Prolacta in the News
Sergio Golombek, MD, MPH, FAAP
Premature and extremely premature infants being cared for in hospital neonatal intensive care units (NICUs) are some of our most fragile and vulnerable patients. Their medical needs are great, and the stakes are high. We know now that their health, growth, and development during the critically important first weeks of life can have effects that will last a lifetime. Our charge to provide the best possible standard of care for these patients includes using evidence-based interventions whenever possible. Increasingly, studies have showed that human milk-based nutritional interventions reduce complications as well as achieve appropriate growth and development. However, it is very important to recognize that not all human-milk based products are interchangeable. Differences in collection, screening, and processing practices by various manufacturers can have a profound impact on the safety and efficacy of the resulting product. In the NICU, we must be guided by clinical evidence when deciding on products, as past experience has taught us that premature infants may not tolerate even the slightest margin of error (remember NICU history as related, for example, to oxygen toxicity and retinopathy of prematurity [ROP], overventilation and intraventricular hemorrhage [IVH], Phisohex soap and “bubbly” brain disease)! Equally important is the fact that premature infants are not just small children or adults, and what is good for an older patient may certainly be dangerous for a premature baby.
The NICU is arguably where the greatest effort is put into avoiding iatrogenic harm. Nevertheless, premature infants are exquisitely fragile, and, unfortunately, harm is sometimes unavoidable despite everyone’s best efforts. An observational, prospective study by Ligi et al. that comprised all 388 patients admitted to the division of neonatology in an academic tertiary neonatal center in southern France between January 1 and September 1, 2005, revealed that 267 iatrogenic events were recorded in 116 patients. Of these, 34% were deemed to be preventable and 29% were severe. Two were fatal.1 In a prospective, observational study of four NICUs in Israel, the rate of iatrogenic events was about 18%, with 8% of these events classified as life-threatening and 45% as harmful. Importantly, 83% were considered preventable. The rate of iatrogenic events was far greater — at 57% — among infants born at 24 to 27 weeks’ gestational age.2
Complications have occurred as a direct result of misguided or inadequately studied interventions to improve outcomes. In a letter to the editor of the Journal of Perinatology, Miller provided a list of well-meaning medical interventions once delivered in the NICU that were ultimately demonstrated to produce more harm than good.3
Ramachandrappa and Jain identified rapid technological advances and new therapeutic modalities in the NICU as sources of iatrogenic harm — they wrote: “Some of them received critical evaluation and withstood the test of time; others managed to slip into use with less critical evaluation. Many of these therapeutic modalities are the major contributors to neoiatrogenesis. … [M]any interventions … although well intentioned, were never subjected to rigorous controlled trials.” Examples they give include IV vitamin E resulting in multiorgan damage as well as hyperalimentation resulting in cholestasis, metabolic acidosis, and essential fatty acid deficiencies.4
An important advance in the management of premature infants in the NICU is the use of human milk-based nutrition. Over the past 20 years, there has been mounting evidence that use of human milk, particularly in the form of an exclusive human milk-based diet (EHMD), results in decreased morbidity and mortality as short-term NICU outcomes,5,6,7,8 as well as improved neurodevelopmental outcomes during the first two years of life.9,10,11,12 It is crucial to recognize, however, that all clinical research in this space has been conducted with milk obtained directly from patients’ mothers, donated milk collected through the Human Milk Banking Association of North America (HMBANA), and/or human milk-based nutritional products made by Prolacta Bioscience (Duarte, CA).
As new players enter the human milk-based nutrition space, it is tempting to assume that the products they offer will be just as safe and effective as mother’s milk, HMBANA milk, and Prolacta® products. After all, it is all breastmilk. Nothing could be further from the truth! At the present time, unfortunately, there are no federal-level quality and safety standards specific to human milk and human milk-based products in the US. As a result, some human milk manufacturers seem to be promoting unproven and untested manufacturing processes absent supporting clinical data on safety and efficacy. Lack of regulation poses a potential risk to NICUs and the fragile premature infants who rely on human milk nutrition for survival.
As with any human tissue, the benefits and safety of the final product depend on collection, screening, and processing practices. Blood transfusions are life-saving, but their benefits are compromised if they are a vector for transmission of bloodborne illness. The same is true for human milk. There is evidence that medications, drugs of abuse, and infectious pathogens can all be found to various degrees in human milk.13 It is only via careful screening of donors and regular testing, including direct testing of milk itself, that we can be sure that human milk and human milk-based nutritional products are free from drugs, pathogens, or adulterants. While many human milk companies only test milk once pooled, Prolacta tests every individual milk donation received. According to Prolacta, its raw milk is directly tested using the nucleic acid amplification test (NAAT) to detect the presence of infectious disease-causing pathogens and bacteria in donated breastmilk, including human immunodeficiency virus type 1 and type 2 (HIV-1, HIV-2), human T-cell lymphotropic virus type I and type II (HTLV-I, HTLV-II), hepatitis virus B and C (HBV, HCV), and Zika virus. This is very important to ensure the safety of the final human milk product.
Prolacta/HMBANA/mother’s milk include:
Another factor that can have a profound impact on the safety and benefits of nutritional products made from human milk is the processing method. Currently, all human milk banks employ some sort of pathogen reduction or sterilization process, but not all of these processes are created equal. The goal is to eliminate pathogens while preserving the highest possible level of bioactive nutrients. Prolacta accomplishes this using a US Food and Drug Administration-regulated vat pasteurization process, similar to Holder pasteurization. Others rely on retort sterilization, a technique used in commercial food processing that lengthens the shelf life of the final product.
To discern the difference in bioactivity resulting from one pathogen reduction process to another, Lima et al. compared Holder pasteurization, retort sterilization, and no pasteurization in 36 breastmilk samples taken from 60 mothers.14 While bioactivity was greatest with raw milk, Holder pasteurization retained far greater bioactivity than retort sterilization for both lysozyme activity (54% vs 0%) and secretory immunoglobulin A (slgA) activity (87% vs 11%).14
The convenience of shelf-stable human milk products is attained at the expense of safety and bioactive proteins. While retort sterilization kills almost everything harmful, it does not eliminate bacterial enterotoxins produced by staphylococci or Bacillus cereus (B. cereus) that may be present in human milk and can be deadly to a premature infant.
Meredith-Dennis et al. compared the composition of human milk samples acquired from three different milk banks in the United States: 1) Holder pasteurized “hospital grade” donor pooled milk from Mother’s Milk Bank (San Jose, CA); 2) vat pasteurized pooled donor milk from Prolacta Bioscience®; and 3) retort sterilized pooled milk from Medolac Laboratories® (Lake Oswego, OR). Once again, retort sterilization came in last with respect to maintaining concentrations of bioactive compounds, including IgA, IgM, IgG, lactoferrin, lysozyme, α-lactalbumin, α-antitrypsin, casein, human milk oligosaccharides (HMOs), and HMOs containing fucose, sialic acid, and nonfucosylated neutral sugars (P < 0.05 for all comparisons of retort sterilization with Holder and vat pasteurization).15
In summary, applying commercial food processing methods to human milk yields products that may contain significantly less bioactivity, are not clinically proven, and are not as safe or effective in providing premature infants with the vital nutrition necessary to continue improving outcomes in the NICU.
Vulnerable infant populations who rely on human milk-based products for vital nutrition deserve clinically proven products manufactured with the highest quality and safety standards available — studies that have been published in journals after being carefully reviewed.
It is not prudent to assume that human milk that has been collected, screened, and/or processed using differing tools and strategies will offer equivalent, or even near equivalent, safety and benefits. It is not evidence-based care if a tested human milk-based product (in terms of safety and efficacy) is substituted for an untested product produced by a different manufacturer.
Given the known differences in screening and processing of human milk-based nutritional products, adoption of products in the NICU that were not tested in large and/or multiple clinical studies is tantamount to conducting an uncontrolled experiment on our most vulnerable patients. As mentioned before, we have done this with other interventions, and the consequences were devastating. Let us learn from the past and reach for evidence-based solutions!
1 Ligi I, Arnaud F, Jouve E, Tardieu S, Sambuc R, Simeoni U. Iatrogenic events in admitted neonates: a prospective cohort study. Lancet. 2008;371(9610):404-410. doi:10.1016/S0140-6736(08)60204-4
2 Kugelman A, Inbar-Sanado E, Shinwell ES, et al. Iatrogenesis in neonatal intensive care units: observational and interventional, prospective, multicenter study. Pediatrics. 2008;122(3):550-555. doi:10.1542/peds.2007-2729
3 Miller, A. Diseases of progress in neonatal care. J Perinatol 25, 557 (2005). https://doi.org/10.1038/sj.jp.7211324
4 Ramachandrappa A, Jain L. Iatrogenic disorders in modern neonatology: a focus on safety and quality of care. Clin Perinatol. 2008;35(1):1-vii. doi:10.1016/j.clp.2007.11.012
5 O’Connor DL, Kiss A, Tomlinson C, et al. Nutrient enrichment of human milk with human and bovine milk–based fortifiers for infants born weighing < 1250 g: a randomized clinical trial. Am J Clin Nutr. 2018;108(1):108-116. doi:10.1093/ajcn/nqy067
6 Huston RK, Markell AM, McCulley EA, Gardiner SK, Sweeney SL. Improving growth for infants ≤1250 grams receiving an exclusive human milk diet. Nutr Clin Pract. 2018;33(5):671-678. doi:10.1002/ncp.10054
7 Delaney Manthe E, Perks PH, Swanson JR. Team-based implementation of an exclusive human milk diet. Adv Neonatal Care. 2019 Dec;19(6):460-467. doi: 10.1097/ANC.0000000000000676. PMID: 31764134.
8 Lucas A, Assad M, Sherman J, Boscardin J, Abrams S. Safety of cow’s milk-derived fortifiers used with an all-human milk based diet in very low birthweight preterm infants. Neonatol Today. 2020;15(7):3-13.
9 Hair AB, Bergner EM, Gollins LA, et al. Long-term outcomes at 2 and 5 years from the randomized controlled trial: human milk cream as a supplement to standard fortification of an exclusive human milk-based diet in VLBW infants. Poster presented at: Pediatric Academic Societies Meeting. April 24 – May 1, 2019. Baltimore, MD.
10 Bergner EM, Shypailo R, Visuthranukul C, et al. Growth, body composition, and neurodevelopmental outcomes at 2 years among preterm infants fed an exclusive human milk diet in the neonatal intensive care unit: a pilot study. Breastfeed Med. 2020. [Epub ahead of print]. doi:10.1089/bfm.2019.0210
11 Rahman A, Kase J, Murray Y, et al. Neurodevelopmental outcome of extremely low birth weight infants fed an exclusive human milk diet is not affected by growth velocity. Breastfeed Med. 2020;15(6):362-369. Doi:10.1089/bfm.2019.0214
12 Hair AB, Patel AL, Kiechl-Kohlendorfer U, et al. Neurodevelopmental outcomes of extremely preterm infants fed an exclusive human milk-based diet versus a bovine milk based diet: a multi-center study. J Perinatol. Forthcoming 2021.
13 Bloom BT. Safety of donor milk: a brief report. J Perinatol. 2016 May;36(5):392-3. doi: 10.1038/jp.2015.207. Epub 2016 Jan PMID: 26741570.
14 Lima H, Wagner-Gillespie M, Perrin M, Fogleman A. Bacteria and bioactivity in Holder pasteurized and shelf-stable human milk products. Curr Dev Nutr. 2017;1(8):e001438. doi:10.3945/cdn.117.001438
15 Meredith-Dennis L, Xu G, Goonatilleke E, Lebrilla CB, Underwood MA, Smilowitz JT. Composition and variation of macronutrients, immune proteins, and human milk oligosaccharides in human milk from nonprofit and commercial milk banks. J Hum Lact. 2018;34(1):120-129. doi:10.1177/0890334417710635
16 Huston R, Lee M, Rider E, et al. Early fortification of enteral feedings for infants <1250 grams birth weight receiving a human milk diet including human milk based fortifier. J Neonatal Perinatal Med. 2020;13(2):215-221. doi:10.3233/ NPM-190300
17 Hair AB, Hawthorne KM, Chetta KE, Abrams SA. Human milk feeding supports adequate growth in infants ≤ 1250 grams birth weight. BMC Res Notes. 2013;6:459. Published 2013 Nov doi:10.1186/1756-0500-6-459