Influence of Early Life Events on Health and Diseases

Abstract

The transition from the fetal to the extrauterine environment is associated with complex physiological adjustments and involves numerous cardiovascular, pulmonary, and metabolic adjustments to ensure successful adaptation to the postnatal life. While such changes are in response to the altered environment in which the newborn finds itself, external changes affecting the fetal environment could impact the integrity of these mechanisms and increase susceptibility to diseases later in life. The present article reviews some of the mechanisms involved in the transition from fetal to postnatal life and focuses of how our health as adults is dependent on the conditions we experienced in-utero.

Introduction

Over the past decade, there has been increasing evidence supporting the concept that adverse factors in the perinatal environment predispose an individual to disease later in life (1–3). Central to this concept, and driven by the initial epidemiological studies of David Barker and colleagues (4), is the well substantiated link between birth weight and the development of a number of adult diseases, including obesity (5), hypertension (6–8), coronary artery disease (9) and insulin resistance (4,10,11). In other words, adverse intrauterine environmental factors, often associated with low birth weight, increase disease risk postnatally (5,12,13).

Traditionally, cardiovascular and metabolic disorders including coronary artery disease, hypertension and type II diabetes have been thought to be caused by lifestyle risk factors acting upon a fixed genetic background. However, based on multiple epidemiological studies, the fetal origin of adult diseases hypothesis suggests that environmental factors acting early in life play an important role in the pathogenesis of these diseases in adulthood (3,14). Changes in the fetal physiological, neuroendocrine or metabolic environment may result in permanent reprogramming of the developmental pattern of cellular proliferation and differentiation, resulting in alterations of organ physiology, morphology and/or metabolism in adult life.

The present review focuses on the relationship between adult cardiovascular disease including hypertension and reduced growth rate during fetal life.

Historical Perspective

In the early 1900, there were widespread concerns about the apparent physical deterioration of the British people. One of ten babies died before the age of one and many of those who survived reached adult life in poor health. To improve the health of children, midwifes and visiting nurses from Hertfordshire in England started systematically to assist women in childbirth and followed these infants thereafter on a regular basis. From 1911 until 1930, they collected data on all newborn babies born in the area and observed them until the age of 5 years (15). Based on these records, it was possible for the first time to relate people’s early growth, feeding and illness to their health later in life. On examining the records of over 10,000 males born during that period, it was found that the standardized mortality ratios for coronary heart diseases decreased as the birth weight increased (15).

Similar studies were performed by Rich-Edwards and colleagues (16) who surveyed 121,701 American female registered nurses aged 30 to 55 years. They found that increasing birth weight was associated with decreasing risk of non-fatal cardiovascular disease. The inverse trend was apparent for both coronary heart disease and stroke and provided strong evidence of an association between birth weight and adult coronary heart disease and stroke.

Based on many systematic reviews (17–19) that examined the association between birth weight and blood pressure later in life, it was observed that birth weight and head circumference at birth were inversely related to systolic blood pressure. A review of multivariate regression coefficients from 28 studies involving a total of 15,000 people estimated that a 1 kg higher birth weight is typically associated with a 2–4 mm Hg lower systolic blood pressure (18).

Potential Mechanisms

There are a number of mechanisms that have been suggested to explain the relationship between low birth weight and the increased incidence of cardiovascular diseases.

Fetal Programming and Glucocorticoids

A number of animal studies suggest that exposure to excess glucocorticoids may mediate the programming of hypertension (20) and diabetes later in life. In rats, administration of synthetic glucocorticoids during the last week of pregnancy results in elevated blood pressure (21). Similarly, increased exposure of the fetus to maternal glucocorticoids, by inhibiting 11β-hydroxysteroid dehydrogenase (11β-HSD2), a placental enzyme that converts active glucocorticoids to inactive metabolites, results in the postnatal development of hypertension and hyperglycemia (21). Experiments using maternal undernutrition and protein restriction during pregnancy, in which the offspring become hypertensive, also suggest that alterations in glucocorticoid hormone action contribute to prenatal programming (22). Maternal protein restriction results in markedly reduced levels of 11β-HSD2 in the placenta and more than 2-fold increases in glucocorticoid receptor expression in the fetal and postnatal kidney and brain (22). The reduction in placenta 11β-HSD2 likely contributes to increased glucocorticoid hormone action on the developing fetus with a consequent increase in blood pressure in the offspring. On the other hand, maternal administration of metapyrone, an inhibitor of glucocorticoid synthesis, inhibits the development of hypertension in offspring following intrauterine protein restriction (23). Taken together, these findings suggest that fetal exposure to maternally derived glucocorticoids is a key first step in programming long term health consequences. In long gestation mammals, such as humans and sheep, the effect of excess glucocorticoid exposure is highly dependent upon the timing of the exposure and the developmental state of the organism. Recent studies by our group (24,25) demonstrated that antenatal glucocorticoids augment sympathetic responses at birth in premature lambs and attenuate the sensitivity of the cardiac baroreflex both in utero and immediately after birth. Taken together these recent studies (24,25) suggest that prenatal glucocorticoid exposure may lead to permanent effects on vascular, hormonal, and central regulatory mechanisms involved in maintaining cardiovascular homeostasis.

Fetal Programming and the Renin-Angiotensin System

It has been suggested that fetal programming of adult onset hypertension may be related to alterations of the renin-angiotensin system (RAS), particularly within the kidney. Maternal protein deprivation or glucocorticoid administration reduces renal renin mRNA, angiotensin II levels and glomerular number in the offspring, which in turn, are associated with hypertension in the adult (26–28). However, early gestation glucocorticoid exposure regulates the RAS in a tissue-specific manner. Fetal exposure to dexamethasone early in gestation also results in increased angiotensin II type 1 (AT₁) receptor mRNA in the medulla and angiotensinogen mRNA levels in the hypothalamus in postnatal lambs (29). The functional importance of this effect on the brain RAS is demonstrated by the finding that as adults, these animals display increased blood pressure response to intracerebroventricular infusion of angiotensin II (30).

Fetal Programming and Sympathetic Function

There is clear evidence that environmental exposures at crucial points in development permanently alter sympathetic function. A well known example of this phenomenon relates to the effects of environmental temperature on thermoregulatory mechanisms. Mammals, including humans, reared at elevated temperatures have improved thermoregulatory responses and are more tolerant of extreme temperatures as adults (31). This adaptation results from altered sympathetic innervation of sweat glands.

There are reasons to believe that altered sympathetic function may contribute to the programming of hypertension and that the effects of adverse intrauterine events on the sympathetic nervous system depend on both the nature and timing of the event. Extensive animal studies detail that exposure to glucocorticoids early in development enhances maturation of catecholaminergic and cholinergic cells, receptor mechanisms and brain synaptogenesis in brain (32–35) but impairs development and activity of cardiac sympathetic projections (35). In the chick, mild hypoxia during embryonic development results in increased basal sympathetic tone and sympathetic hyperinnervation of resistance arteries (36). Studies utilizing sheep and rat undernutrition, and glucocorticoid exposure models of programmed hypertension demonstrate the heart rate baroreflex is shifted towards higher pressure (37). Although these studies were performed after the development of hypertension, preliminary results from our group suggest the arterial baroreflex is reset prior to the development of hypertension and therefore may be a cause rather than a consequence of elevated blood pressure. In particular, infant heart rate variability indices, which are influenced by sympathetic activity, have been correlated with birth weight (38). In young adults, muscle sympathetic activity is inversely correlated with birth weight and length (39). Notably, extensive evaluation of autonomic and baroreflex dysfunction during the neonatal period in programming models has not been performed.

Conclusion

These studies strongly suggest that prenatal environmental stresses, including nutritional stress, are important determinants of postnatal health and may predispose individuals to diseases later in life. Further investigations are needed to elucidate the basic and initiating mechanisms explaining the fetal origin of adult diseases. Epigenetic mechanisms including modifications of DNA, methylation of cytosine residues, and the role of mitochondrial DNA will need to be considered in this context.

DISCUSSION

Luke: Cincinnati: I’d like to challenge the view that nephron number correlates with hypertension. The follow up of kidney donors is 20–30 years plus, and they don’t necessarily get hypertension. I think that there’s an association here, but no evidence of causation. Some of the other factors you’ve talked about (e.g. changes in electrolyte transporters) are much more likely to be associated with salt retention and hypertension.

Robillard: Iowa City: I think you’re right about this. There are multiple factors that can influence this. Interestingly, however, if you follow children who are born with agenesis of just one kidney, their incidence of hypertension later in life is higher. I think there is more than just a decrease in nephron number, also an increase in the number of transporters, channels and pumps. It’s not just one mechanism, and this is not limited strictly to the kidney.

Boxer: Ann Arbor: Jean, could you clarify how sustained the malnutrition effect has to be during fetal life to affect adult health. And two, what happens to babies born to mothers with placental insufficiency from other causes?

Robillard: It really depends on when the fetus is exposed to malnutrition. For example, it has been shown that offspring of mothers exposed to malnutrition in their last trimester during the 1944 Dutch Famine have more diabetes, while those exposed during mid gestation develop more obstructive pulmonary disease and microalbuminuria. Those who were exposed early in gestation have a more atherogenic lipid profile, altered clotting, more obesity, and a 3-fold increase in cardiovascular disease.

Halsted: Davis: Following up on the previous comments, I understand that the offspring of pregnant women who lived through the Dutch famine winter of 1944 were more likely to develop overweight and eventual obesity, which, of course, are associated with hypertension and diabetes. Could you comment further on this potential relationship in the context of your study?

Robillard: Bill Hay who is talking immediately after me will address this issue.

Billings: Baton Rouge: I wonder if there are any studies that have been done with addicts. How do mothers who have crack babies and mothers who are alcoholics relate to the topic that you address?

Robillard: First, it’s been shown that mothers who smoke have small babies. Second, cocaine exposure during fetal life has been reported to be associated with a variety of isolated structural anomalies. However, there is no detectable syndromic clustering, raising doubts about a real causal association or a specific teratogenic action. Finally, fetal alcohol exposure results in a spectrum of adverse outcomes. Fetal alcohol syndrome is characterized by specific facial abnormalities and significant impairments in neurodevelopment and physical growth.