An epidemiologist, a basic researcher, a clinical researcher, and a clinician in practice weigh in on the complex relationship between genetics and environmental factors from conception through a child’s second birthday.
A complex interaction takes place between genetic and environmental factors during the first 1,000 days after conception, up to a child’s second birthday. This is a plastic period during which events and exposures can have significant effects on a child’s development and his or her risk of many chronic non-communicable diseases later in life, including obesity, hypertension, and type 2 diabetes. The right and wrong influences can have a tremendous impact not only on the child but the society in which he or she resides. In this Tri (Tetra)-Point article, epidemiologists discuss the findings of the Hertfordshire Cohort, which provided the first evidence supporting a relationship between early-life influences and chronic endocrine disorders; a basic scientist describes potential mechanisms through which early-life experiences may increase the risk of obesity, diabetes, and other metabolic disorders; a clinical researcher provides an overview of the role of modifiable early-life influences on obesity (a precursor to most chronic non-communicable diseases); and a clinician in practice discusses how emerging evidence should influence pediatric care in the first two years of life and describes guidelines to promote healthy growth and reduce the risk of childhood obesity and other chronic endocrine diseases.
EPIDEMIOLOGIST’S PERSPECTIVE — Cyrus Cooper, FMedSci
History of the Hertfordshire Cohort
Over the last quarter century, intrauterine environment and health in early childhood have become increasingly recognized as important factors in the programming of metabolic function across the life course and subsequent propensity to disease. Physician and epidemiologist, Professor David Barker, was the first to advocate the theory that environmental stimuli act at critical periods during early fetal development and lead to persistent structural and functional changes. His hypothesis originated from the observation of a positive geographical correlation between deaths from cardiovascular disease during 1968-1978 and infant mortality rates 60 years previously. These initial observations triggered a cascade of further studies confirming that adverse environmental influences acting in utero and early life increased the risk of later-life cardiovascular disease and additionally various metabolic, endocrine, and musculoskeletal disorders. A number of these associations were identified in the Hertfordshire Cohort Study, which was made possible by the discovery of ledgers containing birth and infancy records from the early 20th century (1911 – 1948). Specifically, the Hertfordshire Cohort Study has contributed to a wealth of research exploring interactions between the genome, intrauterine and early postnatal environment, and adult lifestyle in the etiology of chronic disorders in later life.
Early-Life Influences and
Early work confirmed the relationship between low birth weight and cardiovascular disease. This was thought to result from impaired glucose tolerance and hypertension, which lead to increased plaque deposition within the arteries. The other contributor to the link between birth weight and heart disease was insulin resistance, which was assessed using oral glucose tolerance tests. Participants with low birth weight were more likely to suffer impaired glucose tolerance. Body composition in later life also impacted this association. A quarter of men with birth weights below the median value, who also had a body mass index (BMI) above the median in later life, suffered impaired glucose tolerance. Whereas, only 5% of men above median for birth weight with low BMI in adulthood had impaired glucose tolerance.
Nutritional and growth factors that determine fetal and infant growth may also influence the size and function of adult pancreatic β-cells. Therefore, a single adverse prenatal influence, such as gestational malnutrition, might be expected to reduce both infant growth and islets of Langerhans development; the latter predisposing to diabetes. Further studies in Hertfordshire have established relationships with diabetes through the measurement of plasma concentrations of insulin and its precursors, such as proinsulin and 33-32 proinsulin.
Early-Life Influences on Bone Health
The influence of environmental factors during intrauterine and early postnatal life on the risk of metabolic bone diseases, such as osteoporosis, has also been investigated, and low birth weight was associated with lower bone mineral content in late adult life. Growth hormone (GH) activation of Jak-Stat signalling pathways stimulates liver production of insulin-like growth factor 1 (IGF-1), leading to growth stimulatory effects on a variety of tissues including osteoblasts and chondrocytes. This can promote chondrogenesis and increased bone formation. Consequently, this pathway has been investigated as a potential mediator of the developmental origin of bone health. Cohort women had their circulating GH profiles examined over a 24-hour period with blood samples taken every 20 minutes. Analyses showed a positive association between circulating GH concentrations and bone mass at lumbar spine sites. Furthermore, women of higher birth weight tended to have higher basal GH concentrations. These data support a role for the GH/IGF-1 axis in the determination of bone health.
Early-Life Influences, Musculoskeletal
Disorders, and Body Composition
In recent years, the Hertfordshire Cohort Study has permitted a more comprehensive evaluation of the life course determinants of musculoskeletal aging. Thus, in addition to enhancing our characterization of risk factor profiles that might be used in the prediction of osteoporotic fractures among patients, the program has extended to understanding the definition, prevalence, and determinants of sarcopenia and osteoarthritis.
In summary, from Professor Barker’s initial ecological observations, epidemiological research has grown in the Hertfordshire Cohort Study to demonstrate additional diseases influenced by early-life experiences and to delineate the potential endocrine mechanisms that may underlie them.
BASIC RESEARCHER PERSPECTIVE — Elizabeth Cottrell, PhD
of Chronic Disease
It is now clear that early-life experiences shape our physiology and can permanently modify long-term susceptibility to disease. The maternal environment influenced by factors such as nutrition, psychological stressors, or disease affects not only pregnancy outcome, but also the longterm health of the off spring. In recent years, significant progress has been made in understanding the mechanisms by which these perturbations in early environment can lead to later metabolic disease risk.
Thrifty Phenotype —
Lessons from Human Studies
Initial epidemiological studies linking poor early development with later disease identified that being born small for gestational age significantly increased the risk of developing both hypertension and type 2 diabetes in later life. These studies formed the basis of the “thrifty phenotype hypothesis,” which proposed that in response to a poor intrauterine environment, the fetus is able to adapt its physiology to promote survival in the short term, by maximizing metabolic efficiency. However, this “thriftiness” becomes maladaptive if nutrients in the postnatal period are plentiful, resulting in an increased risk of metabolic disease. A wealth of data from animal models has since corroborated this hypothesis and has also provided key mechanistic insight into the pathways that may be disrupted and lead to the development of obesity and associated metabolic dysfunction in the off spring.
Mechanistic Insight from Animal Models
A range of animal models have been developed to study pregnancy complications that reduce fetal growth and result in low birth weight (LBW) off spring. Interestingly, despite the variety of manipulations used — from altered maternal nutrition, surgical interventions that restrict blood fl ow to the fetus, or glucocorticoid treatment (to name a few) — the long-term phenotypic outcomes are often remarkably similar. Amongst these models, those that manipulate maternal nutrition are most commonly used. Global nutrient restriction (i.e., a reduction in the overall number of calories) or the feeding of a low protein diet during pregnancy leads to LBW in animals. These LBW off spring display alterations in structure and function of a diverse range of tissues, and crucially these alterations often precede the onset of overt disease.
Within the pancreas, the development of insulin secreting β-cells is compromised in LBW off spring. This is characterized by a decrease in β-cell number, reduced insulin secretory capacity and, as a result, impaired regulation of blood glucose. In the adipose tissue, LBW off spring appear to be programmed to store fat more efficiently, as a result of both enhanced insulin sensitivity as well as a persistent upregulation of key adipogenic signaling pathways. In addition to this tendency for more efficient storage, off spring are often also hyperphagic, due to alterations in central nervous system (CNS) pathways controlling food intake. Leptin, secreted by peripheral fat stores, is one of the key feedback signals that regulates food intake, and CNS leptin resistance is a common feature of many programming models. Combined, these perturbations in multiple tissues generate a phenotype that favors the development of obesity and metabolic syndrome, particularly in the face of excessive nutrient availability postnatally.
The Additional Risk of Catch-Up Growth
In addition to being born small, the rate of growth in early life contributes to later metabolic disease risk. LBW combined with rapid “catch-up” growth during the early postnatal period is associated with increased adipose tissue mass both in childhood and later adult life. This preferential accumulation of adipose tissue not only increases storage in fat depots, but can also lead to the ectopic deposition of lipids in other metabolic tissues including pancreas and skeletal muscle, ultimately impairing insulin secretion and action. Furthermore, LBW individuals attain a lower lean mass in later life, potentially compounding impairments in whole-body insulin sensitivity.
Determining how these permanent alterations in cell and tissue function occur is currently a highly active area of investigation. Epigenetic mechanisms clearly play a role, as altered chromatin structure and DNA methylation status influence target gene expression in a number of different tissues, contributing to the observed metabolic dysfunction. There is now abundant evidence demonstrating that supplementation with specific micronutrients, such as folic acid, can alter epigenetic status. What is currently less clear is whether these epigenetic modifications are reversible. Although some studies have suggested that this is possible, more evidence is required, and it is likely that this will be a key area of future research in the programming field.
Significant progress has been made in understanding how the early environment can negatively affect adult health. It remains to be determined just how permanent these programmed changes are, and whether it is realistically possible to intervene to reduce the risks of subsequent ill health. Ultimately, strategies to optimize maternal nutrition during pregnancy and infant nutrition during critical developmental periods may well allow us to improve the health of future generations.
CLINICAL RESEARCHER PERSPECTIVE — Elsie M. Taveras, MD, MPH
The Chronic Non-Communicable
Obesity rates among adults and children have substantially increased worldwide over the past three decades with all but the poorest countries now struggling with a growing obesity problem. Obesity represents a major threat to public health and results in significant excess burden of non-communicable diseases (NCD) and societal costs. In adults, a body mass index (BMI) as low as 23 kg/m2 is associated with dramatically high rates of type 2 diabetes and cardiovascular disease. In children, obesity is associated with both short- and long-term adverse outcomes including hyperlipidemia, diabetes, and hypertension, and with higher morbidity and mortality in adulthood. If current worldwide trends continue, the number of overweight people is projected to increase from 1.3 billion in 2005 to nearly 2.0 billion by 2030. The underlying causes of obesity and NCDs are modifiable risk factors throughout the life course. These risk factors represent major causes of health inequalities worldwide. Thus, prevention of obesity and NCDs is a global health priority.
A Life-Course Approach to Addressing
the Chronic Disease Epidemic
The life-course approach to chronic disease prevention posits that factors may act in the prenatal period and extend into infancy, childhood, and beyond to determine risk of chronic disease. Today we recognize that the First 1,000 Days — conception through 24 months — is a crucial period for the development, and thus prevention of obesity and its consequences.
During pregnancy, greater postpartum weight retention (PPWR) predicts long-term weight gain, risk of obesity, and altered metabolic state among women. PPWR, estimated as the difference between weight after delivery, usually six or 18 months, and pre-pregnancy weight, averages a seemingly modest ~1.5 kg but 13% – 20% of women experience weight retention >5 kg, especially those who were overweight or obese before pregnancy. Women who retain excess weight after pregnancy also have a higher risk of gestational diabetes and having a large-for-gestational-age infant in their subsequent pregnancies, disadvantaging future off spring.
Epigenetic research is increasingly demonstrating the important role of the father’s diet and obesity on off spring health. Evidence is also demonstrating that the father’s involvement can have a substantial impact on pregnancy and infant outcomes. When fathers are involved during pregnancy, maternal negative health behaviors diminish and risk of preterm birth, low birth weight, and fetal growth restriction is significantly reduced. The father’s involvement has also been associated with infant mortality up to one year after birth. Strengthening the father’s involvement in pregnancy and parenting has been recommended as a potential strategy for reducing health disparities particularly among racial/ethnic minority families.
In children, early obesity and excess weight gain in infancy not only predicts later obesity and cardio-metabolic risk, but also serious morbidity within childhood, including asthma, orthopedic problems, psychosocial adversity, and increasingly, type 2 diabetes. Epidemiologic studies from our group and others suggest that adverse exposures in the intrauterine and infancy periods can “program” trajectories of adiposity and metabolic function throughout life and may increase short- and long-term risks for obesity and its sequelae.
Preventing obesity in the First 1,000 Days can be achieved by developing multi-level, multi-sector strategies, especially those that invoke change at the individual, family, social environment, and systems levels. Such interventions should draw lessons from an understanding of the etiology of obesity, sources of resistance to change, and effective levers of sustainable change. Preventing the pernicious, inter-generational cycle of obesity will also require interrupting the effects of “obesogenic systems” early in life. Such system-level interventions promise new and sustainable approaches for entraining healthful lifelong weight trajectories.
CLINICIAN IN PRACTICE PERSPECTIVE — Maynika V. Rastogi, MBBS
Chronic diseases are becoming more common in childhood. There is a documented prevalence of childhood obesity of 16.9% among children two to 19 years with 12.1% of these in the two- to five-year-old age group. This rises to 18.4% during adolescence. Obesity is associated with metabolic abnormalities that result in type 2 diabetes, hypertension, and hyperlipidemia. Pediatricians are now faced with the care of chronic diseases in our children, an area of increasing research focus. This commentary highlights areas of health supervision where general practitioners can make an impact in the prevention of obesity and slow the rise in prevalence of chronic diseases.
There are several parental indicators associated with a future risk of obesity or chronic disease from the first clinic visit. For example, it is worth noting whether one or both parents are overweight. Maternal smoking and a history of maternal diabetes during pregnancy provide additional clues. Obesity is also more frequent in families with lower household incomes, single-parent homes, and families of African or Hispanic heritage. Families that practice unhealthy eating habits also have a higher risk. The birth history is important as children with birth weights over 4 kg or under 2.5 kg can develop the metabolic phenotype.
Early childhood feeding practices exert a great influence on the future risk of obesity and metabolic disease. During infancy, exclusive breastfeeding may lead to lower rates of obesity with lower rates of weight gain in the first year of life. Promotion of exclusive breastfeeding, avoidance of overfeeding, and an introduction of solid foods at six months of age as recommended by the American Academy of Pediatrics (AAP) should be encouraged. Parents should also be warned about excessive weight gain seen on a growth chart by plotted points climbing rapidly above the given centile lines.
The transition from infancy to toddlerhood provides further opportunities to be proactive. Many, when faced with the challenge of the “picky eater,” resort to giving unhealthy food and snacks; some moral support from their pediatrician can be invaluable to promote healthier choices. Other important practices include limiting fruit juices to 4 – 6 oz. daily, the avoidance of sweetened beverages, and providing a calcium-rich diet with liberal servings of fruits and vegetables. Toddlers should be left to eat as they choose rather than encouraged to “finish the plate” and portion sizes should follow the FDA food pyramid. Practitioners should also be aware of cultural norms that promote “chubby babies” and traditional foods that may be high in calories but low in nutrients. In the Caribbean, for example, a “fl our porridge” paste made with baking fl our or arrowroot is often used in early infancy as a “fattening” agent.
Sleep, screen time, physical activity, and parental issues are also modifiable factors. Children with a healthy sleep schedule (more than 10 hours) have lower tendencies to obesity later in life. Thus, parents should be encouraged to prioritize an early bedtime. While screen time and physical activity may seem to be issues for older children, younger children are also affected. The advent of tablet computers and YouTube has turned many of our toddlers into technology addicts. Parents should be warned of these trends and introduce scheduled playtime without a TV screen so that physical activity becomes the norm rather than the exception. Families should be encouraged to themselves adopt healthy diets and increase physical activity. Timed family meals away from the TV with an emphasis on a variety of home cooked foods is also essential. Additional advice includes giving small portions, allowing children to participate in meal preparation, positive feedback for healthy food choices, and discouraging snacking.
Clinicians should adopt a sensitive approach. Obesity may be a source of depression or viewed as a personal failure by the parents involved. The AAP, therefore, recommends motivational interviewing techniques centered on listening without judgment, giving support, and empathy. Further guidelines can be found in the 2007 Policy Statement on Obesity Prevention.
Obesity and the metabolic syndrome are now common pediatric problems. Modifiable factors include diet, sleeping habits, TV time, and physical activity. Parental influences are strong factors; thus, early encouragement to adopt a healthy family diet, increase exercise, and smaller portion meals can lead to good health habits that decrease risk for obesity and chronic disease in their off spring. Clinicians should employ non-judgmental approaches, emphasizing listening and motivational techniques to address this health problem. Table 1 highlights tips for obesity prevention incorporated into the well-child visit.