Definitions and classifications

PTB occurs when delivery happens before 37 weeks of gestation [1, 2]. Within this broad category:

• Extremely preterm (< 28 weeks): These infants require the most intensive neonatal support and have the highest morbidity and mortality [6, 8].

• Very preterm (28–32 weeks): Infants face significant challenges, though often with better outcomes than extremely preterm newborns [7].

• Moderate to late preterm (33–37 weeks): Although outcomes are comparatively better, moderate/late preterm infants are not exempt from long-term complications, including elevated cardiovascular risks [9].

Although gestational age remains the principal method of classifying PTB, literature underscores that other physiological or intrauterine factors may refine risk stratification [1, 10, 11]. For instance, an infant born at 35 weeks with significant fetal growth restriction (FGR) or compromised placental function could face outcomes similar to or even more severe than a 33-week infant with normal growth and adequate placental support. Moreover, the state of key organ systems—particularly pulmonary, cardiovascular, and neuroendocrine—can vary greatly within the same gestational age bracket, further influencing morbidity and long-term sequelae [12]. As a result, parameters such as fetal growth trajectories, maternal-fetal immune interactions, and uteroplacental circulation are increasingly recognized as critical adjuncts to the standard gestational-age classification for PTBs [13].

Global epidemiology of PTB

Recent estimates reveal that 14.84 million births were preterm in 2014 [14]. The highest rates are found in low- and middle-income countries (LMICs) such as those in Sub-Saharan Africa (~12.0%) and parts of Asia (~13.4%), whereas lower rates are reported in Europe (8.7%) and Oceania (10.0%). This discrepancy reflects socioeconomic, environmental, and healthcare-related factors that significantly influence the incidence and outcomes of PTB [14].

Moreover, the global trend appears to be rising, in part due to:

• Demographic shifts (e.g., advanced maternal age).

• Assisted reproductive technologies and multiple pregnancies.

• Increased prevalence of maternal comorbidities (hypertension, obesity, diabetes).

• Iatrogenic PTBs from improved fetal and maternal surveillance [6, 7].

Impact on long-term health

PTBs carry immediate neonatal complications (respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis) but also longer-term sequelae involving cardiometabolic outcomes [6, 8]. These likely result from incomplete organ development, disturbances in fetal programming, and postnatal neonatal intensive care unit (NICU) exposures (high-flow oxygen, mechanical ventilation, infections), as demonstrated by recent studies that have highlighted persistent cardiovascular alterations following such exposures [15, 16]. In the following paragraph, we will specifically explore how the degree of prematurity influences the onset of cardiovascular and renal diseases in adulthood.

Inverse correlation with gestational age

Numerous epidemiological studies emphasize the inverse relationship between gestational age and risk of HF, IHD, and chronic kidney disease (CKD) [6–8]. In extremely preterm infants, the risk of HF may be increased up to 17-fold, while very PTB confers ~3.6-fold higher risk [6]. Figure 1 (original timeline diagram) illustrates critical phases of cardiac development and how they may be disrupted by PTB.

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Figure 1. 

Timeline diagram of critical phases. NICU: neonatal intensive care unit

Cardiovascular implications in late preterm

Late preterm (34–37 weeks), once thought relatively lower-risk, have also been associated with hypertension, HF, venous thromboembolism, and type 2 diabetes in adulthood [9]. Even moderate degrees of prematurity may incur long-term health impacts due to suboptimal intrauterine organ development and subsequent catch-up growth that predisposes to metabolic and vascular abnormalities.

Risk of CKD

In parallel with cardiovascular issues, CKD risk is higher in preterm-born individuals, particularly those with extremely PTB. Reduced nephron endowment—due to truncated renal organogenesis—compromises long-term renal function [8]. Maternal obesity, preeclampsia, and FGR may further exacerbate neonatal vulnerability.

Maternal BP and pregnancy outcomes

Elevated maternal blood pressure before or during early pregnancy correlates with adverse maternal outcomes [gestational hypertension, preeclampsia, gestational diabetes mellitus (GDM)] and is associated with higher rates of PTB, perinatal mortality, and NICU admissions [17].

Interaction with other maternal risk factors

Relevance to neonatal cardiovascular development

Maternal hemodynamic and metabolic conditions (hypertension, obesity, GDM, vitamin D deficiency) can affect the cardiovascular profile of offspring through placental changes, inflammatory mediators, and epigenetic modifications [24]. These prenatal exposures may intersect with postnatal NICU factors (mechanical ventilation, high-flow oxygen) to compound cardiovascular risks.

Fetal programming and developmental origins of health and disease (DOHaD)

The DOHaD hypothesis posits that adverse or suboptimal intrauterine environments can induce permanent developmental shifts in organ structure and regulatory systems [26]. Key mechanisms include:

• Epigenetic modifications: DNA methylation, histone modifications, and microRNA (miRNA) expression changes profoundly affect cardiomyocyte proliferation, vascular reactivity, and metabolic pathways.

• Intrauterine hypoxia or malnutrition: restrict organ growth, leading to reduced organ reserve.

• Infections or inflammation: trigger immune dysregulation with lifelong consequences.

• PTB amplifies these DOHaD pathways, as critical periods of organogenesis are truncated. Abrupt exposures to the NICU environment (e.g., oxygen fluctuations, mechanical ventilation, infection) can reinforce or further modify epigenetic “programming”, heightening long-term vulnerability [26, 27]. Recent advances indicate that parental genetic factors significantly influence fetal outcomes such as PTB and susceptibility to cardiovascular and metabolic diseases later in life. Notably, genetic variants carried by parents, including maternal and paternal alleles that encode adverse effects, may affect offspring outcomes even when these alleles are not directly transmitted to the subsequent generation. Such non-transmitted parental genetic effects imply mechanisms acting independently of traditional Mendelian inheritance, potentially mediated by the parental environment, epigenetic alterations, or intrauterine signaling pathways. These effects are also reported to vary depending on the sex of both parent and offspring, contributing further complexity to the inheritance patterns and developmental trajectories of diseases linked to PTB and metabolic-cardiovascular risk in adulthood [28–32].

Role of miRNA

Recent data suggest that specific miRNAs significantly influence gene expression in the placenta and fetal tissues. In a study by Ramos et al. [34], distinct miRNA signatures were observed in small extracellular vesicles (sEV) among women undergoing preterm labor (PTL) and preterm premature rupture of membranes (PPROM). miR-612 and others implicated in endocytic and senescence pathways could modulate inflammatory, apoptotic, and metabolic processes. Although direct translation to neonatal cardiovascular outcomes requires further research, these findings highlight the mechanistic potential of miRNA-mediated fetal programming (Figure 2).

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Figure 2. 

Schematic representation of the primary pathophysiological mechanisms linking preterm birth (PTB) to an increased risk of cardiovascular disease (CVD) in later life. Each mechanism interacts with the others, leading to structural and functional alterations that predispose preterm-born individuals to hypertension, heart failure, and ischemic heart disease

Vascular and cardiac alterations

Role of inflammation and oxidative stress

Neuroendocrine and metabolic axis

Catch-up growth and adolescent metabolism

Rapid postnatal growth—often observed when preterm infants “catch up”—may heighten insulin resistance and predispose to obesity or dyslipidemia. Overlapping inflammatory and oxidative mechanisms can further accelerate vascular aging, culminating in early manifestations of atherosclerosis or hypertension. These processes underscore the need for careful nutritional management and metabolic follow-up during childhood and adolescence (Figure 3).

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Figure 3. 

Flowchart summarizing pathophysiological mechanisms. W: week; NICU: neonatal intensive care unit; DOHaD: developmental origins of health and disease

Large Nordic registries

Nordic countries maintain comprehensive national health registries, enabling large-scale, population-based research. These studies demonstrate that individuals born preterm (< 32 weeks) exhibit substantially increased risk of HF and IHD beginning in adolescence [6, 7].

Cosibling analyses

Comparing siblings where one is preterm and the other term—strengthen causal inferences by controlling for genetic and environmental confounders. These consistently reveal higher cardiovascular event rates in the preterm sibling, reinforcing a likely direct effect of PTB on cardiovascular risk [7].

Influence of gestational age strata

When stratifying by gestational age in these cohorts:

• < 28 weeks (“extremely” preterm): The highest incidence of cardiovascular complications, with a notably earlier onset (late teens or early 20s).

• 28–32 weeks (“very” preterm): Elevated risk, though not as pronounced as extremely preterm.

• 33–37 weeks (“moderate/late” preterm): Modestly increased risk, often confounded by maternal conditions or FGR.

These gradients align with the physiologic logic of reduced organ development time, increased NICU interventions, and possibly more severe perinatal complications.

Meta-analytical findings

Meta-analyses of cohort and case-control studies corroborate an inverse gradient between gestational age and cardiovascular outcomes [43, 44]. Extremely preterm children show the highest predisposition to early-onset hypertension and subclinical cardiac dysfunction [36].

Methodological variability

Challenges in these meta-analyses include:

• Heterogeneity: Definitions of prematurity (e.g., cutoff at 37 weeks vs. 36 weeks) and outcome measures vary.

• Different eras: Neonatal care has evolved significantly over the decades, making older studies less comparable to contemporary data.

• Follow-up duration: Many studies track individuals only up to early adulthood, possibly underestimating the full burden of adult-onset CVD.

• Blood pressure assessments: Hospital or single-time measurements may differ from 24 h ambulatory assessments, affecting prevalence estimates of hypertension.

Nevertheless, the overarching conclusion is that prematurity is an independent risk factor for later CVD, and risk rises inversely with gestational age [7, 9, 44, 45].

Socioeconomic and ethnic disparities

PTB disproportionately affects low-resource settings, often correlating with socioeconomic disadvantage, limited prenatal care, and higher exposure to infectious or environmental stressors [14]. Genetic predispositions also shape PTB susceptibility, with recent genome-wide association studies [32, 46] identifying variants linked to preterm delivery.

Pre-existing maternal pathologies

• Gestational diabetes mellitus (GDM): Billionnet et al. [23] demonstrated that infants born to mothers with GDM, especially insulin-treated cases, have increased perinatal risks, including preterm delivery and congenital heart defects.

• Hypertension, obesity, and preeclampsia: These conditions can elevate the risk of prematurity and subsequently intensify the child’s susceptibility to hypertension or IHD [17, 43].

• IVF/ICSI pregnancies: Exhibit higher PTB rates, necessitating specialized perinatal management [20].

Neonates with intrauterine growth restriction (IUGR)

IUGR babies are often considered a separate category from preterm, but the two can overlap. IUGR specifically denotes infants who fail to meet their growth potential in utero [47]. Similar to extremely preterm infants, IUGR neonates are prone to endothelial dysfunction, metabolic syndrome, and eventually CVD in adulthood. The interplay of IUGR and prematurity can further amplify these risks.

Intersection of disparities, maternal pathologies, and IUGR

Socioeconomic deficits, ethnic factors, and maternal complications create a complex environment where PTBs bring additional cardiometabolic vulnerabilities [14, 23]. Infants with both IUGR and prematurity, especially in the context of maternal hypertension or GDM, exhibit some of the highest likelihoods of adverse long-term outcomes, emphasizing the need for targeted interventions (Figure 4—conceptual Venn diagram). Timely identification of these high-risk subgroups enables the implementation of specific clinical pathways and personalized preventive strategies, significantly improving long-term cardiovascular outcomes.

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Figure 4. 

Venn diagram of socioeconomic, ethnic, and healthcare factors. NICU: neonatal intensive care unit

Environmental exposure to toxic metals

Prenatal exposure to lead, mercury, cadmium, arsenic can precipitate PTB and adversely affect postnatal cardiovascular outcomes, as highlighted in recent large-scale reviews and epidemiological studies [48–50]. Mechanisms include oxidative stress, DNA damage, and disruption of endocrine pathways, potentially compounding the baseline vulnerability of preterm infants.

Guidelines for pediatric screening

Major organizations, including the American Academy of Pediatrics (AAP), recommend that children with a history of PTB undergo regular monitoring of:

• Blood pressure.

• Serum lipids.

• Glycemic status [24].

Some authors advocate for echocardiographic evaluations or TDI in certain high-risk cases [3, 36]. The rationale is that early detection of hypertension or subclinical cardiovascular alterations (like LV hypertrophy, diastolic dysfunction) can guide timely interventions (Table 1).

Nutritional counseling and lifestyle

Early screening and telemedicine

Improvements in telemedicine offer promising avenues for consistent blood pressure measurements, metabolic checks, and consultations—especially for families in resource-limited settings. Telemonitoring can identify early deviations in blood pressure or growth curves, prompting referral to specialized care. As Andraweera et al. [24] and Azegami et al. [53] suggest, preterm-born adolescents already show higher blood pressure, underscoring the necessity of sustained monitoring approaches.

Managing neonatal inflammation and sepsis

Given the established role of inflammation in shaping long-term outcomes, minimizing infectious risk is crucial. Cortese et al. [38] delineates prophylactic antibiotic measures and stringent NICU infection-control protocols to reduce sepsis (EOS and LOS). Such efforts can limit chronic inflammation that might aggravate endothelial dysfunction. Additionally, controlling hyperoxia and providing careful ventilation strategies can help reduce oxidative stress.

Holistic neonatal follow-up

A coordinated, multidisciplinary approach—integrating neonatologists, pediatricians, cardiologists, nutritionists, social workers—ensures comprehensive management of PTB survivors [54, 55].

This synergy addresses the multifactorial nature of PTB, providing:

• Structured screening protocols for BP, lipids, and glucose.

• Echocardiographic surveillance in high-risk cases.

• Nutritional support to manage catch-up growth effectively.

• Psychosocial services to address socioeconomic barriers.

These interventions are not only beneficial clinically but also cost-effective by preventing severe outcomes like HF, stroke, or CKD in later life.

Resource allocation and socioeconomic interventions

Policymakers must prioritize:

• Enhancing NICU infrastructure in high-burden regions.

• Training local healthcare providers in recognizing and managing PTB-related risks.

• Developing telemedicine networks to bridge geographic barriers.

• Addressing environmental toxicants (heavy metals), especially in industrial or rural settings with high exposure rates.

Socioeconomic improvements—including maternal education, access to family planning, and improved prenatal care—can reduce PTB incidence and improve follow-up quality, as confirmed by evidence showing a clear decrease in the risk of PTB in more favorable socioeconomic contexts and with better healthcare interventions [14, 56, 57].

Managing maternal conditions

Initiatives focusing on early detection and management of conditions like chronic hypertension, preeclampsia, and gestational diabetes are equally critical. Early referral to specialized centers can curb the incidence of iatrogenic PTBs and lessen the impact of maternal cardiovascular risk factors on fetal development. Dublin et al. [43] highlighted how antihypertensive drug choices and maternal blood pressure control modulate PTB rates.

Multi-omics approaches

Although promising, multi-omics (epigenomics, transcriptomics, proteomics, metabolomics) remain underutilized in large-scale PTB cohorts. Future research should integrate these methods to:

• Identify early biomarkers of CVD risk in neonates.

• Elucidate how maternal factors (BMI, vitamin D status, toxic metals) are translated at the molecular level.

• Develop personalized prevention and intervention strategies [34].

Recognizing preterm infants as high-risk

Healthcare providers should be trained to view PTB as a lifelong cardiovascular risk marker, in line with recent recommendations emphasizing the clinical importance of early identification of this vulnerability [4, 6, 7]. This paradigm shift mandates specialized screening protocols from childhood through adulthood, ensuring timely detection of hypertension, LV hypertrophy, or incipient HF (Figure 5).

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Figure 5. 

Timeline summarizing the progressive stages of cardiovascular risk associated with preterm birth. From initial neonatal alterations (oxidative stress, inflammation), the risk progresses throughout growth, highlighting the necessity of early screening and prevention efforts, ultimately leading to more severe clinical manifestations in adulthood such as hypertension, heart failure, and ischemic heart disease. NICU: neonatal intensive care unit; TDI: tissue doppler imaging

Integrating echocardiography and biomarkers

Advanced echocardiographic techniques (TDI, speckle-tracking) and biomarkers [e.g., N-terminal pro-B-type natriuretic peptide (NT-proBNP), inflammatory cytokines] can identify subclinical systolic or diastolic dysfunction, guiding early interventions. Metabolomic [33] and miRNA [37] signatures may further refine risk stratification.

Preventive approaches in NICUs

Improvements in neonatal care can mitigate long-term damage. Strategies include:

• Minimizing hyperoxia and invasive ventilation to reduce oxidative stress.

• Preventing and managing neonatal infections [38].

• Optimizing nutrition: Sufficient but not excessive catch-up growth, mindful of micronutrient requirements.

Maternal-child health coordination

Given the interlinked nature of maternal conditions (e.g., hypertension, diabetes, obesity) and preterm outcomes, a continuum of care that starts before conception—extending through pregnancy and postpartum—could lower both PTB rates and subsequent cardiovascular sequelae in the offspring [43].

Summary of findings

This review highlights the significant association between PTB and increased risk of CVDs later in life. The major findings are:

• Inverse gradient: The earlier the gestational age at birth, the higher the risk of HF, IHD, hypertension, and CKD [6–8].

• Pathophysiological mechanisms: Fetal programming (DOHaD), incomplete cardiac and vascular remodeling, chronic inflammation, oxidative stress, and neuroendocrine immaturity all converge to raise cardiovascular vulnerability [26, 27, 35].

• Vulnerable populations: Maternal obesity [18, 19], IVF pregnancies [20], LMICs with socioeconomic disadvantages, and toxic metal exposures [49, 50] face compounded risks [14, 23, 47].

• Implications of neonatal care: NICU practices, including oxygen therapy and infection control, can modify these risks by reducing inflammation and stress on the developing CVS [38].

• Echocardiographic and biomarker insights: Early changes in myocardial performance and molecular markers (e.g., PCaaC38:6, miRNAs) may forecast later cardiometabolic complications [3, 33, 37].

Importance of a structured follow-up

Given the consistent evidence linking PTB to long-term cardiovascular risk, health systems must adopt specialized, long-term monitoring for preterm-born individuals. This includes:

• Regular BP and metabolic screening from infancy into adulthood.

• Advanced echocardiography (TDI, speckle-tracking) for at-risk cohorts.

• Lifestyle and nutritional interventions to mitigate catch-up growth issues.

Policy recommendations and future directions

• Policy initiatives: Allocate resources to NICU expansions, staff training, and maternal health programs, with an emphasis on cost-effectiveness.

• Multi-omics research: Large longitudinal cohorts should integrate multi-omics to refine risk prediction and personalize interventions.

• Expanded follow-ups: Track cohorts into middle and older age for a complete picture of CVD incidence.

• Interventional trials: Evaluate the efficacy of targeted therapies (e.g., antihypertensives, vitamin D supplementation, lifestyle interventions) initiated in childhood or adolescence.

• Environmental regulations: Reduce exposure to heavy metals (lead, mercury, cadmium, arsenic) through stricter environmental policies and public health measures.

Call to action

Clinicians must routinely screen PTB survivors for early cardiometabolic abnormalities. Researchers should prioritize large-scale, multi-omics, and intervention studies targeting preterm populations.

Policymakers must invest in maternal-child health, mitigate environmental hazards, and ensure equitable healthcare access—especially in LMICs—thereby reducing the global burden of PTB-related CVD (Table 2).