Premature Birth: Implications for Cardiovascular Health

Keywords:

• aorta
• developmental origins
• hypertension
• preterm birth
• risk factor

Preterm birth (i.e., delivery more than 3 weeks too early) affects millions each year and rates are increasing. In the USA alone, approximately 500,000 infants are born prematurely each year and of those, 80,000 are delivered very preterm (more than 8 weeks before the expected date). Without effective neonatal care, the number of deaths among very preterm infants would equal that of major causes of death in adults, such as Alzheimer‘s disease or essential hypertension. While mortality after preterm birth was high only decades ago, advances in perinatal medicine have resulted in almost universal survival [1] so that prematurity nowadays is shifting from being a pregnancy complication to a developmental one for a whole new generation of young people. Although this progress is well received by professionals and families, there is an increasing concern because preterm birth has been identified as an emerging risk factor for arterial hypertension [2,3], diabetes [4,5], cardiovascular disease [6] and stroke [7] in later life.

Given the associations between preterm birth and suboptimal cardiovascular health, studies of the cardiovascular system in infants, children and young adults born preterm may help to clarify underlying mechanisms and effects. Cardiac structure and function have recently been found to be significantly altered after preterm birth [8]. In young adults born preterm, the left ventricular mass was increased and the left ventricles were smaller, with reduced systolic and diastolic functions also, after taking current blood pressure into account. The effect of prematurity on left ventricular mass equaled the effect that can be associated with a 9 kg/m² higher BMI [8]. These findings are in line with animal data demonstrating that after preterm birth, the myocardium is remodeled and characterized by cellular hypertrophy and increased collagen deposition, as compared with the myocardium in offspring born at term [9].

In addition, the arterial tree develops differently after preterm birth; it stops growing and becomes significantly smaller [10]. It may not be surprising that small and preterm babies have small arteries, but if vessel size does not increase in proportion with the rest of the growing body and arterial narrowing persists, it could have implications for later risk of stroke and ischemic heart disease. In teenagers born preterm, the aortic cross-sectional area was found to be 15–20% smaller (adjusted for body surface area) than in age-matched controls born at term, an effect that exceeds that of smoking during pregnancy [11]. With aging, a slow and natural loss of intraluminal space will inevitably take place. If aortic and other arterial dimensions are already significantly reduced at the start of this process, the critical point at which blood flow will be insufficient to avoid tissue ischemia will be reached sooner than expected.

Pediatric ophthalmologists were among the first to suggest that microvascular changes associated with prematurity could be a lasting and generalized phenomenon [12]. A reduced skin capillary density has been reported in children born preterm [13] and abnormal retinal vasculature after preterm birth persists into adulthood. Such capillary rarefaction may add to increased blood pressure. Whether the microvasculature in other tissues is also altered in subjects born preterm remains to be clarified. If this is the case, it could have important implications. Muscular capillary density is a determinant of the diffusion and tissue concentration of insulin. Functional or structural loss of muscle capillaries could therefore be a mechanism that links preterm birth to later insulin resistance.

Cardiovascular regulation and control is also altered after preterm birth. Compared with their peers born at term, young subjects born preterm exhibit cardiovascular hyperreactivity [14], as well as signs of sympathoadrenal overactivity [15].

Taken together, these findings point to multiple systemic and long-standing effects after preterm birth, all of which – independent of each other or in interaction – may affect cardiovascular function, aging and disease risk later in life. But what could be the underlying causes of such effects associated with preterm birth? Genetic and/or socioeconomic contributions cannot be excluded [16]. In addition, exposure to antenatal corticosteroids for accelerated lung maturation, premature loss of placental circulation with concomitant decrease in systemic blood flow, a postnatal transition to a relatively high pressure system with increased afterload for the immature heart, a drop in IGF-1 levels (an important promotor of cardiovascular growth in fetal life), loss of placental estrogens, neonatal malnutrition, poor postnatal somatic growth, as well as feto-neonatal exposure to inflammation, and finally, oxidative and physical stress (pain) have all been suggested as potential driving forces for adverse cardiovascular adaptations after preterm birth. Given that improved neonatal nutrition and growth have been associated with a lower risk of high blood pressure at the age of 2 and a half years [17] and improved endothelial function in young adults born preterm [18], selected perinatal interventions may be one way forward towards effective cardiovascular risk reduction after preterm birth.

Reassuringly for elderly people, preterm birth was not found to be associated with increased mortality from ischemic heart disease in a historic cohort (collected before the modern era of perinatal medicine and characterized by limited and selective survival) [19]. However, current data suggest that the first adult generation surviving very preterm birth are at significant risk of cardiac events. The most obvious clinical implication of this new knowledge is that young people born very preterm need continued and tailored follow-up, taking the total cardiovascular risk factor burden into account. In particular, increased awareness among both families and professionals regarding preterm birth being a perinatal risk factor for adult hypertension is needed [2,3]. Measurement of blood pressure in children and young people born preterm is recommended in order to detect and treat hypertension in young people born preterm long before end organ damage occurs.

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.