Introduction

Childhood obesity often persists into adulthood posing major public health challenges across the world.1,2,3 The prevalence of obesity has reached epidemic proportions over the last two decades.1,2 As per the latest Centers of Disease Control (CDC) data, about one-third of U.S. children aged 2–19 years are overweight (sex-specific BMI > 85th percentile for age) and nearly 20% have obesity (sex-specific BMI > 95th percentile for age).4,5,6 Once obesity is established at a young age, its reversal is difficult, thus setting these children with the possibility of lifelong health issues.7,8,9 For example, children who are overweight by kindergarten years have a 4-fold greater risk of developing obesity at adolescence.8 A large cohort study (n = 51,505) that tracked the growth data of children from birth to age 18 showed that 90% who had obesity by age three continued to have obesity at age 18.9 Early-onset obesity and its persistence into adolescence and adulthood are also associated with parallel cardiometabolic changes with the potential for long-term adverse events.10,11,12 A large Australian cohort study observed that obesity at age three was significantly associated with subclinical markers of atherosclerosis by age 11.13 These data emphasize that the origin of childhood obesity and related metabolic derangements are often seeded in the first few years of life. Further, early-onset obesity likely to persists into the later years.13,14,15,16

Among the modifiable early risk factors for future obesity and adverse cardiometabolic events, both birth weight and weight gain during infancy are consistently reported. Small for gestational age (SGA, birth weight < 10th percentile for age and sex) and large for gestational age (LGA, birth weight > 90th percentile for age and sex) represent two extremes of fetal growth distribution, but both have links to obesity and related comorbidities later in life.15,17,18,19 The relationship between birth weight and risk for obesity is curvilinear. Thus, both reduced and increased birth weight infants are at higher risk, with infants born as LGA at the greatest risk category for future obesity, especially if they experience rapid postnatal growth.15 The effect of developmental “programming” in fetal growth restriction (for example, SGA) and its relationship with cardiometabolic risks have been somewhat well described.17,18,20,21,22 However, fetal “programming” pathways and mechanisms in LGA are less clear. In this narrative review, our objectives are threefold. First, to summarize the recent literature connecting LGA birth, early postnatal growth pattern, early childhood obesity, and lifetime risk for adverse cardiometabolic outcomes, to highlight an increasingly recognized, but not adequately addressed, public health challenge. Second, to identify potential early biomarkers in LGA infants that predict the risk for future obesity and adverse cardiometabolic outcomes. Finally, to explore potential intervention strategies in early infancy that can potentially modify the risk for developing early childhood obesity in LGA infants.

Methodology

To identify the evidence base connecting LGA birth and early obesity risk, a comprehensive literature search was conducted limited to PubMed, Scopus, Cochrane Central Registry of Controlled Trials, and Google Scholar databases published between January 2010 to March 2021. Only articles published in English were considered. Key search terms included were “large for gestational age,” “birth weight,” “obesity,” “overweight,” “early nutrition,” “breastfeeding,” “developmental programming,” “infant weight gain”, “cardiometabolic risk,” “body composition,” and “biomarkers.” Inclusion was restricted to studies that assessed the association between LGA birth and obesity/cardiometabolic outcomes.

Epidemiology and factors associated with LGA birth

The rate of LGA birth in the US has increased by 24-fold over 30 years; the crude rate (per 1000 live births) of LGA was 0.97 from 1979 to 1981, and increased to 22.97 from 2008 to 2010.23 A recent 5-year (2010–15) single-center retrospective study from Florida, US, that looked at the incidence and significance of LGA/macrosomic (birth weight > 4000 g) (due to varying definitions used to describe macrosomia in the literature, all macrosomic infants are considered as LGA for the purpose of this review) is considered as LGA infants suggested that the rate of neonatal macrosomia is about 10% of all births and about 12% of macrosomic infants required neonatal intensive care unit (NICU) admissions at birth.24 Another large population-based cohort study of ~3 million singleton births using 2012 U.S. Natality data, showed that the prevalence of LGA among women without gestational diabetes mellitus (GDM) was about 9% across different racial/ethnic groups with a slightly higher trend with minority women.25 Data from the WHO’s Global Survey on Maternal and Perinatal Health that looked at the prevalence of macrosomia in 23 developing countries in Africa, Asia, and Latin America observed a large variation in the prevalence of macrosomia, ranging from 0.5% to 14.9%.26

Factors associated with being born LGA include both fetal (genetic and chromosomal disorders, racial and ethnic factors, tumors) and maternal (pregestational diabetes mellitus, GDM, maternal obesity, excess gestational weight gain, and tall maternal height) variables.26 Most LGA infants experience fetal overgrowth secondary to excess fetal nutrition which is the focus of this review. Maternal pre-pregnancy obesity and maternal weight gain during pregnancy are among the strongest risk factors for LGA birth.27,28,29 The 2017–2018 National Health and Nutrition Examination Survey (NHANES) observed the highest ever recorded age-adjusted prevalence rate of obesity in adults standing at 42.4%.30 They also documented that the prevalence of severe obesity (body mass index, BMI ≥ 40 kg/m2) was higher in women than men (11.5% vs. 6.9%).30 This worrying trend was also observed among women of childbearing age (20–39 years), with the obesity prevalence rate of about 40%.30 A predictive model for the risk of LGA birth in parous women with BMI ≥ 30 kg/m2 pre-pregnancy and early pregnancy had an area under the curve (AUC) of 0.80 (95% CI: 0.78–0.82) and 0.81 (95% CI: 0.79–0.82), respectively.31 The risk for LGA increases by 6.9% with each kg weight gain during pregnancy above IOM recommendations.32 Along with the increasing obesity rate, the prevalence of pre-existing diabetes during pregnancy and GDM is also steadily increasing, contributing further to the frequency of LGA birth.33,34,35 The number of pregnant women with obesity and/or GDM has increased more than 30% in the last few decades producing nearly half a million infants each year in the US alone who are born LGA (about 10% of all births)—a number approaching that of infants who are born prematurely each year—a population of infants who are at higher future risk for childhood obesity and cardiometabolic adverse outcomes.19,24

LGA infants: a significant risk factor for future obesity and cardiometabolic events

Being born “LGA” is considered as a marker of events/stressors before and/or during pregnancy rather than the actual cause of adult obesity per se.19 Most LGA infants are exposed to excessive nutrition and high glucose load in utero with resultant increased fetal insulin secretion driving fetal overgrowth and excessive adipose tissue deposition (fetal macrosomia).36 These maladapted prenatal and natal developmental programming of body tissues and the resulting altered metabolism predispose them to early life obesity and a higher risk for future cardiovascular events.37,38 Table 1 summarizes the recent studies (January 2010–March 2021) showing the relationship between being born LGA and future obesity risk and adverse cardiometabolic outcomes.9,19,39,40,41,42,43,44,45,46,47,48 These studies suggest that LGA infants are at higher risk for childhood and adult obesity compared to appropriate for gestational age (AGA) infants. Though studies on cardiometabolic clinical endpoints specific to LGA infants are limited, but considering their potentially higher risk, future-focused studies are needed to address the knowledge gap.

Table 1 Recent studies (January 2010–March 2021) that have shown the relationship between LGA infants and future obesity risk and adverse cardiometabolic outcomes.

LGA infants: early growth patterns influences the obesity risk

Infancy is characterized by rapid growth and development and inadequate nutrition can compromise growth and long-term neurodevelopmental outcomes.49 Current nutritional practices in the NICU are guided by weight gain trends50 and not based on the quality of growth (i.e., changes in body composition). The recommended dietary allowance (RDA) of energy intake in healthy breastfed full-term infants is approximately 90–135 kcal/kg/day in the first three months of life (the equivalent of taking 140–200 ml/kg/day of 20 cal/oz milk) with an expected weight gain of 25–30 g/day.50 These recommendations are universally applied to infants irrespective of their in utero growth status.

There is strong evidence to support that rapid weight gain (an increase of weight z-score > 0.67 from the birth weight) in infancy is associated with later obesity irrespective of the birth weight.51,52,53,54,55 A meta-analysis from 10 cohort studies (n = 47,661) suggested that the risk of obesity increases 2-fold for each one-SD increase in weight between birth and 1 year (OR 1.97; 95% CI: 1.83–2.12).56 In a nested case–control study that tracked the growth trajectories in children with severe obesity (480 with severe obesity and 783 controls), Smego et al. observed that a BMI ≥ 85th percentile as early as 4–6 months increases the risk of severe obesity by age 6 years by 2.5-fold and the risk of clinical obesity by age 6 years by 3-fold.7 A prospective birth cohort study (n = 1971) observed that weight gain z-score in the first four months of life was positively associated with BMI z-score and overweight/obesity at age 2–7 years and the risk of overweight/obesity increased by 50% for every increase of one-SD in weight gain in the first four months (OR 1.5; 95% CI: 1.4–1.7).51 These data suggest that accelerated weight gain during infancy is an important determinant of the lifetime risk for obesity.

However, a prospective study that compared the growth outcomes of LGA infants compared to AGA infants in the first year of life found that the anthropometric differences between AGA and LGA disappeared by 6 months, suggesting that LGA infants tend to have a slower growth velocity in infancy or deceleration in weight gain (slow growth or catch-down growth).57 Catch-down growth in LGA infants was defined as a decrease in weight or height z-score more than 0.67 during the first 2 years of life.57 They also observed that this slower growth was not associated with any significant epigenetic changes (genome-wide DNA methylation analysis).57 The authors postulated that this might be the result of departure from the energy-rich in utero environment and gradually shifting towards their natural genetic growth patterns postnatally.57 Another study from Japan that observed a catch-down growth in infants in the first 6 months of life with high-birth weight (>3.5 kg) vs. low-birth weight (<2.5 kg) suggested that early postnatal growth period are physiological events for recovery of deviated growth during the fetal period (catch-up growth in low-birth weight and catch-down growth in high-birth weight infants).58

An analysis of a large US birth cohort (Collaborative Perinatal Project) that studied the postnatal weight and BMI growth pattern of LGA infants from birth to age 7 years, observed that LGA infants with no catch-down growth in weight (25.2% of cohort) were associated with a higher risk of obesity (aOR 6.4, 95% CI: 5.2–7.7) and hypertension (aOR 1.7, 95% CI: 1.4–2.0), whereas LGA infants (54.3% of cohort) that demonstrated a small catch-down growth beginning at birth were associated with no increased risk of adverse outcomes.59 Similarly, the Generation R study which followed about 4000 children, observed that the greatest risk of obesity at age 4 was for LGA infants who did not experience a catch-down growth in the first 2 years of life (a reduction of <0.67 SD for weight, OR 12.46; 95% CI: 6.07–25.58).60 Other studies in LGA term infants that observed a similar trend that a catch-down growth in the first several months after birth was associated with a lower risk of adverse metabolic outcomes and suggested that the difference in postnatal growth pattern influenced the health outcomes in LGA infants.54,61

The “thrifty phenotype” hypothesis by Hales and Barker, explained the developmental adaptations in SGA infants from poor fetal nutrition placing them at risk for metabolic syndrome when exposed to a postnatal environment with plentiful nutrition.62 In contrast, LGA infants are exposed to excess nutrition in utero and in the postnatal period if provided above a threshold level that is not allowing any catch-down growth in early infancy. The proposed mechanisms associated with altered developmental programming of physiological systems associated with excess nutrition in utero and early postnatal environmental conditions include dysfunction of the adipose tissue (increased total number of adipocytes, increased size of adipocytes, increased adipose tissue inflammation, and altered secretion of adipokines) pancreas (increased inflammation, insulin resistance and compensatory increased insulin production, and reduced islet cell mass), liver (fatty liver, increased oxidative stress, and inflammation), and the vasculature leading to hyperlipidemia.63,64,65 We have summarized the current understanding of the early life developmental programming in LGA infants in a conceptual diagram (Fig. 1). In summary, current data suggest that LGA infants, as a result of developmental programming in utero, are at an elevated risk for early childhood obesity, and this risk is further modified based on whether weight gain accelerates or decelerates in early childhood.

Fig. 1: Current understanding of the early life developmental programming associated with obesity and cardiometabolic diseases in large for gestational age (LGA) infants.
figure 1

(The dashed lines represent the potential opportunities for modifying the early life influences in LGA infants to decrease the transgenerational programming).

LGA infants: body composition

Adverse health consequences of obesity are not contingent on increased absolute weight per se, but they are closely related to the alterations and distribution of body composition parameters. Infant body composition studies have suggested that LGA infants at birth have increased fat mass (FM)% compared to AGA infants.66,67,68 A large prospective cohort study from Colorado, US (n = 979, included 5% macrosomic infants with birth weight > 4 kg) that studied the body composition of infants using air displacement plethysmography (ADP) at birth observed that higher neonatal FM% is associated with a higher risk for childhood overweight and obesity.69 In their cohort, the mean FM% was 9.1 ± 4.0 at birth, and each one-SD increase in FM% was associated with 0.12 kg/m2 higher BMI at 2–6 years which is equivalent to a 2–4% increase in BMI percentile based on the CDC BMI growth charts.69 In LGA infants, FM is more affected than the fat-free mass (FFM) component, and this differentially elevated body fat at birth may be a better predictor of later obesity than total body weight in these infants.19,52,67,68,70 Thus, it is important to consider body composition parameters such as FM and FFM of LGA infants and how they impact the later risk for obesity and cardiometabolic outcomes.52

The majority of the body fat deposition occurs in late fetal life and during infancy, and accelerated fat accrual in either of these two phases increases the risk for future obesity.52,71 A birth cohort study from the Netherlands (n = 401) that studied infant body composition using ADP observed that a rapid increase or catch-up in FM% in the first 6 months of life (defined in the study as > 0.67 SD in FM%) was associated with more adiposity at 2 years of age and suggested that the first few months of postnatal life is a critical window for adiposity programming.72 These data suggest that quality of pre- and postnatal growth is important and the quantity of body fat may be a potentially modifiable early risk factor or biomarker for childhood obesity in LGA infants.

A study that looked at the short-term changes in body composition in LGA and SGA infants at birth and again at 3–4 months of age observed that growth rate and fat accretion were significantly higher in the SGA infants versus LGA infants.67 The majority of the LGA infants in this study were breastfed on demand and demonstrated the slowest gain in weight and FM. Similarly, a longitudinal body composition study LGA and AGA infants who were exclusively breastfed for at least 4 months suggested that FFM remained elevated in LGA infants across the first 2 years of life, while FM accrual slowed down to approach normal FM.73 Although the presence of maternal diabetes during pregnancy, if well-controlled may result in infants of diabetic mothers (IDM) with similar body composition as healthy-term non-IDM infants, the IDM infants are found to have 14% lower resting energy expenditure (REE) and 26% lower fat oxidation, compared to their healthy-term peers.74 This suggests that continued provision of excess calories above the metabolic needs (positive energy balance due to caloric intake higher than caloric expenditure) predisposes them to future obesity. It has also been suggested that longitudinal measurement of REE in infants may help to prescribe and promote individualized nutrition regimens.75 These studies suggest that during the early months of life when the feeding pattern is regulated by the infant, and growth is influenced by nutrition, the inherent patterns of increased or decreased appetite, hunger, and satiety likely steer the infant toward its genetic growth trajectory and normalizing the body composition along the way.

These data also highlight the important role of body composition pattern at birth and its scaffold during infancy on later health consequences among LGA infants. Therefore, body fat trajectory in LGA infants can be a potential therapeutic target for nutritional interventions to modify the risk for obesity and related comorbidities. The LGA infants who do not demonstrate a deceleration in weight and slowing of FM accrual in the first few months of life are likely to be at higher risk for early obesity development. Taken together, in this era of personalized treatment and precision nutrition, it may be time to move beyond the current nutritional strategy of one-size-fits-all dietary prescription for optimal health and disease prevention.59,76

LGA infants: other etiological ties and potential biomarkers of later obesity and cardiometabolic dysregulation

Fetal overgrowth as a result of prolonged exposure to nutrient-rich in utero environment is associated with abnormal fetal programming which includes altered insulin kinetics and excessive adipose tissue deposition predisposing them to the risk of metabolic syndrome.6,77 The trajectory of adipose tissue deposition and distribution in early life may be important in LGA infants as discussed above and attempts have been made to find early and functional biomarkers of adipose tissue that can be linked to future clinical obesity.52 For example, adipose tissue is an especially important contributor to the pool of circulating exosomal microRNAs (miRNAs), a class of non-coding RNAs that play important roles in regulating gene expression that is important in intercellular communication and fetal programming.78 Altered adipose tissue or mass is associated with changes in circulating miRNAs and linked with many metabolic conditions.79 A study that quantified the miRNAs using the dried blood spots on newborn screening cards of different birth weights, as a source of analyzable miRNAs observed that miR-33b and miR-375 were overexpressed 9.8-fold and 1.7-fold respectively in macrosomic newborns and miR-454-3p was overexpressed in both low-birth weight and macrosomic newborns as compared to AGA newborns.80 Another similar study using the newborn screening cards that looked at the circulating miRNAs in macrosomic newborns found that miR-29a-5p, miR-126-3p, miR-221-3p, and miR-486-5p were significantly overexpressed in macrosomic newborns.81 These miRNAs are functional regulators of cholesterol levels and insulin secretion, and are linked with obesity, type-2 diabetes, insulin resistance, and proinflammatory reactions.80,81 These data suggest that birth weight modifies the expression of miRNAs associated with adult metabolic dysfunctions and analyzing miRNAs can be a potential biomarker of fetal programming of adult diseases in LGA infants. Further studies are needed to understand how the overexpressed miRNAs at birth change with different postnatal weight and adipose growth trajectories in LGA infants.

Studies using metabolomics have emerged as effective tools for elucidating early metabolic aberrations in fetal overgrowth.82 A study using cord-blood metabolomics noted metabolites associated with energy production (malate, succinate, fumarate) and nucleotide turnover pathways were elevated in infants with larger birth size, and these metabolites were also associated with higher cord-blood leptin and insulin-like growth factor-1.82 In another cross-sectional study of full-term newborns born to mothers without GDM, cord-blood samples were analyzed acylcarnitine profiles (intermediates of fatty acid oxidation viewed as an indicator of insulin resistance and incomplete fatty acid oxidation) along with newborn measures of adiposity (leptin and FM by ADP) and hyperinsulinemia (c-peptide levels).83 There was an accumulation of acylcarnitine intermediates which was associated with high leptin levels and FM and they have suggested that cord-blood acylcarnitine profiles may be useful early biomarkers for future risk for obesity and insulin resistance.83 Similarly, a large prospective U.S. urban low-income birth cohort follow up study [1402 mothers-child pairs with mothers with pre-pregnancy overweight or obesity (OWO), with 11.1% LGA birth rate] observed that infants born to maternal acylcarnitine levels at delivery in the top quartile were at the highest risk for childhood OWO at 5 years (OR = 3.78; 95% CI: 2.47, 5.79), which explained about one-third of the inter-generational OBO risk in their cohort.84 Future metabolomic studies that can be combined with early preventive intervention strategies are warranted to understand whether such interventions can reverse or mitigate the alterations in metabolic programming associated with early overgrowth in LGA infants.

Briana et al. studied potential prognostic cardiac biomarkers [Cardiotrophin-1 (CT-1), Titin, pentraxin (PTX-3), and soluble CD36 (sCD36)] using cord-blood samples in full-term LGA and AGA infants. LGA infants had higher CT-1 and Titin concentrations, compared to AGA infants, while PTX-3 and sCD36 were similar in both groups.85 A further subgroup analysis of LGA infants showed that CT-1 is up-regulated only in LGAs exposed to maternal diabetes. They suggested that a higher Titin concentration in LGAs may represent the potential molecular mechanism underlying the association between fetal macrosomia and cardiomyocyte/diastolic dysfunction.85

Other potential biomarkers of obesity-related cardiometabolic risk in LGA infants include circulating concentrations of inflammatory markers such as high-sensitivity C-reactive protein, interleukin-6, and tumor necrosis factor-α; satiety factors such as leptin, ghrelin, and obestatin; and adipokines such as adiponectin (both high molecular weight and total), visfatin, vaspin, retinol-binding protein-4, and fatty acid-binding protein-4 (FABP4).63,86 Leptin is produced in proportion to fat mass, but also found in the placenta, informs the brain about the body’s energy and nutrient status while adiponectin is solely secreted by adipocytes, and has insulin-sensitizing effects and its level is inversely related to leptin levels.63 LGA infants born to non-diabetic mothers found to have elevated cord-blood leptin levels and increased leptin/adiponectin ratio compared to AGA infants suggesting a disturbance in adipokines, reported to be associated with subsequent central obesity in children.87,88,89 Another study that investigated the relationship between four circulating adipokines (visfatin, apelin, vaspin, adiponectin) with markers of insulin sensitivity in LGA infants, observed that LGA infants, especially those born to a diabetic mother, had high insulin, visfatin, apelin, and low adiponectin levels, along with elevation of the insulin resistance markers.90 A study that looked at the cord-blood adipokines, chemerin, and obestatin (secreted by adipose tissue and associated with insulin resistance/metabolic syndrome) observed that, compared to AGA infants, LGA infants have higher chemerin (reflecting higher adipose tissue) with similar obestatin levels.91 Another study that looked at hyperinsulinemia and elevated insulin resistance index (Homeostasis Model assessment for insulin resistance, HOMA-IR) at birth, observed that LGA infants, compared to AGA infants, had higher hyperinsulinemia (27.3% vs. 6.9%, OR 5.02; 95% CI: 1.15–22.3; p = 0.01) and elevated insulin resistance index (36.4% vs 13.9%, OR 3.54; 95% CI: 1.03–12.16; p = 0.02).92 Another study that looked at the FABP4-an adipokine associated with obesity and metabolic syndrome—in different birth weight categories at birth found a significant U-shaped correlation between serum FABP4 levels and birth weight with elevated levels both in SGA and LGA infants.86 A novel neuropeptide, spexin, appears to be emerging as an important factor in obesity.93 Studies in both children and adults have also demonstrated significantly lower circulating levels of spexin in those with obesity.94,95 While a potential role for spexin in GDM has been suggested recently,96,97 the evidence is somewhat inconsistent,98 and its implications in the in utero environment and potential influence in LGA weight trajectory and cardiometabolic risk remain to be understood.

Several studies have postulated the connection between the gut microbiome and its metabolites such as short-chain fatty acids (SCFAs) with obesity and metabolic disorders.99,100,101 It has been suggested that maternal obesity and weight gain during pregnancy and the resulting altered in utero environment can influence the offspring microbiota and the associated epigenetic changes further increase the risk of metabolic diseases in the offspring.102 A study that explored the relationship between placental microbiota profile and fetal macrosomia observed that the placental microbiota profile is distinct in macrosomic infants compared to AGA infants.103 Maternal overweight and obesity, which often results in cesarean delivery, is also associated strongly with early childhood obesity, potentially mediated by changes in infant gut microbiome.104 Studies in older children with obesity have observed that achievement of weight loss in response to interventions such as calorie-restricted diet and increased physical activities are found to be influenced by their individual gut microbiota.105 One study evaluated the role of probiotic supplementation starting one month before birth and continuing for 6 months after birth found to be associated with reduced excessive weight gain during infancy.106 Though specific data on LGA infant’s early growth and gut microbiome imbalances are scarce and need further study, considering the growing evidence at large, gut microbiome patterns may be a useful early biomarker for their obesity risk.

The potential and emerging biomarkers of later obesity and cardiometabolic risk in LGA infants are given in Table 2.

Table 2 Potential and emerging biomarkers of later obesity and cardiometabolic risk in LGA infants.

LGA infants: potential early intervention strategies to reduce the childhood obesity risk and future directions

In addition to the primary prevention strategies focused on improving the mother’s health such as regulating maternal obesity and gestational weight gain and better control of diabetes to reduce the risk of LGA birth,107,108 we also need to consider secondary prevention strategies in LGA infants that can be implemented in early infancy to reduce their risk of childhood obesity. A CDC longitudinal study (Infant Feeding Practices Study II) observed that the factors associated with LGA/macrosomic birth from conception to delivery do not necessarily predict the early infant weight trajectories, and suggested that early life influences especially related to postnatal energy balance that drives the continued overgrowth may be better targeted for intervention to reduce the early obesity risk.109 Since postnatal growth trajectories can influence the clinical outcomes in LGA infants, allowing a small catch-down growth in the first few months of life in LGA infants is one such strategy.59,67 Promoting breastfeeding help to prevent excessive weight gain during infancy in LGA infants, e.g., Goetz et al. observed that LGA infants who received proportionately more breast milk had normal weight at 7–12 month of age, while infants who received proportionately more formula milk had excess weight gain.109 A longer duration of breastfeeding was associated with lower risk for childhood obesity in all birth weight categories including LGA infants.110,111 Although breastfeeding potentially mitigates the metabolic sequelae for LGA infants and their mothers, women, especially with GDM, have delayed lactogenesis, less likely to exclusively breastfeed, and are more likely to introduce formula milk.112,113,114 To optimize breastfeeding outcomes, we need to address the barriers to breastfeeding of mothers with GDM which include maternal obesity, increased need for C-section deliveries, mother–infant separation due to infant hypoglycemia, and other perinatal morbidities, and mother’s report of less provider support for breastfeeding.113 However, most studies on breastfeeding and obesity are observational studies and may be explained, at least partly, by confounding.115 In LGA infants who are formula-fed, simple measures such as reducing bottle size can help to reduce excessive weight gain.116 Although not specifically studied in LGA infants, the formula milk composition especially with a lower protein or hydrolyzed protein content was associated with slower gain in weight during infancy.117,118,119 The interpregnancy period is a golden opportunity to support mothers to achieve a healthy weight to prevent future LGA births and combining interventions directed to mothers of LGA infants is also likely to have synergistic effects.120,121 With the recent data that suggest the perinatal use of probiotics in low-birth weight and healthy infants was associated with better growth122,123 and an altered intestinal microbiome can impair postnatal growth, specifically with a propensity for adiposity in early life,123 relatively inexpensive interventions such as probiotic supplementation to modulate early life microbiota may be a potential therapeutic intervention to reduce their early obesity risk. Based on the current evidence, limited to observational studies, some of the possible strategies for secondary prevention of early life obesity in LGA infants are included in Table 3. Since the evidence base for most of these strategies are from observational studies and not specifically in LGA infants, their clinical efficacy either as single or combination of strategies needs to be determined in future studies with adequate sample sizes. Combining the infant-specific strategies along with family-centered nutritional and lifestyle interventions (multicomponent strategies), may potentially have a significant synergistic effect. This needs to be validated in future studies.

Table 3 Potential early intervention strategies for secondary prevention of early life obesity in LGA infants based on observational data.

In conclusion, a great deal remains to be learned about LGA and the underlying regulatory mechanisms in its progression into obesity, especially on their potential lifetime risk for developing obesity-related cardiometabolic diseases. However, as our knowledge is expanding, there are copious and tangible opportunities to develop and implement clinical care approaches specifically for LGA infants incorporating many of the strategies discussed in this review. Potential early biomarkers of risk for obesity and related comorbidities in LGA will lead to a better understanding of the risk and serve as a tool to intervene and facilitate attenuation of adverse health outcomes. For effective implementation of the strategies, the involvement of key stakeholders including parents, pediatricians, and health insurance agencies is crucial. Interventions if implemented at a critical, but narrow, time period may have the potential to influence LGA infant’s metabolism, weight gain, and risk of subsequent obesity-related comorbidities. Additional research in LGA infants is needed to address and avert the risk factors at an early age, thereby impacting the care and the quality of life for these infants and their parents and potentially reducing the elevated lifetime risk of obesity and cardiometabolic diseases.