Jn212415 2084.209

The Journal of Nutrition Nutrient Requirements and Optimal Nutrition Early Protein Intake Is Associated with BodyComposition and Resting Energy Expenditure inYoung Adults Born with Very Low Birth Weight1–3 Hanna-Maria Matinolli,4,5* Petteri Hovi,4,6 Satu Ma¨nnisto¨,4 Marika Sipola-Leppa¨nen,4,5,7Johan G Eriksson,4,8,9,10 Outi Ma¨kitie,6,10 Anna-Liisa Ja¨rvenpa¨a¨,6 Sture Andersson,6 and Eero Kajantie4,6,11 4Department of Health, Chronic Disease Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland; 5Institute ofHealth Sciences, University of Oulu, Oulu, Finland; 6ChildrenÕs Hospital, University of Helsinki and Helsinki University Hospital,Helsinki, Finland; 7Department of Pediatrics and Adolescence, Oulu University Hospital, Oulu, Finland; 8Department of General Practiceand Primary Health Care, Institute of Clinical Medicine, University of Helsinki, Helsinki, Finland; 9Unit of General Practice, HelsinkiUniversity Hospital, Helsinki, Finland; 10Folkha¨lsan Research Centre, Helsinki, Finland; and 11Department of Obstetrics andGynaecology, MRC Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland Background: Suboptimal nutrition during fetal life and early childhood may be important in early programming of health and disease. Preterm infants born with very low birth weight (VLBW; <1500 g) frequently receive inadequate neonatal nutrition; the long-term consequences are poorly known.
Objective: We evaluated the association between early macronutrient intake and body composition in young adults born with VLBW.
Methods: We collected comprehensive information on daily nutritional intake during the initial hospital stay for 127 participants of the Helsinki Study of Very Low Birth Weight Adults. We calculated mean daily intakes of energy, protein, fat, and carbohydrate during the first 9 wk of life. At the mean age of 22.5 y, the subjects underwent measurements of weight, height, body composition by dual-energy X-ray absorptiometry, and resting energy expenditure. The associations were examined by linear regression.
Results: We found that energy, protein, and fat intakes during the first 3 wk of life, all below current recommendations, predicted adult body composition. When adjusted for sex, age, birth weight SD score, and gestational age, a 1 g  kg21  d21 higher protein intake predicted 11.1% higher lean body mass (LBM) (95% CI: 3.7%, 18.9%) and 8.5% higher resting energy expenditure (REE) (95% CI: 0.2%, 17.0%). Among those born before 28 wk of gestation, the numbers were 22.5% (95% CI: 1.9%, 47.4%) for LBM and 22.1% (95% CI: 3.6%, 44.0%) for REE. Similar associations were seen with energy (P = 0.01, P = 0.05) and fat (P < 0.01, P = 0.03) but not with carbohydrate. Energy intake was also associated with BMI (P = 0.01) and fat intake with BMI (P < 0.01) and percentage body fat (P = 0.05). The results were little changed when adjusted for prenatal and postnatal characteristics.
Conclusions: At relatively low neonatal protein intake levels, additional protein intake is reflected in a healthier body composition, accompanied by a higher metabolic rate, in young adults born with VLBW 20 y earlier.
J Nutr 2015;145:2084–91.
preterm birth, very low birth weight, nutrition, early protein intake, body composition, resting energy expenditure life have a profound impact on a personÕs health and well-being in The developmental origins of the health and disease theory, originally adulthood (1–5). The important role of early nutrition as an exposure is proposed by David Barker in the early 1980s, suggest that certain supported by a large body of animal studies, in which relatively modest early life events during critical time windows of prenatal and postnatal alterations in early nutrient intake produce substantial life-long effects 1 Supported by grants from the Academy of Finland, Jenny and Antti Wihuri on risk factors for adult cardiometabolic disease (6–8). Despite the lack Foundation, Emil Aaltonen Foundation, the Finnish Government Special of direct human evidence, modification of early nutrition is widely seen Subsidiary for Health Sciences (EVO), Finnish Medical Societies (Duodecim and as a potential way to intervene in early programming of adult disease.
Finska La¨karesa¨llskapet), Jalmari and Rauha Ahokas Foundation, Juho Vainio Particular attention has recently been devoted to early protein Foundation, Novo Nordisk Foundation, Signe and Ane Gyllenberg Foundation,Sigrid Jus ´elius Foundation, and Yrjo¨ Jahnsson Foundation.
intake. Among infants born preterm (<37 gestational weeks) or 2 Author disclosures: H-M Matinol i, P Hovi, S Ma¨nnisto¨, M Sipola-Leppa¨nen, JG with low (LBW12; <2500 g) or, in particular, very low birth weight Eriksson, O Ma¨kitie, A-L Ja¨rvenpa¨a¨, S Andersson, and E Kajantie, no conflicts of interest.
3 Supplemental Tables 1–3 and Supplemental Figure 1 are available from the 12 Abbreviations used: BPD, bronchopulmonary dysplasia; LBM, lean body ‘‘Online Supporting Material'' link in the online posting of the article and from the mass; LBW, low birth weight; PBF, percentage body fat; REE, resting energy same link in the online table of contents at http://jn.nutrition.org.
expenditure; REE:LBM, ratio of REE to LBM; SGA, small for gestational age; * To whom correspondence should be addressed. E-mail: [email protected]
VLBW, very low birth weight (birth weight , 1500 g).
ã 2015 American Society for Nutrition.
Manuscript received February 13, 2015. Initial review completed March 10, 2015. Revision accepted June 24, 2015.
First published online July 15, 2015; doi:10.3945/jn.115.212415.
(VLBW; <1500 g), protein requirements are relatively high, and the We collected detailed information on enteral and parenteral nutri- key goal was to attain these requirements with formula enrichments tion, medications, and blood transfusions the infant received and daily/ or, during early intensive care, with intravenous nutrition. Although weekly growth measurements from the records of the neonatal intensive there is some evidence of benefits with more healthy body care unit or follow-up units. We excluded medications and blood composition #1 y of age (9–11), the long-term effects on body transfusions from the analysis because of minimal nutritional values formacronutrients. In our analysis, the macronutrient content of the composition and cardiometabolic health are limited and contra- mothersÕ own breast milk was based on figures published by Anderson dictory (12–15). In infants born at term, who have lower protein et al. (21) with measures drawn from preterm milk. The corresponding requirements, the discussion has centered on the early protein content for banked human breast milk was based on values published by hypothesis that suggests that excess protein intake during infancy, Ro¨nnholm et al. (22, 23) with macronutrient content analyzed from the by increasing weight gain in infancy, results in increased risk of banked pasteurized milk from the milk bank of the same hospital where obesity later in life (16). The hypothesis arose from observations the infants of the present study were treated. The contents of fortifiers that breast milk, which contains lower amounts of protein than were based on concentrations received from manufacturers (Nutricia infant formulas, protects from later obesity (17). This hypothesis Baby Oy). For the contents of special preterm formulas or protein has gained support from randomized trials that compared high- fortifiers we used data published during the matching time period in and low-protein formulas among healthy term-born children at 6 y European countries (24, 25).
All infants received pooled, banked, and pasteurized human milk.
of age (18) and among term-born children small for gestational age The practice was to start enteral feedings through a nasogastric tube (SGA; birth weight < 22 SDs) at 5–8 y age (19). However, only the during the first or second day of life with pooled banked human milk.
SGA trials have thus far demonstrated a specific effect on fat mass The daily milk intake was thereafter increased according to individual rather than lean mass. Again, evidence on longer-term outcomes is tolerance until the amount of 200 mL  kg21  d21, which was then maintained until discharge. Calcium, phosphate, and multivitamin To assess the long-term effects of early protein intake, we supplementation was used throughout the study period (23). Milk used the unique natural experiment of the Helsinki Study of Very fortifiers or preterm formulas were being introduced; 28 of the Low Birth Weight Adults (<1500 g). During the postnatal participants (22%) received these during the 9-wk period and only hospital treatment of these preterm infants, typically lasting for 1 participant during the first 3 wk of life. If targeted enteral feeding was 2–4 mo, there is considerable variation in nutrient intake, which not possible, intravenous fluids were started with glucose up to 15% [44participants (35%)]. Parenteral nutrition with amino acids to 22 is recorded in detail daily by the medical staff. We have extracted participants (17%) and lipids to 19 participants (15%) were gradually these data for the first 9 wk of life from the hospital records and introduced from the second or third day.
assessed body composition and resting energy expenditure(REE) in these subjects when they became young adults. Our Clinical measurements. At the mean age of 22.5 y the subjects hypothesis was that higher fat, protein, and total energy intakes attended a clinical examination, after a fasting period of $8 h. During in early life predict overweight and obesity in early adulthood.
the examination height, weight, and waist and hip circumferences were Our specific aim was to assess the role of protein intake in this measured, and BMI was calculated. The participants completed a detailed questionnaire on socioeconomic status, smoking, medicalhistory, and use of medication. Detailed information on maternalpregnancy was collected separately from the records of birth hospitals and maternity clinics.
A whole-body DXA (Hologic Discovery A, software version 12.3:3) The original study cohort, The Helsinki Study of Very Low Birth Weight was used to measure body composition (n = 118) (20, 26). Calibration of Adults, consisted of 335 consecutive infants born with VLBW (<1500 g) the measurements was performed with a spine phantom; inter-CV for the between January 1978 and December 1985 and cared for at the neonatal phantom bone mineral content, area, and bone mineral density were intensive care unit of ChildrenÕs Hospital at Helsinki University Central 0.35%, 0.21%, and 0.41%, respectively. The reproducibility of DXA Hospital (20) (Supplemental Figure 1). When the study cohort reached measurement for bone, fat, and lean mass is 1.2%, 1.9%, and 0.7%, young adulthood, a group for comparison was selected from hospital respectively (27). REE was measured at rest by indirect calorimetry records of infants born at term and not SGA. Participants were group- (Deltatrac II; Datex) when the device was available (n = 96) (28).
matched for age, birth hospital, and sex and were invited to take part in aclinical examination to which 166 of the VLBW subjects and 172 of the Statistical analyses. All statistical analyses were run on IBM SPSS for subjects born at term agreed to participate. All participants gave their Windows 21, and P < 0.05 was used to indicate significance. The chi- written informed consent, and the Ethics Committee of Children and square test was used to compare proportions, and StudentÕs t test was AdolescentsÕ Diseases and Psychiatry at the Helsinki University Central used to compare means. We used multiple linear regression analysis to Hospital approved the study protocol. In the present study we did not assess associations between energy and nutrient intakes at early age use data collected for the comparison group.
(1–3 wk, 4–6 wk, and 7–9 wk) as predictors and body composition We collected the daily nutritional intake during the initial hospital measurements in young adulthood as outcomes. Results of the linear stay from hospital records for 158 subjects born preterm and who regression are presented as B (95% CIs). For the outcome variables with underwent the clinical examination (data were unavailable for 8 skewed distributions [BMI, lean body mass (LBM), and REE] we used subjects). For 17 subjects we were not able to find complete hospital log-transformations for the distributions to attain normality. After records, and they were therefore excluded from the analyses. Compar- analyses the results were back-transformed. The results are therefore ison between subjects included and subjects excluded is shown in expressed as percentages. Potential confounders included in the adjusted Supplemental Table 1. After 9 wk there was a reduction in the number of analyses were sex, age at clinical examination (model 1), gestational age, participants with sufficient data because of discharges from the hospital.
and birth weight SD score (model 2). In addition to the potential Hence, we decided to limit the data to the first 9 wk of life. We then confounders used in the full model, we included highest parental decided to further divide the 9-wk data into three 3-wk periods. We education as an indicator of socioeconomic status in childhood, maternal excluded the subjects with neurosensory impairments (n = 14; cerebral smoking during pregnancy, and maternal preeclampsia and neonatal palsy, n = 13; mental retardation, n = 4; and blindness, n = 2, some of exposure to treatment with ventilator (days), bronchopulmonary these participants had $2 impairments) from the main analyses because dysplasia (BPD; prospectively confirmed by a neonatologist), septicemia these conditions could have a separate association with adult body (diagnosed if the infant had symptoms and if the blood culture was composition and metabolism. The definitions of cerebral palsy and positive), exchange transfusion, or persistent ductus arteriosus. We ran mental retardation were based on self-report.
the analyses also with current smoking and leisure time physical exercise Early protein intake and adult body composition (assessed by questionnaire) (29) as covariates. The potential mediating Characteristics of the young adults born with very low role of height was also tested in the analyses of LBM.
We compared the body size and composition of the subjects included in the study (n = 127) with the VLBW members of the original cohort Missing values, n who attended the clinical examination but who were excluded from ouranalyses because of missing data of early nutrition (n = 25), and no statistically significant differences were found between the groups.
Gestational age, wk Birth weight SD score Small for gestational age Sample description. The characteristics of the study partici-pants are shown in Table 1. At the mean 6 SD age of 22.5 6 2.1 y, as expected, men and women differed in the body composition Apgar score 1 min measurements and REE. Because the interaction between sexand early nutrient intake in the further analysis was not sig- Maternal smoking during pregnancy Maternal preeclampsia nificant, we did not perform sex-specific analyses.
Premature rupture of membranes Energy. Mean energy intake during weeks 1–3 was lower than currently recommended, but it reached the recommended levels Supplemental oxygen, d after week 4 (Table 2). All except 6 of the study participants met Mechanical ventilation, d the recommended level of energy intake by the end of the 9-wkperiod. The associations between energy intake and adult body composition are shown in Table 3. Higher energy intake during Weight SD score at term age weeks 1–3 predicted higher BMI and higher LBM as determinedby DXA (model 1, adjusted for sex and age, and model 2, additionally adjusted for gestational age and birth weight SD score). The association between energy intake and LBM persisted after adjustment for parental education and prenatal and neonatal factors (full model). The results remained the same after further adjustments for current smoking and leisure time physical activity (data not shown). Energy intake was not associated with height, percentage body fat (PBF), or waist Waist circumference, cm Among the subset of 96 subjects who underwent indirect calorimetry, higher energy intake tended to be associated with Percentage body fat higher REE (model 2; P = 0.05) and lower ratio of REE to LBM (REE:LBM) (model 2; P = 0.05) (Table 4). From week 4 onwardenergy intake did not predict adult body size, composition, or Protein. Mean protein intake increased throughout the first 9 postnatal weeks, although it remained substantially below current recommendations with only 1 study participant reaching the currently recommended level during the assessed 9-wk period (Table 2). During weeks 1–3 higher protein intake REE:LBM, kcal  kg21  d21 predicted higher LBM such that 1 g  kg21  d21 higher intake predicted 11.2% higher LBM (Table 3). The association persisted after adjustment for sex; age; parental education; and Parental education prenatal, neonatal, and current lifestyle factors and also after adjustment for height. The associations of protein intake with height (P = 0.08) and BMI (P = 0.06) were borderline statistically significant (model 1) but attenuated after adjustments (full model). The associations between protein intake and PBF or waist circumference were not statistically significant.
Leisure time physical activity2 Higher protein intake also predicted higher total REE and lower REE:LBM (Table 4). Protein intake from week 4 onward did not predict adult body size, composition, or REE.
Fat. Mean fat intake during weeks 1–3 was slightly below 1 Values are n (%), means 6 SDs, or mean [25th, 75th percentiles]; n = 127 unless current recommendations, but it reached the recommended observations were missing. REE, resting energy expenditure; REE:LBM, ratio of levels after week 4 (Table 2). Higher fat intake during weeks 1–3 resting energy expenditure to lean body mass.
2 predicted higher BMI and higher LBM (Table 3); 1 g  kg21  d21 Assessed by the fol owing question: 1) How much do you exercise and stress yourself physical y in your leisure time? 2) I regularly train for competitive sports several times a week; 3) higher intake predicted 3.8% higher BMI and 3.6% higher I exercise to maintain my physical condition for at least 3 h/wk; I walk, cycle, or perform other LBM. The associations persisted after adjustment for sex, age, exercise not causing substantial perspiration at least 4 h/wk; or 4) I do not exercise much.
Matinolli et al.
Intakes of energy and macronutrients among the young adults born with very low birth weight1 Energy, kcal  kg21  d21 Protein, g  kg21  d21 Fat, g  kg21  d21 Carbohydrate, g  kg21  d21 127 94.1 6 15.5 (64.6, 120) 1.4 6 0.4 (0.8, 2.1) 4.3 6 1.1 (2.2, 6.0) 11.1 6 1.29 (9.04, 12.9) 8.08 6 2.47 117 119 6 14.6 (97.1, 142) 1.9 6 0.4 (1.4, 2.8) 5.9 6 1.0 (4.3, 7.6) 12.4 6 1.30 (10.1, 14.9) 11.2 6 2.27 124 6 13.3 (106, 147) 2.1 6 0.5 (1.6, 3.1) 6.1 6 0.9 (5.0, 7.6) 12.9 6 1.28 (10.8, 15.5) 11.3 6 2.56 1 Values are means 6 SDs (5th, 95th percentile).
2 Recommendations published (30); for protein, infant weight: 1) ,1 kg; 2) 1.0–1.8 kg.
parental education, and prenatal and neonatal factors and for predicted adult height, there were statistically significant inter- current lifestyle factors. Higher fat intake tended to be associ- actions between the effects of gestational age and energy (P = ated with PBF (P = 0.08 for model 1, P = 0.05 for model 2) and 0.01 in the full model), protein (P = 0.01), and fat intake (P = waist circumference (P = 0.07 for model 1, P = 0.05 for model 2); 0.01). We conducted the analyses separately among subjects however, the adjustments for neonatal and current characteris- born before 28 wk of gestation (characteristics of this group are tics attenuated the results. Fat intake was not associated with presented in Supplemental Table 2), the commonly used limit for extremely low gestational age, and those born thereafter.
Higher fat intake was associated with higher REE and lower The associations with height were confined to subjects born REE:LBM (Table 4). Fat intake from week 4 onward did not before 28 wk of gestation. For example, among these subjects predict adult body size, composition, or REE.
1 g  kg21  d21 higher protein intake predicted 10.8 cm (95%CI: 1.01, 20.5 cm) taller adult height, 29.1% (95% CI: 7.85%, Carbohydrate. Mean carbohydrate intake during weeks 1–3 54.6%) higher LBM, and 22.3% (95% CI: 5.34%, 41.9%) was slightly below current recommendations, but it reached the higher REE when adjusted for sex and age, whereas no associations recommended levels after week 4 (Table 2). Carbohydrate intake were present among subjects born after 28 wk of gestation. No did not predict adult body size, composition, or REE.
other statistically significant interactions were found betweengestational age and nutrient intake.
Length of gestation, fetal growth, and neonatal condi- The numbers of subjects with specific neonatal conditions are tions. We found no associations between gestational age at birth shown in Table 1. Infants with lung disease that later met the or fetal growth as assessed by birth weight SD score and nutrient criteria for BPD had 9.91 kcal  kg21  d21 (95% CI: 3.23, 16.7 intake during weeks 1–3, a period during which nutrient intake kcal  kg21  d21; P = 0.004) lower energy intake, 0.19 g  kg21  d21 predicted adult outcomes in our study.
(95% CI: 0.03, 0.35 g  kg21  d21; P = 0.018) lower protein We further assessed whether the association of nutrient intake, and 0.76 g  kg21  d21 (95% CI: 0.29, 1.23 g  kg21  d21; intakes during postnatal weeks 1–3 with the adult outcomes P = 0.002) lower fat intake during the weeks 1–3 than infants differed according to the degree of prematurity. In analyses that without BPD. No difference in carbohydrate intake was found Linear regression models for the association between nutrient intake between weeks 1 and 3 and body composition measurements in young adulthood in young adults born with very low birth weight1 Height, cm (n = 127) Waist, cm (n = 127) 0.58 (20.26, 1.41) 2.12 (0.30, 3.87) 2.33 (0.70, 3.98) 0.33 (20.35, 1.00) 0.80 (20.28, 1.88) 0.52 (20.30, 1.34) 2.32 (0.50, 4.19) 2.43 (0.70, 4.08) 0.43 (20.27, 1.13) 0.97 (20.13, 2.06) 0.42 (20.52, 1.36) 1.92 (20.10, 3.98) 2.22 (0.30, 4.19) 0.26 (20.53, 1.06) 0.67 (20.59, 1.94) 3.20 (20.38, 6.78) 7.36 (20.40, 15.8) 11.2 (3.77, 19.1) 0.15 (22.78, 3.09) 2.53 (22.11, 7.17) 2.74 (20.74, 6.22) 6.72 (21.92, 16.0) 10.4 (2.43, 19.1) 0.62 (23.86, 2.63) 1.97 (23.21, 7.16) 0.87 (20.32, 2.07) 3.77 (1.20, 6.29) 3.56 (1.21, 5.97) 0.85 (20.11, 1.81) 1.41 (20.12, 2.94) 0.70 (20.47, 1.86) 3.87 (1.31, 6.61) 3.56 (1.21, 5.97) 0.97 (20.01, 1.95) 1.56 (0.01, 3.10) 0.55 (20.77, 1.87) 3.56 (0.70, 6.61) 3.25 (0.60, 5.97) 0.80 (20.29, 1.90) 1.22 (20.55, 2.98) 0.41 (20.59, 1.40) 0.40 (21.71, 2.53) 1.31 (20.70, 3.36) 20.26 (21.07, 0.55) 0.34 (20.94, 1.62) 0.59 (20.36, 1.55) 0.50 (21.61, 2.63) 1.71 (20.30, 3.67) 20.19 (21.02, 0.63) 0.49 (20.80, 1.77) 0.43 (20.57, 1.42) 0.00 (22.02, 2.12) 1.11 (20.60, 3.46) 20.41 (21.26, 0.45) 0.20 (21.14, 1.55) 1 Values are B (95% CIs). Data were analyzed with linear regression. LBM, lean body mass; PBF, percentage body fat.
2 Adjusted for sex and age at clinical examination.
3 Additionally adjusted for gestational age and birthweight SD score.
4 Additionally adjusted for highest parental education, maternal smoking during pregnancy, and maternal preeclampsia and for neonatal exposures of treatment with ventilator(days), bronchopulmonary dysplasia, septicemia, exchange transfusion, or persistent ductus arteriosus.
Early protein intake and adult body composition Linear regression models showing the association predicted higher BMI, LBM, and REE. The most robust between nutrient intake between weeks 1 and 3 and REE and associations were seen between early protein and fat intakes, REE:LBM in young adults born with very low birth weight1 which in most infants were low by todayÕs standards, and adultLBM (Figure 1). Nutrient intakes were lower in infants who REE:LBM, % (n = 92) were born more immature or who had complications ofprematurity, and, for example, the association between early protein intake and adult LBM was confined to infants born 1.34 (20.43, 3.14) 21.35 (22.46, 20.22) 0.02 before 28 wk of gestation. Otherwise, the associations were 1.82 (0.00, 3.87) 21.15 (22.28, 20.01) 0.05 independent of prenatal and neonatal factors. This natural 1.91 (20.18, 4.06) 21.02 (22.33, 0.31) experiment elucidates the early protein hypothesis from a Full model extended5 2.13 (0.03, 4.28) 21.11 (22.43, 0.22) different angle by showing that at relatively low neonatal protein intake levels, additional protein intake is reflected by a 7.02 (20.86, 15.5) 26.46 (211.0, 21.74) 0.01 more healthy body composition 20 y later.
8.52 (0.16, 17.0) 25.52 (210.0, 20.81) 0.02 Our findings should be compared with findings in other 8.53 (20.18, 18.0) 24.73 (29.72, 0.52) studies in the light of physiologic protein intakes specific to the Full model extended5 9.03 (0.30, 18.5) 24.88 (29.85, 0.38) developmental period. In the healthy fetus, daily fetal protein accretion increases from 1.25 g 2.41 (20.18, 5.07) 22.08 (23.69, 20.44) 0.01  kg21  d21 in gestational week 2.89 (0.23, 5.62) 21.70 (23.32, 20.05) 0.04  kg21  d21 in gestational week 37 and slowly decreases thereafter (31). This, together with increased metabolic requirements, 3.13 (0.14, 6.21) 21.50 (23.35, 0.39) has resulted in the current guideline of Full model extended5 3.39 (0.41, 6.46) 21.64 (23.48, 0.24) ;4 g  kg21  d21 protein (Table 2) in small preterm infants. The mean intakes in our study were less than one-half of this: 1.4 g 1.21 (20.93, 3.23) 20.28 (21.63, 1.08)  kg21  d21 during weeks 1–3, only gradually rising to 2.1 g 1.53 (20.57, 3.68) 20.41 (21.73, 0.93)  kg21  d21 by week 9, accompanied by a much slower growth than would take place in utero. After 1.29 (20.93, 3.56) 20.10 (21.53, 1.36) term birth, physiologic protein intake is reduced. For example, Full model extended5 1.52 (20.72, 3.81) 20.12 (21.58, 1.36) a study showed that protein intake in exclusively breastfed 1 Values are B (95% CIs). Data were analyzed with linear regression. REE, resting infants at 3 mo is 1.1 g  kg21  d21, corresponding to 6.8 g/d energy expenditure; REE:LBM, ratio of resting energy expenditure to lean body mass.
2 (32). In formula-fed infants, protein intake can be roughly 2- Adjusted for sex and age at clinical examination.
3 Additionally adjusted for gestational age and birthweight SD score.
4 Additionally adjusted for highest parental education, maternal smoking during The European Childhood Obesity Project included 1138 pregnancy, and maternal preeclampsia and for neonatal exposures of treatment formula-fed infants randomly assigned to receive isocaloric low- with ventilator (days), bronchopulmonary dysplasia, septicemia, exchange transfusion, or high-protein formula and were compared with breastfed or persistent ductus arteriosus.
5 infants. At 6 y, those who received high-protein formula had Additionally adjusted for leisure time exercise and current daily smoking.
higher BMI than the low-protein formula group, whose BMIwas similar to that of the breastfed infants (18). However,among a subset of 66 infants who underwent body composition between infants diagnosed with BPD and infants without the measurements by isotope dilution at 6 mo, no difference was diagnosis. Infants who were treated longer with ventilators or found in either fat or LBM between the low- and high-protein who were supplied oxygen for a longer time had lower early groups, although both groups had higher fat mass than breastfed intakes of energy, protein, and fat (P < 0.01) and had (P = 0.04) infants (33). Although these results are consistent with the early or tended to have (P = 0.07) a lower intake of carbohydrate.
protein hypothesis, firm evidence of the effects on body Infants who received indomethacin or who underwent surgery composition awaits further follow-up. Clearer evidence was because of persistent ductus arteriosus had lower intakes of provided by trials that randomly assigned infants born at term energy, protein, and fat (P < 0.001 for all associations). Neonatal SGA to receive protein- and energy-enriched formula. At 5–8 y, sepsis or exposure to exchange transfusion was not associated those receiving the enriched formula had higher fat mass but with nutrient intake during weeks 1–3 (P > 0.10 for all similar LBM, as assessed by bioimpedance or isotope dilution We further assessed the effects of key prenatal conditions Only a few previous studies have used a similar design and on our main outcomes. No associations were found between reported long-term follow-up of early nutrient intake in small nutrient intake and being born from preeclamptic or multiple preterm infants. One study assessed adult body composition by pregnancy or between nutrient intake and maternal smoking DXA among 61 adolescents born before 34 wk of gestation. No during pregnancy. Adjustments for these neonatal and prenatal associations were found between neonatal energy or protein conditions are shown in Table 3 (full model). In general, the intake and fat mass, although those who had received more results showed little change.
energy were taller and heavier (13). However, the study used a To take the important role of growth into account, we adjusted dichotomous comparison of high and low intakes which could for growth during the first 3 wk [difference between birth weight mask existing associations that could be revealed by other SD score and weight SD score at age 21 d, available for 122 methods. Another study assessed insulin sensitivity among 37 participants (96%)]. The adjustments did not change our results.
4–10-y-olds born before 32 wk of gestation and found noassociations with early macronutrient intakes and insulin sensitivity (14). Short-term effects of early nutrition on bodycomposition in preterm LBW infants were reported. The results We found that macronutrient intake during the first 3 wk after suggest an association between higher protein provision in both preterm birth predicted body composition and energy metabo- hospital (9, 10) and post-discharge (11) formulas and lower fat lism 20 y later. Higher intakes of total energy, protein, and fat all mass and higher lean mass after relatively short follow-up up to Matinolli et al.


1 y. The consistent evidence of these associations is still lacking(12, 15).
The results of our study could suggest an extension to the early protein hypothesis by proposing that in the light of presentresults and past literature the relations of early protein intakewith body composition are nonlinear. At subphysiologic intakelevels, such as those in our study, a higher protein intake predictsan increase in lean rather than fat mass. At rather high levels,relative to the developmental period, such as in formula-fedinfants, increasing protein intake however will result in higherfat rather than lean mass in later life (19, 33). An analogousphenomenon is seen in studies that assessed the long-term effectsof growth during infancy. In studies in subjects born between1934 and 1944 in Helsinki, Finland (34), and between 1970 and1973 in New Delhi, India (35), a more rapid increase in BMIbetween birth and 2 y predicts higher LBM but not fat mass orpercentage in adult life. These cohorts are likely to include asubstantial proportion of infants with subphysiologic growth.
By contrast, among contemporary Western populations, supra-physiologic weight gain is more common, and in these popula-tions a more rapid growth during infancy will result in anincrease in both lean and fat mass later in life (36). Accordingly,when interventions to reduce infant growth by reducing proteinintake are planned, which may be appropriate in todayÕs infantsborn at term as a group, care should be taken that infants whoare at the lower end of the protein intake distribution do notattain too low levels that could endanger the growth of leantissue.
Our finding of the association between higher energy, protein, and fat intakes and higher REE but lower REE:LBMis also of particular interest when discussing potential pathwaysin the development of overweight and obesity. To our knowledgeno other study has yet assessed this association. We havepreviously shown that, in addition to lower LBM (26), VLBWadults in this cohort have lower REE and higher REE:LBM thanadults born at term (28); we now show that this phenomenon ismost pronounced among VLBW adults with lowest early proteinand fat intakes. The main constituents of LBM include muscleand internal organs, most of which are at rest metabolicallymore active than muscle (37). Our finding of the higher LBM butlower REE:LBM of subjects who received more protein supportsthe view included in the developmental origins of adult healthand disease hypothesis that materno-fetal undernutrition influ-ences the metabolic phenotype later in life so that undernutritionduring early life increases the metabolic activity, resulting inmore active energy metabolism in adulthood.
The design of our study holds a set of strengths and limitations. Our cohort is unique in that the data on neonatalnutrient intake are based on objective recordings by medicalstaff. However, data for weeks 1–3 were unavailable for 25subjects. In addition, a small proportion of infants receivednutritional products for which we have not been able to trace theexact compositions, and we have used compositions of a closelycorresponding product (e.g., the same label with compositionavailable for a different study year). All these inaccuracieswould, however, only be expected to increase random error and Results from linear regression analyses with measure- ments of body composition of the young adults born with very lowbirth weight as dependent variables and nutritional intakes of energy(A), protein (B), fat (C), and carbohydrate (D) during the first 3 wk of life maternal smoking during pregnancy, and maternal preeclampsia and as independent variables. Data represent the unstandardized regres- for neonatal exposure to treatment with ventilator (days), broncho- sion coefficient with 95% CI. *P , 0.05. BMI and LBM were log- pulmonary dysplasia, septicemia, exchange transfusion, or persistent transformed in the analyses so the values presented are expressed as ductus arteriosus. n = 127 for height, BMI, and waist circumference; back-transformed percentages. All models were adjusted for sex, age, n = 118 for LBM and PBF. LBM, lean body mass; PBF percentage birth weight SD score, gestational age, highest parental education, Early protein intake and adult body composition result in a more conservative conclusion. Although selection bias Gluckman PD, Lillycrop KA, Vickers MH, Pleasants AB, Phillips ES, cannot be excluded, a comparison of participants and nonpar- Beedle AS, Burdge GC, Hanson MA. Metabolic plasticity during ticipants (20) showed no difference in perinatal, neonatal, and mammalian development is directionally dependent on early nutritionalstatus. Proc Natl Acad Sci USA 2007;104:12796–800.
socioeconomic variables. Participants who were diagnosed with Desai M, Beall M, Ross MG. Developmental origins of obesity: cerebral palsy by 15 mo were less likely to participate, which is programmed adipogenesis. Curr Diab Rep 2013;13:27–33.
not an issue in the present study that focused on unimpaired Robinson S, Fall C. Infant nutrition and later health: a review of current subjects. As to confounding, the most important concern is evidence. Nutrients 2012;4:859–74.
whether the associations could be due to a medical condition Simon L, Frondas-Chauty A, Senterre T, Flamant C, Darmaun D, Roze that affected both neonatal nutrition and the adult outcomes.
JC. Determinants of body composition in preterm infants at the time of Although residual confounding remains a possibility, the asso- hospital discharge. Am J Clin Nutr 2014;100:98–104.
ciations remained remarkably similar after careful adjustment 10. Roggero P, Gianni ML, Amato O, Orsi A, Piemontese P, Puricelli V, Mosca F. Influence of protein and energy intakes on body composition for such conditions. Confounding by genetic and lifestyle factors of formula-fed preterm infants after term. J Pediatr Gastroenterol Nutr is unlikely because these would not be expected to affect neonatal nutrition. Because the severity of illness is an important 11. Amesz EM, Schaafsma A, Cranendonk A, Lafeber HN. Optimal growth factor that affects the nutrient requirements of VLBW infants, it and lower fat mass in preterm infants fed a protein-enriched is possible that there remains some factors about the early weeks postdischarge formula. J Pediatr Gastroenterol Nutr 2010;50:200–7.
of life we have not been able to assess even though we have made 12. Fenton TR, Premji SS, Al-Wassia H, Sauve RS. Higher versus lower careful adjustments for covariates that describe the severity of protein intake in formula-fed low birth weight infants. CochraneDatabase Syst Rev 2014;4:CD003959.
illness. A further limitation of our study is that we have no data 13. Ludwig-Auser H, Sherar LB, Erlandson MC, Baxter-Jones AD, on body composition in childhood; hence, we cannot assess Jackowski SA, Arnold C, Sankaran K. Influence of nutrition provision body composition trajectories.
during the first two weeks of life in premature infants on adolescent Despite the limitations of the historical perspective, our body composition and blood pressure. Zhongguo Dang Dai Er Ke Za data represent the nutrition the VLBW infants received in the 1970s and early 1980s and how it has affected their body 14. Regan FM, Cutfield WS, Jefferies C, Robinson E, Hofman PL. The composition in adult age. Because of the comprehensive data, impact of early nutrition in premature infants on later childhood insulinsensitivity and growth. Pediatrics 2006;118:1943–9.
we were able to take into account potential confounders at 15. Young L, Morgan J, McCormick FM, McGuire W. Nutrient-enriched different stages of our subjectsÕ lives, prenatal, neonatal, and formula versus standard term formula for preterm infants following current, which seem to have little effect on our results. Because hospital discharge. Cochrane Database Syst Rev 2012;CD004696.
of substantial changes in the nutritional regimen of the VLBW 16. Koletzko B, von Kries R, Monasterolo RC, Subias JE, Scaglioni S, infants, our findings may not be representative of VLBW Giovannini M, Beyer J, Demmelmair H, Anton B, Gruszfeld D, et al.
neonates born today.
Infant feeding and later obesity risk. Adv Exp Med Biol 2009;646:15– In conclusion, our results suggest that early nutritional management of the preterm infants predicts body composition 17. Owen CG, Martin RM, Whincup PH, Davey-Smith G, Gillman MW, Cook DG. The effect of breastfeeding on mean body mass index 20 y later by showing that higher intakes of energy, protein, and throughout life: a quantitative review of published and unpublished fat are associated with especially LBM and energy metabolism observational evidence. Am J Clin Nutr 2005;82:1298–307.
They also extend the early protein hypothesis by showing that at 18. Weber M, Grote V, Closa-Monasterolo R, Escribano J, Langhendries JP, protein intake levels that are low for the developmental period a Dain E, Giovannini M, Verduci E, Gruszfeld D, Socha P, et al. Lower higher protein intake is associated with a more healthy body protein content in infant formula reduces BMI and obesity risk at school composition. When reducing protein and energy intakes in age: follow-up of a randomized trial. Am J Clin Nutr 2014;99:1041–51.
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Early protein intake and adult body composition

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