CCA-13963; No of Pages 4 Clinica Chimica Acta xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Clinica Chimica Acta journal homepage: www.elsevier.com/locate/clinchim
Individualized fortification of breast milk in 41 Extremely Low Birth Weight (ELBW) preterm infants Alessandra Reali a, Francesca Greco b, Guido Marongiu b, Federica Deidda b, Simona Atzeni a, Roberta Campus a, Angelica Dessì a,⁎, Vassilios Fanos a a b
Neonatal Intensive Care Unit, Neonatal Pathology, Puericulture Institute and Neonatal Section, AOU Cagliari, University of Cagliari, Italy 3A Arborea Laboratories, Italy
a r t i c l e
i n f o
Article history: Received 30 October 2014 Received in revised form 14 April 2015 Accepted 14 April 2015 Available online xxxx Keywords: Newborn Extremely Low Birth Weight Human milk Fortification Early neonatal growth Extrauterine growth restriction
a b s t r a c t Background: The use of breast milk presents numerous early and long-term advantages for ELBW preterms. However, breast milk without fortification does not cover the high nutritional needs of such patients. The aim of our study was to assess the effect of individualized fortification of breast milk on the growth of ELBWs hospitalized in a neonatal intensive care unit (NICU). Methods: Retrospective single-center observational study. Results: We assessed the growth of 41 consecutive ELBWs (21 females, 20 males) with gestational ages between 23 and 30 weeks (mean GA 26.31 ± 1.8) fed with breast milk in an individualized way. The rate of growth as the mean weight increase with breast milk fortification was 16.04 ± 3.13 g/kg/day, more than the growth of the fetus in the uterus (~15 g/kg/day). This result was confirmed also among the ELBWs of lower GA. However, only 24.4% of all the ELBWs at the time of discharge from the NICU presented an appropriate weight for their gestational age. No cases of Necrotizing Enterocolitis (NEC) were observed. Conclusions: Despite high growth velocity, the ELBWs failed to remain in the same percentiles of birth and, at discharge, only 27.7% had a weight of N 10 centiles. Further studies are needed to improve growth during early critical phases of development. © 2015 Elsevier B.V. All rights reserved.
1. Introduction In the previous two decades, thanks to improvements in treatment modalities, the survival of Extremely Low Birth Weight preterms has greatly increased, but morbidity remains high in this cohort of patients b1000 g (ELBW). In a vast study performed on 9575 preterm infants with a gestational age from 22 to 28 weeks, the incidence of necrotizing enterocolitis (NEC) was 11% [1]. However, fortification data are not reported. Particularly high (52%) was the finding of chronic lung disease (CLD) as well as the presence of serious cerebral hemorrhages (13.6%) [2,3]. The use of breast milk presents numerous advantages for ELBW preterms: it reduces the onset of NEC and late onset sepsis and is associated with an improvement in long-term neurobehavioral outcomes [4–7]. However, growth is reduced compared to preterms fed with formulas, since breast milk without fortification does not cover the high nutritional needs of such patients [8–11]. In clinical practice, the use of human milk fortifiers has de facto become indispensable, since it allows ⁎ Corresponding author. Tel.: +39 7051093453. E-mail address: [email protected] (A. Dessì).
the overcoming of a lack of calories, proteins and minerals in the mother's milk. A recent meta-analysis, with a systematic overview of the literature on the content of macro- and micronutrients in human milk, underscores the variability that takes place during lactation, especially as concerns protein content, both in preterm and term neonates. From this review we see that there are minimal differences and slight postnatal variability in the lipid content between term and preterm mother's milk, while statistically the variability in protein content is different and significant, with mean protein values at 3/4 w and 10/12 w of 1.4 and 1.0 g/100 ml in preterms and 1.2 and 0.9 in term neonates [12]. Also to be pointed out is an inter- and intraindividual difference in the composition of mother's milk and therefore the amount of fortification necessary to maintain satisfactory growth varies greatly. Individualized fortification, following an analysis of the main nutrients contained in the mother's milk, makes it possible to provide the single preterms with their mother's fortified milk and thus respond to their nutritional requirements. The growth model of reference for preterms, including ELBWs, is the one proposed in 1998 by the American Academy of Pediatrics (AAP), which corresponds to the development of the fetus in the uterus and present-day guidelines on recommended nutritional requirements refer to this model [13]. However, data in the literature show that preterms, especially ELBWs, accumulate
http://dx.doi.org/10.1016/j.cca.2015.04.027 0009-8981/© 2015 Elsevier B.V. All rights reserved.
Please cite this article as: Reali A, et al, Individualized fortification of breast milk in 41 Extremely Low Birth Weight (ELBW) preterm infants, Clin Chim Acta (2015), http://dx.doi.org/10.1016/j.cca.2015.04.027
2
A. Reali et al. / Clinica Chimica Acta xxx (2015) xxx–xxx
a growth deficit during the period of hospitalization, prevalently as concerns weight. This is indicated as extrauterine growth retardation (EUGR) and in the long term is associated with an auxological outcome and unfavorable development [7–9,14]. In the study by Stoll et al., conducted on a vast cohort of VLBWs with a gestational age of ≤ 28 weeks, 79% of 5492 preterms presented a growth retardation at 36 weeks after conception [1]. The primary objective of neonatologists is to promote the appropriate growth and development of preterms, especially of ELBWs, whose morbidity and mortality have improved in recent decades. In 2012, the AAP recommended as standard practice for preterms the use of breast milk which in VLBWs (very low birth weight) must be adequately fortified to cover their high nutritional requirements [4]. Kashyap et al. demonstrated that the growth of low weight preterms fed breast milk is directly correlated with protein intake [15]. Few are the data in the literature concerning the growth of ELBWs and, to the best of our knowledge; our study is the only one that assesses the effect on this cohort of individualized fortification of breast milk. In our experience the protein contribution of breast milk can be optimized by means of individualized fortification, a technique that makes possible the reaching of the recommended protein contribution through the personalized addition of fortifiers [16,17], taking into account the characteristics of single milk samples. The recommendations most followed propose aggressive nutritional contributions so as to imitate intrauterine growth (15 g/kg/day) [18,19]. The aim of our study was to assess the effect of individualized fortification of breast milk on the growth of ELBWs hospitalized in neonatal intensive care units (NICUs).
2. Materials and methods
In patients who showed a tendency to abdominal distension and in particular in those treated with nCPAP, Milupa's PS fortifier was introduced: since it is without carbohydrates and composed of hydrolyzed proteins, it does not cause meteorism. Moreover, in some cases it was associated with Milupa BMF® to reach the protein target without an excessive increase in osmolarity: the latter can occur by increasing the concentration of Milupa BMF®. MilteFR® of the Milte company, composed of non-hydrolyzed proteins, was instead introduced at a later time, after the 34th week of gestational age and once the intestinal barrier had developed. Its use was prescribed for use at home after hospital discharge since it is the only fortifier of breast milk available on the market in Italy for this purpose. This was done to limit extrauterine growth restriction. 2.2. Human milk analysis Small milk samples (~10 ml) taken from a pool collected from the mothers in the preceding 24–48 h were sent twice-weekly by courier to the laboratory of the 3A Company in Arborea (Sardinia). For sample collection, conservation and transport sterility regulations and the cold chain were respected. The microbiological, qualitative and quantitative analyses of the milk components were performed on the single samples. The qualitative and quantitative analysis of the breast milk samples was performed with Milko-scan® 93/133. The results were then sent in real time via internet to our unit where individualized fortification was performed. Taking into account the initial characteristics of the breast milk and in line with ESPGHAN recommendations relating to nutritional requirements, fortification was added with the intention of reaching a protein quotient of 3.5–4.0 g/kg/day [21]. Parents were informed of the possibility of administering individualized fortification of breast milk to their child and accepted.
2.1. Nutritional management 2.3. Auxological data In September of 2005, our unit began the individualized fortification of breast milk. Thanks to the cooperation of a nearby dairy company we could perform analyses of single samples of breast milk with infrared methods [20]. We performed a retrospective study on ELBW preterms fed with fortified breast milk in our NICU from 2005 to 2012. Preterms of ELBW with good nutritional tolerance were recruited at the age of 10 days and/or when the enteral intake was ≥100 ml/kg/day: they followed the fortification protocol up to the beginning of spontaneous breastfeeding. At present, we are able to maintain growth velocity with demand-feeding in our unit; if this goal is not achieved we intervene with supplementary nocturnal feeds with mother's milk fortifiers, when necessary. Patients with chromosomal or genetic diseases, malformations, pathologies of the gastrointestinal tract and/or renal insufficiency were excluded. Since our NICU does not have access to a maternal milk bank, our patients assume milk from their own mothers. The ELBWs included in this study received an intake of breast milk of ≥75% and had constant volumes between 150 and 170 ml/kg/day. In all newborns, during the years of the study, the same formula for VLBW was used: Formulat Pre0, 83 kcal/dl, protein 2.9 g/dl. Once they reached full enteral feeding, for each preterm the auxological data, the total water quotient of the breast milk, the protein quotient together with any vomits, regurgitations and/or bowel alterations for each single preterm were collected and entered on a special form. Fortification of breast milk was performed in a tailored way, taking into account the clinical characteristics of the single newborn and the milk characteristics of the mother: Nestlé FM85® and Milupa BMF® composed of protein hydrolysate of bovine origin, vitamins and mineral salts were used.
The gestational age in our study was calculated on the basis of the date of the last menstruation and the physical report assessed within 24 h of birth: in the case of assisted pregnancy it was calculated from the date of the embryo-transfer or artificial insemination. For auxological classification at the time of birth and at discharge we applied the Italian Neonatal Study (INeS) growth charts prepared in 2011 by the Italian Society of Neonatology [22]. They make it possible to calculate the percentile to which they belong, the z score of standard deviation by weight, length and cranial circumference and also to classify by weight the neonates as small (SGA), appropriate (AGA) and large for gestational age (LGA) for preterm neonates starting from the 23rd week of gestational age (GA). Weight was measured daily using electronic scales. The daily weight increase (GV) was calculated according to the two-point method GV ¼ ½1000 ðWf−W1ÞfðDf−D1Þ ½ðWf þ W1Þ2g where Wf is the weight at the end of fortification, W1 the weight at the beginning of fortification, Df − D1 the duration (days) of fortification and [(Wf + W1)2] the mean weight during fortification [23]. 2.4. Laboratory parameters In our study we evaluated blood urea nitrogen (BUN) first on a weekly basis and then every 15 days. One of the major concerns of neonatologists in milk fortification is that patients may reach high levels of azotemia and assume an excessive amount of phosphates. We used the BUN value not to increase fortification, but only to reduce it in the case of high levels (BUN N14 mg/dl, median 6 mg/dl, range 3–14 mg/dl). In accordance with the policy of our unit to minimize the taking of blood
Please cite this article as: Reali A, et al, Individualized fortification of breast milk in 41 Extremely Low Birth Weight (ELBW) preterm infants, Clin Chim Acta (2015), http://dx.doi.org/10.1016/j.cca.2015.04.027
A. Reali et al. / Clinica Chimica Acta xxx (2015) xxx–xxx Table 1 Breast milk (HM) composition per 100 ml in ELBW with E.G. ≤28 w (mean, ±2 standard deviations, range). HM
≤28 w (n 34/36)
Protein Carbohydrate Fat
1.25 ± 0.19 (0.60–1.64) 6.72 ± 0.30 (5.78–7.12) 3.87 ± 0.62 (2.70–5.04)
samples, we decided to monitor the calcium and phosphorus electrolytes on a weekly basis by means of urine dosage with the cotton ball method.
2.5. Cohort characteristics In our study we assessed the growth of 41 ELBWs fed with breast milk in an individualized way with gestational ages between 23 and 30 weeks (mean GA 26.31 ± 1.8). The mean weight at birth was 776 ± 114 (range 520–990 g), mean length 32.9 ± 2.2, cranial circumference 23.8 ± 1.4. Of the 41 ELBWs, 21 were females and 20 males. As concerns auxological classification, 35 ELBWs were AGA at birth, 5 SGA and only 1 LGA. We further subdivided our cohort into three groups by gestational age. Fourteen preterms had a mean GA of 24.36 ± 0.74 weeks, 22 a mean GA of 26.86 ± 0.83 and only 5 ELBWs had a mean GA above 28 weeks (mean 29.4 ± 0.55 weeks).
3. Results From the analysis of the human milk administered to our ELBWs, it emerges that the values on the mean content of proteins, lipids and carbohydrates are in line with those in the literature and that the interindividual range is evident [12] (Table 1). This is notwithstanding the fact that the protein content of the milk of the mothers of our ELBWs was unable to provide the nutritional requirements of this group of preterms without fortification unless large volumes of milk were provided. Moreover, given the interindividual range, it is evident that it is impossible to fortify mother's milk if the characteristics of the milk of the single preterm were not taken into account. In our cohort of ELBWs the rate of growth as the mean weight increase (g/kg/day) during breast milk fortification was 16.04 ± 3.13 g/kg/day (Table 2), more than growth of the fetus in the uterus (~15 g/kg/day). The weight gain, stratified in the different gestational ages, is presented in Table 3. The ELBWs of 29 to 30 weeks presented a reduced growth rate (14.42 ± 0.75 g/kg/day), which is not surprising if we consider that 60% presented a weight below the 3rd percentile at birth. The analysis of our data also makes it possible to stress that only 24.4% of all the ELBWs at the time of discharge from the NICU presented an appropriate weight for their gestational age. At the time of discharge 71.4% of the AGAs (at birth) weighed less than the 10th percentile despite the fact that the protein intake was kept within the range of 3.5–4.0 g/kg/day (mean value 3.77 ± 0.36, range 3.41–4.2).
Table 3 Weight and gestational age at birth and at discharge.
AGA SGA LGA
At birth
At discharge
85.36% 12.19% 2.44%
24.4% 75.6% –
Assessment of growth at discharge with respect to gestational age showed that as many as 21.4% among those of 23–25 weeks and 31.8% among those of 26–28 weeks were AGA (Fig. 1). If we consider all together the ELBWs of low gestational age (≤ 28 weeks), we see that 27.7% of them were of appropriate weight at the time of discharge. It must be underlined that no cases of NEC were observed in the study population. Pathological urinary electrolyte values were found in no patients and BUN was in all cases within normal values.
4. Discussion The most important result of our work is that when the recommended protein ration is respected, the growth velocity is higher than that of the fetus in the uterus during the stabilization phase (N 15 g/kg/day). This result confirms recent data on VLBW with a GA b 32 weeks who received standardized fortification of human milk [24]. In our study, during the period of fortification the ELBWs with the lowest gestational age (≤28 weeks) presented a mean growth velocity from 15.5 g/kg/day to 16.6 g/kg/day, despite the fact that the ELBWs failed to remain in the same percentiles of birth and, at the time of discharge, only 27.7% had a weight N10 centiles. This datum, quite interesting per se, since to our knowledge it is one of the best reported in the literature, confirms a vast multicentric study performed on a cohort of preterms of extremely low gestational age that demonstrated that growth rate in the uterus is not an adequate target for preterm infants after birth [25]. It must be stressed that more recently a feeding protocol for infants ≤1250 g BW providing an exclusive human milk-based diet (including fortification) with early and rapid advancement of fortification led to growth in line with targeted standards with a low rate of extrauterine growth restriction (43%) [26]. However, the result could be influenced by the lesser severity of illness, as stated by the same authors.
SGA born no. 5 5 SGA discharge no. 31 26 AGA born no. 35
9 AGA discharge no. 10
Table 2 Weight increase g/kg/day. Entire cohort (n = 41) GA 23–25 weeks (n = 14) GA 26–28 weeks (n = 22) GA 29–30 weeks (n = 5)
3
LGA born no. 1 16.04 ± 3.13 15.71 ± 3.27 16.61 ± 3.29 14.42 ± 0.75
1
Fig. 1. Flow chart of the results of the study.
Please cite this article as: Reali A, et al, Individualized fortification of breast milk in 41 Extremely Low Birth Weight (ELBW) preterm infants, Clin Chim Acta (2015), http://dx.doi.org/10.1016/j.cca.2015.04.027
4
A. Reali et al. / Clinica Chimica Acta xxx (2015) xxx–xxx
The curve of intrauterine growth does not reflect the real postnatal growth of the ELBWs: it expresses the situation of the fetus at birth and does not take into account the variables that influence the growth of these patients after their birth, such as for example severe clinical conditions, metabolic alterations such as hypernatremia, hyperglycemia, acidosis, persistent ductus arteriosus and parenteral nutrition [27]. The factor that limits postnatal auxological development is represented by the critical clinical conditions which, especially during the first week of life, do not allow the supplying of adequate allotments. As concerns present-day nutritional recommendations, our study confirms that: – during the stabilization phase these can easily be respected by personalizing the use of fortified breast milk; – during the critical phase the individualization of nutritional choices would make it possible to supply the single patient with the quality and quantity of nutrients he/she requires. We are satisfied with the results of our study because we have obtained a suitable weight increase in our ELBW babies by using not only the qualitatively best food but also by fortifying it in a tailored way. Moreover, to our knowledge it is one of the best results reported in the literature. However, a critical revision of nutritional requirements is essential during the first 7 to 10 days of life, since what occurs in this period also significantly influences the growth of ELBWs. 5. Conclusions Appropriate nutrition, especially of proteins during the stabilization phase, reduces the nutritional deficit and intervenes positively on the linear growth of ELBWs. From the analysis of our data it emerges that by maintaining the shortand long-term benefits of breast milk, the growth of ELBWs improves with accurate calculation of the necessary calories and proteins to be supplied by individualized fortification of such milk. Protein supplements of ≥3.5 g/kg/day during the stabilization phase reduce the auxological difference between birth and discharge. We are aware that growth velocities, whether “too slow” or “too fast”, are associated with long-term metabolic, endocrine and cardiovascular alterations. The main goal of the neonatologist should be the individualization of nutritional choices, taking into account gestational age, postnatal age and the clinical situation of the single newborn patient. Further studies are needed to improve growth during the early critical phases of life (including the first 2 weeks of life) and neonatologists will also have to search for the growth parameters that ensure long-term growth with the best metabolic, cardiovascular and neurobehavioral outcome. References [1] Stoll BJ, Hansen NI, Bell EF, et al. Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network. Pediatrics 2010;126:443–5.
[2] Natarajan G, Pappas A, Shankaran S, et al. Outcomes of extremely low birth weight infants with bronchopulmonary dysplasia: impact of the physiologic definition. Early Hum Dev 2012;88:509–15. [3] Goldstein RF, Cotten CM, Shankaran S, et al. Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Influence of gestational age on death and neurodevelopmental outcome in premature infants with severe intracranial hemorrhage. J Perinatol 2013;33:25–32. [4] No Author listed American Academy of Pediatrics Section on breastfeeding. Breastfeeding and the use of human milk. Pediatrics 2012;129:e827–41. [5] Reynolds RM, Thureen PJ. Special circumstances: trophic feeds, necrotizing enterocolitis and bronchopulmonary dysplasia. J Semin Fetal Neonatal Med 2007;12: 64–70. [6] Ehrenkranz RA, Dusick AM, Vohr BR, et al. Growth in the neonatal intensive care unit influences neurodevelopmental and growth outcomes of extremely low birth weight infants. Pediatrics 2006;117:1253–61. [7] Lucas A, Morley R, Cole TJ. Randomized trial of early diet in preterm babies and later intelligence quotient. Br Med J 1998;317:1481–7. [8] Cooke RJ, Ainsworth SB, Fenton AC. Postnatal growth retardation: a universal problem in preterm infants. Arch Dis Child Fetal Neonatal Ed 2004;89:F428–30. [9] Embleton NE, Pang N, Cooke RJ. Postnatal malnutrition and growth retardation: an inevitable consequence of current recommendations in preterm infants? Pediatrics 2001;107:270–3. [10] Kuschel CA, Harding JE. Protein supplementation of human milk for promoting growth in preterm infants (Cochrane review). Cochrane Database Syst Rev 2000: CD000433. [11] Schanler RJ, Shulman RJ, Lau C. Feeding strategies for premature infants: beneficial outcomes of feeding fortified human milk versus preterm formula. Pediatrics 1999;103:1150–7. [12] Gidrewicz DA, Fenton TR. A systematic review and meta-analysis of the nutrient content of preterm and term breast milk. BMC Pediatr 2014;14:216. [13] American Academy of Pediatrics Committee on Nutrition. Nutritional needs of the preterm infant. 4th ed. Elk Grove Village: Pediatric Nutrition Handbook; 1998. [14] Radmacher PG, Looney SW, Rafail ST. Prediction of extrauterine growth retardation (EUGR) in VVLBW infants. J Perinatol 2003;23:392–5. [15] Kashyap S, Schulze KF, Forsyth M, et al. Growth, nutrient retention, and metabolic response of low-birth-weight infants fed supplemented and un-supplemented preterm human milk. Am J Clin Nutr 1990;52:254–62. [16] Moro GE, Minoli I, Ostrom M, et al. Fortification of human milk: evaluation of a novel fortification scheme and of a new fortifier. J Pediatr Gastroenterol Nutr 1995;20: 162–72. [17] de Halleux V, Close A, Stalport S. Advantages of individualized fortification of human milk for preterm infants. Arch Pediatr 2007;14:S5–S10. [18] Parish A, Bhatia J. Early aggressive nutrition for the premature infant. Neonatology 2008;94:211–4. [19] Hay Jr WW. Strategies for feeding the preterm infant. Neonatology 2008;94:245–54. [20] Reali A, Greco F, Fanaro S, et al. Fortification of maternal milk for very low birth weight (VLBW) pre-term neonates. Early Hum Dev 2010;86:33–6. [21] Agostoni C, Buonocore G, Carnielli VP, et al. Enteral nutrient supply for preterm infants: commentary from the European Society of Paediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition ESPGHAN Committee on Nutrition. J Pediatr Gastroenterol Nutr 2010;50:85–91. [22] Bertino E, Spada E, Occhi L, et al. Neonatal anthropometric charts: the Italian neonatal study compared with other European studies. JPGN 2010;51:353–61. [23] Patel AL, Engstrom JL, Meier PP, et al. Calculating postnatal growth velocity in very low birth weight (VLBW) premature infants. J Perinatol 2009;29:618–22. [24] Maas C, Viechers C, Bernhard W, et al. Early feeding of fortified breast milk and in-hospital-growth in very premature infants: a retrospective cohort analysis. BMC Pediatr 2013;13:178. [25] Martin CR, Brown YF, Ehrenkranz RA, et al. Nutritional practices and growth velocity in the first month of life in extremely premature infants. Pediatrics 2009;124: 649–57. [26] Hair AB, Hawthorne KM, Chetta KE, et al. Human milk feeding supports adequate growth in infants ≤1250 grams birth weight. BMC Res Notes 2013;6:459. [27] Diekmann M, Genzel-Boroviczény O, Zoppelli L, et al. Postnatal growth curves for extremely low birth weight infants with early enteral nutrition. Eur J Pediatr 2005;164:714–23.
Please cite this article as: Reali A, et al, Individualized fortification of breast milk in 41 Extremely Low Birth Weight (ELBW) preterm infants, Clin Chim Acta (2015), http://dx.doi.org/10.1016/j.cca.2015.04.027
Contents lists available at ScienceDirect
Clinica Chimica Acta journal homepage: www.elsevier.com/locate/clinchim
Individualized fortification of breast milk in 41 Extremely Low Birth Weight (ELBW) preterm infants Alessandra Reali a, Francesca Greco b, Guido Marongiu b, Federica Deidda b, Simona Atzeni a, Roberta Campus a, Angelica Dessì a,⁎, Vassilios Fanos a a b
Neonatal Intensive Care Unit, Neonatal Pathology, Puericulture Institute and Neonatal Section, AOU Cagliari, University of Cagliari, Italy 3A Arborea Laboratories, Italy
a r t i c l e
i n f o
Article history: Received 30 October 2014 Received in revised form 14 April 2015 Accepted 14 April 2015 Available online xxxx Keywords: Newborn Extremely Low Birth Weight Human milk Fortification Early neonatal growth Extrauterine growth restriction
a b s t r a c t Background: The use of breast milk presents numerous early and long-term advantages for ELBW preterms. However, breast milk without fortification does not cover the high nutritional needs of such patients. The aim of our study was to assess the effect of individualized fortification of breast milk on the growth of ELBWs hospitalized in a neonatal intensive care unit (NICU). Methods: Retrospective single-center observational study. Results: We assessed the growth of 41 consecutive ELBWs (21 females, 20 males) with gestational ages between 23 and 30 weeks (mean GA 26.31 ± 1.8) fed with breast milk in an individualized way. The rate of growth as the mean weight increase with breast milk fortification was 16.04 ± 3.13 g/kg/day, more than the growth of the fetus in the uterus (~15 g/kg/day). This result was confirmed also among the ELBWs of lower GA. However, only 24.4% of all the ELBWs at the time of discharge from the NICU presented an appropriate weight for their gestational age. No cases of Necrotizing Enterocolitis (NEC) were observed. Conclusions: Despite high growth velocity, the ELBWs failed to remain in the same percentiles of birth and, at discharge, only 27.7% had a weight of N 10 centiles. Further studies are needed to improve growth during early critical phases of development. © 2015 Elsevier B.V. All rights reserved.
1. Introduction In the previous two decades, thanks to improvements in treatment modalities, the survival of Extremely Low Birth Weight preterms has greatly increased, but morbidity remains high in this cohort of patients b1000 g (ELBW). In a vast study performed on 9575 preterm infants with a gestational age from 22 to 28 weeks, the incidence of necrotizing enterocolitis (NEC) was 11% [1]. However, fortification data are not reported. Particularly high (52%) was the finding of chronic lung disease (CLD) as well as the presence of serious cerebral hemorrhages (13.6%) [2,3]. The use of breast milk presents numerous advantages for ELBW preterms: it reduces the onset of NEC and late onset sepsis and is associated with an improvement in long-term neurobehavioral outcomes [4–7]. However, growth is reduced compared to preterms fed with formulas, since breast milk without fortification does not cover the high nutritional needs of such patients [8–11]. In clinical practice, the use of human milk fortifiers has de facto become indispensable, since it allows ⁎ Corresponding author. Tel.: +39 7051093453. E-mail address: [email protected] (A. Dessì).
the overcoming of a lack of calories, proteins and minerals in the mother's milk. A recent meta-analysis, with a systematic overview of the literature on the content of macro- and micronutrients in human milk, underscores the variability that takes place during lactation, especially as concerns protein content, both in preterm and term neonates. From this review we see that there are minimal differences and slight postnatal variability in the lipid content between term and preterm mother's milk, while statistically the variability in protein content is different and significant, with mean protein values at 3/4 w and 10/12 w of 1.4 and 1.0 g/100 ml in preterms and 1.2 and 0.9 in term neonates [12]. Also to be pointed out is an inter- and intraindividual difference in the composition of mother's milk and therefore the amount of fortification necessary to maintain satisfactory growth varies greatly. Individualized fortification, following an analysis of the main nutrients contained in the mother's milk, makes it possible to provide the single preterms with their mother's fortified milk and thus respond to their nutritional requirements. The growth model of reference for preterms, including ELBWs, is the one proposed in 1998 by the American Academy of Pediatrics (AAP), which corresponds to the development of the fetus in the uterus and present-day guidelines on recommended nutritional requirements refer to this model [13]. However, data in the literature show that preterms, especially ELBWs, accumulate
http://dx.doi.org/10.1016/j.cca.2015.04.027 0009-8981/© 2015 Elsevier B.V. All rights reserved.
Please cite this article as: Reali A, et al, Individualized fortification of breast milk in 41 Extremely Low Birth Weight (ELBW) preterm infants, Clin Chim Acta (2015), http://dx.doi.org/10.1016/j.cca.2015.04.027
2
A. Reali et al. / Clinica Chimica Acta xxx (2015) xxx–xxx
a growth deficit during the period of hospitalization, prevalently as concerns weight. This is indicated as extrauterine growth retardation (EUGR) and in the long term is associated with an auxological outcome and unfavorable development [7–9,14]. In the study by Stoll et al., conducted on a vast cohort of VLBWs with a gestational age of ≤ 28 weeks, 79% of 5492 preterms presented a growth retardation at 36 weeks after conception [1]. The primary objective of neonatologists is to promote the appropriate growth and development of preterms, especially of ELBWs, whose morbidity and mortality have improved in recent decades. In 2012, the AAP recommended as standard practice for preterms the use of breast milk which in VLBWs (very low birth weight) must be adequately fortified to cover their high nutritional requirements [4]. Kashyap et al. demonstrated that the growth of low weight preterms fed breast milk is directly correlated with protein intake [15]. Few are the data in the literature concerning the growth of ELBWs and, to the best of our knowledge; our study is the only one that assesses the effect on this cohort of individualized fortification of breast milk. In our experience the protein contribution of breast milk can be optimized by means of individualized fortification, a technique that makes possible the reaching of the recommended protein contribution through the personalized addition of fortifiers [16,17], taking into account the characteristics of single milk samples. The recommendations most followed propose aggressive nutritional contributions so as to imitate intrauterine growth (15 g/kg/day) [18,19]. The aim of our study was to assess the effect of individualized fortification of breast milk on the growth of ELBWs hospitalized in neonatal intensive care units (NICUs).
2. Materials and methods
In patients who showed a tendency to abdominal distension and in particular in those treated with nCPAP, Milupa's PS fortifier was introduced: since it is without carbohydrates and composed of hydrolyzed proteins, it does not cause meteorism. Moreover, in some cases it was associated with Milupa BMF® to reach the protein target without an excessive increase in osmolarity: the latter can occur by increasing the concentration of Milupa BMF®. MilteFR® of the Milte company, composed of non-hydrolyzed proteins, was instead introduced at a later time, after the 34th week of gestational age and once the intestinal barrier had developed. Its use was prescribed for use at home after hospital discharge since it is the only fortifier of breast milk available on the market in Italy for this purpose. This was done to limit extrauterine growth restriction. 2.2. Human milk analysis Small milk samples (~10 ml) taken from a pool collected from the mothers in the preceding 24–48 h were sent twice-weekly by courier to the laboratory of the 3A Company in Arborea (Sardinia). For sample collection, conservation and transport sterility regulations and the cold chain were respected. The microbiological, qualitative and quantitative analyses of the milk components were performed on the single samples. The qualitative and quantitative analysis of the breast milk samples was performed with Milko-scan® 93/133. The results were then sent in real time via internet to our unit where individualized fortification was performed. Taking into account the initial characteristics of the breast milk and in line with ESPGHAN recommendations relating to nutritional requirements, fortification was added with the intention of reaching a protein quotient of 3.5–4.0 g/kg/day [21]. Parents were informed of the possibility of administering individualized fortification of breast milk to their child and accepted.
2.1. Nutritional management 2.3. Auxological data In September of 2005, our unit began the individualized fortification of breast milk. Thanks to the cooperation of a nearby dairy company we could perform analyses of single samples of breast milk with infrared methods [20]. We performed a retrospective study on ELBW preterms fed with fortified breast milk in our NICU from 2005 to 2012. Preterms of ELBW with good nutritional tolerance were recruited at the age of 10 days and/or when the enteral intake was ≥100 ml/kg/day: they followed the fortification protocol up to the beginning of spontaneous breastfeeding. At present, we are able to maintain growth velocity with demand-feeding in our unit; if this goal is not achieved we intervene with supplementary nocturnal feeds with mother's milk fortifiers, when necessary. Patients with chromosomal or genetic diseases, malformations, pathologies of the gastrointestinal tract and/or renal insufficiency were excluded. Since our NICU does not have access to a maternal milk bank, our patients assume milk from their own mothers. The ELBWs included in this study received an intake of breast milk of ≥75% and had constant volumes between 150 and 170 ml/kg/day. In all newborns, during the years of the study, the same formula for VLBW was used: Formulat Pre0, 83 kcal/dl, protein 2.9 g/dl. Once they reached full enteral feeding, for each preterm the auxological data, the total water quotient of the breast milk, the protein quotient together with any vomits, regurgitations and/or bowel alterations for each single preterm were collected and entered on a special form. Fortification of breast milk was performed in a tailored way, taking into account the clinical characteristics of the single newborn and the milk characteristics of the mother: Nestlé FM85® and Milupa BMF® composed of protein hydrolysate of bovine origin, vitamins and mineral salts were used.
The gestational age in our study was calculated on the basis of the date of the last menstruation and the physical report assessed within 24 h of birth: in the case of assisted pregnancy it was calculated from the date of the embryo-transfer or artificial insemination. For auxological classification at the time of birth and at discharge we applied the Italian Neonatal Study (INeS) growth charts prepared in 2011 by the Italian Society of Neonatology [22]. They make it possible to calculate the percentile to which they belong, the z score of standard deviation by weight, length and cranial circumference and also to classify by weight the neonates as small (SGA), appropriate (AGA) and large for gestational age (LGA) for preterm neonates starting from the 23rd week of gestational age (GA). Weight was measured daily using electronic scales. The daily weight increase (GV) was calculated according to the two-point method GV ¼ ½1000 ðWf−W1ÞfðDf−D1Þ ½ðWf þ W1Þ2g where Wf is the weight at the end of fortification, W1 the weight at the beginning of fortification, Df − D1 the duration (days) of fortification and [(Wf + W1)2] the mean weight during fortification [23]. 2.4. Laboratory parameters In our study we evaluated blood urea nitrogen (BUN) first on a weekly basis and then every 15 days. One of the major concerns of neonatologists in milk fortification is that patients may reach high levels of azotemia and assume an excessive amount of phosphates. We used the BUN value not to increase fortification, but only to reduce it in the case of high levels (BUN N14 mg/dl, median 6 mg/dl, range 3–14 mg/dl). In accordance with the policy of our unit to minimize the taking of blood
Please cite this article as: Reali A, et al, Individualized fortification of breast milk in 41 Extremely Low Birth Weight (ELBW) preterm infants, Clin Chim Acta (2015), http://dx.doi.org/10.1016/j.cca.2015.04.027
A. Reali et al. / Clinica Chimica Acta xxx (2015) xxx–xxx Table 1 Breast milk (HM) composition per 100 ml in ELBW with E.G. ≤28 w (mean, ±2 standard deviations, range). HM
≤28 w (n 34/36)
Protein Carbohydrate Fat
1.25 ± 0.19 (0.60–1.64) 6.72 ± 0.30 (5.78–7.12) 3.87 ± 0.62 (2.70–5.04)
samples, we decided to monitor the calcium and phosphorus electrolytes on a weekly basis by means of urine dosage with the cotton ball method.
2.5. Cohort characteristics In our study we assessed the growth of 41 ELBWs fed with breast milk in an individualized way with gestational ages between 23 and 30 weeks (mean GA 26.31 ± 1.8). The mean weight at birth was 776 ± 114 (range 520–990 g), mean length 32.9 ± 2.2, cranial circumference 23.8 ± 1.4. Of the 41 ELBWs, 21 were females and 20 males. As concerns auxological classification, 35 ELBWs were AGA at birth, 5 SGA and only 1 LGA. We further subdivided our cohort into three groups by gestational age. Fourteen preterms had a mean GA of 24.36 ± 0.74 weeks, 22 a mean GA of 26.86 ± 0.83 and only 5 ELBWs had a mean GA above 28 weeks (mean 29.4 ± 0.55 weeks).
3. Results From the analysis of the human milk administered to our ELBWs, it emerges that the values on the mean content of proteins, lipids and carbohydrates are in line with those in the literature and that the interindividual range is evident [12] (Table 1). This is notwithstanding the fact that the protein content of the milk of the mothers of our ELBWs was unable to provide the nutritional requirements of this group of preterms without fortification unless large volumes of milk were provided. Moreover, given the interindividual range, it is evident that it is impossible to fortify mother's milk if the characteristics of the milk of the single preterm were not taken into account. In our cohort of ELBWs the rate of growth as the mean weight increase (g/kg/day) during breast milk fortification was 16.04 ± 3.13 g/kg/day (Table 2), more than growth of the fetus in the uterus (~15 g/kg/day). The weight gain, stratified in the different gestational ages, is presented in Table 3. The ELBWs of 29 to 30 weeks presented a reduced growth rate (14.42 ± 0.75 g/kg/day), which is not surprising if we consider that 60% presented a weight below the 3rd percentile at birth. The analysis of our data also makes it possible to stress that only 24.4% of all the ELBWs at the time of discharge from the NICU presented an appropriate weight for their gestational age. At the time of discharge 71.4% of the AGAs (at birth) weighed less than the 10th percentile despite the fact that the protein intake was kept within the range of 3.5–4.0 g/kg/day (mean value 3.77 ± 0.36, range 3.41–4.2).
Table 3 Weight and gestational age at birth and at discharge.
AGA SGA LGA
At birth
At discharge
85.36% 12.19% 2.44%
24.4% 75.6% –
Assessment of growth at discharge with respect to gestational age showed that as many as 21.4% among those of 23–25 weeks and 31.8% among those of 26–28 weeks were AGA (Fig. 1). If we consider all together the ELBWs of low gestational age (≤ 28 weeks), we see that 27.7% of them were of appropriate weight at the time of discharge. It must be underlined that no cases of NEC were observed in the study population. Pathological urinary electrolyte values were found in no patients and BUN was in all cases within normal values.
4. Discussion The most important result of our work is that when the recommended protein ration is respected, the growth velocity is higher than that of the fetus in the uterus during the stabilization phase (N 15 g/kg/day). This result confirms recent data on VLBW with a GA b 32 weeks who received standardized fortification of human milk [24]. In our study, during the period of fortification the ELBWs with the lowest gestational age (≤28 weeks) presented a mean growth velocity from 15.5 g/kg/day to 16.6 g/kg/day, despite the fact that the ELBWs failed to remain in the same percentiles of birth and, at the time of discharge, only 27.7% had a weight N10 centiles. This datum, quite interesting per se, since to our knowledge it is one of the best reported in the literature, confirms a vast multicentric study performed on a cohort of preterms of extremely low gestational age that demonstrated that growth rate in the uterus is not an adequate target for preterm infants after birth [25]. It must be stressed that more recently a feeding protocol for infants ≤1250 g BW providing an exclusive human milk-based diet (including fortification) with early and rapid advancement of fortification led to growth in line with targeted standards with a low rate of extrauterine growth restriction (43%) [26]. However, the result could be influenced by the lesser severity of illness, as stated by the same authors.
SGA born no. 5 5 SGA discharge no. 31 26 AGA born no. 35
9 AGA discharge no. 10
Table 2 Weight increase g/kg/day. Entire cohort (n = 41) GA 23–25 weeks (n = 14) GA 26–28 weeks (n = 22) GA 29–30 weeks (n = 5)
3
LGA born no. 1 16.04 ± 3.13 15.71 ± 3.27 16.61 ± 3.29 14.42 ± 0.75
1
Fig. 1. Flow chart of the results of the study.
Please cite this article as: Reali A, et al, Individualized fortification of breast milk in 41 Extremely Low Birth Weight (ELBW) preterm infants, Clin Chim Acta (2015), http://dx.doi.org/10.1016/j.cca.2015.04.027
4
A. Reali et al. / Clinica Chimica Acta xxx (2015) xxx–xxx
The curve of intrauterine growth does not reflect the real postnatal growth of the ELBWs: it expresses the situation of the fetus at birth and does not take into account the variables that influence the growth of these patients after their birth, such as for example severe clinical conditions, metabolic alterations such as hypernatremia, hyperglycemia, acidosis, persistent ductus arteriosus and parenteral nutrition [27]. The factor that limits postnatal auxological development is represented by the critical clinical conditions which, especially during the first week of life, do not allow the supplying of adequate allotments. As concerns present-day nutritional recommendations, our study confirms that: – during the stabilization phase these can easily be respected by personalizing the use of fortified breast milk; – during the critical phase the individualization of nutritional choices would make it possible to supply the single patient with the quality and quantity of nutrients he/she requires. We are satisfied with the results of our study because we have obtained a suitable weight increase in our ELBW babies by using not only the qualitatively best food but also by fortifying it in a tailored way. Moreover, to our knowledge it is one of the best results reported in the literature. However, a critical revision of nutritional requirements is essential during the first 7 to 10 days of life, since what occurs in this period also significantly influences the growth of ELBWs. 5. Conclusions Appropriate nutrition, especially of proteins during the stabilization phase, reduces the nutritional deficit and intervenes positively on the linear growth of ELBWs. From the analysis of our data it emerges that by maintaining the shortand long-term benefits of breast milk, the growth of ELBWs improves with accurate calculation of the necessary calories and proteins to be supplied by individualized fortification of such milk. Protein supplements of ≥3.5 g/kg/day during the stabilization phase reduce the auxological difference between birth and discharge. We are aware that growth velocities, whether “too slow” or “too fast”, are associated with long-term metabolic, endocrine and cardiovascular alterations. The main goal of the neonatologist should be the individualization of nutritional choices, taking into account gestational age, postnatal age and the clinical situation of the single newborn patient. Further studies are needed to improve growth during the early critical phases of life (including the first 2 weeks of life) and neonatologists will also have to search for the growth parameters that ensure long-term growth with the best metabolic, cardiovascular and neurobehavioral outcome. References [1] Stoll BJ, Hansen NI, Bell EF, et al. Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network. Pediatrics 2010;126:443–5.
[2] Natarajan G, Pappas A, Shankaran S, et al. Outcomes of extremely low birth weight infants with bronchopulmonary dysplasia: impact of the physiologic definition. Early Hum Dev 2012;88:509–15. [3] Goldstein RF, Cotten CM, Shankaran S, et al. Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Influence of gestational age on death and neurodevelopmental outcome in premature infants with severe intracranial hemorrhage. J Perinatol 2013;33:25–32. [4] No Author listed American Academy of Pediatrics Section on breastfeeding. Breastfeeding and the use of human milk. Pediatrics 2012;129:e827–41. [5] Reynolds RM, Thureen PJ. Special circumstances: trophic feeds, necrotizing enterocolitis and bronchopulmonary dysplasia. J Semin Fetal Neonatal Med 2007;12: 64–70. [6] Ehrenkranz RA, Dusick AM, Vohr BR, et al. Growth in the neonatal intensive care unit influences neurodevelopmental and growth outcomes of extremely low birth weight infants. Pediatrics 2006;117:1253–61. [7] Lucas A, Morley R, Cole TJ. Randomized trial of early diet in preterm babies and later intelligence quotient. Br Med J 1998;317:1481–7. [8] Cooke RJ, Ainsworth SB, Fenton AC. Postnatal growth retardation: a universal problem in preterm infants. Arch Dis Child Fetal Neonatal Ed 2004;89:F428–30. [9] Embleton NE, Pang N, Cooke RJ. Postnatal malnutrition and growth retardation: an inevitable consequence of current recommendations in preterm infants? Pediatrics 2001;107:270–3. [10] Kuschel CA, Harding JE. Protein supplementation of human milk for promoting growth in preterm infants (Cochrane review). Cochrane Database Syst Rev 2000: CD000433. [11] Schanler RJ, Shulman RJ, Lau C. Feeding strategies for premature infants: beneficial outcomes of feeding fortified human milk versus preterm formula. Pediatrics 1999;103:1150–7. [12] Gidrewicz DA, Fenton TR. A systematic review and meta-analysis of the nutrient content of preterm and term breast milk. BMC Pediatr 2014;14:216. [13] American Academy of Pediatrics Committee on Nutrition. Nutritional needs of the preterm infant. 4th ed. Elk Grove Village: Pediatric Nutrition Handbook; 1998. [14] Radmacher PG, Looney SW, Rafail ST. Prediction of extrauterine growth retardation (EUGR) in VVLBW infants. J Perinatol 2003;23:392–5. [15] Kashyap S, Schulze KF, Forsyth M, et al. Growth, nutrient retention, and metabolic response of low-birth-weight infants fed supplemented and un-supplemented preterm human milk. Am J Clin Nutr 1990;52:254–62. [16] Moro GE, Minoli I, Ostrom M, et al. Fortification of human milk: evaluation of a novel fortification scheme and of a new fortifier. J Pediatr Gastroenterol Nutr 1995;20: 162–72. [17] de Halleux V, Close A, Stalport S. Advantages of individualized fortification of human milk for preterm infants. Arch Pediatr 2007;14:S5–S10. [18] Parish A, Bhatia J. Early aggressive nutrition for the premature infant. Neonatology 2008;94:211–4. [19] Hay Jr WW. Strategies for feeding the preterm infant. Neonatology 2008;94:245–54. [20] Reali A, Greco F, Fanaro S, et al. Fortification of maternal milk for very low birth weight (VLBW) pre-term neonates. Early Hum Dev 2010;86:33–6. [21] Agostoni C, Buonocore G, Carnielli VP, et al. Enteral nutrient supply for preterm infants: commentary from the European Society of Paediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition ESPGHAN Committee on Nutrition. J Pediatr Gastroenterol Nutr 2010;50:85–91. [22] Bertino E, Spada E, Occhi L, et al. Neonatal anthropometric charts: the Italian neonatal study compared with other European studies. JPGN 2010;51:353–61. [23] Patel AL, Engstrom JL, Meier PP, et al. Calculating postnatal growth velocity in very low birth weight (VLBW) premature infants. J Perinatol 2009;29:618–22. [24] Maas C, Viechers C, Bernhard W, et al. Early feeding of fortified breast milk and in-hospital-growth in very premature infants: a retrospective cohort analysis. BMC Pediatr 2013;13:178. [25] Martin CR, Brown YF, Ehrenkranz RA, et al. Nutritional practices and growth velocity in the first month of life in extremely premature infants. Pediatrics 2009;124: 649–57. [26] Hair AB, Hawthorne KM, Chetta KE, et al. Human milk feeding supports adequate growth in infants ≤1250 grams birth weight. BMC Res Notes 2013;6:459. [27] Diekmann M, Genzel-Boroviczény O, Zoppelli L, et al. Postnatal growth curves for extremely low birth weight infants with early enteral nutrition. Eur J Pediatr 2005;164:714–23.
Please cite this article as: Reali A, et al, Individualized fortification of breast milk in 41 Extremely Low Birth Weight (ELBW) preterm infants, Clin Chim Acta (2015), http://dx.doi.org/10.1016/j.cca.2015.04.027
