The importance of nutrition in pregnancy and lactation: lifelong consequences.

Most women in the United States do not meet the recommendations for healthful nutrition and weight before and during pregnancy. Women and providers often ask what a healthy diet for a pregnant woman should look like. The message should be "eat better, not more." This can be achieved by basing diet on a variety of nutrient-dense, whole foods, including fruits, vegetables, legumes, whole grains, healthy fats with omega-3 fatty acids that include nuts and seeds, and fish, in place of poorer quality highly processed foods. Such a diet embodies nutritional density and is less likely to be accompanied by excessive energy intake than the standard American diet consisting of increased intakes of processed foods, fatty red meat, and sweetened foods and beverages. Women who report "prudent" or "health-conscious" eating patterns before and/or during pregnancy may have fewer pregnancy complications and adverse child health outcomes. Comprehensive nutritional supplementation (multiple micronutrients plus balanced protein energy) among women with inadequate nutrition has been associated with improved birth outcomes, including decreased rates of low birthweight. A diet that severely restricts any macronutrient class should be avoided, specifically the ketogenic diet that lacks carbohydrates, the Paleo diet because of dairy restriction, and any diet characterized by excess saturated fats. User-friendly tools to facilitate a quick evaluation of dietary patterns with clear guidance on how to address dietary inadequacies and embedded support from trained healthcare providers are urgently needed. Recent evidence has shown that although excessive gestational weight gain predicts adverse perinatal outcomes among women with normal weight, the degree of prepregnancy obesity predicts adverse perinatal outcomes to a greater degree than gestational weight gain among women with obesity. Furthermore, low body mass index and insufficient gestational weight gain are associated with poor perinatal outcomes. Observational data have shown that first-trimester gain is the strongest predictor of adverse outcomes. Interventions beginning in early pregnancy or preconception are needed to prevent downstream complications for mothers and their children. For neonates, human milk provides personalized nutrition and is associated with short- and long-term health benefits for infants and mothers. Eating a healthy diet is a way for lactating mothers to support optimal health for themselves and their infants.

Exogenous amino acids suppress glucose oxidation and potentiate hepatic glucose production in late gestation fetal sheep.

Acute amino acid (AA) infusion increases AA oxidation rates in normal late gestation fetal sheep. Because the fetal oxygen consumption rate does not change with increased AA oxidation, we hypothesized that AA infusion would suppress glucose oxidation pathways and that the additional carbon supply from AA would activate hepatic glucose production. To test this, late gestation fetal sheep were infused intravenously for 3 h with saline or exogenous AA (AA). Glucose tracer metabolic studies were performed and skeletal muscle and liver tissues samples were collected. AA infusion increased fetal arterial plasma branched chain AA, cortisol, and glucagon concentrations. Fetal glucose utilization rates were similar between basal and AA periods, yet the fraction of glucose oxidized and the glucose oxidation rate were decreased by 40% in the AA period. AA infusion increased expression of PDK4, an inhibitor of glucose oxidation, nearly twofold in muscle and liver. In liver, AA infusion tended to increase PCK1 gluconeogenic gene and PCK1 correlated with plasma cortisol concentrations. AA infusion also increased liver mRNA expression of the lactate transporter gene (MCT1), protein expression of GLUT2 and LDHA, and phosphorylation of AMPK, 4EBP1, and S6 proteins. In isolated fetal hepatocytes, AA supplementation increased glucose production and PCK1, LDHA, and MCT1 gene expression. These results demonstrate that AA infusion into fetal sheep competitively suppresses glucose oxidation and potentiates hepatic glucose production. These metabolic patterns support flexibility in fetal metabolism in response to increased nutrient substrate supply while maintaining a relatively stable rate of oxidative metabolism.

Chronically Increased Amino Acids Improve Insulin Secretion, Pancreatic Vascularity, and Islet Size in Growth-Restricted Fetal Sheep.

Placental insufficiency is associated with reduced supply of amino acids to the fetus and leads to intrauterine growth restriction (IUGR). IUGR fetuses are characterized by lower glucose-stimulated insulin secretion, smaller pancreatic islets with less ß-cells, and impaired pancreatic vascularity. To test whether supplemental amino acids infused into the IUGR fetus could improve these complications of IUGR we used acute (hours) and chronic (11 d) direct fetal amino acid infusions into a sheep model of placental insufficiency and IUGR near the end of gestation. IUGR fetuses had attenuated acute amino acid-stimulated insulin secretion compared with control fetuses. These results were confirmed in isolated IUGR pancreatic islets. After the chronic fetal amino acid infusion, fetal glucose-stimulated insulin secretion and islet size were restored to control values. These changes were associated with normalization of fetal pancreatic vascularity and higher fetal pancreatic vascular endothelial growth factor A protein concentrations. These results demonstrate that decreased fetal amino acid supply contributes to the pathogenesis of pancreatic islet defects in IUGR. Moreover, the results show that pancreatic islets in IUGR fetuses retain their ability to respond to increased amino acids near the end of gestation after chronic fetal growth restriction.

Acute supplementation of amino acids increases net protein accretion in IUGR fetal sheep.

Placental insufficiency decreases fetal amino acid uptake from the placenta, plasma insulin concentrations, and protein accretion, thus compromising normal fetal growth trajectory. We tested whether acute supplementation of amino acids or insulin into the fetus with intrauterine growth restriction (IUGR) would increase net fetal protein accretion rates. Late-gestation IUGR and control (CON) fetal sheep received acute, 3-h infusions of amino acids (with euinsulinemia), insulin (with euglycemia and euaminoacidemia), or saline. Fetal leucine metabolism was measured under steady-state conditions followed by a fetal muscle biopsy to quantify insulin signaling. In CON, increasing amino acid delivery rates to the fetus by 100% increased leucine oxidation rates by 100%. In IUGR, amino acid infusion completely suppressed fetal protein breakdown rates but increased leucine oxidation rate by only 25%, resulting in increased protein accretion rates by 150%. Acute insulin infusion, however, had very little effect on amino acid delivery rates, fetal leucine disposal rates, or fetal protein accretion rates in CON or IUGR fetuses despite robust signaling of the fetal skeletal muscle insulin-signaling cascade. These results indicate that, when amino acids are given directly into the fetal circulation independently of changes in insulin concentrations, IUGR fetal sheep have suppressed protein breakdown rates, thus increasing net fetal protein accretion.

Protein for preterm infants: how much is needed? How much is enough? How much is too much?

Preterm infants require considerably more protein to achieve normal intrauterine growth rates than is commonly fed to them during their first postnatal days. Continuing protein nutrition to maintain normal growth rates often is not achieved until several weeks after birth. Most very preterm infants do not receive the protein necessary to produce the 2-3 kilograms of body mass over a 12-16 week period of NICU care and, as a result, end up growth restricted by term, in lean body mass more than fat. This article reviews the requirements for protein and amino acids necessary to achieve normal growth and development of preterm infants. Protein requirements at 24-30 weeks' gestation are as high as 4 g/kg/day, decreasing to 2-3 g/kg/day by term. Individual amino acids are important not just as building blocks for protein synthesis and net protein balance, but also as essential signalling molecules for normal cellular function. Perhaps most importantly, brain growth and later life cognitive function are directly related to protein intake during the neonatal period in preterm infants. Data are reviewed that document successful increase in protein balance in preterm infants achieved with higher than usual rates of amino acid and protein nutrition, noting that positive protein balance requires at least 1.5 g/kg/day, but there still is increased protein balance up to 4 g/kg/day. Further research is necessary to determine optimal amounts and mixtures of protein and amino acids for both intravenous and enteral feeding to improve growth, development, and functional capacity of preterm infants.

Prolonged maternal amino acid infusion in late-gestation pregnant sheep increases fetal amino acid oxidation.

Protein supplementation during human pregnancy does not improve fetal growth and may increase small-for-gestational-age birth rates and mortality. To define possible mechanisms, sheep with twin pregnancies were infused with amino acids (AA group, n = 7) or saline (C group, n = 4) for 4 days during late gestation. In the AA group, fetal plasma leucine, isoleucine, valine, and lysine concentrations were increased (P < 0.05), and threonine was decreased (P < 0.05). In the AA group, fetal arterial pH (7.365 +/- 0.007 day 0 vs. 7.336 +/- 0.012 day 4, P < 0.005), hemoglobin-oxygen saturation (46.2 +/- 2.6 vs. 37.8 +/- 3.6%, P < 0.005), and total oxygen content (3.17 +/- 0.17 vs. 2.49 +/- 0.20 mmol/l, P < 0.0001) were decreased on day 4 compared with day 0. Fetal leucine disposal did not change (9.22 +/- 0.73 vs. 8.09 +/- 0.63 micromol x min(-1) x kg(-1), AA vs. C), but the rate of leucine oxidation increased 43% in the AA group (2.63 +/- 0.16 vs. 1.84 +/- 0.24 micromol x min(-1) x kg(-1), P < 0.05). Fetal oxygen utilization tended to be increased in the AA group (327 +/- 23 vs. 250 +/- 29 micromol x min(-1) x kg(-1), P = 0.06). Rates of leucine incorporation into fetal protein (5.19 +/- 0.97 vs. 5.47 +/- 0.89 micromol x min(-1) x kg(-1), AA vs. C), release from protein breakdown (4.20 +/- 0.95 vs. 4.62 +/- 0.74 micromol x min(-1) x kg(-1)), and protein accretion (1.00 +/- 0.30 vs. 0.85 +/- 0.25 micromol x min(-1) x kg(-1)) did not change. Consistent with these data, there was no change in the fetal skeletal muscle ubiquitin ligases MaFBx1 or MuRF1 or in the protein synthesis regulators 4E-BP1, eEF2, eIF2alpha, and p70(S6K). Decreased concentrations of certain essential amino acids, increased amino acid oxidation, fetal acidosis, and fetal hypoxia are possible mechanisms to explain fetal toxicity during maternal amino acid supplementation.

Insulin is required for amino acid stimulation of dual pathways for translational control in skeletal muscle in the late-gestation ovine fetus.

During late gestation, amino acids and insulin promote skeletal muscle protein synthesis. However, the independent effects of amino acids and insulin on the regulation of mRNA translation initiation in the fetus are relatively unknown. The purpose of this study was to determine whether acute amino acid infusion in the late-gestation ovine fetus, with and without a simultaneous increase in fetal insulin concentration, activates translation initiation pathway(s) in skeletal muscle. Fetuses received saline (C), mixed amino acid infusion plus somatostatin infusion to suppress amino acid-stimulated fetal insulin secretion (AA+S), mixed amino acid infusion with concomitant physiological increase in fetal insulin (AA), or high-dose insulin infusion with euglycemia and euaminoacidemia (HI). After a 2-h infusion period, fetal skeletal muscle was harvested under in vivo steady-state conditions and frozen for quantification of proteins both upstream and downstream of mammalian target of rapamycin (mTOR). In the AA group, we found a threefold increase in ribosomal protein S6 kinase (p70(S6k)) and Erk1/2 phosphorylation; however, blocking the physiological rise in insulin with somatostatin in the AA+S group prevented this increase. In the HI group, Akt, Erk1/2, p70(S6k), and ribosomal protein S6 were highly phosphorylated and 4E-binding protein 1 (4E-BP1) associated with eukaryotic initiation factor (eIF)4E decreased by 30%. These data show that insulin is a significant regulator of intermediates involved in translation initiation in ovine fetal skeletal muscle. Furthermore, the effect of amino acids is dependent on a concomitant increase in fetal insulin concentrations, because amino acid infusion upregulates p70(S6k) and Erk only when amino acid-stimulated increase in insulin occurs.

Strategies for feeding the preterm infant.

According to many experts in neonatal nutrition, the goal for nutrition of the preterm infant should be to achieve a postnatal growth rate approximating that of the normal fetus of the same gestational age. Unfortunately, most preterm infants, especially those born very preterm with extremely low birth weight, are not fed sufficient amounts of nutrients to produce normal fetal rates of growth and, as a result, end up growth-restricted during their hospital period after birth. Growth restriction is a significant problem, as numerous studies have shown definitively that undernutrition, especially of protein, at critical stages of development produces long-term short stature, organ growth failure, and both neuronal deficits of number and dendritic connections as well as later behavioral and cognitive outcomes. Furthermore, clinical follow-up studies have shown that among infants fed formulas, the nutrient content of the formula is directly and positively related to mental and motor outcomes later in life. Nutritional requirements do not stop at birth. Thus, delaying nutrition after birth 'until the infant is stable' ignores the fundamental point that without nutrition starting immediately after birth, the infant enters a catabolic condition, and catabolism does not contribute to normal development and growth. Oxygen is necessary for all metabolic processes. Recent trends to limit oxygen supply to prevent oxygen toxicity have the potential, particularly when the blood hemoglobin concentration falls to less than 8 g/dl, to develop growth failure. Glucose should be provided at 6-8 mg/min/kg as soon after birth as possible and adjusted according to frequent measurements of plasma glucose to achieve and maintain concentrations >45 mg/dl but <120 mg/dl to avoid the frequent problems of hyperglycemia and hypoglycemia. Similarly, lipid is required to provide at least 0.5 g/kg/day to prevent essential fatty acid deficiency. However, the high rate of carbohydrate and lipid supply that preterm infants often get, based on the incomplete assumption that this is necessary to promote protein growth, tends to produce increased fat in organs like the liver and heart as well as adipose tissue. More and better essential fatty acid nutrition is valuable, but more organ and adipose fat has no known benefit and many problems. Amino acids and protein are essential not only for body growth but for metabolic signaling, protein synthesis, and protein accretion. 3.5-4.0 g/kg/day are necessary to produce normal protein balance and growth in very preterm infants. Attempts to promote protein growth with insulin has many problems - it is ineffective while contributing to even further organ and adipose tissue fat deposition. Enteral feeding always is indicated and to date nearly all studies have shown that minimal enteral feeding approaches (e.g., 'trophic feeds') promote the capacity to feed enterally. Milk has distinct advantages over formulas in avoiding necrotizing enterocolitis (NEC), and while feeding is associated with NEC, minimal enteral feeding regimens produce less NEC than those geared towards more aggressive introduction of enteral feeding. Finally, overfeeding has the definite potential to produce adipose tissue, or obesity, which then leads to insulin resistance, glucose intolerance, and diabetes. This scenario occurs more commonly as infants are fed more and gain weight more rapidly after birth, regardless of their birth weight. Infants with IUGR and postnatal growth failure may be uniquely 'set up' for this outcome, while infants with in utero obesity, such as infants of diabetic mothers, already are well along this adverse outcome pathway.

Nutrient supplies for optimal health in preterm infants.

The most commonly recommended standard for postnatal nutrition of very preterm infants is one that meets the unique nutritional requirements of the growing human fetus and duplicates normal in utero human fetal growth (weight and body composition) and development. Normal fetal nutrition, therefore, may be a useful guide for designing postnatal nutritional strategies in very preterm infants who need to grow and develop outside the uterus. Such information indicates that normal fetal nutrition requires certain nutrients in optimal amounts and certain growth-promoting hormones in response to nutrient supply that together support optimal fetal growth and development; these include oxygen, glucose, lipids, amino acids, and insulin. Interestingly, nutrient restriction and nutrient excess in the fetus, while leading to different phenotypes, produce a similar phenotype in later life characterized as the "metabolic syndrome," consisting of obesity, insulin resistance, diabetes, and cardiovascular disease. After birth, preterm infants--who almost universally are not fed as much as normally growing fetuses receive in nutrient supply via the placenta--also end up with a higher incidence of short stature and a predisposition to the metabolic syndrome, whereas those fed excessive amounts of energy and who develop excessive growth primarily of adipose tissue in early life (rapid, positive crossing of weight-for-length centiles) also develop a higher incidence of the metabolic syndrome. It is clear, therefore, that just the right amount of the essential nutrients is required to produce optimal outcome; this is as true for the preterm infant as it is for the fetus.

Maternal nutrition and optimal infant feeding practices: executive summary.

Much recent attention has been paid to the effect of the fetal environment on not only healthy birth outcomes but also long-term health outcomes, including a role as an antecedent to adult diseases. A major gap in our understanding of these relations, however, is the effect of maternal nutrition and nutrient transport on healthy fetal growth and development. In addition, this gap precludes evidence-based recommendations about how to best feed preterm infants. The biological role of the mother and the effect of her nutritional status on infant feeding extend to postnatal infant feeding practices. Currently, evidence is incomplete about not only the composition of human milk, but also the maternal nutritional needs to support extended lactation and the appropriate nutrient composition of foods that will be used to complement breastfeeding at least through the first year of life. Consequently, a conference, organized by the National Institute of Child Health and Human Development, the National Institutes of Health Office of Dietary Supplements, and the US Department of Agriculture Children's Nutrition Research Center was held to explore current knowledge and develop a research agenda to address maternal nutrition and infant feeding practices. These proceedings contain presentations about the effect of maternal nutrition and the placental environment on fetal growth and birth outcomes, as well as issues pertaining to feeding preterm and full-term infants.