Is very preterm birth a risk factor for adult cardiometabolic disease?

Summary

The first infants to experience modern pre- and neonatal care are now in their thirties, an age at which the incidence of cardiometabolic disease is low. However, data from cohorts born preterm prior to the introduction of modern care suggest an increased risk of type 2 diabetes. For young adult cohorts of former very small or very preterm infants, there is accumulating evidence of increased risk factors for later cardiovascular disease, including higher blood pressure, lower lean body mass, impaired glucose regulation, and perhaps a more atherogenic lipid profile. Regarding lifestyle, adults born very small or very preterm undertake less non-conditioning physical activity and may have a lower intake of fruit and milk products. Any intervention reducing risk factors, in particular blood pressure and low physical activity, would have a substantial potential to reduce the lifetime disease burden in small preterm infants. There are now enough data to warrant an expert evaluation of the level of evidence for cardiometabolic disease in individuals born very small or very preterm, which has possible public health implications.

Introduction

Along with improvements in prenatal and neonatal care from the 1970s onwards, the long-term outcomes of the tiniest and most immature infants have received increasing attention. A number of neonatal centres have established follow-up programs and cohorts of survivors born very small or very preterm who are now in their twenties or thirties. Much of the initial focus of these follow-up studies was on outcomes in which the increased risks were immediately obvious, such as neurodevelopmental, respiratory and growth-related outcomes. Parallel to this, early life origins of chronic adult disease have attracted considerable research interest in the public health domain. This interest originally arose from observations linking small body size at term birth with increased rates of cardiovascular disease and type 2 diabetes in adult life. Together with experimental animal research, this led to the Developmental Origins of Health and Disease (DOHaD) theory, which suggests that conditions at specific sensitive developmental periods ‘program’ an individual's cells, tissues and organs in ways that lead to altered function throughout life to adjust to prevailing environmental conditions [1], [2]. Altered function, then, may appear as increased risk for chronic disease. Although birth weight can only be thought of as a surrogate of the early environment, it does predict chronic disease, shown in cohorts born mostly at term with a birth weight distribution similar to that in the general population. Regarding the lower extremes of birth weight, it is natural to assume that the highly abnormal environment small preterm infants experience in neonatal intensive care, and some also in utero, would predict altered risk for disease. Recent research bringing together the preterm follow-up and DOHaD fields has shown that this indeed is true; risk factors for cardiometabolic disease are higher in subjects born very preterm.

Our aim is to review current knowledge on risk factors for key cardiometabolic diseases in people who were born very small or very preterm. Those diseases and conditions include cardiovascular disease (e.g. coronary heart disease and stroke), type 2 diabetes and the metabolic syndrome. Bone health is reviewed elsewhere in this issue (Roberts and Cheong, Chapter 8). We begin by discussing the scanty evidence on hard disease outcomes; our focus is then on risk factors because these diseases manifest only late in life. Our style is narrative: systematic accounts exist in recent meta-analyses on systolic blood pressure [3] and components of the metabolic syndrome *[4], [5] and systematic reviews on the overall adult outcome after preterm birth *[6], [7]. We discuss possible mechanisms that may underlie the findings, their meaning in the prevention of disease, and future research directions. We focus on physiological and lifestyle risk factors, as psychological and mental health outcomes are reviewed elsewhere in this issue (Anderson, Chapter 3; Johnson, Chapter 5). However, it is of note that although some psychological characteristics may confer increased risks of disease, other characteristics such as the personality trait of conscientiousness [8] may actually be associated with a healthy lifestyle. We focus on adults born either very small or very preterm, which in different studies may be defined as very low birth weight (VLBW; <1500 g), extremely low birth weight (ELBW; <1000 g), very preterm (VP; <32 weeks) or extremely preterm (EP; <28 weeks). Studies on adults born moderately preterm are scarce and remain outside the scope of this review. However, the few published studies suggest similar but moderately higher cardiometabolic risk factors among these adults [9], [10], [11], [12], [13], [14], *[15]. As moderately preterm birth is much more common than very preterm birth, even weaker risks may be equally important on a population level.