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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. Keywords Birth weight, Early life, Epidemiology, Genes, Nature, Nurture differential aging. Some people seem to have a normal 1 Introduction aging pattern, going through the different stages of Two features of human beings are fundamental for life, while other people may risk an unsuccessful aging understanding of the development of health and disease with early onset of age-related disease conditions during the life course, and in particular the development , such as CVD and type 2 diabetes (DM2), jointly of chronic conditions such as cardiovascular disease named cardiometabolic disease manifestations. From (CVD). These features are, firstly that we have all been an evolutionary perspective it is also a historical fact children, and secondly that we all undergo aging. Thus, that humans, like other mammals, are not programmed there is a strong argument to study both the early life for long lives in general, but for early survival during influences on adult health as well as the differences infancy and reproduction, even if it is also believed that between chronological and biological aging, i.e., elderly women may increase reproductive fitness for their daughters and their children if they live longer to *Correspondence: provide guidance during critical periods of poor health Peter M. Nilsson in childhood of offspring, the so-called grandmother firstname.lastname@example.org Department of Clinical Sciences, Lund University, Skane University hypothesis . Hospital, Malmö, Sweden © The Author(s) 2023. 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N ilsson Artery Research (2023) 29:28–33 29 archives (including midwife reports) or national registers 2 Early Observational Studies including standardized registration of birth data . 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 3 The Health Consequences of Post‑natal Catch‑Up different mechanisms linked to organ development Growth and physiology, the so-called Developmental Origin of A second phase of this research came when people like Health and Disease (DOHaD) hypothesis . The initial Peter Gluckman and Mark Hanson stated that not only research work presented by epidemiologists such as Arne the pregnancy period and birth weight are of importance, Forsdahl, Norway , Gerhard Gennser, Sweden , but also the post-natal development. It has for example and David J Barker, UK [6–8], could show associations been shown that babies born small-for-gestational age between adverse conditions during pregnancy, as (SGA), or with low birth weight (LBW), and later having mirrored by low birth weight or intrauterine growth a rapid catch-up growth pattern over the first few years retardation, with negative adult health outcomes such of life, may be at increased risk of adult cardiometabolic as hypertension, DM2, coronary heart disease (CHD), problems . Such a risk has now been documented stroke, etc. This initial first phase of research focused in several birth cohorts, not only from the UK  and on the birth outcomes in relation to gestational age Finland , but also from Sweden . This puts a focus for later follow-up of individuals through national or on early nutrition and growth, not only during pregnancy regional register linkages. A wealth of data has now itself, but also in early infancy, what has been called the established these links, especially with hypertension , important first 1000 days of life . It is therefore of even if there are also studies that could not show the great importance to avoid calorie overfeeding by formula expected associations , maybe due to differences in supplementation in premature or SGA babies, if this can methodology applied or population characteristics. For be avoided (not always the case), but instead to promote example, when self-report of birth weight is used, or breastfeeding or provide breast milk from external not adjusted for gestational age, some spurious findings sources in order to avoid too rapid catch-up growth. This may be expected as compared to other studies based is of course based on a compromise with other medical on more solid data derived from searching medical needs in these newborns and often compromised children. Table 1 The early life influences on vascular function and 4 More Focus on the Preconception Period cardiometabolic risk In the current third phase of research dedicated to the importance of early life programming, focus has shifted Preconception to the pre- or periconception period, i.e., months to years Parental genetics before the conception or during a time window of about a Epigenetic influences on oocytes and sperm few weeks around the conception and implantation in the Pre-pregnancy maternal disease or drug treatment uterine mucosa . Negative influences from maternal Assisted reproductive technologies (ART ) obesity, unhealthy lifestyle, chemicals, drugs, infections, Pregnancy dietary deficiencies, and other environmental hazards Placental function may not only impact on fertility itself, including defective Gestational age (prematurity) implantation and loss of fertilized egg cells (about 50% Intrauterine growth retardation are lost during implantation), but also on the biology Birth weight (low, normal, or high) of oocytes and sperm through direct or epigenetic Organ development and function changes . This means that lifestyle habits of both the Post-natal development coming mother and father could influence embryonal Early feeding patterns development which later, after 12 weeks of gestation, Catch-up growth continues as the fetal development during the remaining Neurocognitive function two trimesters of pregnancy. In a recent randomized Health problems study from India, it was shown that a multi-facetted Congenital malformations health package offered to women during preconception, Adolescence pregnancy and the immediate post-partum period was Timing of puberty beneficial for birth outcomes and early child growth and Obesity development development, as well as for markers of maternal health Adverse lifestyle (sedentary, alcohol, smoking) . Socio-economic and educational factors Nilsson Artery Research (2023) 29:28–33 30 In summary, the influences on health from early life of war-time Soviet Union . This could possibly be can be studied during all stages, from preconception, explained by the extreme selection pressure for full-time over embryonic and fetal development, to birth pregnancies and offspring survival during the intense outcomes and finally according to the growth patterns famine period, but also that war-time conditions were (trajectories) during the first few years of life. This means very harsh in all parts of the country, a situation that that there are different time periods (time windows) lasted many years after the war with food rationing when a programming effect can play a role for the further etc. On the other hand, the Dutch Winter Famine  development of the child and function of inner organs. from October 1944 to April 1945 (that occurred only in the northern part of the country) was followed by a far 5 The Influence of Genes or the Environment? better period according to food supply, also for pregnant A classical question is also to try to disentangle the women, after the war. influences of nature (genes) versus nurture (environment) In summary, even if strong arguments exist for the on this development and programming effects, i.e., a importance of genetic factors regulating birth outcomes specific stimulus that during a critical time period might and cardiovascular risk in both parents and offspring, cause permanent changes in the organism. Even if the there is a strong case for preventive work emphasizing early researchers emphasized the importance of the the role of healthy nutrition and vitamin (e.g., folate) environment, for example calorie intake deficiencies in supplementation in pregnant women, as well as pregnant women and the role of maternal infections and avoidance of smoking, alcohol overuse, or infections smoking before and during pregnancy, other researchers (through immunization) during pregnancy. Finally, it have focused more on the importance of genetic factors should be remembered that women are selected by to explain the associations. For example, if maternal evolution to survive many hardships during pregnancy genes affecting the risk of hypertension in pregnant and associated health risks, even if sometimes such women are also transmitted to their offspring and thus mechanisms can back-fire, e.g., in women with APC increasing the risk of later hypertension, this could resistance (to avoid excess bleeding during parturition) explain the association alone, and thus low birth weight being at higher risk of thrombo-embolism . could be a secondary effect caused by hypertension in pregnancy influencing placental function . In a 7 The Normal Development of the Vasculature— similar way, other genetic studies have analyzed several What Can Go Wrong? genes associated with birth weight and found that these For the normal development of the vasculature, its genes are also of importance for adult hypertension and morphology and function, a normal pregnancy means a CHD risk . fully normal development, with some expected post-natal changes, for example the closure of the ductus arteriosus 6 Historical Examples of Environmental Influences at birth . However, prematurity can cause a less on Pregnancy Outcomes and Health developed capillarization with negative consequences A counterargument to this genetic explanation is that for the microcirculation leading to increased total manipulation of the environment, either in animal peripheral resistance during later life, a negative factor studies or following historical exposures to famine in for hemodynamic development and control . pregnant women, could be of importance for both birth Correspondingly, a negative influence on fetal growth outcomes and long-term health risks in offspring. At the may deplete the elastin content of the media layer of intersection between genes and environment influences large elastic arteries  that may, at least in theory, we find epigenetic changes and imprinting of genes. This cause or influence arterial stiffness during later life, could be a more fruitful model to explain how genes and including the Early Vascular Aging (EVA) syndrome . diet, or lifestyle in a wider sense, interact . Historical This is because the elastin content of the arterial wall is cohort studies from periods of war and famine, or civil gradually depleted during the life course and thereby less unrest, have repeatedly shown the negative influence elasticity will be the consequence, when also the collagen on birth outcomes and a worse long-term prognosis content of the media layer undergoes changes with for cardiometabolic disease and mortality, in countries cross-linkages that will also promote stiffness. Increased as diverse as the Netherlands , Nigeria , Kenya arterial stiffness, as measured by pulse wave velocity, is  and China . One exception was a follow-up a marker of future risk of not only fatal and non-fatal of the Leningrad siege during WW2 in Soviet Union, cardiovascular events, but also of total mortality [33, 34]. when children born or surviving childhood in Leningrad Several studies have looked at the relationship between during the famine period 1941 to 1943 were not at factors acting in early life and different measures of higher CVD risk compared to controls from other parts arterial function. Even if the link to hypertension is more N ilsson Artery Research (2023) 29:28–33 31 well-established , it has been difficult to unequivocally 9 The Importance for cardiovascular prevention show the early life programming of for example pulse What could be the clinical implication of these wave velocity (PWV) along the aorta as being the most associations? Firstly, they put greater emphasis on important marker of arterial stiffness. One study in preventive maternal and child health care to facilitate a adolescent from Austria (mean age 16 years) could in fact healthy development in early life and thereby a potential show that PWV was significantly higher in adolescents also for prevention of cardiovascular disease in adults. with a history of being born small-for-gestational age This preventive approach can even be further expanded (SGA) as compared to subject born appropriate for to the pre- and periconceptional period, as recently gestational age (AGA) . On the other hand, such an shown in a randomized study from India with better association with birth weight was not possible to show in birth outcomes as well as improved maternal health . in a mixed group (SGA, AGA, large for gestational age; Secondly, it might be a good idea to think about an LGA) young Finnish children (mean age 6 years) . outreach for screening and prevention of cardiovascular Not even in extremely premature children, examined at risk factors in young adults with a history of being born the age of 11 and 19 years in the EpiCure study, UK, it prematurely  or SGA, especially if this is combined was possible to show any difference in PWV compared to with a catch-up weight trajectory pattern in early life up controls born at term . However, these associations into adolescence. have been more widely shown for Augmentation Index Thirdly, these possible effects should also be kept in (Aix), a complex variable reflecting not only aortic mind when assisted reproductive technologies (ART) are stiffness but also the influence of peripheral vascular becoming more and more common. So far there is no resistance (PVR), and several other determinants (heart, indication of increased cardiovascular risk when children the reflex wave, blood pressure levels, and heart rate) . born after ART have been screened  but of left In fact, studies in premature children as well as in more ventricular diastolic dysfunction , but more studies normal children have shown either group differences in are needed. Aix compared to controls, or an inverse association with birth weight – the lower the birth weight, the higher the 10 Conclusions Aix [30, 38–40]. The study of DOHaD and early life influences on adult These changes in central hemodynamics in relation to cardiometabolic risk offers excellent opportunities for birth weight have also been shown when the mis-match both observational and mechanistic studies, also in concept has been applied, depicting the catch-up growth new areas such as the influence of epigenetics and gut pattern seen in people born with a lower birth weight but microbiota patterns . For more focused studies on reaching a higher adult body mass index in adulthood, or vascular function and development of arterial stiffness at age 20 years, as shown in a study from Sweden . [52–55] we need accurate methods to measure this also in young children, where for example very high-resolution 8 Mechanisms of Importance vascular ultrasound (35–55 MHz) has been applied Some of the potential mechanisms linking early life to evaluate carotid function . This methodology is factors with adverse cardiovascular outcomes have useful to investigate structures close to the skin surface, been investigated. These include less developed arterial but not for examination of deeper structures such as the structure and peripheral microcirculation , but aorta due to technical limitations. also impaired renal function  that in turn can The information described here can be used for risk impact on blood pressure regulation. In addition, prediction and early prevention in subjects with a history neuroendocrine disturbance  and a changed balance of adverse conditions in early life, but there is also a link of the autonomous nervous system with increased to maternal cardiovascular health. For example, women sympathetic nervous activity  as well as increased with a reproductive history of pre-eclampsia , other stress susceptibility  could be of importance. In the pregnancy complications  or multiple SGA births background, factors such as placental dysfunction   are themselves at increased cardiovascular risk and and chronic inflammation could contribute. Further should be offered a follow-up and preventive services. studies are needed to better understand the interplay u Th s, health conditions and nutrition in mothers and between these mechanisms and the development of children should be viewed as interacting  and arterial changes for increased risk of Early Vascular therefore DOHaD perspectives should also include the Aging (EVA) and cardiovascular events . health of mothers, especially for coming pregnancies if health problems affected the previous pregnancy. Nilsson Artery Research (2023) 29:28–33 32 Abbreviations cause-specific mortality: the hertfordshire cohort study. Am J Epidemiol. Aix Augmentation index 2005;161(11):1074–80. AGA Appropriate for gestational age 9. Mu M, Wang SF, Sheng J, Zhao Y, Li HZ, Hu CL, Tao FB. Birth weight APC Activated protein C and subsequent blood pressure: a meta-analysis. Arch Cardiovasc Dis. ART Assisted reproductive technology 2012;105(2):99–113. CVD Cardiovascular disease 10. Fan J, Shi X, Jia X, Wang Y, Zhao Y, Bao J, Zhang H, Yang Y. Birth weight, DM2 Diabet es type 2 childhood obesity and risk of hypertension: a Mendelian randomization DOHaD Developmental origins of health and disease study. J Hypertens. 2021;39(9):1876–83. EVA Early vascular aging 11. Nilsson PM, Ostergren PO, Nyberg P, Söderström M, Allebeck P. Low LGA Large for gestational age birth weight is associated with elevated systolic blood pressure in MHz Megahertz adolescence: a prospective study of a birth cohort of 149378 Swedish PVR Peripheral vascular resistance boys. J Hypertens. 1997;15(12 Pt 2):1627–31. PWV Pulse wave velocity 12. Gluckman PD, Hanson MA, Cooper C, Thornburg KL. Eec ff t of in utero SGA Small for gestational age and early-life conditions on adult health and disease. 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Artery Research – Springer Journals
Published: Jun 1, 2023
Keywords: Birth weight; Early life; Epidemiology; Genes; Nature; Nurture
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