Abstract
Introduction.
Lactoferrin (LF) is a protective protein present in milk with anti-infective and immune-modulating properties.
Objectives.
To determine the association of maternal-LF intake and motheŕs own milk intake in the first 10 days of life on the prevention of late-onset sepsis (LOS), necrotizing enterocolitis (NEC) or death in the first 8 weeks of life in newborns with a birth weight < 2000g.
Methods.
Retrospective cohort, with the exposure being the consumption of motheŕs own LF and motheŕs own milk in the first 10 days of life and the outcome being LOS, NEC or death during days 11 and 56 of life, analyzed by Cox regression.
Results.
299 infants were enrolled, including 240 with human-LF intake information. The average daily human-LF intake over days 4–10 of life was 283 mg/kg/day (IQR 114–606 mg/kg/day). The hazard ratio (HR) of own motheŕs milk LF intake ≥ 100mg/kg/day in days 4–10 for LOS, NEC or death was 0.297 (95% CI 0.156–0.568, p<0.001); the adjusted HR was 0.752 (95%CI 0.301–1.877, p=0.541). The adjusted HR of motheŕs own milk cumulative intake (days 4–10) of 54–344 ml/kg (25–75quartiles) for LOS, NEC or death was 0.414 (95% CI 0.196–0.873, p=0.02). Infants who developed an event (LOS, NEC or death) had significantly less median daily human-LF intake than those that did not (89 vs. 334 mg/kg/day respectively, p<0.0001).
Conclusion.
Consumption of higher amounts of motheŕs own milk in the first days of life is associated with less infections, NEC and death. Early human milk intake should be strongly encouraged in all newborns.
Keywords: breast milk, lactoferin, sepsis, infection, neonates, preterm
Introduction
Breastmilk provides protection against infections and necrotizing enterocolitis (NEC) and improves neurodevelopment, due to its multiple bioactive components [1–3]. Among these is lactoferrin (LF), a glycoprotein with anti-infective and immune-modulating effects [4–6]. There is currently high interest in studying the effects of bovine-LF supplementation on the prevention of neonatal sepsis and NEC [7–16].
Our research group has recently conducted a randomized trial to evaluate the effect of daily supplementation of bovine-LF on the prevention of neonatal late-onset sepsis (LOS) in <2000 g newborns. The study failed to demonstrate a significant effect on the reduction of sepsis [17]. As part of the trial, we obtained breastmilk samples to measure human-LF concentrations [18]. Previous studies have demonstrated that the consumption of colostrum and maternal breastmilk offers protection against sepsis in very low birth weight (VLBW) infants [19–21]. However, there is a gap in knowledge of the true effects of the consumption of human-LF on the protection against infections and death in premature newborns. The aims of this study were to determine the effect of motheŕs own milk (MOM) lactoferrin (human-LF) intake (aim 1) and MOM intake (aim 2) in the first 10 days of life on the prevention of neonatal LOS, NEC, or neonatal death in the first 8 weeks of life in newborns born with <2000 g and in the subgroup of VLBW infants.
Patients and Methods
This is a secondary analysis of the data from the NEOLACTO trial (NCT01525316) [17]. Briefly, this was a randomized double blind placebo controlled study to evaluate the effect of oral supplementation of bovine-LF in 414 newborns enrolled in the first 3 days of life in Lima. We requested a breastmilk sample in the first 6 days of life (colostrum) and between 7 and 14 days (transitional milk) to measure the concentration of human-LF using a commercial ELISA kit (Assaypro, St.Charles, MO, USA) [18]. Study definitions: culture-proven LOS, clinical signs and symptoms of infection and a positive blood culture obtained after 72h of life; probable sepsis or culture-negative infection, clinical signs and symptoms of infection plus at least two abnormal laboratory results; each LOS episode was classified based on a study algorithm [22]. For NEC we included NEC, Belĺs stage ≥ 2 [1].
To measure the effect of maternal-LF intake on the prevention of sepsis we performed a retrospective cohort study. The exposure was the cumulative consumption of maternal-LF (mg/kg) during days 4–10 of life measured by the daily consumption of MOM (ml/kg) multiplied by the concentration of LF in the colostrum and early transitional milk of each mother, which was taken as a homogenous value for the first 10 days of life. No donor milk was used in these hospitals. The volume of maternal milk was measured directly; mothers manually extracted the milk and the corresponding volume was given to the neonate in a syringe directly to the mouth or via a nasogastric tube. The outcome was the first episode of LOS (culture confirmed or probable sepsis), NEC, or death between day 11 to 56 of life.
Statistical analysis.
We performed a multivariate Cox regression model to estimate the effect of consumption of human-LF (cumulative consumption in mg/kg) in the first 10 days of life on the risk of development of LOS, NEC, or death. The analysis was adjusted by (1) breast milk consumption (cumulative intake in ml/kg during the days of exposure), (2) the percentage of breast milk consumption in relation to the total milk intake (breast milk + infant formula), and (3) human LF intake (cumulative breast milk intake in ml/kg during the days of exposure multiplied by the concentration of LF in colostrum [days 1–6] and early transitional milk [days 7–10]). The time to event was calculated from day 11 of life until discharge, day 56 of life (in the absence of an event), or the occurrence of the event. As we excluded all events prior to the completion of the exposure period, we excluded all infants with an event or discharge prior to day 11. Potentially confounding variables, supplementation of bovine-LF (yes/no), gestational age (weeks), birthweight (grams), gender, hospital (1, 2 or 3) and age of milk sample collection were evaluated and added to the model one by one. In order to visualize the effect we created a Kaplan-Meier survival curve. We analyzed the average daily human-LF intake in two groups based on the quartiles. For aim 2, the analysis was adjusted by the percentage of human milk consumption, and adjusted for the same confounding variables. For the Kaplan-Meier survival curve, we analyzed human milk intake in three groups, based on the quartiles.
Results
Of the 414 newborns enrolled in the trial, we excluded 115 infants because they were discharged or had an event before day 11. The total number of eligible infants for the analysis was 299 (Supplemental Table 1). The mean birth weight of enrolled infants was 1410±308g, with a gestational age of 31±2.7weeks; 61.2% were VLBW, 81.3% were born by C-section and 50.5% were randomized to bovine-LF supplementation. Among the VLBW infants the mean birth weight was 1214±216g and the mean gestational age was 29.8±2.6weeks. Information on MOM LF was available in 324 infants ( 277 colostrum samples and 47 early transitional milk); after exclusions, 240 infants were included in the analysis of human-LF intake (Supplemental Table 1). There have been 41 events during the outcome evaluation period (days 11–56 of life), including a total of 15 culture confirmed sepsis episodes (5 CoNS, 3 E.coli, 2 Klebsiella, 2 Enterococcus, 2 Candida, 1 S. aureus). The mean human-LF concentration in colostrum and transitional milk was 14.4±8.1 mg/ml. The concentrations of human-LF varied over time (Figure 1). For infants <2000g the average daily human-LF intake over days 4–10 of life was 283mg/kg/day, interquartile range (IQR) 114–606mg/kg/day. The intake of more than 100mg/kg/day of human-LF (equivalent to the first quartile approximately) over the exposure period was associated with less episodes of LOS, NEC or death, as observed in the Kaplan Meier survival curves (Figure 2A), with a protective crude hazard ratio (HR). (Table 1). For VLBW infants the median daily human-LF intake over days 4–10 of life was 178mg/kg/day, IQR 74–391mg/kg/day.. The adjusted HRs were not significant (Table 1). For extremely low birth weight infants (ELBW, <1000g) the median daily human-LF intake over days 4–10 of life was 66 mg/kg/day, IQR 20–120 mg/kg/day. The adjusted HRs were not significant. We performed a secondary analysis including only the LF values from days 4–10 (12.7± 7.0 mg/ml), and applied this mean value to all infants (n=299). With this analysis the adjusted HR of MOM LF intake ≥100mg/kg/day for LOS, NEC or death was 0.412 (95% CI 0.191–0.888, p=0.024). For infants <2000g the median cumulative intake of MOM (aim 2) over days 4–10 of life was 154ml/kg (IQR 54–344ml/kg). The percentage of human milk consumption was 77±32%. The intake of more MOM over the exposure period was associated with less episodes of LOS, NEC or death as observed in the Kaplan Meier survival curves by quartiles (Figure 2B). The adjusted HR of MOM cumulative intake (days 4–10) of 54–344 ml/kg (25–75 quartiles) for LOS, NEC and death was 0.414 (95% CI 0.196–0.873, p=0.02) (Table 2). If we include in the outcome only culture confirmed sepsis, the HR was not significant. For VLBW infants the median cumulative intake of MOM over days 4–10 of life was 92ml/kg, IQR38–202 ml/kg. The percentage of human milk consumption was 84±28%, and the adjusted HR of MOM cumulative intake was also protective (p=0.034) (Table 2). When comparing the clinical and nutritional characteristics of the infants who developed an event (LOS, NEC or death) or not, the infants who developed an event had significantly lower gestational age and birth weight and less intake of MOM during the exposure period 42 vs. 176ml/kg (Table 3). The infants that developed an event had less average daily human-LF intake during the exposure period compared to the infants without an event, 89 vs. 334mg/kg/day in infants <2000g (p<0.0001) and 77 vs. 184mg/kg/day in VLBW infants (p=0.003) (Table 3 and Figure 3).
Figure 1.
Concentration of human lactoferrin in the first 10 days of life in 240 mothers of infants <2000g.
Figure 2.
Survival curves for LOS, NEC and death by (A) the amount of motheŕs milk lactoferrin intake over days 4–10 of life. The line represent the average daily lactoferrin intake; blue line < 100 mg/kg/day, red line ≥ 100 mg/kg/day; and (B) the amount of motheŕs own milk intake over days 4–10 of life. The line represent the accumulative milk intake separated by quartiles: blue line <25 quartile (< 54 ml/kg), red line 25–75 quartile (54–344 ml/kg) and green line ≥ 75 quartile (≥ 344 ml/kg).
Table 1.
Effect of own mother’s lactoferrin intake on the prevention of LOS, NEC or death
| Birth Weight group | < 2000 g (N=240)* | < 1500 g (N=141)** | ||||||
|---|---|---|---|---|---|---|---|---|
| Variables | Crude HR (95% CI) | p | Adjusted HR (95% CI) | p | Crude HR (95% CI) | p | Adjusted HR (95% CI) | p |
| Average own motheŕs milk LF intake | ||||||||
| < 100 mg/kg/day | reference | reference | reference | reference | ||||
| ≥ 100 mg/kg/day | 0.297 (0.156 – 0.568) | <0.001 | 0.752 (0.301 – 1.877) | 0.541 | 0.319 (0.156 – 0.650) | 0.002 | 0.582 (0.211 – 1.606) | 0.296 |
| Age of milk sample collection, days | 0.288 (0.148 – 0.561) | <0.001 | 1.045 (0.887 – 1.232) | 0.598 | 0.318 (0.153 – 0.660) | 0.002 | 1.054 (0.889 – 1.249 ) | 0.549 |
| Cumulative own motheŕs milk (ml/kg) | 0.994 (0.991 – 0.998) | 0.001 | 0.998 (0.994 – 1.002) | 0.340 | 0.995 (0.992 – 0.999) | 0.019 | 1.000 (0.996 – 1.005) | 0.930 |
| % human milk | 1.008 (0.993 – 1.022) | 0.316 | 1.012 (0.998 – 1.027) | 0.089 | 1.013 (0.992 – 1.035) | 0.214 | 1.019 (0.999 – 1.039) | 0.070 |
| Gestational age, weeks | 0.798 (0.700 – 0.910) | 0.001 | 0.905 (0.778 – 1.052) | 0.193 | 0.797 (0.680 – 0.933) | 0.005 | 0.899 (0.752 – 1.075) | 0.241 |
| Birth weight, >1000 g | reference | reference | reference | reference | ||||
| Birth weight, ≤ 1000 g | 2.585 (1.256 – 5.319) | 0.010 | 1.036 (0.420 – 2.554) | 0.939 | 2.320 (1.102 – 4.882) | 0.027 | 1.094 (0.442 – 2.709) | 0.847 |
| Female | reference | reference | reference | reference | ||||
| Male | 1.551 (0.779 – 3.092) | 0.211 | 1.979 (0.949 – 4.126) | 0.069 | 1.534 (0.735 −3.202) | 0.255 | 1.745 (0.785 – 3.880) | 0.172 |
| Trial intervention, placebo | reference | reference | reference | reference | ||||
| Trial intervention, bovine-LF | 1.264 (0.655 – 2.436) | 0.485 | 1.442 (0.709 – 2.931) | 0.313 | 1.298 (0.630 – 2.674) | 0.480 | 1.631 (0.745 – 3.574) | 0.221 |
| Hospital 1 | reference | reference | reference | reference | ||||
| Hospital 2 | 0.785 (0.221 – 2.785) | 0.708 | 0.425 (0.113 – 1.598) | 0.205 | 0.702 (0.198 – 2.491) | 0.584 | 0.449 (0.113 – 1.784) | 0.256 |
| Hospital 3 | 8.566 (2.965 – 24.746) | <0.001 | 4.942 (1.526 – 16.001) | 0.008 | 5.853 (1.981 – 17.298) | 0.001 | 4.306 (1.190 – 15.587) | 0.026 |
LOS, late onset sepsis; NEC, necrotizing enterocolitis; LF, lactoferrin
37 events;
31 events
Table 2.
Effect of own mother’s milk intake on the prevention of LOS, NEC or death
| Variables | < 2000 g (N=299)* | < 1500 g (N=183)** | ||||||
|---|---|---|---|---|---|---|---|---|
| Crude HR (95% CI) | p | Adjusted HR (95% CI) | p | Crude HR (95% CI) | p | Adjusted HR (95% CI) | p | |
| Cumulative own motheŕs milk intake | ||||||||
| < 25q (ml/kg) | reference | reference | reference | reference | ||||
| 25 – 75q (ml/kg) | 0.325 (0.172 – 0.612) | 0.001 | 0.414 (0.196 – 0.873) | 0.020 | 0.306 (0.150 – 0.624) | 0.001 | 0.427 (0.194 – 0.939) | 0.034 |
| > 75q (ml/kg) | 0.060 (0.008 – 0.446) | 0.006 | 0.140 (0.017 – 1.184) | 0.071 | 0.268 (0.099 – 0.725) | 0.009 | 0.865 (0.233 – 3.213) | 0.828 |
| % human milk | 1.006 (0.993 – 1.020) | 0.348 | 1.011 (0.998 – 1.025) | 0.088 | 1.011 (0.994 – 1.028) | 0.205 | 1.015 (0.999 – 1.032) | 0.074 |
| Gestational age, weeks | 0.809 (0.715 – 0.916) | 0.001 | 0.965 (0.832 – 1.119) | 0.639 | 0.822 (0.713 – 0.946) | 0.006 | 0.965 (0.819 – 1.136) | 0.666 |
| Birth weight, >1000 g | reference | reference | reference | reference | ||||
| Birth weight, ≤ 1000 g | 2.883 (1.487 – 5.591) | 0.002 | 1.596 (0.756 – 3.372) | 0.220 | 2.559 (1.298 – 5.042) | 0.007 | 1.922 (0.886 – 4.169) | 0.098 |
| Female | reference | reference | reference | reference | ||||
| Male | 1.558 (0.817 – 2.972) | 0.179 | 2.118 (1.077 – 4.166) | 0.030 | 1.42 (0.726 – 2.775) | 0.305 | 1.643 (0.819 – 3.294) | 0.162 |
| Trial intervention, placebo | reference | reference | reference | reference | ||||
| Trial intervention, bovine-LF | 1.424 (0.765 – 2.651) | 0.265 | 1.482 (0.776 – 2.831) | 0.234 | 1.343 (0.692 – 2.607) | 0.383 | 1.485 (0.741 – 2.974) | 0.265 |
| Hospital 1 | reference | reference | reference | reference | ||||
| Hospital 2 | 0.976 (0.327 – 2.912) | 0.965 | 0.509 (0.163 – 1.586) | 0.244 | 0.869 (0.291 – 2.594) | 0.801 | 0.751 (0.225 – 2.510) | 0.641 |
| Hospital 3 | 6.258 (2.400 – 16.317) | <0.001 | 3.548 (1.294 – 9.727) | 0.014 | 4.508 (1.696 – 11.978) | 0.003 | 4.380 (1.343 – 14.290) | 0.014 |
LOS, late onset sepsis; NEC, necrotizing enterocolitis; LF, lactoferrin
41 events
36 events
Table 3.
Clinical and nutritional characteristics in the first 10 days of life in infants with and without LOS, NEC or death
| All infants (< 2000g) | VLBW infants (<1500g) | ELBW infants (<1000g) | ||||
|---|---|---|---|---|---|---|
| LOS, NEC or Death (n= 41) | No - Event (n=258) | LOS, NEC or (n=36) | No - Event (n=147) | LOS, NEC or Death (n=14) | No - Event (n=19) | |
| Clinical characteristics | ||||||
| Gender, female, n (%) | 14 (34.2) | 115 (44.67) | 14 (39.0) | 71 (48.3) | 5 (35.7) | 9 (47.4) |
| Birth weight in g, mean ± SD | 1169 ± 305 | 1448 ± 291 | 1090 ± 228 | 1245 ± 202 | 851 ± 98.0 | 842.7 ± 98.6 |
| Gestational age in weeks, mean ± SD | 29 ± 2.4 | 31 ± 2.6 | 29 ± 2.2 | 30 ± 2.5 | 27.4 ± 2.3 | 27.7 ± 2.5 |
| Small for gestational age, n (%) | 7 (17.1) | 71 (27.5) | 7 (19.4) | 41 (27.9) | 4 (28.6) | 6 (31.6) |
| Born by C-section, n (%) | 33 (80.5) | 210 (82.0) | 28 (77.8) | 120 (81.6) | 8 (57.1) | 11 (57.9) |
| Hospital, n (%) | ||||||
| Hospital 1 | 5 (12.2) | 66 (25.6) | 5 (14.0) | 36 (24.5) | 1 (7.14) | 3 (15.8) |
| Hospital 2 | 9 (22.0) | 132 (51.2) | 9 (25.0) | 80 (54.4) | 7 (50.0) | 12 (63.2) |
| Hospital 3 | 27 (65.9) | 60 (23.3) | 22 (61.1) | 31 (21.1) | 6 (42.9) | 4 (21.1) |
| Randomized to bovine LF, n (%) | 24 (58.5) | 127 (49.2) | 21 (58.3) | 75 (51.0) | 9 (64.3) | 10 (52.7) |
| Nutritional characteristics (days 4–10) | ||||||
| Cumulative intake of MOM in ml/kg, median (IQR) | 42 (11–146) | 176 (69–373) | 39 (10–139) | 106 (51–230) | 30 (12–42) | 44 (19–78) |
| % of human milk consumption, mean ± SD | 87.9 ± 28.5 | 75.3 ± 32.0 | 91.9 ± 24.0 | 82.6 ± 29.1 | 99.1 ± 3.5 | 91.9 ± 25.4 |
| Human LF concentration in mg/mL, mean ± SD | 15.28 ± 7.8* | 14.2 ± 8.2* | 13.9 ± 6.8† | 13.3 ± 7.4† | 15.6 ± 7.3§ | 15.8 ± 10.6§ |
| Cumulative human LF intake in mg/kg, median (IQR) | 621 (116–1971)* | 2335 (1051–4946)* | 542 (111–1694)† | 1285 (714–2936)† | 312 (111–621)§ | 531 (320–1225)§ |
| Average daily human LF intake in mg/kg, median (IQR) | 89 (17–282)* | 334 (150–707)* | 77 (16–242)† | 184 (102– 419)† | 45 (16–89)§ | 76 (46– 175)§ |
LOS, late onset sepsis; NEC, necrotizing enterocolitis; LF, lactoferrin; MOM, motheŕs own milk
n=240 infants (37 events and 203 no- events)
n=141 infants (31 events and 110 no- events)
n=25 infants (11 events and 14 no- events)
Figure 3.
Average daily human lactoferrin intake in mg/kg/day over days 4–10 among infants that developed an event (LOS, NEC or death) or not, after day 10 of life. Figure 3A is for infants <2000g, n=240 (37 cases or events: LOS, NEC or death and 203 controls: no event). Figure 3B is for infants <1500g, n=141 (31 cases or events: LOS, NEC or death and 110 controls: no event)
Discussion
This study demonstrates that the consumption of human milk in the first days of life protects against infections and death in the first 8 weeks of life in infants <2000g and in VLBW infants. Neonates with higher human-LF intake were less likely to have an event than neonates with lower intake. The daily human-LF intake depends on the concentration of LF in milk and the amount of human milk intake. In our study the concentration of LF in milk was around 14 mg/ml (first 10 days of life) and around 13 mg/ml (days 4–10 of life), which is higher than what is considered the average in the literature (6–10mg/mL in colostrum) [23].The amount of human milk intake is critical since there are many other factors present that can account for the protective effect, including antibodies, oligosaccharides, lysozyme, mucins, among others [3].
Trend et al [21] in a small case-control study in newborns <32 weeks found that infants with LOS consumed lower quantities of human-LF, measured on days 7 and 21 of life, in comparison with newborns who did not develop LOS. However, this analysis did not consider the consumption of breastmilk prior to the development of sepsis; they measured consumption in general. Nevertheless, these results are in the same line of our findings: infants that develop sepsis have lower intake of human-LF.
To our knowledge, this is the first study to explore human-LF intake and its relation with LOS, NEC and death. This protection early in life may be related to LF effect on (1) modulation of bacterial growth in the gastrointestinal tract; (2) promotion of intestinal cell proliferation, differentiation and maturation, which may decrease intestinal permeability and prevent bacterial translocation from the gut to the bloodstream; and (3) regulation of the host immune response. These protective effects, as demonstrated in vitro and in animal models using bovine- and human-LF, have been extensively reviewed [5,6] and are much more relevant in the premature infant who is at risk of infection, inflammation and oxidative stress injuries [6].
In this study we demonstrated that human milk intake as a whole protects against infections and death in first 8 weeks of life. Several previous studies have shown similar results. Furman et al [24] demonstrated that a daily threshold of at least 50 ml/kg of maternal milk through week 4 of life was needed to decrease the rates of LOS in VLBW infants. In a prospective cohort study in 175 VLBW infants Patel et al [20] demonstrated that the intake of at least 25ml/kg/day over the first 28 days of life was significantly associated with a decrease in sepsis. However, both studies, as recognized in their limitations, have not calculated the human milk intake before the onset of sepsis, or excluded the infants with sepsis episodes during a certain time of human milk exposure, to avoid the potential effect of reverse causality. A well designed study by Corpeleijn et al [19] demonstrated that the consumption of colostrum in the first 5 days of life and higher percentages (>50%) of MOM intake over days 6–10 of life protected against sepsis, NEC, and/or death in the first 60 days of life in VLBW infants. The relevance of this study and ours is that both demonstrated that the consumption of MOM early in life has a protective effect against infection and death for a prolonged period, up to two months of life. Our study adds the information on LF intake. Several research studies have suggested that the early postnatal period (first 14 days of life) is a critical period for feeding human milk to decrease the risk of sepsis and other morbidities, including NEC [1, 25] and even rehospitalizations over the first year of life [26].
In our study we found that VLBW infants who did not develop an event had a daily human-LF intake of around 200 mg/kg in the first 10 days of life. This information is relevant to extrapolate the ideal dosing of bovine-LF supplementation in the current clinical trials, which is not clearly defined. The ELFIN [15] study in the UK used a dose of 150mg/kg of bovine-LF, with no significant protective effect against LOS, suggesting that probably a higher dose is needed in top of the amount that neonates are already receiving from motheŕs own milk. A recent study by Manzoni et al [27] evaluated the effect of bovine-LF supplementation from two previous clinical trials and compared the effect among infants receiving only formula and mixed feeds. This study suggested that bovine-LF supplementation may have a benefit among infants who did not receive MOM, and that probably there is no advantage of giving more LF to infants who are already receiving good quantities of MOM.
This study has some limitations. First, we have not measured LF concentrations in milk daily; only one measurement per mother was used as a homogeneous value for the daily calculations of LF intake. Since LF concentrations are high in colostrum and then decrease over time (Figure 1), we have probably overestimated the amount of LF intake in some infants and underestimated in others. To control for this, we have included in the analysis the date of milk sample collection. Second, we used a non-randomized design for the exposure of interest (high dose of human-LF intake); therefore, the observed associations may have arisen because group differences in variables not measured or not correctly measured. It is possible, for example, that sicker infants –even without LOS/NEC, may have received less MOM in the first 10 days, and will also had a higher subsequent risk of LOS/NEC/death. We have not adjusted by a measure of illness severity in the first 10 days of life. Despite these limitations, our study has several strengths and important implications. The main strengths are the number of infants enrolled in the study and the exclusion from the analysis of all infants with an event during the exposure period. For clinicians, the main implication is that the finding that feeding higher amounts of human LF is associated with less infections and death, highlights the importance of promoting MOM intake in the early postnatal period, especially for infants at risk in the neonatal units. For researchers, the protective doses of human-LF intake reported in this study may aid in calculating the best dose for future clinical trial of bovine-LF supplementation or other related research.
Supplementary Material
Acknowledgement
We would like to thank all members of the NEOLACTO Research Group that conducted the initial clinical trial. We thank the pediatricians, study research nurses, and neonatal nurses from each hospital for their dedication and careful work in this project.
Funding Sources
This study was funded by the National Institute of Child Health & Human Development (NICHD), Grant number: R01-HD067694
Statement of Ethics
The study was approved by the institutional ethical committee of Universidad Peruana Cayetano Heredia. We used data without personal identifiers, only codes.
Footnotes
Statements
Disclosure Statement
The authors have no potential conflicts of interest to declare.
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