Early Nutrition and Its Effect on Growth, Body Composition, and Later Obesity

Author(s):
Jack Ivor Lewis, Sophie Hilario Christensen, Anni Larnkjær, Christian Mølgaard, Kim F. Michaelsen

Introduction

Nutrition and feeding practices in early life are crucial determinants of short- and long-term health. It is well established that breastfeeding is protective against infections during this period [1, 2]. Furthermore, it is increasingly understood to influence the growth and development of an infant, with early growth in itself uniquely associated with the development of later body composition, metabolic health, and quality of life. As with previous editions of this chapter, we have continued to find the body of literature available to us for summarizing early nutrition research of the past 12 months increasing in both size and quality. Not only have we seen a steady but welcome shift towards studies focusing on mechanistic understanding, but also a broader advance in analytical techniques (both statistically and in the lab). Of particular note is the seminal perspective article from Christian et al. [3] stressing “The Need to Study Human Milk as a Biological System,” which undoubtedly has and will continue to shape the future of breastfeeding research. For this review we considered two stages of early nutrition: breastfeeding and complementary feeding, and how components of each associate with growth and development through infancy and childhood. We performed a non-systematic literature search using PubMed with the terms “breastmilk [or] human milk [or] complementary [and] growth [or] body composition” published between July 1, 2020 and June 30, 2021. Of 984 search results, publications were chosen for inclusion based on their quality, novelty, and/or contribution to further understanding in their field. Those selected have been divided between four categories – three papers each under the categories of “human milk hormones and growth,” “human milk and body composition,” “human milk oligosaccharides and growth,” and “complementary feeding and risk of overweight.”

Human Milk Hormones and Infant Growth

Human milk composition differs by maternal BMI in the first 9 months postpartum

Comments: Comments on this article are incorporated in the comments on the following article by Galante et al.


Growth factor concentrations in human milk are associated with infant weight and BMI from birth to 5 years

Comments: Victora et al. [4] stated that breastfeeding probably reduces the risk of overweight and diabetes later in life. Since then, more studies have examined these associations and the specific mechanisms that might be responsible for them. It is possible that specific human milk (HM) components, such as macronutrients and bioactive molecules, influence early growth by altering either adipose tissue deposition directly or by regulating infant milk intake. One of the main challenges in this field of research is the interaction of multiple factors involved in the development of overweight and obesity risk. Addressing this, Bode et al. [5] described the “mother-infant triad,” highlighting the interplay between maternal factors influencing HM composition and HM components influencing infant outcomes. The need to evaluate this triad as a biological system rather than certain aspects, for example specific nutrients, was also presented by Christian et al [3]. We have chosen three studies that investigate this triad of maternal determinants of HM components and the influence on infant growth, which makes these papers especially interesting. The study by Sims et al. investigates how maternal overweight influences HM macronutrients and hormones, and how these affect infant growth outcomes. They included 174 mothers, where 86 were overweight/obese and 88 were normal weight. Milk samples were collected at eight time points during the first 9 months postpartum (0.5, 1, 2, 3, 4, 5, 6, 9 months) and were analyzed for macronutrients as well as leptin, insulin, and C-reactive protein. Infant growth and body composition were measured at all time points and maternal body composition around 10 weeks of gestation. Infant milk intake was derived from infant weights before and after a single feed, in combination with a 3-day weighed food record, making it possible to estimate daily intakes. Firstly, the authors found that overweight/obese mothers compared to normal weight mothers had higher HM concentrations of fat at 6 months, and protein at 5 and 6 months. Secondly, HM leptin concentrations were significantly higher for overweight/ obese mothers at all time points, and HM insulin and C-reactive protein concentrations were higher at some of the time points. This indicates that maternal adiposity affects milk composition, making the milk more energy dense and with higher concentrations of appetite-regulating hormones (ARH). These effects were still present when adjusting for infant daily intakes such that daily intakes of fat and protein and these hormones were also higher by infants of overweight/obese mothers. When looking at how these components affected the infants, the authors report contrasting results. Protein and leptin intakes were positively associated with length-forage z-scores (LAZ), although effect estimates were only 0.05 per g/100 mL and 0.24 per g/mL for protein and leptin, respectively. Fat intake was negatively associated with weight-for-age z-scores (WAZ), whereas protein intake was positively associated with WAZ. This suggests that associations between maternal BMI and infant growth may be mediated, to some degree, by HM composition. As maternal weight status influenced macronutrient concentrations, they also investigated growth outcomes between the two groups. They found that the positive association between protein intake and LAZ and WAZ was only seen in the infants of overweight/obese mothers and not in infants of normal weight mothers. Lastly, the authors also found protein intakes negatively associated with both infants’ fat mass index (FMI) and, to a lesser extent, fat-free mass index (FFMI), indicating that HM protein affects both fat mass (FM) and fat-free mass. Another study investigated whether maternal plasma hormones or maternal body composition predicts HM hormones [6]. They found that both plasma insulin, leptin, and adiponectin concentrations at 1 month were all positively associated with their respective HM concentrations. Furthermore, they report that maternal FM was positively associated with HM insulin and leptin, which strengthens the findings by Sims et al. However, maternal FM was not indexed for height, which may have contributed to these findings. Lastly, the study only included a small group of participants (n = 25), thus power is reduced and further studies are needed to confirm the findings. The study by Galante et al. investigated whether concentrations of metabolic hormones in HM are associated with infant growth beyond the first year of life. They included 501 mother-infant dyads, of which 391 were followed up at 5 years. HM samples were collected around 2.6 months postpartum and analyzed for leptin, adiponectin, insulin-like growth factor-1 (IGF-1) and cyclic glycine-proline (cGP). Anthropometrics were measured at 13 months and at 2, 3, and 5 years. Multiple regression analyses showed that HM IGF-1 was positively associated with weight at 13 months, but negatively associated with weight at 3 and 5 years. Furthermore, higher HM IGF-1 was also associated with lower weight gain from birth to 5 years. HM cGP was also negatively associated with weight at 13 months and with weight z-score across all time points. IGF-1 is one of the main growth factors in childhood. The authors suggest that HM IGF-1 might affect infant endogenous IGF-1 production, thus altering the observed association with infant growth. These associations were not investigated in this study but may be important when trying to understand the influence of total IGF-1 on early growth. The authors report no significant influence of HM leptin and adiponectin on infant growth outcomes. The growth outcomes in this study included weight, weight gain, and BMI z-score, which the authors argue are the primary predictors for childhood obesity. However, other studies have recently suggested that relative adiposity is more important when assessing risk of childhood obesity (see section on body composition). Fat mass estimation would give the authors an opportunity to define how early adiposity is associated with timing of adiposity rebound and the risk of overweight at 5 years. It has long been discussed whether HM bioactive components such as hormones are absorbed in the infant gut, affecting infant outcomes. Galante et al. discuss that a possible mechanism could be that HM markers affect the endogenous production of IGF- 1, for example, and thereby affect infant growth. For future studies, it is therefore important to collect both HM samples and infant blood samples to investigate the interplay between HM and blood markers, which might have a synergistic effect on infant growth. In addition, it could be interesting to investigate whether maternal levels of IGF-1 and other bioactive components predict infant levels via programming mechanisms in pregnancy or through milk composition and breastfeeding.

Appetite-regulating hormone trajectories and relationships with fat mass development in term-born infants during the first 6 months of life

Comments: The study by de Fluiter et al. investigates how infant endogenous production of the ARH leptin, ghrelin, and peptide tyrosine-tyrosine (PYY) are related to infant adiposity (FM%) and HM macronutrients. They included 297 infants, examined at 1, 3, and 6 months of age. Infant anthropometrics and body composition measured by PeaPod were collected at all three time points, whereas blood samples were collected at 3 and 6 months (n = 184) and HM samples (hind milk) were collected at 3 months only. Their main finding is a positive correlation between plasma leptin and FM% at both 3 and 6 months. Furthermore, they report increasing ghrelin and decreasing leptin and PYY from 3–6 months, and did not find any association between plasma ARH and HM macronutrients. The use of raw correlations and stratification may be a limitation due to sample size losses. Adjusting for relevant covariates in a modelling approach would give increased power to their analyses. It could have been relevant to analyze ARH in 

HM as well, to investigate whether intake of HM leptin can predict plasma leptin levels in infants, as discussed in the Galante et al. paper. This study also reported differing hormone concentrations between infant sexes. At 3 months, plasma leptin levels were higher in girls compared to boys, but this difference had diminished at 6 months. Furthermore, leptin was associated with change in FM% from 1 to 6 months, but only in girls. Sex differences in HM composition has gained much attention over the past years and the literature review by Galante et al. summarizes six human studies that investigates this [7]. The results were inconclusive as one study reports higher HM energy content for males, but another study reports higher energy content for females. It could have been interesting to examine sex differences in HM composition in the present study. A key limitation of breastfeeding research is the lack of randomized controlled trials. However, ethical limitations mean that high-quality observational studies investigating the influence of breastfeeding on long-term outcomes are necessary. The papers referenced above are examples thereof, with a strong longitudinal design and several follow-ups. Sims et al. measure participants at eight time points, which strengthens their statistical inferences. Galante et al. includes four time points, but the follow up period of 5 years makes it possible to investigate infant growth over a longer timeframe. When reading these studies, it is clear that there is a need for new studies that collect and combine data on both maternal blood and body composition, HM samples, infant milk intake, infant blood, and growth as suggested by Bode et al. [5] and Christian et al. [3]. Furthermore, it could be relevant to include women already in pregnancy and follow them up through lactation. Whether or not effects seen in infants are caused by programming mechanisms in pregnancy or caused directly from ingested HM components cannot be investigated without combining the above-mentioned data.  

Human Milk and Body Composition

Longitudinal human milk macronutrients, body composition and infant appetite during early life

Comments: The period of growth from birth to 2 years is characterized by windows of developmental plasticity, within which differential growth patterns may confer programming effects on later adiposity and health [8]. Growth trajectories in this period have thus been associated with later risk of overweight and metabolic health [9–11]. Much of the research investigating these sensitive periods of development have relied on homogenous measures of ponderal growth, such as BMI and weight-for-height, due to measurements being more easily taken or more readily available from existing records [12]. When separating total mass into fat and fat-free tissues, we gain a more nuanced perspective of the relationship between early growth and later health. At the same time, it is of great interest to understand the determinants of these tissues’ development in early life. As the sole source of nutrition for an exclusively breastfed infant, variation in HM composition is an interesting area of investigation in relation to growth and later health. Differences in the rate and nature of growth between formula- and breastfed infants are fairly well characterized [13], but we are only just starting to tease apart the effects of variations in HM composition itself on growth and development, while also recognizing its constituents do not act in isolation [3]. Previously, de Fluiter et al. had reported that accelerated adiposity development (FM% SD score) in the first, but not second, 6-month period of life was associated with FM% at 2 years [14]. In the present paper, they investigate associations between HM macronutrients and the development of infant body composition, both measured longitudinally.

Healthy, term-born infants (n = 133) who were exclusively breastfed for 3 months were included from the Sophia Pluto birth cohort study, with anthropometry and body composition assessment at 7 follow-up visits: 1, 3, 6, 9, 12, 18, and 24 months. Adjusted linear regression models showed that HM fat and energy concentration at 3 months, but not 1 month, were associated with FM% at 6 months. This is particularly relevant given the proposed critical window of adiposity programming at 0–6 months and suggests that HM fat and energy content may contribute to accelerated fat accretion during this period. These associations are lost by 2 years, where FM% lost association with any HM macronutrient. This was perhaps surprising, given their previous study found higher FM% gain at 1–6 months was associated with higher FM% at 2 years [14], but highlights the complex interaction between HM components and body composition that likely has multiple effect pathways. The age-specific association is similar to that seen when comparing HM-fed with formula-fed infants, with accelerated fat accretion in the early months followed by a slow down to 2 years, when FM% is often lower in breastfed infants. A large study (n = 614) from 2016 also investigated HM macronutrients, similarly from hind-milk samples, on infant growth and body composition [15]. Results from the study indicate inverse associations between HM energy and fat% at 4–8 weeks, and BMI/adiposity gain from 3 to 12 months. These contradictory outcomes highlight the need for further investigation but also for standardized measurement procedures, both of HM analysis and body composition assessment. HM fat and energy concentrations were positively associated with abdominal subcutaneous fat, whereas HM protein concentration was negatively associated with abdominal visceral fat. This brings into question the contribution of HM composition and breastfeeding practices in general towards the development of visceral and subcutaneous fat depots. This question has since been investigated using the same ultrasound technique, in which the author suggests a differential regulation of these abdominal fat depots in breastfeeding infants [16]. A great strength of this study was the method of body composition assessment, with PeaPod and DXA used at 1–6 months and 9–24 months, respectively. At 6 months, body composition was measured by both techniques on a subsample and showed strong agreement. Interestingly, the use of a vacuum cushion was necessary during DXA scanning to achieve this. The same group previously reported the promising vacuum cushion results in detail [17], which highlighted the potential of DXA scanning in an age group typically unsuited to its requirements. The study went further still, assessing abdominal adiposity using ultrasound. This fat depot is that most associated with adverse metabolic profiles, likely mediating the association of BMI [18– 19]. The relatively large sample size and longitudinal perspective of both HM and body composition assessment further drew us towards the study. The fact that from 1 to 3 months HM protein and energy concentrations reduced, while fat and carbohydrate tended to, supports the use of longitudinal sample collections through lactational stages to avoid false inferences.

Human milk glucocorticoid levels are associated with infant adiposity and head circumference over the first year of life

Comments: Comments on this article are incorporated in the comments on the following article by Gridneva et al.

Human milk immunomodulatory proteins are related to development of infant body composition during the first year of lactation

immune factors, and bioactive component, which have been associated with aspects of infant growth [20], but to a lesser extent with specific fat and fat-free tissue accretion. These two studies have come from the same Australian cohort, where the group has investigated the association between non-nutritive HM components with the development of body composition. It is important to note the relatively small sample sizes; n = 18 and n = 20 for Pundir et al., and Gridneva et al., respectively, but 

they remain interesting explorations and valuable for informing the design of future studies. It is for the high quality of the HM sampling protocol, as well as the novelty, for which these papers were included. Pundir et al. investigated the association of HM concentrations of glucocorticoids, cortisol, and cortisone, with infant adiposity up to 1 year. Their impact on growth has been investigated previously [21], but the effect of HM glucocorticoids on body composition are not well understood. Gridneva et al. investigated body composition in relation to HM immunomodulatory proteins (IMPs): lysozyme, lactoferrin, and secretory immunoglobulin A (sIgA). These IMPs confer critical benefits to the infant during the breastfeeding period, with antibacterial properties and effects on nutrient absorption and gut maturation [22–25]. However, their impact on infant body composition is undefined and the findings herein are the first reported. As both studies come from the same cohort, there is an overlap in participants and methodologies.

Infants were healthy and term-born singleton births, exclusive breastfeeding was maintained until 5 months, and 83% of mothers continued breastfeeding until 12 months. Bioelectrical impedance spectroscopy (BIS) was used to estimate infant body composition longitudinally at visits 2, 5, 9, and/or 12 months after birth. Although BIS has limitations in infants, attention was paid to the choice of equation used to derive body composition estimates. Gridneva et al. additionally included ultrasound skinfold measurements, a technique previously validated against BIS by the same group [26]. HM samples were taken at the same clinic visits, with pre- and post-feed samples collected and combined for analysis. For IMPs only, 24 h test weighing was used to estimate calculated daily intake (CDI). Cortisol, cortisone, and the cortisol:cortisone ratio remained constant across lactation, adding to our current understanding of HM glucocorticoid dynamics. In mixed model analysis, FM% was positively associated with HM cortisol concentration and the HM cortisol:cortisone ratio throughout the first year, but not with HM cortisone. The fact that glucocorticoid measures were not associated with infant weight, height, or BMI support an effect on body composition specifically. It is also interesting that HM cortisol, but not cortisone, showed a positive relationship with maternal height and BMI. This novel finding may indicate a degree of signaling from the mother, as suggested in recent studies looking at maternal stress and cortisol [27]. Unlike the glucocorticoids, no association was found between maternal characteristics and HM IMPs, neither as concentrations nor CDIs. Underlying infection may alter HM sIgA concentrations [28], but other determinants of these HM IMPs are not widely characterized [29]. There was no association reported between HM IMP concentrations and infant body composition (after adjustment). However, this study used CDIs to investigate the true IMP doses to infant. Concentrations increased across lactation, allowing CDIs to remain constant throughout the first year as complimentary foods begin to replace HM.

Lactoferrin CDI was inversely associated with FFMI when estimated by ultrasound skinfold measurements at 4 sites (US4SF), but not 2 sites (US2SF) or BIS. If lean tissue accretion is somewhat inhibited by lactoferrin, it is important to understand the mechanisms if we pursue lactoferrin supplementation in infant formula. Lysozyme CDI was positively associated with infant adiposity (FM and FMI). The lysozyme concentration in HM has previously been reported to increase infant weight gain [30]. Lysozyme CDI at 12 months was also associated with a larger FFMI decrease between 5 and 12 months. It becomes difficult to untangle the differential associations with body composition according to measurement technique, but this leaves great opportunity for future studies with more precise tools such as the Pea-Pod or DXA, as used by de Fluiter et al. Nonetheless, these exploratory findings suggest that IMPs, lactoferrin, and lysozyme in particular may be an interesting avenue of investigation for understanding determinants of body composition in breastfeeding infants.

Human Milk Oligosaccharides and Growth

Human milk oligosaccharide concentrations and infant intakes are associated with maternal overweight and obesity and predict infant growth

Comments: In the study by Saben et al. HMO intake was examined in a cohort of 194 mother-infant dyads and related to both maternal weight status and infant growth from 2 to 6 months. Normal weight (35%), overweight (26%), and obese (39%) mothers were represented. A strength of the paper is that HM intake was measured by test weighing over a 3-day period at the age of 2 months and thereby HMO intake was calculated. Furthermore, growth data included body composition measured by quantitative nuclear magnetic resonance at 2 and 6 months. Maternal BMI was positively associated with three HMOs and negatively with four other HMOs as well as total acidic HMOs. There were no associations between intake of HMOs and change in infant FFM from 2 to 6 months. However, several of the HMOs and total acidic HMOs and total HMOs were associated with change in FM, WLZ, and WAZ from 2 to 6 months. These associations were controlled for maternal BMI. Three of the HMOs, which were positively associated with maternal BMI, were also positively associated with infant growth (3- FL, 3′-SL, 6′-SL). It is especially interesting that the associations are with FM and not FFM, as FM has a central role in early weight gain in breastfed infants. In a small exploratory study, we found that fully breastfed infants with excessive weight gain from
0 to 5 months, and thereby a high FM accretion, received milk with a higher content of 2′-FL and total HMO, compared to a group of breastfed infants with normal weight gain [32]. Furthermore, LNnT content was lower in milk from mothers of normal weight infants.

Human milk oligosaccharides, infant growth, and adiposity over the first 4 months of lactation

Comments: The study by Binia et al. included 370 infants from seven European countries. The infants were followed closely with six visits during the first 4 months when HM samples were taken and anthropometry was measured. Body composition was measured with PeaPod in a subsample of about one quarter of the infants. The overall conclusion of the study was that HMO composition of HM during the first 4 months has little influence on infant growth and body composition, but also that sialylated HMOs may be associated with adiposity during the first months of lactation. 3′-SL and sialyllacto-Ntetraose showed significant associations with weight for length. In the subsample with measurements of body composition, there was no association between FM or FMI and HMOs, which could be due to a low power. A limitation of the studies by Binia et al. and Saben et al., as also pointed out by the authors, is that the infants were only followed for 4 and 6 months, respectively. Binia et al. also mention that in studies following infants for longer periods, growth will also be influenced by factors like introduction and composition of complementary feeding. 

Associations of human milk oligosaccharides and bioactive proteins with infant growth and development among Malawian mother-infant dyads

Comments: The study by Jorgensen et al. is important because it is a large study with infants from a low-income country, and because growth velocity from 6 to 12 months was used as the outcome. HM samples from 659 infants were analyzed for 51 HMOs. They found a positive association between the absolute abundance of HMO on linear growth velocity, but only among the 75% of the mothers who were secretors. They also analyzed the association between HMOs and cognitive outcome and found that the relative abundance of fucosylated and sialylated HMOs were positively associated with language skills at 18 months. The effects of HMOs might be different in low-income countries because of a different microbiota composition. In this study, bifidobacteria comprise the largest proportion of the composition of the microbiota. This was also the case in a smaller study from the Gambia, where they also found positive associations between absolute abundance of HMOs and linear growth [33]. Future studies should focus on improving understanding of how the content of HMOs in HM can optimize infant growth. This is especially important in populations where growth faltering is common. Are there maternal factors which can be modulated to optimize the content of HMOs that can further stimulate growth? Furthermore, the interaction between HMOs, intestinal microbiota, growth, and to what extent these factors are related to intestinal inflammation should be explored further. A better understanding might be important for preventing growth faltering.

Complementary Feeding and Risk of Overweight

Introduction to complementary feeding in the first year of life and risk of overweight at 24 months of age: changes from 2004 to 2015 Pelotas (Brazil) Birth Cohorts

Comments: Comments on this article as well as on the following one by Usheva et al. are incorporated in the comments on the article by Sirkka et al.

Complementary feeding and overweight in European preschoolers: the ToyBox-Study

Feeding patterns and BMI trajectories during infancy: a multi-ethnic, prospective birth cohort

Comments: Childhood overweight and obesity are increasing globally and may track into adulthood. As obesity in adulthood is difficult to reverse and is associated with risk of noncommunicable diseases such as hypertension, diabetes mellitus type II, and cardiovascular diseases, it is important to have strategies for prevention of overweight already in early childhood. The complementary feeding period might offer an important developmental window and a possibility to introduce healthy feeding practices that might have a long-term impact on growth and weight gain. We have selected three articles investigating the impact of complementary feeding on later risk of overweight and they give an important contribution towards understanding the optimal time for introduction and practices of complementary feeding. Furthermore, inconsistent results have been reported regarding the association between aspects of complementary feeding and later overweight. This has been described in the narrative review by Thompson et al. [34] and it is also reflected in the three papers we have chosen. In the study by Schneider et al. the association between the introduction of complementary feeding and overweight at 24 months is investigated. It is interesting that they compare the changes over a decade for two large Brazilian cohorts with comparable data on complementary feeding. They included 3,823 and 3,689 infants from two longitudinal birth cohorts from the same municipality from 2004 and 2015, respectively. Information on food introduction was collected at 3 and 12 months using a categorized list of foods. In addition, the type of cow’s milk ingested was assessed (fresh/powdered) and early introduction was defined as <6 months. The outcome was risk of overweight at 24 months defined BMI z-score >+1 SD using WHO growth standards.

They found that early introduction of complementary foods was associated with an increased risk of overweight at 24 months in formula-fed infants in the 2015 cohort, but they found no association in the 2004 cohort. Remarkably, the prevalence of risk of overweight was almost the same for the two cohorts (33.0 vs. 32.0% for the 2004 and 2015 cohort, respectively) whereas the prevalence of early food introduction was reduced from 93.3% in 2004 to 87.2% in 2015. However, it was still very high, which has also been reported in other studies [35, 36]. It is worth noting that they use a +1 BMI z-score as the outcome, which implies that many will be at risk. It could therefore have been interesting to investigate the association using a +2 BMI z-score as the outcome. Likewise, later follow-up would also be valuable to see if the association persisted over a longer time. The study shows that introduction of complementary foods before 6 months is quite common and influenced by culture and traditions so it may be difficult to change. However, the association of early introduction of foods with later increased risk of overweight was only found in non-breastfed infants in the latest cohort. This stresses the importance of continuing breastfeeding after the initial introduction of complementary foods. The influence of breastfeeding and age of introduction to complementary foods on later risk of overweight was also investigated by Usheva et al. In this study, the BMIs of 6,800 preschool children (mean age 4.75 years) from six European countries were estimated. The outcomes were overweight and obesity defined according to WHO criteria as BMI z-score >+2 SD and >+ 3 SD, respectively, for children under 5 years. For children older than 5 years, BMI z-scores >+1 and >+2 SD defined overweight and obesity, respectively. Information regarding breastfeeding, complementary feeding, and parental characteristics was obtained from the parents by standardized questionnaires. Timely introduction of complementary foods was defined as between 4 and 6 months of age. Complementary feeding included liquids and solid foods. They found that the prevalence of timely complementary feeding and still being breastfed at age 4–6 months was 51.2%. In this study tea was the first item introduced at a median age of 3 months, which resulted in only 6.3% being exclusively breastfed for 4–6 months. At preschool age, 8.0% and 2.8% of the children were overweight and obese, respectively. Early introduction of solid foods was not associated with an increased risk of overweight at preschool age compared with timely introduction, i.e., 4–6 months, and this was independent of being breastfed or formula fed. Compared to the study by Schneider et al. there were several methodological differences that could contribute to the different results. This study had a longer follow-up time and the influence of timing of introduction of complementary foods on later obesity may attenuate over time. Furthermore, different outcome measures of overweight risk were used. Many more children will be at risk of overweight than be overweight (BMI z-scores >+1 vs. BMI z-scores >+2 for children below 5 years) so associations may be easier to detect in the previous study. Furthermore, early introduction of complementary feeding was defined differently. Schneider et al. used the WHO’s definition of exclusive breastfeeding up to 6 months, whereas Usheva et al. used ESPGHAN’s recommendation of introduction of complementary feeding between 4 and 6 months [37].

Interestingly, the studies show that introduction of complementary feeding before 6 months was common both in Europe and in Brazil. In the third paper that we have selected by Sirkka et al. associations between feeding patterns, including type of breastfeeding and start of complementary feeding, and BMI trajectories in infancy were investigated. They included 3,524 primarily Dutch infants (82%) with information on the duration of exclusive breastfeeding, time of introduction of formula, and complementary feeding. The milk feeding type was categorized as exclusive breastfeeding, formula feeding, or mixed feeding at 0–3 months. Early introduction of complementary feeding was defined as <6 months and late as ≥6 months according to WHO recommendations and the three milk feeding categories were combined with the 2 complementary feeding categories giving 6 feeding combinations. BMI trajectories were based on BMI estimated during infancy. Overweight and obesity at the age of 5–6 years was defined by a BMI z-score >+1 SD using WHO growth standards. The most common feeding pattern was “exclusive breastfeeding/ late introduction” (30%) which was used as the reference feeding pattern. Infants with the feeding pattern “formula/early introduction” had lower odds of belonging to the low BMI trajectory than to the high BMI trajectory. Interestingly, the relation between feeding pattern and BMI trajectory was dependent on ethnicity. For Turkish/Moroccan infants, all feeding patterns tended to have lower odds for being in the low BMI trajectory compared with Dutch infants. At 5–6 years of age the lowest percentage of overweight was found for children in the low BMI trajectory during infancy and the highest percentage in the high BMI trajectory (10.1 vs. 34.1%) and more Turkish/Moroccan children were overweight than Dutch children in all trajectories. This study supports the influence of feeding pattern including both type of milk feeding and time of introduction of complementary feeding on BMI during the first years of life. It is worth considering that the milk feeding type was based on a 0- to 3-month period, which is a very short period compared to 6 months exclusive breastfeeding as is recommended by the WHO. This was used due to the low prevalence of infants being exclusively breastfed >3 months but also makes comparison with other studies difficult, as 4–6 months or 6 months are often used for defining exclusive breastfeeding. The strengths of all studies were the large sample sizes and the adjustment for both paternal and infant confounders. Data were collected prospectively in the studies by Sirkka et al. and Schneider et al., whereas in the study by Usheva et al. questionnaires regarding the perinatal period were collected 3–4 years later, increasing the risk of recall bias. Overall, it seems that adherence to recommendations could be improved with special focus on relevant risk groups. Future studies may help to identify relevant risk groups and further understanding of optimal complementary feeding combined with milk feeding practices.

References

1 Duijts L, Ramadhani MK, Moll HA. Breastfeeding protects against infectious diseases during infancy in industrialized countries: a systematic review. Matern Child Nutr. 2009;5:199–210.

2 Kramer M, Kakuma R. The optimal duration of exclusive breastfeeding. Cochrane Database Syst Rev. 2012;8:CD003517.

3 Christian P, Smith ER, Lee SE, Vargas AJ, Bremer AA, Raiten DJ. The need to study human milk as a biological system. Am J Clin Nutr. 2021;113:1063–72.

4 Victora CG, Bahl R, Barros AJD, França GV, Horton S, Krasevec J, et al. Breastfeeding in the 21st century: epidemiology, mechanisms, and lifelong effect. Lancet. 2016;387(10017):475–90.

5 Bode L, Raman AS, Murch SH, Rollins NC, Gordon JI. Understanding the mother-breastmilk-infant “triad.” Science. 2020;367(6482):1070–2.

6 Schneider-Worthington CR, Bahorski JS, Fields DA, Gower BA, Fernández JR, Chandler-Laney PC. Associations among maternal adiposity, insulin, and adipokines in circulation and human milk. J Hum Lact. 2021;37(4):714–22.

7 Galante L, Milan AM, Reynolds CM, Cameron-Smith D, Vickers MH, Pundir S. Sex-specific human milk composition: the role of infant sex in determining early life nutrition. Nutrients. 2018;10:1194.

8 Ekelund U, Ong KK, Linné Y, Neovius M, Brage S, Dunger DB, et al. Association of weight gain in infancy and early childhood with metabolic risk in young adults. J Clin Endocrinol Metab. 2007;92:98–103.

9 Druet C, Stettler N, Sharp S, Simmons RK, Cooper C, Smith GD, et al. Prediction of childhood obesity by infancy weight gain: an individual-level meta-analysis. Paediatr Perinat Epidemiol. 2012;26:19–26.

10 Wells JCK, Chomtho S, Fewtrell MS. Programming of body composition by early growth and nutrition. Proc Nutr Soc. 2007 Aug;66(3):423–34.

11 Woo Baidal JA, Locks LM, Cheng ER, Blake-Lamb TL, Perkins ME, Taveras EM. Risk factors for childhood obesity in the first 1,000 days: a systematic review. Am J Prev Med. 2016;50:761–79.

12 Zhang T, Song Y, Teng H, Zhang Y, Lu J, Tao L, et al. BMI trajectories during the first 2 years, and their associations with infant overweight/obesity: a registered based cohort study in Taizhou, China. Front Pediatr. 2021;9:665655.

13 Butte NF, Wong WW, Hopkinson JM, Smith B, Ellis KJ. Infant feeding mode affects early growth and body composition. Pediatrics. 2000;106:1355–66.

14 de Fluiter KS, van Beijsterveldt IALP, Breij LM, Acton D, Hokken-Koelega ACS. Association between fat mass in early life and later fat mass trajectories. JAMA Pediatr. 2020;174:1141–8.

15 Prentice P, Ong KK, Schoemaker MH, van Tol EA, Vervoort J, Hughes IA, et al. Breast milk nutrient content and infancy growth. Acta Paediatr. 2016;105:641–7.

16 Gridneva Z, Rea A, Lai CT, Tie WJ, Kugananthan S, Murray K, et al. Development of visceral and subcutaneous- abdominal adipose tissue in breastfed infants during first year of lactation. Nutrients. 2021;13:3294.

17 de Fluiter KS, van Beijsterveldt IALP, Goedegebuure WJ, Breij LM, Spaans AMJ, Acton D, et al. Longitudinal body composition assessment in healthy term-born infants until 2 years of age using ADP and DXA with vacuum cushion. Eur J Clin Nutr. 2020;74:642–50.

18 Ferreira APA, da Silva Junior JR, Figueiroa JN, Alves JGB. Abdominal subcutaneous and visceral fat thickness in newborns: correlation with anthropometric and metabolic profile. J Perinatol. 2014;34:932–5.

19 Wajchenberg BL. Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. Endocr Rev. 2000;21:697–738.

20 Eriksen KG, Christensen SH, Lind MV, Michaelsen KF. Human milk composition and infant growth. Curr Opin Clin Nutr Metab Care. 2018;21:200–6.

21 Hahn-Holbrook J, Le TB, Chung A, Davis EP, Glynn LM. Cortisol in human milk predicts child BMI. Obesity. 2016;24:2471–4.

22 Cheng WD, Wold KJ, Bollinger LB, Ordiz MI, Shulman RJ, Maleta KM, et al. Supplementation with lactoferrin and lysozyme ameliorates environmental enteric dysfunction: a double-blind, randomized, placebo-controlled trial. Am J Gastroenterol. 2019;114:671–8.

23 Hassiotou F, Geddes DT. Immune cell-mediated protection of the mammary gland and the infant during breastfeeding. Adv Nutr. 2015;6:267–75.

24 Wada Y, Lönnerdal B. Bioactive peptides derived from human milk proteins: an update. Curr Opin Clin Nutr Metab Care. 2020;23:217–22.

25 Newburg DS, Walker WA. Protection of the neonate by the innate immune system of developing gut and of human milk. Pediatr Res. 2007;61:2–8.

26 Gridneva Z, Hepworth AR, Ward LC, Lai CT, Hartmann PE, Geddes DT. Determinants of body composition in breastfed infants using bioimpedance spectroscopy and ultrasound skinfolds-methods comparison. Pediatr Res. 2017;81:423–33.

27 Mohd Shukri NH, Wells J, Eaton S, Mukhtar F, Petelin A, Jenko-Pražnikar Z, et al. Randomized controlled trial investigating the effects of a breastfeeding relaxation intervention on maternal psychological state, breast milk outcomes, and infant behavior and growth. Am J Clin Nutr. 2019;110:121–30.

28 Hassiotou F, Hepworth AR, Metzger P, Tat Lai C, Trengove N, Hartmann PE, et al. Maternal and infant infections stimulate a rapid leukocyte response in breastmilk. Clin Transl Immunology. 2013;2(4):e3.

29 Villavicencio A, Rueda MS, Turin CG, Ochoa TJ. Factors affecting lactoferrin concentration in human milk: how much do we know? Biochem Cell Biol. 2017;95:12–21.

30 Braun O, Sandkühler H. Relationships between lysozyme concentration of human milk, bacteriologic content, and weight gain of premature infants. J Pediatr Gastroenterol Nutr. 1985;4:583–6.

31 Bode L. Human milk oligosaccharides: structure and functions. Nestle Nutr Inst Workshop Ser. 2020;94:115– 23.

32 Larsson MW, Lind MV, Laursen RP, Yonemitsu C, Larnkjær A, Mølgaard C, et al. Human milk oligosaccharide composition is associated with excessive weight gain during exclusive breastfeeding – an explorative study. Front Pediatr. 2019;7:297.

33 Davis JCC, Lewis ZT, Krishnan S, Bernstein RM, Moore SE, Prentice AM, et al. Growth and morbidity of Gambian infants are influenced by maternal milk oligosaccharides and infant gut microbiota. Sci Rep. 2017;7:40466.

34 Thompson AL. Evaluating the pathways linking complementary feeding practices to obesity in early life. Nutr Rev. 2020;78(Suppl 2):13–24.

35 Hollis JL, Crozier SR, Inskip HM, Cooper C, Godfrey KM, Robinson SM. Age at introduction of solid foods and feeding difficulties in childhood: findings from the Southampton Women’s Survey. Br J Nutr. 2016;116:743–50.

36 Carletti C, Pani P, Monasta L, Knowles A, Cattaneo A. Introduction of complementary foods in a cohort of infants in northeast Italy: do parents comply with WHO recommendations? Nutrients. 2017;9:34.

37 Fewtrell M, Bronsky J, Campoy C, Domellöf M, Embleton N, Fidler Mis N, et al. Complementary feeding: a position paper by the ESPGHAN committee on nutrition. J Pediatr Gastroenterol Nutr. 2017;64:119–32.