ReviewIs very preterm birth a risk factor for adult cardiometabolic disease?
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.
Section snippets
Preterm birth and adult cardiometabolic disease – is there any hard evidence?
The first generations of very small or very preterm infants that have benefited from modern perinatal intensive care have not yet reached old age and there are so far few published data on ‘hard’ cardiometabolic disease outcomes. Circumstantial evidence is provided by a number of studies in older adults. Most of these studies focus on type 2 diabetes (Table 1). Although each study uses a different method to identify subjects with diabetes, the increased risk of diabetes in those born preterm is
Body composition
As discussed by Roberts and Cheong in this issue (Chapter 8), adults born very preterm are shorter and have lower bone mineral density than their counterparts born at term. Lower body mass index is seen in some *[18], [19] but not all [20], [21] studies. Relatively few adult studies have assessed body composition. The Helsinki Study of Very Low Birth Weight Adults (HeSVA) used dual X-ray absorptiometry, and found that VLBW adults had lower lean body mass than controls [18]. This is consistent
Blood pressure
The association between VP birth and higher blood pressure in adult life has been extensively replicated *[3], *[4], *[18], [24], [25], [26], [27], [28], *[29], [30]. A recent meta-analysis, which included studies focusing on survivors born small or preterm, with any degree of prematurity, concluded that the mean difference between adults born preterm and controls was 4.2 mmHg for systolic and 2.6 mmHg for diastolic blood pressure [4]. Another meta-analysis reported a comparison of VLBW or VP
Glucose tolerance
We showed in the HeSVA that young adults born at VLBW have higher blood glucose and insulin concentrations after an oral glucose tolerance test (OGTT) than their peers born at term [18]. The difference was not attributable to the VLBW adults' lower lean body mass. Together with previous findings in prepubertal children born at ≤32 weeks, our preliminary findings by an intravenous glucose tolerance test suggested that the difference in glucose tolerance is due to reduced insulin sensitivity,
Plasma lipids
A recent meta-analysis concluded that adults born preterm have low-density lipoprotein (LDL) cholesterol concentrations 0.15 mmol/l higher than controls [4]. This result was driven by previously unpublished data from one of the cohorts. Although many of the individual studies in VLBW adults have reported no differences in standard lipid measurements [18], higher LDL and total cholesterol were reported in adolescent boys but not girls born at <34 weeks of gestation (M. Sipola-Leppänen et al.,
Lifestyle
Healthy lifestyle is central in preventing cardiometabolic disease. Although we are unaware of any lifestyle intervention studies specific to adults born preterm, there is little reason to expect that the benefits of lifestyle changes would not be similar to the general population with a similar lifestyle. There is, however, increasing evidence that lifestyle at baseline is different between adults born very preterm and their peers born at term. As individuals with a high-risk lifestyle have
Physical activity and fitness
Physical activity is effective in reducing the risks associated with high blood pressure and impaired glucose regulation. Accumulating observations, summarized in Table 2, suggest lower degrees of physical activity and physical self-confidence in adolescents and adults born VP [20], [47], [48], *[49], [50], [51]. The differences are substantial, with up to 68% lower energy expenditure in VLBW as compared with control adults [49], and specific to conditioning physical activity, which means
Diet
Although nutrient intake is closely related to cardiometabolic risk factors, it has been relatively little studied in adults born preterm. In HeSVA we showed by 3-day food diary that VLBW adults consume less fruit, vegetables and berries than controls [53]. Low consumption of fruit is associated with high blood pressure and cardiovascular disease and was ranked by the Global Burden of Disease Study as the fifth most important factor causing worldwide disease burden – more important than
Sleep
The amount and quality of sleep is closely related to cardiometabolic risk factors [56]. VLBW adults report more sleep-disordered breathing [57]. This may be related to adenotonsillar hypertrophy or the anatomy of the pharynx, as they are also two-fold more likely to report a history of adenoidectomy [58]. A more detailed assessment of sleep-disordered breathing would require polysomnography which has to our knowledge not been used in this context. However, a study using accelerometry reported
Smoking and alcohol use
Some [61], [62], although not all [63], studies suggest that adults born VLBW smoke less often than their peers born at term. This difference is at least in part driven by lower smoking rates in VLBW adults with a history of bronchopulmonary dysplasia [64]. Use of alcohol, in particular getting drunk, is also less frequent [61], [62], [63]. These lower rates may be one sign of a general propensity for cautious and less risk-taking behaviour, which among other benefits may also protect from
Are risk factors for cardiometabolic disease different according to the aetiology of preterm birth?
Frequent and often overlapping reasons for medically indicated preterm delivery include intrauterine growth restriction, usually indicated by being born SGA, and maternal pre-eclampsia. Both conditions are, per se, associated with cardiometabolic risk factors among offspring born at term [1], [2], [65]. A general conclusion of most [5], but not all [9], [24], studies of preterm survivors is that these conditions have remarkably little effect on risk factors for disease, including body
Neonatal nutrition and growth
Postnatal events during infancy may play a role in the development of cardiometabolic risk. As recently reviewed, there are no published studies assessing the effects of neonatal nutrition on adult cardiometabolic risk [5], and the few existing studies in children and adolescents show mixed results. In the absence of nutritional data, growth has been used as a surrogate measure of neonatal morbidity and nutrition. These associations are also inconsistent [5]. Blood pressure may, if anything, be
Identification of risk and protective factors requires analysis of pooled data
In terms of prevention, it would be important to identify subgroups of adults born very preterm with particularly high risks of cardiometabolic disease, or subgroups characterized by protective factors. The subgroups could be characterized by intrauterine or postnatal growth, as outlined above, or by complications of prematurity or treatments such as neonatal nutrition or antenatal corticosteroids. Knowledge is thus far very limited. Single follow-up studies usually have limited power to assess
Conclusions
There is now compelling evidence that adults born very small or very preterm have increased risk factors for later cardiometabolic disease. These risk factors include physiological ones such as higher blood pressure, lower lean body mass, impaired glucose regulation, and perhaps a more atherogenic lipid profile, and also lifestyle factors such as low rates of physical activity and a less healthy diet. Any intervention reducing these risk factors would have a substantial potential to reduce the
Conflict of interest statement
None declared.
Funding sources
None.
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