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The Use of Multinutrient Human Milk Fortifiers in Preterm Infants
The Use of Multinutrient H u m a n Mi l k F o r t i f i e r s i n P re t e r m In f a n t s A Systematic Review of Unanswered Questions Francis B. Mimouni, MDa,b, Natalie Nathan, BScb,c, Ekhard E. Ziegler, MDd, Ronit Lubetzky, MDb,c, Dror Mandel, MDb,e,* KEYWORDS Human milk Breastfeeding Fortifier Macronutrients KEY POINTS There is little evidence that early introduction of human milk fortification compared with late fortification affects important outcomes such as early growth. There is no strong evidence that human milk–based fortifiers in otherwise exclusively human milk–fed preterm infants affect important outcomes. There is limited evidence that a bovine fortifier used with a combination of human milk and bovine-based formula places the infant at a higher risk of necrotizing enterocolitis. There is a definite need for additional studies, incorporating also long-term outcomes, to determine whether or not the use of human milk–based fortifiers improves outcomes.
INTRODUCTION
It has long been known that very low birth weight (VLBW) preterm infants fed exclusively breast milk cannot match intrauterine growth patterns and may end up with extrauterine growth restriction.1,2 Efforts have been made to develop liquid or powder multinutrient products for the fortification of human breast milk.3 These fortifiers
The authors have nothing to disclose. a Department of Neonatology, Shaare Zedek Medical Center, 12 Shmuel Bait Street, Jerusalem 913102, Israel; b Sackler Faculty of Medicine, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel; c Department of Pediatrics, Dana Dwek Children’s Hospital, Tel Aviv Sourasky Medical Center, 6 Weizman Street, Tel Aviv 6423906, Israel; d Department of Pediatrics, University of Iowa, Iowa City, IA, USA; e Department of Neonatology, Dana Dwek Children’s Hospital, Tel Aviv Sourasky Medical Center, 6 Weizman Street, Tel Aviv 6423906, Israel * Corresponding author. Department of Neonatology, Dana Dwek Children’s Hospital, Tel Aviv Sourasky Medical Center, 6 Weizman Street, Tel Aviv 6423906, Israel. E-mail address: [email protected] Clin Perinatol - (2016) -–http://dx.doi.org/10.1016/j.clp.2016.11.011 0095-5108/16/ª 2016 Elsevier Inc. All rights reserved.
perinatology.theclinics.com
2
Mimouni et al
increase nutrient intake and are expected to improve both growth and neurodevelopmental outcomes.3 A recent systematic review within the Cochrane collaborative project aimed to determine whether multinutrient fortification of human breast milk improves important growth and developmental outcomes as compared with unfortified breast milk in preterm infants without increasing the risk of adverse effects, such as feeding intolerance or necrotizing enterocolitis (NEC).4 This systematic review identified 14 randomized trials in which a total of 1071 infants participated. It concluded that individual trials were generally small and had weak methodology. Nevertheless, meta-analyses led to low-quality evidence that multinutrient fortification of breast milk increases in-hospital rates of growth by a mean daily weight gain of 1.81 g/kg (with a 95% confidence interval [CI] 1.23–2.40), by a mean weekly length gain of 0.12 cm (95% CI 0.07–0.17), and by a mean weekly head circumference gain of 0.08 cm/wk (95% CI 0.04–0.12). The meta-analyses did not show a positive effect of fortification on developmental outcomes. There was also low-quality evidence that fortification did not increase the risk of NEC in preterm infants with a typical relative risk (RR) 1.57 (95% CI 0.76–3.23). The investigators of this Cochrane review concluded that multinutrient fortified breast milk compared with unfortified breast milk does not significantly affect important outcomes, but that it leads to a slight increase of in-hospital growth rates. As often found in the conclusion of Neonatal Cochrane Systematic reviews,5 the investigators of this important analysis concluded that the trials available “do not provide consistent evidence of effects on longer-term growth or development” and that “additional trials are needed to solve this issue.”4 This excellent review was published in 2016, and there was very little chance that we would be able to reach different conclusions because of additional, new data. We thus elected to address other issues in our systematic review, issues that were purposely not addressed in the Cochrane review.4 We specifically elected to determine whether studies (1) answered the question of early versus late introduction of fortifiers with regard to growth and/or other outcomes; and (2) had compared the efficacy/adverse effects of human milk–based fortifiers (HBF) with that of bovine fortifiers (BF) in otherwise exclusively human milk–fed infants. MATERIALS AND METHODS
We conducted this systematic review in August 2016. We included only studies reporting the use of multinutrient human milk fortifiers. One author (NN) searched MEDLINE, EMBASE, and Google Scholar using the following key words: human milk, human milk fortifier, premature infant, preterm infant, human milk fortification. We also examined the references in studies identified as potentially relevant. Four authors (FB, NN, DM, and RL) screened titles and abstracts of all records identified by the search and coded records as “order” or “exclude.” We then assessed all records coded as “order” and made the final decision about which records to order as full-text articles. We read the full texts to assess each article’s suitability for inclusion on the basis of prespecified inclusion and exclusion criteria. Then the data were extracted independently by using a data collection form to aid extraction of information on design, methods, and participants from each included study. We assessed the quality of evidence at the outcome level using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) (http://www.gradeworkinggroup.org/) approach. Disagreements were discussed until a consensus was reached. If data from a given article were insufficient, the report was excluded from analysis. For the purpose of potential meta-analyses, we aimed to retain only articles that had studied the question of early versus late introduction of fortifiers and studies that compared
Human Milk Fortifier
the efficacy/adverse effects of HBF versus BF in otherwise exclusively human milk–fed preterm infants. RESULTS
Our search allowed us to initially retrieve 2471 articles. The flow chart of Fig. 1 depicts the retrieval and selection processes that were conducted to answer the 2 questions (see Fig. 1). To answer the first question (early vs late introduction), only 5 trials were identified.6–9 The first one, by Tillman and colleagues,6 published in 2012, addressed the issue in a retrospective manner, as a pre-post comparison, and involved 53 earlyfortification infants (from day 1 of feeding), as well as 42 delayed-fortification infants (when feedings reached 50–80 mL/kg per day). The inherent confounders associated with the retrospective study design did not allow this study to be included in a
Comparisons were not Theoretical model (1)
Fig. 1. Flow diagram of the analysis process.
3
4
Mimouni et al
meta-analysis. Nevertheless, the study did not find any differences in weight at 34 weeks postmenstrual age (PMA), but stated that the delayed-fortification group had a “higher incidence of elevated alkaline phosphatase.” The study did not find significant differences in outcomes, such as feeding intolerance or NEC, but was underpowered to reach such conclusions in a definitive manner. The second study, by Maas and colleagues,7 also addressed the issue in a retrospective manner, as a pre-post, comparison of nonconsecutive periods, and involved 206 preterm infants. Analyses did not focus on early versus late fortification, but rather on percentage of human milk in the total feeds. This study also was impossible to include in a meta-analysis, as no conclusion could be drawn from it with regard to the timing of fortification. The third article was retrieved from a non-Medline recorded article (Iranian Journal of Pediatrics) and its full text in the English language could not be obtained.8 In its English abstract, the article stated that no anthropometric differences and no differences in adverse outcomes were found between the early-fortification and the latefortification groups, but the abstract did not define what was meant by early or late. Its sample size was also relatively small (80 infants randomized) and the study is probably underpowered to detect small differences in effects or side effects. Another study, by Shah and colleagues,9 consisted of a randomized controlled trial of early (beginning at an enteral intake of 20 mL/kg per day) versus late fortification (beginning at an enteral intake of 100 mL/kg per day). A population of 100 VLBW (<1500 g) infants was randomized to early (n 5 50) and late (n 5 50) groups. As expected, there were small but significant differences in protein intake between groups that persisted until week 4 of the study. In spite of that, no significant differences were found in anthropometric measurements (head circumference, length, weight, or weight velocity) or feeding intolerance, NEC, bronchopulmonary dysplasia (BPD), patent ductus arteriosus (PDA), or sepsis, although the study did not report post hoc type 2 errors, and was probably underpowered to detect small differences in effects as well as adverse effects. In a study by Sullivan and colleagues,10 2 subgroups of infants were randomized to early (40 mL/kg per day) versus late (100 mL/kg per day) introduction of an HBF, and the study also did not find differences in growth, feeding intolerance, or NEC.10 It was stated only that the 2 groups did not differ between themselves, and quantitative comparisons were not reported. Nevertheless, and because of their heterogeneity, we felt that the study by Shah and colleagues9 and the study by Sullivan and colleagues10 could not be combined in a meta-analysis. We therefore concluded from the first part of this systematic review that the limited available data do not provide strong evidence that early introduction of human milk fortification, compared late fortification, affects important outcomes, except that it leads to slightly increased initial protein intake. To answer the second objective (HBF vs cow milk–based fortifier in otherwise exclusively human milk–fed preterm infants), we identified 5 articles.10–14 Chronologically, the first report by Boehm and colleagues11 compared a bovine-based commercial fortifier (at a concentration of 3 g per 100 mL fresh human milk) with powdered freeze-dried human milk plus minerals (at a concentration of 8 g per 100 mL fresh human milk). The study was conducted in a small number of infants (24 male VLBW infants) who were randomized to the BF group (n 5 13) and the HBF group (n 5 11). The study was very short in duration (14 days), and was not able (maybe in part because of its duration) to determine significant differences in weight or length gain. The HBF in that study seemed to have been custom-produced by the investigators and is not available commercially. This study was a balance study that did not find significant differences in nitrogen or fat intake, excretion, or retention and therefore was not retainable for a meta-analysis.
Human Milk Fortifier
The second study, by Sullivan and colleagues,10 recruited 207 infants fed their own mother’s milk and randomized to 1 of 3 groups: one group received HBF when enteral intake was 40 mL/kg per day, the second one received HBF when enteral intake was 100 mL/kg per day, and the third one received BF when enteral intake was 100 mL/kg weight per day. The first 2 groups received donor human milk whenever their own mother’s milk was not available, whereas the third group received a cow milk–based formula when mother’s milk was not available. The 3 groups did not differ in weight, length, or head circumference patterns. When the outcomes of NEC and late-onset sepsis (LOS) were combined, there were very similar rates among the 3 groups. However, when only NEC was considered, both HBF groups had significantly lower rates, and all but 1 case of surgical NEC was found in the bovine preterm formula combined with human milk and bovine fortifier group. It must be noted that LOS in all 3 groups did not differ significantly (P 5 .3) but the lowest numbers were surprisingly in the bovine group, which had “masked” the effect on NEC when NEC and LOS were analyzed together. The power of the LOS analyses was not provided, and it is unclear whether a larger number of participants might have allowed for reaching statistical significance. A reanalysis of the data of Sullivan and colleagues10 (Ghandehari and colleagues12) was later published and also showed that total parenteral nutrition days were reduced in the HBF groups. Moreover, using the analysis of Sullivan and colleagues,10 Ganapathy and colleagues13 developed a theoretic model of costs of NEC and cost-effectiveness of exclusively human milk products in feeding extremely premature infants and concluded that a 100% human milk–based diet fortified with HBF may result in net savings on medical care resources by preventing NEC. Nevertheless, the study by Sullivan and colleagues,10 as important as it is, does not allow to answer the question of superiority of an HBF over a BF in otherwise exclusively human milk–fed preterm infants. Because the group fed BF received a cow milk–based formula rather than donor human milk, the difference in feedings may have significantly affected the results. The last study, by Cristofalo and colleagues,14 is a randomized trial of infants fed exclusively human milk and human milk–based products compared with infants fed formula and therefore could not be included in the analyses. Thus, at this point, we conclude that there are limited data available and that the data do not provide strong evidence that HBF in otherwise exclusively human milk– fed preterm infants affects important outcomes. There is limited evidence that use of bovine fortifier with a combination of human milk and bovine-based preterm formula places the infant at a higher risk of NEC than use of HBF with exclusively human milk, which confirms previous observations on higher NEC risks in infants fed preterm formula as compared with human milk–fed preterm infants. However, the study design of this trial does not allow the conclusion that the use of human milk–based fortifier would reduce NEC risk as compared with bovine-based fortifier. There is a definite need for additional studies incorporating long-term outcomes to determine in a clean head-tohead comparison whether or not the use of human milk–based fortifiers might improve outcomes and reduce NEC and other adverse outcomes. REFERENCES
1. Kashyap S, Schulze KF, Forsyth M, et al. Growth, nutrient retention, and metabolic response of low-birth-weight infants fed supplemented and unsupplemented preterm human milk. Am J Clin Nutr 1990;52:254–62. 2. Ehrenkranz RA, Younes N, Lemons JA, et al. Longitudinal growth of hospitalized very low birth weight infants. Pediatrics 1999;104:280–9.
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3. Ziegler EE. Human milk and human milk fortifiers. In: Koletzko B, Poindexter B, Uauy R, editors. Nutritional care of preterm infants, vol. 110. Basel (Switzerland): Karger Publishers; 2014. p. 215–27. 4. Brown JV, Embleton ND, Harding JE, et al. Multi-nutrient fortification of human milk for preterm infants [review]. Cochrane Database Syst Rev 2016;(5):CD000343. 5. Mandel D, Littner Y, Mimouni FB, et al. Conclusiveness of the Cochrane neonatal reviews: a systematic analysis. Acta Paediatr 2006;95:1209–12. 6. Tillman S, Brandon DH, Silva SG. Evaluation of human milk fortification from the time of the first feeding: effects on infants of less than 31 weeks gestational age. J Perinatol 2012;32:525–31. 7. Maas C, Wiechers 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. 8. Sajjadian N, Alizadeh TP, Asgharyan FM, et al. A comparison between early and late breast milk fortification in preterm infants: a clinical trial study. Iran J Pediatr 2014;24:45. 9. Shah SD, Dereddy N, Jones TL, et al. Early versus delayed human milk fortification in very low birth weight infants—a randomized controlled trial. J Pediatr 2016; 174:126–31. 10. Sullivan S, Schanler RJ, Kim JH, et al. An exclusively human milk-based diet is associated with a lower rate of necrotizing enterocolitis than a diet of human milk and bovine milk-based products. J Pediatr 2010;156:562–7. 11. Boehm G, Mu¨ller DM, Senger H, et al. Nitrogen and fat balances in very low birth weight infants fed human milk fortified with human milk or bovine milk protein. Eur J Pediatr 1993;152:236–9. 12. Ghandehari H, Lee ML, Rechtman DJ, H2MF Study Group. An exclusive human milk-based diet in extremely premature infants reduces the probability of remaining on total parenteral nutrition: a reanalysis of the data. BMC Res Notes 2012;5:188. 13. Ganapathy V, Hay JW, Kim JH. Costs of necrotizing enterocolitis and costeffectiveness of exclusively human milk-based products in feeding extremely premature infants. Breastfeed Med 2012;7:29–37. 14. Cristofalo EA, Schanler RJ, Blanco CL, et al. Randomized trial of exclusive human milk versus preterm formula diets in extremely premature infants. J Pediatr 2013; 163:1592–5.
INTRODUCTION
It has long been known that very low birth weight (VLBW) preterm infants fed exclusively breast milk cannot match intrauterine growth patterns and may end up with extrauterine growth restriction.1,2 Efforts have been made to develop liquid or powder multinutrient products for the fortification of human breast milk.3 These fortifiers
The authors have nothing to disclose. a Department of Neonatology, Shaare Zedek Medical Center, 12 Shmuel Bait Street, Jerusalem 913102, Israel; b Sackler Faculty of Medicine, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel; c Department of Pediatrics, Dana Dwek Children’s Hospital, Tel Aviv Sourasky Medical Center, 6 Weizman Street, Tel Aviv 6423906, Israel; d Department of Pediatrics, University of Iowa, Iowa City, IA, USA; e Department of Neonatology, Dana Dwek Children’s Hospital, Tel Aviv Sourasky Medical Center, 6 Weizman Street, Tel Aviv 6423906, Israel * Corresponding author. Department of Neonatology, Dana Dwek Children’s Hospital, Tel Aviv Sourasky Medical Center, 6 Weizman Street, Tel Aviv 6423906, Israel. E-mail address: [email protected] Clin Perinatol - (2016) -–http://dx.doi.org/10.1016/j.clp.2016.11.011 0095-5108/16/ª 2016 Elsevier Inc. All rights reserved.
perinatology.theclinics.com
2
Mimouni et al
increase nutrient intake and are expected to improve both growth and neurodevelopmental outcomes.3 A recent systematic review within the Cochrane collaborative project aimed to determine whether multinutrient fortification of human breast milk improves important growth and developmental outcomes as compared with unfortified breast milk in preterm infants without increasing the risk of adverse effects, such as feeding intolerance or necrotizing enterocolitis (NEC).4 This systematic review identified 14 randomized trials in which a total of 1071 infants participated. It concluded that individual trials were generally small and had weak methodology. Nevertheless, meta-analyses led to low-quality evidence that multinutrient fortification of breast milk increases in-hospital rates of growth by a mean daily weight gain of 1.81 g/kg (with a 95% confidence interval [CI] 1.23–2.40), by a mean weekly length gain of 0.12 cm (95% CI 0.07–0.17), and by a mean weekly head circumference gain of 0.08 cm/wk (95% CI 0.04–0.12). The meta-analyses did not show a positive effect of fortification on developmental outcomes. There was also low-quality evidence that fortification did not increase the risk of NEC in preterm infants with a typical relative risk (RR) 1.57 (95% CI 0.76–3.23). The investigators of this Cochrane review concluded that multinutrient fortified breast milk compared with unfortified breast milk does not significantly affect important outcomes, but that it leads to a slight increase of in-hospital growth rates. As often found in the conclusion of Neonatal Cochrane Systematic reviews,5 the investigators of this important analysis concluded that the trials available “do not provide consistent evidence of effects on longer-term growth or development” and that “additional trials are needed to solve this issue.”4 This excellent review was published in 2016, and there was very little chance that we would be able to reach different conclusions because of additional, new data. We thus elected to address other issues in our systematic review, issues that were purposely not addressed in the Cochrane review.4 We specifically elected to determine whether studies (1) answered the question of early versus late introduction of fortifiers with regard to growth and/or other outcomes; and (2) had compared the efficacy/adverse effects of human milk–based fortifiers (HBF) with that of bovine fortifiers (BF) in otherwise exclusively human milk–fed infants. MATERIALS AND METHODS
We conducted this systematic review in August 2016. We included only studies reporting the use of multinutrient human milk fortifiers. One author (NN) searched MEDLINE, EMBASE, and Google Scholar using the following key words: human milk, human milk fortifier, premature infant, preterm infant, human milk fortification. We also examined the references in studies identified as potentially relevant. Four authors (FB, NN, DM, and RL) screened titles and abstracts of all records identified by the search and coded records as “order” or “exclude.” We then assessed all records coded as “order” and made the final decision about which records to order as full-text articles. We read the full texts to assess each article’s suitability for inclusion on the basis of prespecified inclusion and exclusion criteria. Then the data were extracted independently by using a data collection form to aid extraction of information on design, methods, and participants from each included study. We assessed the quality of evidence at the outcome level using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) (http://www.gradeworkinggroup.org/) approach. Disagreements were discussed until a consensus was reached. If data from a given article were insufficient, the report was excluded from analysis. For the purpose of potential meta-analyses, we aimed to retain only articles that had studied the question of early versus late introduction of fortifiers and studies that compared
Human Milk Fortifier
the efficacy/adverse effects of HBF versus BF in otherwise exclusively human milk–fed preterm infants. RESULTS
Our search allowed us to initially retrieve 2471 articles. The flow chart of Fig. 1 depicts the retrieval and selection processes that were conducted to answer the 2 questions (see Fig. 1). To answer the first question (early vs late introduction), only 5 trials were identified.6–9 The first one, by Tillman and colleagues,6 published in 2012, addressed the issue in a retrospective manner, as a pre-post comparison, and involved 53 earlyfortification infants (from day 1 of feeding), as well as 42 delayed-fortification infants (when feedings reached 50–80 mL/kg per day). The inherent confounders associated with the retrospective study design did not allow this study to be included in a
Comparisons were not Theoretical model (1)
Fig. 1. Flow diagram of the analysis process.
3
4
Mimouni et al
meta-analysis. Nevertheless, the study did not find any differences in weight at 34 weeks postmenstrual age (PMA), but stated that the delayed-fortification group had a “higher incidence of elevated alkaline phosphatase.” The study did not find significant differences in outcomes, such as feeding intolerance or NEC, but was underpowered to reach such conclusions in a definitive manner. The second study, by Maas and colleagues,7 also addressed the issue in a retrospective manner, as a pre-post, comparison of nonconsecutive periods, and involved 206 preterm infants. Analyses did not focus on early versus late fortification, but rather on percentage of human milk in the total feeds. This study also was impossible to include in a meta-analysis, as no conclusion could be drawn from it with regard to the timing of fortification. The third article was retrieved from a non-Medline recorded article (Iranian Journal of Pediatrics) and its full text in the English language could not be obtained.8 In its English abstract, the article stated that no anthropometric differences and no differences in adverse outcomes were found between the early-fortification and the latefortification groups, but the abstract did not define what was meant by early or late. Its sample size was also relatively small (80 infants randomized) and the study is probably underpowered to detect small differences in effects or side effects. Another study, by Shah and colleagues,9 consisted of a randomized controlled trial of early (beginning at an enteral intake of 20 mL/kg per day) versus late fortification (beginning at an enteral intake of 100 mL/kg per day). A population of 100 VLBW (<1500 g) infants was randomized to early (n 5 50) and late (n 5 50) groups. As expected, there were small but significant differences in protein intake between groups that persisted until week 4 of the study. In spite of that, no significant differences were found in anthropometric measurements (head circumference, length, weight, or weight velocity) or feeding intolerance, NEC, bronchopulmonary dysplasia (BPD), patent ductus arteriosus (PDA), or sepsis, although the study did not report post hoc type 2 errors, and was probably underpowered to detect small differences in effects as well as adverse effects. In a study by Sullivan and colleagues,10 2 subgroups of infants were randomized to early (40 mL/kg per day) versus late (100 mL/kg per day) introduction of an HBF, and the study also did not find differences in growth, feeding intolerance, or NEC.10 It was stated only that the 2 groups did not differ between themselves, and quantitative comparisons were not reported. Nevertheless, and because of their heterogeneity, we felt that the study by Shah and colleagues9 and the study by Sullivan and colleagues10 could not be combined in a meta-analysis. We therefore concluded from the first part of this systematic review that the limited available data do not provide strong evidence that early introduction of human milk fortification, compared late fortification, affects important outcomes, except that it leads to slightly increased initial protein intake. To answer the second objective (HBF vs cow milk–based fortifier in otherwise exclusively human milk–fed preterm infants), we identified 5 articles.10–14 Chronologically, the first report by Boehm and colleagues11 compared a bovine-based commercial fortifier (at a concentration of 3 g per 100 mL fresh human milk) with powdered freeze-dried human milk plus minerals (at a concentration of 8 g per 100 mL fresh human milk). The study was conducted in a small number of infants (24 male VLBW infants) who were randomized to the BF group (n 5 13) and the HBF group (n 5 11). The study was very short in duration (14 days), and was not able (maybe in part because of its duration) to determine significant differences in weight or length gain. The HBF in that study seemed to have been custom-produced by the investigators and is not available commercially. This study was a balance study that did not find significant differences in nitrogen or fat intake, excretion, or retention and therefore was not retainable for a meta-analysis.
Human Milk Fortifier
The second study, by Sullivan and colleagues,10 recruited 207 infants fed their own mother’s milk and randomized to 1 of 3 groups: one group received HBF when enteral intake was 40 mL/kg per day, the second one received HBF when enteral intake was 100 mL/kg per day, and the third one received BF when enteral intake was 100 mL/kg weight per day. The first 2 groups received donor human milk whenever their own mother’s milk was not available, whereas the third group received a cow milk–based formula when mother’s milk was not available. The 3 groups did not differ in weight, length, or head circumference patterns. When the outcomes of NEC and late-onset sepsis (LOS) were combined, there were very similar rates among the 3 groups. However, when only NEC was considered, both HBF groups had significantly lower rates, and all but 1 case of surgical NEC was found in the bovine preterm formula combined with human milk and bovine fortifier group. It must be noted that LOS in all 3 groups did not differ significantly (P 5 .3) but the lowest numbers were surprisingly in the bovine group, which had “masked” the effect on NEC when NEC and LOS were analyzed together. The power of the LOS analyses was not provided, and it is unclear whether a larger number of participants might have allowed for reaching statistical significance. A reanalysis of the data of Sullivan and colleagues10 (Ghandehari and colleagues12) was later published and also showed that total parenteral nutrition days were reduced in the HBF groups. Moreover, using the analysis of Sullivan and colleagues,10 Ganapathy and colleagues13 developed a theoretic model of costs of NEC and cost-effectiveness of exclusively human milk products in feeding extremely premature infants and concluded that a 100% human milk–based diet fortified with HBF may result in net savings on medical care resources by preventing NEC. Nevertheless, the study by Sullivan and colleagues,10 as important as it is, does not allow to answer the question of superiority of an HBF over a BF in otherwise exclusively human milk–fed preterm infants. Because the group fed BF received a cow milk–based formula rather than donor human milk, the difference in feedings may have significantly affected the results. The last study, by Cristofalo and colleagues,14 is a randomized trial of infants fed exclusively human milk and human milk–based products compared with infants fed formula and therefore could not be included in the analyses. Thus, at this point, we conclude that there are limited data available and that the data do not provide strong evidence that HBF in otherwise exclusively human milk– fed preterm infants affects important outcomes. There is limited evidence that use of bovine fortifier with a combination of human milk and bovine-based preterm formula places the infant at a higher risk of NEC than use of HBF with exclusively human milk, which confirms previous observations on higher NEC risks in infants fed preterm formula as compared with human milk–fed preterm infants. However, the study design of this trial does not allow the conclusion that the use of human milk–based fortifier would reduce NEC risk as compared with bovine-based fortifier. There is a definite need for additional studies incorporating long-term outcomes to determine in a clean head-tohead comparison whether or not the use of human milk–based fortifiers might improve outcomes and reduce NEC and other adverse outcomes. REFERENCES
1. Kashyap S, Schulze KF, Forsyth M, et al. Growth, nutrient retention, and metabolic response of low-birth-weight infants fed supplemented and unsupplemented preterm human milk. Am J Clin Nutr 1990;52:254–62. 2. Ehrenkranz RA, Younes N, Lemons JA, et al. Longitudinal growth of hospitalized very low birth weight infants. Pediatrics 1999;104:280–9.
5
6
Mimouni et al
3. Ziegler EE. Human milk and human milk fortifiers. In: Koletzko B, Poindexter B, Uauy R, editors. Nutritional care of preterm infants, vol. 110. Basel (Switzerland): Karger Publishers; 2014. p. 215–27. 4. Brown JV, Embleton ND, Harding JE, et al. Multi-nutrient fortification of human milk for preterm infants [review]. Cochrane Database Syst Rev 2016;(5):CD000343. 5. Mandel D, Littner Y, Mimouni FB, et al. Conclusiveness of the Cochrane neonatal reviews: a systematic analysis. Acta Paediatr 2006;95:1209–12. 6. Tillman S, Brandon DH, Silva SG. Evaluation of human milk fortification from the time of the first feeding: effects on infants of less than 31 weeks gestational age. J Perinatol 2012;32:525–31. 7. Maas C, Wiechers 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. 8. Sajjadian N, Alizadeh TP, Asgharyan FM, et al. A comparison between early and late breast milk fortification in preterm infants: a clinical trial study. Iran J Pediatr 2014;24:45. 9. Shah SD, Dereddy N, Jones TL, et al. Early versus delayed human milk fortification in very low birth weight infants—a randomized controlled trial. J Pediatr 2016; 174:126–31. 10. Sullivan S, Schanler RJ, Kim JH, et al. An exclusively human milk-based diet is associated with a lower rate of necrotizing enterocolitis than a diet of human milk and bovine milk-based products. J Pediatr 2010;156:562–7. 11. Boehm G, Mu¨ller DM, Senger H, et al. Nitrogen and fat balances in very low birth weight infants fed human milk fortified with human milk or bovine milk protein. Eur J Pediatr 1993;152:236–9. 12. Ghandehari H, Lee ML, Rechtman DJ, H2MF Study Group. An exclusive human milk-based diet in extremely premature infants reduces the probability of remaining on total parenteral nutrition: a reanalysis of the data. BMC Res Notes 2012;5:188. 13. Ganapathy V, Hay JW, Kim JH. Costs of necrotizing enterocolitis and costeffectiveness of exclusively human milk-based products in feeding extremely premature infants. Breastfeed Med 2012;7:29–37. 14. Cristofalo EA, Schanler RJ, Blanco CL, et al. Randomized trial of exclusive human milk versus preterm formula diets in extremely premature infants. J Pediatr 2013; 163:1592–5.