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Postnatal Malnutrition and Growth Retardation: An Inevitable Consequence of Current Recommendations in Preterm Infants? Nicolas E. Embleton, Naomi Pang and Richard J. Cooke Pediatrics 2001;107;270-273 DOI: 10.1542/peds.107.2.270

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://www.pediatrics.org/cgi/content/full/107/2/270

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2001 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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Postnatal Malnutrition and Growth Retardation: An Inevitable Consequence of Current Recommendations in Preterm Infants? Nicolas E. Embleton, MB, BS, BSc, MRCPCH; Naomi Pang, BMedSci; and Richard J. Cooke, MD, FRCPCH, FRCPI, FAAP ABSTRACT. Background. Nutrient intakes meeting recommended dietary intakes (RDIs) take time to establish and once established are rarely maintained throughout hospital stay in preterm infants. A nutrient deficit, therefore, accrues. RDI are based on needs for maintenance and growth, with no provision to replace this deficit. We, therefore, hypothesized that postnatal malnutrition and growth retardation were inevitable in infants fed current RDI. Methodology. Dietary intakes were prospectively collected, by a single observer (N.P.), on a daily basis in a group of preterm infants (n ⴝ 105; birth weight <1750 g; gestational age <34 weeks) admitted to neonatal intensive care unit over a 6-month period. Actual was subtracted from recommended energy (120 kcal/kg/day) and protein (3 g/kg/day) intakes and nutritional deficits calculated. Infants were weighed on admission and throughout hospital stay. The data were analyzed using a combination of repeated measures analysis of variance and stepwise regression analysis. Results. Nutrient intakes meeting current RDIs were rarely achieved during early life. By the end of the first week, cumulative energy and protein deficits were 406 ⴞ 92 and 335 ⴞ 86 kcal/kg and 14 ⴞ 3 and 12 ⴞ 4 g/kg in infants <30 and those at >31 weeks. By the end of the fifth week, cumulative energy and protein deficits were 813 ⴞ 542 and 382 ⴞ 263 kcal/kg and 23 ⴞ 12 and 13 ⴞ 15 g/kg and the z scores were ⴚ1.14 ⴞ .6 and ⴚ.82 ⴞ .5 for infants at <30 and >31 weeks. Stepwise regression analysis indicated that variation in dietary intake accounted for 45% of the variation in changes in z score. Conclusions. Preterm infants inevitably accumulate a significant nutrient deficit in the first few weeks of life that will not be replaced when current RDIs are fed. This deficit can be directly related to subsequent postnatal growth retardation. Pediatrics 2001;107:270 –273; postnatal growth retardation, preterm infants. ABBREVIATIONS. RDI, recommended dietary intake; TPN, total parenteral nutrition; SD, standard deviation; ANOVA, analysis of variance.

From the Special Care Baby Unit, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom. Received for publication Jan 3, 2000; accepted Jun 6, 2000. Address correspondence to Richard J. Cooke, MD, FRCPCH, FRCPI, FAAP, Ward 35, Leaze’s Wing, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom NE1 4LP. E-mail: [email protected] PEDIATRICS (ISSN 0031 4005). Copyright © 2001 by the American Academy of Pediatrics.

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dequate nutrition is critical to prevent early postnatal growth retardation and to optimize long-term growth and development in preterm infants. Current recommendations are to “provide nutrients to approximate the rate of growth and composition of weight gain for a normal fetus of the same post conceptional age.”1 However, nutrient intakes meeting recommended dietary intakes (RDIS) take time to establish and once established are rarely maintained throughout hospital stay.2– 4 We, therefore, hypothesized that postnatal malnutrition and postnatal growth retardation were inevitable in preterm infants fed current RDI. Our purposes were to prospectively document energy and protein intakes, to compare these intakes with RDI, and to examine the relationship between the accumulated deficit and postnatal growth during initial hospital stay in preterm infants admitted to the neonatal intensive care setting. METHODS This prospective study was conducted over a 6-month period on all infants admitted to the neonatal intensive care unit at the Royal Victoria Infirmary, Newcastle on Tyne. The local ethics committee determined that written informed consent was not necessary for the purpose of this audit. Preterm infants with a gestational age of ⱕ34 weeks and a birth weight ⱕ1750 g were considered eligible. Only those alive on day 2 of life were enrolled in the study. Gestational age was assessed using maternal dates and fetal ultrasound. Body weight was measured using standard unit scales, accurate to 5 g. All infants were fed according to a standard protocol that was uniformly applied. The aims of this protocol are to establish an energy intake ⱖ40 kcal/kg/day on day 1, commence total parenteral nutrition (TPN; 10% dextrose, 2.0 g protein/100 mL) on day 2, and commence intravenous lipids (2 kcal/mL) and enteral feeds on day 3. Enteral feeds, with human milk or a term infant formula (20 cal/oz, 2.0 g protein/100 kcal) are begun at .5 to 1.0 mL/kg/ hour and increased at a rate of 20 mL/kg/day. When an enteral intake of 150 mL/kg/day is established infants fed human milk are transitioned to 50% human milk and 50% standard preterm formula (24 kcal/oz, 2.7 g protein/100 kcal) over a 2-day period, fed in alternate syringes. Infants not fed human milk were transitioned to 100% preterm formula over a 4-day period. Infants are fed by continuous infusion until ⬃32 to 33 weeks’ corrected age, at which point bolus feeds are introduced. The unit approach to supplementation of human milk is, perhaps, unusual. Seventy to 80% of our mothers choose to provide breast milk. However, the volume of milk varies and infants may be fed varying amounts of mother’s milk ⫹ human milk fortifier and/or preterm formula. Because infants fed preterm formula grow better than those fed fortified human milk4,5 and because it is easier to implement in a consistent manner we choose to supplement human milk with preterm formula. Intake data, actual not prescribed, were collected on a daily basis by a single observer (N.P.). Human milk was assumed to contain 75 kcal/100 mL and 1.4 g of protein/100 mL.6,7 Formula

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intakes were based on published manufacturer’s figures. An energy intake of 120 kcal/kg/day was assumed to be adequate.1 Recommended protein intakes vary from 3.0 to 3.8 g/kg/day8 and an intake of 3.0 g/kg/day was considered acceptable. Actual intake was subtracted from RDI to calculate daily deficit, which was then summed to calculate cumulative deficit. Weight was converted to standard deviation (SD; z) scores using the British reference standards.9 Changes in z score were calculated by subtracting current z score, corrected for postconceptual age, from that at birth. Infants were stratified by gestational age (ⱕ30 and ⱖ31 weeks’ gestation. The data are presented as mean (⫾ SD) unless otherwise stated and were analyzed using repeated measures analysis of variance (ANOVA), with gestational age as a blocking variable. Stepwise regression analysis was used to examine the relationship between birth weight, gestational age, postnatal age, energy deficit, and protein deficit and changes in z score. Results were considered significant at P ⬍ .05.

RESULTS

One hundred five infants were studied with a mean (⫾ SD) birth weight of 1285 ⫾ 322 g and a gestational age of 30 ⫾ 2.3 weeks. Infants were followed until death (n ⫽ 11), transfer to referral hospital (n ⫽ 57), or discharge home (n ⫽ 37). None of the surviving infants developed necrotizing enterocolitis, a patent ductus arteriosus, or required steroid therapy. TPN was commenced at 3 ⫾ 1 days of age. Enteral feeds were begun at 3 ⫾ 1 days; by 4 days, 84% of infants had received enteral feeds. Full enteral feeds were established at 10 ⫾ 6 days; by 12 days, 80% of infants were tolerating an enteral intake of ⱖ150 mL/kg/day. Daily energy intake and daily cumulative deficits during the first week of life are presented in Fig 1. Although intakes increased rapidly (P ⬍ .0001), infants ⱕ30 had lower daily energy (60 ⫾ 25 ⬍ 72 ⫾ 30 kcal/kg/day; P ⬍ .001) and protein intakes (1.0 ⫾ 1.0 ⬍ 1.4 ⫾ 1.0 g/kg/day; P ⬍ .001) than those at ⱖ31 weeks’ gestation. By the end of the first week, cumulative energy and protein deficits were 406 ⫾ 92 and 335 ⫾ 86 kcal/kg and 14 ⫾ 3 and 12 ⫾ 4 g/kg in infants ⱕ30 and those at ⱖ31 weeks, respectively. Weekly nutrient intakes and cumulative deficits are presented in Fig 2. Intakes and deficits increased between weeks 1 and 2 (ⱖ31 weeks; P ⬍ .001) and between weeks 1 and 5 (ⱕ30 weeks; P ⬍ .001) but stabilized thereafter. Overall, intakes were less and deficits were greater in infants ⱕ30, compared with those at ⱖ31 weeks’ gestation (P ⬍ .0001). By the end of the fifth week, cumulative energy and protein deficits were 813 ⫾ 542 and 382 ⫾ 263 kcal/kg and 23 ⫾ 12 and 13 ⫾ 15 g/kg for those at ⱕ30 and ⱖ31 weeks, respectively. The mean changes in z scores between birth and 7 weeks are also presented in Fig 2. Mean changes in z score fell from 0 at birth to ⫺1.04 ⫾ .8 at 7 weeks (P ⬍ .0001). Between birth and 14 days, scores were similar in infants ⱕ30 and ⱖ31 weeks’ gestation. After 2 weeks, z score stabilized in infants ⱖ31 weeks but continued to decrease until 5 weeks in infants at ⱕ30 weeks’ gestation. Stepwise regression analysis indicated that ⬃52% of the variation in z scores could be explained by the cumulative energy deficit (⬃45%) and gestational age (⬃7%), cumulative protein deficit had no significant effect.

Fig 1. Nutrient intake and cumulative nutrient deficit during the first weeks of life. Data were analyzed using ANOVA. The asterisk indicates the overall level of significant difference between infants at ⱕ30 weeks and ⱖ31 weeks as determined using ANOVA.

DISCUSSION

This was a observational study designed to determine what really happens in this unit and the results are influenced by our approach to nutritional care. Thus, more aggressive TPN with higher energy and protein intakes might have reduced the energy and protein deficit. However, early TPN is limited by glucose and lipid intolerance and concerns regarding amino acid metabolism. Constant energy and protein intakes of ⱖ80 kcal and ⱖ2.0 g/kg/day are rarely established in the smaller sicker infants during early life, irrespective of the regimen used.2– 4 More aggressive enteral feeding might also have reduced the deficit. Nevertheless, enteral feeds were introduced early and full enteral feeds were established in 80% of infants by day 12. No infants developed necrotizing enterocolitis during the study but whether earlier introduction and more rapid advancement in enteral volumes is achievable without adverse effects is not clear. What is clear is that early nutritional deficits were not regained before hospital discharge. This is not

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Fig 2. Nutrient intake, cumulative nutrient deficit, and changes in Z score during hospital stay. The asterisk indicates the overall level of significant difference between infants at ⱕ30 weeks and ⱖ31 weeks as determined using ANOVA. Numbers in enclosed brackets indicate sample size at that time point.

surprising. Infants were fed nutrient intakes designed to meet current RDI. Current RDIs are based on needs for maintenance and normal growth and no provision is made for catch-up growth. The situation is further compounded during subsequent weeks when feeds were interrupted for clinical reasons but a delay ensued before full feeds were reestablished. There is no good evidence to suggest that needs for 272

catch-up are different from those of normal growth. It has, therefore, been suggested that needs for catch-up be added to those of normal growth and replaced before hospital discharge.10 Depending on the size of the deficit, this may or may not be possible but such an approach is not widely practiced and merits consideration. In this study, energy deficit (374 kcal/kg) peaked by 14 days in infants ⱖ31 weeks’ gestation. Assuming that intake was maintained between 14 days and 36 days of age, the mean age at hospital discharge, a further 18 kcal/kg/day would be needed for catchup. Infants at ⱕ30 weeks had an energy deficit of 590 kcal at 14 days. However, this continued to increase to 813 kcal/kg at 35 days and it is unlikely that the deficit (39 kcal/kg/day) could have been replaced before hospital discharge at 56 days of age. The relationship between nutrient intake and growth is intriguing. Carlson and Ziegler4 examining growth in preterm infants noted that poorer gain was more marked in infants fed fortified human milk than preterm formula. Because energy intakes were similar but protein intakes were less, it was suggested that poorer growth reflected inadequate protein intake.4 In this study poorer growth was primarily related to inadequate energy intake. Comparisons between these 2 studies are difficult but might be interpreted to make a point. Nutritional requirements and intake vary depending on patient population; the smaller the infant, the more complicated the perinatal course, the greater the variation in requirements and intake. Feeding practices also vary11,12 further increasing variation in intake. Thus, the nature and amount of the nutritional deficit will differ between infants and nurseries and what is rate-limiting in one situation may not be rate-limiting in another. It is generally assumed that poor growth in preterm infants primarily reflects inadequate nutrient intake. In this study, ⬃45% of the variation in growth was related to intake, with an additional 7% of the variation in growth relating to birth weight. Thus, 45% of the variation in growth was not explained demonstrating the heterogeneous nature of this group of infants. Nonetheless, it does underline the importance of controlling for nonnutritional factors when examining the effects of dietary intervention. The results of this simple study are important. On a day-to-day basis, quality of nutritional care is assessed by examining daily nutrient intake. Data from this study suggest a more realistic picture can be obtained by expressing the data as cumulative nutrient deficit. Whether deficits can be recouped during initial hospital stay is not clear. What is clear is that they will never be recouped if infants are fed intakes meeting current RDI. A randomized, controlled trial will be needed to more closely examine this issue. REFERENCES 1. American Academy of Pediatrics, Committee on Nutrition. Nutritional needs of preterm infants. In: Kleinman R, ed. Pediatric Nutrition Handbook. Elk Grove, IL: American Academy of Pediatrics; 1998:55–79 2. Cooke RJ, Ford A, Werkman S, Conner C, Watson D. Postnatal growth in infants born between 700 and 1,500 g. J Pediatr Gastroenterol Nutr. 1993;16:130 –135

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3. Wilson DC, Cairns P, Halliday HL, Reid M, McClure G, Dodge JA. Randomised controlled trial of an aggressive nutritional regimen in sick very low birthweight infants. Arch Dis Child Fetal Neonatal Ed. 1997;77: F4 –F11 4. Carlson SJ, Ziegler EE. Nutrient intakes and growth of very low birth weight infants. J Perinatol. 1998;18:252–258 5. Schanler RJ, Shulman RJ, Lau C. Feeding strategies for premature infants: beneficial outcomes of feeding fortified human milk versus preterm formula. Pediatrics. 1999;103:1150 –1157 6. Anderson DM, Williams FH, Merkatz RB, Schulman PK, Kerr DS, Pittard WBD. Length of gestation and nutritional composition of human milk. Am J Clin Nutr. 1983;37:810 – 814 7. Lemons J, Moye L, Hall D, Simmons M. Differences in the composition

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of preterm and term human milk during early lactation. Pediatr Res. 1982;16:113–117 Micheli J, Schutz Y. Protein. In: Tsang R, Lucas A, Uauy R, Zlotkin S, eds. Nutritional Needs of the Preterm Infant: Scientific Basis and Practical Guidelines. Baltimore, MD: Williams & Wilkins; 1993:29 – 46 Paul AA, Cole TJ, Whitehead RG. Growth standards for infancy. Arch Dis Child. 1994;70:554 Schulze K, Kashyap S, Ramakrishnan R. Cardiorespiratory costs of growth in low birth weight infants. J Dev Physiol. 1993;19:85–90 Churella HR, Bachhuber WL, MacLean WC. Survey: methods of feeding low-birth-weight infants. Pediatrics. 1985;76:243–249 McClure RJ, Chatrath MK, Newell SJ. Changing trends in feeding policies for ventilated preterm infants. Acta Paediatr. 1996;85:1123–1125

NEW MEDICAL SOCIETY FOUNDED TO IMPROVE THE CARE OF MALTREATED CHILDREN

Physicians working in the area of child maltreatment at many of the nation’s medical schools have founded a national organization dedicated to raising the quality of education and clinical care for abused and neglected children. This organization seeks to honor physicians who have demonstrated expertise and sustained involvement in the area for more than 5 years and involve them in developing new educational programs and public policy. Named in honor of the late Ray F. Helfer, MD, from Michigan State University, the Ray E. Helfer Society was formed out of concerns that medical schools are doing too little to educate physicians and future physicians to recognize and care for children who have experienced abuse or neglect. The mission of the society is to improve the medical response to child maltreatment through education and research. Membership is honorary and conferred by election of nominees by the founding members. The Society will sponsor annual meetings to showcase new medical research in the field of child abuse. Eighty-eight founding members have been elected. The first President of the Ray E. Helfer Society is Dr Cindy Christian from the Children’s Hospital of Philadelphia. Other officers include Larry Ricci, MD, from the Spurwink Clinic in Maine as Vice-President, Desmond K. Runyan, MD, from the University of North Carolina as Secretary-Treasurer, and Carole Jenny, MD, from Brown University as Scientific Program Chair. The organization will hold its first scientific meeting in the year 2000. Submitted by Desmond K. Runyan, MD, DrPH

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Postnatal Malnutrition and Growth Retardation: An Inevitable Consequence of Current Recommendations in Preterm Infants? Nicolas E. Embleton, Naomi Pang and Richard J. Cooke Pediatrics 2001;107;270-273 DOI: 10.1542/peds.107.2.270 Updated Information & Services

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