Lecture held at the 4th Evidence-Based Neonatology conference, Nov 12 2017, in Hyderabad, India. The lecture gives a short overview of the "fetal programming" theory, also referred to as the Developmental Origin of Health and Disease (DOHaD).

1. Fetal Programming of Adult Disease
Stefan Johansson, MD PhD
associate professor, Clinical Epidemiology Unit, Karolinska Institutet
consultant neonatologist, Sachs’ Children and Youth Hospital
Stockholm, Sweden
stefan.johansson@ki.se

2. Financial conflicts of interest
 None.

3. HISTORY AND CONCEPT OF
FETAL PROGRAMMING

5. David Barker 1938-2013
”…the serendipitous discovery...”
From obituary in Lancet 05 October 2013
Lancet. 1989;2(8663):577-80.

6. Lancet. 1989;2(8663):577-80.

7. ”Fetal Programming”

8. Adaption
poor nutrition
during fetal life
Early exposure Predicted ≠ actual
energy
conservation
calorie-rich diet
leads to obesity
A theoretical framework related to ”mismatch”

9. Developmental Origin of Health and Disease (DOHaD)
 Adult health can influenced by exposures during
 fetal life
 infancy
 early childhood

10. POOR NUTRITION DURING
FETAL LIFE

11. Dutch Famine during 2nd World War
 Dutch Famine, or ”Hungerwinter”:
November 1944 to May 1945
 Food rations: 400-800 calories/day
 4.5 million affected, ~1/200 died

12. NEJM. 1976;295:349-353

13. Dutch Famine – obesity prevalence in young men
Exposed to famine at/after birth
Exposed to famine during
first two trimester
NEJM. 1976;295:349-353

14. Dutch Famine Birth Cohort
 Includes 3307 singleton live-births
 2417 births in mothers were exposed to the famine during pregnancy
 a sample of 890 births between 1943 and 1947, unexposed to famine
 Data has been collected from
 birth records
 telephone interviews
 health examinations
Int J Epid. 2007;36:1196-1204.

15. Adults exposed to the Dutch Famine during fetal life
 Blood pressure: systolic BP increased 3 mm Hg per 1 kg lower BW
 Lipid profile: more ”atherogenic profile”
 Coronary heart disease: 9% in exposed; 3% in non-exposed
 OGT: 2h-glucose was 0.5 mmol/L higher in exposed
J Hypertension. 1999;17:325-330.
Am J Clin Nutr. 2000; 72:1101-6.
Heart. 2000;84:595-8.
Lancet. 1998;351:173-7.

16. Biafra Famine during the Nigerian Civil War
 Nigerian Civil War 1967-1970
 Severe starvation
 Médecins Sans Frontières originated in
response to the suffering in Biafra

17. Biafra Famine - health in adults after fetal malnutrition
 Cohort study in 2009 in Enugu, Nigeria
 1339 adults born before, during, or after the famine examined for
 hypertension (BP>140/90)
 impaired glucose tolerance (p-glucose 7.8-11.0)
 diabetes (p-glucose ≥11.1)
PLoS One. 2010;5(10):e13582.

18. PLoS One. 2010;5(10):e13582.
Risk of high systolic blood pressure (≥140 mm Hg

19. Adults subjected to fetal/infant malnutrition
Born after famine
(unexposed)
Born during famine
(fetal/infant malnutrition)
n (%) n (%) OR (95% CI)
IGT 37 (8) 37 (13) 1.8 (1.1-2.8)
Diabetes 6 (1) 11 (4) 3.1 (1.1-8.5)
PLoS One. 2010;5(10):e13582.

20. LOW BIRTH WEIGHT

21. Birth weight – good proxy for fetal environment?
 Many studies have related low birth weight to adulthood disease
 Abnormally low birth weight versus constitutionally small?
 Birth weight for gestational age (SGA/AGA/LGA)?

22. BW<2500g and risk of coronary heart disease
 Absolute risks
 BW<2500g: 4.1%
 BW>2500g: 3.5%
J Dev Orig Health Dis. 2014;5:408-19.

23. CVD mortality risk per 1 kg increase in BW
Int J Epidemiol. 2011;40:647-61.

24. BW<2500g and risk of diabetes type 2
Am J Epidemiol. 2007;165:849-57.

25. PRETERM BIRTH

26. Low birth weight vs preterm birth
 Birth weight is a function of
 fetal growth
 gestational age
 Preterm birth, probably the most common reason for BW<2500g
 Preterm birth also related to life-long health consequences

27. Adaption
poor nutrition
during fetal life
Early exposure Predicted ≠ actual
energy
conservation
calorie-rich diet
leads to obesity
Does the ”mismatch” theory apply to preterm birth?

28. Preterm birth – and the harsh life in the NICU
 the NICU – a dangerous place:
 organ damage
 malnutrition
 inflammation
 oxygen
 stress
 pain
 etc.

29. Disruption
extra-uterine life
is abnormal
Preterm birth Disease
growth and
differentiation
deviate from
normal fetal
development
we cannot
compensate -
full potential
not reached
My take on Preterm birth and DOHaD

30. Preterm birth, low birth weight at term and
hypertension in young men
 Nationwide cohort study in Sweden
 Individually linked data
 Medical Birth Register
 Conscription Register
 Multi-generation Register
 Population and Housing Census
 329 000 young men and their BP when conscripting for military service
Circulation. 2005;112:3430-6.

31. 0.0
0.5
1.0
1.5
2.0
2.5
24-28 29-32 33-36 37-41 42-43
Diastolic BP ≥90 mm Hg
Systolic BP ≥140 mm Hg
gestational age (weeks)
adjustedoddsratio
SGA AGA LGA
birth weight for gestational age
Circulation. 2005;112:3430-6.

32. Sympathoadrenal overactivity
 105 children (mean age 9.6 years)
 born at term, normal birth weight (controls)
 born at term, small for gestational age
 born preterm
 Compared to controls, preterm and term SGA groups
 excreted higher levels of dopamine, adrenaline and noradrenaline in urine
 had heart rates 6-9/min higher at rest and after mental stress test
J Intern Med. 2007;261:480-7.

33. GENES VS ENVIRONMENT

34. ”Couldn’t all this be explained by familial factors?”
Mother with risk of
cardiovascular disease
Pregnancy complicated by
poor intrauterine growth
LBW child inherits risk of
cardiovascular disease

35. LBW and CVD risk – no familial confounding
 Studying risks between and within siblings and twins gives some
control over unmeasured familial and genetic factors
 Association between low birth weight and CVD risk is not confounded
by environmental or genetic factors shared by families
Epidemiology. 2005;16:635-40.
Circulation. 2007;115:2931-8.

36. Risks of diabetes type 2 between and within twins
Cohort analyses
per 500 gram lower birth weight 1.44 (1.28-1.63)
Co-twin case-control analyses
Within dizygotic twin pairs
per 500 gram lower birth weight 1.38 (1.02-1.85)
Within monozygotic twin pairs
per 500 gram lower birth weight 1.02 (0.63-1.64)
Epidemiology. 2008;19:659-65.

37. Genetics factors contribute to the association
between low birth weight and diabetes type 2
 Lower birth weight relate to a higher risk of diabetes type 2
 Birth weight differences within monozygotic twin pairs is not associated
with diabetes risk
 Low birth weight and diabetes type 2 a share a genetic background?
Epidemiology. 2008;19:659-65.

38. HOW CAN THE ENVIRONMENT
PROGRAM THE FETUS

39. Structural and functional deviations from normal
 Organ growth and differentiation
 Endocrine systems
 Metabolism
 Stress responses
J Dev Orig Health Dis. 2017;8:513-519.

40. CAN WE DO SOMETHING
ABOUT THIS?

41. Fetal Life
Rest of Life

42. TO-DO list…
 Work against poverty and starvation
 Prevent preterm birth
 At routine follow-up of children born very SGA or very preterm
 measure the blood pressure
 sensible sharing of what we know, and don’t know about DOHaD
 as to all children, give advice on a healthy life-style

43. ”More research is needed”
 International Society for Developmental Origins of Health and Disease
 https://dohadsoc.org/
 11th DOHaD conference: Oct 20-23, 2019

44. Concluding remarks
 Early life exposures can have life-long impacts
 Starvation, low birth weight and preterm birth contribute to heart disease
 Low birth weight relate to diabetes risk, but genetic confounding?
 Measure blood pressure and councel carefully at policlinical follow-up
 Encourage ”early programmed” children to adopt a healthy life-style
(as all children should do anyway)