumulative pathways component.

5. Early Programming

6. The early programming model posits that exposures in early life – when you were just a baby inside your mother’s womb or during infancy and early childhood – these early life exposures can influence the development of health and disease later on in life.

7. Barker Hypothesis Birth Weight and Coronary Heart Disease
Age Adjusted Relative Risk
Rich-Edwards 1997
For example, there are now numerous studies demonstrating an association between low birth weight and higher risk for coronary heart disease, …

8. Barker Hypothesis Birth Weight and Hypertension
… high blood pressure, …
Law 1993

9. Barker Hypothesis Birth Weight and Insulin Resistance Syndrome
Odds ratio adjusted for BMI
… and diabetes later on in life. Now if I were to ask you to tell me some of the risk factors for heart disease, you’d probably tell me what -- smoking and high blood pressure and cholesterol and obesity and so forth  but low birth weight? How many of you would have told me low birth weight? What does low birth weight have anything to do with developing heart disease forty to fifty years later on in life? .
Barker 1993

10. Prenatal Period is a “Sensitive” or “Critical” Period
Health or Function
What Barker and others have hypothesized is that there are these critical periods in fetal development during which your organs and systems are developing, and the functions of an organ or system are being programmed, and if there is any disruption to that development, then those organs and systems will never function optimally over the life course. For example, if you have undernutrition during the second trimester, you end up with a smaller pancreas, which may not be able to handle blood sugar load as well later on in life, leading to increased susceptibility for the development of diabetes mellitus.
Birth

11. Stress
Obviously it gets a lot more complicated than that, but I started thinking that if that’s true, could one’s reproductive potential be similarly programmed in utero so that one’s future birth outcomes are already determined during fetal development and early infancy? And I’m not just talking about having small uterus and ovaries, but virtually all the body’s organs and systems that are involved in maintaining a healthy pregnancy
Take stress, for example. If mom is stressed out during pregnancy, her brain and placenta put out the CRH which causes the release of all these other stress hormones, ACTH and cortisols and catecholamines. These stress hormones can cross the placenta, and in a sense you are bathing the baby in all these stress hormones while the baby’s neuroendocrine and other systems are developing; you are priming the baby’s hypothalamic-pituitary-adrenal axis with all these stress hormones. Could this exposure cause the baby to have higher stress reactivity later on in life – that is, when they are exposed to stress, they put out a lot more CRH and cortisol that could put them at greater risk for preterm labor when they become pregnant 20 or 30 years later?

12. The biological pathways for this are beginning to get mapped in animal models. Prenatal stress increases the release of glucocorticoids from fetal adrenal glands, which can downregulate glucocorticoid receptors in the fetal hippocampus, resulting in the loss of the negative feedback control on the hypothalamic-pituitary-adrenal axis. In the amygdala, which is a site that produces fear and anxiety, it does the opposite. Prenatal stress upregulates glucocorticoid receptors, thereby accentuating the positive feedback influence on the HPA axis.
The end result is the resetting of the “set point” for the hypothalamic-pituitary-adrenal axis to a more hyperactive system leading to higher stress reactivity as adults.
Welberg LAM, Seckl JR. Prenatal stress, glucocorticoids and the programming of the brain.
J Neuroendocrinol 2001;13:

13. Now remember this programming effect may be permanent – possibly by switching on or off gene expression regulating the amount of glucocorticoid receptors that get expressed in the brain. This can happen simply by tagging a methyl group directly onto the DNA or other components of the chromosome like histones or transposons. So prenatal stress can determine how much stress hormone your body eventually puts out simply by methylating your chromosome – and all of these occur before you were even born.
Scientific American 2003

14. Epigenetics
This is a phenomenon call epigentics – which I think is fascinating. It controls how much genetic materials gets expressed, for example, how much stress hormones get produced. So you can have two people with the exact same genetic code, but they can have very different output of stress hormones depending on their early life exposures, which can turn on or off gene expression for life.

15. Cumulative Pathways
The second component of the life course perspective -- the cumulative pathways model - posits that chronic stress can cause wear and tear on your body’s adaptive system, leading to decline in health and function over time.

16. Allostasis
Let’s take the example of stress again. This time mom doesn’t have to be stressed out during pregnancy, but rather it’s the chronic stress and strain, the daily wear and tear that women experience that cause them to have higher stress reactivity.
How does this happen? What happens when you are stressed? What happens when you see a saber tooth tiger? You run! Your body activates the fight-or-flight response -- the hypothalamic-pituitary-adrenal system and the sympatho-adrenal-medullary system -- to put out more stress hormones -- CRH and ACTH and cortisol and catecholamines -- to help you run faster.
McEwen 1998

17. Allostasis
McEwen 1998
But what happens after you got away? Your heart rate slows down, your blood pressure comes down, and you body calms down. The amazing thing about the human body is that it is self-regulating; it knows to shut itself off once the stressor has been removed. This is called allostasis – maintaining stability through change.

18. Stress and Allostastic Load
McEwen 1998
But what happens when there is no where to run? In the face of repeated or chronic stress, the body loses the ability for self-regulation so you can turn it on, but you can’t shut it off. Biologically speaking, tonically elevated levels of cortisol start to down-regulate the glucocorticoid receptors in the brain leading to the loss of negative feedback. So we find in animals and humans who are chronically stressed that they walk around with higher circulating levels of stress hormones, and if they were to be exposed to some natural or experimental stressors, they put out out much more CRH and cortisol that could increase their vulnerability to preterm labor during pregnancy.

19. Allostasis
Chikanza 2000
And what does stress do to your immune system? In general stress depresses the immune system. This may explain why women who are chronically stressed are more susceptible to infections like bacterial vaginosis, which could increase their risk for preterm labor during pregnancy.
It turns out that this is only half of the story. In the face of an infection, your body activates the immune system to fight off the infection. But as soon as the battle is being won, the body starts to shut off the immune response to avoid a potentially damaging inflammatory overshoot. This occurs largely through activation of the hypothalamic-pituitary-adrenal axis by inflammatory cytokines. Again, the amazing thing about the body is that it is self-regulating.
In the face of chronic and repeated stress, however, the body loses that ability for self-regulation. Biologically speaking, the tonically-elevated levels of cortisol start to down-regulate the glucocorticoid receptors inside the immune cells so you lose that counter-regulation from the hypothalamic-pituitary-adrenal axis. So we find in animal and some humans who are subjected to chronic and repeated stress is that they can turn on the immune response, but they have a really tough time shutting it off, and so they get an excessive output of pro-inflammatory and TH-1 cytokines in response to an infection, even one as innocuous as bacterial vaginosis, that could potentially cause them to go into preterm labor.

20. Life Course Perspective
White
Reproductive Potential
African
American
The point here is that that contribute most to the disparities in birth outcomes like preterm birth or LBW can be traced not only to differential exposures to stress and infections during pregnancy, but also to differential stress reactivity and immune-inflammatory dysregulation that have been programmed over the life course.
So if we want to improve birth outcomes and reduce disparities, we can’t keep looking for a quick fix in prenatal care. To expect prenatal care, in less than nine months, to reverse all the early life disadvantages and the cumulative allostatic load over the life course, may be expecting too much of prenatal care.
Pregnancy
Age

21. Life Course Perspective
White
African
American
Primary Care
for Children
Early
Intervention
Prenatal
Care
If we want to improve birth outcomes and reduce disparties, we have to start taking care of women before they get pregnant. And I don’t mean one visit three months preconceptionally. We’ve got to start when the mother was still a fetus, and an infant, and a child, and an adolescent.
Prenatal
Care
Internatal
Care
Primary Care
for Women
Poor Birth Outcome
Age 5
Puberty
Pregnancy
Lu 2003

22. Closing Black-White Gap in Birth Outcomes A Life-Course Approach
1. Provide interconception care to women with prior adverse pregnancy outcomes
2. Increase access to preconception care to Black women
3. Improve the quality of prenatal care
4. Expand healthcare access over the life course
5. Restore Black fathers to Black families
6. Enhance coordination and integration of family support services
7. Create reproductive social capital in Black 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
This is an example of a life course approach to reduce disparities in birth outcomes that I’ve been working on – which will be published next year and I’d be happy to send the manuscript to those of you who are interested.

23. Prenatal Programming How to make a smart and healthy baby for life?
I was going to talk about this at the break-out session, but in discussion with the conference organizers and given how much interest there is in the science behind prenatal programming, I’ve decided to change the topic of the session to how to make a smart and healthy baby for life. This is still the life course perspective. But instead of looking backward over the mother’s life course for life course influences on perinatal health, today I want to look forward for perinatal influences on future health and development over the baby’s life course.

24. Prenatal Programming Brain development Immune development
Metabolic development
I will focus on prenatal programming of brain development, immune development and metabolic development.

25. Prenatal Programming
Is there prenatal programming of school readiness?
And will be addressing questions such as

26. Prenatal Programming
Is there prenatal programming of obesity?