Improving women's diet quality preconceptionally and during gestation: effects on birth weight and prevalence of low birth weight--a randomized controlled efficacy trial in India (Mumbai Maternal Nutrition Project).

BACKGROUND: Low birth weight (LBW) is an important public health problem in undernourished populations. OBJECTIVE: We tested whether improving women's dietary micronutrient quality before conception and throughout pregnancy increases birth weight in a high-risk Indian population. DESIGN: The study was a nonblinded, individually randomized controlled trial. The intervention was a daily snack made from green leafy vegetables, fruit, and milk (treatment group) or low-micronutrient vegetables (potato and onion) (control group) from ≥ 90 d before pregnancy until delivery in addition to the usual diet. Treatment snacks contained 0.69 MJ of energy (controls: 0.37 MJ) and 10-23% of WHO Reference Nutrient Intakes of ß-carotene, riboflavin, folate, vitamin B-12, calcium, and iron (controls: 0-7%). The primary outcome was birth weight. RESULTS: Of 6513 women randomly assigned, 2291 women became pregnant, 1962 women delivered live singleton newborns, and 1360 newborns were measured. In an intention-to-treat analysis, there was no overall increase in birth weight in the treatment group (+26 g; 95% CI: -15, 68 g; P = 0.22). There was an interaction (P < 0.001) between the allocation group and maternal prepregnant body mass index (BMI; in kg/m(2)) [birth-weight effect: -23, +34, and +96 g in lowest (<18.6), middle (18.6-21.8), and highest (>21.8) thirds of BMI, respectively]. In 1094 newborns whose mothers started supplementation ≥ 90 d before pregnancy (per-protocol analysis), birth weight was higher in the treatment group (+48 g; 95% CI: 1, 96 g; P = 0.046). Again, the effect increased with maternal BMI (-8, +79, and +113 g; P-interaction = 0.001). There were similar results for LBW (intention-to-treat OR: 0.83; 95% CI: 0.66, 1.05; P = 0.10; per-protocol OR = 0.76; 95% CI: 0.59, 0.98; P = 0.03) but no effect on gestational age in either analysis. CONCLUSIONS: A daily snack providing additional green leafy vegetables, fruit, and milk before conception and throughout pregnancy had no overall effect on birth weight. Per-protocol and subgroup analyses indicated a possible increase in birth weight if the mother was supplemented ≥ 3 mo before conception and was not underweight. This trial was registered at www.controlled-trials.com/isrctn/ as ISRCTN62811278.

Prenatal and childhood growth, and hospitalization for alcohol use disorders in adulthood: the Helsinki birth cohort study.

BACKGROUND: Small birth size - an indicator of a sub-optimal prenatal environment - and variation in growth after birth have been associated with non-communicable diseases in later life. We tested whether birth size or growth in childhood associated with the risk of hospital admission for alcohol use disorders (AUDs) from early to late adulthood. METHODS: The sample comprised 6544 men and 6050 women born between 1934 and 1944 in Helsinki, Finland. Data on anthropometric measures were extracted from medical records and diagnoses of AUD from the Finnish Hospital Discharge Register and Causes of Death Register covering a 40-year period from 1969 to 2008. RESULTS: Altogether 171 women (2.8%) and 657 men (10.0%) were diagnosed at a hospital with AUD. After adjusting for major confounders, shorter length at birth, shorter height up to two years of age, and lower weight at two years associated with hospitalization for AUD in women. In men, slower growth in height, particularly from 2 to 7 years, and slower weight gain from 7 to 11 years as well as shorter height and lower weight at 7 and 11 years associated with a diagnosis of AUD in men. CONCLUSIONS: Pre- and postnatal growth associates with the risk for AUD later in life differently in women than in men: the fetal period and infancy seem to be the sensitive periods for women, whereas those for men the occur from toddlerhood onwards.

The developmental origins of chronic rheumatic heart disease.

OBJECTIVES: Programming is the phenomenon whereby the body's structures and functions are permanently set by nutrition and other influences during early development. There is increasing evidence that programming in utero initiates cardiovascular disease. We hypothesized that susceptibility to developing chronic rheumatic heart disease on exposure to Streptococcus pyogenes is programmed. METHODS: We studied hospital admissions and deaths from chronic rheumatic heart disease in 20,431 people born in Helsinki, Finland, during 1924-1944. One hundred and one people, 56 men, and 45 women, had chronic rheumatic heart disease. RESULTS: The disease was not associated with body or placental size at birth. It was, however, associated with a long umbilical cord so that the hazard ratio for the disease was 1.23 (95% CI 1.04-1.45, P = 0.02) for every 10 cm increase in cord length. This association was present in people with mitral valve disease, hazard ratio 1.5 (1.20-1.89, P < 0.0001), but not in people with aortic valve disease, hazard ratio 1.0 (0.76-1.33, P = 0.97). Growing up in large households increased the risk of rheumatic heart disease. CONCLUSION: Longer umbilical cords have more spirals and a greater density of spirals per unit of length. Increased spiraling will increase the resistance to flow and the pressure load on the fetal heart. This could affect the development of the heart's valves and make them more vulnerable to the autoimmune process initiated by Streptococcus pyogenes. The mitral valve may be more vulnerable than the aortic valve because the valve leaflets are larger and therefore have greater wall stress.

Early life stress and physical and psychosocial functioning in late adulthood.

BACKGROUND: Severe stress experienced in early life may have long-term effects on adult physiological and psychological health and well-being. We studied physical and psychosocial functioning in late adulthood in subjects separated temporarily from their parents in childhood during World War II. METHODS: The 1803 participants belong to the Helsinki Birth Cohort Study, born 1934-44. Of them, 267 (14.8%) had been evacuated abroad in childhood during WWII and the remaining subjects served as controls. Physical and psychosocial functioning was assessed with the Short Form 36 scale (SF-36) between 2001 and 2004. A test for trends was based on linear regression. All analyses were adjusted for age at clinical examination, social class in childhood and adulthood, smoking, alcohol intake, physical activity, body mass index, cardiovascular disease and diabetes. RESULTS: Physical functioning in late adulthood was lower among the separated men compared to non-separated men (b = -0.40, 95% confidence interval [95% CI]: -0.71 to -0.08). Those men separated in school age (>7 years) and who were separated for a duration over 2 years had the highest risk for lower physical functioning (b = -0.89, 95% CI: -1.58 to -0.20) and (b = -0.65, 95% CI: -1.25 to -0.05), respectively). Men separated for a duration over 2 years also had lower psychosocial functioning (b = -0.70, 95% CI: -1.35 to -0.06). These differences in physical and psychosocial functioning were not observed among women. CONCLUSION: Early life stress may increase the risk for impaired physical functioning in late adulthood among men. Timing and duration of the separation influenced the physical and psychosocial functioning in late adulthood.

The obstetric origins of health for a lifetime.

There is a new "developmental" model for the origins of a wide range of chronic diseases. Under this model the causes to be identified are linked to normal variations in fetoplacental development. These variations are thought to lead to variations in the supply of nutrients to the baby that permanently alter gene expression, a process known as "programming." According to the developmental model variations in the processes of development program the function of a few key systems that are linked to disease, including the immune system, antioxidant defenses, inflammatory responses, and the number and quality of stem cells.

The shape of the placental surface at birth and colorectal cancer in later life.

OBJECTIVES: Many chronic diseases, including certain cancers, may originate through variations in the supply of nutrients to the fetus. These variations change gene expression and permanently set the structure and function of the body, a process known as programming. Fetal nutrition depends on the mother's metabolism and nutritional reserves, and on the placenta's ability to transfer nutrients from mother to baby. In this study, we examine how colorectal cancer is related to maternal and placental characteristics. METHODS: We ascertained 275 cases of colorectal cancer among the 20,431 people in the Helsinki Birth Cohort, who were born during 1924-1944 and whose body size at birth was recorded, together with the shape and size of the placenta. RESULTS: Hazard ratios for colorectal cancer increased as the placental surface became longer and more oval. The hazard ratio was 2.3 (95% CI 1.2-4.7) among people in whom the difference between the length and breadth of the surface exceeded 6 cm, compared with those in whom there was no difference. Colorectal cancer was unrelated to other placental measurements or to body size at birth. CONCLUSION: An oval placental surface at birth is associated with later colorectal cancer. The shape of the placental surface is determined by events at around 8-12 weeks gestation. We speculate that, if the spiral arteries open prematurely, the surface becomes more oval and the fetus is at risk of oxidative damage at a time when the colon is differentiating.

Early growth and non-alcoholic fatty liver disease in adulthood-the NAFLD liver fat score and equation applied on the Helsinki Birth Cohort Study.

INTRODUCTION: Prenatal and childhood growth influence the risk of developing the metabolic syndrome and type 2 diabetes. Both conditions are associated with non-alcoholic fatty liver disease (NAFLD). Our aim was to explore the associations between early growth and adult NAFLD. METHODS: We studied 1587 individuals from the Helsinki Birth Cohort Study (HBCS) born 1934-44 for whom birth, childhood, and adult clinical data were available. NAFLD was defined using the NAFLD liver fat score and equation. The score was converted into a dichotomous variable, with outcomes defined as either a positive or negative score. The equation predicts liver fat percentage. RESULTS: A positive score was found in 43% of men and 22.5% of women. Several measurements of birth and childhood body size were negatively associated with both NAFLD outcomes after adjustment for adult BMI. Those from the smallest BMI tertile at age 2 who were obese in adulthood had an OR of 18.5 for a positive score compared to those from the same group who were normal weight in adulthood. CONCLUSIONS: A larger childhood body size was negatively associated with NAFLD outcomes. Individuals who are small during early childhood and obese as adults seem to be at the highest risk of developing NAFLD.

Trajectories of physical growth and personality dimensions of the Five-Factor Model.

Although physical growth in early life is associated with the risk of somatic illnesses and psychological disorders in adulthood, few studies have focused upon the associations between growth and dimensional personality traits. We examined the associations between pre- and postnatal growth in height, weight, and body mass index (BMI) and Five-Factor Model dimensions in adulthood. From the Helsinki Birth Cohort Study, 1,682 participants completed the NEO Personality Inventory (NEO-PI) at an average age of 63 years. Growth estimates were derived based on medical records. Adjusting for gestational length and sociodemographic variables, birth weight showed a quadratic association with neuroticism; participants with low birth weight scored the highest on neuroticism. Larger ponderal index at birth predicted higher agreeableness, while average ponderal index predicted higher conscientiousness. BMI and weight growth trajectories from birth to adulthood were associated with agreeableness and conscientiousness. More specifically, less BMI and weight gain between 7 and 11 years and/or between 11 years and adulthood were associated with higher conscientiousness and higher agreeableness. Height and weight growth trajectories from birth to adulthood were associated with extraversion: faster height and weight growth between birth and 6 months, slower height growth between 7 and 11 years, and faster weight gain between 11 years and adulthood were associated with higher extraversion. Openness to experience was not associated with growth. This longitudinal study supports an association between pre- and postnatal physical growth and 4 of the Five-Factor Model personality dimensions in adulthood.

The velocity of fetal growth is associated with the breadth of the placental surface, but not with the length.

OBJECTIVES: Studies of the placenta in pregnancies complicated by pre-eclampsia have led to the suggestion that tissue along the length and breadth of its surface has different functions. A recent study in Saudi Arabia showed that the body size of newborn babies was related to the breadth of the surface at birth but not to its length. We have now examined whether the association between placental breadth and body size reflects large size of the baby from an early stage of gestation or rapid growth between early and late gestation. METHODS: We studied 230 women who gave birth to singleton babies in King Khalid Hospital, Riyadh, Saudi Arabia. In total, 176 had ultrasound measurements both before 28 weeks and at 28 weeks or later, which we define as early and late gestation. We used these to calculate growth velocities between early and late gestation, which we expressed as the change in standard deviation scores over a 10-week period. RESULTS: The breadth of the placental surface was correlated with fetal growth velocity. The correlation coefficients were 0.24 (P = 0.002) for the head circumference, 0.24 (P = 0.001) for the biparietal diameter and 0.34 (P < 0.001) for the abdominal circumference. The length of the surface was not related to fetal growth velocity. CONCLUSIONS: Tissue along the breadth of the placental surface may be more important than tissue along the length in the transfer of nutrients from mother to baby. This may be part of a wider phenomenon of regional differences in function across the placental surface.

Foetal and childhood growth and asthma in adult life.

AIM: Recent research suggests that asthma may originate through defects in the airway epithelium, acquired in utero, and an altered response to infections after birth. Here, we examine whether asthma in adult life is associated with reduced body size at birth and poor living conditions in childhood. METHODS: We studied 658 people taking medication for asthma in a cohort of 13 345 men and women born in Helsinki, Finland, during 1934-1944. Their body and placental size at birth, and their living conditions and growth in childhood, had been recorded. RESULTS: The odds ratios for asthma were 0.93 (95% CI 0.89-0.97, p = 0.001) per cm increase in birth length and 0.92 (0.89-0.96, p < 0.001) per cm increase in the length of placental surface. After allowing for size at birth, growth during childhood was unrelated to asthma. People who were born into families of low socio-economic status were at increased risk of later asthma. CONCLUSION: Slow linear growth in utero, which could be a result of impaired placentation, increases the risk of later asthma. Slow linear growth may be associated with impaired development of the airways. Babies with impaired lung development born into families of low socio-economic status may be most vulnerable to the disease.

The intrauterine origins of Hodgkin's lymphoma.

BACKGROUND: Both small and large body size at birth are now known to predict a range of chronic disorders in adult life, including certain cancers. These associations are thought to reflect "fetal programming." This may lead to impairment of a small number of key systems including the immune system. Hodgkin's lymphoma is a disease of the immune system. We have therefore examined the association between Hodgkin's lymphoma and early development. Our hypothesis was that the disease would be associated with markers of poor fetal growth, specifically small body size or small placental size at birth. METHODS: Using the Finnish Cancer Registry we identified patients with Hodgkin's disease in a cohort of 20,431 people born in Helsinki during 1924-44. Each person has a detailed birth record. RESULTS: There were 12 patients with Hodgkin's disease, giving an incidence comparable to international rates. The disease was associated with prolonged gestation. For every additional week of gestation the hazard ratio was 1.37 (95% CI 1.00-1.87; p = 0.05). The disease was also associated with a short placental surface. After allowing for gestation, for each centimetre increase in surface length, the hazard ratio was 0.70 (0.53-0.92; p = 0.01). The disease was not associated with birth weight or length or maternal body size. CONCLUSIONS: We have shown that Hodgkin's lymphoma is associated with prolonged gestation and a short length of the placental surface. We speculate that Hodgkin's lymphoma is initiated by two events in fetal life. One, which is an immune event, is associated with prolonged gestation, while the other is associated with growth faltering.

Early life origins cognitive decline: findings in elderly men in the Helsinki Birth Cohort Study.

OBJECTIVES: To examine whether the adverse effects of slow prenatal and postnatal growth on cognitive function persist to old age and predict age related cognitive decline. DESIGN AND SETTING: A longitudinal birth cohort study of men born in Helsinki, Finland 1934-44. PARTICIPANTS: Nine-hundred-thirty-one men of the Helsinki Birth Cohort Study, with detailed data on growth from birth to adulthood, aged 20.1 (SD = 1.4) at the first and 67.9 (SD = 2.5) years at the second cognitive testing. MAIN OUTCOME MEASURES: The Finnish Defense Forces Basic Intellectual Ability Test assessed twice over nearly five decades apart. RESULTS: Lower weight, length and head circumference at birth were associated with lower cognitive ability at 67.9 years (1.04-1.55 points lower ability per each standard deviation [SD] unit decrease in body size, 95% Confidence Interval [95%CI]: 0.05 to 2.72) and with cognitive decline after 20.1 years (0.07-0.11 SD decline over time per each SD decrease in body size, 95%CI:0.00 to 0.19). Men who were born larger were more likely to perform better in the cognitive ability test over time (1.22-1.43 increase in odds to remain in the top relative to the lower two thirds in ability over time per each SD increase in body size, 95%CI:1.04 to 1.79) and were more resilient to cognitive decline after 20.1 years (0.69 to 0.76 decrease in odds to decline from than remain in the top third of ability over time per each SD increase in body size, 95%CI:0.49 to 0.99). Slower growth between birth and two years in weight, height and body mass index was associated with lower cognitive ability at 67.9 years, but not with cognitive decline. CONCLUSIONS: Poorer lifetime cognitive ability is predicted by slower growth before and after birth. In predicting resilience to age related cognitive decline, the period before birth seems to be more critical.

Cognitive ability and decline after early life stress exposure.

We examined the effects of early life stress on cognitive ability and decline among men of the Helsinki Birth Cohort Study, 10% of whom were separated temporarily (mean age at separation = 4.1 years) from their parent(s) during World War II. The men underwent the Finnish Defense Forces Basic Intellectual Ability Test twice, at 20 years and retest at 70 years. Compared with the men without childhood separation and matched for year of birth (n = 186), men separated from their parents (n = 93) scored lower by 5.5 (95% confidence interval [CI], -9.2 to -1.7), 4.2 (95% CI, -8.1 to -0.3), 3.1 (95% CI, -7.0 to 0.8), and 4.5 (95% CI, -10.5 to -1.4) standardized points (SD = 15) on verbal, visuospatial, arithmetic, and general cognitive ability, respectively, at 70 years. Longer duration of separation was associated with lower test scores. Though early life stress was also associated significantly with weaker cognitive performance at the ages 20 and 70 years, it was not associated with cognitive decline over the 50-year period within this sample.

Markers of biological fitness as predictors of all-cause mortality.

INTRODUCTION: Within the Helsinki Birth Cohort, men who were tall when they were 7 years old lived for 5 years longer than men who were short. In the present analyses we examined two other influences known to be associated with lifespan: having children and educational attainment. We hypothesized that tall stature, the ability to have children, and high educational attainment reflect three aspects of biological fitness that are acquired during development. METHODS: We examined all-cause mortality in 6975 men and 6370 women born in Helsinki during 1934-1944, whose childhood growth, number of children, and educational attainment were recorded. RESULTS: In contrast to men, tall stature in childhood was not associated with longer lifespan among women. Men and women who had children lived for longer than those who had no children. Among women, having children was only associated with increased lifespan among those whose body mass index increased between 2 and 11 years. High educational attainment was associated with longer lifespan in both sexes. The trends of lower all-cause mortality with higher educational attainment were present in each socio-economic group. The men and women who had children, and attained upper tertiary education, lived for 16 years longer than those who had no children and only basic education. CONCLUSION: We suggest that the associations between having children, educational attainment, and lifespan reflect two different aspects of biological fitness that are acquired during early development.

Maternal hypertensive disorders in pregnancy and self-reported cognitive impairment of the offspring 70 years later: the Helsinki Birth Cohort Study.

OBJECTIVE: We tested whether maternal hypertensive disorders during pregnancy predict self-reported cognitive impairment, which is one of the earliest behavioral markers of dementia, of the offspring 70 years later. STUDY DESIGN: We included 876 participants of the Helsinki Birth Cohort Study 1934-44 who were born after normotensive, preeclamptic, or hypertensive pregnancies that were defined by the use of the mother's blood pressure and urinary protein measurements at maternity clinics and birth hospitals. The participants completed a psychological questionnaire that included questions on cognitive failures and dysexecutive functioning at an average age of 69.3 ± 3.1 (SD) years. RESULTS: In comparison with the offspring who were born after normotensive pregnancies, the offspring who were born after preeclamptic pregnancies reported more frequent complaints of cognitive failures, distractibility, and false triggering. Further, among women we found maternal hypertension without proteinuria that was associated with more frequent complaints of cognitive failures, forgetfulness, and false triggering. CONCLUSION: Hypertensive disorders during pregnancy are associated with more frequent subjective complaints of cognitive failures of the offspring in old age.

Stroke is predicted by low visuospatial in relation to other intellectual abilities and coronary heart disease by low general intelligence.

BACKGROUND: Low intellectual ability is associated with an increased risk of coronary heart disease and stroke. Most studies have used a general intelligence score. We studied whether three different subscores of intellectual ability predict these disorders. METHODS: We studied 2,786 men, born between 1934 and 1944 in Helsinki, Finland, who as conscripts at age 20 underwent an intellectual ability test comprising verbal, visuospatial (analogous to Raven's progressive matrices) and arithmetic reasoning subtests. We ascertained the later occurrence of coronary heart disease and stroke from validated national hospital discharge and death registers. RESULTS: 281 men (10.1%) had experienced a coronary heart disease event and 131 (4.7%) a stroke event. Coronary heart disease was predicted by low scores in all subtests, hazard ratios for each standard deviation (SD) lower score ranging from 1.21 to 1.30 (confidence intervals 1.08 to 1.46). Stroke was predicted by a low visuospatial reasoning score, the corresponding hazard ratio being 1.23 (95% confidence interval 1.04 to 1.46), adjusted for year and age at testing. Adjusted in addition for the two other scores, the hazard ratio was 1.40 (1.10 to 1.79). This hazard ratio was little affected by adjustment for socioeconomic status in childhood and adult life, whereas the same adjustments attenuated the associations between intellectual ability and coronary heart disease. The associations with stroke were also unchanged when adjusted for systolic blood pressure at 20 years and reimbursement for adult antihypertensive medication. CONCLUSIONS: Stroke is predicted by low visuospatial reasoning scores in relation to scores in the two other subtests. This association may be mediated by common underlying causes such as impaired brain development, rather than by mechanisms associated with risk factors shared by stroke and coronary heart disease, such as socio-economic status, hypertension and atherosclerosis.

Body size at birth is associated with food and nutrient intake in adulthood.

BACKGROUND: Small body size at birth is associated with an increased risk of cardiovascular disease and type 2 diabetes. Dietary habits are tightly linked with these disorders, but the association between body size at birth and adult diet has been little studied. We examined the association between body size at birth and intake of foods and macronutrients in adulthood. METHODOLOGY/PRINCIPAL FINDINGS: We studied 1797 participants, aged 56 to 70, of the Helsinki Birth Cohort Study, whose birth weight and length were recorded. Preterm births were excluded. During a clinical study, diet was assessed with a validated food-frequency questionnaire. A linear regression model adjusted for potential confounders was used to assess the associations. Intake of fruits and berries was 13.26 g (95% confidence interval [CI]: 0.56, 25.96) higher per 1 kg/m(3) increase in ponderal index (PI) at birth, and 83.16 g (95% CI: 17.76, 148.56) higher per 1 kg higher birth weight. One unit higher PI at birth was associated with 0.14% of energy (E%) lower intake of fat (95% CI: -0.26, -0.03) and 0.18 E% higher intake of carbohydrates (95% CI: 0.04, 0.32) as well as 0.08 E% higher sucrose (95% CI: 0.00, 0.15), 0.05 E% higher fructose (95% CI: 0.01, 0.09), and 0.18 g higher fiber (95% CI: 0.02, 0.34) intake in adulthood. Similar associations were observed between birth weight and macronutrient intake. CONCLUSIONS: Prenatal growth may modify later life food and macronutrient intake. Altered dietary habits could potentially explain an increased risk of chronic disease in individuals born with small body size.

Hypertensive disorders in pregnancy and cognitive decline in the offspring up to old age.

OBJECTIVE: We tested whether maternal hypertensive disorders in pregnancy predict age-related change in cognitive ability in the offspring up to old age. METHODS: Using mothers' blood pressure and urinary protein measurements from the maternity clinics and birth hospitals, we defined normotensive or hypertensive pregnancies in mothers of 398 men, who participated in the Helsinki Birth Cohort 1934-1944 Study. The men underwent the Finnish Defence Forces basic ability test twice: first during compulsory military service at age 20.1 (SD = 1.4) years and then in a retest at age 68.5 (SD = 2.9) years. The test yields a total score and subscores for tests measuring verbal, arithmetic, and visuospatial reasoning. RESULTS: Men born after pregnancies complicated by a hypertensive disorder, compared with men born after normotensive pregnancies, scored 4.36 (95% confidence interval, 1.17-7.55) points lower on total cognitive ability at 68.5 years and displayed a greater decline in total cognitive ability (2.88; 95% confidence interval, 0.07-5.06) after 20.1 years. Of the subscores, associations were strongest for arithmetic reasoning. CONCLUSION: Maternal hypertensive disorders in pregnancy predict lower cognitive ability and greater cognitive decline up to old age. A propensity to lower cognitive ability and decline up to old age may have prenatal origins.

Human growth and chronic disease: a memorial to Jim Tanner.

CONTEXT: Memorial to Jim Tanner. OBJECTIVE: To examine the links between early growth and chronic disease in later life. METHODS: Literature review. RESULTS: There is now a developmental model for the origins of chronic disease in which the causes to be identified are linked to normal variations in feto-placental, infant and childhood growth and development. These variations lead to variations in the supply of nutrients to the baby that permanently alters gene expression, a process known as 'programming'. CONCLUSIONS: Variations in the processes of development programme the function of a few key systems that are linked to chronic disease-the immune system, anti-oxidant defences, inflammatory responses, the number and quality of stem cells, neuro-endocrine settings and the balance of the autonomic nervous system. There is not a separate cause for each different disease. Which chronic disease originates during development may depend more on timing than on qualitative differences in exposures to external influences.