Safety of Cow’s Milk-Derived Fortifiers used with an All Human Milk Base Diet in Very Low Birthweight Preterm Infants: Part II

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Alan Lucas MD FMedSci, Maushumi Assad MD, MPH, Jan Sherman PhD, John Boscardin PhD, Steven Abrams MD 

Abstract 

Recently we published a meta-analyses of morbidity seen with the use of cow’s milk derived fortifier (CMDF) rather than human milk derived fortifier (HMDF) in very low birthweight (VLBW) infants. Here, we further analyse these data to estimate the annual population risk of CMDF-related major morbidity in the United States and Canada. The outcome used was a mortality/morbidity index which was positive if the infants had one or more of death, necrotising enterocolitis, sepsis retinopathy of prematurity or broncho-pulmonary dysplasia. Using the risk difference (RD) between the CMDF and HMDF groups we estimated, provisionally, that 4150 additional VLBW infants in the United States and Canada each year, or an additional infant approximately every 2 hours, may be expected to develop a positive mortality/morbidity index in relation to being fed CMDF – over and above the number of infants with a positive index if fed HMDF. We provide an in-depth discussion of the limitations of our estimate. This analysis provides preliminary evidence of the magnitude of population risk of major neonatal morbidity with use of CMDF versus HMDF in VLBW infants in current practice. 

Key Words: preterm infant feeding, cow’s milk-derived fortifiers, human milk-derived fortifiers, neonatal morbidity, neonatal mortality 

Abbreviations: MOM: Mothers own milk, CM: Cow’s milk, CMDF: Cow’s milk-derived fortifier, PTF: Preterm fortifier, HMDF: human milk-derived fortifier, NEC: Necrotizing enterocolitis, ROP: Retinopathy of prematurity, BPD: bronchopulmonary dysplasia, NICU: Neonatal intensive care unit 

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Conclusions 

Our preliminary estimates presented here suggest that although about 30% of smaller VLBW babies in the USA are fed with HMDF, more than 4000 VLBW preterm infants in the United States and Canada each year may either die or develop major morbidity in relation to the use of CMDF. The estimated NNH of only 7 is also a concern. However, these estimates have a broad confidence interval and are based on the surprisingly small number of safety studies of this type. Our provisional analysis has several limitations, and we recognize it is difficult to extrapolate from small studies to large populations. Nevertheless, this field has become important to pursue – and these types of estimation will also need to be done on other populations, where the recommended neonatal feeding practices are similar. 

Our study illustrates a larger issue. Because of the broad adverse and beneficial impacts of preterm infant feeding on morbidity, feeding regimes in this sensitive period are helpfully seen as therapeutic interventions where both efficacy and safety are, in general, important metrics. The current recommendations for preterm infant feeding – notably to use DM if MOM is insufficient – were introduced over 20 years ago and have become globally common in the last ten years in part based on key position papers of relevant societies.(17,18) Yet, at the time this guidance was given, there was an absence of randomized trials appropriately designed to address safety in terms of the morbidities examined here, when using CMDF as the sole source of CM – an integral component of this new practice. As data have emerged, it has become clearer that these safety aspects are important to address and quantify. For this reason, we have released these data at an early stage to encourage both further research and discussion on the implications for practice. 

Acknowledgments 

We acknowledge the kind permission of Dr Melinda Elliott for allowing us to reanalyse her raw data for the study by Assad et al. and for retrieving further raw data from the patient records. 

References 

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Acknowledgments 

We acknowledge the kind permission of Dr. Melinda Elliott for allowing us to reanalyze her raw data for the study by Assad et al. and for painstakingly retrieving further raw data from the patient records 

Author Contributions 

Professor Alan Lucas conceived and initiated the study; analyzed raw data; and wrote the paper 

Dr Maushumi Assad provided her raw data (Assad study) and assisted us with the understanding of her database, She read and commented constructively on the manuscript 

Professor Jan Sherman was our advisor on evidence-based medicine. She performed all the meta-analyses and provided the data for figures. She read and advised on the manuscript. 

Dr. John Boscardin was our statistician who advised on: the statistical analysis, interpretation of data and data presentation 

Professor Steven Abrams key collaborator involved in every aspect of the study and made major intellectual input. 

Financial support: None: 

Conflicts of Interest: Dr. Lucas has provided independent scientific advice to Philips, Prolacta, and Nestle.; Dr. Assad, none; Dr. Sherman, none; Dr. Boscardin, none. Dr. Abrams, none 

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