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Extensively-hydrolyzed formula of cow's milk proteins for refeeding preterm infants with necrotizing enterocolitis: Results of national survey Journal: Manuscript ID bmjopen-0-00 Article Type: Research
Extensively-hydrolyzed formula of cow's milk proteins for refeeding preterm infants with necrotizing enterocolitis: Results of national survey Journal: Manuscript ID bmjopen-0-00 Article Type: Research Date Submitted by the Author: 0-Feb-0 Complete List of Authors: Lapillonne, Alexandre; Hopital universitaire Necker-Enfants malades, Neonatology; Universite Paris Descartes, School of Medicine Matar, Maroun; University medical center of Rizk Hospital, Neonatology Adleff, Ariane; Private practice, NA Kermorvant-Duchemin, Elsa; Hopital universitaire Necker-Enfants malades, Neonatology; Universite Paris Descartes, School of Medicine Campeotto, Florence; Hopital universitaire Necker-Enfants malades, Pediatric Gastroenterology; Universite Paris Descartes, School of Pharmacy b primary Subject Heading /b : Paediatrics Secondary Subject Heading: Paediatrics, Surgery, Nutrition and metabolism Keywords: Nutrition TROPICAL MEDICINE, NEONATOLOGY, Gastroenterology INTERNAL MEDICINE, hydrolyzed formula, low birth weight infants, necrotizing enterocolitis : first published as 0./bmjopen-0-00 on July 0. 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Page of Extensively-hydrolyzed formula of cow's milk proteins for refeeding preterm infants with necrotizing enterocolitis: Results of national survey Alexandre LAPILLONNE, M.D., Ph.D.,, Maroun MATAR, M.D., Ariane ADLEFF, M.D., Elsa DUCHEMIN-KERMORVANT, M.D., Ph.D.,, Florence CAMPEOTTO, M.D.PhD., Neonatal Department, APHP Necker-Enfants Malades hospital, Paris, France, Paris Descartes University, Paris, France; Neonatology division, University medical center of Rizk Hospital, Lebanon; Pertuis, France, Pediatric Gastroenterology Department, APHP Necker-Enfants Malades hospital, Paris, France Address for correspondence and reprints: Professor Alexandre Lapillonne, Department of Neonatology, APHP Necker-Enfants Malades hospital, Boulevard Sevres, 0 Paris, France, tel: + (), Mail: Word count (text) = 0 Word count (Abstract) = Number of references =0 Number of figures = 0 Number of tables = - : first published as 0./bmjopen-0-00 on July 0. Downloaded from on September 0, 0 by guest. Protected by copyright. Page of Abstract Objective: The aims of this study were to evaluate the frequency and reasons of use of extensively hydrolyzed formula of cow's milk proteins (EHF) in French neonatal units (NUs) and the modality of use when prescribed for refeeding infants with NEC. Methods: Clinical practice survey by the mean of a questionnaire addressing ) the prevalence of use and the reasons for prescribing an EHF in hospitalized neonates and ) the duration of use for infants who have had NEC, and the protocol used for weaning these infants of EHF. The questionnaire was send to one senior physician per neonatal unit. Results: % of the NUs surveyed used EHF. Out of the infants hospitalized the day of the survey, % were fed an EHF with a higher frequency of use in level II (%) than in level III units (.%) (p 0.000). Eleven percent of the prescriptions of EHF were due to a previous NEC. The main reasons for using an EHF as the preferred milk for feeding infants post NEC were the absence of human milk (%) and the need for surgery (%). When given, EHF was mainly prescribed for a period varying between days and months. None of the units were continuing EHF after months of age. More than half the units declared hospitalizing the infant for the initiation of weaning from EHF but only % of them performed allergic test for cow s milk allergy. Conclusions: The prevalence of use of EHF in the French NUs is high. Refeeding infants with NEC is one the reasons of such high prevalence. The main driver for choosing an EHF is the absence of human milk, either bank human milk or mother s milk. Key Words: hydrolyzed formula, feeding methods, low birth weight infants, milk hypersensitivity, necrotizing enterocolitis Abbreviations: NEC necrotizing enterocolitis; MCT - medium-chain triglycerides; GI gastrointestinal; EHF - extensively hydrolyzed formula of cow's milk proteins; GA - gestational age - : first published as 0./bmjopen-0-00 on July 0. Downloaded from on September 0, 0 by guest. Protected by copyright. Page of Strengths of this study: This nationwide survey shows for the first time that extensively-hydrolyzed formula of cow's milk proteins are frequently used in neonatal departments. Refeeding infants after necrotizing enterocolitis is one of the main reasons for prescribing an extensively-hydrolyzed formula to preterm infants especially when mother s milk or banked human milk is not available. The modalities for weaning from extensively hydrolyzed formula are extremely variable demonstrating a lack of consensus. Limits of this study: This is a clinical practice survey by the mean of a questionnaire The benefits/risk ratio, as well as the modality for weaning of EHF should be evaluated in further studies. - : first published as 0./bmjopen-0-00 on July 0. Downloaded from on September 0, 0 by guest. Protected by copyright. Page of Introduction Necrotizing enterocolitis (NEC) is a major issue in preterm, especially extremely preterm ( weeks gestation) neonates worldwide. Its mean prevalence among very preterm infants is about % with a reported mortality rate of 0 to 0%. Many clinical trials have evaluated the safety and benefits from preventive strategies which include trophic feedings, standardized feeding regimens, provision of breast milk, arginine supplementation, probiotic therapy, and infection control measures. The severity of intestinal involvement influences the decision for medical or surgical management. However some aspects are common to both medical NEC and surgical NEC. The initial management of an infant with NEC includes providing supportive respiratory and hemodynamic care, discontinuation of all enteral feedings and medications, placement of a gastric tube to allow gastric and intestinal decompression, start of parenteral nutrition to support energy and protein needs, and administration of broad-spectrum intravenous antibiotics. Surgical intervention may be required especially if an intestinal perforation is diagnosed, but there is a lack of comparative evidence to support primary anastomosis over enterostomy after intestinal resection during laparotomy for acute NEC in infants. There is a lack of consensus on when enteral feeding should be reintroduced, and on the method and the rate of reaching goal feeding volumes. The choice of feedings post-nec remains controversial. In most instances, breast milk is considered as the optimal feeding when available. In the case of the absence of breast milk, some physicians use premature milks if the gastrointestinal (GI) injury is limited. Some others use banked human milk or hydrolyzed formula. In the case of larger GI injury, hydrolyzed formula with no lactose and variable amounts of medium-chain triglycerides (MCT) or elemental formula preparations are used to improve absorption. - : first published as 0./bmjopen-0-00 on July 0. Downloaded from on September 0, 0 by guest. Protected by copyright. Page of The purpose of this study is to evaluate the frequency of use of extensively hydrolyzed formula of cow's milk proteins (EHF) in French neonatal units and the modality of their use when prescribed for refeeding infants with NEC.. Materials and methods To perform this study, we designed a survey using a questionnaire specially designed to investigate nutrition routine practices in neonatology departments. The survey technique used a closed-answer questionnaire to limit variability of answers and to decrease the number of incomplete answers. It focused on the enteral nutrition protocol after the initial management or postoperatively of the infants with NEC. The first series of questions aimed at determining the frequency of use and the reasons for prescribing an EHF in neonates. To achieve this goal, the physicians answering the questionnaire were asked to report the total number of infants hospitalized in their unit the day of filling the questionnaire as well as the number of infants receiving an EHF because of a previous NEC. The second series of questions focused on the nutritional protocol in the unit and assessed the modality of use of EHF for refeeding infants with NEC. More specifically, questions targeted the duration of use, and the protocol used for weaning the infants from EHF. The extensive list of neonatal departments of metropolitan France and overseas territories was established by combining the lists of national scientific societies involved with newborn care and those of all regional health care services each contacted individually. Neonatal departments that had high acuity or intensive care beds were selected for the study. Only one questionnaire was sent per unit; it was accompanied by a cover letter and a reply envelope, and sent by mail to the head of the department. The senior physician in each NICU was asked to complete the survey questionnaire or delegate the task to a colleague devoting 0% of their time to patient care and with years of clinical experience in neonatal intensive care. - : first published as 0./bmjopen-0-00 on July 0. Downloaded from on September 0, 0 by guest. Protected by copyright. Page of We aimed at surveying at least half of the national neonatal units to have a precise view of the nutritional care of the preterm infants with NEC. One subsequent mailing was sent one month later to the non-respondents to achieve our goal. The units were divided as level II and level III units as previously described. The identity of the physicians contacted and requested to complete the survey remained blinded for the analysis. Statistical analysis Statistical analyses were restricted to completed questionnaires with evaluable results. Data were analyzed using Minitab. software (Minitab Inc., State College, PA, USA). General frequency responses to all survey items were determined and then used to test for associations among the categorical variables. When needed, data were split to cross tabs with respect to various grouping variables. Results from level II and III units were compared by Pearson test of independence. A p-value 0.0 was considered statistically significant. - : first published as 0./bmjopen-0-00 on July 0. Downloaded from on September 0, 0 by guest. Protected by copyright. Page of Results. Characteristics of the units The goal of surveying at least half of the French neonatal units was reached since we received answers from the units contacted (.%). The answer rate was similar to the level III (/ = %) and the level II units (/0 = %) (p=0.). The characteristics of the units are reported in the Table I. Out of the units surveyed, out of them (%) routinely use EHF (Table I).. Prevalence of use and reasons for feeding hospitalized neonates with EHF Out of the infants hospitalized the day of the filling of the questionnaire, received an extensively-hydrolyzed formula (.%) with a higher frequency of use in level II (%) than in level III units (.%) (p 0.000). The main reasons for feeding hospitalized neonates with EHF are indicated in Table II. Shortage of human milk is overall the main reasons for prescribing EHF either for the initiation of feeding in preterm infants or for complementary feeding of breastfed infants. Among the infants receiving EHF, 0.% of the prescriptions were made because of a previous NEC with a higher percentage of the prescriptions for NEC observed in the level III than in the level II units (p=0.0).. Nutritional protocols when using EHF for feeding infants with NEC Out of the units surveyed, (.%) routinely took care of infants with NEC. EHF were routinely used in of them (%) (Table I). The main reasons for using an EHF as the preferred milk for feeding infants post NEC were the absence of human milk (n= /, %) and the need for surgery (n= /, %). The other reasons cited were NEC in term babies for whom EHF is nutritionally adapted, other associated digestive problems, NEC severity at onset, and salvage of bank human milk. - : first published as 0./bmjopen-0-00 on July 0. Downloaded from on September 0, 0 by guest. Protected by copyright. Page of EHF, when given, were mainly prescribed for a period which varies from days to months. None of the units continued giving EHF after months of age (Table III). Table III describes the mode of weaning from EHF. In the absence of breast milk, % of the units declared switching to cow s milk formula, the others using either bank human milk or partially hydrolyzed formula. Most of the units weaned from EHF progressively for a mean (SD) period of. (.) days. More than half of the units declared hospitalizing the infant for the initiation of weaning but only % of them performed allergic test for cow s milk allergy. - : first published as 0./bmjopen-0-00 on July 0. Downloaded from on September 0, 0 by guest. Protected by copyright. Page of Discussion To our knowledge this first study which attempts to determine the frequency of use of EHF in neonatology departments. We found that the prevalence of the prescriptions of EHF is high, reaching % of the prescriptions of enteral or oral nutrition. There are many reasons for prescribing such formula to neonates. They include the absence of human milk, a poor feeding tolerance, a severe gastrointestinal reflux, a family history or clinical signs of cow s milk allergy, or an history of gastrointestinal surgery or intestinal resection 0. Our study clearly shows that the refeeding of infants with NEC is a frequent reason of EHF prescription in sick neonates. We found a statistically significant difference between the prevalence for using EHF in level II units compared to that of level III units. This fits well with the observation that the main reason for using EHF is the shortage of mother s milk. Indeed the availability of pasteurized human milk is lower in the level II units since, in France, the milk banks are usually located close to the level III units, not to the level II units. In contrast, it is not surprising that level III units are more prone to use EHF for refeeding infants after NEC since only these units have high acuity beds and are able to care for such surgical, or potentially surgical, patients. Most of the textbooks and the literature focus on the nutritional prevention, not the treatment of NEC. Furthermore, they are extremely vague with regards to the timing of refeeding and the type of milk that should be used after the initial management or postoperatively of infants who have had NEC. It is, however, recognized that the feeding should be suspended for a period that is dependent of the severity of clinical disease but no clear recommendations for when to restart feeding after the episode of NEC have been made. The choice of formula milk for feeding NEC infants depends on many considerations such as the gestational age of the infant, the availability of human milk, the risk of small bowel syndrome and/or malabsorption, and the risk of cow s milk allergy. Our study clearly shows that the main driver for choosing an EHF is the absence of human milk, either bank human milk or mother s milk. - : first published as 0./bmjopen-0-00 on July 0. Downloaded from on September 0, 0 by guest. Protected by copyright. Page 0 of Prescribing EHF in infants with NEC is not in line with the few guidelines we are aware of, in which it is recommended to start feeding NEC infants with preterm formula in absence of human milk. There are, however, several putative reasons for choosing an EHF. Premature infants recovering from mucosal inflammation and prolonged period of bowel rest are potentially at an increased risk of antigen response to intact protein. Several case reports have shown that cow's milk protein allergy is closely related to NEC or may occur after NEC. This suggests that cow's milk protein tolerance should be evaluated when NEC occurs in the case of absence of classical risk factors. In this context, extensively hydrolyzed formula may be useful for feeding infants with NEC. Cow s milk allergy is well recognized as a significant cause of morbidity in formula-fed term infants () and more recently, in preterm infants. More specifically, it has been shown that allergy to cow's protein milk in surgical newborns is higher than expected and may reach % in absence of family history of allergy. There are also evidence of in vitro sensitization to cow's milk protein in peripheral blood mononuclear cells of preterm infants with NEC. In addition to that, there is a debate on the direct contributory role of cow's milk protein sensitization in the pathogenesis of NEC 0. The use of EHF for feeding infants with NEC in the view of preventing cow's milk protein sensitization should however be tested by further studies since to date, no studies were able to confirm the usefulness of hydrolyzed formula in prevention of allergy, in either unselected cohorts of very low birth weight infants or in preterm infants with an atopic predisposition. The use of EHF may also be considered because of their nutritional values. Indeed they usually do not contain lactose and some of them do contain significant amount of mediumchain triglycerides (MCT). These characteristics may improve the absorption during the refeeding period especially in surgical patients. Lactose is poorly tolerated in neonates with small bowel loss because of the decrease in available mucosal lactase; Medium-chain triglycerides improve fat absorption which is reduced because of loss of absorptive area, rapid transit, bile acid depletion, and/or bacterial overgrowth 0. In contrast, the theoretical : first published as 0./bmjopen-0-00 on July 0. Downloaded from on September 0, 0 by guest. Protected by copyright. Page of advantage for using hydrolyzed protein because of a possible better absorption than the whole protein in face of a reduced absorptive area and decreased pancreatic enzyme output, remains uncertain since it has been shown that dietary protein absorption capacity of the small intestine is normal for most neonates after intestinal surgery. If there are possible nutritional benefits for using EHF for feeding infants after NEC, they should be waited against possible disadvantages. Indeed these formulas have an energy density close to term formula and usually low in minerals and polyunsaturated fatty acids compared to preterm formula. Urinary nitrogen excretion is higher, calcium and phosphorus absorption and nitrogen retention are lower in preterm infants fed hydrolyzed formula compared to those fed whole protein formula. This may alter the quality of growth or decrease lean mass accretion even in absence of similar growth rate of preterm infants receiving hydrolyzed preterm formula vs non-hydrolyzed formula. In the absence of specific recommendations and studies aiming at assessing the risk of food allergy in infants with NEC, it is not surprising that our study shows a great heterogeneity in the protocols for weaning the infants of the EHF. In the contrary of the suggestions made by El Hassani et al and more importantly to the guidelines for prevention of food allergy 0, our study shows that the duration of use is lower than the to months recommended. In addition to that, most of the units introduce cow s milk protein without performing any appropriate diagnostic work-up. It should be recognized that our study has several limitations. It was performed in only one country. On the other hand, it was performed in a large number of neonatal departments ( 0 %) and thus gives a precise picture of the management of the NEC infants in France. Furthermore, since this survey was performed in a large number of neonatal departments and since the respondents were asked to identify, among the infants in their unit, those who were receiving EHF the day the questionnaire was filled, we have a precise estimate of the
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