Long-Term Consequences of Preterm Birth: A Lifespan Perspective

Authors: Lina F. Chalak, Natalie Vega Ortiz, Jennifer Joukhdar, Kara N. Goss

Abstract

Background

Preterm birth is increasingly recognized as a determinant of health across the lifespan, influencing neurodevelopment, psychiatric risk, cardiovascular function, and mortality. This review synthesizes current evidence linking early life adversity, including that associated with prematurity, to the brain-heart axis. We further describe the “fetus to fifty” model, highlighting how the early life experiences of preterm-born infants impact adult trajectories across the lifespan.

Summary

Cardiovascular and neurodevelopmental vulnerabilities in preterm-born infants are closely linked. Emerging evidence suggests that suboptimal perinatal hemodynamics and inflammation contribute to a shared cardio-cerebral phenotype, in which premature cardiovascular aging may impair cerebrovascular reserve and increase the risk of cognitive decline.

Key Messages

We review the fundamental physiology underlying the early origins of diseases relating to mental health, personality, psychiatric diagnosis, neuroanatomical changes, and cardiopulmonary outcomes, emphasizing the interplay between biological vulnerability and social determinants. Lastly, we identify gaps in knowledge and future research directions to better understand preterm-born adults.

Introduction

Each year, approximately 15 million infants worldwide are born prematurely, defined as birth at <37 weeks’ gestation [1]. Approximately 2% of all live births are very preterm (VPT, <32 weeks) or with extremely low birth weight (ELBW <1,000 g), representing the most vulnerable populations. Although advances in neonatal care have improved survival for these infants, emerging evidence shows that they experience persistent and evolving vulnerabilities across the lifespan.

The Developmental Origins of Health and Adult Disease (DOHAD) [2] hypothesis posits that adverse events or inappropriate developmental cues in utero and during the neonatal period determine the development of organ pathology, including within the brain and heart. This hypothesis is supported by numerous human epidemiological, physiological, and animal model studies showing poor long-term outcomes following early-life trauma or injury. Consistent with the DOHAD hypothesis, the disruption of developmental processes caused by preterm birth has long-term consequences, likely because 80% of brain connectivity occurs during the first years of life, a critical and sensitive period of synergistic developmental neuroplasticity.

This review focuses on the effects of premature birth on the brain-heart axis, including evidence for adverse mental health outcomes (i.e., the “preterm behavioral phenotype”) in those born prematurely. Figure 1 summarizes how early-life experiences of preterm-born infants affect development.

Mental Health Outcomes in Adults Born Preterm

Several studies have reported an elevated risk of psychiatric, attention, and personality disorders in those born prematurely, collectively suggesting the existence of a “preterm behavioral phenotype” (Table 1). For example, in one Canadian cohort, preterm-born adults had 2.5-fold higher odds of psychiatric disorders than term-born controls (odds ratio 2.5, 95% confidence interval [CI]: 1.2–5.1; p < 0.05) [3]. Consistent with this finding, data from Scandinavian national registries show that preterm birth is associated with an elevated lifetime risk of psychiatric disorders, autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder with functional impairment [4]. Similarly, Swedish registry studies report increased hospitalization for psychosis, depression, and bipolar disorder, as well as greater prescription of antipsychotics, antidepressants, and hypnotics in adults born prematurely [5–8]. Moreover, in a meta-analysis of 10 cohorts from the Adults Born Preterm International Collaboration (APIC), which includes those born VPT or with very low birth weight (VLBW; n = 1,385) and normal birth weight (NBW) controls (n = 1,780), participants born VPT or with VLBW had 10-fold higher odds of ASD, 5-fold higher odds of attention-deficit/hyperactivity disorder, 3-fold higher risk of anxiety or depression, and 1.5-fold higher odds of mood disorders than those born with NBW [9]. Thus, a growing body of evidence indicates that psychiatric diagnoses are disproportionately represented among preterm-born adults.

Systematic differences in personality profiles have also been observed in those preterm-born compared with those that are term-born. Those born with ELBW exhibit more shyness, behavioral inhibition, and risk aversion and lower sociability, assertiveness, and novelty seeking than those born with NBW [6–8]. These patterns may contribute to lower engagement in risk-taking behaviors, reduced employment rates, and relational difficulties among those born with ELBW. In the APIC [10] study, more internalizing and avoidant personality problems, in addition to fewer externalizing, antisocial, and rule-breaking behaviors, were noted in ELBW individuals than in NBW controls across 6 cohorts from 5 countries [10]. These results reinforce the existence of a “preterm behavioral phenotype,” characterized by increased inattention, anxiety, and social difficulties that disproportionately impact males and those with a lower gestational age [11].

Neuroimaging Mechanisms for Altered Brain Development in Preterm Infants

Neuroimaging data provide structural correlates for the behavioral and psychiatric outcomes observed in preterm-born adults (Table 2). We selected studies based on (1) use of neuroimaging to assess structural brain outcomes, (2) inclusion of preterm-born participants, (3) assessment across different developmental stages (neonatal period through adulthood), and (4) relevance to long-term functional or cognitive outcomes. Notably, magnetic resonance imaging (MRI) studies show smaller absolute brain volumes, with reductions in both gray and white matter, and less cortical complexity in adults born VPT than in adults born with NBW [12]. Reduced brain volume was also associated with lower IQ (−11.9 points [−15.4, –8.5]) and poorer performance in spelling (−8 points [−11.5, −4.6]) and mathematics (−10.3 points [−13.7, −6.9]), explaining 20%–40% of the variance in cognitive outcomes [13].

Studies focusing on 8-year-old preterm subjects have reported a decreased white matter in the central sensory motor regions and temporal lobes. White matter of the precentral and central regions tends to develop more slowly than other areas in preterm neonates; pointing to changes in the myelination process [14]. Fractional anisotropy (FA) is an imaging metric used to quantify white-matter fiber tract organization based on the degree of anisotropic diffusion within brain tissue [15]. Higher FA values indicate greater fiber organization, whereas lower values reflect reduced organization and more isotropic diffusion, approaching zero in fluids [15]. Myers and Ment focused on a subgroup of 26 preterm neonates with the median gestational age of 28.9 weeks and found reduced FA values, particularly in the external capsule, posterior limb of the internal capsule, isthmus, and mid-body of the corpus callosum [15]. Evidence suggests that reduced cerebral reserve in first weeks of life and early childhood is associated with earlier cognitive decline. Whereas FA reflects properties of white-matter tracts, voxel-based morphology can be used to further quantify regional differences in gray and white matter. Reduced thalamic and lentiform volumes in deep gray matter were identified in preterm-born infants when compared with term-born control infants via voxel-based morphology [15]. In another study, Gimenez and colleagues examined individuals at the age of 14 years and observed significantly decreased thalamic volumes in preterm-born infants relative to those born at term [16]. These effects correlated with semantic verbal fluency scores, which were significantly higher in term-born controls than in those born prematurely [16]. Thus, brain-based differences in children born prematurely may explain why they have an increased risk for academic underperformance, specifically in tasks that are governed by the affected brain regions. A systematic review and meta-analysis reported that children born prematurely scored significantly lower in reading comprehension (mean difference, −7.96; [95% CI: −12.15 to −3.76]; I^2^ = 81%) and mathematics (mean difference, −11.41; [95% CI: −17.57 to −5.26]; I^2^ = 91%) [17] when compared to term-born infants. Collectively, these findings reveal a developmental trajectory in which early life modifications to brain structures puts a subset of infants at high risk for academic and cognitive delays later in life.

Cardiovascular Function as a Possible Mediator of Outcomes after Preterm Birth

Consistent with the concept that early life conditions shape long-term health, preterm birth induces persistent alterations in both neurodevelopmental and cardiovascular trajectories (shown in Fig. 2). Preclinical models suggest that cardiovascular alterations associated with preterm birth result from premature exposure to extrauterine stimuli and oxidative stress, activating hypertrophic signaling kinases and transcription factors, leading to cardiac remodeling [19]. In humans, this remodeling manifests as smaller cardiac chambers and reduced myocardial mass, consistent with arrested cardiac growth rather than adaptive hypertrophy.

Clinical studies from Goss et al. [21] found that preterm-born adolescents and young adults exhibit significantly smaller biventricular chamber sizes and lower left ventricular mass index values than term-born peers while maintaining preserved ejection fraction [21]. Mean left ventricular end-diastolic and stroke volume indices were also reduced by approximately 10%–15% in those born prematurely relative to those born at term, suggesting a hypercontractile but volume-limited cardiac phenotype [21]. These findings were consistent across two preterm birth cohorts spanning 2 decades, underscoring the durability of early life cardiac programming.

Another study measured several longitudinal outcomes in those born preterm, including hypertension, ischemic heart disease, and heart failure, as well as body composition and metabolism, which affect the risk for hypertension, type 2 diabetes, and cardiovascular disease [22]. Results showed that alterations to ventricles and their functionality are associated with a 4-fold higher risk of heart failure in those born between 28- and 31-weeks of gestation, with risk increasing 17-fold for gestations below 28 weeks [22]. By adulthood, individuals born prematurely show hypertrophic and impaired hearts, narrowed and stiffened arteries, and vascular dysfunction [22]. Thus, despite limited longitudinal data, evidence supports that lower gestational age is associated with increased cardiovascular pathology in later life.

Importantly, smaller cardiac chamber size in preterm-born adults has been associated with decreased total brain volumes on MRI, linking structural changes within the heart to neurodevelopmental outcomes. Lapidaire et al. [23] linked smaller brain volumes to preceding cardiac abnormalities. In preterm-born individuals, greater left ventricular stroke volume and end-diastolic length were associated with larger right putamen and left thalamic volumes, respectively. Right ventricular performance was associated with both gray and white matter measures, including larger right putamen volume, reduced ventricular volume, and increased corpus callosum fractional anisotropy [23]. These effects were independent of early life factors, suggesting that the underlying physiological pathway persists into adulthood, and that cardiac health in preterm-born adults is closely associated with brain health [23]. Our group further found that increased aortic stiffness and systemic hypertension were associated with adverse neuroimaging markers, suggesting a shared vascular mechanism underlying cardiovascular and neural outcomes [24]. Together, these data show the value of this review, which is to highlight the long-term adverse health problems associated with prematurity [24].

Systemic and Metabolic Markers of Accelerated Biological Aging in Those Born Preterm

Chronic Health Conditions Associated with Aging: Prematurity for Life?

Individuals born prematurely experience multiple chronic health problems that are age-related. Respiratory health problems, such as asthma, can persist to adulthood, particularly those who had bronchopulmonary dysplasia (BPD) in the neonatal period [25]. Visual problems and eye surgery were significantly more common at middle-adulthood in the ELBW cohort, as were chronic health conditions [25]. A recent Swedish registry study reported no major comorbidities in only 22% of those born preterm at ages 18–43 years compared to 63.0% of those born full term [25].

There is a high prevalence of adult-onset medical condition such as hypertension, type 2 diabetes and metabolic syndrome that emerge later in the fourth decade, raising concerns of adverse health impacts affecting the lifespan and multiple organs. In addition, higher prevalence of dysglycemia, hepatic fat content and insulin resistance [26]; all factors known to increase cardiometabolic risk are seen in infants born preterm. The oldest cohort studies have reached only to the fourth decade of life. In some population-based cohort studies, preterm birth is associated with increased risk of ischemic heart disease and cerebrovascular disease [27].

Emerging evidence increasingly suggests that preterm birth triggers multisystem pathways of premature biological aging (Table 3). One New Zealand birth cohort that assessed individuals at the age of 38 years linked perinatal complications to shorter leukocyte telomere length and older appearing age [28]. Following mitotic division telomeres, shorten leading to impaired cellular function. Critically, telomere reduction is associated with a shorter lifespan and an increased risk for disease [29]. An MRI-based study of adults born VPT in the United Kingdom found that these individuals had “older-appearing” brains than term-born controls, suggesting earlier neuroanatomical decline [30]. Consistent with the hypothesis that preterm birth accelerates the biological aging clock, McMaster University data indicate that men with ELBW exhibit significantly older epigenetic age than men with NBW, although no difference was detected in women [31].

Preterm-born individuals also exhibit early declines in immune function, characterized by persistent low-grade inflammation and elevated circulating inflammatory proteins [29]. This pro-inflammatory milieu originates, in part, from perinatal insults, such as prenatal inflammation and neonatal morbidities, such as necrotizing enterocolitis, sepsis, and BPD, which have lasting effects on organ structure and function [29]. In particular, BPD, a hallmark of oxidative and inflammatory lung injury, is associated with reduced lung volumes, diminished gas exchange, and impaired exercise tolerance in adulthood, reflecting patterns of accelerated pulmonary aging [29].

Metabolic and cardiopulmonary sequelae mirror these findings. Adults born with VLBW or ELBW display reduced insulin sensitivity, dyslipidemia with elevated triglyceride-rich lipoproteins, and increased central adiposity, resembling patterns observed in early cardiometabolic aging [29]. Pulmonary studies further reveal that compared with adults born with NBW, those born with VLBW or ELBW are characterized by lower forced expiratory volume in 1 s, heightened airway obstruction, and bronchial hyperresponsiveness, which are features commonly observed in older populations but are rarely observed in young adults [32]. Structural cardiac differences established during the neonatal period predispose individuals to ischemic heart disease and heart failure [33]. Structural cardiac differences established during the neonatal period predispose individuals to ischemic heart disease and heart failure [33]. Ex-preterm infants exhibit structural and functional cardiac remodeling, characterized by smaller ventricles, reduced myocardial compliance, and impaired diastolic function, that persist into adulthood, and these alterations are associated with systemic and cerebral vascular stiffness, impaired perfusion, and microvascular rarefaction [34]. Parallel neuroimaging findings reveal reduced brain volumes, altered white-matter integrity, and early decline in cortical connectivity, mirroring patterns associated with accelerated brain aging. Collectively, these data highlight preterm birth as an initiating event for systemic inflammation, metabolic dysregulation, and cardiopulmonary decline. As such, this would suggest the need for integrated cardio-neurological surveillance across the lifespan to mitigate neurocognitive decline and decrease the risk for cardiometabolic disease.

Summary of Quality-of-Life Studies on Premature Infants

Because quality of life is a uniquely personal perception, denoting the way that individual patients feel about their health status and/or nonmedical aspects of their lives, it can only be measured by determining the opinions of patients [36]. Studies have shown clearly that having a biological impairment does not automatically translate into a poor self-assessed [36]. It is important to remember that some individuals without impairments also provide low scores for their quality of life [36]. At adolescence and young adulthood, health status and health-related quality of life were assessed by either the mother or the child.

The studies of quality of life show time and time again, that despite disabilities former premature infants report their self-reported quality of life to be very high, and in most respects, comparable to that of their term born peers. The phenomenon of high quality of life despite functional limitations has been described in other non-premature populations as “disability paradox” [36].

Effect of Social Determinants on Health Trajectories in Preterm-Born Infants

The DOHAD hypothesis posits that adverse experiences during fetal programming and the early years of development can predispose individuals to metabolic, endocrine, or cardiovascular-related diseases [2]. Crucially, this hypothesis also considers the health trajectories of mothers and the potential impacts of experiences prior to pregnancy on offspring [2]. In particular, social determinants of health, which affect day-to-day functioning and define quality of life, can amplify the biological vulnerabilities of both mother and child, exacerbating the effects of preterm birth [2]. For example, poverty in infancy is associated with reduced brain growth rates, underscoring the need for early life interventions to mitigate the combined impact of social disadvantage and preterm birth.

Education is a key social determinant of health and is strongly associated with neurodevelopmental outcomes. Higher maternal educational attainment is consistently linked with improved cognitive and academic performance in children [37], including those born preterm. These associations likely reflect a combination of factors, including differences in socioeconomic resources, health literacy, and enriched language and learning environments in the home. In children born preterm, these findings are consistent with evidence that long-term neurodevelopmental outcomes may reflect altered developmental trajectories of the brain rather than solely fixed structural injury, suggesting that postnatal environmental factors may influence outcomes.

Summary and Future Directions

Preterm birth is a major adverse early life event that has enduring implications across the lifespan of those affected. Most profoundly, prematurity impacts neurodevelopment, mental health, and cardiovascular integrity. Consistent findings across international cohorts have supported the existence of a “preterm behavioral phenotype,” characterized by elevated risks of anxiety, depression, inattention, and autism spectrum features, together with internalizing personality traits, such as shyness and behavioral inhibition. These psychiatric vulnerabilities extend into adulthood, affecting social engagement, education, job outcomes, and overall quality of life. Most notably, the persistence of these traits in individuals without neonatal brain injury highlights the broader neurodevelopmental impact of prematurity itself (Fig. 3).

Neuroimaging studies provide structural and functional correlates for the behavioral outcomes observed in those born preterm. In particular, these individuals often have reduced brain volumes, altered white-matter microstructure, and lower cortical complexity than those born at term, reflecting disrupted neurodevelopmental trajectories initiated in utero. These changes may reduce cerebral reserve, predisposing those affected to earlier cognitive decline and neurodegenerative processes, particularly when compounded by stress, poor health, or aging-related comorbidities.

Cardiovascular and metabolic outcome data further illustrate the long-term, systemic effects of prematurity. Preterm-born adults consistently show altered cardiac structure (reduced ventricular volumes), increased metabolic risk profiles, lower pulmonary function, and worsened kidney function reflected by hypertension. These changes collectively mirror patterns typically associated with aging. The detection of accelerated biological aging via telomere attrition, advanced epigenetic age, and reduced klotho expression in preterm-born individuals adds compelling molecular evidence to the narrative that early life adversity has lasting biological outcomes.

Although substantial progress has been made toward improving the survival of preterm infants, the data reviewed here argue for a paradigm shift in focus from survival to thriving across the lifespan. To achieve this goal, we endorse a lifespan-oriented model of care, encompassing early life monitoring, neurodevelopmental surveillance, and adult-focused follow-up to detect and address emerging physical and mental health vulnerabilities. Importantly, public health frameworks must begin to incorporate preterm status as a key variable when designing adult screening protocols for cardiovascular, mental, and cognitive health.

We further note that future research integrating multidimensional genomics, epigenetics, imaging, clinical, and social data will be vital for refining risk stratification and enabling precision prevention strategies. Critical to these efforts, longitudinal neuroimaging studies extending into mid- and late adulthood are needed to track the progression of structural and functional brain aging in preterm-born individuals.

Statement of Ethics

This article is a review based exclusively on previously published literature and does not involve human participants or identifiable patient information; therefore, consent for publication is not applicable.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

The authors declare no funding was obtained or used for this study.

Author Contributions

L.F.C. conceived and supervised the review. L.F.C., N.V.O., J.J., and K.N.G. contributed to the literature review and manuscript writing. N.V.O. and J.J. created the figures and tables. All authors reviewed and approved the final manuscript.