The global prevalence of obesity has doubled in the last 30 years, with World Health Organization (WHO) estimates at approximately 10% in men and 14% in women [1
]. This increase has compounded an already considerable public health burden, given the wide range of diseases related to being overweight [2
], with obesity accounting for almost 7% of total healthcare costs globally [3
This heavy disease toll makes it crucial to understand risk factors related to obesity. Among these is childhood obesity, an important predictor of adulthood obesity that has itself become increasingly prevalent. According to WHO, the annual rate of increase in the prevalence of childhood obesity is 10-times that of the 1970s [4
]. Specifically, the global prevalence of overweight and obese children rose from 4.2% in 1990 to 6.7% in 2010 [5
]. These epidemiological changes have long-term implications. A review [6
] reported that overweight and obese children aged two to 17 years were over twice as likely as non-obese children to become overweight adults. Similarly, another review of longitudinal studies [7
] found that individuals who were overweight or obese during infancy were more likely to develop obesity in later childhood, adolescence and adulthood. In addition, a meta-analysis of individual-level data from 10 cohort studies conducted in Finland, France, Seychelles, Sweden, the United Kingdom (U.K.) and the United States (U.S.) also suggested a strong positive association between infant weight gain and obesity, particularly childhood obesity [8
This clear link between obesity in childhood and adulthood in turn invites questions about what influences the development of the condition so early in life. A key focus of interest and research in this area is the possibility that obesity may be programmed by changes in the expression of certain key genes (without the alteration of the genetic sequence) as a result of unfavourable environmental factors in utero and the postnatal period [9
]. These so-called epigenetic changes are in keeping with knowledge that the pre-natal phase is crucial in infant growth and evidence that maternal weight is a key risk factor [10
], perhaps by contributing to unfavourable nutrition of the foetus [9
]. Specifically, maternal obesity has been linked to increased risk of obesity for the offspring later in life [11
]. Furthermore, a systematic review of prospective observational studies that followed children from birth for at least two years found that significant risk factors for being overweight in childhood included the maternal overweight factor [12
The pre-natal influence of maternal weight in programming obesity could be compounded by nutrition in the early post-natal phase, which has also been proposed as an important epigenetic influence [9
]. Of relevance, breast-fed children are less likely than those fed on formula to experience rapid weight gain in infancy and subsequent obesity in childhood or adulthood [13
]. The lower protein content of breast milk appears to contribute to this benefit [11
]. The longer term impacts of consuming lower protein breast milk are achieved by impacting underlying metabolic programming, which in turn impacts the long-term risk of developing obesity [13
The protein content of breast milk falls from up to 2.09 g/100 kcal in the first month after birth to around 1.28 g/100 kcal at three to four months and around 1.24 g/100 kcal by nine to 12 months [13
]. By comparison, the lower regulatory limit for protein content of formula milk for children aged 0 to 12 months is 1.8 g/100 kcal in both the European Union (EU) and the U.S., with the actual protein content in formulas typically exceeding this level [13
]. The differences in the content of breast milk and formula raised the possibility that re-adjusting the content of infant formula might help prevent rapid weight gain and obesity in infancy.
This has now been demonstrated in a trial in Chile, in which infants whose mothers were overweight and who were predominantly formula-fed by three months were randomised either to lower protein infant formula (lpIF), low caloric density and probiotics included or to a currently-used formula [13
]. Those fed the lpIF had gained less weight at 6, 12 and 24 months [13
]. This result is supported by a multicentre European study where 1138 formula-fed infants were randomly assigned to receive cow milk-based infant and follow-on formula with lower or higher protein contents for a year. The lower protein intake was associated with lower weight in the first two years of life [17
]. Other studies demonstrate that the positive effect of low protein intake is persevered over time, especially in children that are genetically predisposed to become obese.
Once such study demonstrated the effect of low-protein infant formula on outcomes at three and five years of age [18
]. These findings complement those of the Childhood Obesity Project, where infants randomised to receive a currently-used formula during the first year of life had a significantly higher body mass index (BMI) and a 2.4-times higher risk of being obese at six years of age than those given lower protein content formula [19
The findings of the trial of lpIF could have major implications, particularly for countries with a significant prevalence of both maternal obesity and formula feeding. One such setting is Mexico. A review by the Organisation for Economic Co-operation and Development (OECD) reported that, in 2012, 37.5% of women in Mexico were obese, a rate exceeding that in all of the other countries considered (including the U.S., various EU countries, Australia and Canada) [20
]. This prevalence exceeds even the very high figure for Chile (30.7%), the setting for the trial of lpIF. Furthermore, a survey of infant feeding practices in Mexico between 1999 and 2006 suggested trends largely towards lower rates of breast feeding, especially among vulnerable groups, such as indigenous people [21
]. These findings suggest that preferential use of the lpIF over other formulas where mothers have stopped breastfeeding may confer significant benefits to their children, in Mexico and other settings.
Against this background, the current study used health economic modelling to investigate whether the benefits observed in the lpIF trial over a short period would translate into long-term clinical and economic advantages for the lpIF formula compared to a currently-used formula in Mexico.
If the current worldwide childhood obesity epidemic carries on into adulthood, the considerable demand this condition already places on healthcare services will increase substantially [4
]. This emphasises the importance of measures that aim to stem the increasing occurrence of obesity, and early childhood may be the best opportunity to employ these [4
]. The findings of the lpIF trial indicate a potential way of limiting the tendency to childhood obesity in a setting such as Mexico, where the risk of this condition is heightened by a high prevalence of maternal obesity and an increase in the protein intake at infancy and early childhood. Through DES modelling, our study shows that, for the children of overweight and obese mothers, reduction in weight gain through the use of the lpIF rather than a currently-used formula would result in a lower BMI in adulthood. This, in turn, would help prevent obesity-related diseases, bring about healthcare cost savings and improvements in productivity.
In considering the results of our analysis, it is important to note that the protein content of the lpIF is below the lower limit set for formula milk by regulatory authorities in the EU and U.S. This raises questions about whether restrictions on the availability of lower protein formulas remains appropriate, given the rising levels of maternal obesity and the mounting evidence of the relationships between higher protein formula intake, rapid weight gain and obesity in early life. It might also raise questions about the safety of the product. However, trial data demonstrate that there are no issues regarding the safety of the product despite the protein level being below the limit set by the regulatory authorities [45
As far as we are aware, this is the first study to use DES modelling to predict the long term clinical and health economic consequences of using lower protein content formula, such as the lpIF. Building such a model is, however, subject to various challenges. Our analysis predicts outcomes for a population in Mexico, but relies on efficacy data from the lpIF trial, which was conducted in Chile. This concern was partly overcome by the use of an individual-level model, which allowed the Mexican population characteristics to be run through a function developed from the Chilean trial data. In addition, volumetric intake was controlled in both arms of the trial. Further work is required to evaluate whether lower protein formula is associated with high volumetric intake in a real-world setting.
Other limitations of our study relate primarily to the challenges in constructing the individual-level model and the uncertainty associated with such long-term modelling. This is evident in the spread of outcomes observed in the PSA results, which indicate that in only 58.2% and 60.6% of model iterations (depending on the threshold used) is lpIF considered cost effective. One of the contributors to this uncertainty is that the modelling of BMI from infanthood through to death required the use of four functions derived from separate sources, each of which may be critiqued as to its suitability for such an application.
For instance, the function used to estimate BMI at age 17 years is derived from an analysis of Swedish data, and published meta-analyses suggest this source underestimated the impact of infant weight gain on adult BMI. Therefore, the functions derived from the Swedish data in our study were adjusted to reflect this underestimate. Further work should be undertaken to generate risk functions based on data sources more representative of the Mexican population.
The BMI trajectory from ages 18 to 49 years also has limitations. It offers advantages by distinguishing a rate of change in BMI for four groups defined by the BMI level at 18 years old. However, while this improves on current modelling approaches, which tend to assume a constant rate of weight gain per year over time [46
], it would be even more accurate if functions were developed to predict the rate of BMI change based on the individual level BMI at 18 years old. In addition, the BMI trajectory after 49 years of age is based on cross-sectional data of the current Mexican population, evidence that cannot therefore reflect different BMI trajectories across the population. The data are further limited for our purposes in that only some of sampled individuals would have been the infants of overweight or obese mothers, and all of them would have lived in a very different Mexico from the one in which our target population is growing up. By comparison, retrospective individual or grouped data would have allowed for different BMI trajectories, as modelled for the ages of 18 to 49 years. These data limitations mean that the gains in BMI that would be observed in reality in the target group during this age band have possibly been underestimated, which would lead to the underestimation by our model of the impact of lpIF on BMI levels.
Finally, our model considers the impact of BMI on health outcomes only after the age of 18 years, as no rigorous evidence was identified on the impact of BMI on health outcomes for the younger age groups. However, increasingly, findings of observational studies seem to point to early deleterious health consequences of being overweight and obesity [47
]. In addition, the model considers only the key cardiovascular impacts of BMI. Further work is therefore needed to explore the BMI-related complications for younger age groups and to extend the model to other associated diseases, including osteoarthritis and colon cancer: two common non-communicable diseases that have clear associations with being overweight and obesity [48