Breastfeeding has a number of short- and long-term benefits for health, but the underlying mechanisms for its effects on long-term outcomes are uncertain. One of the most widely cited advantages of breastfeeding is a lower risk of long-term obesity [¹–⁴] and cardiovascular disease [⁵–⁷], but whether these effects are due to sociobiological differences between infants breast- or formula-fed or to the nutritional composition and intake of breast milk remains controversial. Several mechanisms for the long-term advantages of breastfeeding have been proposed, but recently we suggested that these effects were a consequence of slower early growth in breast-fed compared to formula-fed infants—the growth acceleration hypothesis [⁶].

More than twenty-five studies now support the hypothesis that faster weight gain (upward centile crossing for weight) in infancy influences, or programs, a greater risk of long-term obesity [⁸, ⁹] and cardiovascular disease [⁶, ⁸–¹⁰]. This association has been seen for obesity in adults and children, in high-income and low-income countries [⁸–¹⁰] and is consistent for cohorts over the last 80 years [⁸]. The “critical window” for the effects of growth is not known, but slower weight gain in the first few weeks (regardless of gestation or birth weight) is associated with a lower risk of later obesity [¹¹, ¹²], insulin resistance [¹³], endothelial dysfunction [⁵], and adult obesity [¹⁴]. Therefore, differences in weight gain between formula- and breast-fed infants in the first postnatal weeks, when breast-fed babies often lose weight compared to weight gain in babies given formula [¹⁵, ¹⁶], could partially explain long-term programming advantages of breastfeeding [⁶].

The difference in early weight gain between formula-fed and breast-fed infants is likely to be related to differences between formula and breast milk in both the composition and volume of intake of colostrum (days 1–5) and transitional breast milk (days 6–14). In fact, in contrast to the composition of human milk which varies with the age of the infant, formula composition is constant and designed to meet the nutrient requirements for the whole of the first six to 12 months of life. However, while there has been extensive research on the nutritional composition of human milk, relatively few studies have focused on the composition and volume of intake during the first few weeks after birth. We therefore conducted a systematic review of the literature and meta-analysis of available data on the macronutrient content of human milk and the volume of milk intake in breast-fed and formula-fed infants in the first weeks of life. Such data could help our understanding of the possible mechanisms by which breastfeeding benefits long-term health and helps in the primary prevention of obesity and cardiovascular disease, and in the development of preventative strategies for obesity in formula-fed infants.

To our knowledge, this is the first meta-analysis of the macronutrient content of human milk which includes milk from early lactation. We found that, depending on number of days from birth, in the first two weeks of life, formula-fed infants have a 1.2- to 9.5-fold greater energy intake and a 1.2- to 4.8-fold greater protein intake than those breastfed. This difference is due to the higher energy and protein content of formula and a greater volume of intake which may contribute to greater weight gain in formula-fed compared to breast-fed infants during early infancy. These data are therefore consistent with the hypothesis that formula-fed infants may be overfed early in infancy during a possible critical period of growth that may lead to programming of long-term obesity [⁶, ⁸–¹⁰], and have implications for the optimal composition of infant formulas.

Ideally, the energy content of formula should be equivalent to corresponding energy content of human milk at different stages of lactation. However, formula is designed to be appropriate for the first year of life and most commercially available products have an energy density of approximately 67 kcal/100 mL, far greater than the energy content of early breast milk. We found the metabolizable energy content of mature milk (65.2 kcal/100 mL) was also slightly lower than infant formula (67 kcal/100 mL) and within the range reported by Neville (60.1 kcal/100 mL to 77.6 kcal/100 mL) [⁸²]. Similarly, in a review of 25 studies, Reilly et al. reported a mean ME of mature human milk as 63.9 kcal/100 mL [³⁹], while a doubly labeled water study demonstrated that the energy content of breast milk at five and 11 weeks was 57.4 kcal/100 mL and 59.8 kcal/100 mL, respectively [⁷⁹]. Therefore, our findings suggest that formula-fed infants could have a higher energy intake in the first six months of life and could partially explain greater weight gain in infants given formula compared to breast milk.

Along with the increase in energy density at all stages of lactation, the volume of intake of formula-fed infants was greater than those breast fed on all days analyzed and in particular in the first days of life. There are several potential explanations for this. First, it is likely that milk supply is limited in the first 24–48 hours postpartum which was confirmed by this analysis. Breast-fed infants receive approximately 25 to 100 mL per day in the first two days of life. Second, mothers of formula-fed infants may encourage finishing of the bottle even though appetite has been satisfied, hence a greater volume of intake. The capacity of the stomach of the newborn is very small in the first two days of life and increases in volume capacity after three to four days of life [⁸³].

In support of this, in a pilot study designed to test the hypothesis that a higher nutrient intake in the first postnatal week may increase later obesity risk, infants fed a lower energy formula did not compensate by consuming more volume [¹⁸]. These results are similar to that reported by Fomon et al. who illustrated that between eight and 41 days of life the volume consumed was not different between a calorically dense (100 kcal/100 mL) or calorically dilute (54 kcal/mL) formula. This leads to a greater energy intake and rate of growth in the infants consuming a more concentrated formula [⁸⁴]. It is evident that during the early weeks of life infants drink to volume, not to energy needs.

After this critical period, infants appear to regulate their volume of intake better during ad libitum feedings to meet caloric needs for growth. For instance, at about 6 weeks of age, infants fed either a calorically dilute (54 kcal/100 mL) or calorically dense (100 kcal/100 mL) formula modified their volume of intake so that energy intake was similar to that of infants fed a conventional formula (67 kcal/100 mL) [⁸⁵]. Other studies provide support for this hypothesis. Small for gestation infants fed either a standard formula (65 kcal/100 mL) or calorically dense (87 kcal/mL) formula had similar intakes by two months of age [⁸⁶].

The ability of an older infant (after 41 days) to regulate intake based on growth needs was validated by the fact that the mean weight gain between the two groups (calorically dilute and dense) during the “caloric matching phase” was nearly identical, 24.6 ± 4.6 and 24.9 ± 5.3 g/day [⁸⁴]. Interestingly, during the “early window” where infants consumed similar volumes, there was a significant difference in weight gain between infants fed calorically dilute or dense formula. Infants consuming a calorically dense formula had a mean weight gain 1.4-fold greater (29.8 ± 4.9 versus 41 ± 10.4 g/day, P < 0.01) than those consuming the dilute formula which may be explained by a greater gain in percentage fat. The overall weight gain between the two groups up to 112 days was significantly different (26.3 ± 3.8 versus 30.2 ± 5.8, P < 0.05) which appears to be due to the initial difference in the early feeding period window [⁸⁴]. Therefore, infants in the first weeks of life do not seem to compensate for getting less energy dense milk by drinking more (i.e., during the early weeks of life they drink to volume, not to energy needs). Hence, making the energy content of formula closer to that of breast milk may help reduce rapid weight gain of formula-fed infants in the critical window in the first weeks after birth.

In addition to differences in energy intake between breast-fed and formula-fed infants, protein intake varies considerably between the two groups. Protein concentration of human milk is highest during the initial, colostrum period because it contains large amounts of immunoglobulins and lactoferrin which gradually decline to relatively low levels in mature milk. However, despite this higher protein concentration, the greater volume of milk intake by formula-fed infants means that formula-fed infants have up to a 5-fold higher protein intake in the first two weeks of life compared to those breast fed, a difference which is likely to contribute to faster weight gain in formula-fed compared to breast-fed infants [⁸⁷].

This faster weight gain in formula-fed infants compared to breast-fed infants is already evident in the first week of life. In two separate studies, healthy term breast-fed infants lost a mean 6.4% to 6.6% of birth weight before starting to gain weight compared to formula fed infants who only lost 3.5% to 3.7% [¹⁵, ¹⁶]. Breast-fed infants may not regain their birth weight by eight days of life; however, formula-fed infants generally exceed birth weight at eight days of age by 50–100 g [⁸⁸, ⁸⁹].

Importantly, several observational studies have demonstrated that faster postnatal weight gain in infancy leads to increased childhood and adult overweight status [¹⁷, ⁹⁰–⁹³], hypertension risk [⁹⁴], and insulin resistance [⁹¹]. This has been shown across several different population groups including those of European [¹⁴] and Asian [⁹⁴] decent. The critical window for these programming effects is not known, but recent experimental evidence [⁹⁵] now supports observational data [¹⁴] suggesting that weight gain in the first week of life may be particularly influential for increasing the later risk of obesity. In a small pilot study, infants randomly assigned to receive a lower nutrient formula, designed to mimic the intake of the breast-fed infant for the first seven postnatal days, had lower weight and sum of skin-fold thicknesses at age six and 18 months than those given standard formula [⁹⁵]. Nutrition and growth during a critical window in the first week of life could therefore influence the long-term risk of obesity.

Limitations of this meta-analysis include the relative heterogeneity of the studies used, the small sample size of several studies, and limited data from the first few days of life. A lack of stable isotope studies to measure the energy content of early breast milk, which are difficult to perform in the first weeks of life, is another key limitation. The measurement of breast milk volume (test weighing of infants) may be less accurate than measurement of formula intake. Despite these limitations, a consistent pattern of lower macronutrient intake in breast-fed babies is supported by the data demonstrating a slower rate of weight gain in breast-fed compared to formula-fed infants.

Breastfeeding is clearly the most optimal nutrition for an infant and has major advantages for health. Although clearly it is not possible to replicate these benefits in infant formula, research should continue to strive to mimic, as close as possible, the composition and intake of the breastfed infant to provide similar health benefits to infants who cannot be breastfed. This could possibly be achieved either by reducing energy and/or protein content of formula; or by reducing the volume of intake. Volume of formula intake is more difficult to manipulate safely and could lead to hypernatremia, hypoglycemia, unintended weight loss, and undue stress on the caregiver. Infants fed formula consume larger volumes than those breast fed in the early postnatal period. Therefore, a formula designed to achieve a growth rate similar to that of the breast-fed infant would need a lower protein and energy content than that in breast milk, to compensate for the higher volume of intake.

Here we demonstrate that the energy and macronutrient content of infant formula, as well as the volume of formula intake, may be increased compared to human milk. This difference, particularly in the first weeks of life, could contribute to a faster weight gain. This provides an opportunity to modify the energy content of current infant formulas to more closely match the intake of the breast-fed infant, a strategy that could help in the long-term prevention of obesity, metabolic disease, and cardiovascular disease.

A. Singhal has received honoraria for lectures for Danone, Pfizer, Nestle, and Abbott Nutrition. A. Singhal and coworkers at University College London have developed intellectual property based on the concept of lower nutrient intake in infants during the first weeks of life.

Christina Sherry, Ph.D., RD, is acknowledged for editorial and technical assistance. This work was funded by Abbott Nutrition, Columbus, OH, USA.