Sandra Sullivan

Randomized Trial of Exclusive Human Milk versus Preterm Formula Diets in Extremely Premature Infants

OBJECTIVE To compare the duration of parenteral nutrition, growth, and morbidity in extremely premature infants fed exclusive diets of either bovine milk-based preterm formula (BOV) or donor human milk and human milk-based human milk fortifier (HUM), in a randomized trial of formula vs human milk. STUDY DESIGN Multicenter randomized controlled trial. The authors studied extremely preterm infants whose mothers did not provide their milk. Infants were fed either BOV or an exclusive human milk diet of pasteurized donor human milk and HUM. The major outcome was duration of parenteral nutrition. Secondary outcomes were growth, respiratory support, and necrotizing enterocolitis (NEC). RESULTS Birth weight (983 vs 996 g) and gestational age (27.5 vs 27.7 wk), in BOV and HUM, respectively, were similar. There was a significant difference in median parenteral nutrition days: 36 vs 27, in BOV vs HUM, respectively (P = .04). The incidence of NEC in BOV was 21% (5 cases) vs 3% in HUM (1 case), P = .08; surgical NEC was significantly higher in BOV (4 cases) than HUM (0 cases), P = .04. CONCLUSIONS In extremely preterm infants given exclusive diets of preterm formula vs human milk, there was a significantly greater duration of parenteral nutrition and higher rate of surgical NEC in infants receiving preterm formula. This trial supports the use of an exclusive human milk diet to nourish extremely preterm infants in the neonatal intensive care unit.

Effect of early breast milk expression on milk volume and timing of lactogenesis stage II among mothers of very low birth weight infants: a pilot study

Objective:The purpose of this randomized pilot study was to collect preliminary data regarding the feasibility and effects of early initiation of milk expression on the onset of lactogenesis stage II and milk volume in mothers of very low birth weight (VLBW) infants.Study Design:Twenty women were randomized to initiate milk expression within 60 min (group 1) or 1 to 6 h (group 2) following delivery. Milk volume and timing of lactogenesis stage II was compared between groups using Wilcoxons rank sum tests.Result:Group 1 produced statistically significantly more milk than group 2 during the first 7 days (P=0.05) and at week 3 (P=0.01). Group 1 also demonstrated a significantly earlier lactogenesis stage II (P=0.03).Conclusion:Initiation of milk expression within 1 h following delivery increases milk volume and decreases time to lactogenesis stage II in mothers of VLBW infants.

Circulating Concentrations of Chemokines in Cord Blood, Neonates, and Adults

Chemokines are critical for the movement of leukocytes. Chemotaxis is deficient in neonates, particularly those delivered prematurely, and this likely contributes to their increased vulnerability to sepsis. The concentrations of circulating chemokines in neonates have not been reported, nor is it known whether low chemokine concentrations contribute to their defective chemotaxis. We hypothesized that serum concentrations of chemokines 1) would be lower in preterm than term neonates, and 2) would be lower in preterm and term neonates than adults. Samples were obtained from preterm and term neonates with normal neutrophil and eosinophil counts, umbilical cord blood samples from pregnancies without clinical evidence of intra-amniotic infection, and healthy adult volunteers. The concentrations of epithelial neutrophil activating peptide-78, growth-related oncogene-α, eotaxin, RANTES (regulated upon activation, normal T cell expressed and secreted), and macrophage inflammatory protein-1α were measured using specific ELISA. Serum concentrations from preterm infants were either similar to or higher than those measured in term neonates and adults. We conclude that the chemotactic defect observed in premature neonates is not the result of diminished circulating concentrations of any of the specific chemokines we measured.

Tolerance of Simulated Amniotic Fluid in Premature Neonates

OBJECTIVE: To assess the tolerance of simulated amniotic fluid enterally administered in premature neonates. DESIGN: A multicentered, Phase I, dose-escalation trial was accomplished among 30 preterm neonates. Groups of 10 patients received 5, 10, or 20 mL/kg/d enterally of the amniotic fluid solution, divided into every-3-hour dosing, for 3 days. MAIN OUTCOME MEASURES: Amount and character of emesis, stools, and gastric residuals; changes in abdominal girth; presence of a skin rash; blood pressure instability; the diagnosis of necrotizing enterocolitis (NEC) or intestinal perforation. RESULTS: Thirty patients were studied: 10 received 5 mL/kg/d, 10 received 10 mL/kg/d, and 10 received 20 mL/kg/d of amniotic solution. Gestational ages ranged from 25 to 31 weeks. The Data Safety and Monitoring Board met after each group of 10 patients completed the study, reviewed the outcome measurements, and recommended continuance of the study. Dosing was discontinued for 3 patients prior to receiving all 24 doses because of gastric residuals (n = 1; 5 mL/kg), stage I NEC (n = 1; 10 mL/kg), or symptomatic patent ductus arteriosus (n = 1; 20 mL/kg). The remaining patients completed the doses with no evidence of intolerance: specifically, no increased gastric residuals, increased abdominal girth, diarrhea, blood pressure change, rash, NEC, or intestinal perforation. CONCLUSIONS: Enteral administration of an amniotic fluid—like solution to preterm neonates is well tolerated in doses ≤20 mL/kg/d.

Ankyloglossia, Exclusive Breastfeeding, and Failure to Thrive

A 6-month-old term boy was hospitalized to evaluate the cause of his failure to thrive, mandated as part of an investigation by the Department of Children and Families after an allegation of medical neglect was made. On admission the patient was below birth weight, and a medical workup for failure to thrive was pursued; however, he was noted to have severe ankyloglossia and was an exclusively breastfed infant. The only interventions during his hospitalization were frenotomy and assistance to the mother to increase her milk supply. The infant immediately experienced weight gain and has continued to show slow, but steady, weight gain as an outpatient. We illustrate here many of the controversies concerning ankyloglossia.

G-CSF and Erythropoietin Stability in Amniotic Fluid during Simulated in vitro Digestion Conditions

Objective: To determine the stability of granulocyte colony-stimulating factor (G-CSF) and erythropoietin (Epo) in human amniotic fluid and recombinant G-CSF (Neupogen) and Epo (Epogen) in simulated amniotic fluid to digestions at pH concentrations of 3.2, 4.5, and 5.8 to assess their bioavailability to the neonate. Design: A simulated amniotic fluid containing Neupogen and Epogen was subjected to in vitro conditions that mimicked preprandial and postprandial neonatal intestinal digestion. Human amniotic fluid was tested using identical digestion conditions as well as human amniotic fluid to which Epogen and Neupogen had been added. Main Outcome Measures: The percentages of G-CSF/Epo and Neupogen/Epogen remaining after 1 and 2 hours of simulated digestions were compared with those at time zero, and concentrations at 2 hours were compared with those at 1 hour and time zero. Results: In simulated amniotic fluid at pH 3.2, significant degradation of G-CSF was observed at 1 hour (p = 0.03). No differences were observed at 1 or 2 hours for either pH 4.5 (p = 0.30 and 0.11, respectively) or pH 5.8 (p = 0.20 and 0.49, respectively). Human amniotic fluid exhibited significant degradation pH 3.2 (p = 0.04) and pH 4.5 (p < 0.05) at 1 hour; no difference was noted at pH 5.8 at 1 hour (p = 0.34). When additional Neupogen was added to human amniotic fluid, significant degradation was observed at pH 3.2 (p < 0.05) and pH 4.5 (p = 0.03) at 1 hour; no difference was noted at 1 hour at pH 5.8 (p = 0.11). In simulated amniotic fluid at pH 3.2, significant degradation of Epo occurred at 1 hour (p < 0.05). There were no differences at 1 hour for pH 4.5 (p = 0.50) or pH 5.8 (p = 0.17). Human amniotic fluid exhibited significant degradation at pH 3.2 (p < 0.05) and pH 4.5 (p < 0.05) at 1 hour; no difference was noted at 1 hour at pH 5.8 (p = 0.34). When additional Epogen was added to human amniotic fluid, significant degradation was observed at pH 3.2 (p = 0.001) and pH 4.5 (p = 0.003); no difference was noted at 1 hour at pH 5.8 (p = 0.31). Conclusions: G-CSF/Epo in human amniotic fluid and Neupogen/Epogen in simulated amniotic fluid are preserved to varying degrees during simulated digestion conditions. The degree of degradation of both cytokines was time- and pH-dependent. Measurable quantities of G-CSF and Epo are biologically available when swallowed by the fetus or a preterm neonate.

EOSINOPHILIA IN THE NEONATAL INTENSIVE CARE UNIT

Although common in the neonatal intensive care unit, eosinophilia is often overlooked or ignored. The latter might be, at least in part, because evaluating the neonate with eosinophilia can be a complex process. This article reviews the physiologic features of eosinophilia, reference ranges, and clinical conditions associated with eosinophilia in the neonate. Recommendations for the evaluation of the neonate with eosinophilia are presented.

Granulocyte-Macrophage Colony-Stimulating Factor and Interleukin-5 Concentrations in Premature Neonates With Eosinophilia

OBJECTIVE:Eosinophilia is common among premature neonates, but little is known about the cytokines responsible for influencing its onset in neonates. In adults and transgenic mice, granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-5 (IL-5) influence the development of eosinophilia. We sought to prospectively determine whether these cytokines correlated with the development of eosinophilia in premature infants.STUDY DESIGN:We measured the absolute eosinophil count (AEC) and serial serum concentrations of GM-CSF and IL-5 in premature neonates with eosinophilia.RESULTS:Among 201 premature neonates, 21 had an eosinophil count of >700/μl (occurrence, 10.5%). Of these 21 neonates, 4 had mild (700/μl to 999/μl), 13 had moderate (1000/μl to 2999/μl), and 4 had severe (>3000/μl) eosinophilia. No differences in gestational age or age at onset of eosinophilia were observed between the groups, but the duration of eosinophilia was less with mild than with moderate or severe eosinophilia. A total of 20 of the 21 patients had an infection or necrotizing enterocolitis diagnosed within 48 hours of the onset of eosinophilia. In patients with mild and moderate eosinophilia, serial GM-CSF and IL-5 concentrations were below the lowest enzyme-linked immunosorbent assay standard. There was no correlation between AEC and GM-CSF or IL-5 concentration in these infants. However, in one patient with severe eosinophilia, two distinct elevations in IL-5 were noted (34.6 and 46.0 pg/ml); each peak occurred 7 to 8 days before a peak in eosinophil count.CONCLUSION: Eosinophilia is relatively common, and in those neonates with the highest AECs, the duration of eosinophilia can last for >6 weeks. The majority of cases of eosinophilia occurred in temporal proximity to an infectious illness or necrotizing enterocolitis. Serum concentrations of IL-5 were elevated in only one of our patients with severe eosinophilia.

Baby and breast: a dynamic interaction

doi:10.1038/pr.2011.35 I a comparison of before and after white blood cell, cytokine, immunoglobulin A (IgA), and lactoferrin responses in milk of mothers of babies with putative infectious illness vs. controls, Riskin et al. (1) have found that during active infection in the nursing infant, the total number of white blood cells—specifically, the number of macrophages—and levels of tumor necrosis factor-α increase. This study supports a very dynamic interaction between an infant’ s health status and the mother’s response that likely enhances the immunologic defenses of the mother’s milk. This interplay between the infant’s health status and the response in the mother’s milk is highly reminiscent of the concept that Kleinman and Walker (2) introduced more than 30 years ago, termed the “enteromammary system.” In their conceptual framework, antigen presented from the infant to the maternal gut via contact between the mother and the baby is brought into proximity to the mother’s lymphoid follicles, which in turn commit lymphoblasts to specific IgA production, which then migrate to the breast and secrete sIgA, which is ingested by the infant. Furthermore, in this concept, T cells, B cells, and macrophages are also thought to extrude into the breast milk and are immunologically active. However, at the time the “enteromammary system” was conceptualized, the basis was primarily studies done in animals. The present study supports this concept nicely by showing responses in human infant mothers’ milk (consisting of increased white blood cells, primarily macrophages, tumor necrosis factor-α to infectious illness thought to originate from the infant. Secretory IgA and lactoferrin have been thought to be primary defenses in human milk, yet, curiously, neither showed a significant response in this study. While the total concentration of sIgA did not change, it is not known whether production shifted toward the specific, causative infectious agent. Although it is known that human milk changes in response to developmental changes in infant nutritional needs, the literature reports this more as a species phenomenon than as an individual mother–baby dyad interaction (3–6). One caveat to these studies that Riskin et al. aptly raise is that it is possible that some of the findings in the first milk samples from the mothers of the sick infants (e.g., more CD45 cells and higher tumor necrosis factor-α levels, especially in comparison with those found in the controls) actually reflect a nonspecific stress response of the mothers whose infants were hospitalized. Although this is unlikely given the nature of the response, it cannot be ruled out. Another interesting point is that approximately a third of the mothers reported being ill at the same time as the infant, although it was not specifically stated whether they had symptoms similar to those of their infant. The authors recognized this as a potential confounder and excluded these samples in additional analysis. It is reassuring that their findings of significant decrease of CD45 leukocytes and fraction of macrophages persisted and that trends for other markers persisted. Overall, this study provides support of the dynamic nature of human milk and how the mother’s immune system adjusts to her infant’s infectious status. It is not known, though, how long this interaction continues. As the infant becomes more immunocompetent, does the maternal milk response wane? One also might wonder whether examination of maternal milk would be a useful adjunctive tool for diagnosis of infection in infants. Would skin-to-skin practices trigger antigenspecific antibodies and other defenses in milk that would aid preterm infants in neonatal intensive care units? Clearly, this paper accomplishes more than adding to the body of knowledge; it begs for more study on the mysteriously modulating mothers’ milk.

Eosinophilia in Premature Infants in the Neonatal Intensive Care Unit: A Prospective Study of the Incidence, Significance, and Responsible Mechanism

Eosinophilia in Premature Infants in the Neonatal Intensive Care Unit: A Prospective Study of the Incidence, Significance, and Responsible Mechanism