Growth in the first few months: a critical window for programming of obesity and CVD

Plausible explanations for the effects of breastfeeding on later obesity and CVD risk have included residual confounding by socio-economic, demographic and behavioural differences between infants breast- or formula-fed. However, based on the previous epidemiological evidence of an association between infant weight gain and later risk of obesity, randomised trials in infants born preterm⁽ Reference Singhal and Lucas ^{3 )}, and subsequently in infants born at term but small for gestational age (SGA)⁽ Reference Singhal, Cole and Fewtrell ^{13 ,} Reference Singhal, Kennedy and Lanigan ^{14 )}, we suggested that the benefits of breastfeeding for later risk factors for CVD may be due to slower growth and relative undernutrition in breast-fed compared with formula-fed infants: the Growth Acceleration hypothesis⁽ Reference Singhal and Lucas ^{3 )}. This hypothesis proposed that faster postnatal growth (upward centile crossing for weight or length) programmed the major components of the metabolic syndrome, including higher blood pressure, obesity and endothelial dysfunction. Furthermore, postnatal growth acceleration could also explain, in part, adverse programming effects seen in infants born SGA who show catch-up growth immediately after birth⁽ Reference Singhal and Lucas ^{3 )}.

Since this early research, more than fifty studies now support the growth acceleration concept. For instance, faster weight gain in infancy (upward centile crossing for weight) is associated with a greater risk of later obesity in more than thirty studies (summarised in five systematic reviews,⁽ Reference Baird, Fisher and Lucas ^{8 –} Reference Weng, Redsell and Swift ^{12 )} including an individual-level meta-analysis in 47 661 participants from ten cohorts⁽ Reference Druet, Stettler and Sharp ^{11 )}). This association is seen for the main components of the metabolic syndrome, in breast-fed and formula-fed populations, in high- and low-income countries representing many different ethnic groups⁽ Reference Stettler ^{7 –} Reference Weng, Redsell and Swift ^{12 )}, and is consistent for cohorts during the past 80 years⁽ Reference Baird, Fisher and Lucas ^{8 )}. The association is biologically plausible and experimentally reproducible in several animal models⁽ Reference Stettler ^{7 )}. For example, in mice faster growth during lactation, after growth restriction in the fetal period, alters the expression of several genes encoding enzymes involved in lipid/carbohydrate metabolism⁽ Reference Bol, Delattre and Reusens ^{28 )}. In fact, the idea that faster growth in early life adversely affects long-term survival (concept of grow now, pay later) appears to be a widespread, evolutionary conserved phenomenon seen across diverse animal species⁽ Reference Metcalfe and Monaghan ^{29 )}.

The association of faster early growth with adverse effects on long-term health is not confined to infants with low birth weight⁽ Reference Singhal, Embleton, Katz and Ziegler ^{5 ,} Reference Ong and Loos ^{10 )}, is evident in both infants born preterm and at term⁽ Reference Singhal and Lucas ^{3 –} Reference Singhal, Embleton, Katz and Ziegler ^{5 )}, and can be detected even as early as the first few years of life⁽ Reference Durmus, Mook-Kanamori and Holzhauer ^{20 ,} Reference Soto, Bazaes and Peña ^{30 )}. For instance, faster weight gain in infancy was associated with abdominal adiposity at age 2 years⁽ Reference Durmus, Mook-Kanamori and Holzhauer ^{20 )}, and SGA infants who showed catch-up growth (weight gain >0·67 sd score) had higher fasting insulin concentration at age 1 year than those without catch-up growth⁽ Reference Soto, Bazaes and Peña ^{30 )}. The effect of faster infant growth appears to be the greatest for central or visceral adiposity⁽ Reference Durmus, Mook-Kanamori and Holzhauer ^{20 –} Reference Demerath, Reed and Choh ^{22 )}, a key risk factor for CVD and type 2 diabetes, and, at least in the data from observational studies, is seen in adults as well as children. Leunissen et al. showed that faster weight gain in the first 3 months of life was associated with lower insulin sensitivity and HDL-cholesterol concentrations, and greater waist circumference, TAG concentrations, percentage body fat and central adiposity at age 18–24 years⁽ Reference Leunissen, Kerkhof and Stijnen ^{16 )}. These studies suggest a large effect size. For example, over 20 % of later obesity risk can be explained by the rate of infant weight gain (as reviewed⁽ Reference Singhal, Embleton, Katz and Ziegler ^{5 )}) and the relative risk of later obesity associated with more rapid weight gain in infancy ranges from 1·2 to as high as 5·7⁽ Reference Baird, Fisher and Lucas ^{8 )}.

However, despite extensive epidemiological data linking faster infant weight gain with later cardiovascular risk factors, data for an effect of growth patterns in infancy on long-term clinical outcomes are contradictory. In a cohort from New Delhi, rapid gain in BMI in the first year was associated with development of the metabolic syndrome in adulthood but (in contrast to this finding) low gain in BMI was associated with glucose intolerance⁽ Reference Fall, Sachdev and Osmond ^{15 )}. In fact, previously, faster growth over the first 2 years has been suggested to offset the adverse programming effects of fetal growth restriction and low birth weight⁽ Reference Barker, Osmond and Forsén ^{31 )}. For example, in the Helsinki and New Delhi Birth cohorts, individuals with low birth weight who had lower weight gain in the first 2 years, and upward crossing of weight centiles in childhood were noted to be at highest risk of CVD and type 2 diabetes⁽ Reference Barker, Osmond and Forsén ^{31 ,} Reference Bhargava, Sachdev and Fall ^{32 )}. These data have supported the practice of actively promoting rapid weight gain in infancy to benefit long-term health especially in countries in transition such as India where undernutrition in childhood is common and of more immediate concern.

The discrepancy in the effects of early weight gain for later obesity and CVD risk can be partly explained if different periods within the first year of life have different programming effects. Gillman noted that in the Helsinki cohort, the BMI of those who eventually developed CVD had actually increased in the first 3 months before decreasing⁽ Reference Gillman ^{33 )}. Similarly, in the New Delhi cohort, gain in BMI in the first 6 months was associated with greater BMI in adulthood⁽ Reference Gillman ^{33 )}. Recent studies have confirmed the role of weight gain in the first 3 months on programming of obesity and CVD. Chomtho et al., in a study focused on the effect of weight gain in different periods in infancy on body composition in childhood (age 11·4 (sd 3·8) years), showed that faster weight gain between 0–3 and 3–6 months (but not between 6 and 12 months) was associated with greater total and truncal fat mass in childhood⁽ Reference Chomtho, Wells and Williams ^{17 )}. Faster weight gain during a critical window in the first few months of life may therefore have adverse consequences for the risk of later NCD in diverse populations.

Experimental (randomised) evidence for growth acceleration

The concept that faster infant growth can causally impact on later risk factors for CVD is now strongly supported by randomised studies in infants born prematurely⁽ Reference Singhal and Lucas ^{3 )}, SGA at term⁽ Reference Singhal, Cole and Fewtrell ^{13 ,} Reference Singhal, Kennedy and Lanigan ^{14 )}, and in healthy term infants⁽ Reference Weber, Grote and Closa-Monasterolo ^{18 ,} Reference Inostroza, Haschke and Steenhout ^{19 )}. For example, infants born preterm randomly assigned to a nutrient-enriched diet that promoted faster weight gain in the first few weeks after birth, had higher fasting concentrations of insulin, cholesterol and C-reactive protein, as well as leptin resistance in adolescence than controls⁽ Reference Singhal and Lucas ^{3 )}. Similarly, infants born SGA at term and randomly assigned to nutrient-enriched formula that increased weight gain had higher diastolic blood pressure at age 6–8 years⁽ Reference Singhal, Cole and Fewtrell ^{13 )} and, in two trials, 18–38 % greater fat mass at age 5–8 years than controls⁽ Reference Singhal, Kennedy and Lanigan ^{14 )}. Notably, differences in fat mass or blood pressure in childhood were related to the rate of weight gain in infancy suggesting a dose–response association between early growth and later CVD risk⁽ Reference Singhal, Cole and Fewtrell ^{13 ,} Reference Singhal, Kennedy and Lanigan ^{14 )}. More recently, programming effects of infant nutrition/growth have been confirmed in experimental studies of term infants with appropriate birth weight for gestation. These effects have been seen in both high- and low-income countries (e.g. ChileReference Inostroza, Haschke and Steenhout ¹⁹ ), thereby supporting the concept that programming of CVD risk by faster early growth is a fundamental biological finding seen across populations⁽ Reference Weber, Grote and Closa-Monasterolo ^{18 ,} Reference Inostroza, Haschke and Steenhout ^{19 )}.

Central to the growth acceleration hypothesis is that fact that breast-fed infants grow more slowly than those fed formula, particularly in the first few weeks after birth and again between ages 3 and 12 months. This effect is probably because of the lower protein content of breast-milk (approximately 10 g/l compared with up to 15 g/l in some formulas), which means that formula-fed infants receive on average 0·5 g/kg per d greater protein than breast-fed infants⁽ Reference Michaelsen and Greer ^{34 )}. These differences in the rate of weight gain and protein intake between the bottle- and breast-fed infants has provided an opportunity to investigate the growth acceleration concept using randomised trials in healthy term infants.

In the largest study, the European Childhood Obesity Trial, formula-fed babies were randomly assigned to formulas with different protein concentrations and followed to age 6 years⁽ Reference Weber, Grote and Closa-Monasterolo ^{18 )}. The assigned diets were given as a standard infant formula (after the parents had decided to add formula) to age 6 months (1·25 g/100 ml in the lower protein formula v. 2·05 g/100 ml in the higher protein formula) followed by a follow-on formula to age 12 months (1·6 g/100 ml in the lower protein formula v. 3·2 g/100 ml in the higher protein formula). Consistent with an effect of protein intake on infant growth and the later risk of obesity, babies given the higher protein formula had a faster rate of weight gain in the first year, higher BMI at age 2 years, and 2·4× greater risk of obesity at age 6 years than those in the lower protein group⁽ Reference Weber, Grote and Closa-Monasterolo ^{18 )}. However, although strongly supporting the growth acceleration concept, the protein content of formulas used in this trial was much higher than those commonly used today, thereby limiting the practical relevance of this study.

Nonetheless, the possibility that a lower protein intake in the first year can reduce the later risk of obesity is strongly supported by a randomised trial from Chile in which infants of mothers with a BMI >25 kg/m², were randomised to one of two infant formulas between ages 3 and 12 months. Infants were assigned either a standard-nutrient (protein, 1·77 g/100 ml; energy, 274·47 kJ (65·6 kcal) /100 ml); or a new low-nutrient formula with much lower protein concentration than conventional formula (protein, 1·04 g/100 ml; energy, 262·76 kJ (62·8 kcal) /100 ml)⁽ Reference Inostroza, Haschke and Steenhout ^{19 )}. Compared with controls, infants given the lower protein formula had 1·8 g/d slower weight gain between ages 3 and 6 months (primary outcome) and lower BMI at age 2 years⁽ Reference Inostroza, Haschke and Steenhout ^{19 )}. However, whether these effects on adiposity persist into later life and are observed in infants whose mothers are not overweight are unknown and remain key research questions.

Overall, although five randomised studies now support a causal link between faster infant weight gain and later risk factors for CVD, several research questions remain. Four out of five previous studies are in children aged 2–8 years⁽ Reference Singhal, Cole and Fewtrell ^{13 ,} Reference Singhal, Kennedy and Lanigan ^{14 ,} Reference Weber, Grote and Closa-Monasterolo ^{18 ,} Reference Inostroza, Haschke and Steenhout ^{19 )}, (the fifth study was in adolescents⁽ Reference Singhal and Lucas ^{3 )}) and therefore the impact of growth acceleration in infancy on adult CVD risk is unknown. Furthermore, these studies have not been able to demonstrate a causal link between early growth and later visceral adiposity, a suggested intermediate risk factor by which faster infant growth increases CVD risk⁽ Reference Durmus, Mook-Kanamori and Holzhauer ^{20 –} Reference Demerath, Reed and Choh ^{22 )}. Finally, it is unknown whether there is a particularly sensitive or critical window in infancy for these programming effects and whether programming effects of infant nutrition/growth persist into adult life and amplify with age (as in animal models), or are ‘overwhelmed’ by conventional CVD lifestyle risk factors in adulthood.

Mechanisms

A major limitation of the Development Origins of Health and Disease field is a relatively poor understanding of the underlying biological mechanisms involved. Nonetheless, there has been some progress in our knowledge of the coupling mechanisms that link early nutrition/growth with later CVD. These can be grouped into four main inter-related categories.

Nutrition programming and low-income countries

Low-income countries face a massive increase in NCD. For example, in India alone, by 2030 there will be an estimated eighty million people with type 2 diabetes and Asian Indians will account for approximately 40 % of the global burden of CVD⁽ Reference Wild, Roglic and Green ^{46 )}. There is therefore an urgent need for primary prevention programmes, but whether the growth acceleration concept is relevant to low-income countries is uncertain⁽ Reference Jain and Singhal ^{47 )}. This question is particularly relevant for countries such as India which have the highest global burden of term infants born SGA, who are at higher risk of CVD⁽ Reference Barker ^{2 )}, but in whom the optimal pattern of weight gain for long-term health is not known⁽ Reference Jain and Singhal ^{47 )}.

Clearly, growth patterns in infancy are likely to have a different impact on health according to the environment in which the population lives. For instance, infants with slower weight gain may be at higher risk of infections and undernutrition and hence the overall risk–benefit may favour faster infant growth in many populations from low-income countries. However, low-income countries have very heterogeneous populations with a growing middle class at risk of long-term obesity and CVD. As in the West, faster weight gain in infancy is associated with the later risk of obesity in several middle- and low-income countries such as India, Seychelles, Brazil and South Africa⁽ Reference Monteiro and Victora ^{9 )}. In many of these countries promotion of rapid weight gain in infancy is normal cultural practice and, in order to achieve this, inappropriate addition of animal milks (including cow's milk, buffalo milk and donkey's milk) is common. Further research is therefore needed to define the risk–benefits of growth acceleration and guide infant nutrition policy in these countries⁽ Reference Jain and Singhal ^{47 )}.

Public health implications

The impact of infant nutrition/growth on future risk of NCD has considerable implications for public health and nutrition practice. For instance, there is substantial agreement, from systematic reviews and meta-analyses conducted by scientific advisory authorities (Dutch State Institute for Nutrition and Health 2005; WHO 2007; US Agency for Healthcare Research and Quality 2007; and the UK Scientific Advisory Committee on Nutrition 2011; as summarised⁽ Reference Fewtrell ^{48 )}) supporting a protective effect of breastfeeding against the risk of later obesity. Breastfeeding should therefore be promoted for its long-term as well as short-term health benefits. The strength of the evidence supporting the growth acceleration hypothesis has also led to changes in the nutritional practice. Professional bodies such as the Institute of Medicine in the USA, and the Royal College of Paediatrics and Child Health and the Scientific Advisory Committee on Nutrition in the UK have recognised the role of faster infant weight gain in increasing the risk of long-term obesity. Consequently, health care professionals are advised to prevent inappropriate upward centile crossing as well as growth faltering in infancy. The new WHO growth charts based on the exclusively breast-fed infant are likely to help in the prevention of overfeeding in infancy. Furthermore, contrary to the previous medical and public opinion, promoting catch-up growth by nutritional supplementation in healthy term infants born SGA may not be appropriate⁽ Reference Clayton, Cianfarani and Czernichow ^{49 )}.

Finally, the benefits of a slower rate of infant weight gain as seen in breast-fed compared with formula-fed infants has led to changes in infant formula to try to reduce the risk of overfeeding in formula-fed infants. These include reduction in the protein content of infant formulas and changes in recommendations for the composition of formula. For example, the European Food Safety Authority recently recommended a reduction in the maximum permitted protein content in infant formula and suggested recently that ‘infant formula and infant follow-on formula should ensure that the growth and development of infants fed infant formula are similar to those of infants who are exclusively breast-fed during the first 6 months of life’^{( 50 )}.