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Randomized Controlled Trial of Lactoferrin for Prevention of Sepsis in Peruvian Neonates Less than 2500 g

Ochoa, Theresa J. MD*†‡; Zegarra, Jaime MD†§; Cam, Luis MD; Llanos, Raul MD; Pezo, Alonso MD*; Cruz, Karen MD*; Zea-Vera, Alonso MD*; Cárcamo, Cesar MD, PhD**; Campos, Miguel MD, PhD††; Bellomo, Sicilia MD†§ for the NEOLACTO Research Group

Author Information
The Pediatric Infectious Disease Journal: June 2015 - Volume 34 - Issue 6 - p 571-576
doi: 10.1097/INF.0000000000000593


Four million neonates die each year, mostly in low-income countries1. The 3 major causes of neonatal death are asphyxia, infection and complications of preterm birth, which account for 86% of deaths1. Globally almost one million newborns die because of infections (neonatal sepsis, pneumonia and meningitis)1. In developing countries, infection may be responsible for as many as 42% of deaths in the first week of life2. Up to 80% of newborn deaths are among low-birth weight (BW) babies, most of whom are preterm1.

Multiple strategies have been designed to reduce infant mortality. Among these, breast-feeding is the most cost–effective intervention for protection from infection and prevention of all causes of infant mortality3. Breast milk has a beneficial effect in term and preterm infants including improved cognitive and behavior skills, and decreased rates of infection4–7. The protective effects of human milk are thought to be because of multiple anti-infective, anti-inflammatory and immunoregulatory factors 8,9. We hypothesize that lactoferrin (LF) is the major milk factor responsible for decreased rates of infection because of its antimicrobial and immunomodulatory properties10. Recently, 472 very low-birth weight infants (VLBW; BW less than 1500 g) were randomly assigned to receive orally administered bovine LF, LF plus the probiotic Lactobacillus rhamnosus (LGG) (LF + LGG) or placebo for 30 days11. The incidence of sepsis was significantly lower in the LF and LF + LGG groups compared with the placebo group (5.9% and 4.6% versus 17.3%). Whether LF has an effect in higher risk populations in developing countries remains to be determined. Therefore, we conducted a hospital (HOS)-based randomized placebo-controlled double blind study in 190 infants less than or equal to 2500 g in Neonatal Units in Peru to determine whether bovine LF prevents the first episode of late-onset sepsis in neonatal setting from a low-income country.


Study Design

We conducted a randomized double blind placebo-controlled clinical trial in neonates, comparing daily supplementation with bovine LF versus placebo administered for 4 weeks.

Study Population

We included neonates with a BW between 500 and 2500 g born in or referred in the first 72 hours of life to the Neonatal Intermediate and Intensive Care Units of one of the participating HOSs: Hospital Nacional Cayetano Heredia (Cayetano), Hospital Nacional Guillermo Almenara Irigoyen (Almenara) and Hospital Nacional Alberto Sabogal Sologuren (Sabogal). We excluded neonates with underlying gastrointestinal problems that prevent oral intake, predisposing conditions that profoundly affect growth and development (chromosomal abnormalities, structural brain anomalies, etc.), family history of cow milk allergy, neonates that lived far from Lima, and neonates whose parents declined to participate. Consecutive patients who qualified for the study were approached by the attending neonatologist who explained the study and obtained written informed consent from both parents before the 72-hour cut-off.


Patients were assigned a consecutive study number in the order they were enrolled. The numbers were previously randomly assigned to the intervention with fixed, equal allocation to each group, stratified by weight (500–1000 g, 1001–1500 g, 1501–2000 g and 2001–2500 g), and randomized with block size of 4. This randomization list was prepared by a third party (not the clinical investigators) and was known only by the research pharmacist who prepared the weekly treatment packages based on neonates’ weight. Randomization occurred immediately after recruitment of each patient.


Neonates received oral bovine LF (Tatua Co-operative Dairy Co, Ltd., Morrinsville, New Zealand; 200mg/kg/d in 3 divided doses each day) or placebo (maltodextrin, Montana S.A., Lima, Peru; 200mg/kg/d in 3 divided doses each day) for 4 weeks since the day of enrollment. The intervention product was composed of 97.1% bioactive protein of which 94.5% was LF, without additives. The iron saturation was 12%. Capsules containing LF or placebo were opened and mixed with whatever the neonates were taking orally or by tube at that time (breast milk, infant formula or dextrose); the intervention was given as soon as the patient started receiving any amount of oral or tube feedings. After discharge from the HOS, a research nurse visited the family weekly until the end of the first month of life. All children had a clinic visit at 1 and 3 months of chronological age.


The physicians and study personnel were blinded to the treatment assignment throughout the study period. The data manager, statistician and all investigators remained blinded to the group assignment until the end of the data analysis.

Study Definitions

For this study, we determined the effect of LF on clinically defined sepsis. We included both culture-proven sepsis and culture-negative clinical infection (probable or possible sepsis). Late-onset proven sepsis was defined by a positive blood culture and/or cerebrospinal fluid culture obtained after 72 hours of life in the presence of clinical signs and symptoms of infection12. Culture-negative clinical infection or “probable sepsis” was defined by the presence of clinical signs and symptoms of infection (temperature instability, heart rate greater than 2 SD above normal for age, respiratory rate greater than 60 breaths/min plus grunting or desaturations, lethargy/altered mental status, glucose intolerance defined as plasma glucose greater than 10mmol/L, feed intolerance, blood pressure less than 2 SD normal for age, capillary refill greater than 3 seconds, plasma lactate greater than 3 mmol/L) and at least 2 abnormal inflammatory variables12: leukocytosis (WBC count greater than 34,000 × 109/L), leukopenia (WBC count less than 5000 × 109/L), immature neutrophils greater than 10%, immature-to-total neutrophil ratio (I/T) greater than 0.2, thrombocytopenia less than 100,000 × 109/L, and C-reactive protein greater than 10 mg/L or greater than 2 SD above normal. We have not measured procalcitonin, IL-6 or IL-8 or 16S polymerase chain reaction, which are other variables evaluated in Haque’s criteria. “Possible sepsis” was defined by the presence of clinical signs and symptoms of infection and raised C-reactive protein with negative blood culture. An independent diagnostic board reviewed all sepsis episodes.


The primary outcome was risk of first episode of late-onset clinically defined sepsis (culture-proven sepsis and culture-negative clinical infection) within 4 weeks (28 days) from enrollment. Secondary outcomes were frequency of culture-proven sepsis, pathogen-specific late-onset sepsis, necrotizing enterocolitis (NEC), duration of hospitalization, overall mortality rate, infection-related mortality, frequency of adverse events and treatment intolerance.

Sample Size

The reduction in sepsis episodes with LF supplementation was 66% in the Italian study11. Based on data from local neonatal units, we expected 30% of sepsis episodes in the placebo group during the 4-week follow-up. Assuming 5% drop outs, 95 children were needed in each group to detect a 60% reduction in the number of sepsis episodes (α 0.05; power 0.80). We, therefore, planned to recruit 190 neonates.

Data Management and Analysis

Data were collected and then double entered into databases using EpiInfo v3.4.5. Data entry formats had predefined ranges for acceptable values. Consistency checks were performed in STATA v8.0. Statistical analysis was performed in STATA and R v3.0.2. P values from the Student’s t test and Fisher’s exact test are presented for the univariate analysis comparing baseline demographic characteristics, risk factors, medical and surgical complications, and weight during follow-up. Unadjusted relative risks as cumulative incidence ratios with their corresponding confidence intervals and P values were used to compare sepsis outcomes. BW-adjusted relative risks were calculated using generalized linear models. Cox proportional hazards regression model was applied for survival analysis. The primary outcome variable was the occurrence of the first episode of confirmed, possible or probable late-onset-sepsis, and time was counted as days from birth to that first episode or last day of follow-up, whichever happened first. The initial terms included were treatment group (TX), BW (in grams), HOS, peripartum maternal infection (dichotomous), age at start of follow-up and the following interaction terms: TX:BW, TX:HOS, TX:BW:HOS and BW:HOS. The model selection proceeded in 4 steps: initial set of terms, nonsignificant interaction terms removed, nonsignificant terms (except LF) removed and the final model with removal of remaining nonsignificant terms.

Data Safety Monitoring Board

The data safety monitoring board (DSMB), composed of an independent group of experts (neonatologists, pediatrician, epidemiologist, microbiologist), met every other month to review data for safety and study compliance. Any child experiencing a severe adverse event was referred to the DSMB for study continuation assessment.

Ethical and Regulatory Aspects

The study ( NCT01264536) was approved by the Institutional Review Board of Universidad Peruana Cayetano Heredia, University of Texas Health Science Center and by each of the three participating HOSs. The study was also approved by the Peruvian Regulatory Institutions (INS and DIGEMID).


During the enrollment (January 31 to August 6, 2011), 375 infants were assessed for eligibility, 185 were excluded (Fig. 1). We enrolled 190 neonates; 80 (42.1%) had a BW less than 1500 g. The gestational age was 32.1 ± 2.6 weeks (26–38 weeks) and mean BW was 1591 ± 408 g. There were no significant baseline differences between groups in demographic and clinical characteristics or risk factors for late-onset sepsis (Table 1), except for peripartum maternal infections, which were more frequent in the placebo group, and more days of third and fourth-generation cephalosporin use in the placebo group. During the in-HOS follow-up period nutritional characteristics were similar in both groups: approximately, half of all the days infants were fed only breast milk and approximately one third of days they were fed both infant formula and breast milk (Table 1). Additional information on the comparison between groups is presented in the Table, Supplemental Digital Content 1,

Comparison Between Lactoferrin and Placebo Groups
Study flow diagram. Enrollment: 375 neonates were assessed for eligibility. Allocation: 95 were randomized to LF and 95 to placebo; all received the allocated intervention. Follow-up: there were 7 and 3 drop-outs in the LF and placebo groups, respectively. None were excluded from the analysis.

The intervention was administered completely per protocol in 82% of 3244 child-days of observation. It was started on average at 4.0 ± 1.4 days of life. Some neonates started the treatment a few days after enrollment because the treating neonatologist considered them too sick to tolerate any amount of oral or tube feeding. The diluents used in the 7796 doses administered were breast milk in 67%, infant formula in 32% and dextrose in 1%. Ten patients (5.3%) were withdrawn from the study due to patients return to a distant province or transfer to a different HOS (n = 6), or parental request (n = 4).

Overall, there were 37 clinically defined late-onset sepsis episodes during the 4 weeks after enrollment, 33 of them were first episodes, including 8 culture-proven (24.2%), 14 probable (42.4%) and 11 possible (33.3%), based on study definitions. Six of the 33 episodes occurred before starting the treatment intervention. The overall sepsis rate was 17.4% (33/190), and 28.8% (23/80) among infants with a BW less than 1500 g.

Sepsis occurred less frequently in the LF group than in the control group. In the intention-to-treat analysis, the cumulative sepsis incidence in the LF group was 12/95 (12.6%) versus 21/95 (22.1%) in the placebo group (Table 2). For the VLBW neonates (less than 1500 g), the sepsis rates in the LF group was 8/40 (20.0%) versus 15/40 (37.5%) in the placebo group, a 46% reduction in sepsis. The crude risk ratio (RR) between groups was 0.57 (95% CI: 0.30–1.09). The RR adjusted for BW category was 0.57 (95% CI: 0.30–1.07) using generalized linear models. Upon reviewing baseline and simple outcome tables, covariates were selected to be included in the adjusted analysis using Cox regression. The only significant term found in the Cox model was BW; the 95% confidence limits of the hazard ratio was 0.997–0.999, P < 0.001. No statistically significant effect of LF upon hazard rate of first sepsis episode was detected. The hazard ratio of LF, after adjustment by BW, was 0.507 and the 95% confidence limits was between 0.249 and 1.034 (P = 0.062). A nonadjusted Kaplan–Meier plot illustrates constraints of the confidence limits (Fig. 2). Of interest, after day 10 of intervention, there was one sepsis episodes in the LF group versus 6 in the placebo (Fig. 2).

Sepsis Outcomes
Kaplan–Meier survival estimates: time to event of late-onset sepsis by treatment group. Gray line lactoferrin; black line placebo; light gray shadow lactoferrin 95% confidence interval; dark gray shadow placebo 95% confidence intervals. LOS indicates late-onset sepsis.

There were 4 episodes of culture-proven sepsis in the LF group (Serratia sp., Enterobacter aerogenes, Klebsiella sp. and coagulase-negative Staphylococcus), versus 4 in the placebo group (Pseudomonas sp., Group B Streptococcus, Enterococcus faecalis and coagulase-negative Staphylococcus). All pathogens were isolated from blood cultures, none from CSF. There were no significant differences with respect to other secondary outcomes.

Considering that children did not receive treatment until the start of oral or tube feeding (which was later for VLBW), we ran a secondary exploratory model using time since the start of the treatment. In this model, LF achieved significance (P = 0.03); the 95% confidence limits for the hazard ratio of LF, after adjustment by BW, is between 0.0003 and 0.665.

There are no known risks related to LF intake13,14. Over 300 preterm newborns had taken bovine LF in a previous study with no LF-related side effects11. However, because there was the remote possibility of an allergic reaction to cow milk proteins, we closely monitored for possible signs (allergic rhinitis, diarrhea, vomiting and eczema). There were no signs of allergy or treatment intolerance in 99.7% of observed days; there were only 3 episodes of vomiting during the intervention period. The overall medical and surgical complications/conditions during follow-up were similar between groups, as well as growth measurements at 1 and 3 months of age (Table, Supplemental Digital Content 2, Fourteen patients (7.4%) were rehospitalized during the first 3 months of life, primarily for bronchiolitis (n = 7), probable sepsis (n = 3), pneumonia (n = 2), anemia (n = 1) and complication of an inguinal hernia (n = 1). There were 11 deaths, 2 after the first month of life. The overall case-fatality rate was 5.8% (11/190); 38.9% (7/18) in the 500–1000 g BW group. The DSMB had 7 meetings to assess the safety of the intervention. None of the severe adverse events (14 rehospitalizations and 11 deaths) were attributable to the intervention; all events were evaluated by the DSMB.


We were not able to demonstrate a statistically significant effect of LF on the rate of first late-onset sepsis episodes in infants with a BW less than 2500 g. However, the confidence limits for the hazard ratio of LF are suggestive of an effect that may be confirmed with a larger sample size. Although nonsignificant, there were less sepsis episodes in infants receiving LF, especially for VLBW neonates (46% reduction in sepsis). However, the study was not powered to detect significant difference in specific BW groups. Because many sepsis episodes occurred in the first week of life (Fig. 2), and many of the infants had not received the intervention (LF or placebo) until the beginning of oral feeds, we have explored as a secondary analysis the effect of LF on sepsis using in the model time since the start of the treatment. Although in this model LF achieved significance, we do not consider it conclusive, because it was not the primary outcome in our trial design.

Our results are in concordance with Manzoni´s study11 and consistent with the potential for bovine LF to decrease infections in premature infants. The Italian study found a 66% reduction on sepsis episodes using LF in VLBW infants (RR 0.34, 95% CI: 0.17–0.70). However, there are some differences in study design that could explain some findings. First, we included infants with a BW up to 2500 g; they included only infants less than 1500g. Second, we used a standardized dose by weight (200 mg/kg/d); they used a fixed dose of 100 mg/d for all infants. Third, we included as our main study outcome, not only culture-proven sepsis but also clinical-defined sepsis (probable and possible). This study addressed some of the most important limitations in the Manzoni trial and presented important differences specific to resource-limited settings. Also, the LF we used was different from that used in Manzoni’s trial, the variation in the additives and purity of the LF could affect the results. In a follow-up study, Mazoni found a significant reduction in the incidence of NEC in VLBW neonates with LF supplementation15. In our study, we were not able to evaluate the effect on NEC because of the small sample size.

Despite its preliminary nature and small sample size, our study included larger BW group infants to investigate the effect of LF on this population. The overall neonatal mortality rate is low for late preterm infants; however, infections among these infants increase the risk of complications, prolong HOS stay and increase mortality16. In developing countries, many neonatal deaths occur in non-low-BW infants2. Thus, we enrolled neonates up to 2500 g. We included high-risk babies, typical of those admitted in most HOSs in Latin America. However, neonates with a BW greater than 1500 g have less risk of sepsis, and obviously impacted the overall sepsis rates in the study.

In the Italian study, as noted both by the authors themselves and subsequent editorial critiques17, the dose may have been inadequate for larger infants; no adjustments were made for BW. The protective effect of LF was clear for infants weighing less than 1000 g, who received the higher dose per kilo. We standardize the dose by weight (200 mg/kg/d), based on the dose effective in the smallest infants (500 g) in Manzoni´s study. Other ongoing LF trials, like the ELFIN study in the United Kingdom (Enteral LactoFerrin In Neonates; and the LIFT study in Australia (Lactoferrin Infant Feeding Trial; are also using a LF dose by weight (150 mg/kg/d).

This study has some limitations. First, the small sample size and power, because of the small number of high-risk VLBW infants. Second, the inclusion of culture-negative clinically defined sepsis is not as precise as culture-proven infections as an outcome measurement. However, in developing countries, rates of clinically diagnosed neonatal sepsis are as high as 170/1000 live births, whereas culture-confirmed sepsis are approximately 5.5/1000 live births because of the limited laboratory capabilities2. Therefore, investigating the effect of LF on these clinically defined sepsis episodes is of paramount importance in low- and middle-income countries. For this trial, we standardized sepsis definitions, using strict clinical and laboratory criteria, and evaluated each episode with an independent team of physicians. Third, we were not able to completely blind the study intervention. Both, LF and maltodextrin, were placed in capsules, which were then opened and diluted in breast milk or infant formula. However, the dilution of LF in milk still had a mild pink color. Thus, the nurses administering the intervention were not blinded; however, the physicians and the investigators that evaluated sepsis episodes as well as the statisticians remained blinded to treatment assignment throughout the study period. Fourth, in our study, the treatment began when oral or tube feeding started. This is critically important and could explain the lack of significance. It is known from in vitro studies that LF (both bovine and human) is extremely active on the nascent enterocytes; it promotes cell proliferation in the first days of life18,19. This is why many authors speculate that the anti-infectious role of LF relies strongly on its ability to interact with the immature enterocytes in the very first hours or days of life20. Nevertheless, despite these limitations, we suspect that the fundamental observation (LF decreases sepsis in neonates) is correct because it is consistent with experimental literature that has demonstrated LF’s protective effect against infections.

LF protects against pathogens in multiple ways: it sequesters iron essential for bacterial growth; binds to lipopolysaccharide on the cell surface of Gram-negative bacteria, disrupting the bacterial cell membrane; it has antilipoteichoic acid (against Gram-positive organisms) and antiCandida cell wall activities; LF peptide fragments have in vitro bactericidal properties10. LF impairs the ability of pathogens to adhere/invade mammalian cells, by binding to, or degrading, specific virulence proteins21. In addition to the direct antimicrobial effect, LF protects against infection because of its immunomodulatory properties22,23. This wide range of LF beneficial properties is related to its functional structure24.

In summary, this study shows feasibility of improving preterm infant health in developing countries by providing “added protection” with ingestion of a major milk protein. Within its preliminary nature, it has allowed more confident predictions of safety, cost, sepsis incidence in the target population, sample size power and feasibility for extending it in resource-limited settings. Currently, we are conducting a larger trial on 414 neonates with a BW less than 2000 g. In addition to confirming the suggested results of this preliminary study on sepsis prevention, we will follow infants up to 24 months of age to determine the effect of LF on growth and neurodevelopment (NICHD, R01-HD067694).

Given the high incidence and high morbidity and mortality of sepsis in preterm infants, efforts to reduce the rates of infection are among the most important interventions in neonatal care25. The use of LF as a broad-spectrum nonpathogen-specific antimicrobial protective protein is an innovative approach that needs to be confirmed by multiple trials. If further studies confirm LF’s protective role, they will profoundly affect clinical care of neonates both in developed and developing countries, serving as a cost–effective strategy to decrease infections and its long-term consequences on growth and development.


NEOLACTO Research Group: In addition to the bylined authors the research group also includes: Ana Lino MD (NICU, Hospital Nacional Alberto Sabogal Sologuren), Augusto Cama MD (NICU, Hospital Nacional Alberto Sabogal Sologuren), Anne Castañeda MD (NICU, Hospital Nacional Guillermo Almenara Irigoyen), Oscar Chumbes MD (NICU, Hospital Nacional Guillermo Almenara Irigoyen), Maria Luz Rospigliosi MD (NICU, Hospital Nacional Cayetano Heredia), Geraldine Borda MD (NICU, Hospital Nacional Cayetano Heredia), Margarita Llontop MD (NICU, Hospital Nacional Cayetano Heredia), and Thomas G. Cleary MD (Center for Infectious Diseases, University of Texas School of Public Health). We would like to thank all members of the participating Neonatal Units for their support and collaboration in the study. We also thank the study Research Nurses Cristina Suarez, Rocio Lucas and Lourdes Tucto; and the Neonatal Unit nurses Ivone Jara, Amelia Bautista, Ana Ulloa, Brígida Mejía, Iris Jara, Marlene Caffo, Rosa Atencio, Tania Quintana, Dina Irazabal, Amalia Escalante, Elizabeth Rojas, Iris Huamaní, Luisa Osorio, María Marres, Martha Torres, Rosa Quijano, Virginia Loo, Nelly Valverde, Clarisa Diaz, Giovana García and Nancy Cabrera for their dedication and careful work in this project. We also thank the members of the DSMB for their independent and critical review of the data and safety of the study.


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bovine; preterm; newborn; infant; late-onset sepsis

Supplemental Digital Content

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