Promotion of long-term health in early life

Abstract

Noncommunicable chronic diseases (NCDs) are on the rise in high-income countries, leading to substantial morbidity and mortality and contributing to increased resource demands and healthcare costs. Early-life exposures can initiate trajectories that culminate in NCDs later in life. Examples include the metabolic–endocrine pathway to obesity, diabetes, and cardiovascular diseases; the immune-mediated pathway to asthma and allergies; or the neurodevelopmental–psychological pathway to mental health problems. The interconnected trajectories involving microbiome composition, epigenetic signatures, nutrition, and psychological factors in early life can establish a basis for long-term health. While universal vaccination programs are in place to prevent infectious diseases, a coordinated effort to mitigate the rise of NCDs is missing. Examples of how to balance short- and long-term effects in early life include the use of appropriate medications, balanced healthcare interventions, optimized nutrition, and a nurturing care in early life. While these examples will not provide simple answers, they may stimulate important discussions and research into the overarching question: How can we deliver care in early life that achieves optimal short-term outcomes while promoting long-term health trajectories and well-being? While it is imperative to underscore the significance of subsequent periods to circumvent a deterministic conceptualization of a singular period as the primary catalyst for the development of physical and mental health, early life remains an underexploited window of opportunity fostering long-term health and mitigating the growing resource challenges faced by healthcare systems.

Over recent decades, a pandemic of noncommunicable chronic diseases (NCDs) has emerged, and the response in high-income countries has been mainly reactive. We manage diseases once a diagnosis has been made. Since 1990, the prevalence of childhood obesity has doubled, currently affecting three-quarters of adults and children in the United States and contributing to healthcare costs of around US$173 billion per year (1–3). Cardiovascular diseases (CVDs) associated with metabolic syndrome are the leading cause of age-standardized mortality (1, 2). The prevalence of asthma and food allergies is increasing among both children and adults in high-income countries, affecting more than 10% of the population (4, 5). The prevalence of mental health disorders across childhood, adolescence, and the adult population is reported to be between 10% and 20% (6, 7). Many other, less common NCDs are also becoming more prevalent and current efforts to halt the rise of NCDs have been largely ineffective and failed to address early prevention (1, 2, 8). Moreover, the healthcare sector is hurtling toward a major resource problem due to a shortage of qualified healthcare professionals and resources, which adds to the challenges of NCDs in health systems.

Modern medicine mainly focuses on diagnosing and treating existing diseases. However, the basis of many NCDs can start in early life. The fetal origin’s (Barker) hypothesis proposed that undernutrition during gestation contributed to improper fetal growth and a predisposition, or fetal programming, to later metabolic syndrome and CVDs (9). While Barker’s original work emphasized maternal malnutrition, it is now recognized that fetal malnutrition, the key driver of adverse developmental programming, can also result from placental insufficiency or maternal-placental disease, even when maternal nutrition is adequate (10, 11). In addition, epidemiological evidence shows that postnatal catch-up growth shows even stronger and more consistent association with later cardiometabolic risk than birth weight alone (12). Therefore, birth weight is an imprecise indicator of intrauterine adversity, and confounding factors play an important role in some of the associations identified by Barker’s hypothesis (13, 14). The concept has been further expanded to include other early life environmental exposures and other diseases. Notably, the Developmental Origins of Health and Disease (DOHaD) paradigm emphasizes the role of both prenatal and postnatal environmental exposures on disease risk in the immediate and long-term perspective (10). In recent years, it has become clear that the fetal programming of many NCDs is controlled by epigenetic factors (15). Nevertheless, causal interference is the main methodological challenge, and mechanistic plausibility is stronger than definitive human evidence, which carries the risk of overinterpreting the impact of epigenetics (16). James Heckman, winner of the 2000 Nobel Prize in Economics, argues strongly that the return on investments is greatest if investing in health care early in life, and highest in the prenatal period (17). Nevertheless, other periods in life, such as adolescence, are also critical time windows with heightened plasticity that impact future physical and mental health (18). This raises questions about the impact of Heckman’s human-capital theory in relation to other periods of life (19). While it is imperative to underscore the significance of subsequent periods to circumvent a deterministic conceptualization of a singular period as the primary catalyst for the development of physical and mental health, early life remains an underexploited window of opportunity. The precise nature of the impact of early life interventions on the development of future physical and mental health remains to be elucidated. However, it is reasonable to promote balanced care, and to avoid unnecessary and futile therapies at the beginning of life.

The aim of this Perspective is, first, to highlight the current understanding of the underlying mechanisms by which early life is linked to NCDs, using three trajectories as examples 1) the metabolic–endocrine trajectory of obesity, diabetes, and CVD as the leading cause of age-standardized mortality; 2) the immune-mediated trajectory of asthma and allergies and 3) the neurodevelopmental–psychological trajectory of mental health as the most prevalent morbidities in later life. The correlation between early life and NCDs is a multifaceted, complex system. The three trajectories are highly interrelated, and the separation is used to enhance comprehensibility. In addition, these three trajectories are not mutually exclusive, and others relating to cancer and other NCDs have been omitted due to the scope and length of this article. Second, we aim to provide examples of some of the current efforts to promote long-term health in early life. The “first 1,000 d” paradigm advocates interventions in nutrition and care during the first 1,000 d, including pregnancy and the first 2 y of life (20). We aim to take a more specific and in-depth approach and focus here on the period from conception to 4 wk after birth, which we define as “early life.” Consequently, this perspective does not extend to subsequent periods such as infancy, school days, and adolescence. The provided examples will not give simple answers, but they may leverage important discussions and research into the overarching question: How can we deliver care in early life that achieves optimal short-term outcomes while promoting long-term health trajectories and well-being? Finally, we will outline a roadmap on how to use this “early life window of opportunity” to tackle the significant challenges of the health care system in the near future.

Evidence and Pathways Linking Early Life and Long-Term Health

The Metabolic–Endocrine Trajectory.

The metabolic–endocrine trajectory is triggered by numerous interrelated pathways, and it is important to recognize that some of these factors may have long-term effects and may influence the efficacy of interventions initiated later in life. Genomic imprinting, characterized by gene expression specific to the parent of origin, can play an essential role in growth, metabolism, and development (21). There is increasing evidence that epigenetic information can be inherited across generations in mammals. This was demonstrated using a mouse model that showed the genotype of male parents that was not passed on to their offspring could still influence their phenotype (22). Maternal prepregnancy obesity, excessive gestational weight gain, and diabetes during pregnancy can lead to epigenetic changes that predispose offspring to metabolic disorders, including altered lipid metabolism, insulin resistance, and vascular dysfunction (23, 24). This is explained by altered methylation patterns at imprint control regions, which affect offspring growth, metabolism, and disease risk. Maternal prepregnancy body mass index (BMI) has been associated with altered methylation at multiple imprint control regions that regulate growth and metabolic pathways (25). Gestational diabetes has also been linked to significant changes in the methylation of the GNAS (guanine nucleotide-binding protein, alpha stimulating) gene in offspring, which influence energy metabolism and glucose homeostasis (26). Analyses of the Dutch Hunger winter during World War 2 showed an association between sugar rationing within the first 1,000 d of life and a reduced risk of type 2 diabetes and arterial hypertension, with the onset of these diseases occurring between the age of 50 and 60 y (27). Gene analyses comparing the DNA of sugar rationing exposed and unexposed siblings in adulthood revealed significant differences in methylation (28).

In addition, the maternal and infant microbiomes play a critical role in shaping the trajectory of diabetes, obesity, and long-term health (29–31). A mother’s diet during pregnancy and her infant’s diet during the first year of life, if high in unhealthy components such as saturated fats, refined sugars, and ultraprocessed foods, or if the infant is exposed to antibiotics during this period, can alter the infant’s microbiome (32–34). There is evidence from cohort studies that early life disruption of the infant microbiome is associated with metabolic inflammation, energy imbalances, and an increased risk of obesity (29, 35). Antibiotic-induced perturbations in the gut microbiome composition also can affect host-metabolism, leading to reduced short chain fatty acid (butyrate) levels, and increased utilization of glucose as energy source, which may in turn affect glucose homeostasis and thereby growth (30). Moreover, butyrate and acetate regulate satiety (31). These disruptions may increase the risk of chronic diseases through gut microbiota-mediated inflammation and metabolic dysregulation. Early microbial exposures and their influence on gut composition remain key factors in determining lifelong health trajectories.

Obesity promotes insulin resistance and stimulates the release of inflammatory cytokines. Insulin resistance contributes to endothelial dysfunction and promotes a prothrombotic state. At the same time, chronic inflammation facilitates atherosclerotic plaque formation through endothelial damage and oxidative stress, while also destabilizing coronary plaques ultimately predispose to myocardial infarction (36). Taken together, these mechanisms highlight the interrelated pathways through which epigenetic signatures, microbiome composition, nutrition, and psychological factors in early life can contribute to the development of obesity, diabetes, and CVDs.

The Immune-Mediated Trajectory.

Early life constitutes a critical window in which microbial and nutritional signals shape innate and adaptive immunity. A maternal diet that is rich in fermentable fiber increases the production of short-chain fatty acids (SCFAs), such as acetate, butyrate, and propionate. These SCFAs cross the placenta and, via G-protein-coupled receptors on hematopoietic and dendritic cell progenitors, can promote tolerogenic antigen presentation and T-regulatory cell differentiation. In animal models, this reduces allergic airway inflammation, establishing a gut–lung axis (37, 38). Microorganisms living in and on the human body form an ecosystem which is critical for the normal functioning of every organ system of the host, including the development and regulation of the immune system (39). To understand its role, it may be important to understand that the microbiome, though an “external organ system” is only seeded and developing from delivery onward. Its composition, and consequently interaction with the host, is therefore significantly affected by external factors, such as the maternal microbiome, mode of delivery, antibiotics, nutrition, and environmental influences (40). Vaginal delivery and exclusive breastfeeding promote the early maturation of the gut microbiome, characterized by the presence of bacteria that produce SCFAs. However, in particular perinatal- and early life antibiotic exposure appears to be the most damaging determinant to the infant’s physiological microbiome development as it most drastically affects the initial microbial population of the human body (33, 34). Across large cohorts, the composition of gut microbes in the first year of life is a predictor of subsequent asthma at the age of five (41).

Antibiotic-exposed infants show a general decrease in abundance of the important genus Bifidobacterium, with a simultaneous increase in proinflammatory bacteria such as Klebsiella and Enterococcus species (33). Delayed microbial maturation and certain gut microbiome profiles can alter epithelial immune crosstalk. This results in a reduction in mucosal T-regulatory cells and an increase in epithelial responsiveness. These changes predispose the immune system to develop into type 2 helper T cell (Th2) skewing, IgE class switching, and eosinophilic airway inflammation. These are all hallmarks of pediatric allergic asthma (42, 43). Gnotobiotic transfers and metabolomic complementation in animals have been shown to restore tolerance, supporting a causal relationship (44).

In general, a state of dysbiosis, with overgrowth of proinflammatory bacteria such as nontypeable Haemophilus species, and absence of beneficial commensals are associated with asthma diagnoses later in childhood (45, 46). It is suggested that early-life interactions between respiratory microbial communities, including viruses such as the respiratory syncytial virus, may result in impaired mucosal and systemic immune training, as well as epigenetic alterations, and consequently may affect both short- and long-term respiratory outcomes (47). In addition, nutrition may modulate this trajectory. In a randomized, placebo-controlled trial, long-chain polyunsaturated fatty acids taken in the third trimester reduced the absolute risk of persistent wheezing and asthma through early childhood, which is consistent with the concept of lipid-mediated programming of epithelial and dendritic cell function and downstream type 2 responses (48). Taken together, the interconnected pathways between maternal and infant nutrition and the microbiome play a crucial role in the development of the innate and adaptive immunity and the occurrence of allergies and asthma later in life. Yet, there is need for more research on the early-life microbiome as a modifiable factor in reducing disease risk (49).

The Neurodevelopmental–Psychological Trajectory.

During early life, the brain exhibits particularly high plasticity, making a child’s development highly susceptible (50, 51). During pregnancy, exposure to nicotine, alcohol, tetrahydrocannabinol, cocaine, and opioids can lead to congenital anomalies, growth restriction, withdrawal syndrome and disruption of maternal regulation, resulting in associated neurodevelopmental signatures in offspring (52, 53). Opioid use in pregnancy has escalated dramatically in recent decades, paralleling the opioid epidemic observed in the US (54). Moreover, it has been demonstrated that maternal stress, depression, and other mental diseases can have a detrimental effect on the development of the child through multiple pathways. While antidepressants effectively treat maternal depression, some cross the placenta and enter the breast milk. It is imperative that not only the impact of mental health disorders but also the exposure to medications is given careful consideration, as there is evidence that they may have long-term adverse consequences for child development. This can result from the disruption of a positive experience-expectancy environment or the manifestation of adverse treatment effects (52, 53, 55, 56).

For normal brain development to unfold after birth, an experience-expectant environment is essential, one in which a child is exposed to specific stimuli within a critical timeframe (57, 58). The multidimensional model of childhood adversity identifies several types of experiences that fail to meet the requirements of an experience-expectant environment and can thereby disrupt typical development (59). Experiences of threat typically involve exposure to violence, abuse, or noxious stimuli such as invasive medical procedures (interpersonal intentional trauma, effects of witnessing trauma or incidental trauma). Psychosocial deprivation, on the other hand, refers to the absence of adequate social, emotional, and cognitive stimulation in children who are otherwise physically well-cared for (60). This may include deficits in basic sensory and perceptual input, as well as the absence of a consistent, sensitive, responsive, and nurturing caregiver (61).

Numerous studies have demonstrated that exposure to both threat and deprivation can result in long-term adverse effects on physical and mental health, cognitive functioning, communication skills, and life opportunities, such as education, employment, and income. It is also associated with increased risk-taking behavior, delinquency, substance abuse, and a heightened risk of premature death (61–64). Two recently published studies found that early deprivation of nurturing care and stimulation affected cognitive function, mental and physical health across the life span and reduced life expectancy significantly (63, 65). A further study demonstrated alterations to the integrity of neural pathways connecting Wernicke’s and Broca’s areas. This provides an explanation for impairment of receptive and expressive language processing after adverse childhood experiences (66). The cumulative risk model highlights that the greater the number of risks a child encounters, the more likely their developmental and health outcomes will be compromised (67). For example, Emmy Werner’s landmark population-based study revealed that the combination of biological and psychosocial risks poses the greatest threat to a child’s developmental and health trajectory (68).

One of the key mechanisms of how exposure to adverse circumstances affect health and development is so-called toxic stress, which affects the hypothalamic–pituitary–adrenal axis and the immune, endocrine, circulatory and endocrine systems, with particularly grave consequences if exposure takes place during early childhood (69–71). However, a child’s development is also influenced by promotive and protective factors, which include environmental, genetic, and biological conditions that support development and mitigate the impact of adverse experiences (72, 73). Among the most significant protective factors is the presence of a nurturing caregiver. For a caregiver to be sensitive and nurturing, it is essential that they are able to understand the language of infants, so-called infant cues (74). These are well-defined behaviors with which the infant communicates positive and negative responses, but these behaviors may not be intuitive to caregivers and can be misinterpreted. A young child needs a caregiver for support in physiological and behavioral regulation through coregulation (75). For this purpose, the child uses stimuli through all senses—somatosensory such as temperature and touch, olfactory, such as the smell of the caregiver, visual when seeing the caregiver’s face, or auditory through the caregiver’s voice (76). Through scaffolding, the adult facilitates the infant’s next developmental step and enables them to participate in increasingly complex interactions that match the sensitive period of their brain and therefore improve the child’s regulatory competence (77, 78).

These developmental mechanisms are even more crucial when it comes to the care of vulnerable children: Children in neonatal care, for example, are often exposed to experiences of deprivation as well as noxious stimuli that overwhelm the immature brain, such as pain and intrusive procedures, loud noises and bright light, as well as deprivation, such as limited sensory and perceptual input (79). Furthermore, neonatal care may involve separation from parents, leading to a lack of nurturing care during a critical developmental period (80). In fact, separation from parents has been identified as one of the key sources for toxic stress in neonates (81).

Examples of Current Efforts Promoting Long-Term Health in Early Life

While universal vaccination programs had been successfully implemented for decades to prevent infectious diseases in early life, a coordinated strategy to mitigate the growing burden of NCDs is still missing. There is currently a lack of evidence on the best strategy for managing care at the beginning of life to ensure an optimal basis for long-term health. Often, clinical decision-making favors short-term outcomes, and care at the beginning of life with short-term benefits may be outweighed by unanticipated long-term effects (82). For neonates with risk factors (e.g., preterm birth) that precede or are associated with a higher likelihood of negative outcomes such as NCDs, protective interventions that buffer risk factors and reduce the likelihood of NCDs are paramount. Many other aspects, such as early diagnosis of rare diseases, assessments of polygenic risk scores and family history of disorders or comorbidities are crucial for effective identification and management of at-risk infants. Although these infants are particularly vulnerable, they represent only a small proportion of the total population. On the other hand, promoting factors that are associated with a higher likelihood of positive outcomes, such as long-term health, regardless of the presence of risk factors, is critical for all individuals in early life (61, 83).

The above mentioned three trajectories highlight some critical effects of several key components. Taken together, the interrelated pathways of microbiome composition, epigenetic signature, nutrition, and psychological factors in early life can provide a key basis for long-term health (Fig. 1). Nutrition and nurturing care have been recognized as important components in normal development for decades (84, 85). It is evident that there is currently a growing body of knowledge in relation to the microbiome and epigenetics (15, 86, 87). In instances where the long-term benefits remain unproven, it is rational to prioritize best practice, encompassing optimized nutrition, balanced nurturing care and stimulation, and to exercise caution and refrain from unnecessary therapy and interventions (SI Appendix, Table S1). In the following paragraphs, we describe some current interventions potentially promoting long-term health by optimizing early life. The reported interventions are not mutually exclusive, but they reflect important aspects minimizing epigenetic changes and disruption of the normal development of the microbiome, supporting optimal nutrition, and nurturing care. These examples will not give simple answers, but they may leverage important discussions and research into how care can be delivered in early life to optimize long-term health trajectories and well-being.

Fig. 1.

The microbiome composition, epigenetic signatures, nutrition, and nurturing care potentially play important roles in promoting long-term health. These factors lay the foundations early in life, while subsequent factors, including preventive care, education, activity, diet and food scarcity, air pollution influence the risk of noncommunicable diseases later in life.

Appropriate Medication Use in Early Life.

The unborn child, via the placenta, and neonates are exposed to a number of medications that have beneficial effects on short-term outcomes but may have potentially adverse effects on long-term health. Antenatal corticosteroids are a cornerstone of management of pregnancies at risk of very early birth between 22 and 34 wk, as they decrease both death and major morbidity associated with prematurity, and their use in the late preterm period has been advocated by some (88). Corticosteroids cross the placenta in their biologically active forms at much higher concentrations than endogenous steroids (89). The first randomized controlled trial of steroids was conducted in 1972 by Liggins and Howie, and several dozen more trials followed using the same doses (88). The impacts of steroids are potentially widespread, as there are abundant glucocorticoid receptors in many organs, including the brain, affecting the transcription of up to 10 to 20% of the human genome (90). Animal research shows steroids result in smaller brains even with the current standard double doses compared to placebo (91). This raises concerns about potential adverse neurodevelopment with the standard doses of steroids, recently suggested by some, although not all, human observational studies (92, 93). If ongoing randomized controlled trials of lower doses give similar neonatal benefits as standard doses, then we should use lower doses, and in the meantime, judicious timing of steroids is warranted.

At least 40% of pregnant women receive at least one course of antibiotics during pregnancy and/or delivery, potentially increasing epigenetic changes and affecting the microbiome development of their child (94). The partial overlap of antibiotic resistance genes (ARGs) between mothers and neonates suggests that neonates inherit the legacy of their mother’s past antibiotic exposure through transmission of ARGs (95). Many antibiotics also cross the placenta, whereas the extent of fetal exposure varies by drug class and is influenced by placental transporters and maternal–fetal conditions (96). Urinary tract infection during pregnancy is an important indication for antibiotic treatment. While antibiotic treatment is mandatory for true bacterial infections, there are controversies about the benefits of treating asymptomatic bacteriuria, and overdiagnosis based on positive dipsticks alone is common (97). In case of preterm premature rupture of membranes, antibiotic therapy is routinely administered empirically, regardless of intra-amniotic infection and based on historical randomized controlled trials, rather than tailored to infection status (98). In a few specialized centers, amniocentesis is performed to assess for intra-amniotic infection or inflammation and guide targeted antibiotic treatment (99). Antibiotic exposure in the first week of life for suspected early-onset sepsis (EOS) varies widely, from 1.2% to more than 10% of all late preterm and term babies. The rate of culture-proven EOS is about 100 times lower (100). Fear of sepsis, bias and noise in decision-making, time-preferences, as well as gaps in up-to-date knowledge are important drivers for antibiotic overuse in pregnancy and the neonatal period. A more factual approach, new algorithms leveraging AI, and improved care bundles reducing hospital-acquired infections can minimize exposure to antibiotics at the beginning of life (82). Overall, while antibiotics are beneficial in reducing infectious morbidity, overexposure increases epigenetic changes, affecting the normal development of the microbiome, hindering breastfeeding and the bonding process through hospitalization of the baby on a neonatal unit with separation from the mother (82, 101).

Balanced Health Care Interventions in Early Life.

Caesarean section rates are increasing across the world particularly in rich countries and private healthcare settings. Already 1 in 5 babies are born by this route, projected to increase to nearly 30% of all births by 2030 and up to 50% in specific areas of the world (102). While essential for a safe birth in specific situations, unnecessary caesarean section disrupts neonatal adaptation, resulting in increased short-term respiratory morbidity, long-term increases in allergy, atopy, asthma, and other NCDs due to reduced intestinal gut microbiome diversity and an increased rate of epigenetic changes (103, 104). In addition, caesarean sections may hinder the important physiological bonding process and breastfeeding, which is reported to be significantly lower compared to natural birth (105). Reducing unnecessary caesarean sections is an achievable goal through educational interventions for women and families, clinician guidelines and training, and organizational approaches, including financial incentives related to inpatient reimbursement systems (106).

Clamping of the umbilical cord may be the first and most common medical intervention a neonate is exposed too. Investigation over the past quarter century has confirmed that in most cases, “nature knows best”; delaying cord clamping optimizes neonatal transition, improving hemodynamic stability, increasing early hemoglobin concentrations, iron stores, and stem cells (107, 108). Neurodevelopmental outcomes of term and preterm and survival of preterm infants will potentially be improved, whereas an impact on the incidence of NCDs later in life remains speculative (108, 109). Widespread implementation of delayed cord clamping is supported by international guidelines, but at a practical level requires training and education, and multidisciplinary teamwork (110).

Optimized Nutrition in Early Life.

Thanks to widespread routine supplementation of infants, several severe micronutrient deficiency disorders, such as rickets and vitamin K deficiency bleeding, have been virtually eradicated in high-income countries. However, certain risk groups, such as preterm infants, are still at risk of nutrient deficiencies even in high-income countries. It may be beneficial to further evaluate the iron status of these infants, as it has been shown that iron supplementation of low-birth-weight infants reduces the risk of behavioral problems at 7 y of age (111). Enteral supplementation with arachidonic acid and docosahexaenoic acid may also reduce risk of severe retinopathy in extremely preterm infants (112).

Breast milk is the optimal nutrition for infants and confers several important health benefits compared to formula feeding (113). Some benefits are well known, such as reduced overall infant mortality shown in low-income countries, reduced risk of infections, such as gastrointestinal and respiratory tract infections, reduced rate of sudden infant death syndrome, and reduced risk of necrotizing enterocolitis in preterm infants (113–115). Furthermore, recently published reports show that breastfeeding is associated with reduced incidence of obesity, diabetes, asthma, IBD, and a higher IQ at school age, underlining the importance of breastfeeding for long-term health (113, 116). A large European randomized controlled trial has shown that high protein intake from infant formula increases the risk of obesity at school age (117). Human breast milk has a relatively low protein content, and exclusive breastfeeding for the first 4 to 6 mo is beneficial in preventing metabolic and CVDs later in life (87, 113, 116). It is therefore recommended by the WHO and other authorities that infants should breastfeed exclusively during the first 6 mo of life and partially up to 2 y. Exclusive breastfeeding rates in the first 6 mo of life are worldwide at 48%, and the target of at least 50% by 2025, as set by the WHO, is almost achieved (118). To promote breastfeeding, the mothers need to be supported by the health care system, such as lactation consultants or other health workers trained in lactation, their communities, and families. Protocols for early breastmilk hand expression and pumping after delivery of a preterm or other high-risk infant significantly increase the breast milk supply for this at risk population (119).

Nurturing Care and Stimulation in Early Life.

Interventions to improve neonates’ health and development are most effective when they include a focus on the parent–child interaction and responsive parenting (78). Central to these approaches is enhancing parents’ ability to interpret their infant’s behavioral cues and respond appropriately to their developmental needs. Specifically, interventions that improve caregiver sensitivity through improving their ability to read “infants” cues not only strengthen the foundational conditions for learning in an integrated manner but also foster bonding and attachment (78, 79, 81). In addition, improving caregiver sensitivity has been shown to improve white matter microstructure in premature infants’ brains (120). Overall, evidence demonstrates that the quality of parent–infant interaction mediates the impact of neonatal risk on cognitive development (79). One evidence-based best practice is Kangaroo Care, in which parents hold their infant skin-to-skin (121). Kangaroo Care provides healthy multisensory stimulation, promotes emotional and physical closeness, supports bonding, and facilitates physiological and behavioral coregulation through multisensory cues. Benefits include improved oxygenation and temperature regulation, reduced pain in infants, and less stress for both infants and parents, enhanced parental confidence, shorter hospital stays, and better long-term health and developmental outcomes in the infant (81, 122).

Parental stress has been shown to impair parents’ capacity for nurturing caregiving (123). Nurturing care is particularly vital in neonatal intensive care settings, as evidence suggests that, for example, preterm infants’ cues are more challenging to read and that these infants are more prone to dysregulation, putting them at additional developmental risks and child maltreatment (78, 124, 125). At least since the 1980s, neuro-promoting care in NICUs has been fostered with a family integrative approach to improve neonatal outcomes (126). Family Integrated Care (FIC), has demonstrated high efficacy (80, 127). FIC emphasizes the critical role of parents in their infant’s health and development. Parents of children in neonatal care often experience heightened stress and suffer from increased rates of depression, anxiety, and posttraumatic stress disorders (79–81). In FIC, parents play a central role in preventing, assessing, and managing their infant’s pain and stress, which reduces feelings of helplessness and preserves their parental role, mitigating the risk of alienation from their baby (81). The provision of psychosocial services for parents further helps to decrease stress and improve their caregiving capacity (80). Importantly, psychosocial and peer support should begin during pregnancy for at-risk families, given that maternal stress in utero can negatively impact fetal development (128). This is especially important for families facing social adversity, as such families are at heightened risk for stress and psychopathology (78, 80) It has been demonstrated that the determinants of maternal health, and consequently that of the neonate, are the result of multifactorial processes, including social determinants. Inequity in healthcare has a significant impact on neurodevelopmental and psychological trajectories (129).

Given the profound and long-term consequences of child maltreatment for development and health, systematic approaches to its early identification are essential. Different methodologies have been proposed to assess childhood adversity. Standardized screening tools include the Childhood Trauma Questionnaire or the Adverse Childhood Experiences (ACE) Questionnaire (130, 131). However, these instruments rely on self-report, and parental reporting may be biased or incomplete, particularly when maltreatment occurs within the family. Screening approaches that focus on more proximal indicators such as observable signs of maltreatment, child distress, or established risk factors conducted or the validated Traumatic Events Screening Inventory (TESI) may offer a feasible and sensitive strategy for early detection (132, 133).

Future Perspectives

While the Barker hypothesis, DOHaD, Heckman’s human-capital theory, and the first 1,000 d framework each illuminate vital aspects, none of them individually encompasses a holistic view, including aspects of care management (10, 11, 17, 20). Moreover, although an association between early-life adversity and future physical and mental health can be observed on a population level, the accuracy at the individual level remains poor (63). This finding underscores the importance of two aspects: First, susceptibility is highly variable through individual differences and resilience (68). Second, other time periods after early life, such as adolescence, have a high degree of plasticity and are also important (18). Concurrently, the objective of enhancing public health systems and screening methodologies is not solely to assist individuals, but to attain quantifiable gains at the population level (134). Raising awareness to create a sense of urgency and an integrative conceptual model could inform a new healthcare agenda aimed at improving the quality of early life care and maximizing the return on investment.

The implications of such a unified model are 1) evidence-based and scalable multidomain early interventions combining microbiome support, balanced health care interventions, optimal maternal and child nutrition, and nurturing care; 2) Clinical and economic evaluation leveraging epigenomic, microbiome, nutritional, psychosocial, and cognitive outcomes as early indicators of long-term impact in health and well-being integrating health benefits with human-capital returns, strengthening the case for interdisciplinary investment in such interventions; 3) Education and communication strategies to spread knowledge, encourage buy-in, facilitating a collaborative culture involving healthcare, society, policymakers, insurance companies, and other partners; and 4) an innovation and implementation agenda fostering best practice and new multidomain early interventions. International and interprofessional collaboration within a learning health system is essential to overcome the problem of short-term decisions that neglect a long-term perspective, and to maximize the efficacy and scalability of early promotion of health and well-being. Those most involved in early life care, such as obstetricians and neonatologists in collaboration with policy makers who are able to influence the environmental factors affecting early life, must take the lead in initiating this endeavor (SI Appendix, Fig. S1).

Potential next steps to achieve and analyze multidomain early life interventions are to design an adequate innovation and research agenda. A crucial element for achieving widespread success is the scalability of interventions and evaluations. Evaluation metrics need to be defined and standardized at multiple time points in the lifespan. Multidomain panels including epigenetic signatures, gut microbiome diversity and signature, or multiomics biomarkers may help to leverage precision medicine in the field of health promotion and to optimize implementation (135). For economic evaluation, there is a need for novel modeling approaches combining intervention-mediated reductions in NCD risk with enhanced lifetime earnings and reduced costs, and for performing cost-effectiveness and benefit–cost analyses benchmarking against Heckman’s established early-childhood interventions to optimize resource allocation (17). A mandatory step in data management is to create a digital record for neonates, linked to maternal data, from conception to later life. These data will include routine, real-world data such as continuous biophysical signs, biomarkers, and key health-related issues throughout the lifespan. New wireless sensors and wearables, which are becoming increasingly available, will help collect biophysical data that can feed into predictive analytics leveraging AI (136). Importantly, these sensors have also been designed and tested in low resource settings, ensuring future data collection is equitable and translatable globally (136). New sensor technologies for monitoring biochemical molecules in various body fluids, such as sweat, saliva, and breath, will further expand the possibilities for obtaining minimally invasive data (137). This new and continuous data, analyzed by AI, will facilitate the development of new strategies for early life management to ensure future health and well-being.

Limitations

There are several limitations to this perspective. First, we present our framework from the perspective of high-income countries. Considering the big picture and long-term health is a luxury. The situation in middle- and low-income countries is different, with much higher morbidity and mortality from acute and infectious diseases (1). Nevertheless, in the poorest one billion people, the burden of NCDs is high, with around 50% affecting children and young adults (138). While the applicability of our framework to less privileged settings has to be assessed, the implementation of Kangaroo care may serve as an example that parts of it can be successfully implemented at low costs with a high impact (139). Second, and most importantly, there is a window of several years or decades between the start of life and the onset of the burden of NCDs. Other periods in life, such as adolescence, are highly plastic and have a significant impact on future health and well-being (18). What happens in this window influences the development of NCDs and health. Therefore, management at the beginning of life is never a complete strategy for long-term health, but it serves as an important backdrop for achieving long-term well-being later in life.

Conclusions

The rise of NCDs poses significant challenges to the healthcare system. It is imperative that we deliver care in early life that achieves optimal short-term outcomes while promoting long-term health trajectories and well-being. The precise nature of the impact of early life interventions on the development of future physical and mental health remain to be elucidated. However, it is reasonable to promote optimized nutrition and nurturing care, and to balance medical interventions avoiding unnecessary and futile therapies at the beginning of life with potential negative impact on future health and well-being. Raising awareness to create a sense of urgency, and the development of an integrative conceptual model, are the first steps to prompt the development of a new healthcare agenda aimed at improving the quality of early life care and maximizing the return on investment.

Supplementary Material

Appendix 01 (PDF)

Data, Materials, and Software Availability

There are no data underlying this work.