Early-life events. Effects on aging

Environmental cues during early-life may have a fundamental impact on the organism’s later development, structure, function and lifespan. This phenomenon has been long recognised in many fields of life sciences. It has been interpreted as an evolutionarily advantageous ability to adjust an individual’s metabolism and behaviour to environmental conditions that are likely to prevail during the individual’s life.¹ Only recently has this idea gained wider acceptance in medical sciences. This was first prompted by a growing number of epidemiological studies, from the late 1980s onwards, that linked the prevalence of various common adult disorders with body size at birth. For example, a large number of studies in different populations^2-14 have shown an association of small body size at birth in subjects born at term with increased risk of adult cardiovascular disease. The evidence is equally clear regarding type 2 diabetes^15-18 and hypertension.^19-24 Other epidemiological studies have suggested an effect of small size at birth on a much wider range of disease, including osteoporosis,²⁵ spontaneous hypothyroidism,²⁶ schizophrenia²⁷ and depression,^28-31 whereas cancer has been associated, with large size at birth.^32,33

DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE

Epidemiological findings together with experimental work in animals produced the concept of programming, a process whereby a stimulus or insult at a sensitive period of development has lasting or lifelong influence.³⁴ In other words, one genotype may give rise to different phenotypes based on conditions during early development, which is referred to as ‘developmental plasticity’.¹ In evolutionary terms, such plasticity during development may be advantageous in adjusting the metabolic needs or behaviour of an individual to environmental conditions that are likely to prevail during the life-course. However, the effects may be harmful, particularly if the environmental forecast is incorrect, for example, if the deficient nutritional conditions adjusted for in utero are not sustained during later life.^1,35 From a medical point of view, these long-term effects of early-life conditions are commonly referred to as the Developmental Origins of Health and Disease (DOHaD) concept.^36,37 The DOHaD concept may have a fundamental impact on the prevention of aging-related loss of function and disease. Studying the early-life determinants of adult health and disease has therefore been identified as a key target of research by numerous policy and funding agencies including the US National Institute for Child Health and Development,³⁸ the National Institute of Aging³⁹ and the WHO.⁴⁰

The aim of this paper is to summarise epidemiological findings that link markers of early-life conditions with diseases that cause a significant burden to the aging population. In the interest of space, I will focus on cardiovascular disease, type 2 diabetes, cognitive impairment, depression and osteoporosis. For other common disorders such as cancer, the reader is referred to recent reviews.^32,33

EARLY-LIFE ORIGINS OF SPECIFIC ADULT DISEASES

Cardiovascular disease. Low birth weight has consistently been shown as a risk factor of coronary heart disease^{3,5,6,9-14,41} and stroke^4,11,13,42 in tens of studies from different populations in more and less affluent countries. The relationship is not limited to the extremes but is graded and linear, operating across the range of normal birth weights. Although more recent observations have suggested that premature birth is associated at least with risk factors of cardiovascular disease^23,43-46 and possibly rates of stroke,^11,47 most of the population-attributable risk is due to low birth weight in relation to duration of gestation, i.e. diminished fetal growth.^{4,5,8,11,20,48} Human and animal studies suggest a number of different mechanisms that link early-life events with cardiovascular disease, but the contribution of each mechanism on a population level and their associations with specific pregnancy conditions remains poorly known. Many of these putative mechanisms operate through known cardiovascular risk factors. The association of lower birth weight with higher blood pressure is modest, approximately 2 mmHg per kilogram birth weight,^19,24 whereas the association with frank hypertension is stronger⁴⁹ and has in part been attributed to the number of nephrons⁵⁰ or the amount of elastin in blood vessel walls,⁵¹ which are lower in individuals born small, a deficit that is likely to persist into adult life. The association of low birth weight with plasma lipids is also relatively modest: two recent meta-analyses have reported an overall association of approximately 0.04 mmol/l higher total cholesterol per one kg lower birth weight.^52,53 It is, however, of note that birth weight is only a rough indicator of intrauterine conditions. An illustrative example is provided by a study which showed that exposure to the Dutch World War II famine during early gestation was associated with an atherogenic lipid profile despite being unrelated to birth weight.⁵⁴

Type 2 diabetes and impaired glucose tolerance are major risk factors of cardiovascular disease, most studies showing graded, linear associations with lower birth weight or thinness at birth.^15,17,55 However, in some studies an inverse J-shaped association is apparent,^56,57 with rates again increasing at the highest birth weights, perhaps because of genetic or programming effects associated with gestational diabetes. Again, on a population level, most of the association with low birth weight is probably attributable to slow fetal growth in people born at term,¹⁷ although recent observations have also suggested an independent association of preterm birth with impaired glucose regulation.^18,43 Babies who have low birth weight lack muscle,⁵⁸ a deficiency that will persist into childhood, since there is little cell replication in muscle after infancy.⁵⁹ Insulin resistance is thought to reflect poor muscular development and the development of a body composition with high fat but low lean mass, which are also associated with low birth weight.^49,60

Childhood growth, cardiovascular disease and its risk factors. During recent years, it has been recognized that developmental phases predisposing to adult cardiovascular outcomes include not only periods during fetal life but extend into infancy and childhood as well. Growth trajectories may be dissimilar for different outcomes. Data from the Helsinki Birth Cohort Study have shown that the risk for coronary heart disease and type 2 diabetes or impaired glucose tolerance is further increased in 60-to 70-year-olds who are small at birth, thin or short in infancy, but put on weight rapidly between 2 and 11 years of age.^2,55 A similar growth trajectory has been shown to predispose to type 2 diabetes or impaired glucose tolerance in 26-to 32-year-olds in Delhi, India.⁶¹. People who suffer stroke are also thin or short at 2 years; however, their body mass index (BMI) and height remain at average or below at age eleven.⁸ Recent findings also from the Helsinki Birth Cohort suggest that both of these trajectories of growth may lead to hypertension, which is an important risk factor for both coronary heart disease and stroke.²² A number of mechanisms have been suggested to explain these links. Detailed studies of body composition in adults have shown that gain in weight and body mass index during infancy predict predominantly lean body mass, whereas fat mass is predicted by gain in weight and BMI later during childhood.^62,63 On a more general level, slow growth in height, in particular before the age of 2 years, is a well accepted indicator of childhood socioeconomic adversities, acting through a number of causal pathways that may be associated with increased risk of disease in later life.⁶⁴

However, it would be a risky oversimplification to conclude that rapid growth during infancy is beneficial for all infants.⁶⁵ Findings in contemporary cohorts for example have shown associations of a more rapid weight gain in infancy with signs of insulin resistance at 8 years66 and blood pressure at 22 years.⁶⁷ This is further illustrated by a series of randomised trials in infants born preterm, which have shown that the administration of nutrient-enriched formula or rapid weight gain during the first two weeks of life, are associated with cardiovascular risk factors such as increased fasting proinsulin concentration,⁶⁸ lower endothelium-dependent flow mediated artery dilatation⁶⁹ and higher LDL to HDL cholesterol ratio.⁷⁰ While it is difficult to extend these findings to the general population of healthy term infants, randomised trials of early feeding of healthy infants are currently underway⁷¹ and are likely to shed more light on this question.

Of special note is breastfeeding, which is associated with modest but consistent associations with a more favourable lipid profile,⁷² lower blood pressure,^73,74 reduced risk of type 2 diabetes⁷⁵ and probably reduced risk of obesity^76,77 in later life. Breastfed infants grow more slowly than formula-fed infants, particularly after the age of 3 months.⁷⁸

Depression. An association between lower birth weight and depression, evaluated at the age of 68 years by the self-reported Geriatric Depression Scale and the Geriatric Mental State semi-structured interview conducted by trained research nurses, has been shown among men born in Hertfordshire, England.²⁹ Data from the Hertfordshire cohort did not include length of gestation, and thus it remains unclear whether this association is attributable to slower intrauterine growth or shorter length of gestation, or both. A role of slow intrauterine growth is argued for by studies in 26-year-old women³⁰ and in women and men across ages 23, 33 and 42 years,³¹ showing that the association between lower birth weight and depressive symptoms, measured by the self-reported Malaise Inventory is present —even though slightly weakened— after adjustment for gestational length. Associations between gestational length and depression were not, however, reported in these studies. A role of shorter gestational age was supported by a recent study in 1,371 members of the Helsinki Birth Cohort, showing an association of shorter gestational age with increased depressive symptoms as assessed by the Beck Depression Inventory (administered twice) and Center for Epidemiological Studies Depression scale.⁷⁹ The effect of low birth weight on depressive symptoms showed a threshold effect, being confined to people with a birth weight below 2,500 g. These findings suggest that mechanisms linking early environment with late-life susceptibility to depressive symptoms may include mechanisms leading to shorter duration of gestation as well as those related to slower intrauterine growth.

Cognitive function. People who are taller or have larger heads have better cognitive function. This has been known for more than a century and is observed throughout childhood,^80-84 adolescence^80,81,84 and adulthood^80,81,84,85 and in late life.^86,87 Longitudinal studies have concluded that body size at birth^81,83,88-90 and postnatal growth^81,83,89 have independent roles in predicting intelligence in later childhood or adulthood, although much of the benefit of adult height or head circumference on intelligence can largely be predicted by growth during the first years of life.^80,83 Nutritional influences and recurrent infections during early-life may play a major role in explaining these links.⁸⁰

Tall height and large head circumference protect from cognitive impairments during late life.^86,87,91 It is therefore logical to assume that this protective effect has its origins during early-life. Although few studies have been able to assess this directly, there is circumstantial evidence from a number of studies. Gale et al⁸⁷ reported that higher intelligence test scores and slower decline in cognitive function over a 3.5-year period in 66-75-year-olds were predicted by head circumference in adulthood, not at birth. This was interpreted as an effect of early childhood because most of the postnatal head growth occurs during the first few years after birth. Abbott et al⁸⁶ showed in the Honolulu-Asia Aging Study that cognitive impairments were more common in 71-93-year-old men who were short; shortness and cognitive impairments were both associated with a range of childhood socio-economic adversities. The role of early-life cognitive function was further supported by the Nun Study, in which low idea density and low grammatical complexity in autobiographies written in early-life predicted low cognitive test scores and neuropathologically confirmed Alzheimer’s disease in late life.⁹²

Osteoporosis. Peak bone mass, which is attained in young adulthood, accounts for a major proportion of the variation in bone mass later in adult life.⁹³ More than 60% of peak bone mass is gained during puberty, which is an obvious target period to optimize peak bone mass accrual by interventions such as calcium supplementation or exercise. However, there is a growing body of evidence suggesting that a substantial proportion of peak bone mass is determined in part by growth earlier in life.⁹⁴ Epidemiological studies have demonstrated a relationship between body size at birth or in infancy with adult bone mass.^25,94,95 Low birth weight and slow growth in height during childhood are also directly associated with the risk of hip fracture.⁹⁶ In addition to pure bone mass accrual, the relationship has been suggested as being mediated through modulation of the set point for basal activity of endocrine systems such as the hypothalamic-pituitary-adrenal (HPA) and GH/IGF I axes.⁹⁴

HOW THE MEMORY OF EARLY EVENTS IS STORED AND LATER EXPRESSED: PROGRAMMING OF HPA AXIS (HPAA) FUNCTION

Figure 1 summarises current understanding of key mechanisms of programming. However, to what extent each mechanism contributes to the development of each phenotype is poorly understood. Perhaps the most obvious alterations are those in organ size, for example the lower amount of muscle,^58,59 of nephrons⁵⁰ or elastin in blood vessel walls⁵¹ in individuals born small, which were discussed above in the context of insulin sensitivity and blood pressure. Early-life effects on immune function and inflammation have also been put forward as potentially important determinants of aging-related changes.⁹⁷ Equally well established is the concept of hormonal programming, i.e. permanent alterations in the regulation and the set point of the feedback systems of different hormonal axes.⁹⁸ The exact mechanisms by which hormonal alterations persist into adult life is, however, less clear, although there is evidence of changes in DNA methylation caused by early environmental conditions and sustained in adult life.⁹⁹

In experimental animals, various interventions that increase fetal glucocorticoid exposure result in an offspring which is born small and presents in adulthood elevated blood pressure, hyperglycemia, anxiety and increased HPAA activity. However, more detailed studies have shown that the effects vary greatly depending on the time and nature of the stimulus and are associated with complex sets of alterations, among others, in the number of glucocorticoid, mineralocorticoid and corticotrophin-releasing hormone (CRH) receptors in different parts of the brain and in other organs. There are several recent reviews on experimental studies of HPAA programming^100-103 which are not reviewed here in detail.

Programming of the HPAA function by early-life conditions constitutes an illustrative example of how epidemiological observations can provide essential information in linking early-life events with adult health and disease. This is discussed in the following paragraphs, with focus on events during the fetal period and their repercussions in later life.

Early-life factors and HPAA function in later life. Early programming of HPAA has been assessed in a number of human epidemiological studies searching for a relationship of early-life markers such as body size and gestational age at birth with HPAA function later in life. (For a review of published studies, see ref 98). A number of papers, in particular those on children, have reported that non-stimulated cortisol concentrations in general are unrelated to body size at birth.^104-107 By contrast, studies that have used a biochemical or psychosocial stimulation of the axis have mostly, although not always, shown an association of small size at birth with signs of hyperactive adult HPAA. This association has in turn been related to known cardiovascular risk factors, suggesting HPAA programming as a mechanism linking small size at birth with adult cardiovascular disease.^108-112 It has been stated that venipuncture for morning cortisol measurement, carried out in an unfamiliar clinic, may actually serve as a stress stimulation.¹¹¹ Both slow fetal growth and early gestational age are likely to play a role: some studies have shown high morning cortisol concentrations in adults born preterm¹¹³ or, of borderline statistical significance, between higher morning cortisol and lower gestational age across its normal range.^104,111 One study showed that the association between low birth weight and high morning cortisol was confined to people born at a low-normal gestational age¹¹⁴. However, some studies have shown counterintuitive associations of low birth weight with low cortisol after a dexamethasone-CRH test,¹¹⁵ or with low cortisol and ACTH during psychosocial stress.¹¹⁶ This has been suggested as being a consequence of long-term hyperactivity of the HPAA in susceptible individuals,¹¹⁶ although to confirm this further studies are needed.

HPAA function, fetal growth and gestational age. It is obvious that low birth weight or short gestational age are a sum of a complex interplay of different mechanisms regulating fetal growth and parturition.¹¹⁷ Whether they can be used as markers of fetal glucocorticoid exposure is crucial in interpreting the epidemiological findings linking their variation with adult disease or HPAA function. Glucocorticoids are key regulators of fetal growth,¹¹⁷ and the major regulator of fetal glucocorticoid exposure is the placental enzyme 11β-hydroxysteroid dehydrogenase 2 (11β HSD2), which converts cortisol to inactive cortisone and maintains fetal cortisol concentrations at several-fold lower levels compared to the maternal ones.^98,101,118 The activity and expression of this enzyme is reduced in intrauterine growth retardation^119,120 and pre-eclampsia^121,122 and some,¹²³ although not all,¹²⁴ observations suggest that its activity varies across the normal range of birth weights. Glucocorticoids have in addition an important role in the initiation of labour. A key regulator of human parturition is CRH, secreted in abundance by the placenta.¹²⁵ Glucocorticoids increase placental CRH synthesis.¹²⁶ CRH, by stimulating in turn fetal and/or maternal cortisol synthesis, creates a positive feedback loop that again raises CRH concentrations and subsequently leads to delivery.¹²⁵ It is therefore plausible that both weight and gestational age at birth serve as useful albeit non-specific indicators of existing individual differences in fetal or maternal glucocorticoid metabolism.

HPAA and adult disease. It has long been appreciated that increased HPAA activity is associated with many cardiovascular risk factors, depression, cognitive impairments and osteoporosis. A classical example is cortisol overproduction in Cushing’s syndrome, key symptoms of which include abdominal obesity, impaired glucose tolerance, elevated blood pressure, depression, impaired cognitive function and osteoporosis.^127-130 However, several cross-sectional observations have shown that similar associations occur within the normal variation of HPAA function.^{110,111,114,116,131-134} Although there remains a lack of carefully conducted longitudinal studies associating individual variations in HPAA function with subsequent development of disease, early-life programming of HPAA function is one of the best characterised candidate mechanisms to link early-life events with adult disease. It is also obvious that these effects are not limited to the fetal period. The effects of childhood abuse or neglect on adult HPAA function are well documented.¹³⁵ Also, normal variation in childhood environment is accompanied by individual differences in HPAA responsiveness to stress,¹³⁶ although little is thus far known about how these normal variations are related to HPAA function in adult life.

When interpreting studies in this field, it is important to remember that a hypoactive HPAA is also a key feature of disorders such as posttraumatic stress disorder,^137-139 fibromyalgia^139,140 and chronic fatigue syndrome.^139-141 While there is emerging evidence that susceptibility to these disorders could be programmed during early-life,⁹⁸ data so far remain inconclusive.

ASSOCIATIONS OF ADULT HEALTH STATUS WITH SPECIFIC PRENATAL CONDITIONS

Although birth measurements are convenient indicators of fetal environment, their value in indicating specific pregnancy conditions is relatively poor. The programming consequences of specific pregnancy conditions are important to recognise because they might offer different strategies for prevention. This is especially true for the programming of the HPAA, which in animal models can be achieved by various kinds of maternal stress, nutrient restriction and various postnatal conditions. In humans, the data are considerably more sparse.

There are some epidemiological studies that have assessed the effects of maternal undernutrition, most notably the Dutch Hunger Winter study. This study, in which the period of famine was sharply defined, has shown that the effects of undernutrition vary according to the time of the exposure.¹⁴² For example, exposure to famine during the first trimester, while unrelated to birth weight, is associated with an atherogenic lipid profile⁵⁴ and increased blood pressure response to psychosocial stress;¹⁴³ insulin secretion seems to be most sensitive to exposure during the second trimester,¹⁴⁴ and exposure during the second or third trimester is associated with increased risk of hospital treatment for major affective disorder.¹⁴⁵ However, exposure to famine was not associated with HPAA function, as assessed by 0.25 mg dexamethasone or 1 μg ACTH tests¹⁴⁶ or psychosocial stress test,¹⁴⁷ although the stressor used produced only small cortisol responses.

It is well established that maternal psychosocial stress is associated with shortened duration of gestation148 and alterations in the child’s subsequent behaviour.^103,149 While maternal stress during pregnancy and maternal salivary cortisol concentrations have also been directly associated with salivary cortisol in prepubertal children and adolescents,^150,151 not much is known about the significance of this phenomenon with regard to health during later life. This is an important arena of research because maternal psychosocial stress may be more accessible to prevention than many medical disorders of pregnancy.

Preeclampsia is a disorder which complicates 3-5% of pregnancies and is characterised by maternal hypertension, proteinuria and, frequently, placental dysfunction and fetal growth retardation. Preeclampsia is associated with reduced activity of placental 11β HSD2.^121,122 It thus seems that preeclampsia constitutes a promising model of fetal glucocorticoid excess, although there are surprisingly few studies assessing its long-term effects on the fetus. In comparing 60 12-year-old children born after a preeclamptic pregnancy with controls matched for sex, gestational age and intrauterine growth restriction, exposure to preeclampsia was associated with higher blood pressure but no difference in cortisol or DHEAS concentrations.¹⁵² However, the careful matching of the controls may have attenuated the differences. Other maternal conditions likely to have specific relevance to HPAA programming include polycystic ovary syndrome^153,154 and associated hyperandrogenemia, chorioamnionitis, which is associated with reduced placental 11β HSD2 function,¹⁵⁵ and maternal treatment with antenatal glucocorticoids administered to reduce the complications of preterm birth.

FUTURE PROSPECTS

The hypothesised effects of early-life environment on aging-related adult disease may have a fundamental impact on our understanding of these disorders and their prevention. Considerable research effort is however required before specific hypotheses with practical relevance to disease prevention are proved or disproved.

It is often not sufficiently acknowledged that commonly used indicators of early environment, such as birth weight, are a product of a large number of factors during pregnancy. Common pregnancy conditions that may result in low birth weight or short duration of gestation include maternal malnutrition, maternal psychosocial stress, disorders associated with placental insufficiency such as preeclampsia and maternal infection. These and other disorders may be dissimilar with regard to their programming effects on later stress-related disease. Studying the possible programming effects of specific pregnancy conditions will be a crucial step in translating the information into disease prevention.

REFERENCES

1. Bateson P, Barker D, Clutton-Brock T, et al, 2004 Developmental plasticity and human health. Nature 430: 419-421.
2. Barker DJ, Osmond C, Forsen TJ, Kajantie E, Eriksson JG, 2005 Trajectories of growth among children who have coronary events as adults. N Engl J Med 353: 1802-1809.
3. Barker DJ, Winter PD, Osmond C, Margetts B, Simmonds SJ, 1989 Weight in infancy and death from ischaemic heart disease. Lancet 2: 577-580.
4. Eriksson JG, Forsen T, Tuomilehto J, Osmond C, Barker DJ, 2000 Early growth, adult income, and risk of stroke. Stroke 31: 869-874.
5. Forsen T, Eriksson JG, Tuomilehto J, Osmond C, Barker DJ, 1999 Growth in utero and during childhood among women who develop coronary heart disease: longitudinal study. BMJ 319: 1403-1407.
6. Forsen T, Eriksson JG, Tuomilehto J, Teramo K, Osmond C, Barker DJ, 1997 Mother’s weight in pregnancy and coronary heart disease in a cohort of Finnish men: follow-up study. BMJ 315: 837-840.
7. Osmond C, Barker DJ, Winter PD, Fall CH, Simmonds SJ, 1993 Early growth and death from cardiovascular disease in women. BMJ 307: 1519-1524.
8. Osmond C, Kajantie E, Forsen T, Eriksson JG, Barker DJ, 2007 Infant growth and stroke in adult life: the Helsinki birth cohort study. Stroke 38: 264-270.
9. Stein CE, Fall CH, Kumaran K, Osmond C, Cox V, Barker DJ, 1996 Fetal growth and coronary heart disease in south India. Lancet 348: 1269-1273.
10. Leon DA, Lithell HO, Vagero D, et al, 1998 Reduced fetal growth rate and increased risk of death from ischaemic heart disease: cohort study of 15 000 Swedish men and women born 1915-29. BMJ 317: 241-245.
11. Lawlor DA, Ronalds G, Clark H, Smith GD, Leon DA, 2005 Birth weight is inversely associated with incident coronary heart disease and stroke among individuals born in the 1950s: findings from the Aberdeen Children of the 1950s prospective cohort study. Circulation 112: 1414-1418.
12. Huxley R, Owen CG, Whincup PH, et al, 2007 Is birth weight a risk factor for ischemic heart disease in later life? Am J Clin Nutr 85: 1244-1250.
13. Rich-Edwards JW, Stampfer MJ, Manson JE, et al, 1997 Birth weight and risk of cardiovascular disease in a cohort of women followed up since 1976. BMJ 315: 396-400.
14. Frankel S, Elwood P, Sweetnam P, Yarnell J, Smith GD, 1996 Birthweight, body-mass index in middle age, and incident coronary heart disease. Lancet 348: 1478-1480.
15. Hales CN, Barker DJ, Clark PM, et al, 1991 Fetal and infant growth and impaired glucose tolerance at age 64. BMJ 303: 1019-1022.
16. Eriksson JG, Osmond C, Kajantie E, Forsen T, Barker DJ, 2006 Patterns of growth among children who later develop type 2 diabetes or its risk factors. Diabetologia 49: 2853-2858
17. Newsome CA, Shiell AW, Fall CH, Phillips DI, Shier R, Law CM, 2003 Is birth weight related to later glucose and insulin metabolism?–A systematic review. Diabet Med 20: 339-348.
18. Lawlor DA, Davey Smith G, Clark H, Leon DA, 2006 The associations of birthweight, gestational age and childhood BMI with type 2 diabetes: findings from the Aberdeen Children of the 1950s cohort. Diabetologia 49: 2614-2617.
19. Huxley RR, Shiell AW, Law CM, 2000 The role of size at birth and postnatal catch-up growth in determining systolic blood pressure: a systematic review of the literature. J Hypertens 18: 815-831.
20. Yliharsila H, Eriksson JG, Forsen T, Kajantie E, Osmond C, Barker DJ, 2003 Self-perpetuating effects of birth size on blood pressure levels in elderly people. Hypertension 41: 446-450.
21. Barker DJ, Forsen T, Eriksson JG, Osmond C, 2002 Growth and living conditions in childhood and hypertension in adult life: a longitudinal study. J Hypertens 20: 1951-1956.
22. Eriksson JG, Forsen TJ, Kajantie E, Osmond C, Barker DJ, 2007 Childhood Growth and Hypertension in Later Life. Hypertension 49: 1415-1421.
23. Jarvelin MR, Sovio U, King V, et al, 2004 Early life factors and blood pressure at age 31 years in the 1966 northern Finland birth cohort. Hypertension 44: 838-846.
24. Hardy R, Kuh D, Langenberg C, Wadsworth ME, 2003 Birthweight, childhood social class, and change in adult blood pressure in the 1946 British birth cohort. Lancet 362: 1178-1183.
25. Dennison EM, Syddall HE, Sayer AA, Gilbody HJ, Cooper C, 2005 Birth weight and weight at 1 year are independent determinants of bone mass in the seventh decade: the Hertfordshire cohort study. Pediatr Res 57: 582-586.
26. Kajantie E, Phillips DI, Osmond C, Barker DJ, Forsen T, Eriksson JG, 2006 Spontaneous hypothyroidism in adult women is predicted by small body size at birth and during childhood. J Clin Endocrinol Metab 91: 4953-4956.
27. Wahlbeck K, Forsen T, Osmond C, Barker DJ, Eriksson JG, 2001 Association of schizophrenia with low maternal body mass index, small size at birth, and thinness during childhood. Arch Gen Psychiatr 58: 48-52.
28. Raikkonen K, Pesonen AK, Kajantie E, et al, 2007 Length of gestation predicts depressive symptoms at age 60. British Journal of Psychiatry (In press).
29. Thompson C, Syddall H, Rodin I, Osmond C, Barker DJ, 2001 Birth weight and the risk of depressive disorder in late life. Br J Psychiatry 179: 450-455.
30. Gale CR, Martyn CN, 2004 Birth weight and later risk of depression in a national birth cohort. Br J Psychiatry 184: 28-33.
31. Cheung YB, Khoo KS, Karlberg J, Machin D, 2002 Association between psychological symptoms in adults and growth in early life: longitudinal follow-up study. BMJ 325:749
32. Okasha M, Gunnell D, Holly J, Davey Smith G, 2002 Childhood growth and adult cancer. Best Pract Res Clin End Metab 16: 225-241.
33. Okasha M, McCarron P, Gunnell D, Smith GD, 2003 Exposures in childhood, adolescence and early adulthood and breast cancer risk: a systematic review of the literature. Breast Cancer Res Treat 78: 223-276.
34. Barker DJ, 1998 Programming the baby. In: Mothers, babies and health in later life, Edinburgh, Churchill Livingstone; pp, 13-41.
35. Gluckman PD, Hanson M, 2004 The Fetal Matrix: evolutions, development and disease. Cambridge: Cambridge University Press.
36. Barker DJ, 2004 The developmental origins of adult disease. J Am Coll Nutr 23: 588S-595S.
37. Gillman MW, 2005 Developmental origins of health and disease. N Engl J Med 353: 1848-1850.
38. National Institute of Child Health and Development, 2003 Pregnancy and Perinatology Branch (PPB). A strategic plan 2005-2010. Appendix B3 http://www.nichd.nih.gov/publications/pubs/ppb_strategicplan_2010/upload/PartI.pdf. National Institute of Child Health and Development
39. National Institute of Aging, 2003 Determinants of aging and health across the life span: potential new insights from longitudinal studies. Report of the July 2003 meeting of the NIA longitudinal data on aging work group http://wwwnianihgov/NR/rdonlyres/9904C479-4ADD-4494-984E-B1FC7AFA3718
/1955/July2003LDA1pdf
40. WHO 2006 Promoting optimal fetal development. Report of a technical consultation. http://www.who.int/nutrition/publications/fetal_dev_report_EN.pdf. World Health Organization
41. Barker DJ, Osmond C, Forsen TJ, Kajantie E, Eriksson JG, 2005 Trajectories of growth among children who have coronary events as adults. N Engl J Med 353: 1802-1809.
42. Osmond C, Kajantie E, Forsen TJ, Eriksson JG, Barker DJ, 2007 Infant growth and stroke in adult life: the Helsinki birth cohort study. Stroke 38: 264-270.
43. Hovi P, Andersson S, Eriksson JG, et al, 2007 Glucose regulation in young adults with very low birth weight – The Helsinki Study of Very Low Birth Weight Adults. N Engl J Med 356: 2053-2063.
44. Johansson S, Iliadou A, Bergvall N, Tuvemo T, Norman M, Cnattingius S, 2005 Risk of high blood pressure among young men increases with the degree of immaturity at birth. Circulation 112: 3430-3436.
45. Doyle LW, Faber B, Callanan C, Morley R, 2003 Blood pressure in late adolescence and very low birth weight. Pediatrics 111: 252-257.
46. Hack M, 2006 Young adult outcomes of very-low-birth-weight children. Semin Fetal Neonatal Med 11: 127-137.
47. Koupil I, Leon DA, Lithell HO, 2005 Length of gestation is associated with mortality from cerebrovascular disease. J Epidemiol Community Health 59: 473-474.
48. Eriksson JG, Forsιn T, Tuomilehto J, Winter PD, Osmond C, Barker DJ, 1999 Catch-up growth in childhood and death from coronary heart disease: longitudinal study. BMJ 318: 427-431.
49. Ylihδrsila H, Kajantie E, Osmond C, Forsen T, Barker DJ, Eriksson JG, 2007 Birth size, adult body composition and muscle strength in later life. Int J Obes (Lond) 31: 1392-1399.
50. Luyckx VA, Brenner BM, 2005 Low birth weight, nephron number, and kidney disease. Kidney Int Suppl: S68-77.
51. Martyn CN, Greenwald SE, 2001 A hypothesis about a mechanism for the programming of blood pressure and vascular disease in early life. Clin Exp Pharmacol Physiol 28: 948-951.
52. Huxley R, Owen CG, Whincup PH, Cook DG, Colman S, Collins R, 2004 Birth weight and subsequent cholesterol levels: exploration of the “fetal origins” hypothesis. JAMA 292: 2755-2764.
53. Kivimaki M, Lawlor DA, Smith GD, et al, 2006 Early socioeconomic position and blood pressure in childhood and adulthood: the Cardiovascular Risk in Young Finns Study. Hypertension 47: 39-44.
54. Roseboom TJ, van der Meulen JH, Osmond C, Barker DJ, Ravelli AC, Bleker OP, 2000 Plasma lipid profiles in adults after prenatal exposure to the Dutch famine. Am J Clin Nutr 72: 1101-1106.
55. Eriksson JG, Osmond C, Kajantie E, Forsen TJ, Barker DJ, 2006 Patterns of growth among children who later develop type 2 diabetes or its risk factors. Diabetologia 49: 2853-2858.
56. Wei JN, Sung FC, Li CY, et al, 2003 Low birth weight and high birth weight infants are both at an increased risk to have type 2 diabetes among schoolchildren in Taiwan. Diabetes Care 26: 343-348.
57. McCance DR, Pettitt DJ, Hanson RL, Jacobsson LT, Knowler WC, Bennett PH, 1994 Birth weight and non-insulin dependent diabetes: thrifty genotype, thrifty phenotype, or surviving small baby genotype? BMJ 308: 942-945.
58. Koo WW, Walters JC, Hockman EM, 2004 Body composition in neonates: relationship between measured and derived anthropometry with dual-energy X-ray absorptiometry measurements. Pediatr Res 56: 694-700.
59. McMillen IC, Robinson JS, 2005 Developmental origins of the metabolic syndrome: prediction, plasticity, and programming. Physiol Rev 85: 571-633.
60. Phillips DI, 1996 Insulin resistance as a programmed response to fetal undernutrition. Diabetologia 39: 1119-1122.
61. Bhargava SK, Sachdev HS, Fall CH, et al, 2004 Relation of serial changes in childhood body-mass index to impaired glucose tolerance in young adulthood. N Engl J Med 350: 865-875.
62. Yliharsila H, Kajantie E, Osmond C, Forsen T, Barker DJ, Eriksson JG, 2007 Body mass index during childhood and adult body composition in men and women aged 56 to 70 years. Am J Clin Nutr (In press)
63. Sachdev HS, Fall CH, Osmond C, et al, 2005 Anthropometric indicators of body composition in young adults: relation to size at birth and serial measurements of body mass index in childhood in the New Delhi birth cohort. Am J Clin Nutr 82: 456-466.
64. WHO 1995 Physical status: the use and interpretation of anthropometry. Report of a WHO Expert Committee. World Health Organ Tech Rep Ser 854: 1-452.
65. Singhal A, Lucas A, 2004 Early origins of cardiovascular disease: is there a unifying hypothesis? Lancet 363: 1642-1645.
66. Ong KK, Petry CJ, Emmett PM, et al, 2004 Insulin sensitivity and secretion in normal children related to size at birth, postnatal growth, and plasma insulin-like growth factor-I levels. Diabetologia 47: 1064-1070.
67. Law CM, Shiell AW, Newsome CA, et al, 2002 Fetal, infant, and childhood growth and adult blood pressure: a longitudinal study from birth to 22 years of age. Circulation 105: 1088-1092.
68. Singhal A, Fewtrell M, Cole TJ, Lucas A, 2003 Low nutrient intake and early growth for later insulin resistance in adolescents born preterm. Lancet 361: 1089-1097.
69. Singhal A, Cole TJ, Fewtrell M, Deanfield J, Lucas A, 2004 Is slower early growth beneficial for long-term cardiovascular health? Circulation 109: 1108-1113.
70. Singhal A, Cole TJ, Fewtrell M, Lucas A, 2004 Breastmilk feeding and lipoprotein profile in adolescents born preterm: follow-up of a prospective randomised study. Lancet 363: 1571-1578.
71. Demmelmair H, von Rosen J, Koletzko B, 2006 Long-term consequences of early nutrition. Early Hum Dev 82: 567-574.
72. Owen CG, Whincup PH, Odoki K, Gilg JA, Cook DG, 2002 Infant feeding and blood cholesterol: a study in adolescents and a systematic review. Pediatrics 110: 597-608.
73. Owen CG, Whincup PH, Gilg JA, Cook DG, 2003 Effect of breast feeding in infancy on blood pressure in later life: systematic review and meta-analysis. BMJ 327: 1189-1195.
74. Martin RM, Gunnell D, Smith GD, 2005 Breastfeeding in infancy and blood pressure in later life: systematic review and meta-analysis. Am J Epidemiol 161: 15-26.
75. Owen CG, Martin RM, Whincup PH, Smith GD, Cook DG, 2006 Does breastfeeding influence risk of type 2 diabetes in later life? A quantitative analysis of published evidence. Am J Clin Nutr 84: 1043-1054.
76. Owen CG, Martin RM, Whincup PH, Smith GD, Cook DG, 2005 Effect of infant feeding on the risk of obesity across the life course: a quantitative review of published evidence. Pediatrics 115: 1367-1377.
77. Owen CG, Martin RM, Whincup PH, Davey-Smith G, Gillman MW, Cook DG, 2005 The effect of breastfeeding on mean body mass index throughout life: a quantitative review of published and unpublished observational evidence. Am J Clin Nutr 82: 1298-1307.
78. Dewey KG, Peerson JM, Brown KH, et al, 1995 Growth of breast-fed infants deviates from current reference data: a pooled analysis of US, Canadian, and European data sets. World Health Organization Working Group on Infant Growth. Pediatrics 96: 495-503.
79. Raikkonen K, Pesonen AK, Kajantie E, et al, 2007 Length of gestation and depressive symptoms at age 60 years. Br J Psychiatry 190: 469-474.
80. Case A, Paxson C, 2006 Stature and status: height, ability, and labor market outcomes. https://wwwprincetonedu/~rpds/downloads/Case_Paxson_Stature_Status_8312006pdf
81. Richards M, Hardy R, Kuh D, Wadsworth ME, 2002 Birthweight, postnatal growth and cognitive function in a national UK birth cohort. Int J Epidemiol 31: 342-348.
82. Boas F, 1941 The relation between physical and mental development. Science 93: 339-342.
83. Gale CR, O’Callaghan FJ, Bredow M, Martyn CN, 2006 The influence of head growth in fetal life, infancy, and childhood on intelligence at the ages of 4 and 8 years. Pediatrics 118: 1486-1492.
84. Kind D, 1876 Ueber das Langenwachstum der Idioten. Archiv fur Psychiatrie 6: 447-472.
85. Wickett JC, Vernon PA, Lee DH, 2000 Relationships between factors of intelligence and brain volume. Person Individ Differ 29: 1095-1122.
86. Abbott RD, White LR, Ross GW, et al, 1998 Height as a marker of childhood development and late-life cognitive function: the Honolulu-Asia Aging Study. Pediatrics 102: 602-609.
87. Gale CR, Walton S, Martyn CN, 2003 Foetal and postnatal head growth and risk of cognitive decline in old age. Brain 126: 2273-2278.
88. Nilsson PM, Nilsson JA, Ostergren PO, Rasmussen F, 2004 Fetal growth predicts stress susceptibility independent of parental education in 161991 adolescent Swedish male conscripts. J Epidemiol Community Health 58: 571-573.
89. Silva A, Metha Z, O’Callaghan FJ, 2006 The relative effect of size at birth, postnatal growth and social factors on cognitive function in late childhood. Ann Epidemiol 16: 469-476.
90. Shenkin SD, Starr JM, Deary IJ, 2004 Birth weight and cognitive ability in childhood: a systematic review. Psychol Bull 130: 989-1013.
91. Beeri MS, Davidson M, Silverman JM, Noy S, Schmeidler J, Goldbourt U, 2005 Relationship between body height and dementia. Am J Geriatr Psychiatry 13: 116-123.
92. Snowdon DA, Kemper SJ, Mortimer JA, Greiner LH, Wekstein DR, Markesbery WR, 1996 Linguistic ability in early life and cognitive function and Alzheimer’s disease in late life. Findings from the Nun Study. JAMA 275: 528-532.
93. Ferrari S, Rizzoli R, Slosman D, Bonjour JP, 1998 Familial resemblance for bone mineral mass is expressed before puberty. J Clin Endocrinol Metab 83: 358-361.
94. Cooper C, Westlake S, Harvey N, Javaid K, Dennison E, Hanson M, 2006 Review: developmental origins of osteoporotic fracture. Osteoporos Int 17: 337-347.
95. Cooper C, Cawley M, Bhalla A, et al, 1995 Childhood growth, physical activity, and peak bone mass in women. J Bone Miner Res 10: 940-947.
96. Cooper C, Eriksson JG, Forsen T, Osmond C, Tuomilehto J, Barker DJ, 2001 Maternal height, childhood growth and risk of hip fracture in later life: a longitudinal study. Osteoporos Int 12: 623-629.
97. Crimmins EM, Finch CE, 2006 Infection, inflammation, height, and longevity. Proc Natl Acad Sci USA 103: 498-503.
98. Kajantie E, 2006 Fetal origins of stress-related adult disease. Annals of the New York Academy of Sciences 1083: 11-27.
99. Weaver IC, Cervoni N, Champagne FA, et al, 2004 Epigenetic programming by maternal behavior. Nat Neurosci 7: 847-854.
100. Matthews SG, 2002 Early programming of the hypothalamo-pituitary-adrenal axis. Trends Endocrinol Metab 13: 373-380.
101. Seckl JR, Meaney MJ, 2004 Glucocorticoid programming. Ann N Y Acad Sci 1032: 63-84.
102. Kaiser S, Sachser N, 2005 The effects of prenatal social stress on behaviour: mechanisms and function. Neurosci Biobehav Rev 29: 283-294.
103. Huizink AC, Mulder EJ, Buitelaar JK, 2004 Prenatal stress and risk for psychopathology: specific effects or induction of general susceptibility? Psychol Bull 130:115-142.
104. Koupil I, Mann V, Leon DA, Lundberg U, Byberg L, Vagero D, 2005 Morning cortisol does not mediate the association of size at birth with blood pressure in children born from full-term pregnancies. Clin Endocrinol (Oxf) 62: 661-666.
105. Dahlgren J, Boguszewski M, Rosberg S, Albertsson-Wikland K, 1998 Adrenal steroid hormones in short children born small for gestational age. Clin Endocrinol (Oxf) 49: 353-361.
106. Rosmalen JG, Oldehinkel AJ, Ormel J, de Winter AF, Buitelaar JK, Verhulst FC, 2005 Determinants of salivary cortisol levels in 10-12 year old children; a population-based study of individual differences. Psychoneuroendocrinology 30: 483-495.
107. Kajantie E, Eriksson J, Osmond C, et al, 2004 Size at birth, the metabolic syndrome and 24-h salivary cortisol profile. Clin Endocrinol (Oxf) 60: 201-207.
108. Wust S, Entringer S, Federenko IS, Schlotz W, Hellhammer DH, 2005 Birth weight is associated with salivary cortisol responses to psychosocial stress in adult life. Psychoneuroendocrinology 30: 591-598.
109. Levitt NS, Lambert EV, Woods D, Hales CN, Andrew R, Seckl JR, 2000 Impaired glucose tolerance and elevated blood pressure in low birth weight, non-obese, young South African adults: early programming of cortisol axis. J Clin Endocrinol Metab 85: 4611-4618.
110. Phillips DI, Barker DJ, Fall CH, et al, 1998 Elevated plasma cortisol concentrations: a link between low birth weight and the insulin resistance syndrome? J Clin Endocrinol Metab 83: 757-760.
111. Phillips DI, Walker BR, Reynolds RM, et al, 2000 Low birth weight predicts elevated plasma cortisol concentrations in adults from 3 populations. Hypertension 35: 1301-1306.
112. Reynolds RM, Walker BR, Syddall HE, Andrew R, Wood PJ, Phillips DI, 2005 Is there a gender difference in the associations of birthweight and adult hypothalamic-pituitary-adrenal axis activity? Eur J Endocrinol 152: 249-253.
113. Szathmαri M, Vasarhelyi B, Reusz G, Tulassay T, 2000 Adult cardiovascular risk factors in premature babies. Lancet 356: 939-940.
114. Kajantie E, Phillips DI, Andersson S, et al, 2002 Size at birth, gestational age and cortisol secretion in adult life: foetal programming of both hyper- and hypocortisolism? Clin Endocrinol (Oxf) 57: 635-641.
115. Ward AM, Syddall HE, Wood PJ, Chrousos GP, Phillips DI, 2004 Fetal programming of the hypothalamic-pituitary-adrenal (HPA) axis: low birth weight and central HPA regulation. J Clin Endocrinol Metab 89: 1227-1233.
116. Kajantie E, Feldt K, Raikkonen K, et al, 2007 Body size at birth predicts Hypothalamic-Pituitary-Adrenal axis response to psychosocial stress at age 60 to 70 years. J Clin Endocrinol Metab 92: 4094-4100.
117. Murphy VE, Smith R, Giles WB, Clifton VL, 2006 Endocrine regulation of human fetal growth: the role of the mother, placenta, and fetus. Endocr Rev 27: 141-169.
118. Valsamakis G, Kanaka-Gantenbein C, Malamitsi-Puchner A, Mastorakos G, 2006 Causes of intrauterine growth restriction and the postnatal development of the metabolic syndrome. Ann N Y Acad Sci 1092: 138-147.
119. Kajantie E, Dunkel L, Turpeinen U, et al, 2003 Placental 11 beta-hydroxysteroid dehydrogenase-2 and fetal cortisol/cortisone shuttle in small preterm infants. J Clin Endocrinol Metab 88: 493-500.
120. Shams M, Kilby MD, Somerset DA, et al, 1998 11Beta-hydroxysteroid dehydrogenase type 2 in human pregnancy and reduced expression in intrauterine growth restriction. Hum Reprod 13: 799-804.
121. McCalla CO, Nacharaju VL, Muneyyirci-Delale O, Glasgow S, Feldman JG, 1998 Placental 11 beta-hydroxysteroid dehydrogenase activity in normotensive and pre-eclamptic pregnancies. Steroids 63: 511-515.
122. Schoof E, Girstl M, Frobenius W, et al, 2001 Decreased gene expression of 11beta-hydroxysteroid dehydrogenase type 2 and 15-hydroxyprostaglandin dehydrogenase in human placenta of patients with preeclampsia. J Clin Endocrinol Metab 86: 1313-1317.
123. Stewart PM, Rogerson FM, Mason JI, 1995 Type 2 11 beta-hydroxysteroid dehydrogenase messenger ribonucleic acid and activity in human placenta and fetal membranes: its relationship to birth weight and putative role in fetal adrenal steroidogenesis. J Clin Endocrinol Metab 80: 885-890.
124. Rogerson FM, Kayes KM, White PC, 1997 Variation in placental type 2 11beta-hydroxysteroid dehydrogenase activity is not related to birth weight or placental weight. Mol Cell Endocrinol 128: 103-109.
125. McLean M, Smith R, 2001 Corticotrophin-releasing hormone and human parturition. Reproduction 121: 493-501.
126. Robinson BG, Emanuel RL, Frim DM, Majzoub JA, 1988 Glucocorticoid stimulates expression of corticotropin-releasing hormone gene in human placenta. Proc Natl Acad Sci USA 85: 5244-5248.
127. Ziegler R, Kasperk C, 1998 Glucocorticoid-induced osteoporosis: prevention and treatment. Steroids 63: 344-348.
128. Newell-Price J, Trainer P, Besser M, Grossman A, 1998 The diagnosis and differential diagnosis of Cushing’s syndrome and pseudo-Cushing’s states. Endocr Rev 19: 647-672.
129. Bourdeau I, Bard C, Forget H, Boulanger Y, Cohen H, Lacroix A, 2005 Cognitive function and cerebral assessment in patients who have Cushing’s syndrome. Endocrinol Metab Clin North Am 34: 357-369
130. Makras P, Toloumis G, Papadogias D, Kaltsas GA, Besser M, 2006 The diagnosis and differential diagnosis of endogenous Cushing’s syndrome. Hormones (Athens) 5: 231-250.
131. Filipovsky J, Ducimetiere P, Eschwege E, Richard JL, Rosselin G, Claude JR, 1996 The relationship of blood pressure with glucose, insulin, heart rate, free fatty acids and plasma cortisol levels according to degree of obesity in middle-aged men. J Hypertens 14: 229-235.
132. Reynolds RM, Walker BR, Syddall HE, et al, 2001 Altered control of cortisol secretion in adult men with low birth weight and cardiovascular risk factors. J Clin Endocrinol Metab 86: 245-250.
133. Ilias I, Alesci S, Gold PW, Chrousos GP, 2006 Depression and osteoporosis in men: association or casual link? Hormones (Athens) 5: 9-16.
134. Brown ES, Varghese FP, McEwen BS, 2004 Association of depression with medical illness: does cortisol play a role? Biol Psychiatry 55: 1-9.
135. Heim C, Plotsky PM, Nemeroff CB, 2004 Importance of studying the contributions of early adverse experience to neurobiological findings in depression. Neuropsychopharmacology 29: 641-648.
136. Gunnar M, Quevedo K, 2007 The neurobiology of stress and development. Annu Rev Psychol 58: 145-173.
137. Yehuda R, Engel SM, Brand SR, Seckl J, Marcus SM, Berkowitz GS, 2005 Transgenerational effects of posttraumatic stress disorder in babies of mothers exposed to the World Trade Center attacks during pregnancy. J Clin Endocrinol Metab 90: 4115-4118.
138. Yehuda R, 2002 Post-traumatic stress disorder. N Engl J Med 346: 108-114.
139. Fries E, Hesse J, Hellhammer J, Hellhammer DH, 2005 A new view on hypocortisolism. Psychoneuroendocrinology 30: 1010-1016.
140. Parker AJ, Wessely S, Cleare AJ, 2001 The neuroendocrinology of chronic fatigue syndrome and fibromyalgia. Psychol Med 31: 1331-1345.
141. Cleare AJ, 2003 The neuroendocrinology of chronic fatigue syndrome. Endocr Rev 24: 236-252.
142. Roseboom TJ, van der Meulen JH, Ravelli AC, Osmond C, Barker DJ, Bleker OP, 2001 Effects of prenatal exposure to the Dutch famine on adult disease in later life: an overview. Mol Cell Endocrinol 185: 93-98.
143. Painter RC, de Rooij SR, Bossuyt PM, et al, 2006 Blood pressure response to psychological stressors in adults after prenatal exposure to the Dutch famine. J Hypertens 24: 1771-1778.
144. de Rooij SR, Painter RC, Phillips DI, et al, 2006 Impaired insulin secretion after prenatal exposure to the Dutch famine. Diabetes Care 29: 1897-1901.
145. Brown AS, van Os J, Driessens C, Hoek HW, Susser ES, 2000 Further evidence of relation between prenatal famine and major affective disorder. Am J Psychiatry 157: 190-195.
146. de Rooij SR, Painter RC, Phillips DI, et al, 2006 Hypothalamic-pituitary-adrenal axis activity in adults who were prenatally exposed to the Dutch famine. Eur J Endocrinol 155: 153-160.
147. de Rooij SR, Painter RC, Phillips DI, et al, 2006 Cortisol responses to psychological stress in adults after prenatal exposure to the Dutch famine. Psychoneuroendocrinology 31: 1257-1265.
148. Glynn LM, Wadhwa PD, Dunkel-Schetter C, Chicz-Demet A, Sandman CA, 2001 When stress happens matters: effects of earthquake timing on stress responsivity in pregnancy. Am J Obstet Gynecol 184: 637-642.
149. Van den Bergh BR, Mulder EJ, Mennes M, Glover V, 2005 Antenatal maternal anxiety and stress and the neurobehavioural development of the fetus and child: links and possible mechanisms. A review. Neurosci Biobehav Rev 29: 237-258.
150. Van den Bergh BR, Van Calster B, Smits T, Van Huffel S, Lagae L, 2008 Antenatal Maternal Anxiety is Related to HPA-Axis Dysregulation and Self-Reported Depressive Symptoms in Adolescence: A Prospective Study on the Fetal Origins of Depressed Mood. Neuropsychopharmacology 33: 536-545.
151. Gutteling BM, de Weerth C, Buitelaar JK, 2005 Prenatal stress and children’s cortisol reaction to the first day of school. Psychoneuroendocrinology 30: 541-549.
152. Tenhola S, Rahiala E, Martikainen A, Halonen P, Voutilainen R, 2003 Blood pressure, serum lipids, fasting insulin, and adrenal hormones in 12-year-old children born with maternal preeclampsia. J Clin Endocrinol Metab 88: 1217-1222.
153. Boomsma CM, Eijkemans MJ, Hughes EG, Visser GH, Fauser BC, Macklon NS, 2006 A meta-analysis of pregnancy outcomes in women with polycystic ovary syndrome. Hum Reprod Update 12: 673-683.
154. Diamanti-Kandarakis E, Christakou CD, Kandaraki E, Alexandraki KI, 2007 Early onset adiposity: a pathway to polycystic ovary syndrome in adolescents? Hormones (Athens) 6: 210-217.
155. Johnstone JF, Bocking AD, Unlugedik E, Challis JR, 2005 The effects of chorioamnionitis and betamethasone on 11beta hydroxysteroid dehydrogenase types 1 and 2 and the glucocorticoid receptor in preterm human placenta. J Soc Gynecol Investig 12: 238-245.

Address for correspondence:
Eero Kajantie, National Public Health Institute,
Mannerheimintie 166, 00300 Helsinki, Finland,
Tel.: +358-9-47448610, Fax: +358-9-47448934,
e-mail: eero.kajantie@helsinki.fi

Received 16-10-07, Revised 10-12-07, Accepted 20-01-08