Shihua Cui1,2,3†Fengying Deng2†
Muxue Lu2†
Meihua Zhang3
Zedong Yang1,3Yuchen Ma1,3Linlin Fan1,3
Qinqin Gao2,3*Dairong Feng1,2,3*- 1School of Life Science and Technology, Shandong Second Medical University, Weifang, China
- 2Institute for Fetology, The First Affiliated Hospital of Soochow University, Suzhou, China
- 3Key Laboratory of Maternal and Fetal Medicine of National Health Commission of China, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, China
The prenatal period is a critical window for cardiovascular development in offspring. Accumulating evidence demonstrates that maternal nutritional imbalances during pregnancy—encompassing undernutrition, overnutrition, and specific nutrient deficiencies—elicit adverse adaptations in fetal vascular systems, thereby predisposing offspring to cardiovascular disease (CVD) in later life. This review synthesizes current knowledge on the impact of macronutrient (e.g., high-sugar, high-fat diets) and micronutrient (e.g., vitamin D, folate) imbalances, as well as exposures to alcohol and caffeine, on offspring cardiovascular health. Key mechanisms such as epigenetic regulation (e.g., DNA methylation, histone modifications), oxidative stress, and endothelial dysfunction are discussed. Furthermore, we highlight future research directions and potential early nutritional interventions aimed at mitigating long-term cardiovascular risks and breaking the cycle of intergenerational metabolic disease. By integrating mechanistic insights and epidemiological evidence, this review underscores the importance of optimizing maternal nutrition as a pivotal public health strategy for preventing offspring CVD.
1 Introduction
Cardiovascular disease (CVD) remains the leading cause of global mortality and disability, accounting for over 18 million annual deaths—32% of all non-communicable disease-related mortality (1). Traditional preventive approaches have focused predominantly on adult risk factors such as smoking, obesity, and hypertension. However, growing epidemiological evidence suggests that a substantial proportion of CVD cases originate from adverse environmental exposures during fetal development (2–4). This concept was first systematically articulated by Barker as the “fetal origins hypothesis” and later expanded into the Developmental Origins of Health and Disease (DOHaD) framework. The DOHaD posits that suboptimal intrauterine conditions can induce developmental reprogramming, leading to persistent structural and functional changes in fetal organs and an increased lifelong susceptibility to CVD (5–7). As research in this area advances, the fetal origins of CVD have emerged as an important interdisciplinary field. Investigating the underlying mechanisms not only deepens our understanding of CVD etiology but also opens a critical window for early-life interventions.
Maternal nutrition during pregnancy plays a fundamental role in fetal programming and long-term cardiovascular health (8–10). Beyond supplying essential nutrients—proteins, lipids, vitamins, and minerals—maternal diet conveys nutrient-derived signals across the placenta, influencing gene expression, cellular differentiation, and organogenesis, with lasting consequences for offspring metabolism and vascular function (11, 12). Modern dietary patterns exacerbate these effects. Overnutrition, driven by rising rates of pre-pregnancy obesity and excessive gestational weight gain, contributes to gestational diabetes and fetal metabolic dysfunction through hyperglycemia, dyslipidemia, and inflammation (13, 14). Concurrently, micronutrient deficiencies (e.g., iron, folate, vitamin D) remain widespread due to dietary inadequacy or socioeconomic barriers, impairing placental function and epigenetic regulation, and elevating CVD risk in offspring (11, 15, 16). In addition, emerging dietary behaviors introduce additional risks. High caffeine intake, prevalent in fast-paced societies, has been epidemiologically associated with adverse birth outcomes. However, the specific mechanisms through which caffeine influences the fetal cardiovascular system remain poorly understood (17, 18). Similarly, excessive salt consumption—common in processed and restaurant foods—has been linked in animal and human studies to programming effects on blood pressure and renal development (19, 20). Alcohol use during pregnancy, even at low levels, continues to pose significant teratogenic risks to cardiac structure and vascular function (21).
Encouragingly, increasing public and scientific awareness has spurred rigorous epidemiological and mechanistic research, particularly in the fields of epigenetics and metabolic programming, thereby strengthening the evidence base linking maternal nutrition to cardiovascular outcomes in offspring (8). Key markers such as blood pressure, vascular reactivity, lipid metabolism, and insulin sensitivity now show consistent associations with prenatal nutritional exposures (4, 22, 23). This review synthesizes current evidence on the role of maternal nutrition—encompassing undernutrition, overnutrition, and specific dietary components—in the developmental origins of CVD. By integrating mechanistic insights and clinical implications, we aim to inform effective preventive strategies, guide public health practice, and ultimately improve cardiovascular health across generations.
2 Literature search strategy
A systematic literature search was performed across three electronic databases: PubMed, Web of Science Core Collection, and Embase, covering records from their inception to November 2025, with no language restrictions applied initially. The search strategy was developed in consultation with a subject librarian, combining Medical Subject Headings (MeSH) terms and free-text keywords centered on three core concepts: maternal exposures (e.g., hyperglycemia, high-fat diet), fetal or developmental programming, and cardiovascular outcomes in offspring. Additional studies were identified by manually screening the reference lists of relevant articles. Study selection followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Eligible studies were original research articles investigating the association between specific maternal exposures and offspring cardiovascular outcomes while exploring underlying developmental programming mechanisms. Data were extracted using a standardized form and synthesized narratively, with evidence organized into two main sections: epidemiological findings from human studies and mechanistic insights from experimental research.
3 Excessive maternal nutrition during pregnancy
Excessive maternal nutrition during pregnancy commonly stems from a chronic high-calorie diet, characterized by abundant refined sugars (e.g., sucrose and fructose) and foods high in saturated or trans fats—such as fried foods and processed meats. These dietary patterns induce metabolic disturbances, including dysregulated glucose homeostasis, abnormal lipid profiles, and chronic inflammation. Such alterations disrupt fetal cardiovascular development via placenta-mediated metabolic reprogramming and epigenetic modifications (10, 24). Maternal body weight serves as a direct reflection of nutrient intake. A large Swedish cohort study demonstrated a dose-dependent association between maternal obesity and offspring CVD risk. Specifically, children of severely obese mothers exhibited a 60% increased CVD risk compared to those of normal-weight mothers (25). Studies on prenatal high-glucose exposure associate elevated maternal carbohydrate intake with higher offspring blood pressure, including significant increases in both systolic and diastolic pressures (26, 27). Similarly, a prospective cohort study in the United States suggested that the intake of a high-fat, high-sugar, and high-sodium diet in early pregnancy would significantly increase the compound risk of adverse pregnancy outcomes, including preeclampsia, gestational diabetes, preterm delivery, and small for gestational age (SGA) infants (28). Additionally, it should be noted that combined exposure to high sugar and high fat—as typified by Western-style diets—exerts additive adverse effects on offspring cardiovascular health, directly induces maternal metabolic dysfunction, alters maternal-fetal nutrient partitioning, and imposes long-term consequences on maternal and infant health (29).
Prenatal high glucose exposure contributes to fetal-origin CVD through multiple pathological mechanisms, such as metabolic dysregulation, epigenetic alterations, oxidative stress, and inflammation. Evidence from animal studies supports these pathways. For instance, a hyperglycemic intrauterine environment disrupts normal cardiac development by inducing fetal cardiac hypertrophy—particularly in late gestation—and impairing key processes including cardiac neural crest cell migration, conotruncal formation, and endocardial cushion mesenchymal development (30). Moreover, high glucose alters the expression of specific miRNAs (e.g., miR-181a) in fetal endothelial cells, resulting in offspring endothelial dysfunction (31). In rat models, maternal diabetes influences fetal cardiac angiogenesis and oxidative stress via miRNA-mediated gene silencing (32). Elevated levels of TNF-α and IL-6 have also been detected in placental tissues under hyperglycemic conditions, correlating with increased placental weight, reduced fetal weight, and diminished placental efficiency (33). Both human and animal studies further indicate that offspring of mothers with gestational diabetes display impaired vasculogenic capacity in endothelial progenitor cells, significantly increasing their susceptibility to CVD in adulthood (32).
Similarly, the pathological mechanisms by which prenatal high-fat exposure contributes to fetal-origin CVD also involve multiple pathways, including dysregulated lipid metabolism, altered placental function, oxidative stress, and epigenetic regulation. These are discussed below with support from relevant animal studies (34). Prenatal high-fat exposure leads to abnormally elevated lipid levels in the fetal circulation. Since the fetal heart primarily relies on carbohydrates for energy, premature exposure to high lipid levels alters myocardial metabolic preference and suppresses cardiac energy metabolism (35, 36). A study indicates that although lipid uptake-related genes (such as CD36 and Carnitine Palmitoyltransferase 1A/B) are upregulated in fetal cardiomyocytes following lipid exposure, overall metabolic activity is reduced, ultimately impairing cardiac function (37). Maternal high-fat diets also alter the expression of placental lipid transporters (e.g., ATP-Binding Cassette Transporters), influencing fetal lipid exposure (38). In rat models, maternal lipopolysaccharide administration disrupts the expression of these transporters, resulting in adult offspring that are more susceptible to diet-induced CVD (39, 40). Furthermore, a high-fat diet induces oxidative stress and activates inflammatory pathways (such as NF-κB) in both the mother and fetus, leading to cardiomyocyte apoptosis and endothelial dysfunction (35). Offspring of mice fed a high-fat diet during gestation exhibit elevated blood pressure and cardiac hypertrophy in adulthood, even when maintained on a normal diet (34). This effect may be linked to programmed alterations in the leptin signaling pathway. Maternal high-fat exposure appears to induce epigenetic modifications—such as DNA hypomethylation—that affect the expression of metabolic genes in the fetal heart, increasing the offspring’s susceptibility to hypertension and atherosclerosis in later life (34). Additionally, following maternal exposure to a high-fat diet, offspring exhibit sex-specific cardiovascular responses. For instance, one study suggests that male offspring demonstrate more severe alterations in cardiovascular function (such as elevated blood pressure and enhanced vasoconstriction), while female offspring may adapt or compensate through different mechanisms (41).
The Western-style diet is an obesogenic dietary pattern characterized by high fat and sugar content and elevated energy density. Beyond macronutrient imbalance, a Western-style diet triggers a cascade of adverse metabolic and physiological effects. Notably, exposure during the critical period of pregnancy can impose profound detrimental consequences on the health of both the mother and offspring (29). The pathogenic mechanisms underlying combined sugar and fat exposure are notably complex (Table 1).
Table 1. Pathogenic mechanisms of maternal western-style diet (high fat/high sugar) exposure on offspring cardiovascular development.
In summary, maternal high-sugar and high-fat diets disrupt normal cardiovascular development and functional programming in the fetus. Excessive macronutrient intake is particularly characterized by inducing profound metabolic disturbances (e.g., hyperglycemia, dyslipidemia) and mitochondrial dysfunction in the fetal heart, which, coupled with diet-specific epigenetic reprogramming, sets the stage for offspring CVD risk. These findings underscore the importance of nutritional intervention and metabolic management during pregnancy as critical strategies for preventing fetal-origin CVDs.
4 Inadequate nutrition during pregnancy
Inadequate nutrition during pregnancy is a key driver of fetal-origin cardiovascular disease, primarily involving deficiencies in macronutrients (such as carbohydrates, lipids, and proteins) and micronutrients (including folate, vitamin B12, zinc, copper, and selenium) (47).
4.1 Inadequate macronutrient intake during pregnancy
Inadequate macronutrient intake during pregnancy has been identified as a significant risk factor for fetal-origin CVD. Fetal growth restriction (FGR), a common consequence of such deficiency, is strongly associated with an increased risk of cardiovascular disorders in adulthood. Epidemiological data indicate that adults who experienced FGR have a 2–3 times higher incidence of hypertension, atherosclerosis, and chronic kidney disease compared to those with normal birth weight (48, 49). Furthermore, both animal studies and human observational research suggest that insufficient maternal caloric or protein intake during gestation can lead to a “thrifty phenotype” adaptation in the fetus. This metabolic reprogramming prioritizes brain development at the expense of cardiovascular health, resulting in long-term consequences such as insulin resistance, endothelial dysfunction, and elevated blood pressure (49, 50).
Among the forms of macronutrient deficiency, maternal protein deficiency (MPD) and maternal caloric restriction (MCR) are the most extensively studied in relation to developmental cardiovascular programming. The underlying mechanisms through which MPD and MCR contribute to fetal-origin CVD involve multi-level physiological and molecular alterations, which can be summarized as follows:
MPD during critical developmental windows disrupts cardiovascular structure and physiological function. Specifically, MPD leads to aberrant protein expression in cardiac tissue, impairing myocardial growth and energy metabolism, thereby increasing the risk of CVD in adulthood (51). For instance, animal studies have shown that MPD in pregnant rats induces FGR, alters the cardiac proteome, and results in structural and functional cardiac abnormalities (52). MPD is also associated with mitochondrial dysfunction and increased oxidative stress, contributing to cardiac tissue damage (53). In both cerebral and cardiac tissues, protein deficiency disrupts mitochondrial metabolic balance, promotes the accumulation of free radicals, and induces oxidative damage. These changes impair energy production and cellular function in cardiomyocytes, leading to compromised cardiac bioenergetics and ultimately manifesting as cardiomyocyte hypertrophy and cardiac dysfunction (51, 54). Additionally, protein deficiency causes permanent alterations in renal function, including reduced sodium excretion and dysregulation of the renin–angiotensin–aldosterone system (RAAS) (55). These alterations result in diminished sodium handling capacity in offspring, promoting water and sodium retention and facilitating the development of hypertension (56, 57). Epigenetic mechanisms may also play a role. Evaluations of adult male offspring exposed to prenatal protein deficiency show altered cardiac morphology—including abnormal left ventricular microRNA expression and dysregulation of related target genes—supporting the involvement of epigenetic regulation in cardiac hypertrophy and dysfunction (58). Moreover, studies have indicated that there are sex differences in the cardiovascular disease risk among offspring induced by MPD. Specifically, the incidence of cardiovascular diseases in female offspring is significantly lower than that in male offspring. This phenomenon is primarily attributed to the protective effect of estrogen (53).
MCR significantly impairs placental development and function. Studies indicate that a 50% reduction in caloric intake disrupts placental angiogenesis by downregulating miRNA-regulated pathways—such as those involving Vegfa and Tgfβ—leading to impaired vascularization, increased oxidative stress, and elevated apoptosis (59). MCR also compromises trophoblast function, reducing the transport of critical nutrients such as glucose across the placenta, which directly contributes to fetal hypoglycemia and nutrient deficiency (48). These placental alterations are accompanied by profound structural and metabolic reprogramming in the fetal heart. Studies in sheep models demonstrate that severe FGR resulting from MCR is associated with ventricular wall thickening, reduced heart weight, and disordered myocardial fiber arrangement—structural abnormalities linked to an increased risk of CVD in adulthood (60, 61). In rats, maternal nutrient restriction leads to reduced protein synthesis and downregulated mitochondrial protein expression in the neonatal heart (52). Furthermore, MCR induces fetal cardiac mitochondrial dysfunction, characterized by decreased complex I activity, impaired ATP production (50), and reduced fatty acid oxidation. This metabolic shift forces greater reliance on glucose for energy, exacerbating energetic deficiency—a pattern that persists into adulthood, as observed in sheep FGR models (61). MCR also promotes oxidative stress and cellular damage. In guinea pig models, maternal hypoxia—a common consequence of caloric restriction—results in failed placental vascular remodeling, causing chronic fetal hypoxia and subsequent cardiomyocyte apoptosis and cardiac fibrosis (62). The MCR-exposed placenta exhibits reduced antioxidant capacity, leading to increased reactive oxygen species (ROS) that enter fetal circulation and directly damage the developing cardiovascular system. Notably, vitamin C supplementation in animal models has been shown to partially mitigate this damage (56). Endocrine and neuroregulatory dysfunctions also contribute to MCR-related cardiovascular programming. MCR induces structural changes in the fetal hypothalamus, leading to sustained overexpression of glucocorticoid receptors and adult-onset blood pressure dysregulation (63). Offspring exposed to MCR exhibit reduced baroreflex sensitivity and sympathetic overactivation, which promote ventricular remodeling (64). Finally, MCR induces persistent epigenetic changes. Rat studies demonstrate that maternal caloric restriction leads to lasting alterations in the expression of cardiovascular-related genes through DNA methylation. These include upregulation of RAAS components and suppression of insulin signaling pathways (64, 65), resulting in a heightened predisposition to hypertension and insulin resistance in adulthood.
Collectively, macronutrient deficiency (MPD and MCR) programs offspring CVD primarily through structural compromises in the heart and kidneys, severe placental insufficiency, and associated metabolic and neuroendocrine reprogramming, distinct from the mechanisms highlighted in overnutrition.
4.2 Micronutrient deficiency during pregnancy
Epidemiological studies, primarily based on prospective cohort and case–control studies, indicate that deficiencies in specific micronutrients during pregnancy are associated with an increased risk of long-term CVD in offspring. For instance, low maternal folate levels have been linked to elevated blood pressure, impaired endothelial function, and increased carotid intima-media thickness in children and adolescents (66). Vitamin D deficiency during pregnancy has been negatively correlated with early cardiovascular risk markers in offspring, including hypertension, left ventricular hypertrophy, and arterial stiffness (67). Evidence regarding other micronutrients such as iron, zinc, and vitamin B12 remains limited, though some studies suggest that deficiencies may contribute to elevated blood pressure or metabolic abnormalities in offspring (68).
The mechanisms through which maternal micronutrient deficiency contributes to fetal-origin CVD can be summarized as follows, based on current evidence (Table 2).
Table 2. Mechanisms of maternal micronutrient deficiencies to fetal-origin cardiovascular disease.
In summary, maternal micronutrient deficiency contributes to fetal-origin CVD. A key distinctive aspect of micronutrient deficiencies lies in their disruption of one-carbon metabolism (e.g., folate, B12) and their role as cofactors for antioxidant enzymes (e.g., Zn, Se, Cu), leading to unique patterns of epigenetic dysregulation and oxidative damage that impair cardiovascular development. These findings highlight potential molecular targets for nutritional interventions during pregnancy, such as combined supplementation with zinc, selenium, and antioxidants, which may more effectively disrupt these pathological pathways.
5 Specific dietary behaviors during pregnancy
Specific dietary behaviors during pregnancy represent a significant global public health concern. Among these, alcohol abuse, high salt intake, and excessive caffeine consumption are particularly notable due to their widespread prevalence and established developmental toxicity. These factors are considered modifiable risk factors for fetal-origin CVD (79–81). Epidemiological data indicated that despite increasing public health warnings, approximately 10% of pregnant women worldwide report alcohol consumption during pregnancy, with rates reaching as high as 25% in some regions. Exposure is especially common during the early stages of pregnancy, often before pregnancy is recognized (79). High salt (sodium) intake is even more prevalent, largely driven by the widespread consumption of processed foods and cultural dietary patterns. In the majority of regions, daily sodium intake among pregnant women significantly exceeds the WHO-recommended limit of <5 g of salt per day, with particularly high levels observed in East Asia and Western countries where high-salt diets are common (81). Similarly, high caffeine consumption (>200 mg per day) affects a substantial proportion of pregnant women, with an estimated 15–30% reporting regular intake from sources such as coffee, tea, or energy drinks (82, 83). Against this backdrop, the following sections will focus on examining the specific effects of prenatal alcohol exposure, high-salt diets, and caffeine exposure on the cardiovascular health of offspring.
5.1 Prenatal alcohol exposure
Prenatal alcohol exposure (PAE), referring to fetal contact with ethanol through maternal consumption, represents a significant global public health issue (84). According to the WHO reports, a considerable proportion of women continue to consume alcohol during pregnancy, including episodes of heavy drinking (85) (Figure 1). PAE is characterized by several parameters, including alcohol dosage, exposure pattern (e.g., binge versus chronic drinking), timing during gestation (e.g., first or third trimester), and duration (86). It is important to note that no safe threshold of alcohol consumption during pregnancy has been established, and any exposure may pose risks to the fetus (79). While a majority of the current evidence derives from animal studies, further large-scale prospective cohort studies in human populations are needed.
Figure 1. The prevalence (%) of any amount of alcohol use and binge drinking during pregnancy and the estimated proportion of women who binge drank during pregnancy by World Health Organization region. AFR = African Region, AMR = Region of the Americas, EMR = Eastern-Mediterranean Region, EUR = European Region, SEAR = South-East Asia Region, WPR = Western Pacific Region (The prevalence of any amount of alcohol use during pregnancy is inclusive of the prevalence of binge drinking during pregnancy). Created using Figdraw.com.
Regarding pathogenic mechanisms, rat models demonstrate that administration of ethanol (4.5 g/kg body weight) during prenatal and early postnatal stages leads to increased markers of oxidative stress (e.g., malondialdehyde) and elevated pro-inflammatory cytokines (e.g., TNF-α) in cardiac tissue, accompanied by enhanced cardiomyocyte apoptosis (87). Offspring exposed to PAE exhibit aortic medial thickening, disrupted elastic fibers, increased collagen deposition, and impaired endothelium-dependent vasodilation at 21 and 90 days after birth, suggesting an elevated risk for early atherosclerotic lesions. These findings indicate that ethanol induces myocardial damage through oxidative stress, inflammatory responses, and apoptosis (88, 89). Additionally, mouse models reveal that PAE disrupts the transcription of genes involved in calcium signaling and cardiac metabolism, resulting in abnormal myocardial structure and function (90). Another rat study suggests that alcohol exposure leads to fetal anemia by upregulating hepcidin and erythropoietin, thereby disrupting iron homeostasis. This functional iron deficiency may contribute to subsequent cardiovascular dysfunction, such as reduced cardiac output related to anemia (91, 92).
Ethanol exposure has also been shown to directly induce structural remodeling (e.g., wall thickening) and functional impairment (e.g., endothelial dysfunction) in the fetal aorta, associated with pro-inflammatory factors and oxidative stress (93). Specifically, aortas from PAE offspring are more susceptible to atherosclerosis, with inflammatory mediators promoting cell adhesion and endothelial injury (89). In ex vivo models, such as pressurized cerebral arteries, ethanol-induced vasodilation was mediated through the activation of cannabinoid receptors (CB1 and CB2), as confirmed by inhibitor experiments (94). Similar mechanisms affecting vascular reactivity have been observed in baboon models, providing insight into potential mechanisms underlying human cerebrovascular pathology (84). These findings collectively indicate that PAE promotes vascular disease through inflammatory and remodeling processes. In the rat studies mentioned, aortic abnormalities were partly attributed to cytokine-mediated vascular remodeling (89). Epigenetic mechanisms have also been implicated in mouse models, where PAE altered DNA methylation patterns and affected cardiac signaling pathways (95).
In summary, PAE induces cardiovascular abnormalities in animal models. Beyond common pathways, alcohol exhibits direct teratogenic effects, causing specific structural defects in the heart and aorta, and uniquely disrupts calcium signaling and iron homeostasis, contributing to its cardiotoxic profile.
5.2 High salt intake during pregnancy
Prenatal high salt intake (PHSI) is commonly defined as a daily consumption exceeding 5.75 g (based on 24-h urinary sodium excretion), with very high intake classified as greater than 10.25 g per day (96). Numerous studies highlight that salt intake among pregnant women exceeds the WHO-recommended limit of 5 g/day in many populations worldwide (97, 98). A prospective cohort study involving 184 pregnant women used 24-h urine collection to assess sodium excretion and identified high salt intake as a significant predictor of pregnancy-induced hypertension (81), suggesting a potential indirect increase in offspring cardiovascular risk. Another cohort study found that salt intake exceeding 6 g/day significantly elevated the risk of preeclampsia (20), a condition linked to placental dysfunction and adverse perinatal outcomes that may contribute to fetal programming of CVD (19).
The mechanisms through which PHSI contributes to fetal-origin CVD involve several pathways. PHSI suppresses local RAAS activity in the fetoplacental unit and reduces the levels of placental vascular endothelial growth factor (VEGF), leading to impaired placental vascular function (96). An animal study has shown that offspring of dams fed a high-salt diet exhibit coronary arterial wall thickening, endothelial degeneration, and altered expression of key RAAS components (such as AT1R downregulation and ACE2 upregulation), resulting in enhanced vascular sensitivity to angiotensin II (99). These offspring also demonstrate structural renal abnormalities (e.g., enlarged glomerular area) and myocardial fibrosis soon after birth, accompanied by local RAAS overactivation, indicating early impairment of organ development (100). Additionally, adult male offspring from high-salt-fed dams exhibit impaired endothelium-dependent vasodilation in response to acetylcholine in mesenteric arteries, associated with increased superoxide production and reduced nitric oxide bioavailability (101). Elevated levels of ROS and decreased antioxidant enzyme activity have also been observed in vascular tissues, contributing to oxidative damage (102). Another rat model revealed that prenatal high salt intake leads to elevated resting blood pressure and increased salt sensitivity in adulthood. This effect is mediated by inflammatory activation (e.g., increased TNF-α and IL-1β) in the hypothalamic paraventricular nucleus (PVN) and sympathetic overactivity, promoting the development of hypertension in offspring (103).
In summary, PHSI interferes with fetal cardiovascular developmental programming. A hallmark of high salt exposure is its pronounced suppression of the local placental RAAS and its programming of sustained salt sensitivity in offspring, often mediated by central inflammatory activation and sympathetic overactivity, leading to hypertension.
5.3 High caffeine intake during pregnancy
Current epidemiological studies commonly define high caffeine intake during pregnancy as consumption exceeding 200 mg per day. Multiple reports indicate that prenatal high-caffeine intake (PHCI) is associated with an increased risk of SGA and LBW infants (80). Both SGA and LBW are established risk factors for cardiovascular disease in later life, likely mediated through impaired development of key organs such as the heart and blood vessels. Data from the Finnish KuBiCo cohort showed that caffeine intake of 51–200 mg/day during early pregnancy was associated with an 87% increased risk of SGA, while intake exceeding 200 mg/day increased the risk by 51% (104). A Japanese study also found that caffeine consumption above 200 mg/day during the second trimester significantly elevated the risk of delivering a LBW infant (105).
Animal studies provide mechanistic insights into these observations. Rat models demonstrate that PHCI leads to elevated total cholesterol levels in adult offspring, increasing the risk of hypercholesterolemia. This metabolic reprogramming appears to be driven by caffeine-induced epigenetic modifications—such as changes in DNA methylation of key regulatory genes, including SREBP2, which is involved in cholesterol metabolism (106, 107). Another study reported cerebrovascular dysfunction in 24-month-old offspring following PHCI, resulting from caffeine-mediated inhibition of placental 11β-HSD2 enzyme activity. This leads to fetal overexposure to maternal glucocorticoids, activating downstream metabolic pathways that contribute to dysregulated cholesterol metabolism and cardiovascular dysfunction in adulthood, suggesting an elevated long-term risk of cerebrovascular disease (108). Mouse models further reveal that PHCI (equivalent to 2–4 cups of coffee per day in humans) induces cardiac functional abnormalities in offspring, with evidence suggesting these effects may be transmitted across generations, highlighting the persistent impact of caffeine on the cardiovascular system (109). Another experimental study showed that PHCI (120 mg/kg/day) significantly reduces placental maternal blood perfusion, triggering compensatory fetal vascular proliferation and disrupting angiogenic balance. This placental hypoperfusion and hypoxia impair fetal cardiovascular development via hypoxia-inducing signaling pathways (e.g., HIF), ultimately leading to fetal growth restriction and establishing a foundation for cardiovascular disease in later life (110, 111).
Collectively, these findings indicate that prenatal caffeine exposure contributes to fetal-origin cardiovascular disease. A predominant mechanism specific to caffeine is the inhibition of placental 11β-HSD2, resulting in fetal overexposure to maternal glucocorticoids, and the induction of placental hypoperfusion, which jointly drive adverse metabolic and cardiovascular outcomes.
These factors have been identified as significant modifiable risk factors for fetal-origin cardiovascular disease, with far-reaching and complex implications. Through mechanisms such as oxidative stress, inflammatory activation, epigenetic reprogramming, and placental dysfunction, suboptimal maternal nutrition adversely influences the developmental trajectory of the fetal cardiovascular system. These processes collectively increase the offspring’s susceptibility to cardiometabolic diseases in adulthood (88, 103, 106).
This section focuses on examining the potential long-term effects of three typical adverse dietary behaviors during pregnancy—alcohol consumption, high salt intake, and excessive caffeine intake—on offspring cardiovascular health, along with their underlying biological mechanisms. These maternal dietary behaviors disrupt the normal developmental programming of the fetal cardiovascular system, thereby creating long-term health risks for the offspring. Their common pathways of action primarily involve inducing oxidative stress, promoting inflammatory responses, triggering epigenetic modifications, and causing placental dysfunction. Through these mechanisms, fetal cardiovascular development is disrupted, potentially leading to adaptive changes in structure and function. This, in turn, elevates the risk of developing cardiovascular diseases such as hypertension and atherosclerosis in adulthood (Figure 2).
Figure 2. Pathogenic mechanisms linking maternal-specific adverse dietary patterns during pregnancy to fetal-origin cardiovascular disease. Created using Figdraw.com.
6 Conclusion and outlook
This review synthesizes evidence that maternal nutritional imbalances during pregnancy—encompassing overnutrition, macro- and micronutrient deficiencies, and specific dietary behaviors—significantly shape the developmental origins of offspring cardiovascular disease (CVD) (Figure 3).
Figure 3. The outline of this review. Created using Figdraw.com.
Accumulating evidence identifies “developmental programming” as the core mechanism, wherein suboptimal intrauterine nutrition induces persistent alterations in fetal cardiovascular development (5, 7). Across the diverse exposures discussed, several interconnected mechanistic pathways—including oxidative stress, inflammatory activation, and epigenetic modifications—recur as a common pathogenic network (31, 53, 87), disrupting placental function and fetal programming (34, 95). Beyond these shared mechanisms, specific nutritional insults exhibit distinct emphases: overnutrition is particularly characterized by profound metabolic disturbances and mitochondrial dysfunction (10, 24, 35); macronutrient deficiency drives structural compromises and severe placental insufficiency (48, 51, 52); micronutrient imbalances distinctly disrupt one-carbon metabolism and antioxidant defenses (16, 69, 70); and exposures to alcohol, high salt, and caffeine exert direct teratogenic effects, program neuroendocrine dysregulation, or induce specific placental dysfunction (87, 99, 108).
Maternal nutrition during gestation is thus a key determinant of offspring cardiovascular risk (112). Imbalances during this sensitive period program elevated disease susceptibility later in life. These insights not only deepen our understanding of the developmental origins of CVD but also underscore pregnancy as a strategic window for early intervention (8, 13). Given the growing prevalence of suboptimal prenatal nutrition and its long-term health implications, there is an urgent need to integrate evidence-based nutritional guidance into maternal health programs and chronic disease prevention initiatives. Promoting optimal prenatal nutrition represents a powerful approach to mitigating the global burden of CVD. Future research should aim to elucidate complex nutrient–environment interactions, refine targeted interventions, evaluate long-term outcomes, and support the translation of scientific evidence into public health practice.
Author contributions
SC: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing. FD: Writing – original draft, Writing – review & editing. ML: Conceptualization, Writing – review & editing. MZ: Data curation, Software, Writing – review & editing. ZY: Conceptualization, Writing – review & editing. YM: Investigation, Writing – review & editing. LF: Investigation, Writing – review & editing. QG: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing. DF: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing.
Funding
The author(s) declared that financial support was received for this work and/or its publication. Supported partly by the National Nature and Science Foundation of China (82571952, 82271724, and 81873841), General Programs of Jiangsu Commission of Health (M2021087), and Suzhou basic research pilot project (SSD2024046). Suzhou Municipal Key Laboratory of Maternal and developmental origins of chronic diseases (SZS2025009), and Suzhou Municipal Key Discipline of Obstetrics and Gynecology (SZXK202504). Shandong Provincial Health Science and Technology Innovation Team Construction Project, and the Open Project of the Key Laboratory of Maternal and Fetal Medicine of National Health Commission of the People’s Republic of China and Shandong Provincial Maternity and Child Health Care Hospital (2025002 and 2025004).
Acknowledgments
We gratefully acknowledge the support of Figdraw. All the figures in this article were created using Figdraw.
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The author(s) declared that Generative AI was used in the creation of this manuscript. The author(s) verify and take full responsibility for the use of generative AI in the preparation of this manuscript.
Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Abbreviations
DOHaD, Developmental origins of health and disease; CVD, Cardiovascular disease; RAAS, Renin–angiotensin–aldosterone system; GDM, Gestational diabetes mellitus; GLUTs, Glucose transporter; FGR, Fetal growth restriction; MPD, Maternal protein deficiency; MCR, Maternal caloric restriction; IGF, Insulin-like growth factor; PAE, Prenatal alcohol exposure; VEGF, Vascular endothelial growth factor; PHCI, Prenatal high-caffeine intake; SGA, Small for gestational age; LBW, Low birth weight.
References
1. World Health Organization. World health statistics 2021: monitoring health for the SDGs, sustainable development goals. (2021). Available online at: https://www.who.int/publications/i/item/9789240027053 (Accessed September 26, 2025).
2. Sulyok, E, Farkas, B, and Bodis, J. Pathomechanisms of prenatally programmed adult diseases. Antioxidants (Basel). (2023) 12:1354. doi: 10.3390/antiox12071354
3. Khan, SS, Brewer, LC, Canobbio, MM, Cipolla, MJ, Grobman, WA, Lewey, J, et al. Optimizing prepregnancy cardiovascular health to improve outcomes in pregnant and postpartum individuals and offspring: a scientific statement from the American Heart Association. Circulation. (2023) 147:e76–91. doi: 10.1161/CIR.0000000000001124,
4. Gaillard, R, and Jaddoe, VWV. Maternal cardiovascular disorders before and during pregnancy and offspring cardiovascular risk across the life course. Nat Rev Cardiol. (2023) 20:617–30. doi: 10.1038/s41569-023-00869-z,
5. Briana, DD, and Malamitsi-Puchner, A. Developmental origins of adult health and disease: the metabolic role of BDNF from early life to adulthood. Metabolism. (2018) 81:45–51. doi: 10.1016/j.metabol.2017.11.019,
6. Fleming, TP, Watkins, AJ, Velazquez, MA, Mathers, JC, Prentice, AM, Stephenson, J, et al. Origins of lifetime health around the time of conception: causes and consequences. Lancet. (2018) 391:1842–52. doi: 10.1016/S0140-6736(18)30312-X,
8. Vickers, MH. Utility of preclinical models of altered maternal nutrition to support the developmental origins of health and disease hypothesis. Clin Sci Lond. (2022) 136:711–4. doi: 10.1042/CS20211175,
9. Hoffman, DJ, Powell, TL, Barrett, ES, and Hardy, DB. Developmental origins of metabolic diseases. Physiol Rev. (2021) 101:739–95. doi: 10.1152/physrev.00002.2020,
10. Lippert, RN, Hess, S, Klemm, P, Burgeno, LM, Jahans-Price, T, Walton, ME, et al. Maternal high-fat diet during lactation reprograms the dopaminergic circuitry in mice. J Clin Invest. (2020) 130:3761–76. doi: 10.1172/JCI134412,
11. Rees, WD. Interactions between nutrients in the maternal diet and the implications for the long-term health of the offspring. Proc Nutr Soc. (2019) 78:88–96. doi: 10.1017/S0029665118002537,
12. McGee, M, Bainbridge, S, and Fontaine-Bisson, B. A crucial role for maternal dietary methyl donor intake in epigenetic programming and fetal growth outcomes. Nutr Rev. (2018) 76:469–78. doi: 10.1093/nutrit/nuy006,
13. Gawlińska, K, Gawliński, D, Filip, M, and Przegaliński, E. Relationship of maternal high-fat diet during pregnancy and lactation to offspring health. Nutr Rev. (2021) 79:709–25. doi: 10.1093/nutrit/nuaa020,
14. Loche, E, Blackmore, HL, Carpenter, AA, Beeson, JH, Pinnock, A, Ashmore, TJ, et al. Maternal diet-induced obesity programmes cardiac dysfunction in male mice independently of post-weaning diet. Cardiovasc Res. (2018) 114:1372–84. doi: 10.1093/cvr/cvy082,
15. Noble, RMN, Soni, S, Liu, SN, Rachid, JJ, Mast, HE, Wiedemeyer, A, et al. Maternal ketone supplementation throughout gestation improves neonatal cardiac dysfunction caused by perinatal iron deficiency. Clin Sci Lond. (2024) 138:1249–64. doi: 10.1042/CS20241386,
16. Mendes Garrido Abregú, F, Caniffi, C, Arranz, CT, and Tomat, AL. Impact of zinc deficiency during prenatal and/or postnatal life on cardiovascular and metabolic diseases: experimental and clinical evidence. Adv Nutr. (2022) 13:833–45. doi: 10.1093/advances/nmac012,
17. Chen, LW, Fitzgerald, R, Murrin, CM, Mehegan, J, Kelleher, CC, Phillips, CM, et al. Associations of maternal caffeine intake with birth outcomes: results from the lifeways cross generation cohort study. Am J Clin Nutr. (2018) 108:1301–8. doi: 10.1093/ajcn/nqy219,
18. Polinski, KJ, Purdue-Smithe, A, Robinson, SL, Zhao, SK, Schliep, KC, Silver, RM, et al. Maternal caffeine intake and DNA methylation in newborn cord blood. Am J Clin Nutr. (2022) 115:482–91. doi: 10.1093/ajcn/nqab348,
19. Fujita, T. Recent advances in hypertension: epigenetic mechanism involved in development of salt-sensitive hypertension. Hypertension. (2023) 80:711–8. doi: 10.1161/HYPERTENSIONAHA.122.20588,
20. Birukov, A, Andersen, LB, Herse, F, Rakova, N, Kitlen, G, Kyhl, HB, et al. Aldosterone, salt, and potassium intakes as predictors of pregnancy outcome, including preeclampsia. Hypertension. (2019) 74:391–8. doi: 10.1161/hypertensionaha.119.12924,
21. Naik, VD, Lee, J, Wu, G, Washburn, S, and Ramadoss, J. Effects of nutrition and gestational alcohol consumption on fetal growth and development. Nutr Rev. (2022) 80:1568–79. doi: 10.1093/nutrit/nuab119,
22. Hossin, MZ, Kazamia, K, Faxén, J, Rudolph, A, Johansson, K, Sandström, A, et al. Pre-existing maternal cardiovascular disease and the risk of offspring cardiovascular disease from infancy to early adulthood. Eur Heart J. (2024) 45:4111–23. doi: 10.1093/eurheartj/ehae547,
23. Cochrane, ALK, Murphy, MP, Ozanne, SE, and Giussani, DA. Pregnancy in obese women and mechanisms of increased cardiovascular risk in offspring. Eur Heart J. (2024) 45:5127–45. doi: 10.1093/eurheartj/ehae671,
24. Grzęda, E, Matuszewska, J, Ziarniak, K, Gertig-Kolasa, A, Krzyśko-Pieczka, I, Skowrońska, B, et al. Animal foetal models of obesity and diabetes - from laboratory to clinical settings. Front Endocrinol (Lausanne). (2022) 13:785674. doi: 10.3389/fendo.2022.785674,
25. Razaz, N, Villamor, E, Muraca, GM, Bonamy, AKE, and Cnattingius, S. Maternal obesity and risk of cardiovascular diseases in offspring: a population-based cohort and sibling-controlled study. Lancet Diabetes Endocrinol. (2020) 8:572–81. doi: 10.1016/S2213-8587(20)30151-0,
26. Eitmann, S, Mátrai, P, Németh, D, Hegyi, P, Lukács, A, Bérczi, B, et al. Maternal overnutrition elevates offspring’s blood pressure-a systematic review and meta-analysis. Paediatr Perinat Epidemiol. (2022) 36:276–87. doi: 10.1111/ppe.12859,
27. van Elten, TM, Karsten, MDA, van Poppel, MNM, Geelen, A, Limpens, J, Roseboom, TJ, et al. Diet and physical activity in pregnancy and offspring’s cardiovascular health: a systematic review. J Dev Orig Health Dis. (2019) 10:286–98. doi: 10.1017/S204017441800082X,
28. Bodnar, LM, Kirkpatrick, SI, Yu, YH, Kennedy, E, Parisi, SM, and Naimi, AI. Heterogeneity in the association between a dietary pattern high in fat, sugar, and sodium and adverse pregnancy outcomes by maternal characteristics: a United States pregnancy cohort study. Am J Clin Nutr. (2025) 122:1103–10. doi: 10.1016/j.ajcnut.2025.07.005,
29. Musial, B, Vaughan, OR, Fernandez-Twinn, DS, Voshol, P, Ozanne, SE, Fowden, AL, et al. A western-style obesogenic diet alters maternal metabolic physiology with consequences for fetal nutrient acquisition in mice. J Physiol. (2017) 595:4875–92. doi: 10.1113/JP273684,
30. Nakano, H, Fajardo, VM, and Nakano, A. The role of glucose in physiological and pathological heart formation. Dev Biol. (2021) 475:222–33. doi: 10.1016/j.ydbio.2021.01.020,
31. Sultan, S, and Sabeeh, R. Impact of gestational and type 2 diabetes on fetal endothelial cell miRNA expression. J Diabetes Complicat. (2025) 39:109106. doi: 10.1016/j.jdiacomp.2025.109106,
32. Kwon, H, Jung, YJ, Lee, Y, Son, GH, Kim, HO, Maeng, YS, et al. Impaired angiogenic function of fetal endothelial progenitor cells via PCDH10 in gestational diabetes mellitus. Int J Mol Sci. (2023) 24:16082. doi: 10.3390/ijms242216082
33. Dela Justina, V, Gonçalves, JS, de Freitas, RA, Fonseca, AD, Volpato, GT, Tostes, RC, et al. Increased O-linked N-acetylglucosamine modification of NF-ΚB and augmented cytokine production in the placentas from hyperglycemic rats. Inflammation. (2017) 40:1773–81. doi: 10.1007/s10753-017-0620-7,
34. Lin, XH, Gao, L, Tian, S, Klausen, C, Guo, MX, Gao, Q, et al. Maternal high-fat-diet exposure is associated with elevated blood pressure and sustained increased leptin levels through epigenetic memory in offspring. Sci Rep. (2021) 11:316. doi: 10.1038/s41598-020-79604-4,
35. Larsen, TD, Sabey, KH, Knutson, AJ, Gandy, TCT, Louwagie, EJ, Lauterboeck, L, et al. Diabetic pregnancy and maternal high-fat diet impair mitochondrial dynamism in the developing fetal rat heart by sex-specific mechanisms. Int J Mol Sci. (2019) 20:3090. doi: 10.3390/ijms20123090
36. Ahmed, A, and Delgado-Olguin, P. Embryonic programming of heart disease in response to obesity during pregnancy. Biochim Biophys Acta Mol basis Dis. (2020) 1866:165402. doi: 10.1016/j.bbadis.2019.01.028,
37. Chattergoon, NN, Bose, K, Louey, S, and Jonker, SS. Lipid exposure leads to metabolic dysfunction in fetal sheep cardiomyocytes. Physiol Rep. (2025) 13:e70386. doi: 10.14814/phy2.70386,
38. Kappen, C, Kruger, C, Jones, S, Herion, NJ, and Salbaum, JM. Maternal diet modulates placental nutrient transporter gene expression in a mouse model of diabetic pregnancy. PLoS One. (2019) 14:e0224754. doi: 10.1371/journal.pone.0224754,
39. Yu, S, Wen, Y, Li, J, Zhang, H, and Liu, Y. Prenatal lipopolysaccharide exposure promotes dyslipidemia in the male offspring rats. Front Physiol. (2018) 9:542. doi: 10.3389/fphys.2018.00542,
40. Reginatto, MW, Fontes, KN, Monteiro, VRS, Silva, NL, Andrade, CBV, Gomes, HR, et al. Effect of sublethal prenatal endotoxaemia on murine placental transport systems and lipid homeostasis. Front Microbiol. (2021) 12:706499. doi: 10.3389/fmicb.2021.706499,
41. Alsiraj, Y, Huang, H, Shoemaker, R, Schanbacher, B, Murphy, M, Giannone, P, et al. Maternal nutritional programming: sex-specific cardiovascular and immune outcomes following perinatal high-fat diet exposure. Nutrients. (2025) 17:1464. doi: 10.3390/nu17091464
42. Duan, Y, Sun, F, Li, Y, and Yang, S. High glucose and high lipid induced mitochondrial dysfunction in JEG-3 cells through oxidative stress. Open Life Sci. (2023) 18:20220561. doi: 10.1515/biol-2022-0561,
43. Louwagie, EJ, Larsen, TD, Wachal, AL, and Baack, ML. Placental lipid processing in response to a maternal high-fat diet and diabetes in rats. Pediatr Res. (2018) 83:712–22. doi: 10.1038/pr.2017.288,
44. Contreras-Duarte, S, Carvajal, L, Fuenzalida, B, Cantin, C, Sobrevia, L, and Leiva, A. Maternal dyslipidaemia in pregnancy with gestational diabetes mellitus: possible impact on foetoplacental vascular function and lipoproteins in the neonatal circulation. Curr Vasc Pharmacol. (2019) 17:52–71. doi: 10.2174/1570161115666171116154247,
45. Ji, B, Deng, F, Zhou, B, Zhao, C, Lei, J, Xu, T, et al. Maternal high glucose and fat diet exposure impaired vascular constriction via miR-325-3P/SHIP2/NOX2 pathway axis in offspring vessels. Cell Mol Life Sci. (2024) 82:12. doi: 10.1007/s00018-024-05549-w,
46. Pan, HT, Xiong, YM, Zhu, HD, Shi, XL, Yu, B, Ding, HG, et al. Proteomics and bioinformatics analysis of cardiovascular related proteins in offspring exposed to gestational diabetes mellitus. Front Cardiovasc Med. (2022) 9:1021112. doi: 10.3389/fcvm.2022.1021112
47. Ricci, TA, Boonpattrawong, N, Laher, I, and Devlin, AM. Maternal nutrition and effects on offspring vascular function. Pflugers Arch. (2023) 475:877–87. doi: 10.1007/s00424-023-02807-x,
48. Van Gronigen Case, G, Storey, KM, Parmeley, LE, and Schulz, LC. Effects of maternal nutrient restriction during the periconceptional period on placental development in the mouse. PLoS One. (2021) 16:e0244971. doi: 10.1371/journal.pone.0244971,
49. Rock, CR, White, TA, Piscopo, BR, Sutherland, AE, Miller, SL, Camm, EJ, et al. Cardiovascular and cerebrovascular implications of growth restriction: mechanisms and potential treatments. Int J Mol Sci. (2021) 22:7555. doi: 10.3390/ijms22147555
50. Pereira, SP, Tavares, LC, Duarte, AI, Baldeiras, I, Cunha-Oliveira, T, Martins, JD, et al. Sex-dependent vulnerability of fetal nonhuman primate cardiac mitochondria to moderate maternal nutrient reduction. Clin Sci (Lond). (2021) 135:1103–26. doi: 10.1042/CS20201339
51. Folguieri, MS, Franco, ATB, Vieira, AS, Gontijo, JAR, and Boer, PA. Transcriptome and morphological analysis on the heart in gestational protein-restricted aging male rat offspring. Front Cell Dev Biol. (2022) 10:892322. doi: 10.3389/fcell.2022.892322,
52. Zouridis, A, Manousopoulou, A, Potiris, A, Sarli, PM, Aravantinos, L, Pervanidou, P, et al. Impact of maternal food restriction on heart proteome in appropriately grown and growth-restricted Wistar-rat offspring. Nutrients. (2021) 13:466. doi: 10.3390/nu13020466
53. de Sousa, SM, Braz, GRF, Freitas, C d M, de Santana, DF, Sellitti, DF, Fernandes, MP, et al. Oxidative injuries induced by maternal low-protein diet in female brainstem. Nutr Neurosci. (2018) 21:580–8. doi: 10.1080/1028415X.2017.1325974,
54. Santana, DF, Ferreira, DS, Braz, GRF, Sousa, SMS, Silva, TL d A, Gomes, DA, et al. Maternal protein restriction in two successive generations impairs mitochondrial electron coupling in the progeny’s brainstem of Wistar rats from both sexes. Front Neurosci. (2019) 13:203. doi: 10.3389/fnins.2019.00203
55. Makayes, Y, Resnick, E, Hinden, L, Aizenshtein, E, Shlomi, T, Kopan, R, et al. Increasing mTORC1 pathway activity or methionine supplementation during pregnancy reverses the negative effect of maternal malnutrition on the developing kidney. J Am Soc Nephrol. (2021) 32:1898–912. doi: 10.1681/ASN.2020091321,
56. Mariano, VS, Boer, PA, and Gontijo, JAR. Fetal undernutrition programming, sympathetic nerve activity, and arterial hypertension development. Front Physiol. (2021) 12:704819. doi: 10.3389/fphys.2021.704819,
57. Kawarazaki, W, and Fujita, T. Kidney and epigenetic mechanisms of salt-sensitive hypertension. Nat Rev Nephrol. (2021) 17:350–63. doi: 10.1038/s41581-021-00399-2,
58. Assalin, HB, Gontijo, JAR, and Boer, PA. miRNAs, target genes expression and morphological analysis on the heart in gestational protein-restricted offspring. PLoS One. (2019) 14:e0210454. doi: 10.1371/journal.pone.0210454,
59. Gallagher, LT, Bardill, J, Sucharov, CC, Wright, CJ, Karimpour-Fard, A, Zarate, M, et al. Dysregulation of miRNA-mRNA expression in fetal growth restriction in a caloric restricted mouse model. Sci Rep. (2024) 14:5579. doi: 10.1038/s41598-024-56155-6,
60. Masoumy, EP, Sawyer, AA, Sharma, S, Patel, JA, Gordon, PMK, Regnault, TRH, et al. The lifelong impact of fetal growth restriction on cardiac development. Pediatr Res. (2018) 84:537–44. doi: 10.1038/s41390-018-0069-x,
61. Dimasi, CG, Darby, JRT, Cho, SKS, Saini, BS, Holman, SL, Meakin, AS, et al. Reduced in utero substrate supply decreases mitochondrial abundance and alters the expression of metabolic signalling molecules in the fetal sheep heart. J Physiol. (2024) 602:5901–22. doi: 10.1113/JP285572,
62. Turan, S, Aberdeen, GW, and Thompson, LP. Chronic hypoxia alters maternal uterine and fetal hemodynamics in the full-term pregnant guinea pig. Am J Physiol Regul Integr Comp Physiol. (2017) 313:R330–9. doi: 10.1152/ajpregu.00056.2017,
63. Frapin, M, Guignard, S, Meistermann, D, Grit, I, Moullé, VS, Paillé, V, et al. Maternal protein restriction in rats alters the expression of genes involved in mitochondrial metabolism and epitranscriptomics in fetal hypothalamus. Nutrients. (2020) 12:1464. doi: 10.3390/nu12051464
64. Masiero, BC, Calsa, B, Oliveira, CA, de Moretti Andra, TA, Esquisatto, MAM, and Catisti, R. Morphofunctional and immunological cardiac evaluation of protein restriction on rat offspring. Ann Anat. (2022) 241:151889. doi: 10.1016/j.aanat.2022.151889
65. Miles, TK, Allensworth-James, ML, Odle, AK, Silva Moreira, AR, Haney, AC, LaGasse, AN, et al. Maternal undernutrition results in transcript changes in male offspring that may promote resistance to high fat diet induced weight gain. Front Endocrinol (Lausanne). (2023) 14:1332959. doi: 10.3389/fendo.2023.1332959,
66. Wang, H, Mueller, NT, Li, J, Sun, N, Huo, Y, Ren, F, et al. Association of maternal plasma folate and cardiometabolic risk factors in pregnancy with elevated blood pressure of offspring in childhood. Am J Hypertens. (2017) 30:532–40. doi: 10.1093/ajh/hpx0003,
67. Sangüesa, J, Márquez, S, Montazeri, P, Fochs, S, Pey, N, Anguita-Ruiz, A, et al. Role of maternal vitamin D3 levels in shaping adolescent vascular health: evidence from a Spanish population-based birth cohort. J Am Heart Assoc. (2025) 14:e035273. doi: 10.1161/JAHA.124.035273,
68. Lindberg, J, Norman, M, Westrup, B, Domellöf, M, and Berglund, SK. Lower systolic blood pressure at age 7 y in low-birth-weight children who received iron supplements in infancy: results from a randomized controlled trial. Am J Clin Nutr. (2017) 106:475–80. doi: 10.3945/ajcn.116.150482,
69. Morales, E, Prieto-Sánchez, MT, Mendiola, J, Cutillas-Tolín, A, Adoamnei, E, Valera-Gran, D, et al. Maternal non-compliance with recommended folic acid supplement use alters global DNA methylation in cord blood of newborns: a cohort study. Clin Nutr. (2024) 43:1191–8. doi: 10.1016/j.clnu.2024.04.007,
70. Qu, Y, Liu, X, Lin, S, Bloom, MS, Wang, X, Li, X, et al. Maternal serum folate during pregnancy and congenital heart disease in offspring. JAMA Netw Open. (2024) 7:e2438747. doi: 10.1001/jamanetworkopen.2024.38747,
71. Kanasaki, K, and Kumagai, A. The impact of micronutrient deficiency on pregnancy complications and development origin of health and disease. J Obstet Gynaecol. (2021) 47:1965–72. doi: 10.1111/jog.14770,
72. Monasso, GS, Felix, JF, Heil, SG, de Rijke, YB, Gaillard, R, and Jaddoe, VWV. Vitamin B12, folate and homocysteine concentrations during pregnancy and early signs of atherosclerosis at school-age. Clin Nutr. (2021) 40:5133–40. doi: 10.1016/j.clnu.2021.08.001,
73. Huang, L, Gao, W, He, X, Yuan, T, Zhang, H, Zhang, X, et al. Maternal zinc alleviates tert-butyl hydroperoxide-induced mitochondrial oxidative stress on embryonic development involving the activation of Nrf2/PGC-1α pathway. J Anim Sci Biotechnol. (2023) 14:45. doi: 10.1186/s40104-023-00852-1,
74. Manik, KA, Joice, PPS, Jagadal, IA, T K, J, Samundeeswari, V, Madompoyil, B, et al. The role of Lp-PLA2 as a mediator between serum magnesium and zinc levels and cardiovascular risk in patients with metabolic syndrome. Cureus. (2024) 16:e72107. doi: 10.7759/cureus.72107
75. Kalisch-Smith, JI, Ved, N, Szumska, D, Munro, J, Troup, M, Harris, SE, et al. Maternal iron deficiency perturbs embryonic cardiovascular development in mice. Nat Commun. (2021) 12:3447. doi: 10.1038/s41467-021-23660-5,
76. Naowar, M, Dickton, D, and Francis, J. Cardiometabolic risk factors associated with magnesium and vitamin D nutrients during pregnancy-a narrative review. Nutrients. (2024) 16:2630. doi: 10.3390/nu16162630
77. Hu, R, Huang, Y, Jiang, X, Xu, Y, Zheng, Z, Shi, Y, et al. Maternal dietary copper deficiency induces cardiomyopathy and liver injury in mice by activating autophagy. Nutr Res. (2024) 126:1–10. doi: 10.1016/j.nutres.2024.02.010,
78. Monangi, NK, Xu, H, Fan, YM, Khanam, R, Khan, W, Deb, S, et al. Association of maternal prenatal copper concentration with gestational duration and preterm birth: a multicountry meta-analysis. Am J Clin Nutr. (2024) 119:221–31. doi: 10.1016/j.ajcnut.2023.10.011,
79. Popova, S, Charness, ME, Burd, L, Crawford, A, Hoyme, HE, Mukherjee, RAS, et al. Fetal alcohol spectrum disorders. Nat Rev Dis Primers. (2023) 9:11. doi: 10.1038/s41572-023-00420-x,
80. Jin, F, and Qiao, C. Association of maternal caffeine intake during pregnancy with low birth weight, childhood overweight, and obesity: a meta-analysis of cohort studies. Int J Obes. (2021) 45:279–87. doi: 10.1038/s41366-020-0617-4,
81. Inoue, M, Tsuchihashi, T, Hasuo, Y, Ogawa, M, Tominaga, M, Arakawa, K, et al. Salt intake, home blood pressure, and perinatal outcome in pregnant women. Circ J. (2016) 80:2165–72. doi: 10.1253/circj.CJ-16-0405,
82. Qian, J, Chen, Q, Ward, SM, Duan, E, and Zhang, Y. Impacts of caffeine during pregnancy. Trends Endocrinol Metab. (2020) 31:218–27. doi: 10.1016/j.tem.2019.11.004,
83. Chen, LW, Murrin, CM, Mehegan, J, Kelleher, CC, and Phillips, CM. Maternal, but not paternal or grandparental, caffeine intake is associated with childhood obesity and adiposity: the lifeways cross-generation cohort study. Am J Clin Nutr. (2019) 109:1648–55. doi: 10.1093/ajcn/nqz019,
84. Tobiasz, AM, Duncan, JR, Bursac, Z, Sullivan, RD, Tate, DL, Dopico, AM, et al. The effect of prenatal alcohol exposure on fetal growth and cardiovascular parameters in a baboon model of pregnancy. Reprod Sci. (2018) 25:1116–23. doi: 10.1177/1933719117734317,
85. Dejong, K, Olyaei, A, and Lo, JO. Alcohol use in pregnancy. Clin Obstet Gynecol. (2019) 62:142–55. doi: 10.1097/GRF.0000000000000414,
86. Steane, SE, Fielding, AM, Kent, NL, Andersen, I, Browne, DJ, Tejo, EN, et al. Maternal choline supplementation in a rat model of periconceptional alcohol exposure: impacts on the fetus and placenta. Alcohol Clin Exp Res. (2021) 45:2130–46. doi: 10.1111/acer.14685,
87. Andreu-Fernández, V, Serra-Delgado, M, Almeida-Toledano, L, García-Meseguer, À, Vieiros, M, Ramos-Triguero, A, et al. Effect of postnatal epigallocatechin-gallate treatment on cardiac function in mice prenatally exposed to alcohol. Antioxidants (Basel). (2023) 12:1067. doi: 10.3390/antiox12051067
88. Shirpoor, A, Gaderi, R, and Naderi, R. Ethanol exposure in prenatal and early postnatal induced cardiac injury in rats: involvement of oxidative stress, Hsp70, ERK 1/2, JNK, and apoptosis in a 3-month follow-up study. Cell Stress Chaperones. (2019) 24:917–26. doi: 10.1007/s12192-019-01015-w,
89. Soraya, H, Sheikholeslami, S, Shirpoor, A, Nezami Majd, F, Naderi, R, and Rasmi, Y. Influence of maternal ethanol exposure on systemic hemodynamic variables and histopathological changes in the aorta wall of male rat offspring: a three-month follow-up. Iran J Med Sci. (2022) 47:468–76. doi: 10.30476/IJMS.2021.91047.2205,
90. Atum, ALB, de Matos, LP, de Jesus, BC, Nasuk, GR, da Silva, GA, Gomes, CP, et al. Impact of prenatal alcohol exposure on the development and myocardium of adult mice: morphometric changes, transcriptional modulation of genes related to cardiac dysfunction, and antioxidant cardioprotection. Antioxidants (Basel). (2023) 12:256. doi: 10.3390/antiox12020256
91. Helfrich, KK, Saini, N, Kwan, STC, Rivera, OC, Mooney, SM, and Smith, SM. Fetal anemia and elevated hepcidin in a mouse model of fetal alcohol spectrum disorder. Pediatr Res. (2023) 94:503–11. doi: 10.1038/s41390-023-02469-6,
92. Huebner, SM, Helfrich, KK, Saini, N, Blohowiak, SE, Cheng, AA, Kling, PJ, et al. Dietary iron fortification normalizes fetal hematology, hepcidin, and iron distribution in a rat model of prenatal alcohol exposure. Alcohol Clin Exp Res. (2018) 42:1022–33. doi: 10.1111/acer.13754,
93. Legault, LM, Dupas, T, Breton-Larrivée, M, Filion-Bienvenue, F, Lemieux, A, Langford-Avelar, A, et al. Sex-specific DNA methylation and gene expression changes in mouse placentas after early preimplantation alcohol exposure. Environ Int. (2024) 192:109014. doi: 10.1016/j.envint.2024.109014,
94. Seleverstov, O, Tobiasz, A, Jackson, JS, Sullivan, R, Ma, D, Sullivan, JP, et al. Maternal alcohol exposure during mid-pregnancy dilates fetal cerebral arteries via endocannabinoid receptors. Alcohol. (2017) 61:51–61. doi: 10.1016/j.alcohol.2017.01.014,
95. Gutherz, OR, Deyssenroth, M, Li, Q, Hao, K, Jacobson, JL, Chen, J, et al. Potential roles of imprinted genes in the teratogenic effects of alcohol on the placenta, somatic growth, and the developing brain. Exp Neurol. (2022) 347:113919. doi: 10.1016/j.expneurol.2021.113919,
96. Vulin, M, Drenjančević, I, Muller, A, Mihaljević, Z, Kolobarić, N, Šušnjara, P, et al. Placenta may exert fetal protection against maternal high salt diet intake via renin-angiotensin-aldosterone system. Placenta. (2024) 158:136–44. doi: 10.1016/j.placenta.2024.10.003,
97. Barakat, N, Olabi, A, Nasreddine, L, Ismaeel, H, Kharroubi, S, Jaoude, LA, et al. Determination of salt contents of bread types and estimation of salt intake from bread in Lebanon. PLoS One. (2025) 20:e0325857. doi: 10.1371/journal.pone.0325857,
98. Bhattarai, S, Bista, B, Yadav, BK, Gynawali, P, Poudyal, A, Jha, AK, et al. Estimation of mean population salt intakes using spot urine samples and associations with body mass index, hypertension, raised blood sugar and hypercholesterolemia: findings from STEPS survey 2019, Nepal. PLoS One. (2022) 17:e0266662. doi: 10.1371/journal.pone.0266662,
99. Li, W, Lv, J, Wu, J, Zhou, X, Jiang, L, Zhu, X, et al. Maternal high-salt diet altered PKC/MLC20 pathway and increased ANG II receptor-mediated vasoconstriction in adult male rat offspring. Mol Nutr Food Res. (2016) 60:1684–94. doi: 10.1002/mnfr.201500998,
100. Seravalli, P, de Oliveira, IB, Zago, BC, de Castro, I, Veras, MM, Alves-Rodrigues, EN, et al. High and low salt intake during pregnancy: impact on cardiac and renal structure in newborns. PLoS One. (2016) 11:e0161598. doi: 10.1371/journal.pone.0161598,
101. Liu, Y, Qi, L, Wu, J, Xu, T, Yang, C, Chen, X, et al. Prenatal high-salt diet impaired vasodilatation with reprogrammed renin-angiotensin system in offspring rats. J Hypertens. (2018) 36:2369–79. doi: 10.1097/HJH.0000000000001865,
102. Vulin, M, Muller, A, Drenjančević, I, Šušnjara, P, Mihaljević, Z, and Stupin, A. High dietary salt intake attenuates nitric oxide mediated endothelium-dependent vasodilation and increases oxidative stress in pregnancy. J Hypertens. (2024) 42:672–84. doi: 10.1097/HJH.0000000000003645,
103. Su, Q, Yu, XJ, Yang, Q, Wang, XM, Xia, WJ, Li, HB, et al. Inhibition of maternal c-Src ameliorates the male offspring hypertension by suppressing inflammation and neurotransmitters in the paraventricular nucleus. Cardiovasc Toxicol. (2021) 21:820–34. doi: 10.1007/s12012-021-09672-z,
104. Kukkonen, A, Hantunen, S, Voutilainen, A, Ruusunen, A, Backman, K, Kirjavainen, PV, et al. Maternal caffeine intake during pregnancy and the risk of delivering a small for gestational age baby: Kuopio birth cohort. Arch Gynecol Obstet. (2024) 310:359–68. doi: 10.1007/s00404-024-07538-7,
105. Kobayashi, S, Sata, F, Murata, K, Saijo, Y, Araki, A, Miyashita, C, et al. Dose-dependent associations between prenatal caffeine consumption and small for gestational age, preterm birth, and reduced birthweight in the Japan environment and children’s study. Paediatr Perinat Epidemiol. (2019) 33:185–94. doi: 10.1111/ppe.12551,
106. Xu, D, Luo, HW, Hu, W, Hu, SW, Yuan, C, Wang, GH, et al. Intrauterine programming mechanism for hypercholesterolemia in prenatal caffeine-exposed female adult rat offspring. FASEB J. (2018) 32:5563–76. doi: 10.1096/fj.201701557R,
107. Hu, S, Liu, K, Luo, H, Xu, D, Chen, L, Zhang, L, et al. Caffeine programs hepatic SIRT1-related cholesterol synthesis and hypercholesterolemia via A2AR/cAMP/PKA pathway in adult male offspring rats. Toxicology. (2019) 418:11–21. doi: 10.1016/j.tox.2019.02.015,
108. Li, N, Shi, R, Tang, J, Zhang, W, Liu, B, Chen, X, et al. Prenatal caffeine exposure induces down-regulation of the protein kinase a/ryanodine receptor/large-conductance Ca2+−activated K+ pathway in the cerebral arteries of old offspring rats. J Hypertens. (2020) 38:679–91. doi: 10.1097/HJH.0000000000002303,
109. Fang, X, Poulsen, RR, Rivkees, SA, and Wendler, CC. In utero caffeine exposure induces transgenerational effects on the adult heart. Sci Rep. (2016) 6:34106. doi: 10.1038/srep34106
110. Yu, P, Zhou, J, Ge, C, Fang, M, Zhang, Y, and Wang, H. Differential expression of placental 11β-HSD2 induced by high maternal glucocorticoid exposure mediates sex differences in placental and fetal development. Sci Total Environ. (2022) 827:154396.doi: 10.1016/j.scitotenv.2022.154396
111. Paula, T d MDE, Cardoso, LC, Felicioni, F, Caldeira-Brant, AL, Santos, TG, Castro-Oliveira, H, et al. Maternal chronic caffeine intake impairs fertility, placental vascularization and fetal development in mice. Reprod Toxicol. (2023) 121:108471. doi: 10.1016/j.reprotox.2023.108471,
112. Jiao, P, Lu, H, Hao, L, Degen, AA, Cheng, J, Yin, Z, et al. Nutrigenetic and epigenetic mechanisms of maternal nutrition-induced glucolipid metabolism changes in the offspring. Nutr Rev. (2025) 83:728–48. doi: 10.1093/nutrit/nuae048,
Keywords: adverse dietary patterns, cardiovascular disease, offspring, overnutrition, undernutrition
Citation: Cui S, Deng F, Lu M, Zhang M, Yang Z, Ma Y, Fan L, Gao Q and Feng D (2026) Maternal nutritional imbalance during pregnancy and the development of fetal-origin cardiovascular diseases. Front. Nutr. 13:1717069. doi: 10.3389/fnut.2026.1717069
Edited by:
Marion Korach-André, University of Franche-Comté, FranceReviewed by:
Nafisa M. Jadavji, University of Arizona, United StatesFernanda Priviero, University of South Carolina, United States
Copyright © 2026 Cui, Deng, Lu, Zhang, Yang, Ma, Fan, Gao and Feng. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Qinqin Gao, c2RmZnlnYW9xaW5xaW5AMTYzLmNvbQ==; Dairong Feng, ZGFpcm9uZ2ZlbmdAMTI2LmNvbQ==
†These authors have contributed equally to this work