ISSN: 2763-5724 / Vol. 06 - n 03 - ano 2026

FETAL PROGRAMMING AND THE DEVELOPMENT OF

CARDIOMETABOLIC DISEASES: THE ROLE OF EPIGENETIC CHANGES

Isabela da Silva Vieira1

Emily Amaral Gonçalves2

Júlia Sander Santos3

Danieli Gomes Giacomin4

Laura Nascimento Freitas5

Mariana Costa dos Santos6

Ana Luiza Latini Girolamy Daﬂ on7

Claudete Lúcia Carvalho Oliveira8

Fernanda Mazzelli Almeida Maio9

Abstract: Cardiometabolic diseases are among the leading causes of morbidity and mortality

worldwide and are inﬂ uenced not only by genetic and environmental factors during adulthood but also

1 Centro Universitário FAMESC – UniFAMESC, Bom Jesus do Itabapoana, Rio de Janeiro, Bra-

sil.

2 Centro Universitário FAMESC – UniFAMESC, Bom Jesus do Itabapoana, Rio de Janeiro, Bra-

sil.

3 Centro Universitário FAMESC – UniFAMESC, Bom Jesus do Itabapoana, Rio de Janeiro, Bra-

sil.

4 Centro Universitário FAMESC – UniFAMESC, Bom Jesus do Itabapoana, Rio de Janeiro, Bra-

sil.

5 Centro Universitário FAMESC – UniFAMESC, Bom Jesus do Itabapoana, Rio de Janeiro, Bra-

sil.

6 Centro Universitário FAMESC – UniFAMESC, Bom Jesus do Itabapoana, Rio de Janeiro, Bra-

sil.

7 Centro Universitário FAMESC – UniFAMESC, Bom Jesus do Itabapoana, Rio de Janeiro, Bra-

sil.

8 Centro Universitário FAMESC – UniFAMESC, Bom Jesus do Itabapoana, Rio de Janeiro, Bra-

sil.

9 Centro Universitário FAMESC – UniFAMESC, Bom Jesus do Itabapoana, Rio de Janeiro, Bra-

sil.

ISSN: 2763-5724 / Vol. 06 - n 03 - ano 2026

by exposures occurring during intrauterine life. In this context, the Developmental Origins of Health

and Disease (DOHaD) theory highlights the importance of fetal programming in determining future

disease risk. This study aimed to analyze the role of epigenetic alterations in fetal programming and

their relationship with the development of cardiometabolic diseases throughout life. An integrative

literature review was conducted following the PRISMA 2020 guidelines. Searches were performed in

PubMed/MEDLINE, Scopus, Web of Science, Embase, and the Virtual Health Library using descriptors

related to fetal programming, epigenetics, and cardiometabolic diseases. Articles published between

2020 and 2026 in English, Portuguese, and Spanish were included, resulting in a ﬁ nal sample of 17

studies after applying the eligibility criteria. The ﬁ ndings demonstrated that gestational factors such as

maternal obesity, gestational diabetes, intrauterine growth restriction, and inadequate dietary patterns

can induce persistent epigenetic modiﬁ cations, including DNA methylation, histone alterations, and

regulation by non-coding RNAs. These changes inﬂ uence fetal gene expression and are associated

with an increased risk of obesity, insulin resistance, metabolic syndrome, type 2 diabetes mellitus,

and cardiovascular diseases in the offspring. Furthermore, the placenta was found to play a signiﬁ cant

role in mediating maternal inﬂ ammatory and metabolic effects on fetal development. It is concluded

that epigenetic mechanisms constitute a fundamental link between adverse gestational exposures

and the future development of cardiometabolic diseases, highlighting the importance of preventive

strategies focused on maternal health before and during pregnancy, as well as the need for further

research to deepen the understanding of fetal programming processes.

Keywords: Fetal programming; Epigenetics; Cardiometabolic diseases; Maternal obesity; DOHaD.

INTRODUCTION

Cardiometabolic diseases represent one of the greatest contemporary challenges for health

systems worldwide, constituting an important cause of morbidity and mortality and signiﬁ cantly

impacting the quality of life of populations. Conditions such as obesity, type 2 diabetes mellitus,

ISSN: 2763-5724 / Vol. 06 - n 03 - ano 2026

systemic arterial hypertension and metabolic syndrome have shown signiﬁ cant growth in recent

decades, including among children and adolescents, evidencing the need to understand etiological

factors that go beyond the habits acquired throughout adult life. In this context, susceptibility to

the development of these diseases can be determined during intrauterine life, through biological

processes capable of permanently inﬂ uencing the structure and function of different organs and

systems (HARARY; AKINYEMI; CHARRON, 2022; FAA et al., 2024).

From this perspective, the concept of the Developmental Origins of Health and Disease

(DOHaD) was consolidated, initially based on Barker’s Hypothesis. This theory proposes that stimuli

or aggressions occurring during critical periods of fetal development promote physiological adaptations

aimed at the immediate survival of the fetus, but that they may result in a greater predisposition to the

emergence of chronic diseases in childhood, adolescence and adulthood. Epidemiological evidence

accumulated over the last decades has demonstrated an association between low birth weight,

inadequate fetal growth, and increased risk of cardiovascular and metabolic diseases in later stages

of life, consolidating fetal programming as an important ﬁ eld of biomedical investigation (FAA et al.,

2024; TOHI et al., 2022).

The intrauterine environment plays a fundamental role in this process, since maternal factors

can signiﬁ cantly modify fetal development. Among the main determinants studied are maternal obesity,

gestational diabetes, inadequate nutrition, and inﬂ ammatory changes present during pregnancy.

These conditions promote modiﬁ cations in the supply of nutrients, hormones, and inﬂ ammatory

mediators to the fetus, triggering metabolic adaptations capable of persisting after birth. It is possible

that children of pregnant women who are obese or have gestational diabetes have a higher risk of

developing obesity, insulin resistance, metabolic syndrome, and cardiovascular diseases throughout

their lives, reinforcing the importance of the gestational period as a critical window for determining

future health (ALBA-LINARES et al., 2023; SCHEIDL et al., 2023; LOWE JR., 2023).

In addition to immediate metabolic changes, recent research indicates that many of the

effects observed in offspring are mediated by epigenetic mechanisms. Epigenetics refers to the set of

ISSN: 2763-5724 / Vol. 06 - n 03 - ano 2026

modiﬁ cations capable of regulating gene expression without altering the DNA sequence, including

processes such as DNA methylation, histone modiﬁ cations, and the action of non-coding RNAs. These

alterations constitute fundamental mechanisms of fetal adaptation to the intrauterine environment,

allowing rapid responses to maternal conditions. However, when persistent, they can promote long-

lasting metabolic reprogramming, inﬂ uencing the expression of genes related to energy metabolism,

inﬂ ammation, cell growth, and cardiovascular function (CARLBERG, 2023; SAAVEDRA et al.,

2024).

DNA methylation stands out among the most investigated mechanisms in the context of fetal

programming. Recent evidence has shown that maternal obesity and gestational diabetes are capable

of modifying epigenetic patterns in genes involved in lipid metabolism, glycemic homeostasis, and

cardiovascular development, producing molecular signatures detectable at birth. These modiﬁ cations

may persist during childhood and inﬂ uence the future risk of cardiometabolic diseases, suggesting

that part of the vulnerability observed in individuals exposed to adverse gestational environments

is due to epigenetic changes established early during development (ALBA-LINARES et al., 2023;

KWEON et al., 2024).

In addition, maternal diets rich in fats and sugars can induce epigenetic changes in metabolic

tissues and appetite regulatory centers located in the central nervous system of the offspring. These

modiﬁ cations affect energy control mechanisms, insulin sensitivity, and inﬂ ammatory responses,

contributing to the development of obesity and cardiometabolic dysfunction. These ﬁ ndings reinforce

the notion that the gestational period represents a phase of high biological plasticity, in which

environmental exposures can have lasting effects on the individual’s health (ELGAZZAZ et al., 2024;

KWEON et al., 2024).

In view of this scenario, understanding the epigenetic mechanisms involved in fetal

programming becomes essential for the development of preventive strategies aimed at reducing the

global burden of chronic non-communicable diseases. The recognition that gestational factors can

inﬂ uence future cardiometabolic risk ampliﬁ es the importance of preconception and prenatal care,

ISSN: 2763-5724 / Vol. 06 - n 03 - ano 2026

highlighting the need for early interventions aimed at maternal health. In addition, the identiﬁ cation of

potentially modiﬁ able epigenetic markers can open new perspectives for prevention, early diagnosis,

and personalized therapies in the context of cardiometabolic diseases (SAAVEDRA et al., 2024;

TOHI et al., 2022).

Thus, the present study aims to analyze the role of epigenetic alterations in fetal programming

and their relationship with the development of cardiometabolic diseases, discussing the main

gestational factors involved, the molecular mechanisms described in the recent literature, and the

clinical and preventive implications resulting from this process.

MATERIAL AND METHODS

The present study consists of an integrative literature review, conducted based on the

recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses

(PRISMA 2020), with the objective of synthesizing scientiﬁ c evidence about fetal programming and

its relationship with the development of cardiometabolic diseases mediated by epigenetic alterations.

The bibliographic search was carried out in the PubMed/MEDLINE, Scopus, Web of Science,

Embase and Virtual Health Library (VHL) databases, as they are widely recognized for their scope

and relevance in the indexing of biomedical studies. The search strategy was elaborated from the

combination of controlled descriptors and keywords related to the theme, using the Boolean operators

AND and OR. Among the main terms used, “Fetal Programming”, “Developmental Origins of Health

and Disease”, “Epigenetics”, “DNA Methylation”, “Maternal Obesity”, “Gestational Diabetes”,

“Cardiometabolic Diseases”, “Metabolic Syndrome” and “Cardiovascular Disease” stood out.

Studies published between January 2020 and July 2026, in English, Portuguese, and

Spanish, available in full and addressing the association between gestational exposures, epigenetic

mechanisms, and cardiometabolic outcomes in offspring, were included. Observational studies,

experimental trials, systematic reviews, meta-analyses, and narrative reviews that presented relevant

ISSN: 2763-5724 / Vol. 06 - n 03 - ano 2026

data for understanding the mechanisms involved in fetal programming were considered eligible.

Duplicate articles among the databases consulted, abstracts of scientiﬁ c events, letters to

the editor, editorials, dissertations, theses, book chapters, studies without access to the full text, and

publications that did not have a direct relationship with the proposed theme were excluded. Studies

whose main focus was not related to epigenetic mechanisms, fetal programming, or cardiometabolic

outcomes were also excluded.

The study selection process took place in four stages, as recommended by the PRISMA

ﬂ owchart. Initially, the articles were identiﬁ ed through search strategies in the selected databases.

Then, the duplicates were removed and the titles and abstracts were sorted. Subsequently, potentially

eligible studies were submitted to full reading for evaluation of the inclusion and exclusion criteria. At

the end of the process, 20 articles that presented greater methodological and scientiﬁ c relevance were

selected to compose the ﬁ nal sample of this review.

After searching the databases, 287 studies were identiﬁ ed. After the removal of 58 duplicates,

229 records were submitted to screening by title and abstract. Of these, 195 were excluded because

they did not meet the eligibility criteria. A total of 34 full-text articles were evaluated, of which 17

were excluded after full reading. In the end, 17 studies made up the ﬁ nal sample of this integrative

review, as shown in the PRISMA ﬂ owchart (FIGURE 1).

ISSN: 2763-5724 / Vol. 06 - n 03 - ano 2026

Figure 1: PRISMA ﬂ owchart of the studies

Source: Authors, 2026

For each included study, information was extracted regarding the authors, year of publication,

country of origin, methodological design, population studied, gestational factors assessed, epigenetic

mechanisms investigated, and main cardiometabolic outcomes observed. The data were organized in

ISSN: 2763-5724 / Vol. 06 - n 03 - ano 2026

electronic spreadsheets to facilitate the comparison between the studies and the identiﬁ cation of the

main patterns found in the literature.

Data analysis was performed in a qualitative and descriptive manner, allowing the synthesis

of available evidence on the inﬂ uence of gestational factors, especially maternal obesity, gestational

diabetes, inadequate maternal diet, and intrauterine growth restriction, on epigenetic mechanisms

such as DNA methylation, histone modiﬁ cations, and regulation by non-coding RNAs. From this

analysis, we sought to understand how these alterations can contribute to the development of obesity,

insulin resistance, metabolic syndrome, arterial hypertension and other cardiometabolic diseases

throughout the life of the offspring.

As this is an integrative review based exclusively on secondary data available in the scientiﬁ c

literature, this study did not involve human beings directly and, therefore, did not require consideration

by the Research Ethics Committee, in accordance with current regulations.

RESULTS AND DISCUSSION

Characterization of the selected studies

After applying the eligibility criteria and the selection steps proposed by the PRISMA

protocol, 17 studies were included to compose the ﬁ nal sample of this review. The analyzed

publications were produced between 2022 and 2024, including narrative reviews, systematic reviews,

experimental studies, and observational research. The selected studies presented as a common axis

the investigation of fetal programming associated with adverse gestational factors and the epigenetic

mechanisms involved in the development of cardiometabolic diseases in offspring.

The studies were developed in different geographical contexts, including North America,

Europe, Asia, and Oceania, reﬂ ecting the global interest in the Developmental Origins of Health and

Disease (DOHaD) paradigm. Among the main factors investigated were maternal obesity, gestational

diabetes, inadequate dietary patterns during pregnancy, placental inﬂ ammatory processes, and

ISSN: 2763-5724 / Vol. 06 - n 03 - ano 2026

intrauterine growth restriction. Taken together, the evidence indicates that environmental exposures

occurring during critical periods of fetal development are capable of inducing persistent biological

adaptations that inﬂ uence susceptibility to metabolic and cardiovascular diseases throughout life.

In order to systematize the evidence identiﬁ ed and facilitate the comparison between the

included studies, a summary table was prepared containing the main methodological characteristics

and the main ﬁ ndings of the selected publications. Information regarding the authors and year of

publication, study title, methodological design, objectives, main results and conclusions were

extracted. This organization allowed us to identify convergences and divergences between the studies

analyzed, as well as to understand in a more comprehensive way the inﬂ uence of gestational factors

and epigenetic mechanisms on fetal programming and the development of cardiometabolic diseases

throughout the life of the offspring. Chart 1 presents the synthesis of the studies included in this

review.

ISSN: 2763-5724 / Vol. 06 - n 03 - ano 2026

Au t ho r/ Ye a r Title (Portuguese) Method Objective Results

BURDEN et al., 2024 Maternal obesity and

cardiovascular remodeling of

offspring

Systematic review To assess the impact of

maternal obesity on the fetal

cardiovascular system

He showed cardiac and vascular

structural alterations in the

offspring

ELGAZZAZ et al., 2024 Maternal Western diet and

cardiometabolic dysfunction of

offspring

Experimental study Investigate epigenetic effects of

maternal diet

Observed hypothalamic

inﬂ ammation and persistent

metabolic changes

FAA et al., 2024 The Fetal Programming

Theory of Adult Diseases

Narrative review Review the foundations of

Barker’s hypothesis

Conﬁ rmed association between

fetal environment and chronic

diseases

KWEON et al., 2024 Maternal obesity and myeloid

reprogramming of offspring

Review Analyze epigenetic mechanisms

related to maternal obesity

Identiﬁ ed persistent

immunometabolic alterations

PANAGIOTIDOU et al.,

2024

Maternal diet, physical activity

and epigenome of offspring

Review To assess the inﬂ uence of

maternal lifestyle

Identiﬁ ed epigenetic modiﬁ cations

associated with healthy and

unhealthy habits

SAAVEDRA et al., 2024 Epigenetic programming of

obesity and chronic diseases

Narrative review Discuss epigenetic mechanisms

of fetal programming

Demonstrated association between

epigenetics and metabolic diseases

SKOWRONSKI; LEIBEL;

LEDUC, 2024

Neurodevelopmental

programming of adiposity

Review Assess neural development

associated with obesity

Identiﬁ ed alterations in

hypothalamic appetite circuits

TEZIKOV et al., 2024 Epigenetic modiﬁ cations in

fetal metabolic programming

Review Describe epigenetic mechanisms

involved in fetal programming

Highlighted DNA methylation,

histones, and non-coding RNAs

YANG et al., 2024 Maternal adiposity and

perinatal and offspring

outcomes

Umbrella Review Synthesize evidence on maternal

adiposity

Consistent association with

obesity and metabolic syndrome

in offspring

ZHANG; CANDIA;

SFERRUZZI-PERRI,

2024

Placental inﬂ ammation and

maternal obesity

Review Evaluate placental mechanisms

related to obesity

Oxidative stress and placental

inﬂ ammation

ZURITA-CRUZ, 2024 Fetal programming and

cardiometabolic risk

Narrative review Review evidence on fetal

programming

Identiﬁ ed association between

gestational exposures and future

diseases

Table 1: Summary and data from the included studies

ISSN: 2763-5724 / Vol. 06 - n 03 - ano 2026

ALBA-LINARES et al.,

2023

Maternal obesity, gestational

diabetes, and epigenetic

reprogramming

Observational

study

Evaluate epigenetic changes in

newborns

Detected epigenetic signatures

related to metabolism

CARLBERG, 2023 Nutrition and epigenetic

programming

Review Explore the relationship between

nutrients and epigenetics

Demonstrated nutritional

inﬂ uence on gene expression

LOWE JR., 2023 Genetics and epigenetics in

gestational diabetes

Review Assess implications of gestational

diabetes

Showed persistent metabolic

alterations in the offspring

SCHEIDL et al., 2023 Maternal obesity and metabolic

syndrome programming

Review Investigate mechanisms involved

in offspring metabolic syndrome

Identiﬁ ed participation of

adipocyte progenitors

HARARY; AKINYEMI;

CHARRON, 2022

Fetal growth and epigenetic

programming of obesity

Review Discuss fetal growth and

cardiometabolic diseases

Showed association between

intrauterine growth and metabolic

risk

TOHI et al., 2022 DOHaD and adolescence as a

critical period

Review Evaluate strategies to interrupt

intergenerational transmission of

NCDs

He highlighted adolescence as a

strategic phase for intervention

Source: Authors, 2026

ISSN: 2763-5724 / Vol. 06 - n 03 - ano 2026

Fetal programming and gestational risk factors

The concept of fetal programming is based on the ability of the developing organism to

adapt its structure and function to the environmental conditions present during pregnancy (TOHI

et al., 2022; FAA et al., 2024). While these adaptations are critical to immediate fetal survival, they

can result in permanent metabolic consequences when the postnatal environment differs from the

conditions for which the organism was programmed. This hypothesis has been widely used to explain

the increasing incidence of chronic non-communicable diseases in populations exposed to adverse

gestational conditions (FAA et al., 2024).

According to the DOHaD model, nutritional, hormonal, and inﬂ ammatory stimuli received

during intrauterine life inﬂ uence processes of cell differentiation, tissue growth, and gene expression.

In this way, maternal factors such as obesity, gestational diabetes and nutritional alterations are

no longer understood only as isolated clinical conditions and are now recognized as biological

determinants capable of permanently modifying the health trajectory of the offspring (HARARY;

AKINYEMI; CHARRON, 2022; TOHI et al., 2022).

The intrauterine environment acts as an important regulator of fetal gene expression through

epigenetic mechanisms. These modiﬁ cations allow the body to adapt to gestational conditions, but

can simultaneously increase the predisposition to obesity, insulin resistance, arterial hypertension and

metabolic syndrome in the later stages of life. Thus, fetal programming constitutes a biological link

between early exposures and the late onset of cardiometabolic diseases (SAAVEDRA et al., 2024;

CARLBERG, 2023).

Maternal obesity as a factor in cardiometabolic programming

Among the gestational factors evaluated in the recent literature, maternal obesity stands

out as one of the main determinants of fetal metabolic programming. The global increase in the

ISSN: 2763-5724 / Vol. 06 - n 03 - ano 2026

prevalence of obesity among women of reproductive age has aroused growing concern due to its

effects on intrauterine development and on the future risk of chronic diseases in offspring (SCHEIDL

et al., 2023).

Obesity during pregnancy is associated with a metabolic environment characterized by

insulin resistance, hyperinsulinemia, dyslipidemia, and chronic low-grade inﬂ ammation. These

changes promote greater transfer of nutrients to the fetus, especially glucose and fatty acids, stimulating

adaptive modiﬁ cations in fetal tissues. As a consequence, there is a greater predisposition to the

accumulation of adipose tissue, changes in energy regulation, and persistent metabolic dysfunctions

after birth (SCHEIDL et al., 2023).

In addition to direct metabolic alterations, recent studies have shown that maternal obesity

promotes epigenetic modiﬁ cations in genes involved in energy metabolism and cardiovascular

development. Alba-Linares et al. (2023) identiﬁ ed signiﬁ cant changes in DNA methylation patterns in

newborns exposed to maternal obesity and gestational diabetes, suggesting that these exposures are

capable of inducing epigenetic signatures detectable from birth. Such modiﬁ cations were observed

mainly in pathways related to glucose metabolism, cell growth and tissue differentiation.

Another relevant aspect refers to the participation of the immune system in fetal programming.

Kweon et al. (2024) demonstrated that maternal obesity can promote epigenetic reprogramming of

fetal myeloid cells, favoring a persistent pro-inﬂ ammatory state. This phenomenon contributes to the

development of insulin resistance and early metabolic alterations, expanding the understanding of the

mechanisms by which gestational obesity inﬂ uences the future health of offspring.

The placenta also plays a central role in this process. Maternal obesity is associated with

increased placental inﬂ ammation, oxidative stress, and the production of inﬂ ammatory cytokines.

These alterations modify the intrauterine environment and directly inﬂ uence fetal metabolic

programming. In addition, they can compromise mechanisms that regulate growth and energy

homeostasis, increasing the risk of obesity and metabolic syndrome in childhood and adulthood

(ZHANG; CANDIA; SFERRUZZI-PERRI, 2024).

ISSN: 2763-5724 / Vol. 06 - n 03 - ano 2026

The inﬂ uence of maternal obesity can exceed a single generation. Epigenetic alterations

induced during pregnancy have the potential to persist throughout development and can be transmitted

to subsequent generations, contributing to the intergenerational perpetuation of cardiometabolic

diseases. This phenomenon reinforces the need for preventive strategies aimed at the preconception

and gestational period, with a focus on promoting maternal metabolic health (SAAVEDRA et al.,

2024).

Gestational diabetes and fetal metabolic reprogramming

Gestational diabetes is another important factor associated with fetal programming of

cardiometabolic diseases. Characterized by glucose intolerance diagnosed during pregnancy, this

disorder exposes the fetus to high levels of circulating glucose, triggering metabolic adaptations that

can persist throughout life (LOWE JR., 2023).

Maternal hyperglycemia promotes an increase in fetal production of insulin, a hormone

that exerts an important anabolic effect during development. Although this response contributes to

fetal growth, its prolonged maintenance can permanently alter regulatory mechanisms of energy

metabolism. As a result, children of mothers with gestational diabetes have a higher incidence of

childhood obesity, insulin resistance, glucose intolerance, and type 2 diabetes mellitus at earlier ages

when compared to the general population (LOWE JR., 2023).

Alterations in DNA methylation patterns have been identiﬁ ed in genes related to glucose

metabolism, insulin signaling, and pancreatic development of offspring exposed to intrauterine

hyperglycemia. These modiﬁ cations contribute to persistent functional changes that can compromise

metabolic homeostasis throughout life (ALBA-LINARES et al., 2023).

In addition to metabolic effects, gestational diabetes also inﬂ uences inﬂ ammatory and

cardiovascular processes. Long-term exposure to intrauterine hyperglycemia is associated with

increased oxidative stress, endothelial dysfunction, and structural changes in developing cardiovascular

ISSN: 2763-5724 / Vol. 06 - n 03 - ano 2026

tissues. Such modiﬁ cations can favor the early onset of hypertension and other cardiovascular diseases,

expanding the impact of fetal programming on different organ systems (LOWE JR., 2023).

Intrauterine growth restriction and fetal adaptations

In addition to maternal obesity and gestational diabetes, intrauterine growth restriction

(IUGR) is one of the main biological models used to explain the fetal programming of cardiometabolic

diseases. According to the sparing phenotype hypothesis, in situations of nutritional limitation or

reduction of the placental supply of nutrients, the fetal organism promotes metabolic adaptations

aimed at the preservation of vital organs, especially the brain and heart. Although these adaptations

favor survival during pregnancy, they can result in permanent changes in energy and cardiovascular

homeostasis when the individual is later exposed to environments with nutritional abundance

(HARARY; AKINYEMI; CHARRON, 2022).

Individuals born small for gestational age have a higher prevalence of arterial hypertension,

insulin resistance, abdominal obesity and metabolic syndrome during adulthood. This phenomenon

suggests that adaptations developed during critical periods of development promote structural and

functional changes in metabolic organs, including the liver, pancreas, adipose tissue, and cardiovascular

system (FAA et al., 2024; ZURITA-CRUZ, 2024). Part of these changes is mediated by epigenetic

mechanisms.

Tezikov et al. (2024) highlight that epigenetic modiﬁ cations established during periods of

nutritional deprivation can permanently alter the expression of genes related to energy metabolism,

cell growth, and vascular function. Thus, intrauterine growth restriction represents an important

example of how early environmental stimuli can inﬂ uence cardiometabolic risk throughout life.

ISSN: 2763-5724 / Vol. 06 - n 03 - ano 2026

Epigenetic mechanisms involved in fetal programming

Epigenetics is currently the main biological mechanism capable of explaining the persistence

of the effects of fetal programming after birth. Unlike genetic mutations, epigenetic alterations do

not modify the DNA sequence, but regulate gene expression in response to environmental stimuli.

Among the most studied mechanisms are DNA methylation, histone modiﬁ cations, and the action of

non-coding RNAs (CARLBERG, 2023; TEZIKOV et al., 2024).

DNA methylation is considered the most widely investigated epigenetic mechanism in the

context of DOHaD. Recent evidence shows that factors such as maternal obesity, gestational diabetes,

and inadequate diet during pregnancy can alter methylation patterns in genes involved in insulin

signaling, lipid metabolism, and cardiovascular development. These changes are detectable at birth

and may persist during childhood, contributing to an increased risk of future cardiometabolic diseases

(ALBA-LINARES et al., 2023; TEZIKOV et al., 2024).

Histone modiﬁ cations also play a relevant role in fetal programming. These processes

regulate the degree of chromatin compaction and directly inﬂ uence the transcriptional activity of

different genes. According to Saavedra et al. (2024), changes in histones associated with adverse

nutritional exposures can modify metabolic pathways related to energy storage, inﬂ ammation, and

cell differentiation, favoring the development of obesity and metabolic syndrome.

Another important mechanism involves non-coding RNAs, especially microRNAs. These

molecules regulate gene expression in a post-transcriptional way and participate in fundamental

processes for fetal development. Changes in the expression of these RNAs can inﬂ uence the formation

of metabolic tissues, insulin sensitivity, and cardiovascular function, increasing the complexity of the

mechanisms involved in fetal programming (TEZIKOV et al., 2024; SAAVEDRA et al., 2024).

ISSN: 2763-5724 / Vol. 06 - n 03 - ano 2026

Maternal nutrition, fetal epigenome, and metabolic development

Maternal feeding during pregnancy represents one of the most important environmental

factors for fetal epigenetic modulation. Speciﬁ c nutrients act as methyl group donors or inﬂ uence

enzymes responsible for epigenetic regulation, exerting direct effects on the gene expression of the

conceptus (CARLBERG, 2023).

Panagiotidou et al. (2024) demonstrated that healthy dietary patterns during pregnancy are

associated with epigenetic proﬁ les that are more favorable to the metabolic development of offspring.

On the other hand, diets high in saturated fats, simple sugars, and ultra-processed foods can promote

epigenetic changes related to increased risk of obesity, insulin resistance, and future cardiovascular

diseases.

Corroborating these ﬁ ndings, Elgazzaz et al. (2024) observed that fetal exposure to Western

diets promotes epigenetic changes in hypothalamic regions responsible for controlling appetite and

energy expenditure. These modiﬁ cations result in persistent metabolic alterations, reinforcing the

importance of maternal nutritional quality as a determinant of the future health of the offspring.

Development of cardiometabolic diseases in offspring

The fetal programming mechanisms discussed above converge to increase susceptibility to

different cardiometabolic diseases. Among the outcomes most frequently described in the literature

are childhood obesity, insulin resistance, type 2 diabetes mellitus, systemic arterial hypertension, and

metabolic syndrome (ZURITA-CRUZ, 2024).

Obesity represents one of the earliest manifestations of metabolic programming. Skowronski,

Leibel, and LeDuc (2024) demonstrated that adverse intrauterine exposures can modify the

development of hypothalamic neural circuits involved in the control of hunger, satiety, and energy

balance. These changes favor higher food intake and predisposition to excessive weight gain during

ISSN: 2763-5724 / Vol. 06 - n 03 - ano 2026

childhood and adolescence.

In the cardiovascular sphere, evidence indicates that exposure to unfavorable gestational

environments can promote structural and functional remodeling of the fetal cardiovascular system.

Burden et al. (2024) observed that children of pregnant women with obesity have early changes in

cardiac and vascular structure, potentially associated with increased risk of hypertension and future

cardiovascular diseases.

In addition, the multi-review analysis performed by Yang et al. (2024) demonstrated a

consistent association between maternal adiposity and adverse metabolic outcomes in offspring,

including obesity, insulin resistance, and metabolic syndrome. These ﬁ ndings reinforce the existence

of a causal relationship between gestational conditions and the development of chronic non-

communicable diseases throughout life.

Clinical implications and preventive strategies

The prevention of cardiometabolic diseases should be started even before birth. The

recognition of the gestational period as a critical window for future health planning ampliﬁ es the

importance of preconception, prenatal, and neonatal care strategies (TOHI et al., 2022).

In this context, measures aimed at maternal weight control, prevention of gestational diabetes,

promotion of healthy eating habits, and adequate monitoring of pregnancy can signiﬁ cantly reduce

fetal exposure to metabolic risk factors. In addition, the identiﬁ cation of epigenetic biomarkers may in

the future contribute to the development of early screening strategies and personalized interventions

aimed at individuals with greater cardiometabolic vulnerability (PANAGIOTIDOU et al., 2024;

YANG et al., 2024).

ISSN: 2763-5724 / Vol. 06 - n 03 - ano 2026

FINAL CONSIDERATIONS

It was possible to verify that the intrauterine environment exerts a determining inﬂ uence on

the future health of the offspring, acting as an important modulator of physiological processes capable

of reverberating from childhood to adulthood.

The results found reinforce the foundations of the concept of Developmental Origins of

Health and Disease (DOHaD), demonstrating that exposures occurring during critical periods of fetal

development can promote permanent biological adaptations. Although these adaptations are initially

compensatory and contribute to the survival of the fetus in the face of adverse conditions, they can

result in structural and functional changes that increase susceptibility to the development of chronic

non-communicable diseases in later stages of life.

Among the gestational factors most frequently associated with fetal programming were

maternal obesity, gestational diabetes, nutritional inadequacy during pregnancy, and intrauterine

growth restriction. Evidence has shown that these conditions alter the metabolic, hormonal, and

inﬂ ammatory environment to which the fetus is exposed, triggering adaptive responses capable of

inﬂ uencing the development of organs and systems involved in energy, metabolic, and cardiovascular

regulation. Thus, pregnancy should be understood not only as a period of fetal development, but also

as a critical phase for determining the future risk of illness.

Epigenetic mechanisms constitute the main biological link between gestational exposures

and cardiometabolic outcomes observed in offspring. Modiﬁ cations such as DNA methylation,

histone alterations, and regulation mediated by non-coding RNAs have been widely associated with

modulation of gene expression in tissues that are fundamental for energy metabolism and cardiovascular

function. These alterations have the ability to persist after birth, inﬂ uencing the activity of genes

related to insulin sensitivity, lipid metabolism, appetite control, inﬂ ammatory response, and vascular

homeostasis.

Another relevant aspect identiﬁ ed in this review refers to the multifactorial and complex

ISSN: 2763-5724 / Vol. 06 - n 03 - ano 2026

nature of fetal programming. There is no single mechanism responsible for the development

of cardiometabolic diseases, but rather a dynamic interaction between genetic, environmental,

nutritional, and epigenetic factors. This interaction occurs continuously throughout development and

can be inﬂ uenced by maternal characteristics, placental conditions, environmental exposures, and

lifestyle habits. This ﬁ nding reinforces the need for integrated approaches to understand the processes

involved in the genesis of these diseases.

Among the main outcomes associated with fetal programming were childhood obesity,

insulin resistance, metabolic syndrome, type 2 diabetes mellitus, systemic arterial hypertension and

other cardiovascular alterations. The evidence analyzed suggests that many of these diseases originate

in biological processes initiated during intrauterine life, which signiﬁ cantly expands the traditional

understanding of their etiology. Thus, cardiometabolic risk should not be interpreted exclusively as a

consequence of behavioral factors acquired in adult life, but also as a result of early exposures capable

of permanently modifying the individual’s health trajectory.

From a clinical and public health perspective, the ﬁ ndings of this review have important

implications. The recognition of pregnancy as a critical window for the prevention of future diseases

reinforces the importance of preconception and prenatal care, especially with regard to maternal

weight control, prevention and adequate management of gestational diabetes, promotion of healthy

eating habits, and strict monitoring of fetal growth. Interventions performed during these periods

have the potential to signiﬁ cantly reduce fetal exposure to risk factors and, consequently, decrease the

burden of cardiometabolic diseases in future generations.

In addition, the advancement of research in epigenetics opens up promising prospects for the

development of biomarkers capable of early identiﬁ cation of individuals with greater susceptibility

to the development of these diseases. The identiﬁ cation of epigenetic signatures associated with fetal

programming may in the future contribute to screening, monitoring, and individualized intervention

strategies, allowing for more effective and targeted preventive approaches.

However, despite the advances observed in recent years, there are still important gaps in

ISSN: 2763-5724 / Vol. 06 - n 03 - ano 2026

scientiﬁ c knowledge. Many of the epigenetic mechanisms involved in fetal programming remain

partially understood, especially as it relates to their persistence throughout life and the potential for

intergenerational transmission. In addition, the methodological heterogeneity among the available

studies highlights the need for long-term longitudinal investigations to allow a more comprehensive

understanding of the relationship between gestational exposures, epigenetic alterations and the

development of cardiometabolic diseases.

It is concluded, therefore, that epigenetic alterations play a central role in fetal programming

and constitute one of the main mechanisms responsible for the association between adverse gestational

factors and the development of future cardiometabolic diseases. The evidence analyzed demonstrates

that the intrauterine environment has the capacity to permanently inﬂ uence gene expression and

the function of different organ systems, contributing to the determination of health throughout the

life cycle. Thus, the understanding of these mechanisms strengthens the importance of preventive

strategies aimed at maternal and fetal health, highlighting the need for investments in research,

qualiﬁ ed prenatal care, and public policies capable of promoting better health conditions from the

early stages of life.

REFERENCES

ALBA-LINARES, Juan José et al. Maternal obesity and gestational diabetes reprogram the methylome

of offspring beyond birth by inducing epigenetic signatures in metabolic and developmental pathways.

Cardiovascular Diabetology, London, v. 22, n. 44, 2023. DOI: 10.1186/s12933-023-01774-y. Available

at: https://doi.org/10.1186/s12933-023-01774-y. Accessed on: 8 ago. 2026.

BURDEN, Samuel J. et al. Maternal obesity and offspring cardiovascular remodelling: the effect

of preconception and antenatal lifestyle interventions: a systematic review. International Journal of

Obesity, London, 2024. DOI: 10.1038/s41366-024-01536-0.

CARLBERG, Carsten. Nutrition and epigenetic programming. Current Opinion in Clinical Nutrition

and Metabolic Care, Philadelphia, v. 26, n. 2, p. 105-111, 2023. DOI: 10.1097/MCO.00000000000000900.

ISSN: 2763-5724 / Vol. 06 - n 03 - ano 2026

Available at: https://doi.org/10.1097/MCO.0000000000000900. Accessed on: 8 ago. 2026.

ELGAZZAZ, Mona et al. Maternal Western diet programs cardiometabolic dysfunction and

hypothalamic inﬂ ammation via epigenetic mechanisms predominantly in the male offspring.

Molecular Metabolism, v. 79, 2024. DOI: 10.1016/j.molmet.2023.101864. Available at: https://doi.

org/10.1016/j.molmet.2023.101864. Accessed on: 8 ago. 2026.

FAA, Gavino et al. The fascinating theory of fetal programming of adult diseases: a review

of the fundamentals of the Barker hypothesis. Global Pediatric Health, v. 11, 2024. DOI:

10.1177/22799036241226817. Available at: https://doi.org/10.1177/22799036241226817. Accessed on: 8

ago. 2026.

HARARY, David; AKINYEMI, Ayodele; CHARRON, Maureen J. Fetal growth and intrauterine

epigenetic programming of obesity and cardiometabolic disease. NeoReviews, Itasca, v. 23, n. 6,

p. e363-e375, 2022. DOI: 10.1542/neo.23-6-e363. Available at: https://doi.org/10.1542/neo.23-6-e363.

Accessed on: 8 ago. 2026.

KWEON, Joo Young; MUN, Hyeonji; CHOI, Myeong Ryeol; KIM, Hong Seok; AHN, Yong Joo.

Maternal obesity induced metabolic disorders in offspring and myeloid reprogramming by epigenetic

regulation. Frontiers in Endocrinology, Lausanne, v. 14, 2024. DOI: 10.3389/fendo.2023.1256075.

Available at: https://doi.org/10.3389/fendo.2023.1256075. Accessed on: 8 ago. 2026.

LOWE JR., William L. Genetics and epigenetics: implications for the life course of gestational diabetes.

International Journal of Molecular Sciences, Basel, v. 24, n. 7, 2023. DOI: 10.3390/ijms24076047.

Available at: https://doi.org/10.3390/ijms24076047. Accessed on: 8 ago. 2026.

PANAGIOTIDOU, Anastasia; CHATZAKIS, Christos; VERVERI, Athina; ELEFTHERIADES,

Makarios; SOTIRIADIS, Alexandros. The effect of maternal diet and physical activity on the

epigenome of the offspring. Genes, Basel, v. 15, n. 1, art. 76, 2024. DOI: 10.3390/genes15010076.

Available at: https://doi.org/10.3390/genes15010076. Accessed on: 8 ago. 2026.

SAAVEDRA, Lucas Paulo Jacinto et al. Epigenetic programming for obesity and noncommunicable

disease: from womb to tomb. Reviews in Endocrine and Metabolic Disorders, New York, v. 25,

2024. DOI: 10.1007/s11154-023-09854-w. Available at: https://doi.org/10.1007/s11154-023-09854-w.

Accessed on: 8 ago. 2026.

ISSN: 2763-5724 / Vol. 06 - n 03 - ano 2026

SCHEIDL, Taylor B.; BRIGHTWELL, Amy L.; EASSON, Sarah H.; THOMPSON, Jennifer A.

Maternal obesity and programming of metabolic syndrome in the offspring: searching for mechanisms

in the adipocyte progenitor pool. BMC Medicine, London, v. 21, n. 50, 2023. DOI: 10.1186/s12916-

023-02730-z. Available at: https://doi.org/10.1186/s12916-023-02730-z. Accessed on: 8 ago. 2026.

SKOWRONSKI, Alicja A.; LEIBEL, Rudolph L.; LEDUC, Charles A. Neurodevelopmental

programming of adiposity. Endocrine Reviews, Oxford, vol. 45, no. 3, p. 313–356, 2024. DOI: 10.1210/

endrev/bnad031. Available at: https://doi.org/10.1210/endrev/bnad031. Accessed on: 8 ago. 2026.

TEZIKOV, Y. V.; LIPATOV, I. S.; TYUTYUNNIK, V. L.; KAN, N. E.; KURBANOVA, A. M. The

concept of epigenetic modiﬁ cations in fetal metabolic programming. Obstetrics and Gynecology,

2024. DOI: 10.18565/aig.2024.60.

TOHI, Melenaite; BAY, Jacquie Lindsay; TU’AKOI, Siobhan; VICKERS, Mark Hedley. The

developmental origins of health and disease: adolescence as a critical lifecourse period to break

the transgenerational cycle of NCDs. International Journal of Environmental Research and Public

Health, Basel, v. 19, n. 10, 2022. DOI: 10.3390/ijerph19106024. Available at: https://doi.org/10.3390/

ijerph19106024. Accessed on: 8 ago. 2026.

YANG, Ziyi; FENG, Gengchen; GAO, Xueying et al. Maternal adiposity and perinatal and offspring

outcomes: an umbrella review. Nature Human Behaviour, London, v. 8, n. 12, p. 2406–2422, 2024. DOI:

10.1038/s41562-024-01994-6. Available at: https://doi.org/10.1038/s41562-024-01994-6. Accessed on:

8 ago. 2026.

ZHANG, Cindy X. W.; CANDIA, Alejandro A.; SFERRUZZI-PERRI, Amanda N. Placental

inﬂ ammation, oxidative stress, and fetal outcomes in maternal obesity. Trends in Endocrinology &

Metabolism, Vol. 35, No. 5, 2024. DOI: 10.1016/j.tem.2024.02.002.

ZURITA-CRUZ, Jessie Nallely. Fetal programming and cardiometabolic risk. Revista Mexicana de

Pediatría, Mexico City, v. 91, n. 5, 2024. DOI: 10.35366/119370.