Developmental origins of health and disease

The DOHaD approach has its empirical origins in epidemiological research by Barker and colleagues in the 1980s. The evidence from this research provided the foundation for what Barker referred to as the fetal origins of adult disease hypothesis, sometimes called Barker’s hypothesis of fetal origins. ^{Reference Thiele and Anderson9,Reference Barker10} Barker’s research challenged the notion that coronary heart disease (CHD) could be solely attributed to lifestyle factors and genetic predisposition, as these explanations did not sufficiently account for changing incidence patterns. For example, while CHD incidence fluctuated between the mid-1980s and early 2000s, adult lifestyle behaviors remained stable.^{Reference Barker10} Additionally, risk factors of smoking, high blood pressure, and cholesterol levels were correlated with CHD, yet even men with minimal risk factors experienced high mortality rates from the disease.^{Reference Barker10} Therefore, Barker hypothesized that additional predisposing factors must contribute to the development of CHD beyond lifestyle choices and genetics.^{Reference Barker10}

Through geographical epidemiological studies using early 20th-century data from midwife postnatal visits, Barker’s team examined 23 common causes of death in adults.^{Reference Thiele and Anderson9} The authors used historical infant mortality rates, closely associated with poor social conditions such as low socioeconomic status, food insecurity, and limited healthcare access, as a proxy for adverse environmental influences during early life. They found that adult mortality from bronchitis, rheumatic heart disease, stomach cancer, and CHD exhibited similar geographic distributions to historical infant mortality rates.^{Reference Barker10} However, the temporal trends diverged. Over the prior century, infant mortality, bronchitis, rheumatic heart disease, and stomach cancer declined in prevalence, while the rates of CHD increased. The authors ruled out poor social conditions as a precursor to adult lifestyle choices by looking at the rates of lung cancer (as a proxy for smoking) and dietary fat consumption (a contributor to CHD), neither of which aligned with past infant mortality patterns. They concluded that poor social conditions leading to health-damaging lifestyle choices could not be the sole explanation linking infant mortality and heart disease. The authors hypothesized that prenatal and early postnatal environmental factors, such as nutritional deficiencies, could permanently alter physiology and metabolism through DP, predisposing individuals to CHD and stroke later in life.^{Reference Barker10} Subsequent studies by Barker and colleagues revealed associations between low birth weight and increased risk of cardiovascular disease, metabolic syndrome, and type 2 diabetes.^{Reference Thiele and Anderson9,Reference Lacagnina11} In the years that followed, additional research, particularly in large cohorts exposed to famine, built upon this foundational evidence, with findings that reinforced Barker’s hypothesis.^{Reference Forsdahl12–Reference Hinkle17}

In 1999, the International Council on the Fetal Origins of Adult Disease was formed, and in 2001, it was renamed the Society for the Fetal Origins of Adult Disease (the Society). In 2003, following discussions among the scientific community at two consecutive meetings of the World Congress on Fetal Origins of Adult Disease, the DOHaD was adopted in place of the Fetal Origins of Adult Disease to reflect the evolving understanding of the impacts of environmental exposures during and beyond the in-utero period.^{Reference Wadhwa, Buss, Entringer and Swanson18} In 2020, the Society became the International DOHaD Society, and they continue to support collaborative interdisciplinary research and knowledge translation about DOHaD.¹⁹

In 2022, Barker’s original observations^{Reference Barker10} were validated and extended by Baker et al.^{Reference Baker, Biroli, van Kippersluis and von Hinke20} using data from over 370,000 participants in the UK Biobank. The authors replicated Barker’s finding that the relationship between infant mortality rates and ischemic heart disease persisted after accounting for geographic variation, supporting the robustness of this relationship. In addition, elevated infant mortality rates were strongly associated with lower socioeconomic status, indicating that early-life conditions linked to social disadvantage contribute to later cardiovascular disease risk through pathways extending beyond prenatal undernutrition.^{Reference Baker, Biroli, van Kippersluis and von Hinke20}

The authors further argue that infant mortality rates may act as a proxy for unobserved characteristics of socioeconomic status and environmental factors that vary between families, such as household income, food security, exposure to environmental pollutants, parental genetics and health status, and effects of individual home environments or family infrastructure. Additionally, Baker et al.^{Reference Baker, Biroli, van Kippersluis and von Hinke20} incorporated polygenic risk scores for ischemic heart disease and demonstrated effect-modification by early-life environment. Among individuals with high genetic risk, higher infant mortality rates were associated with a significantly greater risk of ischemic heart disease. Conversely, where infant mortality rates were lower, genetic risk was not statistically significant. These findings provide empirical evidence that adverse early-life environments may amplify genetic susceptibility, while more favorable early-life conditions may attenuate the expression of genetic risk. Collectively, this work strengthens the evidence for gene-environment interplay in the developmental origins of cardiovascular disease.

The evolution of developmental programming as a concept

DOHaD is the overarching paradigm, of which programming is a tenet. Programming describes the physiological and biological mechanisms by which lasting changes to an organism’s structure, function, and metabolism occur due to exposures during specific periods.^{Reference Thiele and Anderson9,Reference Sutton, Gilmore and Dunger21} The earliest work that laid the foundations for developmental theory is that of Douglas Alexander Spalding in the 1870s (see Figure 1). Spalding examined animal behaviors and transferred attachment, and hypothesized that critical periods can influence development.^{Reference Gray22} Subsequent animal studies building on this foundation led to the work of Konrad Lorenz in the 1930s, who described a phenomenon where birds immediately imprint upon or firmly attach to objects they were exposed to upon hatching.^{Reference Padmanabhan, Cardoso and Puttabyatappa23} Lorenz’s theory purported that this behavioral programming, or imprinting as he called it, was influenced by early exposures experienced during a specific period, and the resulting changes persisted through adulthood.^{Reference Waterland and Garza7}

Figure 1. The evolution of developmental programming as a concept. The term developmental programming has evolved over the last eighty years. It is intricately linked with the developmental origins of health and disease. Currently, various terms describe similar phenomena, primarily influenced by disciplinary perspectives. Created in https://BioRender.com.

Dörner was the first to introduce the term programming. In 1974, his work examined the impact of neurotransmitters, hormones, and metabolites during critical periods of early development on neurodevelopment and disease onset in adulthood.^{Reference Koletzko24} Dörner also proposed the potential for gene-environment interactions. Barker’s research in the 1980s connected programming to the fetal origins of health and disease as the mechanistic underpinning.

In the 1990s, Hertzman and Wiens examined the impacts of early experience on health and disease development from an epidemiological and public health lens.^{Reference Hertzman and Wiens4,Reference Hertzman25,Reference Hertzman26} The authors referred to the biological embedding of early experiences of social gradients in health status, although their theory was founded on the same animal models as programming theory.^{Reference Hertzman26} Like programming, embedding describes a mechanistic process,^{Reference Nelson6} emphasizing the social determinants of health and the influence of psychosocial conditions on child development. The key contribution of this theory was the link between human development and population health, and the consideration of the environment to include factors outside the womb. In addition to recognizing critical periods, Hertzman proposed that health behaviors that contribute to long-term health outcomes and cumulative effects further compound health impacts.^{Reference Nist27} This term became commonly used in health equity research.^{Reference Louvel and Soulier28} In 1991, the programming concept was further refined by Lucas, who coined the term “developmental programming.” ^{Reference Lucas29} However, this term faced criticism for implying a fixed set of instructions, which did not accurately capture the dynamic nature of developmental processes.^{Reference Hanson and Gluckman8}

Toward the end of the decade (1999), Waterland and Garza^{Reference Waterland and Garza7} suggested metabolic imprinting was a more appropriate term to refer to the specific relationship between early nutritional exposures and the onset of disease later in life. It was intended to refer specifically to the biological mechanisms occurring,^{Reference Waterland and Garza7} and it appears to be more commonly used in developmental biology. The term biological programming gained popularity in the late 1990s and into the 2000s. A concept analysis to distinguish between biological programming and biological embedding identified that the former is less frequently used and has a high degree of variation in how it is interpreted and applied.Reference Nist²⁷Biological programming tends to be used more broadly, without restriction to development. Biological embedding has a more consistently used definition and is more commonly used in sociology, psychology, and developmental medicine.^{Reference Nist27} However, there is significant overlap between the two terms, and they are often used interchangeably.^{Reference Nist27,Reference Louvel and Soulier28}

In 2014, Hanson and Gluckman expressed a preference for priming, induction, or conditioning, believing these terms were less deterministic than programming.^{Reference Hanson and Gluckman8} Their conceptual framing was rooted in developmental physiology, developmental biology, and evolutionary biology. Priming refers to the presence of an environmental stimulus that elicits a phenotypic response, whereas conditioning similarly denotes a stimulus-response relationship, further implying the adaptive modification of biological systems which may become more efficient or reliable with repeated exposure.^{Reference Hanson and Gluckman8} Despite this proposed shift in terminology, the articles included in this review suggest that DP remains frequently utilized in DOHaD research.

This review revealed an expansive body of literature on DP, including numerous recent publications. However, no universally accepted definition was found. To enhance clarity, it would be beneficial to have a shared conceptual definition so that researchers, regardless of their discipline, can collaborate in advancing the science of DOHaD.

Epigenetics

Epigenetics is the scientific study of how the environment influences the expression of an individual’s genes.^{Reference Wallack and Thornburg33} It was previously thought that genes were deterministic; one’s DNA sequence was fixed, and one’s genetic code determined phenotypes and health outcomes. It is now known that epigenetic mechanisms can regulate gene expression, impacting protein production and potentially altering an organism’s phenotype or disease state.^{Reference Lacagnina11} Barouki et al.^{Reference Barouki, Gluckman, Grandjean, Hanson and Heindel34} aptly described this by stating, “each individual has one genome but will hold multiple epigenomes.”

DNA methylation is the most frequently studied epigenetic mechanism, and in humans, it commonly involves transferring a methyl group to the cytosine-guanine (CpG) dinucleotide by DNA methyltransferase.^{Reference Mohandas N.L.Y.Wong, Stephenson, Craig, Tarnoki and Segal35,Reference Tirado-Magallanes, Rebbani, Lim, Pradhan and Benoukraf36} Hypermethylation is often present in promoter regions, and for many years, it has been thought to contribute to gene suppression.^{Reference Tirado-Magallanes, Rebbani, Lim, Pradhan and Benoukraf36,Reference Phillips37} However, it is now more appropriately considered repression. Conversely, hypomethylation can occur, activating gene expression.^{Reference Tirado-Magallanes, Rebbani, Lim, Pradhan and Benoukraf36} Hence, DNA methylation functions like a dimmer switch that can up- or down-regulate expression to various degrees.^{Reference Gibney and Nolan38} Advancing technology has allowed the realization of other consequences of DNA methylation, including splicing, transcription factor recruitment, and the positioning of nucleosomes.^{Reference Tirado-Magallanes, Rebbani, Lim, Pradhan and Benoukraf36} As a result, DNA methylation can alter the phenotype (within the limitations of the genotype). As such, DNA methylation is a dynamic process that begins in utero and continues after birth.^{Reference Sutton, Gilmore and Dunger21} For example, alterations in DNA methylation patterns in offspring have been linked to lower maternal prenatal intake of methyl-group donors, such as folate, betaine, methionine, and choline, and associated with phenotypic outcomes, including congenital heart and neural tube defects, and cleft lip and palate.^{Reference Bokor, Vass, Funke, Ertl and Molnár39} In the Agouti mouse model, supplements containing methyl donors provided to pregnant dams increased offspring DNA methylation at the Agouti allele. These offspring were born with a different coat color.^{Reference Richmond, Sharp and Herbert40} Animal studies have shown that early adversity, such as poor or neglectful maternal care, can lead to epigenetic changes in infants that persist into adulthood.^{Reference Cecil, Zhang and Nolte41} Human studies have also shown that child maltreatment is associated with altered epigenetic regulation in genes that impact physiological and psychological outcomes related to stress, such as NR3C1. ^{Reference Cecil, Zhang and Nolte41} Although much of the research in humans is associative, methodologies such as Mendelian randomization (MR) offer greater strength in making causal inferences about associations between DNA methylation and health outcomes. A recent study employed a two-sample MR to examine DNA methylation loci across multiple developmental stages.Reference Schuurmans, Dunn and Lussier⁴² The authors identified potentially causal associations between DNA methylation at sites associated with adversity and physical and mental health outcomes, including attention deficit hyperactivity disorder, depression, and asthma.^{Reference Schuurmans, Dunn and Lussier42}

Although DNA methylation is the most frequently studied, histone modification and chromatin remodeling are other epigenetic mechanisms. Histones are proteins that help condense the large volume of DNA to fit inside the nucleus. They provide structural support for chromosomes and are involved in gene expression.^{Reference Gibney and Nolan38,Reference Gilchrist43} Enzymes can modify histones, altering gene expression without changing the DNA sequence. Gene expression can be regulated through variant histones or modification of histone tails post-translation.^{Reference Goyal, Limesand and Goyal44} There are also epigenetic mechanisms specific to RNA, such as microRNA (miRNA) and long noncoding RNA, which may be implicated in DP. However, the role of noncoding RNA is still being fully explored. MicroRNAs are also noncoding but are only 21–25 nucleotides long.^{Reference Goyal, Limesand and Goyal44} They can modify gene expression post-transcriptionally by pairing with messenger RNAs and targeting the 3’ untranslated region, suppressing translation.^{Reference Goyal, Limesand and Goyal44} Gene expression can be repressed or activated by controlling the miRNA produced.^{Reference Goyal, Limesand and Goyal44} Therefore, epigenetics is a multimodal molecular mechanism of DP, which can act as an intermediary between environmental influences and phenotypic expression.

Ontogeny

Ontogeny is the development of an organism throughout its lifecycle from fertilization to adulthood. The organism’s genetic program is realized under exogenous factors during ontogenesis.^{Reference Sutton, Gilmore and Dunger21} In situations of nutritional scarcity, vital organs, such as the brain, consume most of the limited available nutrients at the expense of other less essential organs, such as the pancreas or kidneys.^{Reference Padmanabhan, Cardoso and Puttabyatappa23,Reference Wallack and Thornburg33} Studies have shown that alterations to cellular structure and function could remain permanent if this occurs at a critical juncture in fetal development.^{Reference Wallack and Thornburg33} This attribute highlights the vulnerability of fetal organ development to external influences while recognizing that environmental factors can impact health outcomes at various developmental stages.

Critical or sensitive periods

Critical periods are fundamental to DP as they are periods where an organism is more vulnerable to environmental influences that can have long-term implications for health and disease. These periods are windows of opportunity for preventative measures and interventions that may shape health outcomes. The idea of critical periods in fetal and infant life is derived from embryological studies examining the effects of exposure to toxic substances on the developing fetus.^{Reference Stockard49} The earlier the insult occurred in utero, the more damaging the effects. Thus, there was an inverse relationship between maturity and vulnerability.^{Reference Stockard49} Further research on critical periods came from studies where birds immediately imprinted upon or firmly attached to objects they were exposed to upon hatching.^{Reference Lorenz50} However, it has been argued that the preferable term is “sensitive” periods, as this confers a degree of reversibility of detrimental programming or possible future benefit from a positive environmental influence.Reference Colombo, Gustafson and Carlson⁵¹In contrast, “critical period” conveys greater rigidity and inflexibility in the induced changes.^{Reference Colombo, Gustafson and Carlson51} Additionally, sensitive periods have been used to refer specifically to neurobiological development and the brain’s plasticity.^{Reference Gabard-Durnam and McLaughlin52}

Preconception and the perinatal period are critical for fetal development, in the context of DOHaD and DP.Reference Colombo, Gustafson and Carlson⁵¹In infancy, the period of vulnerability for the later development of physical and psychological diseases occurs during the first 1000 days (i.e., from conception to two years of age).^{Reference Wallack and Thornburg33,Reference Barnes, Heaton, Goates and Packer53} During this time, rapid growth and normal development will occur in the presence of appropriate stimuli or conditions.^{Reference Colombo, Gustafson and Carlson51}

Another sensitive period is adolescence, when neuroendocrine and reproductive changes accompany puberty.^{Reference dos Santos, Miranda and Saavedra54} This is also a time of increasing independence from the family, often accompanied by freedom to make diet and lifestyle choices.^{Reference Tohi, Bay, Tu’akoi and Vickers55} Adolescents may use tobacco products, drink alcohol, or ingest drugs. Patterns of physical activity are also often established in this period. Animal studies have found that a high-fat diet during puberty is associated with metabolic dysfunction in rats.^{Reference dos Santos, Miranda and Saavedra54} Including sensitive periods in any definition of DP is essential to emphasize the time-dependency of the concept. Any adverse environmental exposures during these periods may permanently impact physiological development or metabolic pathways. During these periods, organisms are thought to be more malleable.^{Reference Colombo, Gustafson and Carlson51}

Plasticity

Despite the focus on the first 1000 days as a critical period of vulnerability, the ability of the body’s organs and systems to adapt to environmental conditions extends beyond the neonatal period, throughout life, and is referred to as plasticity.^{Reference Thiele and Anderson9} This allows phenotypic adaptation of the genotype to suit environmental conditions. For example, suppose the fetus develops in an environment of nutritional scarcity. It may adapt by conserving fat and glucose stores and altering the regulation of adipokines (e.g. leptin and adiponectin) within the hypothalamus to regulate metabolism,^{Reference Lacagnina11} and will be prepared to enter a world where food will continue to be limited in supply. If food is abundant in the post-natal environment, these adaptations can increase the risk of developing chronic diseases related to metabolism, such as obesity or type 2 diabetes.^{Reference Lacagnina11} Plasticity changes with age, differs for various organs and tissues, and sometimes becomes fixed.^{Reference Hsu and Tain56} Barker^{Reference Barker10} illustrated this theory by explaining that all humans are born with the same number of non-functioning sweat glands. The number of sweat glands that become functional in the first three years of life depends on the environment the child is exposed to; hotter environments require more sweat glands. After three years, the number of glands is fixed.^{Reference Barker10} Thus, plasticity is essential in defining DP because it is a key mechanism linking early life experiences and developmental outcomes.

Maternal nutrition

Several factors can contribute to fetal DP (see Figure 3). Of these, maternal nutrition has been one of the most comprehensively studied. Nutrition is a key antecedent to DP, given that in 2022, the World Health Organization reported that 29.6% of the global population (or 2.4 billion people) did not have adequate access to food to meet nutritional requirements.⁵⁷ Further, 900 million people experienced severe food insecurity.⁵⁷ This creates a high potential that many women will not meet the daily recommended nutritional intake during pregnancy.

Figure 3. The antecedents, attributes and consequences of developmental programming. The antecedents of developmental programming include maternal nutrition, disease and medication, lifestyle, environmental toxins, and stress. The consequences of these exposures are in developmental programming that predispose the fetus to adverse health outcomes such as cardiovascular disease, metabolic disease, type 2 diabetes, obesity, and mental health challenges. Developmental programming is mediated by attributes such as epigenetics, ontogeny, and plasticity. Some epigenetic changes can be transmitted intergenerationally to grandchildren. Individuals are more vulnerable to the effects of the antecedents during specific sensitive periods of development. Created in https://BioRender.com.

The studies by Barker et al. and subsequently, those in cohorts exposed to famine, demonstrated that maternal malnutrition may predispose the offspring to develop cardiovascular disease, metabolic disease, type 2 diabetes, and mental health issues.^{Reference Thiele and Anderson9–Reference Lacagnina11,Reference Goyal, Limesand and Goyal44} Animal models and previous large-scale studies of cohorts experiencing famine also demonstrated a dose-response relationship.^{Reference Hsu and Tain56} Minor nutritional deficits or overages can exert an impact, particularly on organs or systems undergoing periods of rapid fetal development. However, more significant deviations from recommended dietary requirements have larger effects.^{Reference Hsu and Tain56}

Conversely, some studies have demonstrated that fetal overnutrition, resulting from excessive weight gain in pregnancy or gestational diabetes, is also associated with adverse health outcomes. Babies born to mothers with pre-pregnancy obesity, indicated by a high body mass index (BMI), were observed to be large for gestational age and at elevated risk of developing obesity and metabolic disease, including type 2 diabetes, as adults.^{Reference Lacagnina11,Reference Padmanabhan, Cardoso and Puttabyatappa23,Reference Barouki, Gluckman, Grandjean, Hanson and Heindel34} Animal models have provided further evidence of causal mechanisms. For example, female rats given a high-fat diet produced offspring with reduced insulin hypersensitivity, hypertension, and obesity.^{Reference Padmanabhan, Cardoso and Puttabyatappa23} Additionally, sheep overfed in pregnancy produced dysglycemic offspring.^{Reference Padmanabhan, Cardoso and Puttabyatappa23}

The placenta is essential for fetal development, nutrient and oxygen exchange, and waste transportation between the maternal and fetal systems.Reference Reynolds, Diniz and Crouse⁵⁸When there is nutritional scarcity, the vascular development of the placenta is reduced in early pregnancy.^{Reference Reynolds, Diniz and Crouse58} Reynolds et al.^{Reference Reynolds, Diniz and Crouse58} conducted studies on livestock, demonstrating that placental development is altered in pregnancy in response to over- or undernutrition. The authors found that nutritional scarcity could also decrease the expression of angiogenic factors and nutrient transporters and significantly impact gene expression in the fetal liver, muscle, and cerebrum. The authors concluded that defects in placental growth are associated with altered fetal growth and organ development. They also found that nutritional interventions had a mitigating effect on placental vascular development.^{Reference Reynolds, Diniz and Crouse58}

Maternal nutrition may also indirectly influence fetal development through its effects on the maternal intestinal microbiota. Diet is a primary determinant of microbial composition and metabolic activity, which can influence maternal immune function, micronutrient availability, inflammatory regulation, and the production of bioactive metabolites.^{Reference Barrientos, Ronchi and Conrad2} Microbial-derived components and metabolites may interact with the placenta and influence fetal development. Evidence from human studies remains limited and does not currently support stable programming of the intestinal microbiota during the first 1000 days of life.^{Reference Michel and Blottière3} However, experimental evidence, particularly from animal models, suggests that the microbiota may act as a mechanistic relay through which nutritional exposures influence developmental trajectories or susceptibility to later pathophysiology.^{Reference Michel and Blottière3} Accordingly, microbiota-related effects can be conceptualized as intermediaries or modifiers within the DOHaD framework rather than as defining elements of DP.

Maternal disease and medication

Homeostasis of the maternal-fetal environment during pregnancy is essential to maintaining and permitting typical growth and development. Maternal diseases, particularly ones that create hormonal imbalances, such as polycystic ovary syndrome (PCOS), gestational diabetes, or pre-eclampsia, can significantly impact this homeostasis.^{Reference Padmanabhan, Cardoso and Puttabyatappa23} PCOS in mothers has been associated with the development of PCOS in their infants as well as metabolic disorders or reproductive issues.^{Reference Padmanabhan, Cardoso and Puttabyatappa23} Maternal diabetes has been linked to long-term metabolic and cardiovascular complications in offspring.^{Reference King and Laplante59} Further, preeclampsia affects about 2%–8% of pregnancies and is associated with premature births, intrauterine growth restriction, and increased risk of hypertension and stroke for offspring in adulthood.^{Reference Padmanabhan, Cardoso and Puttabyatappa23} In animals with induced diabetes, their offspring had normal glucose metabolism at birth. However, as adults, they developed diabetes during periods of metabolic stress, such as pregnancy.^{Reference Padmanabhan, Cardoso and Puttabyatappa23}

Medication effects can also constitute adverse exposures, which can disrupt typical developmental processes, such as organ formation and neurodevelopment, and result in atypical morphological or physiological development. An unplanned pregnancy may lead to unintended exposure of the fetus to teratogenic drugs. At times, taking medication for pre-existing or new health conditions is unavoidable during pregnancy, and the teratogenic risks of medications are not always known. A notorious example of a problematic legal drug taken during pregnancy without known risks was Thalidomide, which was given to prevent nausea in pregnant mothers and led to severe malformation of limbs in the fetus.⁶⁰ This practice was discontinued in 1962 in Canada/North America once the consequences were realized. However, one study demonstrated that from 2006 to 2017, fetuses from 1 in 16 pregnancies continued to be exposed to commonly used teratogenic drugs, such as Valproic Acid, Topiramate, and Methotrexate.^{Reference Sarayani, Albogami and Thai61} While rates of exposure to known teratogens declined over the study period, exposure to potentially teratogenic drugs increased.^{Reference Sarayani, Albogami and Thai61} Therefore, assessing exposure to teratogenic or potentially teratogenic drugs during the periods before and during pregnancy is crucial.

Maternal lifestyle choices

There is significant evidence of maternal lifestyle factors such as substance use, including smoking, consumption of alcoholic beverages, and legal and illicit drugs, as antecedents that are disruptive to DP.^{Reference Thiele and Anderson9} Exposures to these substances in utero may be detrimental to the health of a fetus, potentially altering growth and development and predisposing the fetus to future disease development.Reference Thiele and Anderson⁹Substance use in pregnancy has been associated with low offspring birth weight, intrauterine growth restriction, neurodevelopmental disorders, and congenital abnormalities in humans.^{Reference Padmanabhan, Cardoso and Puttabyatappa23} Studies in pregnant animals exposed to drugs were linked to reduced birth weights and cognitive and motor deficits.^{Reference Padmanabhan, Cardoso and Puttabyatappa23} Additionally, maternal smoking during pregnancy increases the risk of obesity in offspring during childhood and the risk of hypertension in adulthood.^{Reference Bianco and Josefson62} Conversely, optimizing pregnancy health through physical activity, which contributes to maintaining a healthy weight, regulation of metabolism, and hormone balance, may act as a protective factor to mitigate metabolic programming from environmental insults.^{Reference Krassovskaia, Chaves, Houmard and Broskey63–Reference Castro-Rodríguez, Rodríguez-González, Menjivar and Zambrano65} Physical activity has the added advantage of reducing perceived stress,⁶⁶ another antecedent of DP.

Maternal environmental chemical exposures

Since hormones are critical components of the maternal-fetal milieu, substances that mimic hormones can alter normal fetal development.^{Reference Haugen, Schug, Collman and Heindel67} Endocrine-disrupting chemicals (EDCs) can interfere with endogenous hormones, altering their production and action or even causing their elimination.^{Reference Barouki, Gluckman, Grandjean, Hanson and Heindel34} Thus, exposure to EDCs has been associated with DP.^{Reference Barouki, Gluckman, Grandjean, Hanson and Heindel34} These chemicals are commonly found in today’s environment in plastics, solvents, lubricants, pesticides, and pharmaceutical agents.^{Reference Padmanabhan, Cardoso and Puttabyatappa23}

Animal models have shown that the EDCs to which humans are regularly exposed to, including phthalates, bisphenol A, nicotine, perfluorooctane compounds, and polybrominated diphenyl ethers (the chemical component found in household fire retardants), have been associated with a range of adverse clinical endpoints, including preterm birth, diminished immune responses, disrupted metabolism, early puberty,^{Reference Barouki, Gluckman, Grandjean, Hanson and Heindel34} obesity, endometriosis, type 2 diabetes,^{Reference England-Mason, Merrill and Gladish68} and neurodevelopmental disorders such as Attention-Deficit/Hyperactivity Disorder (ADHD).^{Reference Barouki, Gluckman, Grandjean, Hanson and Heindel34,Reference England-Mason, Merrill and Gladish68} In humans, EDCs have been associated with various adult disorders, including type 2 diabetes, cancer, obesity, male infertility, reproductive dysfunction, and metabolic disorders, with epigenetic changes believed to contribute to these outcomes.^{Reference Padmanabhan, Cardoso and Puttabyatappa23} Studies have associated EDCs with epigenetic changes, including alterations in DNA methylation, introducing a potential mechanistic process driving the associations between exposures and health outcomes.^{Reference England-Mason, Merrill and Gladish68–Reference Khodasevich, Holland, Harley, Eskenazi, Barcellos and Cardenas70} Although most research has focused on EDCs, the DOHaD concept has evolved to consider other environmental chemical exposures such as pesticides, persistent organic pollutants, and heavy metals.

Maternal stress and adversity

Maternal stress experienced during pregnancy may also impact the growing fetus.^{Reference Padmanabhan, Cardoso and Puttabyatappa23} Maternal stressors can include daily life events, mental illness, acts of nature, war, and other traumatic experiences. This is particularly relevant as more countries are currently experiencing conflict than since the Second World War.⁷¹ Furthermore, a staggering 1 in 8 people worldwide have a mental health condition.⁷² Conditions such as anxiety and depression increased globally by 25% in the wake of the COVID-19 pandemic.^72,73 This is partly due to health disparities, where many affected people face barriers to accessing medical or psychological services.^74,75

Stress and adversity are subjective experiences, with individual perceptions and responses based on their unique experiences and circumstances. Each person has their level of tolerance to what feels manageable or overwhelming. The ability to manage stress may depend on coping mechanisms, support, the presence of compounding stressors, and resilience. Maternal stress produces hormones such as glucocorticoids and catecholamines associated with DNA methylation changes in gene expression.^{Reference Goyal, Limesand and Goyal44} Similar effects have been reported in survivors of the holocaust and natural disasters.^{Reference Padmanabhan, Cardoso and Puttabyatappa23} Experiencing the stress of losing a loved one during pregnancy has been shown to impact the offspring’s immune function and can predispose one to develop obesity or mental health issues.^{Reference Padmanabhan, Cardoso and Puttabyatappa23} More recent research has focused on how toxic stress from experiences of systemic racism and oppression is associated with disease development and heritable epigenetic changes.^{Reference Wallack and Thornburg33} Animal models have demonstrated similar findings. Rodents subjected to perinatal stress produced offspring with higher adipose tissue levels, impaired glycemic control, low birth weight, reduced glucocorticoid and mineralocorticoid receptor expression in the hippocampus, and impaired hypothalamic-pituitary-adrenal axis feedback regulation.^{Reference Padmanabhan, Cardoso and Puttabyatappa23}

Stress during pregnancy has also been associated with developmental delays in offspring. For example, Project Ice Storm studied the effects of maternal stress on pregnancy during the Quebec ice storm of January 1998, which resulted in more than three million people living without electricity for up to five weeks.Reference King and Laplante⁵⁹The authors found that a stressful life event experienced in pregnancy can negatively impact cognitive and language development at age two, mainly when exposure occurred in the first two trimesters, with the most significant effects experienced with second-trimester exposure and moderate-to-high stress.^{Reference King and Laplante59} However, given the challenges in measuring the subjective experience of stress, it remains unclear what factors might tip the balance to predispose an individual to altered health outcomes.

Application of the model case

Maternal undernutrition and stress resulted in intrauterine growth restriction, predisposing the child to several health risks, including cardiovascular disease, obesity, metabolic disease, and mental health issues. During ontogenesis, vital organs would have consumed limited resources at the expense of other, less critical organs, such as the pancreas. This might contribute to impaired endocrine or exocrine (i.e., diabetes) function later in life. Epigenetic modifications through DNA methylation programmed in utero will have primed Mariyam’s fetus to live in an environment of nutritional scarcity, with the ability to store extra nutritional factors, manifesting as noncommunicable diseases throughout the life course if exposed to nutritional abundance. This and subsequent adverse environmental exposures during sensitive periods in the child’s life could have interactive effects, predisposing the child to future disease. However, due to the child’s plasticity, there would still be an opportunity to mitigate risk, mainly if interventions were targeted during sensitive periods in childhood and adolescence. From a transgenerational epigenetic inheritance perspective, epigenetic changes could be passed along by the child’s germ cells, priming the next generation (i.e., grandchild) for disease risk when this child has offspring. A healthcare professional working with this family can connect them to services to provide financial support, food security, and dedicated early child development services. From a public health perspective, addressing the social determinants of health and applying the DP model to this case can guide healthcare professionals to take an upstream approach to setting a positive developmental trajectory.

Epigenetics

In a research context, epigenetic changes can be observed by examining changes in DNA methylation patterns using bisulfite sequencing or nanopore technologies.^{Reference Kurdyukov and Bullock78} Histone modifications and non-coding RNAs can also be observed. Preserved methylation changes across generations might indicate that transgenerational epigenetic inheritance has occurred. Additionally, a family history of metabolic or other disease traits may be linked to common exposures to toxins, stress, or diet.

Ontogeny

Ontogeny reflects the growth of an organism throughout its lifetime. Typical physiological development can be assessed through physical assessment. Developmental milestones in infancy and childhood can be evaluated using several validated screening tools that assess psychosocial, cognitive, psychomotor, language, visual, and auditory development.^{Reference Zubler, Wiggins and Macias79} Critical and sensitive periods are measured by the age and stage of development. This can be quantified by calculating chronological age, measuring pubertal hormone levels, weight and height, or using screening tools for developmental milestones.

Plasticity

Plasticity is more challenging to quantify. The appropriate adaptation of an organism to its environment demonstrates plasticity. Birth weight variability due to maternal nutrition is one example. The recent application of statistical algorithms to estimate deviations in biological age from chronological age, presumed to reflect underlying cellular and molecular processes, represents an example of differential development, potentially in response to environmental influences. The empirical referents contribute to the ability to apply DP in research and practice.