Born Large for Gestational Age: Bigger Is Not Always Better

Abstract

During the past 60-90 years, there has been a change in the growth trajectories of large for gestational age (LGA) babies and the associated health effects later in life. Subjects classified as large at birth in the 1920s were found to have reduced morbidity and mortality in their seventh decade compared with those born of lower birth weight.1Hales C.N. Barker D.J. Clark P.M. Cox L.J. Fall C. Osmond C. et al.Fetal and infant growth and impaired glucose tolerance at age 64.BMJ. 1991; 303: 1019-1022Crossref PubMed Scopus (2206) Google Scholar, 2Barker D.J. Hales C.N. Fall C.H. Osmond C. Phipps K. Clark P.M. Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth.Diabetologia. 1993; 36: 62-67Crossref PubMed Scopus (2148) Google Scholar Indeed, across the birth weight range there was a progressive increase in cardiovascular and metabolic risk with a decrease in birth weight, even among those in the normal range.1Hales C.N. Barker D.J. Clark P.M. Cox L.J. Fall C. Osmond C. et al.Fetal and infant growth and impaired glucose tolerance at age 64.BMJ. 1991; 303: 1019-1022Crossref PubMed Scopus (2206) Google Scholar, 2Barker D.J. Hales C.N. Fall C.H. Osmond C. Phipps K. Clark P.M. Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth.Diabetologia. 1993; 36: 62-67Crossref PubMed Scopus (2148) Google Scholar These findings suggested that, historically, larger size at birth provided metabolic advantages that contributed to improved health and possibly longevity. Long-term outcomes in those born LGA have dramatically changed in the last 30 years, with LGA being now associated with early obesity and increased cardiovascular and metabolic risk.3Johnsson I.W. Haglund B. Ahlsson F. Gustafsson J. A high birth weight is associated with increased risk of type 2 diabetes and obesity.Pediatr Obes. 2015; 10: 77-83Crossref PubMed Scopus (122) Google Scholar, 4Yu Z.B. Han S.P. Zhu G.Z. Zhu C. Wang X.J. Cao X.G. et al.Birth weight and subsequent risk of obesity: a systematic review and meta-analysis.Obes Rev. 2011; 12: 525-542Crossref PubMed Scopus (364) Google Scholar The association between birth weight and the risk of later adult diseases currently seems to be U-shaped.5Wei J.N. Sung F.C. Li C.Y. Chang C.H. Lin R.S. Lin C.C. et al.Low birth weight and high birth weight infants are both at an increased risk to have type 2 diabetes among schoolchildren in Taiwan.Diabetes Care. 2003; 26: 343-348Crossref PubMed Scopus (217) Google Scholar It is likely that this relatively recent increased risk of adult disease in those born large is related to the underlying factors influencing fetal growth as well as changes in postnatal environmental conditions. For instance, from 1910 to the late 1940s, events including the World Wars and the Great Depression were characterized by limited available nutrition to the wider population.6Tapia Granados J.A. Diez Roux A.V. Life and death during the Great Depression.Proc Natl Acad Sci U S A. 2009; 106: 17290-17295Crossref PubMed Scopus (154) Google Scholar, 7Roseboom T. de Rooij S. Painter R. The Dutch famine and its long-term consequences for adult health.Early Hum Dev. 2006; 82: 485-491Abstract Full Text Full Text PDF PubMed Scopus (713) Google Scholar Thus, in the past, babies were much less likely to be overnourished in utero, as shown by lower maternal weight gain and overweight/obesity rates during pregnancy,8Gunderson E.P. Abrams B. Epidemiology of gestational weight gain and body weight changes after pregnancy.Epidemiol Rev. 1999; 21: 261-275Crossref PubMed Scopus (159) Google Scholar, 9Gunderson E.P. Childbearing and obesity in women: weight before, during, and after pregnancy.Obstet Gynecol Clin North Am. 2009; 36: 317-332Abstract Full Text Full Text PDF PubMed Scopus (291) Google Scholar so that LGA babies were more likely to have been long and lean. Much greater rates of postterm births and increased sibship may represent risk factors for lean LGA babies.10Walsh J.M. McAuliffe F.M. Prediction and prevention of the macrosomic fetus.Eur J Obstet Gynecol Reprod Biol. 2012; 162: 125-130Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar, 11Langer O. Fetal macrosomia: etiologic factors.Clin Obstet Gynecol. 2000; 43: 283-297Crossref PubMed Scopus (134) Google Scholar Before active obstetric intervention to avoid prolonged pregnancies, the postterm birth rate was 10%12Hauth J.C. Goodman M.T. Gilstrap III, L.C. Gilstrap J.E. Post-term pregnancy. I.Obstet Gynecol. 1980; 56: 467-470PubMed Google Scholar compared with approximately 3% currently.13Savitz D.A. Terry Jr., J.W. Dole N. Thorp Jr., J.M. Siega-Riz A.M. Herring A.H. Comparison of pregnancy dating by last menstrual period, ultrasound scanning, and their combination.Am J Obstet Gynecol. 2002; 187: 1660-1666Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar Conversely, there has been a nutritional excess in utero in recent decades,14Dabelea D. Crume T. Maternal environment and the transgenerational cycle of obesity and diabetes.Diabetes. 2011; 60: 1849-1855Crossref PubMed Scopus (243) Google Scholar leading to LGA neonates that are long and fat,15Vohr B.R. McGarvey S.T. Growth patterns of large-for-gestational-age and appropriate-for-gestational-age infants of gestational diabetic mothers and control mothers at age 1 year.Diabetes Care. 1997; 20: 1066-1072Crossref PubMed Scopus (66) Google Scholar with postnatal exposure to an “obesogenic” environment responsible for a further acceleration in growth.16Cetin C. Ucar A. Bas F. Poyrazoglu S. Bundak R. Saka N. et al.Are metabolic syndrome antecedents in prepubertal children associated with being born idiopathic large for gestational age?.Pediatr Diabetes. 2013; 14: 585-592Crossref PubMed Scopus (8) Google Scholar There has been a progressive increase in the prevalence of large babies during the last 3 decades17Weissmann-Brenner A. Simchen M.J. Zilberberg E. Kalter A. Weisz B. Achiron R. et al.Maternal and neonatal outcomes of macrosomic pregnancies.Med Sci Monit. 2012; 18: PH77-PH81Crossref PubMed Scopus (40) Google Scholar that is now approximately 10% of all newborns18Pasupathy D. McCowan L.M. Poston L. Kenny L.C. Dekker G.A. North R.A. Perinatal outcomes in large infants using customised birthweight centiles and conventional measures of high birthweight.Paediatr Perinat Epidemiol. 2012; 26: 543-552Crossref PubMed Scopus (32) Google Scholar; however, the literature is conflicting regarding the definition of “large” at birth, which would indirectly estimate the severity of adiposity. Birth weight appears to be the most widely adopted variable to define large babies, because weight represents a crude measure of fetal growth, involving length, head circumference, and fatness.19Barker D.J. Osmond C. Simmonds S.J. Wield G.A. The relation of small head circumference and thinness at birth to death from cardiovascular disease in adult life.BMJ. 1993; 306: 422-426Crossref PubMed Scopus (599) Google Scholar The terms LGA and macrosomia have been used somewhat interchangeably, although different criteria have been adopted for both, leading to conflicting classifications. LGA babies usually are defined as having a birth weight >90th percentile according to gestational age and sex,20Bocca-Tjeertes I.F. Kerstjens J.M. Reijneveld S.A. Veldman K. Bos A.F. de Winter A.F. Growth patterns of large for gestational age children up to age 4 years.Pediatrics. 2014; 133: e643-e649Crossref PubMed Scopus (16) Google Scholar and macrosomia tends to refer to babies with a birth weight >4000 g.21Koyanagi A. Zhang J. Dagvadorj A. Hirayama F. Shibuya K. Souza J.P. et al.Macrosomia in 23 developing countries: an analysis of a multicountry, facility-based, cross-sectional survey.Lancet. 2013; 381: 476-483Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar Because LGA is a more precise term, it is more commonly used to identify larger babies. Greater birth weight and greater neonatal adiposity represent the expression of a complex fetal–maternal interaction, which is driven by fetal genetic factors and the intrauterine environment.22Chawla R. Badon S. Rangarajan J. Reisetter A. Armstrong L.L. Lowe L.P. et al.A genetic risk score for prediction of newborn adiposity and large for gestational age birth.J Clin Endocrinol Metab. 2014; 99: E2377-E2386Crossref PubMed Scopus (16) Google Scholar Although the factors that have led to large birth weight in previous generations are unclear, the current underlying causes of LGA appear to be mainly attributable to nutritional excess in utero, which either directly or via epigenetic mechanisms results in increasing obesity postnatally.23Haworth K.E. Farrell W.E. Emes R.D. Ismail K.M. Carroll W.D. Hubball E. et al.Methylation of the FGFR2 gene is associated with high birth weight centile in humans.Epigenomics. 2014; 6: 477-491Crossref PubMed Scopus (23) Google Scholar, 24Fraser A. Lawlor D.A. Long-term health outcomes in offspring born to women with diabetes in pregnancy.Curr Diab Rep. 2014; 14: 489Crossref PubMed Scopus (104) Google Scholar, 25Lawlor D.A. The Society for Social Medicine John Pemberton Lecture 2011. Developmental overnutrition—an old hypothesis with new importance?.Int J Epidemiol. 2013; 42: 7-29Crossref PubMed Scopus (86) Google Scholar This increased in utero nutrition most likely reflects maternal nutrition, in particular obesity and maternal diabetes mellitus. Greater rates of maternal obesity and gestational diabetes represent some of the main components of a proposed “obesity cycle,” responsible for in utero programming of later adiposity and transgenerational amplification of obesity.14Dabelea D. Crume T. Maternal environment and the transgenerational cycle of obesity and diabetes.Diabetes. 2011; 60: 1849-1855Crossref PubMed Scopus (243) Google Scholar, 26Catalano P.M. Obesity and pregnancy–the propagation of a viscous cycle?.J Clin Endocrinol Metab. 2003; 88: 3505-3506Crossref PubMed Scopus (277) Google Scholar This theory was first proposed by Pedersen,27Pedersen J. The pregnant diabetic and her newborn. William & Wilkins, Baltimore (MD)1967Google Scholar who hypothesized that mothers who were obese and/or with diabetes provided increased nutrition to the fetuses, who then became larger with greater adiposity. Increasing fetal adiposity/overnutrition “programs” the fetuses to grow more rapidly postnatally and develop early obesity. As obesity tracks with age, these children are more likely to become obese adults. The classification of infants as LGA based on customized percentiles for birth weight has been proposed,18Pasupathy D. McCowan L.M. Poston L. Kenny L.C. Dekker G.A. North R.A. Perinatal outcomes in large infants using customised birthweight centiles and conventional measures of high birthweight.Paediatr Perinat Epidemiol. 2012; 26: 543-552Crossref PubMed Scopus (32) Google Scholar, 28McCowan L. Stewart A.W. Francis A. Gardosi J. A customised birthweight centile calculator developed for a New Zealand population.Aust N Z J Obstet Gynaecol. 2004; 44: 428-431Crossref PubMed Scopus (130) Google Scholar, 29Larkin J.C. Speer P.D. Simhan H.N. A customized standard of large size for gestational age to predict intrapartum morbidity.Am J Obstet Gynecol. 2011; 204: 499.e1-499.e10Abstract Full Text Full Text PDF Scopus (53) Google Scholar which have strengths and limitations. Customized percentiles incorporate maternal and infant factors, such as maternal weight, height, parity, gestational age, and infant sex, resulting in some LGA infants being recategorized as appropriate for gestational age (AGA).18Pasupathy D. McCowan L.M. Poston L. Kenny L.C. Dekker G.A. North R.A. Perinatal outcomes in large infants using customised birthweight centiles and conventional measures of high birthweight.Paediatr Perinat Epidemiol. 2012; 26: 543-552Crossref PubMed Scopus (32) Google Scholar Ethnicity also could be taken into account, because, for example, American Indian and Pacific Islander mothers are at increased risk of having LGA infants.28McCowan L. Stewart A.W. Francis A. Gardosi J. A customised birthweight centile calculator developed for a New Zealand population.Aust N Z J Obstet Gynaecol. 2004; 44: 428-431Crossref PubMed Scopus (130) Google Scholar, 30Boulet S.L. Alexander G.R. Salihu H.M. Pass M. Macrosomic births in the United States: determinants, outcomes, and proposed grades of risk.Am J Obstet Gynecol. 2003; 188: 1372-1378Abstract Full Text Full Text PDF PubMed Scopus (420) Google Scholar Adjusting for maternal height is reasonable, because a longer baby would be proportionally heavier but not necessarily fatter. In a large prospective cohort study, newborns defined LGA by customized percentiles had a 4-fold increase in risk of severe neonatal morbidity/mortality compared with those born macrosomic or defined as LGA by population percentiles.18Pasupathy D. McCowan L.M. Poston L. Kenny L.C. Dekker G.A. North R.A. Perinatal outcomes in large infants using customised birthweight centiles and conventional measures of high birthweight.Paediatr Perinat Epidemiol. 2012; 26: 543-552Crossref PubMed Scopus (32) Google Scholar There are issues, however, with customized percentiles. In the aforementioned study,18Pasupathy D. McCowan L.M. Poston L. Kenny L.C. Dekker G.A. North R.A. Perinatal outcomes in large infants using customised birthweight centiles and conventional measures of high birthweight.Paediatr Perinat Epidemiol. 2012; 26: 543-552Crossref PubMed Scopus (32) Google Scholar mothers of large babies who were defined as AGA by customized percentiles had a 1.6-fold increase in the overall rate of cesarean delivery. Further, it is important to consider that prepregnancy maternal body mass index (BMI) is likely to be the main predictor of birth weight. Maternal obesity represents the main factor leading to fetal obesity at any maternal height,31Ay L. Kruithof C.J. Bakker R. Steegers E.A. Witteman J.C. Moll H.A. et al.Maternal anthropometrics are associated with fetal size in different periods of pregnancy and at birth. The Generation R Study.BJOG. 2009; 116: 953-963Crossref PubMed Scopus (93) Google Scholar and the increasing prevalence of LGA infants mirrors increasing maternal adiposity. As a result, the use of percentiles adjusting for maternal weight may be misguided; if the mother is obese, the adjustment of the baby's weight would be inappropriate because it would likely normalize obesity-driven fetal growth and adiposity. In addition, certain ethnic groups have increased incidences of adult obesity that may contribute to increased size of their babies, and adjustment for ethnicity may lead to the inappropriate classification of newborns. Therefore, moving an LGA infant to an AGA category should not diminish birth-size related pathology, and recent reviews have criticized the substantive support for clinical use of customized percentiles in classifying babies as LGA.32Sjaarda L.A. Albert P.S. Mumford S.L. Hinkle S.N. Mendola P. Laughon S.K. Customized large-for-gestational-age birthweight at term and the association with adverse perinatal outcomes.Am J Obstet Gynecol. 2014; 210: 63.e1-63.e11Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar Birth weight does not define body composition, an issue critically important in LGA newborns. For more than 3 decades, ponderal index (g/cm3) has been considered a practical approach to characterize neonatal adiposity,33Holston A. Stokes T. Olsen C. Choi Y.S. Curtis J. Higginson J. et al.Novel noninvasive anthropometric measure in preterm and full-term infants: normative values for waist circumference:length ratio at birth.Pediatr Res. 2013; 74: 299-306Crossref PubMed Scopus (11) Google Scholar which differs from BMI (kg/m2) for providing greater adjustment for length and, thus, is a more reliable measure of neonatal adiposity.34Demerath E.W. Fields D.A. Body composition assessment in the infant.Am J Hum Biol. 2014; 26: 291-304Crossref PubMed Scopus (101) Google Scholar In infants born LGA, ponderal index score was significantly greater than in those born AGA,35Lepercq J. Lahlou N. Timsit J. Girard J. Mouzon S.H. Macrosomia revisited: ponderal index and leptin delineate subtypes of fetal overgrowth.Am J Obstet Gynecol. 1999; 181: 621-625Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar, 36Davies D.P. Size at birth and growth in the first year of life of babies who are overweight and underweight at birth.Proc Nutr Soc. 1980; 39: 25-33Crossref PubMed Scopus (39) Google Scholar, 37Chiavaroli V. Cutfield W.S. Derraik J.G. Pan Z. Ngo S. 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Lee N. et al.Birth status, child growth, and adult outcomes in low- and middle-income countries.J Pediatr. 2013; 163: 1740-1746.e4Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar In addition, ponderal index does not distinguish between fat mass and lean mass and does not clarify which body compartment is overrepresented in LGA babies; indeed, a poor correlation has been shown between ponderal index and fat mass estimated by direct assessments of neonatal body composition.34Demerath E.W. Fields D.A. Body composition assessment in the infant.Am J Hum Biol. 2014; 26: 291-304Crossref PubMed Scopus (101) Google Scholar, 42de Bruin N.C. van Velthoven K.A. Stijnen T. Juttmann R.E. Degenhart H.J. Visser H.K. Body fat and fat-free mass in infants: new and classic anthropometric indexes and prediction equations compared with total-body electrical conductivity.Am J Clin Nutr. 1995; 61: 1195-1205PubMed Google Scholar, 43De Cunto A. Paviotti G. Ronfani L. Travan L. Bua J. Cont G. et al.Can body mass index accurately predict adiposity in newborns?.Arch Dis Child Fetal Neonatal Ed. 2014; 99: F238-F239Crossref PubMed Scopus (41) Google Scholar Therefore, in recent years, direct techniques have been proposed to measure neonatal adiposity, such as dual-energy x-ray absorptiometry and air displacement plethysmography.43De Cunto A. Paviotti G. Ronfani L. Travan L. Bua J. Cont G. et al.Can body mass index accurately predict adiposity in newborns?.Arch Dis Child Fetal Neonatal Ed. 2014; 99: F238-F239Crossref PubMed Scopus (41) Google Scholar, 44Ma G. Yao M. Liu Y. Lin A. Zou H. Urlando A. et al.Validation of a new pediatric air-displacement plethysmograph for assessing body composition in infants.Am J Clin Nutr. 2004; 79: 653-660Crossref PubMed Scopus (204) Google Scholar, 45Hammami M. Walters J.C. Hockman E.M. Koo W.W. Disproportionate alterations in body composition of large for gestational age neonates.J Pediatr. 2001; 138: 817-821Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar These methods consistently have shown increased fat mass in LGA babies compared with AGA babies.45Hammami M. Walters J.C. Hockman E.M. Koo W.W. Disproportionate alterations in body composition of large for gestational age neonates.J Pediatr. 2001; 138: 817-821Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar, 46Schmelzle H.R. Quang D.N. Fusch G. Fusch C. Birth weight categorization according to gestational age does not reflect percentage body fat in term and preterm newborns.Eur J Pediatr. 2007; 166: 161-167Crossref PubMed Scopus (46) Google Scholar Nevertheless, these studies have not estimated body fat distribution, which would help clarify whether greater birth weight is associated with increased central adiposity. Lean and fat mass have been reported differently (as total or percentage mass), which may have created confusion regarding the body composition of LGA infants. Greater adiposity in LGA infants has been found in combination with an increased lean mass (as absolute values) measured by dual-energy x-ray absorptiometry, consistent with an increased muscularity compared with AGA infants.46Schmelzle H.R. Quang D.N. Fusch G. Fusch C. Birth weight categorization according to gestational age does not reflect percentage body fat in term and preterm newborns.Eur J Pediatr. 2007; 166: 161-167Crossref PubMed Scopus (46) Google Scholar, 47de Zegher F. Perez-Cruz M. Diaz M. Gomez-Roig M.D. Lopez-Bermejo A. Ibanez L. Less myostatin and more lean mass in large-born infants from nondiabetic mothers.J Clin Endocrinol Metab. 2014; 99: E2367-E2371Crossref PubMed Scopus (8) Google Scholar Specifically, breastfed LGA infants born to mothers without diabetes were found to have greater adiposity at birth and increased muscularity by age 4 months.47de Zegher F. Perez-Cruz M. Diaz M. Gomez-Roig M.D. Lopez-Bermejo A. Ibanez L. Less myostatin and more lean mass in large-born infants from nondiabetic mothers.J Clin Endocrinol Metab. 2014; 99: E2367-E2371Crossref PubMed Scopus (8) Google Scholar Similarly, an increase in lean mass in children born LGA through age 47 months also has been shown.48Hediger M.L. Overpeck M.D. Kuczmarski R.J. McGlynn A. Maurer K.R. Davis W.W. Muscularity and fatness of infants and young children born small- or large-for-gestational-age.Pediatrics. 1998; 102: E60Crossref PubMed Scopus (234) Google Scholar In other studies, the proportion of lean body mass as a percentage of body weight was lower in LGA babies with greater absolute values of lean mass.45Hammami M. Walters J.C. Hockman E.M. Koo W.W. Disproportionate alterations in body composition of large for gestational age neonates.J Pediatr. 2001; 138: 817-821Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar, 49Akcakus M. Kurtoglu S. Koklu E. Kula M. Koklu S. The relationship between birth weight leptin and bone mineral status in newborn infants.Neonatology. 2007; 91: 101-106Crossref PubMed Scopus (16) Google Scholar Collectively, these studies of LGA infants suggest an increase in fat mass and often a smaller increase in lean mass, so that percentage body fat is increased, notably in those born to mothers who are obese and or with diabetes45Hammami M. Walters J.C. Hockman E.M. Koo W.W. Disproportionate alterations in body composition of large for gestational age neonates.J Pediatr. 2001; 138: 817-821Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar; however, more robust studies are needed to clarify the pattern of fat distribution and levels of adiposity in these babies, ideally by using direct methods for assessment of neonatal body composition. There are contradictory long-term outcomes reported in those born LGA for adiposity and cardiometabolic disorders.3Johnsson I.W. Haglund B. Ahlsson F. Gustafsson J. A high birth weight is associated with increased risk of type 2 diabetes and obesity.Pediatr Obes. 2015; 10: 77-83Crossref PubMed Scopus (122) Google Scholar, 50Schellong K. Schulz S. Harder T. Plagemann A. Birth weight and long-term overweight risk: systematic review and a meta-analysis including 643,902 persons from 66 studies and 26 countries globally.PLoS One. 2012; 7: e47776Crossref PubMed Scopus (248) Google Scholar, 51Renom Espineira A. Fernandes-Rosa F.L. Bueno A.C. de Souza R.M. Moreira A.C. de Castro M. et al.Postnatal growth and cardiometabolic profile in young adults born large for gestational age.Clin Endocrinol (Oxf). 2011; 75: 335-341Crossref PubMed Scopus (35) Google Scholar, 52Stuart A. Amer-Wahlin I. Persson J. Kallen K. Long-term cardiovascular risk in relation to birth weight and exposure to maternal diabetes mellitus.Int J Cardiol. 2013; 168: 2653-2657Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 53Lawlor D.A. Ronalds G. Clark H. Smith G.D. Leon D.A. Birth weight is inversely associated with incident coronary heart disease and stroke among individuals born in the 1950s: findings from the Aberdeen Children of the 1950s prospective cohort study.Circulation. 2005; 112: 1414-1418Crossref PubMed Scopus (227) Google Scholar As discussed previously, this contradiction probably reflects subjects from different eras with different environmental factors affecting intrauterine nutrition, neonatal anthropometry, postnatal nutritional exposure, and growth trajectories during infancy and childhood. Nutrition before conception and during pregnancy plays a fundamental role in influencing maternal weight gain, fetal growth, and neonatal outcomes,54Imdad A. Bhutta Z.A. Maternal nutrition and birth outcomes: effect of balanced protein-energy supplementation.Paediatr Perinat Epidemiol. 2012; 26: 178-190Crossref PubMed Scopus (152) Google Scholar, 55Gresham E. Byles J.E. Bisquera A. Hure A.J. Effects of dietary interventions on neonatal and infant outcomes: a systematic review and meta-analysis.Am J Clin Nutr. 2014; 100: 1298-1321Crossref PubMed Scopus (66) Google Scholar, 56Muhlhausler B.S. Gugusheff J.R. Ong Z.Y. Vithayathil M.A. Nutritional approaches to breaking the intergenerational cycle of obesity.Can J Physiol Pharmacol. 2013; 91: 421-428Crossref PubMed Scopus (23) Google Scholar but the evidence is limited in the case of LGA births. A lower prevalence of LGA infants was observed among healthy mothers who followed a low-glycemic diet compared with those assigned to a high-glycemic diet (3.1% vs 33.3%).57Moses R.G. Luebcke M. Davis W.S. Coleman K.J. Tapsell L.C. Petocz P. et al.Effect of a low-glycemic-index diet during pregnancy on obstetric outcomes.Am J Clin Nutr. 2006; 84: 807-812Crossref PubMed Scopus (172) Google Scholar Conversely, a randomized controlled trial involving women who had previously delivered a large infant showed that a low-glycemic diet did not reduce incidence of LGA babies,58Walsh J.M. McGowan C.A. Mahony R. Foley M.E. McAuliffe F.M. Low glycaemic index diet in pregnancy to prevent macrosomia (ROLO study): randomised control trial.BMJ. 2012; 345: e5605Crossref PubMed Scopus (223) Google Scholar although there was an associated reduction in gestational weight gain and in the prevalence of gestational diabetes.58Walsh J.M. McGowan C.A. Mahony R. Foley M.E. McAuliffe F.M. Low glycaemic index diet in pregnancy to prevent macrosomia (ROLO study): randomised control trial.BMJ. 2012; 345: e5605Crossref PubMed Scopus (223) Google Scholar Further, a recent meta-analysis showed that dietary interventions in pregnancy were associated with increased birth size (by both weight and length) and reduced incidence of low birth weight, but there was no significant effect on the prevalence of infants born LGA or small for gestational age.55Gresham E. Byles J.E. Bisquera A. Hure A.J. Effects of dietary interventions on neonatal and infant outcomes: a systematic review and meta-analysis.Am J Clin Nutr. 2014; 100: 1298-1321Crossref PubMed Scopus (66) Google Scholar Overall, it is difficult to differentiate the effects of maternal obesity from those of an obesogenic diet on the prevalence of LGA births because both tend to be closely intertwined.56Muhlhausler B.S. Gugusheff J.R. Ong Z.Y. Vithayathil M.A. Nutritional approaches to breaking the intergenerational cycle of obesity.Can J Physiol Pharmacol. 2013; 91: 421-428Crossref PubMed Scopus (23) Google Scholar The early postnatal nutritional environment, particularly breastfeeding, also has been suggested to be a modulator of long-term risks of obesity,59Arenz S. Ruckerl R. Koletzko B. von Kries R. Breast-feeding and childhood obesity—a systematic review.Int J Obes Relat Metab Disord. 2004; 28: 1247-1256Crossref PubMed Scopus (948) Google Scholar which may affect outcomes among those born LGA. Unfortunately, many epidemiologic studies do not report information on feeding practices in infants born LGA, such as data on early infant feeding and age at weaning into solid foods. Breastfeeding is associated with a small but consistent reduction in later childhood obesity (OR 0.78 compared with formula-fed infants).59Arenz S. Ruckerl R. Koletzko B. von Kries R. Breast-feeding and childhood obesity—a systematic review.Int J Obes Relat Metab Disord. 2004; 28: 1247-1256Crossref PubMed Scopus (948) Google Scholar A similar or longer breastfeeding duration has been observed in LGA infants compared with those born AGA,60Surber C.D. Breastfeeding among obese women: the role of infant size and providing additional support. Cornell University, Ithaca (NY)2007Google Scholar except for large babies of obese women with diabetes or extremely obese women without diabetes, who are more likely to experience breastfeeding failure and/or breastfeed for a shorter period of time.61Cordero L. Gabbe S.G. Landon M.B. Nankervis C.A. Breastfeed