Early Life Programming of Vascular Aging and Cardiometabolic Events: The McDonald Lecture 2022

The early life programming of adult health and disease (Developmental Origins of Adult Health and Disease; DOHaD) concept has attracted increased attention during recent years. In this review evidence is presented for epidemiological associations between early life factors (birth weight, prematurity) and cardiometabolic traits and risk of disease in adult life. Even if not all studies concur, the evidence in general is supporting such links. This could be due to either nature or nurture. There is evidence to state that genetic markers influencing birth weight could also be of importance for offspring hypertension or risk of coronary heart disease, this supporting the nature argument. On the other hand, several studies, both historical and experimental, have found that the change of maternal dietary intake or famine in pregnancy may cause permanent changes in offspring body composition as well as in hemodynamic regulation. Taken together, this also supports the strategy of preventive maternal and child health care, starting already during the preconception period, for lowering the risk of adult cardiometabolic disease in the affected offspring. Further studies are needed to better understand the mediating mechanisms, for example concerning arterial function, hemodynamic regulation, renal function, and neuroendocrine influences, related to the development of early vascular aging (EVA) and cardiovascular disease manifestations.


Introduction
Two features of human beings are fundamental for understanding of the development of health and disease during the life course, and in particular the development of chronic conditions such as cardiovascular disease (CVD). These features are, firstly that we have all been children, and secondly that we all undergo aging. Thus, there is a strong argument to study both the early life influences on adult health as well as the differences between chronological and biological aging, i.e., differential aging. Some people seem to have a normal aging pattern, going through the different stages of life, while other people may risk an unsuccessful aging with early onset of age-related disease conditions [1], such as CVD and type 2 diabetes (DM2), jointly named cardiometabolic disease manifestations. From an evolutionary perspective it is also a historical fact that humans, like other mammals, are not programmed for long lives in general, but for early survival during infancy and reproduction, even if it is also believed that elderly women may increase reproductive fitness for their daughters and their children if they live longer to provide guidance during critical periods of poor health in childhood of offspring, the so-called grandmother hypothesis [2].

Early Observational Studies
Against this background it makes sense to study different periods of early life exposures for their associations with adult health outcomes (Table 1), as mediated by different mechanisms linked to organ development and physiology, the so-called Developmental Origin of Health and Disease (DOHaD) hypothesis [3]. The initial research work presented by epidemiologists such as Arne Forsdahl, Norway [4], Gerhard Gennser, Sweden [5], and David J Barker, UK [6][7][8], could show associations between adverse conditions during pregnancy, as mirrored by low birth weight or intrauterine growth retardation, with negative adult health outcomes such as hypertension, DM2, coronary heart disease (CHD), stroke, etc. This initial first phase of research focused on the birth outcomes in relation to gestational age for later follow-up of individuals through national or regional register linkages. A wealth of data has now established these links, especially with hypertension [9], even if there are also studies that could not show the expected associations [10], maybe due to differences in methodology applied or population characteristics. For example, when self-report of birth weight is used, or not adjusted for gestational age, some spurious findings may be expected as compared to other studies based on more solid data derived from searching medical archives (including midwife reports) or national registers including standardized registration of birth data [11].

The Health Consequences of Post-natal Catch-Up Growth
A second phase of this research came when people like Peter Gluckman and Mark Hanson stated that not only the pregnancy period and birth weight are of importance, but also the post-natal development. It has for example been shown that babies born small-for-gestational age (SGA), or with low birth weight (LBW), and later having a rapid catch-up growth pattern over the first few years of life, may be at increased risk of adult cardiometabolic problems [12]. Such a risk has now been documented in several birth cohorts, not only from the UK [13] and Finland [14], but also from Sweden [15]. This puts a focus on early nutrition and growth, not only during pregnancy itself, but also in early infancy, what has been called the important first 1000 days of life [16]. It is therefore of great importance to avoid calorie overfeeding by formula supplementation in premature or SGA babies, if this can be avoided (not always the case), but instead to promote breastfeeding or provide breast milk from external sources in order to avoid too rapid catch-up growth. This is of course based on a compromise with other medical needs in these newborns and often compromised children.

More Focus on the Preconception Period
In the current third phase of research dedicated to the importance of early life programming, focus has shifted to the pre-or periconception period, i.e., months to years before the conception or during a time window of about a few weeks around the conception and implantation in the uterine mucosa [17]. Negative influences from maternal obesity, unhealthy lifestyle, chemicals, drugs, infections, dietary deficiencies, and other environmental hazards may not only impact on fertility itself, including defective implantation and loss of fertilized egg cells (about 50% are lost during implantation), but also on the biology of oocytes and sperm through direct or epigenetic changes [18]. This means that lifestyle habits of both the coming mother and father could influence embryonal development which later, after 12 weeks of gestation, continues as the fetal development during the remaining two trimesters of pregnancy. In a recent randomized study from India, it was shown that a multi-facetted health package offered to women during preconception, pregnancy and the immediate post-partum period was beneficial for birth outcomes and early child growth and development, as well as for markers of maternal health [19].

Socio-economic and educational factors
In summary, the influences on health from early life can be studied during all stages, from preconception, over embryonic and fetal development, to birth outcomes and finally according to the growth patterns (trajectories) during the first few years of life. This means that there are different time periods (time windows) when a programming effect can play a role for the further development of the child and function of inner organs.

The Influence of Genes or the Environment?
A classical question is also to try to disentangle the influences of nature (genes) versus nurture (environment) on this development and programming effects, i.e., a specific stimulus that during a critical time period might cause permanent changes in the organism. Even if the early researchers emphasized the importance of the environment, for example calorie intake deficiencies in pregnant women and the role of maternal infections and smoking before and during pregnancy, other researchers have focused more on the importance of genetic factors to explain the associations. For example, if maternal genes affecting the risk of hypertension in pregnant women are also transmitted to their offspring and thus increasing the risk of later hypertension, this could explain the association alone, and thus low birth weight could be a secondary effect caused by hypertension in pregnancy influencing placental function [20]. In a similar way, other genetic studies have analyzed several genes associated with birth weight and found that these genes are also of importance for adult hypertension and CHD risk [21].

Historical Examples of Environmental Influences on Pregnancy Outcomes and Health
A counterargument to this genetic explanation is that manipulation of the environment, either in animal studies or following historical exposures to famine in pregnant women, could be of importance for both birth outcomes and long-term health risks in offspring. At the intersection between genes and environment influences we find epigenetic changes and imprinting of genes. This could be a more fruitful model to explain how genes and diet, or lifestyle in a wider sense, interact [22]. Historical cohort studies from periods of war and famine, or civil unrest, have repeatedly shown the negative influence on birth outcomes and a worse long-term prognosis for cardiometabolic disease and mortality, in countries as diverse as the Netherlands [23], Nigeria [24], Kenya [25] and China [26]. One exception was a follow-up of the Leningrad siege during WW2 in Soviet Union, when children born or surviving childhood in Leningrad during the famine period 1941 to 1943 were not at higher CVD risk compared to controls from other parts of war-time Soviet Union [27]. This could possibly be explained by the extreme selection pressure for full-time pregnancies and offspring survival during the intense famine period, but also that war-time conditions were very harsh in all parts of the country, a situation that lasted many years after the war with food rationing etc. On the other hand, the Dutch Winter Famine [23] from October 1944 to April 1945 (that occurred only in the northern part of the country) was followed by a far better period according to food supply, also for pregnant women, after the war. In summary, even if strong arguments exist for the importance of genetic factors regulating birth outcomes and cardiovascular risk in both parents and offspring, there is a strong case for preventive work emphasizing the role of healthy nutrition and vitamin (e.g., folate) supplementation in pregnant women, as well as avoidance of smoking, alcohol overuse, or infections (through immunization) during pregnancy. Finally, it should be remembered that women are selected by evolution to survive many hardships during pregnancy and associated health risks, even if sometimes such mechanisms can back-fire, e.g., in women with APC resistance (to avoid excess bleeding during parturition) being at higher risk of thrombo-embolism [28].

The Normal Development of the Vasculature-What Can Go Wrong?
For the normal development of the vasculature, its morphology and function, a normal pregnancy means a fully normal development, with some expected post-natal changes, for example the closure of the ductus arteriosus at birth [29]. However, prematurity can cause a less developed capillarization with negative consequences for the microcirculation leading to increased total peripheral resistance during later life, a negative factor for hemodynamic development and control [30]. Correspondingly, a negative influence on fetal growth may deplete the elastin content of the media layer of large elastic arteries [31] that may, at least in theory, cause or influence arterial stiffness during later life, including the Early Vascular Aging (EVA) syndrome [32]. This is because the elastin content of the arterial wall is gradually depleted during the life course and thereby less elasticity will be the consequence, when also the collagen content of the media layer undergoes changes with cross-linkages that will also promote stiffness. Increased arterial stiffness, as measured by pulse wave velocity, is a marker of future risk of not only fatal and non-fatal cardiovascular events, but also of total mortality [33,34]. Several studies have looked at the relationship between factors acting in early life and different measures of arterial function. Even if the link to hypertension is more well-established [9], it has been difficult to unequivocally show the early life programming of for example pulse wave velocity (PWV) along the aorta as being the most important marker of arterial stiffness. One study in adolescent from Austria (mean age 16 years) could in fact show that PWV was significantly higher in adolescents with a history of being born small-for-gestational age (SGA) as compared to subject born appropriate for gestational age (AGA) [35]. On the other hand, such an association with birth weight was not possible to show in in a mixed group (SGA, AGA, large for gestational age; LGA) young Finnish children (mean age 6 years) [36]. Not even in extremely premature children, examined at the age of 11 and 19 years in the EpiCure study, UK, it was possible to show any difference in PWV compared to controls born at term [30]. However, these associations have been more widely shown for Augmentation Index (Aix), a complex variable reflecting not only aortic stiffness but also the influence of peripheral vascular resistance (PVR), and several other determinants (heart, the reflex wave, blood pressure levels, and heart rate) [37]. In fact, studies in premature children as well as in more normal children have shown either group differences in Aix compared to controls, or an inverse association with birth weight -the lower the birth weight, the higher the Aix [30,[38][39][40].
These changes in central hemodynamics in relation to birth weight have also been shown when the mis-match concept has been applied, depicting the catch-up growth pattern seen in people born with a lower birth weight but reaching a higher adult body mass index in adulthood, or at age 20 years, as shown in a study from Sweden [41].

Mechanisms of Importance
Some of the potential mechanisms linking early life factors with adverse cardiovascular outcomes have been investigated. These include less developed arterial structure and peripheral microcirculation [42], but also impaired renal function [43] that in turn can impact on blood pressure regulation. In addition, neuroendocrine disturbance [44] and a changed balance of the autonomous nervous system with increased sympathetic nervous activity [45] as well as increased stress susceptibility [46] could be of importance. In the background, factors such as placental dysfunction [47] and chronic inflammation could contribute. Further studies are needed to better understand the interplay between these mechanisms and the development of arterial changes for increased risk of Early Vascular Aging (EVA) and cardiovascular events [32].

The Importance for cardiovascular prevention
What could be the clinical implication of these associations? Firstly, they put greater emphasis on preventive maternal and child health care to facilitate a healthy development in early life and thereby a potential also for prevention of cardiovascular disease in adults. This preventive approach can even be further expanded to the pre-and periconceptional period, as recently shown in a randomized study from India with better birth outcomes as well as improved maternal health [19].
Secondly, it might be a good idea to think about an outreach for screening and prevention of cardiovascular risk factors in young adults with a history of being born prematurely [48] or SGA, especially if this is combined with a catch-up weight trajectory pattern in early life up into adolescence.
Thirdly, these possible effects should also be kept in mind when assisted reproductive technologies (ART) are becoming more and more common. So far there is no indication of increased cardiovascular risk when children born after ART have been screened [49] but of left ventricular diastolic dysfunction [50], but more studies are needed.

Conclusions
The study of DOHaD and early life influences on adult cardiometabolic risk offers excellent opportunities for both observational and mechanistic studies, also in new areas such as the influence of epigenetics and gut microbiota patterns [51]. For more focused studies on vascular function and development of arterial stiffness [52][53][54][55] we need accurate methods to measure this also in young children, where for example very high-resolution vascular ultrasound  has been applied to evaluate carotid function [56]. This methodology is useful to investigate structures close to the skin surface, but not for examination of deeper structures such as the aorta due to technical limitations.
The information described here can be used for risk prediction and early prevention in subjects with a history of adverse conditions in early life, but there is also a link to maternal cardiovascular health. For example, women with a reproductive history of pre-eclampsia [57], other pregnancy complications [58] or multiple SGA births [59] are themselves at increased cardiovascular risk and should be offered a follow-up and preventive services. Thus, health conditions and nutrition in mothers and children should be viewed as interacting [60] and therefore DOHaD perspectives should also include the health of mothers, especially for coming pregnancies if health problems affected the previous pregnancy.