Quality of Growth, Body Composition and Longer-Term Metabolic Outcomes

Abstract

The optimum growth and body composition of the preterm baby is unknown despite nonevidence-based opinions that this should mimic that of the full-term infant. The relationship between body composition at birth, in both preterm and full-term babies, and later cardio- metabolic outcomes is also unknown. Newborn body composition is influenced by maternal adiposity and diabetes, gestational age at birth, infant sex, and intrauterine growth restriction. Nutritional intake, breast and formula feeding, illness severity, and possibly growth velocity, are subsequent influences. It is not known whether differences in newborn body composition between ethnic groups are a consequence of genetic endowment, or intrauterine influences. Progress in this area requires funders and investigators to collaborate to establish high-quality, longitudinal cohort studies designed to have the ability to elicit causal inferences, and randomized controlled trials aiming to influence body composition that are of sufficient size to identify effects on functional outcomes at multiple time points across the life course, be generalizable across populations, and have power to detect important interactions.    

Introduction

In children and adults, higher body mass index is associated with higher risk of cardiovascular morbidity and mortality. However, risk prediction in these popula-tions is by no means precise, especially within the “normal” body mass index range, and if physical activity is not taken into account. This realization led to consideration of body composition, adipose tissue compartments and their distribution, and the ratio of adipose to lean body mass as biomarkers of risk. In infancy, the recognition that weight gain alone provides poor information about the accrual of adipose tissue and lean body mass has led to interest in body composition to guide nutritional practice. In addition, the American Academy of Pediatrics has recommended for many decades that it is desirable for the preterm infant to achieve the body composition and size of the baby born at full-term. However, although this recommendation has been repeated by many authors, whether or not this goal leads to improved long-term outcomes is unknown. Here, I will summarize knowledge of body composition in infancy, the determinants, and what is known about the relationship with functional health outcomes. I will avoid the term “low birth weight” as this is imprecise, failing to distinguish between low birth weight because of prematurity, and low birth weight because of growth restriction.

Assessing Body Composition in Infancy

A number of methods have been used to evaluate body composition in infants. These include indirect methods reliant on assumptions that vary in the strength of their applicability in infancy. These are isotope dilution studies, bioelectrical impedance, total electrical conductivity, dual-energy X-ray absorptiometry (DEXA), skinfold thickness measurements, and air displacement plethysmogra-phy. Adipose tissue magnetic resonance (MR) imaging is a direct, non-invasive method. Unlike DEXA, MR imaging is radiation-free and also enables quantifi-cation of regional adipose tissue depots, by taking serial “slice” images of the whole body, quantifying adipose and non-adipose compartments and summating them to provide an objective measure of each compartment (Fig. 1) [1]. However, infants must be still during whole-body MR imaging to avoid movement artefacts. As it would not be ethical to sedate infants for research MR imaging, the utility of this technique in infancy is limited to the early months when it is possible to use the “feed, swaddle, and sleep” technique [2].



The various methods of body composition analyses are not readily inter-changeable, and the applicability of techniques changes with age, making longi-tudinal comparisons problematic. A further difficulty in combining or comparing studies is the use of the terms “adipose tissue” and “fat” interchangeably. Adipose tissue consists of cellular membranes, predominantly protein and water, and intracellular lipid, which can be highly variable ranging, e.g. from 40% to over 90% in very obese individuals. As many authors do not provide clear definitions, it is often uncertain whether their data refer to adipose tissue, or lipid content. A further area of confusion is in the methods used to adjust adiposity for body size. This is important if comparisons in infants over time or between infants of different sizes are to be meaningful and reliably identify differences in relative adiposity. In infancy, presenting adipose tissue content as a percentage of body weight or a ratio to length is statistically unwise as the index is correlated with the denominator to a degree that changes over time. This is particularly problematic when comparing groups that differ in size, such as preterm and full-term infants. We examined the statistical validity of approaches used and recommend that in the neonatal period, adjustment of adipose tissue content is made using the denominator length3 and in later infancy, length2 [3].

Body Composition in the Neonatal Period and Infancy

Approximately 90% of third-trimester weight gain is adipose tissue, and human infants are among the most adipose of all species. Fat mass comprises around 10-15% of body weight in full-term human infants, though the range is wide, compared to about 3% in our closest primate relation, the chimpanzee. It is sug-gested that this substantial accrual of adipose tissue provides nutritional insurance, providing protection for the high energy requirement of the brain [4]. Human full-term infants experience a period of relative mandatory fasting immediately after birth, while maternal lactation is established and as colostrum is low in energy content. Thus, high adiposity of the human infant is normal and is amplified over the first 3-6 months [5, 6]. In contrast, very and extremely preterm infants miss out on third-trimester intrauterine development and are born with very little adipose tissue. This is also the case for babies who suffer intrauterine growth restriction; here, nutrition is directed towards the brain, leading to the phenomenon of “brain-sparing” and “asymmetrical growth restriction” where brain growth is sustained at the cost of somatic growth.

A number of factors influence body composition in infancy in addition to infant sex. Babies with intrauterine growth restriction have reduced adiposity. We compared adipose tissue content and distribution using MR imaging at birth and 6 weeks of age in appropriately grown and growth-restricted full-term infants [7]. At birth, adiposity was significantly less in growth-restricted infants, but by 6 weeks, they had shown complete catch-up in head growth and adiposity, but not length and weight. The highest adiposity at 6 weeks was seen in exclusively breastfed growth-restricted infant. There were no significant differences between the groups in adipose tissue distribution. We speculated as to whether adipose tissue quantity at birth is involved in the signaling of growth, especially catch-up head growth.

Maternal Phenotype

Maternal adiposity influences newborn body composition. We have shown that newborn adiposity and hepatic lipid increase across the normal range of maternal body mass index [8]. Newborn adiposity is increased in diabetic mothers [9] and amplified in early infancy even when hyperglycemia is well controlled and pre-dominant breastfeeding [10]. As the risk of offspring developing diabetes is in-creased as much as 11-fold in diabetic and obese pregnancies, data such as these indicate that these may be the initiating determinants of a lifelong trajectory lead-ing to adverse metabolic health, marked by aberrant neonatal body composition.

We studied whole-body adipose tissue content and partitioning in healthy full-term Asian Indian and white European newborn infants born in Pune, India, and London, UK, respectively [11]. The Indian babies were lighter and smaller and had similar whole-body adipose tissue content, but the distribution differed. The Indian babies had significantly greater absolute adiposity in all abdominal compartments (internal, deep subcutaneous, and superficial subcutaneous) and significantly less in the non-abdominal subcutaneous compartment. This led us to speculate that genetic determinants related to ethnicity, or intrauterine influences may contribute to higher cardiometabolic risk and marked predisposition to abdominal adiposity that is well-recognized in Indians and other south Asians. Of note, hyperinsulinemia appears to be present at birth in Indian babies [12]. Other authors have noted increased deep subcutaneous abdominal adipose tissue in Indian and Malay neonates in comparison with Indian infants [13]. Data such as these suggest that differences in body composition, in keeping with known ethnicity-related cardiometabolic disease susceptibility, are evident at birth. However, what is unknown is whether these indicate genetic differences in susceptibility, or the influence of the intrauterine environment, the extent to which differences persist as the children grow older and hence their predictive value to ethnic disparities in cardiometabolic disease in adult life.

Preterm Birth

By term, babies born preterm are significantly lighter and shorter than full-term infants. However, in our initial study comparing preterm-at-term and full-term infants, we found no significant differences in head circumference z-score or total adiposity, but a marked difference in adipose tissue distribution with a decrease in subcutaneous adipose tissue and increase in intra-abdominal adipose tissue in the former group [14]. We also showed that accelerated postnatal weight gain was accompanied by an increase in total and subcutaneous adiposity, and that the degree of illness severity while in the neonatal unit was associated with greater intra-abdominal adiposity.

Cerasani et al. [15] performed a literature review on human milk feeding, and growth and body composition in preterm infants. Their general conclusions are that most studies report that human milk feeding in preterm infants is positively associated with fat-free mass. The exception was our prespecified secondary analysis of pooled data from a randomized controlled trial in very preterm infants in which we found a predominant diet of formula compared with exclusive human milk was associated with higher lean body mass and weight, but not with Neonatal Body Composition and Long-Term Outcomes    49 greater adiposity at term age [16]. Cerasani et al. [15] also conclude that growth following hospital discharge does not appear to be associated with increased fat mass in exclusively human milk-fed preterm infants. We compared weight at term in preterm infants following surgically and medically managed necrotizing enterocolitis, in comparison to preterm infants that did not develop the disease [17]. We found that lower weight in the necrotizing enterocolitis group was due to a reduction in adipose tissue content but not lean body mass, leading us to suggest that typical preterm nutritional regimens may be inadequate to support rapid third-trimester deposition of adipose tissue. Similar findings of low fat- free mass at term in preterm compared with full-term babies have been found in a review of fat and fat-free mass from birth to 6 months [18]. Caution is advised in interpreting these studies because of variation in techniques, analytical methods, study design, and populations, and in particular as none have elucidated the relationship between body composition in infancy and later functional health outcomes.

Long-Term Metabolic Outcomes after Preterm Birth

A substantial and growing body of literature from around the world indicates that preterm birth is a risk factor for the early onset of diseases that are characteristic of ageing such hypertension, cardiovascular diseases, renal impairment, and diabetes, and are associated with altered body composition, especially intraabdominal (visceral) adiposity [19]. Life span is also reduced following preterm birth [20]. Large-scale studies and meta-analyses [21, 22] have shown that adults born preterm have higher blood pressure and risk of hypertension than their full-term counterparts with average increases of around 4.2 mm Hg for systolic and 2.6 mm Hg for diastolic pressure [22]. Though often viewed as small at an individual level, these differences equate to important risks at a population level as a 2 mm Hg increase in diastolic pressure equates to a 10% increase in mortality from ischemic heart disease and stroke [23]. There also appears to be a clear correlation between higher systolic blood pressure and increasing immaturity, and raised systolic and diastolic blood pressures have been detected in preterm born children as young as 2-3 years old. Preterm birth increases the odds of developing the metabolic syndrome (insulin resistance, dyslipidemia, central obesity, and hypertension) with alterations in atherogenic biomarkers indicative of risk to future cardiovascular health, including total cholesterol, apoprotein B and lower high-density lipoprotein cholesterol, and in insulin resistance and sensitivity, detectable in infancy [19]. Preterm-born individuals are also at significantly increased risk of type 1 and type 2 diabetes [24]. We have shown that outwardly healthy young adults born preterm have altered body composition in comparison with full-term counterparts, marked by increases in intra-abdomi- nal adiposity [25, 26]. Observations such as these have added to consideration of the possibility that body composition can be used to define risk, and responses to interventions, and to whether nutritional and other care practices in infancy might exacerbate these risks.

Evidence Gaps and Future Directions

Published literature to date is strong on associations but weak on the well- powered, longitudinal studies that are necessary to determine the predictive ability of body composition indices at a particular point in infancy, for later outcomes. The European Childhood Obesity Trial provides high-quality evidence in healthy, full-term babies, that protein intake in infancy is a causal determinant of later risk of obesity, abdominal adiposity, and renal function [27]. Equivalent data in growth-restricted and preterm infants is lacking [28]. The consequences of these knowledge gaps are that there is little to guide clinical nutritional practice. This leads on the one hand to wide variation in practice and on the other to didactic “expert” opinion-based guidelines. Both approaches engender anxiety among parents and clinicians and are dangerous for patients [28].

Descriptive studies are emerging that provide valuable reference data for in-vestigators. A few birth cohort studies, such as Growing up in Singapore [13] and the Pune Maternal Nutrition Study [12] are evaluating the early developmental origins of cardiometabolic disease. The Guangzhou Preterm Birth Cohort Study [29] will carry out body composition assessment using DEXA at ages 3, 6, 12, and 18 years in preterm children. A search of birth cohorts (www.birth- cohorts.net) on June 5th 2021 revealed no other preterm studies. Data are beginning to emerge that depict longitudinal changes in body composition [30]. However, what is urgently needed is for funders and investigators to collaborate to establish high-quality, longitudinal cohort studies designed to have ability to elicit causal inferences, and randomized controlled trials of sufficient size to identify relationships with functional outcomes at multiple time points across the life course, be generalizable across populations, and have power to detect important interactions.
 
Conflict of Interests Statement

The author reports grants outside the submitted work from the Medical Research Council, National Institute of Health Research, March of Dimes, British Heart Foundation, HCA International, Health Data Research UK, Shire Pharmaceuticals, Chiesi Pharmaceuticals, Prolacta Life Sciences, and Westminster Children's Research Fund; N.M. is a member of the Nestlé Scientific Advisory Board and accepts no personal remuneration for this role. N.M. reports travel and accommodation reimbursements from Chiesi, Nestlé, and Shire.

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