Fetal Origins of Disease Hypothesis

Grace M. Egeland, Ph.D.University of Bergen

Lecture Objectives

This lecture provides a basic reviewof 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.

05

10

1520

2530

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

LowMed

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 pe

r 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.

Any questions so far?

“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

“How important is birth weight relative to other risk 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.

Recommendations

• Further evaluation of potential effect modifiers, such as breastfeeding, is important, particularly in terms of identifying prevention strategies;

• Maternal nutrition campaigns and universal prenatal health care should be promoted world-wide.