fetal origins of disease hypothesis grace m. egeland, ph.d. university of bergen
TRANSCRIPT
Lecture Objectives
This lecture provides a basic review
of the Fetal Origins of Disease Hypothesis
and
the status of the current literature.
“What exactly is the fetal origins of disease hypothesis ? “
The hypothesis states that susceptibility to cardiovascular
disease (CVD), non-insulin-dependent diabetes mellitus
(NIDDM), and the insulin resistance syndrome (IRS) is
programmed in utero as a response to fetal undernutrition.
Prevalence of non-insulin dependent diabetes and impaired glucose tolerance
in men by their birth weight (N=370)
Fetal and infant growth and impaired glucose tolerance at age 64.
0
5
10
15
20
25
30
35
40
%
Birth weight ( lbs. )< 5.5 > 9.5
Hales CN, et al. BMJ 1991;303:1019-22.
Effects of birth weight and adult weight on the metabolic syndrome in women.
0
5
10
15
20
25
30
Low Med High
Low
Med
High
LowMedHigh
Birth weight
Adult BMI
Yarbrough DE, et al. Diabetes Care 1998; 21:1652-1658.
Childhood and Adolescents
Studies among children, and adolescents have shown a similar direction in their results,
….BUT…..
overall the evidence is not as consistent or as strong as studies among middle-aged and older adults;
Birth weight and systolic blood pressure among children
Country Betacoefficient
(95% CI)
Chile - 4.9 (-7.7, -2.1)Guatemala - 2.7 (- 4.7, -0.7)China -0.3 (-2.5, 1.9)Nigeria 0.4 (-2.1, 2.9)
Sweden -0.9 (-2.6, 0.8)
Law CM, et al. IJE 2000;29:52-59.
Pregnancy
Certain pregnancy-related complications predict future chronic disease occurrence;
Pregnancy is a stress test for conditions considered to be precursors to NIDDM, CVD, and the adult insulin resistance syndrome.
Prevalence rate and adjusted odds ratios for gestational diabetes by women’s own
birth weight
0
1
2
3
4
5
6
1 2 3 4 5 6
B. Weight OR (95% CI)
< 2,500g 1.8 (1.1 -3.0)
2,500 - 2,999 1.6 (1.1 -2.3)
3,000 - 3,499 1.4 (1.0 -2.0)
3,500 -3,999 1.1 (0.8 -1.5)
4,000 -4,500 1.0
> 4,500g 1.4 (0.7 - 2.8)
Rat
e p
er 1
,000
wom
en
Birth weight groupEgeland GM, et al. BMJ 2000; 321:546-547.
“What about prematurity? May be its just babies born too early and not necessarily intrauterine growth retardation ? ”
Prevalence rate and adjusted odds ratios for gestational diabetes by women’s gestational age
0
1
2
3
4
5
6
< 34 35-36 37-39 40 41-42 43-44
Rate per 1,000 women
Gestational age categories (weeks)
Gestational Age OR (95%CI)
< 34 weeks 1.6 (0.8 -3.3)35-36 0.9 (0.5 -1.7)37-39 1.0 (0.8 -1.2)40 (referent) 1.0 41-42 1.1 (0.9 - 1.4)43-44 1.1 (0.7 - 1.7)
Egeland GM, et al. BMJ 2000; 321:546-547.
*
*
Odds ratios for preeclampsia by women’s own gestational age and birth weight
0
0.5
1
1.5
2
2.5
0
0.5
1
1.5
2
2.5
3
Birth weight (lbs.)Gestational age (weeks)< 34 43-46 < 4.5 >8.5
Innes KE, et al. Epidemiol 1999;10:153-160.
“Earlier you said the fetal origins of disease hypothesis states that nutrition plays a role in fetal programming …
….what evidence supports this ?”
Animal Studies
BIRTH
Reduced size of offspring at birth.
ADULTHOOD
Elevated blood pressureand glucose intolerance in offspring in adulthood.
Reduced Proteinin Diet of Pregnant Rats
Dahri S, et al. Diabetes 1991;40:115-20.Langley SC, et. al. Clin Sci 1994;86:217-22.
Observations among humans
• Dutch Hunger Winter -- some evidence;
• Siege of Leningrad -- no evidence;
• Nutrition epidemiologic studies --mixed evidence.
“What is the role of socioeconomic
status in contributing to the
associations observed in all of these studies?
Do we have a confounder here? ”
The role of socioeconomic status
Sub-optimalnutrition
smokingobesity
Physical activity
Other factors
Covariates of socioeconomic status
Adulthood ChronicDiseases
Intrauterinegrowth restriction
Prenatal care
Crude and SES adjusted rate ratios for mortality from ischaemic heart
disease by birth weight: Cohort from Uppsala, Sweden.
<3.25 3.25-3.7
3.75-4.24
>4.25 P value fortrend
Crude 1.0 0.8 0.7 0.7 0.001
Adjusted * 1.0 0.9 0.7 0.7 0.01
Birth weight (kg)
Leon DA, et al. BMJ 1998;317:241-5. *adjusted for SES-related factors
“Could there be an alternative
hypothesis to that of the fetal programming of adult diseases
that could explain the associations observed ?
Low Birth Weight Infants
AdulthoodInsulin Resistance
Genetic Influences
Alternative Hypothesis: Genetic Influences
Hattersley AT, Tooke JE. Lancet 1999;353:1789-92.
Fetal Insulin Hypothesis
Maternal glucose concentrations
Glucose sensing by fetal pancreas
Insulin secretion by fetal pancreas
Insulin-mediated growth
Infant’s birth weight
Fetal genetically determined responses
Integrating hypotheses
Fetal programming genetics
Prenatal Nutrition andother factors
Adulthood nutrition andother risk factors
Adult Chronic Diseases
Summary
• Consistent evidence among adults that markers of fetal growth are inversely associated with the later development of CVD, NIDDM, and IRS;
• Good evidence of nutritional fetal programming from animal studies;
• Good evidence of an interaction between birth weight and adult measures of obesity; and
Summary
• SES is not likely to explain the associations observed;
• Determining the optimal maternal diet is difficult in epidemiologic studies;
• Fetal insulin hypothesis also has merit.
Recommendations
• Research should explore ways to integrate the fetal programming hypothesis with that of the genetic fetal insulin hypothesis;
Recommendations
• Publications should provide information in a more meaningful public health framework, such as
–the % variation in disease associated with the exposure (r2), or
–the population attributable fraction.