Background
Prematurity accounts for almost 10 % of births worldwide and 7.2 % of births in Korea with increasing tendency [
1,
2]. Despite improvements in the overall survival of preterm infants in recent decades [
3,
4], health inequalities emerge later in life in this population. Since the term “thrift phenomenon” was coined by Barker and colleagues [
5], an association between low birth weight or small for gestational age (SGA) babies and cardiometabolic problems, such as insulin resistance and increased blood pressure (BP), has been consistently demonstrated by many prospective and cohort studies [
6‐
8]. Insulin resistance plays an important role in the development of metabolic syndrome [
9].
For preterm births, the association between cardiovascular diseases and metabolic syndrome in later life has been demonstrated in several studies [
10‐
13]. In very preterm infants or extremely preterm infants, these cardiometabolic changes typically begin during infancy or school age [
14‐
16]. A cohort study from New Zealand reported that extreme prematurity and high body mass index (BMI) at age 7–8 years were significant predictors of metabolic syndrome in young adulthood [
6]. Obesity and accelerated postnatal growth during childhood were also suggested as risk factors for adverse cardiometabolic outcomes in children born with very low birthweight [
17]. However, it is not typical for children who were born prematurely to be fat or obese during childhood, even though they have cardiometabolic risks during this period [
18,
19]. So far, the association between preterm birth and cardiometabolic risks at early school age, considering adiposity and growth velocity, has been scarcely studied.
This study aimed to investigate whether there are differences in the cardiometabolic factors such as insulin resistance, fasting glucose, and systolic and diastolic BPs in early school-aged children born prematurely compared to term infants and whether these adverse cardiometabolic findings are associated with adiposity and growth velocity.
Discussion
In this retrospective cohort study, VP/VLBW infants were compared with term infants for cardiometabolic outcomes at school age, and important factors associated with outcomes such as post-discharge growth, weight, lean body mass, and fat mass were considered and adjusted. Early school-aged children who were born as VP/VLBW had higher BP, more insulin resistance, and higher fasting glucose than those who were term infants, while weight and fat mass were lower in the VP/VLBW group. Insulin resistance and BPs were consistently associated with VP/VLBW, independent of LMI, FMI, and weight-for-age z-score change, as shown in all three models in the multivariate analysis. The weight-for-age z-score change from the neonatal period to school age was not associated with BPs but did have a significant correlation with insulin resistance and fasting glucose in the multivariate analysis.
Patterns of growth, as well as alterations in adipose tissue, were different between SGA infants and preterm infants. Previous SGA studies have reported that these infants had less adipose tissue at birth, becoming similar after the neonatal period [
23], and a higher fat distribution was observed in childhood and adolescence [
24,
25]. However, for the preterm infants, lower BMI and fat mass were frequently seen in infancy and school age compared with term infants [
26,
27], even though they had higher BMIs and fat mass with adverse cardiometabolic outcomes in adulthood [
28‐
31].
Although the interaction between obesity and insulin resistance is a key pathogenesis factor in the development of metabolic syndrome [
32], cardiometabolic problems in preterm infants at school age have been reported, despite a lower BMI during this period [
15,
33]. In the present study, to elucidate the effect of body composition more clearly, fat mass and lean body mass were measured and adjusted, and the results showed that preterm birth was associated with increased BP, fasting glucose, and HOMA-IR, independent of LMI and FMI (Models I and II).
Moreover, as catch-up growth is an important factor in the development of insulin resistance [
34], weight-for-age z-score change until school age was considered and adjusted, and it was found to be associated with insulin resistance. The weight-for-age z-score was much lower in preterm infants at discharge compared to term infants, with a subsequent increase by early school age, resulting in a higher weight gain velocity in preterm infants in this study, even though the weight-for-age z-score was still lower than that of term infants at 6–8 years of age. As with SGA infants [
35,
36], preterm infants experienced the development of insulin resistance during rapid weight gain [
37].
To explore the role of weight gain velocity in the development of a cardiometabolic problem, a third multivariate analysis was conducted. In Model III, the weight-for-age z-score change was additionally adjusted for and the results showed that preterm birth was associated with HOMA-IR, and systolic and diastolic BP. Fasting glucose was no longer associated with preterm birth and the coefficient of preterm birth for HOMA-IR became smaller than in the first two models, while the coefficient of preterm birth for systolic and diastolic BP was similar or higher compared with the other two models. These interactions of the weight-for-age z-score change with other confounding factors and cardiometabolic outcomes suggested that glucose and insulin metabolism could be mediated by weight gain velocity in preterm infants.
In contrast, while higher BPs were associated with preterm birth in the three multivariate models, the weight-for-age z-score change was not associated with BPs at school age in the multivariate analysis. Although the mechanisms of elevated BP in children born prematurely are not fully understood, impaired development of the glomeruli with decreased nephrons, microvascular growth arrest, and sympathoadrenal overactivity might be contributing factors [
14,
38,
39]. These conditions were associated with preterm birth and related morbidities during a neonatal intensive care unit stay, rather than the pattern of growth beyond the neonatal period. However, the influence of weight gain velocity on increased BP should not be ignored because a longitudinal cohort study from the UK showed that growth gain velocity from 1 year of age until adolescence was correlated with systolic and diastolic BP [
40].
When preterm infants were further categorized according to their growth velocity, cardiometabolic factors were consistently higher in the preterm infants with improved growth group, compared to term infants with negative growth. However, there were no differences in the HOMA-IR and fasting glucose levels between the term infants with or without positive growth and the preterm infants with negative growth, and fasting glucose was lower in the preterm infant group with negative growth than in the group with positive growth. Interestingly, systolic and diastolic BPs were higher in both preterm infant groups, regardless of growth velocity after discharge, than in the term infants with negative growth and there were no differences in the systolic and diastolic BPs between the two preterm groups. Notwithstanding the small sample sizes used for these subgroup analyses, they did demonstrate an impact of the growth pattern in preterm infants on adverse cardiometabolic findings, as shown in the multivariate analysis.
There are several limitations to our study. A relatively small patient population was analyzed, and the growth velocity of the early post-discharge period, such as the time between discharge and 1 year of age, was not compared. Also, the fat mass was not measured by dual energy X-ray absorptiometry (DEXA). However, bioelectrical impedance analysis is a useful method for estimating body composition and has been used in both clinical and research fields in the pediatric population [
41,
42]. The aforementioned New Zealand Very Low Birth Weight Study also used bioelectrical impedance as a method to measure fat mass [
6].
Conclusions
In this study, VP/VLBW was found to represent an important risk factor for elevated BP at 6–8 years, independent of weight, fat mass, and growth velocity after discharge. VP/VLBW, as well as growth velocity, was also related to increased insulin resistance at 6–8 years. Despite the low weight and low fat mass, children born prematurely may be at a higher risk for increased BP, and VP/VLBW infants with greater weight gain after discharge may be at risk of insulin resistance during early school age. Further studies are required to investigate the growth pattern of VP/VLBW infants, including detailed fat distribution, to determine an appropriate growth in this population to minimize the risk of adverse cardiometabolic outcomes.
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