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Effect of different composition of human milk and its fortification on body composition and neurodevelopment in a cohort of very preterm infants
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Orientador(es)
Resumo(s)
RESUMO: Introdução
Em recém-nascidos muito prematuros, o suporte nutricional inicial adequado é de extrema importância para a qualidade do crescimento e neurodesenvolvimento a curto, médio e longo prazo. O leite humano (LH) tem vantagens bem conhecidas em relação às fórmulas infantis, nomeadamente no desenvolvimento cerebral.
Objectivos
Determinar, numa amostra homogénea de recém-nascidos muito pré-termo, alimentados com leite humano, a associação do aporte proteico, energético e da relação proteína-energia (RPE) durante o internamento hospitalar, com a velocidade de aumento ponderal, a composição corporal e o perímetro cefálico (PC) na idade corrigida (IC) de termo, assim como o neurodesenvolvimento aos 18 meses de IC.
Métodos
Foi efetuado um estudo de coorte, sendo elegíveis recém-nascidos consecutivos nascidos na Maternidade com menos de 33 semanas de idade de gestação (IG), exclusiva ou predominantemente alimentados com LH (leite materno – LM e/ou leite de dadora).
O estudo foi aprovado pelas Comissões de Ética do Hospital e da Faculdade e está registado no ISRCTN (ID: 27916681). Foi obtido consentimento informado escrito dos pais ou representante legal de cada criança.
Foi seguido o protocolo de nutrição da nossa Unidade, baseado em recomendações internacionais e nacionais. Foi utilizado o método de fortificação padrão com adição de modo estimado de proteína e lípidos modulares, considerando o menor teor de proteína do leite humano descrito na literatura e as recomendações nutricionais mínimas recomendadas para o peso.
Para medir o conteúdo de macronutrientes do LH administrado, foi utilizado o analisador de LH por espectroscopia de infravermelhos. A antropometria foi efetuada utilizando as técnicas recomendadas. A avaliação da composição corporal, por intermédio da pletismografia de deslocação de ar, foi agendada após a alta para a IC de termo; a percentagem de massa gorda (%MG) e o índice de massa de gorda (IMG) foram utilizados como indicadores da adiposidade. A avaliação do Índice de Desenvolvimento Mental (IDM) e do Índice de Desenvolvimento Psicomotor (IDP), utilizando as Escalas de Desenvolvimento Bayley versão II, foram agendadas para os 18 meses de idade corrigida.
Análise estatística: estimaram-se dimensões amostrais mínimas de 70 e 75 crianças para detetar, respetivamente, diferenças significativas na composição corporal e nos resultados do neurodesenvolvimento. Foi efetuada análise univariável, utilizando testes paramétricos ou não paramétricos adequados ao tipo de dados e distribuição encontrados, avaliando associações entre os aportes proteico, energético e da RPE, com a velocidade de aumento ponderal, a massa gorda (MG), a massa isenta de gordura (MIG), a %MG, o IMG, o PC, o IDM e o IDP. Os mesmos métodos estatísticos foram utilizados para avaliar as potenciais variáveis confundentes, usando p<0,10 para inclusão nos modelos multivariáveis. Foram utilizados modelos mistos lineares para calcular os valores da composição do leite materno nas amostras em não foi possível efetuar a sua medição e análises de regressão linear múltipla para avaliar o efeito ajustado entre variáveis independentes e dependentes. Utilizou-se uma análise caso-controlo anichada para determinar as associações entre os limites inferior (≤ -1 z-score) e superior (≥ +1 z-score) de adiposidade e os aportes proteico, energético e da RPE.
Resultados
Foram incluídas na coorte 33 crianças, com medianas (intervalos interquartílicos) de 30 (28-31) semanas de IG e peso ao nascer de 1175 (1010-1408) g. Comparando com os 56 lactentes excluídos do estudo, alimentados com formula, os 33 lactentes que completaram o estudo tinham IG significativamente menor, menor prevalência de gémeos e maior tempo de internamento.
Foram analisadas 832 amostras de LH, representando 65,0% do total das amostras administradas.
Desvendadas as medições de macronutrientes do LH, verificou-se que foram atingidos os aportes mínimos recomendados por peso em 63,6%, 15,2%, 93,9% dos lactentes em relação às proteínas, energia e RPE, respetivamente. Os aportes diários de proteína, energia e RPE, do nascimento até às 35 semanas de IC, variaram entre 2,7-4,2 g/kg, 53,7-109,2 kcal/kg e 3,4-5,6, respetivamente.
A velocidade de aumento ponderal intra-hospitalar média (DP) foi de 10,1 (3,8) g/kg/dia. O peso médio (DP) foi de 2817,6 (504,3) g, a MG de 441,5 (184,0) g, a MIG de 2376,1 (376,0) g, a %MG de 15,3 (4,8) e o IMG de 2,0 (0,7).
O neurodesenvolvimento foi avaliado aos 20 meses de IC. Globalmente, o IDM médio (DP) foi 100,2 (11,5) e o IDP 97,4 (8,0). O IDM médio foi inferior ao normal em 6,2% dos lactentes, normal em 78,1% e acelerado em 15,6%; O IDP médio foi inferior ao normal em 6,2% dos lactentes e normal em 93,8%.
Na análise multivariável, apenas a IG se associou com menor velocidade de aumento ponderal (p<0,0001). Após ajustamento para a IG, apenas a MIG se associou com menores aportes proteico (p=0,008) e energético (p=0,001). Na análise caso-controlo anichada, nos lactentes com menor adiposidade, uma %MG ≤ -1 z-score associou-se a menores aportes de energia e proteína (p=0,050) e um IMG ≤ -1 z-score associou-se a menor aporte de RPE (p=0,026); em lactentes com maior adiposidade, um IMG ≥ +1 z-score associou-se a menor aporte de energia (p <0,0001) e maior aporte de RPE (p <0,0001).
Na análise multivariável, a IG e o sexo foram preditores de maior PC na IC de termo, ajustado para os aportes proteico (p=0,010), energético (p=0,013) e RPE (p=0,013). Os aportes intra-hospitalares cumulativos proteico, energético e da RPE não se associaram significativamente com as pontuações IDM e IDP na idade média de 20 meses de IC, nem reuniram os critérios para entrada na análise multivariável.
Conclusões:
Nesta coorte de crianças nascidas muito pré-termo exclusivamente ou quase exclusivamente alimentadas com LH, os aportes intra-hospitalares cumulativos proteico, energético e da RPE correlacionaram-se fraca a moderadamente com o aumento da velocidade ponderal, mas não com a composição corporal na IC de termo. Analisando os lactentes com extremos de adiposidade, os com menor adiposidade receberam significativamente menos proteína, energia e RPE, enquanto os com maior adiposidade receberam significativamente menor aporte energético, mas maior RPE, do que a restante amostra. A IG e o sexo foram preditores significativos de maior PC na IC de termo, ajustado para os aportes proteico, energético e da RPE. Os aportes intra-hospitalares cumulativos proteico, energético e da RPE não se correlacionaram significativamente com o IDM nem com o IDP aos 20 meses de IC. O método de fortificação padrão com adição de modo estimado de proteína e lípidos modulares resultou no aporte insuficiente de energia e proteína.
A amostra subdimensionada pode ter sido insuficiente para testar as hipóteses admitidas de associação do aporte de macronutrientes com a composição corporal e o neurodesenvolvimento. Contudo, as nossas análises basearam-se na medição do conteúdo proteico e energético do LH e não na sua composição estimada, sendo um ponto forte do estudo.
ABSTRACT: Background In very preterm infants, adequate early nutritional support is of utmost importance for the quality of growth and neurodevelopmental outcomes in the short-, medium- and long-term. Human milk (HM) has well-known advantages over infant formulas, including for brain development. Objectives To determine, in a homogeneous sample of HM-fed very preterm infants, the associations of in-hospital measured protein, energy, and protein-to-energy ratio (PER) intake with weight gain velocity, body composition and head circumference (HC) at term corrected age (CA), and with neurodevelopmental outcome at 18 months CA. Methods A cohort study was conducted, being eligible consecutive inborn neonates with less than 33 weeks of gestation, who were exclusively or predominantly HM-fed (own’s mother milk and/or donor human milk). The study was approved by the Hospital and Medical School ethics committees and is registered at the ISRCTN (ID: 27916681). Informed written consent was obtained from the parents or legal representative of each infant. Our unit nutrition protocol, based on international and national recommendations, was followed. A standard fortification method with the blinded addition of modular protein and/or fat supplements was used, considering the lowest reported HM protein content and the minimum recommended intake for weight. A mid-infrared analyzer was used to measure the macronutrients content of administered HM. Anthropometry was performed using the recommended techniques. Body composition assessment, using air displacement plethysmography (ADP), was scheduled after discharge, at 40 weeks CA; fat mass percentage (FM%) and fat mass index (FMI) were used as surrogates of adiposity. The assessment of the Mental Developmental Index (MDI) and Psychomotor Developmental Index (PDI), using the Bayley Infant Development Scales version II, were scheduled at 18 months CA. Statistical analysis: required samples of 70 and 75 infants were estimated to detect significant differences in body composition and neurodevelopmental outcomes, respectively. Univariate analysis, using parametric or nonparametric tests as adequate, assessed the associations of cumulative in-hospital protein, energy, and PER intake with weight gain velocity, fat mass (FM), fat-free mass (FFM), FM%, FMI, HC, MDI, and PDI. The same statistical methods were used to assess potential confounding variables, using p<0.10 for inclusion in models. Linear mixed models were used to input missing measured values of own’s mother milk composition and linear multiple regression analyses were used to assess the adjusted effect between independent and dependent variables. A nested case-control analysis was used to determine the associations of lower (≤ -1 z-score) and higher (≥ +1 z-score) adiposity with protein, energy, and PER intake. Results Thirty-three infants were included in the cohort, with a median (interquartile range) gestational age of 30 (28-31) weeks and birthweight of 1175 (1010-1408) g. Compared with the 56-excluded formula-fed infants, the 33 infants who completed the study had significantly lower gestational age, lower prevalence of twins and stayed longer in hospital. Eight hundred and thirty-two pooled HM samples were analyzed, representing 65.0% of the total administered samples. After disclosing the HM macronutrients measurements, it was found that the minimum recommended intake for weight were achieved in 63.6% of infants for protein, 15.2% for energy, and 93.9% for PER. The median daily protein, energy, and PER intake from birth to 35 weeks CA ranged from 2.7-4.2 g/kg, 53.7-109.2 kcal/kg, and 3.4-5.6, respectively. The mean (standard deviation - SD) in-hospital weight gain velocity was 10.1 (3.8) g/kg/day. At mean (SD) 39.9 (1.9) weeks, body mass was of 2817.6 (504.3) g, FM of 441.5 (184.0) g, FFM of 2376.1 (376.0) g, FM% of 15.3 (4.8), and FMI of 2.0 (0.7). Neurodevelopment was assessed at 20 months CA. Overall, the mean (SD) score for MDI was 100.2 (11.5) and for PDI 97.4 (8.0). The mean MDI score was below normal in 6.2% infants, normal in 78.1%, and accelerated in 15.6%; the mean PDI score was below normal in 6.2% infants and normal in 93.8%. In multivariate analysis, only gestational age was associated with low weight gain velocity (p<0.0001). After adjustment for gestational age, only FFM was associated with low protein (p=0.008) and energy (p=0.001) intake. In the nested case-control analysis, in infants with lower adiposity, a FM% ≤ -1 z-score was associated with low energy and protein intake (p=0.050) and a FMI ≤ -1 z-score was associated with low PER intake (p=0.026); in infants with higher adiposity, a FMI ≥ +1 z-score was associated with low energy intake (p<0.0001) and high PER intake (p<0.0001). In multivariate analysis, it was found that GA and sex were predictors of high HC at term CA, adjusted for protein (p=0.010), energy (p=0.013) and PER intake (p=0.013). In-hospital cumulative protein, energy, and PER intake were neither significantly correlated with any MDI or PDI scores at mean 20 months CA, nor met the defined criteria to enter multivariate analysis. Conclusions In this cohort of exclusively or almost exclusively HM-fed very preterm infants, the cumulative in-hospital protein, energy, and PER intake were weakly-to-moderately correlated with weight gain velocity, but not with body composition at term CA in the entire sample. Analyzing infants with extremes of adiposity, those with lower adiposity received significantly lower energy, protein, and PER intake, while infants with higher adiposity received significantly lower energy intake but higher PER intake, compared with the remaining infants. The GA and sex were significant predictors of high HC at term CA, adjusted for protein, energy and PER intake. In-hospital cumulative protein, energy, and PER intake were not significantly correlated with MDI or PDI scores at a mean of 20 months CA. The method of standard fortification with blinded modular protein and fat supplements resulted in insufficient energy and protein intake. The undersized sample might be insufficient to test the hypothesized associations of macronutrient intake with body composition and neurodevelopmental outcome.Notwithstanding, our analyses have relied on measured protein and energy HM content and not on its assumed composition, which is a strength of the study.
ABSTRACT: Background In very preterm infants, adequate early nutritional support is of utmost importance for the quality of growth and neurodevelopmental outcomes in the short-, medium- and long-term. Human milk (HM) has well-known advantages over infant formulas, including for brain development. Objectives To determine, in a homogeneous sample of HM-fed very preterm infants, the associations of in-hospital measured protein, energy, and protein-to-energy ratio (PER) intake with weight gain velocity, body composition and head circumference (HC) at term corrected age (CA), and with neurodevelopmental outcome at 18 months CA. Methods A cohort study was conducted, being eligible consecutive inborn neonates with less than 33 weeks of gestation, who were exclusively or predominantly HM-fed (own’s mother milk and/or donor human milk). The study was approved by the Hospital and Medical School ethics committees and is registered at the ISRCTN (ID: 27916681). Informed written consent was obtained from the parents or legal representative of each infant. Our unit nutrition protocol, based on international and national recommendations, was followed. A standard fortification method with the blinded addition of modular protein and/or fat supplements was used, considering the lowest reported HM protein content and the minimum recommended intake for weight. A mid-infrared analyzer was used to measure the macronutrients content of administered HM. Anthropometry was performed using the recommended techniques. Body composition assessment, using air displacement plethysmography (ADP), was scheduled after discharge, at 40 weeks CA; fat mass percentage (FM%) and fat mass index (FMI) were used as surrogates of adiposity. The assessment of the Mental Developmental Index (MDI) and Psychomotor Developmental Index (PDI), using the Bayley Infant Development Scales version II, were scheduled at 18 months CA. Statistical analysis: required samples of 70 and 75 infants were estimated to detect significant differences in body composition and neurodevelopmental outcomes, respectively. Univariate analysis, using parametric or nonparametric tests as adequate, assessed the associations of cumulative in-hospital protein, energy, and PER intake with weight gain velocity, fat mass (FM), fat-free mass (FFM), FM%, FMI, HC, MDI, and PDI. The same statistical methods were used to assess potential confounding variables, using p<0.10 for inclusion in models. Linear mixed models were used to input missing measured values of own’s mother milk composition and linear multiple regression analyses were used to assess the adjusted effect between independent and dependent variables. A nested case-control analysis was used to determine the associations of lower (≤ -1 z-score) and higher (≥ +1 z-score) adiposity with protein, energy, and PER intake. Results Thirty-three infants were included in the cohort, with a median (interquartile range) gestational age of 30 (28-31) weeks and birthweight of 1175 (1010-1408) g. Compared with the 56-excluded formula-fed infants, the 33 infants who completed the study had significantly lower gestational age, lower prevalence of twins and stayed longer in hospital. Eight hundred and thirty-two pooled HM samples were analyzed, representing 65.0% of the total administered samples. After disclosing the HM macronutrients measurements, it was found that the minimum recommended intake for weight were achieved in 63.6% of infants for protein, 15.2% for energy, and 93.9% for PER. The median daily protein, energy, and PER intake from birth to 35 weeks CA ranged from 2.7-4.2 g/kg, 53.7-109.2 kcal/kg, and 3.4-5.6, respectively. The mean (standard deviation - SD) in-hospital weight gain velocity was 10.1 (3.8) g/kg/day. At mean (SD) 39.9 (1.9) weeks, body mass was of 2817.6 (504.3) g, FM of 441.5 (184.0) g, FFM of 2376.1 (376.0) g, FM% of 15.3 (4.8), and FMI of 2.0 (0.7). Neurodevelopment was assessed at 20 months CA. Overall, the mean (SD) score for MDI was 100.2 (11.5) and for PDI 97.4 (8.0). The mean MDI score was below normal in 6.2% infants, normal in 78.1%, and accelerated in 15.6%; the mean PDI score was below normal in 6.2% infants and normal in 93.8%. In multivariate analysis, only gestational age was associated with low weight gain velocity (p<0.0001). After adjustment for gestational age, only FFM was associated with low protein (p=0.008) and energy (p=0.001) intake. In the nested case-control analysis, in infants with lower adiposity, a FM% ≤ -1 z-score was associated with low energy and protein intake (p=0.050) and a FMI ≤ -1 z-score was associated with low PER intake (p=0.026); in infants with higher adiposity, a FMI ≥ +1 z-score was associated with low energy intake (p<0.0001) and high PER intake (p<0.0001). In multivariate analysis, it was found that GA and sex were predictors of high HC at term CA, adjusted for protein (p=0.010), energy (p=0.013) and PER intake (p=0.013). In-hospital cumulative protein, energy, and PER intake were neither significantly correlated with any MDI or PDI scores at mean 20 months CA, nor met the defined criteria to enter multivariate analysis. Conclusions In this cohort of exclusively or almost exclusively HM-fed very preterm infants, the cumulative in-hospital protein, energy, and PER intake were weakly-to-moderately correlated with weight gain velocity, but not with body composition at term CA in the entire sample. Analyzing infants with extremes of adiposity, those with lower adiposity received significantly lower energy, protein, and PER intake, while infants with higher adiposity received significantly lower energy intake but higher PER intake, compared with the remaining infants. The GA and sex were significant predictors of high HC at term CA, adjusted for protein, energy and PER intake. In-hospital cumulative protein, energy, and PER intake were not significantly correlated with MDI or PDI scores at a mean of 20 months CA. The method of standard fortification with blinded modular protein and fat supplements resulted in insufficient energy and protein intake. The undersized sample might be insufficient to test the hypothesized associations of macronutrient intake with body composition and neurodevelopmental outcome.Notwithstanding, our analyses have relied on measured protein and energy HM content and not on its assumed composition, which is a strength of the study.
Descrição
Palavras-chave
Aporte energético Aporte proteico Composição corporal Leite humano Neurodesenvolvimento Perímetro cefálico Recém-nascidos muito pré-termo Velocidade de aumento ponderal Body composition Energy intake Head circumference Human milk Neurodevelopmental outcome Protein intake Very preterm infants Weight gain velocity.