Optimizing Neurodevelopment without increasing Metabolic Risk
Sara Ramel, MD Division of Neonatology University of Minnesota Masonic Childrens Hospital Minneapolis, MN Objectives Describe the influence of early growth and nutrition on later neurodevelopment in various populations, including SGA and AGA term and preterm infants. Recognize potential trade-offs to accelerated growth in various populations. Describe various methods of growth measurement available for neonates and the importance of following length and body composition in addition to weight gain. Improved/Increased Nutrition
Improved Growth Improved Neurodevelopment Given the tremendous changes occurring in the brain throughout pregnancy, infancy and childhood it is not surprising as well that early nutrition and growth have a strong influence on later cognition. Therefore it has been long agreed that improved nutrition will lead to improved growth and in turn improved neurodevelopment. In some areas this continues to be true but as nutritional and outcomes research has evolved it has become much more complicated with more rapid weight gain benefitting some infants by improving neurodevelopment and harming others by increasing risk for later obesity and metabolic syndrome. MORE may not be better!! Weight gain cannot be the only metric used to determine optimal growth. Early life experiences have long-term effects on many body systems
Strong evidence to support that sub-optimal in-utero growth leads to increase risk of later metabolic disease in certain populations It is becoming increasingly clear that early life experiences (both nutritional and non-nutritional) and in-utero and in infancy have lasting effects on many body systems. There is also good data to show that suboptimal in-utero growth, especially when combined with rapid post-natal growth acceleration, leads to an increased risk of metabolic disease in later life in certain populations. Most specifically a strong association has been shown between term growth restricted infants who later experience insulin resistance. Given this surge of new data, initially focused specifically on SGA term infants, along with the data supporting increased growth and its benefit to later neurodevelopment we must ask the question is more better and is it the same for all infants? Neurocognitive Development
Rapid Infant Growth More rapid infant weight gain is associated with long term benefits, such as better neurodevelopmental outcomes for some infants, but also with harms, such as increased risk of obesity and metabolic syndrome. Determining the optimal rate of growth requires balancing these benefits and risks, the magnitude of which differ for specific populations. Obesity, Metabolic Syndrome Risk Preterm Infants Weight gain, Linear Growth and Fat-Free Mass Gains
Energy and Protein Improved Neuro- development You remember from my previous talk that in preterm infants specifically improved growth both while in the NICU and after hospital discharge, periods during which tremendous growth and development of the brain are occurring, are associated with improved neurodevelopment. Specifically, increases in weight, length and fat free mass gains improve speed of processing, language, cognitive and motor scores and decrease rates of cerebral palsy. Also, we discussed that increased amounts of calories and protein given early lead to not only improved growth throughout infancy but also improved neurodevelopment. Metabolic Risk in Preterm Infants?
Reduced insulin sensitivity Increased risk to develop type II diabetes Elevated blood pressure and resting heart rate Increased low-density lipoprotein Higher truncal fat Why not just give more and see if we can improve later neurodevelopment. Given concerns for increased adiposity among preterm infants after hospital discharge coupled with the large increase in concern about negative consequences of catch-up growth in other growth restricted populations it is tempting to apply that same degree of concern to preterm infants who undergo growth restriction after birth. Is it a real concern?? Multiple large studies and systematic reviews have recently been published stating that preterm birth alone is associated with reduced insulin sensitivity elevated blood pressure and resting heart rate and slightly increased low-density lipoprotein Tinnion R. Arch Dis Child. 2014 Parkinson JRC. Pediatrics. 2013 de Jong F. Hypertension. 2012 Kerkhof GF. J Pediatr Meta-analysis of 10 observational studies (Preterm vs Term SBP)
Childhood BP ~2.5 mmHg higher in preterm Twice as likely to be hypertensive as adults In adolescence and young adulthood former preterm infants have ~ 2.5 mm Hg higher systolic BP than full-term infants. And are twice as likely to be hypertensive as adults. de Jong F. Hypertension. 2012 Metabolic risk is real for preterm infants
Metabolic risk is real for preterm infants. is it due to rapid growth or excess nutrition?? Nutrition and Metabolic Risk
Several studies documenting increased Fat Free Mass (NOT FAT MASS) with increased calories and protein Infants on fortified feeds have higher fasting insulin levels Preterm infants who received more aggressive nutrition during the first 2 weeks of life remained taller and heavier as adolescents No increase in percent body fat, systolic or diastolic BP Costa-Orvay. J Nutr 2011 Rachow N. Clin Nutr. 2011 Ramel SE. JPGN 2011 Ludwig-Auser H. Chin. J Contemp Pediatr. 2013 Singhal A. Lancet. 2003; Growth and Metabolic Risk
Early differences in body composition resolve Multiple studies revealing no association between early growth and later HTN, lipid profiles and insulin sensitivity Increased BMI and weight gain in first 1-2 years post-term associated with obesity in childhood Childhood growth (>18 months) has shown small associations with metabolic syndrome While it is clear that risks for the components of metabolic syndrome are high in preterm infants what isn't as clear is whether these risks are due to nutrition and growth in early infancy, a time when the benefits for this growth are clear. The evidence linking weight gain and later metabolic risks are very inconsistent. Pfister Kand Ramel SE. Current Pediatrics. 2014 Belfort M. Nestle Nutr Inst Workshop Ser. 2013 Growth and Metabolic Risk
More study needed on early growth Early aggressive nutrition Avoid early growth restriction and need for catch-up growth Monitor proportionality and linear growth and potentially body composition Neurocognitive Development
PRETERM Rapid Infant Growth Among preterm infants vulnerable to neurodevelopmental impairment the rationale is strong to promote rapid growth even out of proportion to linear growth early by aggressive nutrition early in life. After term excess weight gain in proportion to length is unlikely beneficial and may increase risk of later metabolic complications. Later rapid growth especially after one year of life is unlikely to provide additional neurodevelopmental benefit and will increase later risk. Obesity, Metabolic Syndrome Risk Small for Gestational Age Term Infants
Rapid growth in weight and length in the first months after birth Most catch up to peers by 6-12 months Poorer neurodevelopmental outcomes than AGA term infants More prone to later metabolic disease Given the extensive literature on preterm infants and the benefits of aggressive nutrition the question arises what about SGA term infants. Those that undergo growth restriction while in utero. How much weight gain is optimal
How much weight gain is optimal? Infant weight gain in IUGR infants: BMI and IQ at 7 years Given the metabolic harms it is important to also look at the potential benefits of rapid weight gain to later neurodevelopment. Most studies that look at SGA include both term and preterm despite the fact that the benefits and risks may be different. Only study that separated term from preterm SGA and looked specifically at early growth This is an analysis of Collaborative Perinatal Project data . Both slower and more rapid weight gain from birth to 16 weeks was associated lower IQ at age 7 years. National Collaborative Perinatal Project Data Pylipow et al., 2008, J. Peds. Fortification for SGA Term Infants
Increased calories (68 vs 72 kcals/100 mls) and protein (+0.4 g/100mls) Given for 9 months Improved length and OFC gains at 9 and 18 months Similar IQ scores at 18 months (MDI 88.6 vs 87) and PDI (90.4 vs 90.7) Control BF group with much improved scores (MDI 99.5 and PDI 96.5) 9 month DQ actually worse in fortified group Singhal.AJCN, 2010 Morely. Pediatrics. 2004 Later Metabolic Outcomes
Several studies linking rapid weight gain in first 4 months to increased BMI, higher BP and insulin resistance at school age/adolescence Body composition and cardiometabolic risk factors assessed at follow-up (6-8 years of age) Fat Mass Standard: 2.0 kg Enriched: 2.7 (p=0.04) FFM Standard: 19.3 Nutrient: 19.8 (p=0.2) Blood Pressure Standard: 61.3 Enriched: 64.5 (p=0.02) Enriched = 20% formula in relationto energy 284 kJ/100 ml energy vs enriched = 301 kJ/100 ml 0.4 more grams of protein Singhal et al. AJCN. 2010 Singhal. Circulation. 2007 Neurocognitive Development
TERM SGA Rapid Infant Growth While full term SGA infants are at risk relative to AGA in terms of both neurodevelopmental deficit and cardio-metabolic disease later in life, more rapid growth likely leads to increased risk for insulin resistance, high BP and increased FM but does not appear to improve neurodevelopmental outcomes. More rapid infant weight gain is associated with long term benefits, such as better neurodevelopmental outcomes for some infants, but also with harms, such as increased risk of obesity and metabolic syndrome. Determining the optimal rate of growth requires balancing these benefits and risks, the magnitude of which differ for specific populations. Obesity, Metabolic Syndrome Risk AGA Healthy Term Infants
No positive association between rapid weight gain and IQ at 49 months or 8 years No linear association between weight gain or linear growth and IQ Systematic literature review of 14 studies that addressed associations between any kind of early weight gain and cognitive outcome in non-SGA children. Rapid weight gain was identified as increase of >0.67 in the SD score of weight or length between birth and 25 months of age. No positive association between rapid weight gain and IQ scores either at 49 months or 8 years. Subgroup analysis by sex of children and with rapid length gain revealed similar results. Supplementary analysis revealed no linear association between weight gain and IQ. Beyerlein A. Am J Clin Nutr 2010 Healthy AGA Term Infants
US cohort of ~900 infants Neither weight gain from birth to 8 weeks nor from 8 weeks to 6 months was related to cognition at age 3 years (or 7 years-unpublished). Additional dutch study of twins in adolescnece showed lower IQ by 3.2 points in the twin who gained greater weight (p=0.002). Belfort MB. Pediatrics. 2008 Metabolic Risk In Term Infants
In a systematic review of 21 studies, all reported positive associations of infant weight gain and later obesity risk. For each 0.67 SD excess weight gain from birth to 4-24 months, obesity risk increased fold! Other reviews have also found positive associations with increased BP and increased metabolic score as well. Ong KK. Acta Paediatr. 2006 Neurocognitive Development
TERM non-SGA Rapid Infant Growth In AGA term populationample data supporting a strong association between rapid infant weight gain and later obesity and limited evidence regarding other cardio-metabolic disease risk factors. In contrast, studies of early weight gain and later neurodevelopmental outcomes have shown small to no associations. Obesity, Metabolic Syndrome Risk Goals of Growth Growth goals to replicate fetal growth per AAP
Unclear if this is achievable and/or optimal The American Academy of Pediatrics has recommended that growth goals for preterm infant replicate that of fetal growth. Unfortunately, whether this goal is achievable OR optimal remains to be seen 3 decades after this recommendation was made. Determining optimal growth goals requires studies collecting long-term outcome data not only on growth, but also neurodevelopment and metabolic outcomes. This work is beginning to be done, but there is still much more to learn. AAP Committee on Nutrition. Pediatrics 1985;75:97686 Definitions of Growth Weight Gain Head Circumference Linear Growth
Proportionality Indices Body Composition I will now finish my talk with a discussion on methods of growth monitoring in neonates, as this is still the best method of determining the adequacy of nutrient intake. As previously mentioned, adequate and/or optimal growth has been defined as weight gain for the past several decades. Until recently publications addressing growth and later outcomes were based solely on this measure. This is likely because it is the easiest measure to obtain and most accurate measure obtained in the clinical setting. In the past several years as I have now shown you, the importance of linear growth and FFM gains have also been investigated. Linear growth and FFM accretion are more closely associated with organ growth (specifically the brain) and are important biomarkers of later cognitive outcomes. However, length can be a more difficult measure to obtain and requires appropriate equipment (length boards) to obtain accurate repeated measures. Weight for length measures have become more popular recently as a marker of proportionality and surrogate for true body composition measures. These measures have been shown to be appropriate for older children and adults, but have not been validated in young infants or preterm infants yet. Body composition devices are available but remain expensive and therefore not routinely used outside of the research setting yet. Weight Gain Weight gain alone does not give a clear picture of nutritional status Recommended weight gain velocity is g/kg/d to mimic fetal growth Does not account for catch-up often needed in ELBWs who had very poor or no weight gain initially May need g/kg/d Weight gain is the traditional metric of growth in the neonate and represents the balance between energy intake and expenditure. Although weight gain is associated with neurodevelopmental outcomes and there are distinct recommendations for rates of weight gain in preterm neonates, this metric alone does not give a complete picture of the overall nutritional state of the infant, and can be confounded by non-nutritional weight gain (eg, edema). While fetal weight gain is approximately grams per kilo per day, this goal does not account for the significant growth restriction that occurs in the first weeks of life amongst preterm infants. For this reason, a better goal for optimizing growth and neurodevelopment is likely closer to grams per kilo per day of weight gain. Head Circumference Goal ~1 cm/week Correlates with brain growth
Microcephaly associated with loss of gray matter1 Suboptimal head growth (1-2 SD below norm) associated with poorer neurodevelopmental outcomes2 Fetal head circumference gains are approximately 1 cm per week and correlate with brain growth. Microcephaly has been shown to be associated with loss of gray matter. Also, while head circumference appears to be relatively spared when compared to weight and linear growth, up to 30% of preterm infants continue to have suboptimal head growth. This suboptimal growth has also been associated with poorer neurodevelopment. For these reasons, head circumference should be measured at least weekly and if restriction occurs early, catch up growth should be monitored and optimized with goals of at least 1 cm per week. 1Cheong, Pediatrics 2008 2Neubauer, Acta Paediatrica 2013 Linear Growth Represents lean body mass, protein accretion and indexes organ growth Goal ~1-2 cm/wk Linear growth which represents lean body mass and protein accretion, is an often underutilized measurement. It is obviously a difficult measurement to obtain in utero and therefore fetal linear growth rates are difficult to interpret. This figure is looking at fetal crown heel length growth throughout gestation with age in weeks along the x axis and crown heel length velocity in centimeters per 4 weeks along the y axis. As you can see, fetuses between 20 and 30 weeks grow more than 1 cm per week and in fact closer to 2 cm per week. Linear growth should be measured weekly using a length board to be most accurate with goals of 1-2 cm per week. As length is an important marker of brain development, it should be followed closely and optimized as able. Crown-heel length velocity, cm per 4 weeks of gestational age. From Tanner JM Foetus Into Man. Cambridge, Massachusetts. Harvard University Press. BMI curves BMI measurement may help identify disproportionate growth
What is the ideal BMI for growing preterm infants? BMI is correlated with body fatness and risk of related diseases in children >5 years and adults. Proportionality indexes are proposed as complementary measures in neonatal growth assessment, but are not commonly used in neonates. Recently Olsen et al published BMI curves for preterm infants which may allow for closer monitoring of proportionality amongst this group of at risk infants. Unfortunately, what remains unclear is what is the ideal BMI for growing preterm infants. Hopefully, the release of these curves will now allow for studies looking at longitudinal changes in BMI and outcomes both neurodevelopmental and metabolic. Olsen et al. Pediatrics. 2015 BMI in Term Born Infants
Body mass index or BMI is correlated with body fatness and risk of related diseases in children ages 5 years through adulthood. Proportionality indexes have also been proposed as complementary measures in neonatal growth assessment, but are not yet commonly used in this population. This study published in looked at 200 term neonates and found strong associations between BMI and body fat %. However, the predictive value was quite poor given the large amount of variability seen at each z-score. As you can see on this scatter plot comparing BMI z-scores to % body fat, a BMI z-score of 0(click) is consistent with a body fat percent ranging from 2% (click) to as high as 17% (click). DeCuntoet al.Arch Dis Child Fetal Neonatal Ed 2014. All Proportionality Indices Poorly Predict %Body Fat
The best predictor was BMI (W/L2) Another uncertainty is whether BMI is an accurate predictor of body composition in newborns and specifically preterm infants. We performed an analysis on 218 preterm infants born between weeks gestation who had their body composition measured near birth. We looked at associations between multiple proportionality indices and body composition and found that all measures including BMI, ponderal index and weight for length are poor predictors of body fat percent. However,Weight for length squared or BMI was the best predictor of those tested with an R squared value of only As you can see on this scatter plot comparing BMI to % fat mass these two measures are correlated, but with a large amount of variance noted. For example, an infant with a BMI of 10 (click) could have a percent body fat ranging from near 0% (click) to 20%. A similar analysis was performed in term infants with similar findings. Body Composition Measurement
DEXA MRI Air Displacement Plethysmography Anthropometric Measures Isotope Dilution Bioelectrical Impedance Analysis While this area of research, specifically for preterm infants, remains relatively young, increases in the availability of devices allowing for infant body composition assessment have allowed for a surge of data on body composition. The chart in the top left corner is an illustration of this massive increase in publications on infant body composition between 1952 and 2012.ranging from 0.95) Validated against gold standard methods More Rapid than DXA, MRI, dilution methods Lower cost than DXA and MRI Does not require highly trained technician to operate Does not expose to radiation or require sedation Well-tolerated by infants Has extensions for older infants and young children 2-6 years, and for children and adults 6 and above Air displacement plethysomography has many advantages over other methods used for infant body composition. (click) It is highly reliable and has been validated against gold standard methods for both term and preterm infants. (click)Measurements are quick lasting less than 5 minutes total. (click)While the equipment is pricey it is much lower cost than MRI or DXA and since it does not require a technician to operate once the equipment is purchased there are not continued ongoing costs associated with its use. (click)ADP does not expose to radiation or require sedation and is (click)well tolerated by infants as young as 30 weeks gestation shortly after birth. Finally, (click) there are extensions now available allowing for longitudinal body composition tracking through toddlerhood, childhood and adulthood! Ramel et al. Pediatr Obesity 2014 Roggero et al. Pediatr Research 2012 ADP for Preterm Infant Body Composition Measurement
Disadvantages: Infants must be stable for ~5 minutes on RA Infants must be disconnected from all IVs and lines Uses constants for fat and fat-free mass Expensive, large equipment Despite its many advantages, there are still a few disadvantages to using ADP for body composition measurement in preterm neonates. Perhaps the biggest problem is that in order to be measured infants must be able to tolerate ~ 5 minutes of time without being connected to any respiratory support or IV lines. While most infants are able to tolerate this once they reach the feeding and growing portion of their hospital stay, this necessity limits the ability to measure the smallest and sickest infants early on in their stay. Additionally, the device measures volume and calculates density using weight and length. It then uses constants for fat and fat free mass to calculate the percent body fat and fat-free mass. These values have been obtained using gold standard methods but the differences between infants at different gestational ages as well as different timing after birth are still being investigated. Finally, the equipment remains expensive and large, especially when compared to the cost and space taken up of a length board and scale -Preterm in preparation
Growth curves developed from live-born infants are used as standards for determining the adequacy of weight gain and linear growth. Weight/Length and BMI Normative body composition along with a body composition tool will allow for monitoring of quality of weight gain. Term curves now exist -Preterm in preparation Intrauterine growth curves that plot weight against gestational ages have been developed from live-born premature infants and are used as standards for determining the adequacy of weight gain of individual infants (Lubchenco et al, Fenton, Babson and Benda) Similarly, normative body composition data plotted against gestational ages would allow for monitoring of the quality of weight gain together with a body composition assessment tool Preterm Infant Body Composition
Reference data on preterm infants using ADP As was discussed with BMI, The first step in determining optimal body composition for preterm infants is defining normal fetal gains in fat and fat free mass. Unfortunately due to the number and rigor of measurements needed for multicomponent body composition assessment, studies in the past have been limited to very small numbers and performed on still born infants and infants of varying ages up to several months of age. With the advent of an infant ADP however it has become possible to obtain rapid, non-invasive measurements on infants as small as 1kg. We have collected cross-sectional data on fat and fat free mass in ~220 infants born between 30 and 36 weeks gestation, shortly after birth and will soon be submitting a manuscript containing these growth curves with centiles for both fat and fat free mass. Again, the goal of these curves was to represent as closely as possible fetal fat and fat free mass accretion and will hopefully allow us to determine what the ideal body composition is in terms of long term metabolic and neurodevelopmental outcomes and also aid in developing nutritional strategies to meet these goals. Demerath et al. Manuscript in preparation. Summary Infant growth must not be defined as weight gain alone!
Different Populations = Different goals, risks and benefits Amongst preterm infants early rapid growth is beneficial More work on timing of interventions and types of nutritional alterations Non-nutritional factors Summary Term SGA infants early growth may increase later metabolic risk without cognitive benefit. Term AGA infants need closer growth monitoring to determine later risk Further work into ideal formulas if breast milk is not available