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Assessing the impact of preterm nutrition
Early Human Development (2007) 83, 813–818
a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m
w w w. e l s e v i e r. c o m / l o c a t e / e a r l h u m d e v
Assessing the impact of preterm nutrition Vimal Vasu, Neena Modi ⁎ Division of Medicine, Imperial College London, Chelsea & Westminster Campus, London, UK
KEYWORDS Infant; Premature; Nutritional status
Abstract Growth is the traditional means of assessing the impact of newborn nutrition. We argue that this approach is flawed as the optimum pattern of postnatal growth after extremely preterm birth is unknown and both growth restraint and growth acceleration are associated with beneficial as well as adverse outcomes. Clinical trials examining nutritional regimens should be designed to achieve specific patterns of postnatal growth. Clinical practice should include the systematic capture of neonatal nutritional intake. As the ultimate goals are adult health and wellbeing, long-term follow-up is essential. © 2007 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Nutritional support for extremely preterm infants has always been problematic. The practical and clinical complexities of providing intensive care and delivering enteral and parenteral nutrition have been sufficiently challenging to have justified a focus on short-term goals. But over the last decades illness severity has reduced, physiological stability has improved and the likelihood of survival to adult life has increased. It is time to consider long-term goals. By the time a preterm infant reaches term equivalent age clear differences in brain and somatic development are apparent in comparison to healthy term-born counterparts. Many of these differences are now known to persist and alter trajectories of normal development for life. The nutritional support of the preterm infant is likely to be a key determinant in establishing this altered phenotype. How should the success of nutritional support for the preterm infant be assessed? This review will discuss the ⁎ Corresponding author. Division of Medicine, Imperial College London, Chelsea & Westminster Campus, 369 Fulham Road, London SW10 9NH, UK. Tel.: +44 20 8846 7892; fax: +44 20 8740 8282. E-mail address: [email protected] (N. Modi).
differences that exist between the preterm infant at term age and beyond in comparison to healthy term-born infants, the evidence demonstrating the impact of early nutrition on trajectories of development, the conundrums faced by neonatologists when considering nutritional support, and the outcomes that might best be used to assess nutritional stratagems.
2. Somatic growth Growth, particularly weight gain has traditionally been the favoured means of assessing the adequacy of nutritional support. But what is optimal growth for preterm babies? Preterm birth is the end result of a compromised pregnancy. Thus it is not surprising that an infant born preterm usually weighs less than a fetus remaining in utero at equivalent gestational age, indicating that some degree of deceleration in intrauterine growth has occurred. At 25–26 weeks gestation, newborn weights are about 90–150 g less than that of a reference fetus and this difference rises to around 200–350 g by 30–31 weeks [1]. Superimposed upon poor intrauterine growth, is a period of postnatal growth deceleration regarded by many as nigh universal in contemporary neonatal intensive care [2,3]. By term age, preterm infants at term are lighter and shorter than their
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814 term-born counterparts though head growth is preserved and may even be accelerated [4]. Anthropometric assessment in early adulthood reveals preterm infants to be at a disadvantage with respect to growth attainment despite evidence of catch up growth during childhood. This effect is variable between studies and is more pronounced in males than in females [5]. A point worthy of attention is that despite slow growth in infancy, the majority of preterm infants catch-up into the normal range for height as well as weight over several years [6]. It is likely that this occurs irrespective of the nature of early nutritonal support. The goal of targeting the growth outcomes of the healthy baby born at term is adopted by clinicians who aim to attain the trajectory of growth depicted in preterm charts. Regardless of whether they are derived from longitudinal measurements of fetal growth or, as in the case of the UK 1990 Growth Reference, from cross-sectional measurements of newborn babies these growth curves are constructed such that an infant born preterm attains the size of a term-born infant by 40 weeks postmenstrual age. The assumption implicit in this clinical goal is that by promoting a spurt of accelerated growth during a short period of time between preterm birth and 40 weeks postmenstrual age, we can fix the harm caused by the earlier periods of intrauterine and postnatal growth restraint. Is this biologically plausible? Is there evidence in support of this view? Poor growth, regardless of whether this occurs during antenatal or early postnatal life, is associated with increased risk to long-term health. However the acceleration that follows on from a period of poor growth in utero or infancy also increases risk. What is not known is the optimal growth velocity during recovery. There is compelling evidence that accelerated growth increases the risks of adverse metabolic and cardiovascular outcomes. Increased risks of visceral adiposity [7], obesity [8], insulin resistance [9], dyslipidaemia [10] hypertension [11] and coronary artery disease [12] have all been reported. Possibly the most powerful arguments against rapid postnatal growth acceleration come from animal studies spanning five decades that demonstrate that a rate of growth that is sub-maximal, rather than maximal, is associated with increased longevity and improved adult health. In these animal models postnatal dietary interventions that attenuate catch-up growth not only increase longevity but also protect against the added risks posed by a high carbohydrate, high fat diet in later life. Ozanne and Hales compared longevity using a cross fostering technique in male mice exposed to a low protein intake to induce growth restriction in either fetal or early postnatal life. The shortest lifespan was seen in the animals that were protein deprived and growth restricted during fetal life and then underwent a period of rapid postnatal growth acceleration. In contrast they found that slowing the growth rate of mice during suckling not only increased longevity (to the remarkable extent of approximately 50%) but also protected against the lifeshortening effect of a later obesity-inducing diet [13]. The relevance of such studies to the human preterm infant is obviously uncertain. What does appear a reasonable inference is that the same dietary manipulation during different phases of early development (in this case fetal and immediate postnatal) can have a radically different impact upon longterm outcomes though whether this is mediated by nutrient deprivation (in this case protein), or by subsequent growth velocity is unclear. Interpretation of such dietary manipulation
V. Vasu, N. Modi studies requires recognition that any isocaloric deprivation model will result in nutritional imbalance (e.g. low-protein high carbohydrate). The greatest risk of morbidity related to accelerated postnatal growth appears to occur when there is a mismatch between the fetal and postnatal nutritional environment. Cleal et al. studied male offspring of ewes subject to 50% nutrient restriction or normal nutrient intake in early gestation, and then to postnatal nutritional deprivation or a control diet for the first 12 weeks of life, to create 4 groups, in two of which the pre and postnatal nutritional environment were matched and in two where they were mismatched. Cardiovascular function (cardiac hypertrophy, endothelial dysfunction, blood pressure control and altered vascular tone) assessed at adult age was abnormal in those groups in which the pre and postnatal environments were mismatched when compared with the matched group [14]. Human epidemiological data provide support for the concept that adaptive responses made by the fetus in response to a poor nutritional environment may be deleterious to adult health if the postnatal nutritional environment is one of nutritional excess. Of interest is the observation that the effects induced by maternal undernutrition can be reversed in rats given recombinant leptin in the neonatal period. Leptin treatment resulting in a slowing of neonatal weight gain, normalized caloric intake, locomotor activity, body weight, fat mass, and fasting plasma glucose, insulin, and leptin concentrations in adult life [15]. This raises the possibility of future therapeutic interventions to reverse the impact of an adverse intrauterine environment. A more immediately realistic research goal is to establish whether slower postnatal growth velocity in human preterm infants leads to more favourable long-term outcomes. In term-born infants the growth performance of those breastfed is now considered the gold-standard although growth velocity is slower than that of formula-fed infants. The new World Health Organization (WHO) growth charts [16] indicate that by one year of age, breast-fed infants are 500 g lighter than the weight depicted in the UK 1990 Growth Reference. Perhaps the preterm infant would be better served by weighing less by term than the infant born at term.
3. Cardiovascular outcomes The now landmark epidemiological observations of Barker demonstrating an association between birth size and adult coronary vascular disease [17] have been extended and amplified though data published to date still present an inconsistent picture. It has been suggested that individuals of low birth weight who show rapid weight gain in infancy have the highest risk of adult cardiovascular morbidity though these researchers found no adverse effect on vascular function (measured by flow mediated dilation of the brachial artery) in individuals who were of low birth weight secondary to preterm birth, unless they were also growth restricted [18]. A large Finnish population based cohort study has shown a negative correlation between increasing gestational age and systolic and diastolic blood pressure measured in young adults at the time of conscription for army duty. When compared to individuals born at term (37–41 weeks) the adjusted odds ratio for systolic hypertension (N 140 mm Hg) increased from 1.25 in those born between 33–36 weeks to 1.93 in those born between 24–28 weeks [19]. In contrast
Assessing the impact of preterm nutrition data from the Dutch POPS-19 cohort found no association between birth weight, birth gestation and early patterns of growth and blood pressure or lipid profiles at 19 years of age though the incidence of hypertension in the preterm group (b32 weeks and /or b 1500 g) was higher than in the age matched general population [20]. Current weight and body mass index were the strongest predictors of hypertension and dyslipidaemia in this cohort. Thus though it appears that preterm infants are at greater risk of higher adult blood pressure, the causes are unclear. Singhal et al. have suggested a beneficial effect of breast milk in preterm infants on mean arterial and diastolic blood pressures measured at 13–16 years of age [21]. They describe a 10% increase in human milk consumption conferring a 0.3 mm Hg reduction in mean arterial blood pressure even after adjustment for confounders. Of note is that the breast fed babies displayed a slower early growth velocity. The same group has described a beneficial effect of human milk on insulin resistance in preterm infants at 13–16 years of age [9]. Once again however it is unclear whether the determinant of the more favourable outcome is the type of neonatal nutrition (in this case human milk) or the resulting pattern of postnatal growth (a slower velocity).
4. Renal function Aberrant renal development is a further contributor to the adult preterm phenotype. Preterm infants are at risk of exposure to many nephrotoxic insults but reduced nephron number related to poor early nutrition followed by hyperfiltration, exacerbated by a high protein intake has been suggested as an additional determinant of preterm and intrauterine growth restriction associated hypertension [22]. However reduced total renal mass, secondary to congenital unilateral kidney or nephrectomy does not increase the risk of hypertension. An alternative explanation for preterm nephropathy is offered by preliminary data suggesting that glomerulosclerosis develops in intrauterine growth restricted rats only when subjected to growth acceleration. In humans 60% of nephrons develop during the third trimester and nephrogenesis is complete by 36 weeks gestation. Thus clinical and therapeutic options to preserve long-term renal function may differ in preterm and term-born growth restricted infants, with preservation of nephrogenesis through adequate nutrition the focus in the former, and avoidance of rapid growth in the latter. These hypotheses have yet to be tested.
5. Metabolic outcomes Reduced insulin sensitivity in infants born preterm (b 32 weeks gestation) has been demonstrated at 4–10 years [55] and 18– 27 years of age [23]. In the former study no association was demonstrated between neonatal macronutrient intakes and insulin sensitivity. However there was a significant negative association between rapid growth in infancy and insulin sensitivity. In the latter study preterm adults had higher 2-hour glucose, fasting insulin and 2-hour insulin concentrations. We have found higher pre-feed blood glucose levels and lower insulin sensitivity in preterm babies at term in comparison to term-born infants (unpublished data). These data suggest that preterm infants have reduced insulin sen-
815 sitivity that is amplified by rapid growth in childhood. What is unclear is the impact on later outcomes of growth velocity from preterm birth to term. Hovi et al. [23] noted that in preterm infants who were growth restricted an increase of one weight standard deviation score between birth and term corresponded to a 30.8% increase (95% CI, 0.13 to 70.8) in fasting insulin and a 22.8% increase (95% CI, −4.4 to 57.7) in 2-hour insulin concentration. No such association was apparent in the non-growth restricted preterm group. However the mean change in weight standard deviation score between birth and term in the growth restricted group was −0.2 compared to −1.4 for the entire preterm group indicating faster growth in the former. Thus the growth constraint experienced by the majority of extremely preterm infants may be protective against later insulin resistance. The extent to which preterm adults will manifest overt type 2 diabetes and whether this alters over time as neonatologists improve growth performance between birth and term are now highly relevant issues.
6. Body composition Weight gain is a poor indicator of the success of preterm nutrition as this provides no insight into body composition. Magnetic resonance imaging (MRI) allows direct assessment of adipose tissue (AT) content and it able to quantify individual AT depots [24]. Using whole body MR imaging, we have shown that there is aberrant deposition of AT, with an excess of intraabdominal AT, in preterm infants by the age of term and reduced lean body mass in comparison to their term-born counterparts [25]. Our recent data suggest that the exclusive feeding of preterm infants with fortified human milk seems to attenuate this aberrant deposition of adipose tissue (unpublished data). Our group has also demonstrated an increase in intrahepatocellular lipid content in preterm infants at term equivalent age using 1H magnetic resonance spectroscopy (submitted). It needs to be established whether this aberrant phenotype persists to adult life as these observations offer a possible explanation for the reduced insulin sensitivity of the preterm infant and are cause for concern as they indicate that these infants are likely to be at increased risk of type-2 diabetes. In older age groups visceral adiposity is a strong predictor of cardio-metabolic illness and all cause mortality [26] and is associated with hepatic steatosis [27], a risk factor for liver cirrhosis.
7. Brain growth and development The preterm infant is born during a critical period for brain growth. Processes such as cellular migration, cellular differentiation, synaptogenesis, myelination, neurogenesis and development of neurotransmitter pathways may all be susceptible to nutritional deprivation during this period. Studies of perinatal protein undernutrition in rats consistently demonstrate a reduction in brain weight [28], a reduction in dendritic spine density in different neuronal populations [29– 31] and reduced cortical blood vessel density [32]. Studies in term-born human infants subject to severe protein calorie malnutrition demonstrate similar dendritic spine pathology [33] and reduced intellectual development [34]. Evidence of the sensitivity of long-term cognitive outcome comes from randomised controlled trial data demonstrating that in preterm infants even brief periods of relative
816 under nutrition during a “sensitive” period of development may have demonstrable adverse effects. Preterm infants b1850 g from 5 UK neonatal units were randomised to either a preterm enriched formula or a standard term formula. The trial formula was continued until the infant had reached a weight of 2200 g or had been discharged from hospital. Follow up at 7.5–8 years of age demonstrated a significant reduction in overall IQ in males with the most marked effect being in verbal IQ in the standard term formula group [35]. In human very low birth weight infants’ undernutrition delays EEG maturation [36] and subnormal head growth is a predictor of poor neurodevelopmental outcome at school age [37]. Preterm infants who are in the highest quartile for in-hospital growth velocity have improved Mental Developmental and Psychomotor Developmental indices along with lower rates of cerebral palsy at 18–22 months corrected age [38]. These and similar observations, coupled with concerns about poor early postnatal growth, have provided impetus to arguments that neonatal nutritional regimens should promote rapid catch-up growth. Though animal and human data point to an undoubted association between poor growth and adverse neurodevelopmental outcome, the corollary that faster growth must equate with neurodevelopmental advantage is not implicit. In breast fed infants growth is slower yet several lines of evidence indicate that neurocognitive outcomes are better. A metaanalysis of controlled studies showed that after adjustment for co-variates breast feeding is associated with a 3.16 point higher cognitive developmental score compared with formula feeding [39]. This effect appears to be dose dependent and observed as early as 6 months and through to 15 years of age. Moreover, the beneficial effects are amplified in low birth weight infants. We have shown that accelerated head growth follows preterm birth in a contemporaneous cohort of infants b32 weeks and that this is related to the extent of breast milk exposure [4]. Maturation of brain stem auditory evoked responses in preterm infants between 28–32 weeks gestation is enhanced in infants fed breast milk compared with those fed formula [40]. Vohr et al. describe a beneficial effect of maternal breast milk intake in a cohort of just over 1000 extremely low birth weight infants at 18–22 months corrected age as evidenced by improved Bayley scales of infant development II (BSID II) and behaviour rating scale (BRS) after correction for important confounders [41]. A dose response relationship was noted, with infants in the highest breast milk quintile (N80th) having significantly higher BSID II and BRS percentile scores when compared with infants who received no breast milk (BSID II 87.3 v 75.8, BRS 58.8 v 45.6, P b 0.01). Head circumference is frequently used as an index of global brain growth though this is unsatisfactory in view of the increased extra-cerebral space often observed in preterm infants. MRI reveals a number of subtle differences between premature infants at term and the term-born infant. These include the appearance of diffuse enhanced high signal intensity (DEHSI) in conjunction with elevated white matter apparent diffusion coefficient (ADC) values [42], reduced proximal cerebral vessel tortuosity [43], reduced cortical folding [44] and reduced cortical surface area [45]. None of these findings have thus far have been demonstrated in association with a particular nutrient deficiency or growth pattern following preterm birth. That there is a paucity of data looking examining the interplay
V. Vasu, N. Modi between preterm birth, nutrition and neurocognitive outcomes is disconcerting. We accept that the interpretation of any such studies would be heavily confounded by the background rate of preterm perinatal brain injury but given that recent years have seen this decline perhaps now is an opportune moment to focus on this vital area of research.
8. Preterm nutrition It has long been argued and is currently widely accepted that adequate nutrition of the preterm infant equates with achieving the equivalent of third trimester intrauterine weight gain (14–18 g/kg/day) and nutrient accretion (1.8–2 g/kg/day of protein and 1.4–1.9 g/kg/day of fat). An obvious limitation of this strategy is that data on human fetal body composition are derived mainly from stillborn fetuses [46]. Ehrenkranz et al. have provided a comprehensive assessment of longitudinal postnatal growth in preterm infants with a birth weight range of 501–1500 g [2]. Mean growth rates were 14 g/kg/day in the smallest infants (501–600 g at birth) rising to 16 g/kg/day in the larger infants (1401–1500 g at birth). Although these growth rates are similar to third trimester fetal growth rates, by discharge the majority of these preterm infants were b 10th centile when plotted against the reference fetus of comparable post menstrual age. Observations such as these have led to the view that target intakes for preterm babies should be calculated from the nutrient accretion rate of the “reference” fetus to which is added nutrition necessary to redress the cumulative shortfall acquired by preterm infants during the early postnatal period. Although such an approach has merit in recognising that an individualised approach to neonatal nutrition is necessary, it takes us no further in questioning the validity of aiming to mimic the growth of the term-born infant. The diet of the preterm neonates in intensive care is high in fat and carbohydrate and low in protein. This is in marked contrast to third trimester intrauterine diet which is high in amino acids, moderate in glucose and low in lipid [47]. Though yet to be demonstrated in human studies, animal models strongly suggest that early protein deprivation followed by a high fat intake results in the most marked adverse impact on later glucose tolerance [13,48]. Increasing the immediate protein intake of extremely preterm infants requires a reliance on parenteral nutrition. Early initiation of parenteral nutrition on the first postnatal day of life appears safe and parenteral formulations containing approximately 3 g/kg/day of amino acids result in improved nitrogen balance and growth parameters by discharge [49]. However evidence of long-term benefit from such an approach remains elusive. In a trial examining the parenteral intakes of infants weighing 401–1000 g and comparing outcomes in two distinct nutritional groups (infants receiving greater or less than 3 g/kg/day parenteral amino acids during the first 5 days of life) no difference was found in neurodevelopmental outcomes at 18 month corrected age. However in the group receiving b 3 g/kg/day there was an increased number of infants with head circumferences b 5th centile (OR 2.2, 95% CI 1.2–4.1) [50]. Consensus guidelines regarding the nutritional support of the preterm infant from several different panels have been published each following generally the rationale described above [51–54]. There are however potential dangers in early aggressive nutritional strategies. High fat and carbohydrate
Assessing the impact of preterm nutrition intakes are associated with rapid early growth [55]. Limited data point to an association between very high protein intakes and poorer neurodevelopmental outcomes in preterm infants [56,57]. Remarkably there are no randomised trial data demonstrating improved neurodevelopmental outcomes in association with early aggressive nutrition and more rapid growth.
9. Conclusions and future directions The question for the neonatal clinician is clear: what outcome or outcomes best represent the impact of preterm nutrition? We suggest that it is time for a shift in emphasis when evaluating preterm nutrition, away from short-term growth. The use of growth as the sole or principal outcome measure to assess preterm nutrition is flawed as we do not know what represents optimal growth. We only know that there are problems at both ends of the spectrum, with poor and rapid early growth associated with unfavourable health outcomes. It appears time to concede that the unquestioned view of yesteryear that the faster the growth of a baby born preterm, the better, may be incorrect. If this is indeed the case what represents the best growth target? If the target is to mimic the growth velocity of the term-born infant the final growth attainment of preterm infant will inevitably be decreased. If the target is to catch-up to the size of the term-born infant as quickly as possible there will inevitably need to be a period of rapid catch-up. Should our aim be slow catch-up to meet the trajectory of healthy term-born infants over a period of several years? If catch-up over a longer period of time attenuates the risks of rapid growth acceleration to metabolic and cardiovascular health, without compromise to brain growth and development, the answer will be clear. What research is needed now? Clinical trials evaluating nutritional regimens are clearly called for but there are difficulties here. Randomised trials require unambiguous, achievable end-points but given that nutritional goals remain uncertain and outcomes may extend decades into the future, their design is problematic. It is estimated that only half of the variance in early postnatal growth can be attributed to nutrition. Non-nutritional constraints upon growth, summarised in terms such as illness severity and stress, are many, varied and operate across a wide temporal continuum. Considerable methodological ingenuity is required to ensure they do not confound the interpretation of outcomes. Infant feeding is also an issue that evokes strong personal views and many find equipoise difficult. These issues pose serious barriers to clinical research. However nihilism has never been the wont of the scientist. The systematic documentation of nutritional intakes coupled to standardised clinical variables, in powerful electronic databases should be promoted as a means to explore variations in practice and outcome, to generate hypotheses and to facilitate clinical trials. These databases could also be harnessed to acquire longitudinal growth data from large numbers of infants representing the full range of variations in clinical practice. Though no preterm growth standard exists, a United Kingdom preterm growth reference, constructed from longitudinal growth measurements of weight, length and head circumference in large cohorts of preterm infants would illustrate the range of growth performance given contemporary medical management and provide a baseline for comparisons. In the
817 United States, the National Institute of Child Health and Human Development (NICHD) Neonatal Research Network have developed such a preterm growth reference though this data now reflects the growth patterns and neonatal practices from over a decade ago [58]. Reproducing the achievements of the NICHD for different populations is a realistic and realizable target. Additionally, we have an obligation to ensure careful long-term follow-up of the preterm infant and utilise the ever expanding armamentarium of sophisticated investigative tools to attempt to detect early markers of potential adverse long-term outcome before these are clinically manifest. For the moment, until we know more, it might be prudent for neonatal clinicians to concentrate on improved early nutritional support and elimination of the all-too-common period of prolonged postnatal deprivation, and subsequently to avoid the temptation to “fatten-up” an otherwise healthy preterm baby.
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a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m
w w w. e l s e v i e r. c o m / l o c a t e / e a r l h u m d e v
Assessing the impact of preterm nutrition Vimal Vasu, Neena Modi ⁎ Division of Medicine, Imperial College London, Chelsea & Westminster Campus, London, UK
KEYWORDS Infant; Premature; Nutritional status
Abstract Growth is the traditional means of assessing the impact of newborn nutrition. We argue that this approach is flawed as the optimum pattern of postnatal growth after extremely preterm birth is unknown and both growth restraint and growth acceleration are associated with beneficial as well as adverse outcomes. Clinical trials examining nutritional regimens should be designed to achieve specific patterns of postnatal growth. Clinical practice should include the systematic capture of neonatal nutritional intake. As the ultimate goals are adult health and wellbeing, long-term follow-up is essential. © 2007 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Nutritional support for extremely preterm infants has always been problematic. The practical and clinical complexities of providing intensive care and delivering enteral and parenteral nutrition have been sufficiently challenging to have justified a focus on short-term goals. But over the last decades illness severity has reduced, physiological stability has improved and the likelihood of survival to adult life has increased. It is time to consider long-term goals. By the time a preterm infant reaches term equivalent age clear differences in brain and somatic development are apparent in comparison to healthy term-born counterparts. Many of these differences are now known to persist and alter trajectories of normal development for life. The nutritional support of the preterm infant is likely to be a key determinant in establishing this altered phenotype. How should the success of nutritional support for the preterm infant be assessed? This review will discuss the ⁎ Corresponding author. Division of Medicine, Imperial College London, Chelsea & Westminster Campus, 369 Fulham Road, London SW10 9NH, UK. Tel.: +44 20 8846 7892; fax: +44 20 8740 8282. E-mail address: [email protected] (N. Modi).
differences that exist between the preterm infant at term age and beyond in comparison to healthy term-born infants, the evidence demonstrating the impact of early nutrition on trajectories of development, the conundrums faced by neonatologists when considering nutritional support, and the outcomes that might best be used to assess nutritional stratagems.
2. Somatic growth Growth, particularly weight gain has traditionally been the favoured means of assessing the adequacy of nutritional support. But what is optimal growth for preterm babies? Preterm birth is the end result of a compromised pregnancy. Thus it is not surprising that an infant born preterm usually weighs less than a fetus remaining in utero at equivalent gestational age, indicating that some degree of deceleration in intrauterine growth has occurred. At 25–26 weeks gestation, newborn weights are about 90–150 g less than that of a reference fetus and this difference rises to around 200–350 g by 30–31 weeks [1]. Superimposed upon poor intrauterine growth, is a period of postnatal growth deceleration regarded by many as nigh universal in contemporary neonatal intensive care [2,3]. By term age, preterm infants at term are lighter and shorter than their
0378-3782/$ - see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.earlhumdev.2007.09.008
814 term-born counterparts though head growth is preserved and may even be accelerated [4]. Anthropometric assessment in early adulthood reveals preterm infants to be at a disadvantage with respect to growth attainment despite evidence of catch up growth during childhood. This effect is variable between studies and is more pronounced in males than in females [5]. A point worthy of attention is that despite slow growth in infancy, the majority of preterm infants catch-up into the normal range for height as well as weight over several years [6]. It is likely that this occurs irrespective of the nature of early nutritonal support. The goal of targeting the growth outcomes of the healthy baby born at term is adopted by clinicians who aim to attain the trajectory of growth depicted in preterm charts. Regardless of whether they are derived from longitudinal measurements of fetal growth or, as in the case of the UK 1990 Growth Reference, from cross-sectional measurements of newborn babies these growth curves are constructed such that an infant born preterm attains the size of a term-born infant by 40 weeks postmenstrual age. The assumption implicit in this clinical goal is that by promoting a spurt of accelerated growth during a short period of time between preterm birth and 40 weeks postmenstrual age, we can fix the harm caused by the earlier periods of intrauterine and postnatal growth restraint. Is this biologically plausible? Is there evidence in support of this view? Poor growth, regardless of whether this occurs during antenatal or early postnatal life, is associated with increased risk to long-term health. However the acceleration that follows on from a period of poor growth in utero or infancy also increases risk. What is not known is the optimal growth velocity during recovery. There is compelling evidence that accelerated growth increases the risks of adverse metabolic and cardiovascular outcomes. Increased risks of visceral adiposity [7], obesity [8], insulin resistance [9], dyslipidaemia [10] hypertension [11] and coronary artery disease [12] have all been reported. Possibly the most powerful arguments against rapid postnatal growth acceleration come from animal studies spanning five decades that demonstrate that a rate of growth that is sub-maximal, rather than maximal, is associated with increased longevity and improved adult health. In these animal models postnatal dietary interventions that attenuate catch-up growth not only increase longevity but also protect against the added risks posed by a high carbohydrate, high fat diet in later life. Ozanne and Hales compared longevity using a cross fostering technique in male mice exposed to a low protein intake to induce growth restriction in either fetal or early postnatal life. The shortest lifespan was seen in the animals that were protein deprived and growth restricted during fetal life and then underwent a period of rapid postnatal growth acceleration. In contrast they found that slowing the growth rate of mice during suckling not only increased longevity (to the remarkable extent of approximately 50%) but also protected against the lifeshortening effect of a later obesity-inducing diet [13]. The relevance of such studies to the human preterm infant is obviously uncertain. What does appear a reasonable inference is that the same dietary manipulation during different phases of early development (in this case fetal and immediate postnatal) can have a radically different impact upon longterm outcomes though whether this is mediated by nutrient deprivation (in this case protein), or by subsequent growth velocity is unclear. Interpretation of such dietary manipulation
V. Vasu, N. Modi studies requires recognition that any isocaloric deprivation model will result in nutritional imbalance (e.g. low-protein high carbohydrate). The greatest risk of morbidity related to accelerated postnatal growth appears to occur when there is a mismatch between the fetal and postnatal nutritional environment. Cleal et al. studied male offspring of ewes subject to 50% nutrient restriction or normal nutrient intake in early gestation, and then to postnatal nutritional deprivation or a control diet for the first 12 weeks of life, to create 4 groups, in two of which the pre and postnatal nutritional environment were matched and in two where they were mismatched. Cardiovascular function (cardiac hypertrophy, endothelial dysfunction, blood pressure control and altered vascular tone) assessed at adult age was abnormal in those groups in which the pre and postnatal environments were mismatched when compared with the matched group [14]. Human epidemiological data provide support for the concept that adaptive responses made by the fetus in response to a poor nutritional environment may be deleterious to adult health if the postnatal nutritional environment is one of nutritional excess. Of interest is the observation that the effects induced by maternal undernutrition can be reversed in rats given recombinant leptin in the neonatal period. Leptin treatment resulting in a slowing of neonatal weight gain, normalized caloric intake, locomotor activity, body weight, fat mass, and fasting plasma glucose, insulin, and leptin concentrations in adult life [15]. This raises the possibility of future therapeutic interventions to reverse the impact of an adverse intrauterine environment. A more immediately realistic research goal is to establish whether slower postnatal growth velocity in human preterm infants leads to more favourable long-term outcomes. In term-born infants the growth performance of those breastfed is now considered the gold-standard although growth velocity is slower than that of formula-fed infants. The new World Health Organization (WHO) growth charts [16] indicate that by one year of age, breast-fed infants are 500 g lighter than the weight depicted in the UK 1990 Growth Reference. Perhaps the preterm infant would be better served by weighing less by term than the infant born at term.
3. Cardiovascular outcomes The now landmark epidemiological observations of Barker demonstrating an association between birth size and adult coronary vascular disease [17] have been extended and amplified though data published to date still present an inconsistent picture. It has been suggested that individuals of low birth weight who show rapid weight gain in infancy have the highest risk of adult cardiovascular morbidity though these researchers found no adverse effect on vascular function (measured by flow mediated dilation of the brachial artery) in individuals who were of low birth weight secondary to preterm birth, unless they were also growth restricted [18]. A large Finnish population based cohort study has shown a negative correlation between increasing gestational age and systolic and diastolic blood pressure measured in young adults at the time of conscription for army duty. When compared to individuals born at term (37–41 weeks) the adjusted odds ratio for systolic hypertension (N 140 mm Hg) increased from 1.25 in those born between 33–36 weeks to 1.93 in those born between 24–28 weeks [19]. In contrast
Assessing the impact of preterm nutrition data from the Dutch POPS-19 cohort found no association between birth weight, birth gestation and early patterns of growth and blood pressure or lipid profiles at 19 years of age though the incidence of hypertension in the preterm group (b32 weeks and /or b 1500 g) was higher than in the age matched general population [20]. Current weight and body mass index were the strongest predictors of hypertension and dyslipidaemia in this cohort. Thus though it appears that preterm infants are at greater risk of higher adult blood pressure, the causes are unclear. Singhal et al. have suggested a beneficial effect of breast milk in preterm infants on mean arterial and diastolic blood pressures measured at 13–16 years of age [21]. They describe a 10% increase in human milk consumption conferring a 0.3 mm Hg reduction in mean arterial blood pressure even after adjustment for confounders. Of note is that the breast fed babies displayed a slower early growth velocity. The same group has described a beneficial effect of human milk on insulin resistance in preterm infants at 13–16 years of age [9]. Once again however it is unclear whether the determinant of the more favourable outcome is the type of neonatal nutrition (in this case human milk) or the resulting pattern of postnatal growth (a slower velocity).
4. Renal function Aberrant renal development is a further contributor to the adult preterm phenotype. Preterm infants are at risk of exposure to many nephrotoxic insults but reduced nephron number related to poor early nutrition followed by hyperfiltration, exacerbated by a high protein intake has been suggested as an additional determinant of preterm and intrauterine growth restriction associated hypertension [22]. However reduced total renal mass, secondary to congenital unilateral kidney or nephrectomy does not increase the risk of hypertension. An alternative explanation for preterm nephropathy is offered by preliminary data suggesting that glomerulosclerosis develops in intrauterine growth restricted rats only when subjected to growth acceleration. In humans 60% of nephrons develop during the third trimester and nephrogenesis is complete by 36 weeks gestation. Thus clinical and therapeutic options to preserve long-term renal function may differ in preterm and term-born growth restricted infants, with preservation of nephrogenesis through adequate nutrition the focus in the former, and avoidance of rapid growth in the latter. These hypotheses have yet to be tested.
5. Metabolic outcomes Reduced insulin sensitivity in infants born preterm (b 32 weeks gestation) has been demonstrated at 4–10 years [55] and 18– 27 years of age [23]. In the former study no association was demonstrated between neonatal macronutrient intakes and insulin sensitivity. However there was a significant negative association between rapid growth in infancy and insulin sensitivity. In the latter study preterm adults had higher 2-hour glucose, fasting insulin and 2-hour insulin concentrations. We have found higher pre-feed blood glucose levels and lower insulin sensitivity in preterm babies at term in comparison to term-born infants (unpublished data). These data suggest that preterm infants have reduced insulin sen-
815 sitivity that is amplified by rapid growth in childhood. What is unclear is the impact on later outcomes of growth velocity from preterm birth to term. Hovi et al. [23] noted that in preterm infants who were growth restricted an increase of one weight standard deviation score between birth and term corresponded to a 30.8% increase (95% CI, 0.13 to 70.8) in fasting insulin and a 22.8% increase (95% CI, −4.4 to 57.7) in 2-hour insulin concentration. No such association was apparent in the non-growth restricted preterm group. However the mean change in weight standard deviation score between birth and term in the growth restricted group was −0.2 compared to −1.4 for the entire preterm group indicating faster growth in the former. Thus the growth constraint experienced by the majority of extremely preterm infants may be protective against later insulin resistance. The extent to which preterm adults will manifest overt type 2 diabetes and whether this alters over time as neonatologists improve growth performance between birth and term are now highly relevant issues.
6. Body composition Weight gain is a poor indicator of the success of preterm nutrition as this provides no insight into body composition. Magnetic resonance imaging (MRI) allows direct assessment of adipose tissue (AT) content and it able to quantify individual AT depots [24]. Using whole body MR imaging, we have shown that there is aberrant deposition of AT, with an excess of intraabdominal AT, in preterm infants by the age of term and reduced lean body mass in comparison to their term-born counterparts [25]. Our recent data suggest that the exclusive feeding of preterm infants with fortified human milk seems to attenuate this aberrant deposition of adipose tissue (unpublished data). Our group has also demonstrated an increase in intrahepatocellular lipid content in preterm infants at term equivalent age using 1H magnetic resonance spectroscopy (submitted). It needs to be established whether this aberrant phenotype persists to adult life as these observations offer a possible explanation for the reduced insulin sensitivity of the preterm infant and are cause for concern as they indicate that these infants are likely to be at increased risk of type-2 diabetes. In older age groups visceral adiposity is a strong predictor of cardio-metabolic illness and all cause mortality [26] and is associated with hepatic steatosis [27], a risk factor for liver cirrhosis.
7. Brain growth and development The preterm infant is born during a critical period for brain growth. Processes such as cellular migration, cellular differentiation, synaptogenesis, myelination, neurogenesis and development of neurotransmitter pathways may all be susceptible to nutritional deprivation during this period. Studies of perinatal protein undernutrition in rats consistently demonstrate a reduction in brain weight [28], a reduction in dendritic spine density in different neuronal populations [29– 31] and reduced cortical blood vessel density [32]. Studies in term-born human infants subject to severe protein calorie malnutrition demonstrate similar dendritic spine pathology [33] and reduced intellectual development [34]. Evidence of the sensitivity of long-term cognitive outcome comes from randomised controlled trial data demonstrating that in preterm infants even brief periods of relative
816 under nutrition during a “sensitive” period of development may have demonstrable adverse effects. Preterm infants b1850 g from 5 UK neonatal units were randomised to either a preterm enriched formula or a standard term formula. The trial formula was continued until the infant had reached a weight of 2200 g or had been discharged from hospital. Follow up at 7.5–8 years of age demonstrated a significant reduction in overall IQ in males with the most marked effect being in verbal IQ in the standard term formula group [35]. In human very low birth weight infants’ undernutrition delays EEG maturation [36] and subnormal head growth is a predictor of poor neurodevelopmental outcome at school age [37]. Preterm infants who are in the highest quartile for in-hospital growth velocity have improved Mental Developmental and Psychomotor Developmental indices along with lower rates of cerebral palsy at 18–22 months corrected age [38]. These and similar observations, coupled with concerns about poor early postnatal growth, have provided impetus to arguments that neonatal nutritional regimens should promote rapid catch-up growth. Though animal and human data point to an undoubted association between poor growth and adverse neurodevelopmental outcome, the corollary that faster growth must equate with neurodevelopmental advantage is not implicit. In breast fed infants growth is slower yet several lines of evidence indicate that neurocognitive outcomes are better. A metaanalysis of controlled studies showed that after adjustment for co-variates breast feeding is associated with a 3.16 point higher cognitive developmental score compared with formula feeding [39]. This effect appears to be dose dependent and observed as early as 6 months and through to 15 years of age. Moreover, the beneficial effects are amplified in low birth weight infants. We have shown that accelerated head growth follows preterm birth in a contemporaneous cohort of infants b32 weeks and that this is related to the extent of breast milk exposure [4]. Maturation of brain stem auditory evoked responses in preterm infants between 28–32 weeks gestation is enhanced in infants fed breast milk compared with those fed formula [40]. Vohr et al. describe a beneficial effect of maternal breast milk intake in a cohort of just over 1000 extremely low birth weight infants at 18–22 months corrected age as evidenced by improved Bayley scales of infant development II (BSID II) and behaviour rating scale (BRS) after correction for important confounders [41]. A dose response relationship was noted, with infants in the highest breast milk quintile (N80th) having significantly higher BSID II and BRS percentile scores when compared with infants who received no breast milk (BSID II 87.3 v 75.8, BRS 58.8 v 45.6, P b 0.01). Head circumference is frequently used as an index of global brain growth though this is unsatisfactory in view of the increased extra-cerebral space often observed in preterm infants. MRI reveals a number of subtle differences between premature infants at term and the term-born infant. These include the appearance of diffuse enhanced high signal intensity (DEHSI) in conjunction with elevated white matter apparent diffusion coefficient (ADC) values [42], reduced proximal cerebral vessel tortuosity [43], reduced cortical folding [44] and reduced cortical surface area [45]. None of these findings have thus far have been demonstrated in association with a particular nutrient deficiency or growth pattern following preterm birth. That there is a paucity of data looking examining the interplay
V. Vasu, N. Modi between preterm birth, nutrition and neurocognitive outcomes is disconcerting. We accept that the interpretation of any such studies would be heavily confounded by the background rate of preterm perinatal brain injury but given that recent years have seen this decline perhaps now is an opportune moment to focus on this vital area of research.
8. Preterm nutrition It has long been argued and is currently widely accepted that adequate nutrition of the preterm infant equates with achieving the equivalent of third trimester intrauterine weight gain (14–18 g/kg/day) and nutrient accretion (1.8–2 g/kg/day of protein and 1.4–1.9 g/kg/day of fat). An obvious limitation of this strategy is that data on human fetal body composition are derived mainly from stillborn fetuses [46]. Ehrenkranz et al. have provided a comprehensive assessment of longitudinal postnatal growth in preterm infants with a birth weight range of 501–1500 g [2]. Mean growth rates were 14 g/kg/day in the smallest infants (501–600 g at birth) rising to 16 g/kg/day in the larger infants (1401–1500 g at birth). Although these growth rates are similar to third trimester fetal growth rates, by discharge the majority of these preterm infants were b 10th centile when plotted against the reference fetus of comparable post menstrual age. Observations such as these have led to the view that target intakes for preterm babies should be calculated from the nutrient accretion rate of the “reference” fetus to which is added nutrition necessary to redress the cumulative shortfall acquired by preterm infants during the early postnatal period. Although such an approach has merit in recognising that an individualised approach to neonatal nutrition is necessary, it takes us no further in questioning the validity of aiming to mimic the growth of the term-born infant. The diet of the preterm neonates in intensive care is high in fat and carbohydrate and low in protein. This is in marked contrast to third trimester intrauterine diet which is high in amino acids, moderate in glucose and low in lipid [47]. Though yet to be demonstrated in human studies, animal models strongly suggest that early protein deprivation followed by a high fat intake results in the most marked adverse impact on later glucose tolerance [13,48]. Increasing the immediate protein intake of extremely preterm infants requires a reliance on parenteral nutrition. Early initiation of parenteral nutrition on the first postnatal day of life appears safe and parenteral formulations containing approximately 3 g/kg/day of amino acids result in improved nitrogen balance and growth parameters by discharge [49]. However evidence of long-term benefit from such an approach remains elusive. In a trial examining the parenteral intakes of infants weighing 401–1000 g and comparing outcomes in two distinct nutritional groups (infants receiving greater or less than 3 g/kg/day parenteral amino acids during the first 5 days of life) no difference was found in neurodevelopmental outcomes at 18 month corrected age. However in the group receiving b 3 g/kg/day there was an increased number of infants with head circumferences b 5th centile (OR 2.2, 95% CI 1.2–4.1) [50]. Consensus guidelines regarding the nutritional support of the preterm infant from several different panels have been published each following generally the rationale described above [51–54]. There are however potential dangers in early aggressive nutritional strategies. High fat and carbohydrate
Assessing the impact of preterm nutrition intakes are associated with rapid early growth [55]. Limited data point to an association between very high protein intakes and poorer neurodevelopmental outcomes in preterm infants [56,57]. Remarkably there are no randomised trial data demonstrating improved neurodevelopmental outcomes in association with early aggressive nutrition and more rapid growth.
9. Conclusions and future directions The question for the neonatal clinician is clear: what outcome or outcomes best represent the impact of preterm nutrition? We suggest that it is time for a shift in emphasis when evaluating preterm nutrition, away from short-term growth. The use of growth as the sole or principal outcome measure to assess preterm nutrition is flawed as we do not know what represents optimal growth. We only know that there are problems at both ends of the spectrum, with poor and rapid early growth associated with unfavourable health outcomes. It appears time to concede that the unquestioned view of yesteryear that the faster the growth of a baby born preterm, the better, may be incorrect. If this is indeed the case what represents the best growth target? If the target is to mimic the growth velocity of the term-born infant the final growth attainment of preterm infant will inevitably be decreased. If the target is to catch-up to the size of the term-born infant as quickly as possible there will inevitably need to be a period of rapid catch-up. Should our aim be slow catch-up to meet the trajectory of healthy term-born infants over a period of several years? If catch-up over a longer period of time attenuates the risks of rapid growth acceleration to metabolic and cardiovascular health, without compromise to brain growth and development, the answer will be clear. What research is needed now? Clinical trials evaluating nutritional regimens are clearly called for but there are difficulties here. Randomised trials require unambiguous, achievable end-points but given that nutritional goals remain uncertain and outcomes may extend decades into the future, their design is problematic. It is estimated that only half of the variance in early postnatal growth can be attributed to nutrition. Non-nutritional constraints upon growth, summarised in terms such as illness severity and stress, are many, varied and operate across a wide temporal continuum. Considerable methodological ingenuity is required to ensure they do not confound the interpretation of outcomes. Infant feeding is also an issue that evokes strong personal views and many find equipoise difficult. These issues pose serious barriers to clinical research. However nihilism has never been the wont of the scientist. The systematic documentation of nutritional intakes coupled to standardised clinical variables, in powerful electronic databases should be promoted as a means to explore variations in practice and outcome, to generate hypotheses and to facilitate clinical trials. These databases could also be harnessed to acquire longitudinal growth data from large numbers of infants representing the full range of variations in clinical practice. Though no preterm growth standard exists, a United Kingdom preterm growth reference, constructed from longitudinal growth measurements of weight, length and head circumference in large cohorts of preterm infants would illustrate the range of growth performance given contemporary medical management and provide a baseline for comparisons. In the
817 United States, the National Institute of Child Health and Human Development (NICHD) Neonatal Research Network have developed such a preterm growth reference though this data now reflects the growth patterns and neonatal practices from over a decade ago [58]. Reproducing the achievements of the NICHD for different populations is a realistic and realizable target. Additionally, we have an obligation to ensure careful long-term follow-up of the preterm infant and utilise the ever expanding armamentarium of sophisticated investigative tools to attempt to detect early markers of potential adverse long-term outcome before these are clinically manifest. For the moment, until we know more, it might be prudent for neonatal clinicians to concentrate on improved early nutritional support and elimination of the all-too-common period of prolonged postnatal deprivation, and subsequently to avoid the temptation to “fatten-up” an otherwise healthy preterm baby.
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