Oropharyngeal ColostrumAdministration in ExtremelyPremature Infants: An RCTJuyoung Lee, MDa, Han-Suk Kim, MD, PhDa, Young Hwa Jung, MDa, Ka Young Choi, MDb,Seung Han Shin, MDa, Ee-Kyung Kim, MD, PhDa, Jung-Hwan Choi, MD, PhDa

abstractOBJECTIVE: To determine the immunologic effects of oropharyngeal colostrum administration inextremely premature infants.

METHODS: We conducted a double-blind, randomized, placebo-controlled trial involving48 preterm infants born before 28 weeks’ gestation. Subjects received 0.2 mL of their mother’scolostrum or sterile water via oropharyngeal route every 3 hours for 3 days beginning at48 to 96 hours of life. To measure concentrations of secretory immunoglobulin A, lactoferrin,and several immune substances, urine and saliva were obtained during the first 24 hours oflife and at 8 and 15 days. Clinical data during hospitalization were collected.

RESULTS: Urinary levels of secretory immunoglobulin A at 1 week (71.4 vs 26.5 ng/g creatinine,P = .04) and 2 weeks (233.8 vs 48.3 ng/g creatinine, P = .006), and lactoferrin at 1 week(3.5 vs 0.9 mg/g creatinine, P = .01) were significantly higher in colostrum group. Urineinterleukin-1b level was significantly lower in colostrum group at 2 weeks (55.3 vs 91.8 mg/gcreatinine, P = .01). Salivary transforming growth factor-b1 (39.2 vs 69.7 mg/mL, P = .03) andinterleukin-8 (1.2 vs 4.9 ng/mL, P = .04) were significantly lower at 2 weeks in colostrumgroup. A significant reduction in the incidence of clinical sepsis was noted in colostrum group(50% vs 92%, P = .003).

CONCLUSIONS: This study suggests that oropharyngeal administration of colostrum may decreaseclinical sepsis, inhibit secretion of pro-inflammatory cytokines, and increase levels ofcirculating immune-protective factors in extremely premature infants. Larger studies toconfirm these findings are warranted.

WHAT’S KNOWN ON THIS SUBJECT: Immune-related bioactive proteins are highlyconcentrated in the colostrum of mothers whodeliver preterm infants. Oropharyngealadministration was proposed as a safe andfeasible alternative method of providingcolostrum to immunocompromised prematureinfants.

WHAT THIS STUDY ADDS: Oropharyngeallyadministered colostrum during the first few daysof life increased urinary secretoryimmunoglobulin A and lactoferrin, decreasedurinary interleukin-1b, reduced salivarytransforming growth factor-b1 and interleukin-8,and reduced the occurrence of clinical sepsis inextremely premature infants.

aDepartment of Pediatrics, Seoul National University College of Medicine, Seoul, Korea; and bDepartment ofPediatrics, Dongtan Sacred Heart Hospital, Hallym University Medical Center, Hwaseong, Korea

Dr Lee conceptualized and designed the study, carried out the initial analyses, and drafted the initialmanuscript; Dr Kim conceptualized and designed the study and reviewed and revised themanuscript; Drs Jung, Choi, and Shin collected data and reviewed and revised the manuscript;Drs Kim and Choi coordinated and supervised data collection and critically reviewed themanuscript; and all authors approved the final manuscript as submitted.

This trial has been registered at www.clinicaltrials.gov (identifier NCT01536093).

www.pediatrics.org/cgi/doi/10.1542/peds.2014-2004

DOI: 10.1542/peds.2014-2004

Accepted for publication Nov 24, 2014

Address correspondence to Han-Suk Kim, MD, PhD, Department of Pediatrics, Seoul NationalUniversity College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 110-799, Korea. E-mail: kimhans@snu.ac.kr

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2015 by the American Academy of Pediatrics

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During the first few days after birth,open tight junctions of the mammaryepithelium allow for paracellulartransport of many bioactive immunesubstances from the mother’scirculation into the colostrum.1 Thissmall volume of breast milk containsincreased concentrations of secretoryimmunoglobulin A (sIgA), growthfactors, lactoferrin, anti-inflammatorycytokines, pro-inflammatorycytokines, and other protectivecomponents, compared with maturebreast milk.2–5 Several studiesindicate that immunoprotectivefactors are more highly concentratedin the colostrum of mothers whodeliver preterm infants than thosewho give birth at term.6–8 Similarly,studies suggest that closure of thetight junctions in the mammaryepithelium might be delayed afterpreterm compared with termbirth.9,10 However, many preterminfants cannot tolerate enteralfeedings because of clinical instabilityand therefore do not receive maternalcolostrum, possibly resulting inincreased susceptibility to variousinfections and inflammatoryconditions.

Recently oropharyngealadministration of colostrum(so-called oral immune therapy) hasbeen advocated for preterm infants.11

Oropharyngeal administration doesnot involve the infant’s swallowing ofmilk. During this intervention, a smallamount of colostrum is placeddirectly onto the oropharyngealmucosa in the buccal cavity forabsorption.12 In theory, the abundantimmune factors in colostrum interactwith lymphoid tissues in theoropharynx and stimulate theimmature neonatal immune systemwhen administered via theoropharyngeal route.11,13 Althoughtheoretical and preclinical support forthis practice exists, there isinsufficient evidence thatoropharyngeal administration ofcolostrum is beneficial to date.13–16

We aimed to evaluate the

immunologic effects of oropharyngealcolostrum administration inextremely premature infants.

METHODS

Study Design

A randomized, double-blind, placebo-controlled, intervention trial wasconducted from January 2012 toDecember 2013 in the NICU of SeoulNational University Children’sHospital in Seoul, Korea. The localinstitutional review board approvedthe protocol. The entirety of thisstudy was conducted in accordancewith the current revisions of theDeclaration of Helsinki and GoodClinical Practice guidelines.

Participants

Neonates born before 28 weeks’gestation were enrolled. Infants withcongenital gastrointestinal or renalanomalies or a maternal history ofsubstance abuse or HIV infectionwere excluded. After informedparental consent was obtained,regardless of twin or higher-ordermultiples, each neonate wasrandomly assigned independently tothe colostrum or placebo group ina 1:1 ratio on the randomization Website of Medical Research CollaboratingCenter of Seoul National UniversityHospital. Randomization wasconducted using a computer-generated allocation sequence (blocksizes of 8). Allocation was concealedfrom all investigators, nurses, doctors,and parents, with the exception of1 independent research staff member,who prepared the colostrum andplacebo syringes. The feeding statusof each patient was decided by theattending physicians under theprinciple that trophic feeding shouldbe started as soon as possible if nocontraindication was found(eg, bilious gastric remain, fixeddilated bowel loop on radiograph,severe hemodynamic instability).Both groups of neonates were fedbreast milk or preterm formula,whichever was prepared first. The

probiotic Duolac Baby (Cell Biotech,Seoul, Korea) was added according tothe local practice protocol when theamount of each feeding was .2 mL.

Intervention

Investigators who qualified asinternational board-certified lactationconsultants met the mothers of eachenrolled neonate within 24 hoursof delivery and educated themabout hand-expression and electricpumping of breast milk every 2 to3 hours. Mothers were givenprelabeled sterile milk collectionbags and instructed to collect theircolostrum by using a sanitaryhand-expression method and thento send the colostrum to the NICUimmediately for refrigeration.

Tuberculin syringes were used toadminister colostrum or placebo viathe oropharyngeal route. Oneunblinded investigator prepared48 syringes with 0.1 mL of mother’scolostrum or sterile distilled waterusing aseptic techniques. Thesesyringes were then labeled andwrapped with opaque covers tomaintain blinding. The syringes wereplaced in prelabeled plastic cups andstored at 4°C in a specified milkrefrigerator.

Beginning at 48 to 96 hours afterbirth, each neonate received 0.2 mL ofhis or her mother’s colostrum orsterile water every 3 hours for 72consecutive hours, regardless ofwhether the infant was being fedenterally. At each session, 2 prefilledsyringes with 0.1 mL of colostrum orsterile water were warmed in theinfant’s incubator for 5 minutes. Onesyringe was placed on the patient’sright or left buccal mucosa, and thecolostrum or placebo drops wereadministered toward the posteriororopharynx for at least 10 seconds(Fig 1 and Supplemental Video). Thesame process was repeated on theopposite site, as described ina previous study.14 Heart rate (HR),respiratory rate (RR), blood pressure,and pulse oxygen saturation (SpO2)

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were recorded immediately beforeand after every intervention session.Colostrum or sterile water was notadministered during surgery undergeneral anesthesia. A session wasdiscontinued if any of the followingissues developed: requirement of anincrease in fraction of inspiratoryoxygen.0.1 to maintain a SpO2 .85%,bradycardia (HR ,100/minute) ortachycardia (HR .200/minute), andtachypnea (RR .80/minute).

Assessments and Monitoring

To evaluate the salivary production ofbioactive proteins after activation oforopharyngeal mucosa-associatedlymphoid tissue (MALT) and theurinary excretion of bioactiveproteins after systemic circulation, wemeasured the concentrations ofimmunologic factors in saliva andurine. We also looked at the incidenceof late-onset sepsis and otherinflammatory medical comorbiditiesof prematurity, such as necrotizingenterocolitis (NEC),bronchopulmonary dysplasia,ventilator-associated pneumonia(VAP), retinopathy of prematurity,intraventricular hemorrhage, clinicalor proven sepsis, time to reach fullfeeding (100 mL/kg/day),hospitalization duration, andmortality. We defined VAP as clinicalsigns of pneumonia combined withpneumonic infiltration on $2 serialchest radiographs in patientsreceiving mechanical ventilation for.48 hours. Clinical signs of

pneumonia included worsening gasexchange, increased oxygenrequirements, increased ventilatordemand, and $1 clinical symptoms(new onset of purulent sputum,temperature instability, leukopenia/leukocytosis with left shift, apnea/tachypnea, or bradycardia/tachycardia). Clinical sepsis wasdefined as clinical signs of infectionaccompanied by concurrent antibiotictreatment of.3 days. Clinical signs ofinfection included all 3 of thefollowing categories and at least 1 signin each of the 3 categories: generalsigns (fever, apnea/tachypnea,respiratory distress, positive fluidbalance), laboratory results(leukopenia/leukocytosis, increasedC-reactive protein), and hemodynamicalterations (hypotension, tachycardia,altered skin perfusion, decreasedurine output, increased base deficit).17

Proven sepsis was defined as bacterialgrowth in at least 1 blood culture andfulfillment of clinical sepsis.

Vital signs were monitoredthroughout the study, and anyoccurrence of adverse events wasrecorded. Clinical data from eachpatient’s hospitalization werecollected at discharge from the NICU.

An independent data and safety-monitoring board supervised theinvestigation and reviewed the datafrom the first 3 patients and aftercompletion of the study. The boardhad access to all data, and none oftheir analyses resulted in

modifications or termination of thisstudy.

Specimen Collection and Assays

To measure the concentrations ofimmunologic factors, urine and salivawere collected during the first 24hours and at 8 and 15 days of life.Urine was obtained by using a sterileattachable urine bag for neonates.Unstimulated whole saliva wascollected in a sterile container usingweak suction. All specimens werecentrifuged, aliquoted, and stored at–70°C until biochemical analysis.

The concentrations of sIgA,lactoferrin, transforming growthfactor (TGF)-b1, and interleukin(IL)-10 from the urine and salivaspecimens were measured usingenzyme-linked immunosorbent assaykits (sIgA: USCN Life Science, Wuhan,China; lactoferrin: EMD Millipore,Billerica, MA; TGF-b1 and IL-10: R&DSystems, Minneapolis, MN) accordingto the manufacturer’s protocols.Epidermal growth factor (EGF),tumor necrosis factor–a, interferon-g,IL-1b, IL-2, IL-4, IL-6, and IL-8 weremeasured using luminex fluorescentbead human cytokine immunoassays(MILLIPLEX MAP, Millipore).

Sample Size Calculation andStatistical Analysis

On the basis of results froma previous study,18 we assumeda mean difference in urinary sIgA of29.75 µg/mL between the 2 groups,and the SDs were 41.55 µg/mL forthe colostrum group and 9.75 µg/mLfor the placebo group. Given anasymptotic relative efficacy on the80% power and a 5% significancelevel with the independent t test, therequired sample size for the Mann-Whitney U test was calculated as 21infants for each group. Therefore,assuming a 10% dropout rate, weestimated that 48 subjects wereneeded.

Analysis of the clinical data wasperformed on an intention-to-treatbasis, and the biochemical data ofspecimens from subjects who

FIGURE 1A still image at 00:05 from the sample video demonstrating oropharyngeal administration ofcolostrum (corresponding Supplemental Video).

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completed the protocol wereanalyzed. Statistical analyses wereperformed by using SPSS version 21.0(SPSS, Chicago, IL). Mann-Whitney Utests or Fisher’s exact tests andregression analyses were used forgroup comparisons.

RESULTS

Of 75 extremely premature infantsborn ,28 weeks’ gestation fromJanuary 2012 to December 2013, 48were included and randomly assignedto the placebo or colostrum group(Fig 2). Two of 24 infants wereexcluded from the placebo groupbecause of death before studyinitiation, and 1 infant waswithdrawn from the study due toparental wishes. Three infants wereexcluded from the colostrum group: 2due to the absence of colostrum until96 hours after birth, and 1 due todeath before study initiation. Forty-two of 48 infants completed theprotocol. The median number ofreceived doses was 24 (interquartilerange [IQR]: 23–24) in both groups.Fifteen and sixteen infants receivedall 24 doses for the placebo andcolostrum group, respectively. Themedian gestational age of thepopulation was 26+5 weeks (range:23+1–27+6 weeks), and the medianbirth weight was 815 g (range:400–1450 g).

Table 1 shows no differences in thebaseline characteristics of the studypopulation or in the number thatreceived formula before starting theprotocol, during 3 days ofintervention, and during a 2-weekperiod after birth. Approximately halfof the enrolled infants were nil per os(NPO) before the study, and 18(37.5%) infants did not start enteralfeeding during the first week of life.

Figure 3 demonstrates urine levels ofimmune substances based oncreatinine concentrations. Theurinary sIgA level at 1 week wassignificantly increased in thecolostrum group (71.4 vs 26.5 ng/gcreatinine, P = .04), and remained

elevated at 2 weeks (233.8 vs 48.3ng/g creatinine, P = .006). Urinarylactoferrin level was also significantly

increased at 1 week in the colostrumgroup (3.5 vs 0.9 mg/g creatinine, P =.01). Among the interleukins, urinary

FIGURE 2Study profile. aExcluded from the placebo group because of death before intervention (n = 2).bExcluded from the colostrum group because of the absence of maternal colostrum (n = 2) or death beforeintervention (n = 1). cOne infant discontinued the study based on the parents’ withdrawal of consent.

TABLE 1 Patient Demographics and Baseline Characteristics

Placebo Group (N = 24) Colostrum Group (N = 24)

Gestational age, wk 26+5 (24+3–27+1) 26+5 (24+2–27+4)Birth wt, g 815 (610–1003) 830 (701–993)Male/female ratio 10:14 (42:58) 12:12 (50:50)Apgar score at 1 min 3 (2–5) 3 (2–5)Apgar score at 5 min 7 (5–7) 6 (5–7)Multiple gestation 16 (67) 22 (92)Vaginal delivery 11 (46) 11 (46)Antenatal steroid use 20 (83) 21 (88)Histologic chorioamnionitisa 14 (58) 8 (33)Surfactant use 20 (83) 17 (71)Feeding before the protocol 12 (50) 11 (46)Feeding during the protocol 15 (63) 15 (63)Breast milk 5 4Preterm formula 9 8Mixed 1 3None 9 9

Feeding for 2 wk after birth 20 (83) 20 (83)Breast milk 5 6Preterm formula 11 11Mixed 4 3None 4 4

Mechanical ventilation at randomization 18 (75) 14 (58)$1 transfusion during 2 wk after birth 18 (75) 17 (71)Prostaglandin inhibitor use 11 (46) 11 (46)Postnatal steroid use 8 (33) 12 (50)H2 blocker use 7 (29) 8 (33)Probiotic use 18 (75) 19 (79)

Values are median (IQR) or number (%).a Presence of acute inflammatory changes on fetal membranes (subchorion, chorion, amnion, or umbilicus).

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FIGURE 3Urinary levels of immune substances based on creatinine concentrations on days 1, 8, and 15, from 42 infants who completed the protocol. Each errorbar represents 1 SE. Mann-Whitney U tests were used for group comparisons, * P , .05 versus placebo group.

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IL-1b level was significantly reducedat 2 weeks in the colostrum group(55.3 vs 91.8 mg/g creatinine, P =.01). Regarding the immunesubstances in saliva (Fig 4), theconcentrations of sIgA (5.4 vs 2.1µg/mL, P = .02) and EGF (464.3vs 258.4 pg/mL, P = .04) weresignificantly increased at 1 weekin the colostrum group but weredecreased to levels similar to thatof the placebo group at 2 weeks.Salivary TGF-b1 (39.2 vs 69.7 mg/mL,P = .03) and IL-8 (1.2 vs 4.9 ng/mL,P = .04) were significantly reduced inthe colostrum group at 2 weekscompared with the placebo group.

The colostrum group had less clinicalsepsis (50% vs 92%, P = .003) andshorter total antibiotic duration (6[IQR: 3.8–8.5] vs 9.5 [IQR: 7–19] days,P = .014), but no difference in culture-proven sepsis (46% vs 58%, P = .56)(Table 2). The significant effect ofcolostrum administration on clinicalsepsis was also validated ina regression analysis with all possibleconfounders, including mechanicalventilation, H2 blocker use, probioticuse, postnatal steroid use, feedingstatus and types (exp[B] = 67.3, 95%confidence interval: 3.8–1186.9, P =.004). No differences in NEC,bronchopulmonary dysplasia, VAP,grade $3 intraventricularhemorrhage, retinopathy ofprematurity that required lasersurgery, time to reach full enteralfeeding, hospitalization duration, ormortality were noted. Blood pressure,HR, RR, and SpO2 remained stableduring each administration session.No episodes of agitation, aspirationevents, bradycardia or tachycardia,hypotension, or other acute adverseevents were noted in any of theinfants during the interventions.

DISCUSSION

To the best of our knowledge, this isthe first double-blind, randomized,placebo-controlled trial to provideimmunologic and clinical evidenceregarding the advantages of

oropharyngeal colostrumadministration in extremelypremature infants. A prospectivestudy of 15 extremely low birthweight infants demonstrated thatthe time to reach full enteral feedingwas reduced,15 and 1 retrospectivestudy reported that oropharyngealadministration of colostrum resultedin starting feeding earlier andreaching birth weight sooner.16

However, no published data haveillustrated the clinical advantages oforopharyngeal colostrumadministration in relation to theimmune system.

Colostrum contains higherconcentrations of immunoprotectiveagents compared with mature humanmilk,5 and these agents are believedto compensate for the delayedimmune system development ofpremature infants by conductingimmunomodulatory reactions atmucosal and systemic sites.12 Despitethe theoretical advantages, providingmaternal colostrum to extremelypremature infants in the earlypostnatal period presents a variety ofchallenges. During this time, enteralfeedings are frequently disturbed byimmature gastrointestinal functionand comorbidities that compromisesplanchnic perfusion, such as patentductus arteriosus, umbilicalcatheterization, or hypotension.19

The oropharyngeal mucosal routewas recently proposed as a solutionfor providing maternal colostrum tothe sickest infants during the earlypostnatal period.11–14,16 Rodriguezet al12 described the expectedmechanisms through which cytokinesand other immunologic factors incolostrum stimulate the immatureneonatal immune system vialymphoid tissues in the oropharynxand gut, resulting in the developmentof a protective mucosal immunebarrier.

We observed that urinary excretion ofsIgA and lactoferrin was significantlyincreased by oropharyngealcolostrum administration in

extremely premature infants (Fig 3).This result could be interpretedmainly as excretion after theirpassage through the systemiccirculation after being absorbed bythe oral or gastrointestinal mucosa.The half-lives of sIgA and lactoferrinare 3 to 6 days, and their uptake frombreast milk via neonatal gut mucosawith subsequent excretion of theirintact maternal forms in the urinewere well demonstrated in previousstudies.7,20–22 This exceptionalmucosal absorption might beexpected to occur only in preterminfants, particularly before “gutclosure,” and our findings supportthis hypothesis.23,24 On the otherhand, in addition to mucosalabsorption, the result of continuedincrease of urinary sIgA at 2 weeks ofage might be reflective thatoropharyngeal stimulation bycolostrum enhances endogenousproduction and/or excretion of sIgA.

Interestingly, the urinary excretion ofIL-1b was significantly decreased byoropharyngeal administration ofcolostrum (Fig 3). Cytokines haveshort half-lives of several hours andare known to be involved in mucosalimmunity mainly by binding tocellular receptors.2 Because thepassive uptake of cytokines bymucosal barriers during the neonatalperiod has not been elucidated,urinary levels of cytokines mightreflect endogenous production byimmune systems. Contrary toevidence suggesting that theproduction of several cytokines byneonatal T cells are either slightly(tumor necrosis factor-a)25 ormarkedly reduced (IL-4, IL-6, IL-8,IL-10, and interferon-g),26–29 IL-1bis known to be overproduced inpreterm neonates and to be involvedin excessive intestinal and systemicinflammation.30 It has been notedthat IL-1b initiates inflammatorycascades and enhances the expressionof a powerful chemokine, IL-8, inimmature intestinal cells.30–32 Inthis regard, our data suggest thehypothesis that oropharyngeal

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FIGURE 4Salivary levels of immune substances on days 1, 8, and 15 from 42 infants who completed the protocol. Each error bar represents 1 SE. Mann-WhitneyU tests were used for group comparisons, * P , .05 versus placebo group.

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colostrum administrationdownregulates production and/orexcretion of IL-1b, which in turndecreases the production of IL-8.

Significantly decreased salivary levelsof TGF-b1 and IL-8 in the colostrumgroup could be interpreted ina similar manner (Fig 4). TGF-b1 isthe predominant isoform of TGF-bproduced by immune cells within themucosal lamina propria, and thesalivary secretion of TGF-b1 is knownto play a key role in active inordinatemucosal inflammation.33–35 IL-8, animportant chemotactic factor forneutrophils, is a known initiator ofexcessive intestinal inflammatoryresponses in preterm NECmodels.2,30,31,36 Evidence suggeststhat human milk factors suppress theinduction of IL-8 expression incultured mucosal epithelial cells; thissuppression is more pronounced inimmature cells.37

Abrupt increases in salivary sIgA andEGF concentrations in the colostrumgroup at 1 week were potentiallyinfluenced by orally administeredcolostrum (Fig 4). Because theprotocol had been performed for 3days, from the second to fourthpostnatal day, a large amount of sIgAand EGF included in colostrum couldremain in the oral cavity and might besubsequently collected with saliva at1 week.

Our results demonstrate a significantreduction in the incidence of clinicalbut not proven sepsis in thecolostrum group (Table 2). Becausewe confined proven sepsis tobacterial growth in any blood culture,viral infection or other systemicinflammatory responses precludeda diagnosis of proven sepsis.However, the results of severalstudies support that abundantimmunomodulatory molecules incolostrum seem to have the capacity

to decrease infection caused bybacteria, viruses, and possibly fungiwithout the use of inflammatorymechanisms.32,36,38,39 If the mainimmunologic effect of colostrum is tosuppress mucosal and systemicinflammatory responses, thesignificant reduction of clinical sepsisby colostrum might reflect itscapacity to downregulate immature,excessively exaggerated inflammatoryresponses to a variety of stimuli innewborns. In this sense,oropharyngeal administration ofcolostrum might be beneficial inpreventing NEC or VAP. However, thenumber of infants in our study wastoo small to draw any conclusionabout decreased risk of NEC or VAP.

Our trial had several otherlimitations. There was a highincidence of clinical and provensepsis. The incidence of NEC was alsorelatively high, despite probiotic use.Furthermore, breastfeeding ratesduring postnatal 2 weeks were as lowas ∼35%; however, there was nodifference in the pattern of feeding orother factors that could affect theimmune response, includingchorioamnionitis, transfusion, andthe use of postnatal steroids, H2blockers, and probiotics, between the2 groups.

Although this small study cannotdraw a conclusive statement aboutthe clinical benefit of colostrum, itprovides evidence suggesting thatoropharyngeal administration ofcolostrum during the first few days oflife can potentially enhance immunefunction in the sickest prematureinfants. Additionally, our findingssuggest the possible usefulness ofcolostrum as an oropharyngealimmune-boosting agent to preventsepsis and excessive mucosalinflammation in the pretermpopulation. Larger-scale studies areneeded to prove these effects.

ACKNOWLEDGMENTS

We thank Kyeung Yeup Lee andJiyeon Lee for their involvement withthe specimen assay. We also thank themembers of the Medical ResearchCollaborating Center at the SeoulNational University Hospital for theirstatistical assistance and advice. Thecontributions of all nurses andmedical staff members of the SeoulNational University Children’sHospital NICU, especially You JungLim and Hye Jung Jin, who providedvaluable professional assistance inconducting this clinical trial, aregratefully acknowledged.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

FUNDING: Supported by a grant from the Department of Pediatrics, Seoul National University College of Medicine (2012-01).

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

TABLE 2 Clinical Outcomes at the Time of Discharge

Placebo Group (N = 24) Colostrum Group (N = 24) Pa

NEC, Bell stage $2 6 (25) 4 (17) .72Bronchopulmonary dysplasiab 14 (58) 15 (63) .58Ventilator-associated pneumonia 8 (33) 3 (12.5) .17Proven sepsis 14 (58) 11 (46) .56Clinical sepsis 22 (92) 12 (50) .003Total antibiotic days 9.5 (7–19) 6 (3.8–8.5) .014Intraventricular hemorrhage, grade $3 3 (12.5) 4 (16.7) .34Laser surgery for ROP 7 (29) 11 (46) .26Postnatal days to reach full feeding 17 (14.3–25.8) 20 (13–27) .86Hospital stay, d 81.5 (56.5–99) 89 (69.3–109.8) .44Death 6 (25) 3 (12.5) .46

Values are median (IQR) or number (%). ROP, retinopathy of prematurity.a Fisher’s exact test or Mann-Whitney U test was used for analysis.b Defined as requiring supplemental oxygen at 36 wk.

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DOI: 10.1542/peds.2014-2004; originally published online January 26, 2015; 2015;135;e357Pediatrics

Ee-Kyung Kim and Jung-Hwan ChoiJuyoung Lee, Han-Suk Kim, Young Hwa Jung, Ka Young Choi, Seung Han Shin,

RCTOropharyngeal Colostrum Administration in Extremely Premature Infants: An

  

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RCTOropharyngeal Colostrum Administration in Extremely Premature Infants: An

  

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