Probiotic supplementation and risk of necrotizing enterocolitis and mortality among extremely preterm infants-the Probiotics in Extreme Prematurity in Scandinavia (PEPS) trial: study protocol for a multicenter, double-blinded, placebo-controlled, and registry-based randomized controlled trial.

BACKGROUND: Extremely preterm infants, defined as those born before 28 weeks' gestational age, are a very vulnerable patient group at high risk for adverse outcomes, such as necrotizing enterocolitis and death. Necrotizing enterocolitis is an inflammatory gastrointestinal disease with high incidence in this cohort and has severe implications on morbidity and mortality. Previous randomized controlled trials have shown reduced incidence of necrotizing enterocolitis among older preterm infants following probiotic supplementation. However, these trials were underpowered for extremely preterm infants, rendering evidence for probiotic supplementation in this population insufficient to date. METHODS: The Probiotics in Extreme Prematurity in Scandinavia (PEPS) trial is a multicenter, double-blinded, placebo-controlled and registry-based randomized controlled trial conducted among extremely preterm infants (n = 1620) born at six tertiary neonatal units in Sweden and four units in Denmark. Enrolled infants will be allocated to receive either probiotic supplementation with ProPrems® (Bifidobacterium infantis, Bifidobacterium lactis, and Streptococcus thermophilus) diluted in 3 mL breastmilk or placebo (0.5 g maltodextrin powder) diluted in 3 mL breastmilk per day until gestational week 34. The primary composite outcome is incidence of necrotizing enterocolitis and/or mortality. Secondary outcomes include incidence of late-onset sepsis, length of hospitalization, use of antibiotics, feeding tolerance, growth, and body composition at age of full-term and 3 months corrected age after hospital discharge. DISCUSSION: Current recommendations for probiotic supplementation in Sweden and Denmark do not include extremely preterm infants due to lack of evidence in this population. However, this young subgroup is notably the most at risk for experiencing adverse outcomes. This trial aims to investigate the effects of probiotic supplementation on necrotizing enterocolitis, death, and other relevant outcomes to provide sufficiently powered, high-quality evidence to inform probiotic supplementation guidelines in this population. The results could have implications for clinical practice both in Sweden and Denmark and worldwide. TRIAL REGISTRATION: ( Clinicaltrials.gov ): NCT05604846.

Assessment of food supplements for the prevention of necrotizing enterocolitis in preterm neonates: A systematic review and network meta-analysis.

BACKGROUND: The network meta-analysis (NMA) investigated the efficacy of six food supplements, namely glutamine, arginine, lactoferrin, prebiotics, synbiotics, and probiotics, in preventing necrotizing enterocolitis in premature infants. METHODS: MEDLINE, Embase, and Cochrane Library were searched. Randomized controlled trials comparing different food supplements for premature infants were included. RESULTS: Probiotics (OR, 0.47; 95% CrI, 0.33-0.63), arginine (OR, 0.38; 95% CrI, 0.14-0.98), glutamine (OR, 0.30; 95% CrI, 0.079-0.90), and synbiotics (OR, 0.13; 95% CrI, 0.037-0.37). were associated with a decreased incidence of NEC. Only probiotics (OR, 0.81; 95% CrI, 0.69-0.95) and lactoferrin (OR, 0.74; 95% CrI, 0.54-0.92) achieved lower risk of sepsis. Probiotics (OR, 0.58; 95% CrI, 0.40-0.79), prebiotics (OR, 0.23; 95% CrI, 0.043-0.86), and synbiotics (OR, 0.15; 95% CrI, 0.035-0.50) were associated with lower odds of mortality. Probiotics (MD, -2.3; 95% CrI: -3.7- -0.63) appeared to have earlier age of attainment of full feeding. CONCLUSIONS: Based on this NMA, probiotics and synbiotics had the potential to be the top two preferable food supplements.

Phototherapy: a new risk factor for necrotizing enterocolitis in very low birth weight preterm infants? a retrospective case-control study.

OBJECTIVE: To investigate the association between phototherapy (PT) and the development of necrotizing enterocolitis (NEC) in very low birth weight (VLBW) infants. STUDY DESIGN: A retrospective case-control study was conducted on VLBW infants with or without NEC (stage IIA or greater) born at ≤35 weeks' gestation in a tertiary hospital over 7 years. Sample size calculation, trend test, as well as univariate and multiple logistic regression analyses were employed. RESULTS: A total of 824 VLBW infants were reviewed, with 74 cases and 122 controls finally enrolled. The odds of NEC increased with the duration and number of PT sessions. Exposure to >120 h and >4 instances of PT were significantly associated with NEC in multivariate analysis. CONCLUSION: This is the first study suggesting a potential association between PT and development of NEC in VLBW infants. This association needs further exploration.

The effect of oropharyngeal colostrum administration on the clinical outcomes of premature infants: A meta-analysis.

BACKGROUND: Preterm complications are now the second leading cause of death in children under five years of age. Colostrum is essential to prevent infection and promote maturation in preterm infants. Guidelines recommend that preterm infants be fed colostrum by the oral and pharyngeal routes as early as possible after birth to provide immune protection; however, due to disease and an uncoordinated sucking and swallowing function, it is challenging to provide colostrum through the oropharyngeal route, which limits the immune protection it provides. OBJECTIVE: To update the existing meta-analysis, evaluate the effect of oropharyngeal colostrum administration on related outcomes in preterm infants and explore the optimal frequency and duration of oropharyngeal colostrum administration through subgroup analysis. METHODS: The Cochrane Library, PubMed, Web of Science, ScienceDirect, and Ovid databases were searched for randomized control trials (RCTs) of oropharyngeal colostrum administration for preterm infants. Two researchers screened the literature strictly according to the inclusion and exclusion criteria and evaluated the quality. Primary data and data from the included literature were extracted. Finally, the data were statistically analyzed by the Review Manager 5.3 software. RESULTS: A total of 1736 preterm infants were included in 16 RCTs. The meta-analysis showed that the incidence of necrotizing enterocolitis, late-onset sepsis, feeding intolerance, and death was lower, the time to full enteral feeding was shorter, and the day of recovery to birth weight was earlier in the intervention group (oropharyngeal colostrum administration group) than in the control group, and this difference was statistically significant. Subgroup analysis: Frequency of oropharyngeal colostrum administration: The incidence of necrotizing enterocolitis and late-onset sepsis in the once every 4 h group was lower than that in the control group, and the time to complete enteral feeding was shorter. Duration of oropharyngeal colostrum administration: In the 1-3 days group and 4-7 days group, the time to full enteral feeding in the intervention group was shorter. In the 8-10 days group, the incidence of necrotizing enterocolitis and late-onset sepsis was lower in the intervention group. CONCLUSIONS: Oropharyngeal colostrum administration can reduce the incidence of necrotizing enterocolitis, late-onset sepsis, feeding intolerance and mortality, shorten the time to full enteral feeding, and lead to a faster recovery to birth weight in preterm infants. The appropriate oropharyngeal colostrum administration frequency may be 4 h, and the optimal duration may be 8-10 days. Therefore, it is recommended that clinical medical staff implement oropharyngeal colostrum administration for premature infants based on existing evidence. TWEETABLE ABSTRACT: Oropharyngeal colostrum administration can reduce the incidence of complications in preterm infants and shorten the time to full enteral feeding.

The efficacy of glycerin suppositories for preterm infants: A meta-analysis of randomized controlled studies.

BACKGROUND: The effect of glycerin suppositories on full enteral feeds remained controversial in preterm infants, and thus we conducted this meta-analysis to identify the influence of glycerin suppositories on full enteral feeds in preterm infants. METHODS: The protocol was registered in PROSPERO (CRD20214283090). We searched PubMed, EMbase, Web of science, EBSCO and Cochrane library databases through February 2020, and included randomized controlled trials assessing the effect of glycerin suppositories on full enteral feeds in preterm infants. This meta-analysis was performed using the random-effect model. RESULTS: Six Randomized controlled trials were included in the meta-analysis. Overall, compared with control group in preterm infants, glycerin suppositories demonstrated no significant effect on days to full enteral feeds (mean difference = -0.26; 95% confidence interval [CI] = -1.16 to 0.65; P = .58), the incidence of necrotizing enterocolitis (odd ratio = 3.62; 95% CI = 0.56-23.32; P = .18) or death (odd ratio = 1.46; 95% CI = 0.40-5.40; P = .57), but may increase the days under phototherapy (mean difference = 0.50; 95% CI = 0.43-0.57; P < .00001). Only low heterogeneity was seen among all outcomes. CONCLUSIONS: Glycerin suppositories may provide no additional benefits to preterm infants.

Bovine colostrum as a fortifier to human milk in very preterm infants - A randomized controlled trial (FortiColos).

BACKGROUND: Human milk for very preterm infants need fortification for optimal growth and development but the optimal fortification product remains to be identified. AIMS: To investigate feasibility, safety and preliminary efficacy on growth and blood biochemistry when using intact bovine colostrum (BC) as a fortifier to human milk in very preterm infants. METHODS: In an open-label, multicenter, randomized controlled pilot trial (infants 26-31 weeks' gestation), mother's own milk or donor human milk was fortified with powdered BC (n = 115) or a conventional fortifier (CF, bovine-milk-based, n = 117) until 35 weeks' postmenstrual age. Fortifiers and additional micronutrients were added to human milk according to local guidelines to achieve optimal growth (additional protein up to +1.4 g protein/100 mL human milk). Anthropometry was recorded weekly. Clinical morbidities including necrotizing enterocolitis (NEC) and late-onset sepsis (LOS) were recorded. Clinical biochemistry included plasma amino acid (AA) levels to assess protein metabolic responses to the new fortifier. RESULTS: A total of 232 infants, gestational age (GA) 28.5 ± 1.4 (weeks + days), fulfilled inclusion criteria. Birthweight, GA and delta Z scores from birth to end of intervention on weight, length or head circumference did not differ between groups, nor between the subgroups of small for gestational age infants. Likewise, incidence of NEC (BC: 3/115 vs. CF: 5/117, p = 0.72, unadjusted values), LOS (BC: 23/113 vs. CF: 14/116, p = 0.08) and other morbidities did not differ. BC infants received more protein than CF infants (+10%, p < 0.05) and showed several elevated AA levels (+10-40%, p < 0.05). CONCLUSION: Infants fortified with BC showed similar growth but received more protein and showed a moderate increase in plasma AA-levels, compared with CF. Adjustments in protein composition and micronutrients in BC-based fortifiers may be required to fully suit the needs for very preterm infants.

Oropharyngeal application of colostrum or mother's own milk in preterm infants: a systematic review and meta-analysis.

CONTEXT: Many preterm neonates often cannot be fed enterally and hence do not receive the benefits of colostrum. Oropharyngeal application of colostrum is a novel way of harnessing the immunological benefits of colostrum. Randomized controlled trials (RCTs) investigating the efficacy of this approach have shown variable results. OBJECTIVE: The aim of this systematic review was to synthesize available data on the effect of oropharyngeal application of colostrum or mother's own milk (CMOM) in preterm infants. DATA SOURCES: Six electronic databases (MEDLINE, Embase, CINAHL, Scopus, Web of Science, and Cochrane Library) were searched until January 13, 2022. Only RCTs comparing oral application of CMOM with placebo/routine care in preterm infants were eligible. Studies enrolling term neonates or administering enteral feeds were excluded. DATA EXTRACTION: Two investigators independently extracted data using a structured proforma. DATA ANALYSIS: The Cochrane Risk of Bias 2 tool was used to assess bias. Random-effects meta-analysis was undertaken using RevMan 5.4 software. From 2787 records identified, 17 RCTs enrolling 4106 preterm infants were included. There was no significant difference between groups in incidence of necrotizing enterocolitis (NEC) stage 2 or higher (RR = 0.65; 95%CI, 0.36-1.20; 1089 participants in 12 trials). Application of CMOM significantly reduced the incidence of sepsis (RR = 0.72; 95%CI, 0.56-0.92; 1511 participants in 15 studies) and any stage of NEC (RR = 0.58; 95%CI, 0.37-0.92; 1616 participants in 16 trials). The CMOM group achieved full enteral feeds 1.75 days sooner (95%CI, 0.3-3.2 days; 1580 participants in 14 studies) and had higher weight at discharge (MD = 43.9 g; 95%CI, 3-85 g; 569 participants in 3 studies). There were no statistically significant differences in other outcomes. CONCLUSIONS: Evidence with low to very low certainty suggests CMOM has a beneficial effect on NEC (any stage), sepsis, and time to full enteral feeds. Given its low cost and minimal risk of harm, routine CMOM use may be considered in preterm neonates. PROSPERO REGISTRATION NUMBER: CRD42021262763.

Oral Application of Colostrum and Mother's Own Milk in Preterm Infants-A Randomized, Controlled Trial.

OBJECTIVES: To evaluate the effects of oral application of mother's own milk (OMOM) on clinical outcomes in preterm infants of 260/7-306/7 wk gestation. METHODS: In this placebo-controlled randomized trial, subjects received either OMOM or sterile water, beginning at 24-72 h of life, until the infant reached 32 wk postmenstrual age or spoon-feeds were initiated, whichever was earlier. The primary outcome was a composite adverse health outcome, defined as the occurrence of either mortality, late-onset sepsis (LOS), necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH), bronchopulmonary dysplasia (BPD), or retinopathy of prematurity (ROP). Antibiotic usage and time to full enteral feed were secondary outcomes. Salivary IgA (sIgA) levels at baseline and after 7 d of application in a subset of infants were also compared. RESULTS: A total of 133 neonates (66 colostrum and 67 placebo) were analyzed for the primary outcome. OMOM group had lower incidence of composite adverse health outcome (43.9% vs. 61.2%, RR: 0.70; 95% CI: 0.50-0.99, p = 0.046) and LOS (22.7% vs. 43.3%, RR: 0.73; 95% CI: 0.57-0.93; p = 0.012). There were no significant differences in mortality, NEC, IVH, BPD, ROP, and time to full feeds. The effects were more pronounced in the 290/7-306/7 wk subgroup, in whom the colostrum group also achieved full feeds earlier. There were no differences in the change of sIgA levels from baseline to the seventh day of the application. No adverse effects related to the OMOM application were found. CONCLUSIONS: OMOM decreases the incidence of late-onset sepsis in preterm neonates (260/7-306/7 wk) and is safe. TRIAL REGISTRATION: Clinical Trials Registry-India CTRI/2017/03/008031.

The impact of donor breast milk on metabolic bone disease, postnatal growth, and neurodevelopmental outcomes at 18 months' corrected age.

BACKGROUND: Preterm infants are at risk for metabolic bone disease (MBD). Analysis of donor breast milk (DBM) shows lower levels of macronutrients compared with mother's own milk (MOM). The purpose of this study was to investigate the prevalence of MBD, rate of postnatal growth, and long-term neurodevelopmental outcomes in infants fed predominantly MOM vs DBM. METHODS: Retrospective observational study of infants born <1500g and <32 weeks at New York University Langone Health or Bellevue Hospital from January 2014 to January 2018. Infants were divided into two groups: those who received >70% of feeds with either MOM or DBM by 34 weeks' corrected age (CA). MBD was assessed using alkaline phosphatase (AlkPO4) levels and radiographic findings. Data was also collected on growth, feeding tolerance, and long-term neurodevelopmental outcomes. RESULTS: A total of 210 infants were included (MOM =156 and DBM =54). The DBM group had higher AlkPO4 levels for the first 3 weeks of life (P < .01). Growth was similar between the groups, and both groups demonstrated catch-up growth after discharge. No difference was seen in feeding intolerance, incidence of necrotizing enterocolitis, or sepsis. The DBM group had lower cognitive (odds ratio [OR], 0.93 [0.88-0.98]; P < .01) and language (OR, 0.95 [0.90-0.99]; P < .01) scores at 18 months' CA. CONCLUSION: Infants fed predominantly DBM had elevated AlkPO4 levels suggestive of MBD but did not develop osteopenia. Despite appropriate growth and comparable short-term outcomes, infants fed DBM had lower cognitive and language scores at 18 months' CA.

Oropharyngeal administration of colostrum for preventing necrotizing enterocolitis and late-onset sepsis in preterm infants with gestational age ≤ 32 weeks: a pilot single-center randomized controlled trial.

BACKGROUND: Oropharyngeal administration of colostrum (OAC) may provide immunoprotective and anti-inflammatory effects that potentially reduce the incidence of necrotizing enterocolitis (NEC) and late-onset sepsis and improve short-term outcomes. Our objective was to evaluate the role of OAC in the early prevention of NEC and late-onset sepsis in preterm infants with gestational age (GA) ≤ 32 weeks. METHODS: A pilot, single-center, 1:1 parallel randomized controlled trial was conducted in a 40-bed tertiary neonatal intensive care unit (NICU) in China from 1 January 2019 to 30 September 2020. Preterm infants were randomly divided into two groups with GA ≤ 32 weeks. The OAC group included preterm infants who received 0.4 ml of maternal colostrum via the oropharyngeal route every 3 h for 10 days beginning within the first 48 h after birth, and the control group included preterm infants who received normal saline instead. Data from the two groups were collected and compared. RESULTS: A total of 127 infants in the OAC group and 125 infants in the control group were enrolled. The incidence of NEC (Bell stage 2 or 3) and late-onset sepsis were lower in the OAC group [2.36% vs. 10.40%, relative risk (RR) 0.23 (95% confidence interval (CI) 0.07, 0.78), adjusted RR 0.23 (95% CI 0.06, 0.84); 4.72% vs. 13.60%, RR 0.35 (95% CI 0.14, 0.85), adjusted RR 0.36 (95% CI 0.14, 0.95)]. In addition, the incidence of proven sepsis and intraventricular hemorrhage (IVH) (stage 3 or 4) were lower in the OAC group [2.36% vs. 8.80%, RR 0.27 (95% CI 0.08, 0.94); 1.57% vs. 7.20%, RR 0.22 (95% CI 0.05, 0.99)], and the time to achieve full enteral feeding was shorter (23.13 ± 9.45 days vs. 28.50 ± 14.80 days). No adverse reactions were observed in either group. CONCLUSIONS: Oropharyngeal administration of colostrum is a safe and simple NICU procedure that may yield a potential effect in decreasing the incidences of NEC, late-onset sepsis, and severe IVH and shorten the time to achieve full enteral feeding in preterm infants with GA ≤ 32 weeks. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR1900023697 , Registered 8 June 2019, retrospectively registered.

Nutritional management in newborn babies receiving therapeutic hypothermia: two retrospective observational studies using propensity score matching.

BACKGROUND: Therapeutic hypothermia is standard of care for babies with moderate to severe hypoxic-ischaemic encephalopathy. There is limited evidence to inform provision of nutrition during hypothermia. OBJECTIVES: To assess the association during therapeutic hypothermia between (1) enteral feeding and outcomes, such as necrotising enterocolitis and (2) parenteral nutrition and outcomes, such as late-onset bloodstream infection. DESIGN: A retrospective cohort study using data held in the National Neonatal Research Database and applying propensity score methodology to form matched groups for analysis. SETTING: NHS neonatal units in England, Wales and Scotland. PARTICIPANTS: Babies born at ≥ 36 gestational weeks between 1 January 2010 and 31 December 2017 who received therapeutic hypothermia for 72 hours or who died during treatment. INTERVENTIONS: Enteral feeding analysis - babies who were enterally fed during therapeutic hypothermia (intervention) compared with babies who received no enteral feeds during therapeutic hypothermia (control). Parenteral nutrition analysis - babies who received parenteral nutrition during therapeutic hypothermia (intervention) compared with babies who received no parenteral nutrition during therapeutic hypothermia (control). OUTCOME MEASURES: Primary outcomes were severe and pragmatically defined necrotising enterocolitis (enteral feeding analysis) and late-onset bloodstream infection (parenteral nutrition analysis). Secondary outcomes were survival at neonatal discharge, length of neonatal stay, breastfeeding at discharge, onset of breastfeeding, time to first maternal breast milk, hypoglycaemia, number of days with a central line in situ, duration of parenteral nutrition, time to full enteral feeds and growth. RESULTS: A total of 6030 babies received therapeutic hypothermia. Thirty-one per cent of babies received enteral feeds and 25% received parenteral nutrition. Seven babies (0.1%) were diagnosed with severe necrotising enterocolitis, and further comparative analyses were not conducted on this outcome. A total of 3236 babies were included in the matched enteral feeding analysis. Pragmatically defined necrotising enterocolitis was rare in both groups (0.5% vs. 1.1%) and was lower in babies who were fed during hypothermia (rate difference -0.5%, 95% confidence interval -1.0% to -0.1%; p = 0.03). Higher survival to discharge (96.0% vs. 90.8%, rate difference 5.2%, 95% confidence interval 3.9% to 6.6%; p < 0.001) and higher breastfeeding at discharge (54.6% vs. 46.7%, rate difference 8.0%, 95% confidence interval 5.1% to 10.8%; p < 0.001) rates were observed in enterally fed babies who also had a shorter neonatal stay (mean difference -2.2 days, 95% confidence interval -3.0 to -1.2 days). A total of 2480 babies were included in the matched parenteral nutrition analysis. Higher levels of late-onset bloodstream infection were seen in babies who received parenteral nutrition (0.3% vs. 0.9%, rate difference 0.6%, 95% confidence interval 0.1% to 1.2%; p = 0.03). Survival was lower in babies who did not receive parenteral nutrition (90.0% vs. 93.1%, rate difference 3.1%, 95% confidence interval 1.5% to 4.7%; p < 0.001). LIMITATIONS: Propensity score methodology can address imbalances in observed confounders only. Residual confounding by unmeasured or poorly recorded variables cannot be ruled out. We did not analyse by type or volume of enteral or parenteral nutrition. CONCLUSIONS: Necrotising enterocolitis is rare in babies receiving therapeutic hypothermia, and the introduction of enteral feeding is associated with a lower risk of pragmatically defined necrotising enterocolitis and other beneficial outcomes, including rates of higher survival and breastfeeding at discharge. Receipt of parenteral nutrition during therapeutic hypothermia is associated with a higher rate of late-onset infection but lower mortality. These results support introduction of enteral feeding during therapeutic hypothermia. FUTURE WORK: Randomised trials to assess parenteral nutrition during therapeutic hypothermia. TRIAL REGISTRATION: Current Controlled Trials ISRCTN474042962. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 36. See the NIHR Journals Library website for further project information.

Every year, approximately 1200 babies in the UK suffer a lack of oxygen to the brain around birth. This is called hypoxic­ischaemic encephalopathy and can lead to brain injury or death. To treat hypoxic­ischaemic encephalopathy, babies receive cooling treatment in which their body temperature is lowered. Doctors do not know the best way to give nutrition to babies receiving cooling treatment. Babies can either be fed milk into their stomach (enteral nutrition) or be given nutrients through their veins (parenteral nutrition). We compared babies who were fed milk while they were being cooled with babies from whom milk was withheld while they were being cooled to see if there was a difference in the frequency of necrotising enterocolitis, a severe gut disease. In addition, we compared babies who received parenteral nutrition while they were being cooled with babies who did not to see if there was a difference in infections. Finally, we looked at other outcomes, including survival and breastfeeding. We used the National Neonatal Research Database, which holds de-identified (i.e. no baby can be identified) information on all babies who have received NHS neonatal care. We used a statistical approach to match babies in each group (i.e. fed babies and not fed babies) as closely as possible so that any difference in outcomes was because of different nutrition and not because of other differences. We included > 6000 babies with hypoxic­ischaemic encephalopathy. Approximately one in three babies received milk feeds and one in four babies received parenteral nutrition during cooling. Necrotising enterocolitis was very rare. More babies who were fed milk during cooling had good outcomes (e.g. being breastfed at discharge) and fewer had necrotising enterocolitis. Most of these babies received only a small amount of milk in the first 3 days. More babies given parenteral nutrition had infections, but also more survived. This suggests that it is probably safe and may be beneficial to feed babies milk during cooling. More research should look at milk feeding and parenteral nutrition during cooling.

Administration of parenteral nutrition during therapeutic hypothermia: a population level observational study using routinely collected data held in the National Neonatal Research Database.

BACKGROUND: Parenteral nutrition is commonly administered during therapeutic hypothermia. Randomised trials in critically ill children indicate that parenteral nutrition may be harmful. OBJECTIVE: To examine the association between parenteral nutrition during therapeutic hypothermia and clinically important outcomes. DESIGN: Retrospective, population-based cohort study using the National Neonatal Research Database; propensity scores were used to create matched groups for comparison. SETTING: National Health Service neonatal units in England, Scotland and Wales. PARTICIPANTS: 6030 term and near-term babies, born 1/1/2010 and 31/12/2017, who received therapeutic hypothermia; 2480 babies in the matched analysis. EXPOSURE: We compared babies that received any parenteral nutrition during therapeutic hypothermia with babies that did not. MAIN OUTCOME MEASURES: Primary outcome: blood culture confirmed late-onset infection; secondary outcomes: treatment for late onset infection, necrotising enterocolitis, survival, length of stay, measures of breast feeding, hypoglycaemia, central line days, time to full enteral feeds, discharge weight. RESULTS: 1475/6030 babies (25%) received parenteral nutrition. In comparative matched analyses, the rate of culture positive late onset infection was higher in babies that received parenteral nutrition (0.3% vs 0.9%; difference 0.6; 95% CI 0.1, 1.2; p=0.03), but treatment for presumed infection was not (difference 0.8%, 95% CI -2.1 to 3.6, p=0.61). Survival was higher in babies that received parenteral nutrition (93.1% vs 90.0%; rate difference 3.1, 95% CI 1.5, 4.7; p<0.001). CONCLUSIONS: Receipt of parenteral nutrition during therapeutic hypothermia is associated with higher late-onset infection but lower mortality. This finding may be explained by residual confounding. Research should address the risks and benefits of parenteral nutrition in this population.

Gut priming with bovine colostrum and T regulatory cells in preterm neonates: a randomized controlled trial.

BACKGROUND: Necrotizing enterocolitis (NEC) and neonatal sepsis are still considered major problems, especially in formula-fed preterm neonates. This study aimed to investigate the effect of bovine colostrum on T regulatory cells, NEC, and late-onset sepsis in preterm neonates ≤34 weeks. METHODS: This prospective double-blind randomized controlled trial was conducted on 80 preterm infants who were randomly assigned to either the bovine colostrum group (n = 32) or control group (n = 48). T lymphocytes and their subsets, necrotizing enterocolitis, late-onset sepsis (LOS) and its severity, feeding tolerance, growth, length of hospital stay, and mortality were documented. RESULTS: The bovine colostrum group showed higher follow-up levels of CD4+CD25+ FOXP3+ T lymphocyte % (FOXP3 Tregs). FOXP3 Tregs and its difference in change levels between baseline and follow-up were considered as the most related factors to the bovine colostrum. Bovine colostrum group showed positive trends for reduction of sepsis severity and mortality with no significant difference in the incidence of NEC, LOS, and length of hospital stay. CONCLUSIONS: Preterm neonates who received bovine colostrum showed a higher FOXP3 Treg level. IMPACT: Bovine colostrum has no significant effect on the incidence of necrotizing enterocolitis. FOXP3 T regulatory cells and their increased level between baseline and follow-up is considered as the most influencing factors related to the bovine colostrum. Positive trends were noted for reduction of sepsis severity and concomitant mortality, but the study lacked the power to assess these outcomes.

Individualized versus standard diet fortification for growth and development in preterm infants receiving human milk.

BACKGROUND: Human milk as compared to formula reduces morbidity in preterm infants but requires fortification to meet their nutritional needs and to reduce the risk of extrauterine growth failure. Standard fortification methods are not individualized to the infant and assume that breast milk is uniform in nutritional content. Strategies for individualizing fortification are available; however it is not known whether these are safe, or if they improve outcomes in preterm infants. OBJECTIVES: To determine whether individualizing fortification of breast milk feeds in response to infant blood urea nitrogen (adjustable fortification) or to breast milk macronutrient content as measured with a milk analyzer (targeted fortification) reduces mortality and morbidity and promotes growth and development compared to standard, non-individualized fortification for preterm infants receiving human milk at < 37 weeks' gestation or at birth weight < 2500 grams. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 9), in the Cochrane Library; Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Daily and Versions(R); and the Cumulative Index to Nursing and Allied Health Literature (CINAHL), on September 20, 2019. We also searched clinical trials databases and the reference lists of retrieved articles for pertinent randomized controlled trials (RCTs) and quasi-randomized trials. SELECTION CRITERIA: We considered randomized, quasi-randomized, and cluster-randomized controlled trials of preterm infants fed exclusively breast milk that compared a standard non-individualized fortification strategy to individualized fortification using a targeted or adjustable strategy. We considered studies that examined any use of fortification in eligible infants for a minimum duration of two weeks, initiated at any time during enteral feeding, and providing any regimen of human milk feeding. DATA COLLECTION AND ANALYSIS: Data were collected using the standard methods of Cochrane Neonatal. Two review authors evaluated the quality of the studies and extracted data. We reported analyses of continuous data using mean differences (MDs), and dichotomous data using risk ratios (RRs). We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS: Data were extracted from seven RCTs, resulting in eight publications (521 total participants were enrolled among these studies), with duration of study interventions ranging from two to seven weeks. As compared to standard non-individualized fortification, individualized (targeted or adjustable) fortification of enteral feeds probably increased weight gain during the intervention (typical mean difference [MD] 1.88 g/kg/d, 95% confidence interval [CI] 1.26 to 2.50; 6 studies, 345 participants), may have increased length gain during the intervention (typical MD 0.43 mm/d, 95% CI 0.32 to 0.53; 5 studies, 242 participants), and may have increased head circumference gain during the intervention (typical MD 0.14 mm/d, 95% CI 0.06 to 0.23; 5 studies, 242 participants). Compared to standard non-individualized fortification, targeted fortification probably increased weight gain during the intervention (typical MD 1.87 g/kg/d, 95% CI 1.15 to 2.58; 4 studies, 269 participants) and may have increased length gain during the intervention (typical MD 0.45 mm/d, 95% CI 0.32 to 0.57; 3 studies, 166 participants). Adjustable fortification probably increased weight gain during the intervention (typical MD 2.86 g/kg/d, 95% CI 1.69 to 4.03; 3 studies, 96 participants), probably increased gain in length during the intervention (typical MD 0.54 mm/d, 95% CI 0.38 to 0.7; 3 studies, 96 participants), and increased gain in head circumference during the intervention (typical MD 0.36 mm/d, 95% CI 0.21 to 0.5; 3 studies, 96 participants). We are uncertain whether there are differences between individualized versus standard fortification strategies in the incidence of in-hospital mortality, bronchopulmonary dysplasia, necrotizing enterocolitis, culture-proven late-onset bacterial sepsis, retinopathy of prematurity, osteopenia, length of hospital stay, or post-hospital discharge growth. No study reported severe neurodevelopmental disability as an outcome. One study that was published after our literature search was completed is awaiting classification. AUTHORS' CONCLUSIONS: We found moderate- to low-certainty evidence suggesting that individualized (either targeted or adjustable) fortification of enteral feeds in very low birth weight infants increases growth velocity of weight, length, and head circumference during the intervention compared with standard non-individualized fortification. Evidence showing important in-hospital and post-discharge clinical outcomes was sparse and of very low certainty, precluding inferences regarding safety or clinical benefits beyond short-term growth.

Protein supplementation of human milk for promoting growth in preterm infants.

BACKGROUND: Preterm infants require high protein intake to achieve adequate growth and development. Although breast milk feeding has many benefits for this population, the protein content is highly variable, and inadequate to support rapid infant growth. This is a 2020 update of a Cochrane Review first published in 1999. OBJECTIVES: To determine whether protein-supplemented human milk compared with unsupplemented human milk, fed to preterm infants, improves growth, body composition, cardio-metabolic, and neurodevelopmental outcomes, without significant adverse effects. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search Cochrane Central Register of Controlled Trials (CENTRAL 2019, Issue 8) in the Cochrane Library and MEDLINE via PubMed on 23 August 2019. We also searched clinical trials databases and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: Published and unpublished RCTs were eligible if they used random or quasi-random methods to allocate hospitalised preterm infants who were being fed human milk, to additional protein supplementation or no supplementation. DATA COLLECTION AND ANALYSIS: Two review authors independently abstracted data, assessed risk of bias and the quality of evidence at the outcome level, using GRADE methodology. We performed meta-analyses, using risk ratio (RR) for dichotomous data, and mean difference (MD) for continuous data, with their respective 95% confidence intervals (CIs). We used a fixed-effect model and had planned to explore potential causes of heterogeneity via subgroup or sensitivity analyses. MAIN RESULTS: We included six RCTs, involving 204 preterm infants. The risk of bias for most methodological domains was unclear as there was insufficient detail reported. Low-quality evidence showed that protein supplementation of human milk may increase in-hospital rates of growth in weight (MD 3.82 g/kg/day, 95% CI 2.94 to 4.7; five RCTs, 101 infants; I² = 73%), length (MD 0.12 cm/wk, 95% CI 0.07 to 0.17; four RCTs, 68 infants; I² = 89%), and head circumference (MD 0.06 cm/wk, 95% CI 0.01 to 0.12; four RCTs, 68 infants; I² = 84%). Protein supplementation may lead to longer hospital stays (MD 18.5 days, 95% CI 4.39 to 32.61; one RCT, 20 infants; very low-quality evidence). Very low quality evidence means that the effect of protein supplementation on the risk of feeding intolerance (RR 2.70, 95% CI 0.13 to 58.24; one RCT, 17 infants), or necrotizing enterocolitis (RR 1.11, 95% CI 0.07 to 17.12; one RCT, 76 infants) remains uncertain. No data were available about the effects of protein supplementation on neurodevelopmental outcomes. AUTHORS' CONCLUSIONS: Low-quality evidence showed that protein supplementation of human milk, fed to preterm infants, increased short-term growth. However, the small sample sizes, low precision, and very low-quality evidence regarding duration of hospital stay, feeding intolerance, and necrotising enterocolitis precluded any conclusions about these outcomes. There were no data on outcomes after hospital discharge. Our findings may not be generalisable to low-resource settings, as none of the included studies were conducted in these settings. Since protein supplementation of human milk is now usually done as a component of multi-nutrient fortifiers, future studies should compare different amounts of protein in multi-component fortifiers, and be designed to determine the effects on duration of hospital stay and safety, as well as on long-term growth, body composition, cardio-metabolic, and neurodevelopmental outcomes.

Carbohydrate supplementation of human milk to promote growth in preterm infants.

BACKGROUND: Preterm infants are born with low glycogen stores and require higher glucose intake to match fetal accretion rates. In spite of the myriad benefits of breast milk for preterm infants, it may not adequately meet the needs of these rapidly growing infants. Supplementing human milk with carbohydrates may help. However, there is a paucity of data on assessment of benefits or harms of carbohydrate supplementation of human milk to promote growth in preterm infants. This is a 2020 update of a Cochrane Review first published in 1999. OBJECTIVES: To determine whether human milk supplemented with carbohydrate compared with unsupplemented human milk fed to preterm infants improves growth, body composition, and cardio-metabolic and neurodevelopmental outcomes without significant adverse effects. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search Cochrane Central Register of Controlled Trials (CENTRAL 2019, Issue 8) in the Cochrane Library and MEDLINE via PubMed on 22 August 2019. We also searched clinical trials databases and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: Published and unpublished controlled trials were eligible if they used random or quasi-random methods to allocate preterm infants in hospital fed human milk to supplementation or no supplementation with additional carbohydrate. DATA COLLECTION AND ANALYSIS: Two review authors independently abstracted data and assessed trial quality and the quality of evidence at the outcome level using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) method. We planned to perform meta-analyses using risk ratios (RRs) for dichotomous data and mean differences (MDs) for continuous data, with their respective 95% confidence intervals (CIs). We planned to use a fixed-effect model and to explore potential causes of heterogeneity via sensitivity analyses. We contacted study authors for additional information. MAIN RESULTS: One unblinded, quasi-randomised controlled trial (RCT) assessing effects of carbohydrate supplementation of human milk in the form of a prebiotic in 75 preterm infants was eligible for inclusion in this review. We identified two publications of the same trial, which reported different methods regarding blinding and randomisation. Study authors confirmed that these publications pertain to the same trial, but they have not yet clarified which method is correct. We were unable to reproduce analyses from the data presented. At 30 days of age, the mean weight of preterm infants in the trial was greater in the prebiotic carbohydrate-supplemented group than in the unsupplemented group (MD 160.4 grams, 95% CI 12.4 to 308.4 grams; one RCT, N = 75; very low-quality evidence). We found no evidence of a clear difference in risk of feeding intolerance (RR 0.64, 95% CI 0.36 to 1.15; one RCT, N = 75 infants; very low-quality evidence) or necrotising enterocolitis (NEC) (RR 0.2, 95% CI 0.02 to 1.3; one RCT, N = 75 infants; very low-quality evidence) between the prebiotic-supplemented group and the unsupplemented group. Duration of hospital stay was shorter in the prebiotic group than in the control group at a median (range) of 16 (9 to 45) days (95% CI 15.34 to 24.09) and 25 (11 to 80) days (95% CI 25.52 to 34.39), respectively. No other data were available for assessing effects of carbohydrate supplementation on short- and long-term growth, body mass index, body composition, and neurodevelopmental or cardio-metabolic outcomes. AUTHORS' CONCLUSIONS: We found insufficient evidence on the short- and long-term effects of carbohydrate supplementation of human milk in preterm infants. The only trial included in this review presented very low-quality evidence, and study authors provided uncertain information about study methods and analysis. The evidence may be limited in its applicability because researchers included a small sample of preterm infants from a single centre. However, the outcomes assessed are common to all preterm infants, and this trial demonstrates the feasibility of prebiotic carbohydrate supplementation in upper-middle-income countries. Future trials should assess the safety and efficacy of different types and concentrations of carbohydrate supplementation for preterm infants fed human milk. Although prebiotic carbohydrate supplementation in preterm infants is currently a topic of active research, we do not envisage that further trials of digestible carbohydrates will be conducted, as this is currently done as a component of multi-nutrient human milk fortification. Hence we do not plan to publish any further updates of this review.

S100A8 and S100A9 Are Important for Postnatal Development of Gut Microbiota and Immune System in Mice and Infants.

BACKGROUND & AIMS: After birth, the immune system matures via interactions with microbes in the gut. The S100 calcium binding proteins S100A8 and S100A9, and their extracellular complex form, S100A8-A9, are found in high amounts in human breast milk. We studied levels of S100A8-A9 in fecal samples (also called fecal calprotectin) from newborns and during infancy, and their effects on development of the intestinal microbiota and mucosal immune system. METHODS: We collected stool samples (n = 517) from full-term (n = 72) and preterm infants (n = 49) at different timepoints over the first year of life (days 1, 3, 10, 30, 90, 180, and 360). We measured levels of S100A8-A9 by enzyme-linked immunosorbent assay and analyzed fecal microbiomes by 16S sRNA gene sequencing. We also obtained small and large intestine biopsies from 8 adults and 10 newborn infants without inflammatory bowel diseases (controls) and 8 infants with necrotizing enterocolitis and measured levels of S100A8 by immunofluorescence microscopy. Children were followed for 2.5 years and anthropometric data and medical information on infections were collected. We performed studies with newborn C57BL/6J wild-type and S100a9-/- mice (which also lack S100A8). Some mice were fed or given intraperitoneal injections of S100A8 or subcutaneous injections of Staphylococcus aureus. Blood and intestine, mesenterial and celiac lymph nodes were collected; cells and cytokines were measured by flow cytometry and studied in cell culture assays. Colon contents from mice were analyzed by culture-based microbiology assays. RESULTS: Loss of S100A8 and S100A9 in mice altered the phenotypes of colonic lamina propria macrophages, compared with wild-type mice. Intestinal tissues from neonatal S100-knockout mice had reduced levels of CX3CR1 protein, and Il10 and Tgfb1 mRNAs, compared with wild-type mice, and fewer T-regulatory cells. S100-knockout mice weighed 21% more than wild-type mice at age 8 weeks and a higher proportion developed fatal sepsis during the neonatal period. S100-knockout mice had alterations in their fecal microbiomes, with higher abundance of Enterobacteriaceae. Feeding mice S100 at birth prevented the expansion of Enterobacteriaceae, increased numbers of T-regulatory cells and levels of CX3CR1 protein and Il10 mRNA in intestine tissues, and reduced body weight and death from neonatal sepsis. Fecal samples from term infants, but not preterm infants, had significantly higher levels of S100A8-A9 during the first 3 months of life than fecal samples from adults; levels decreased to adult levels after weaning. Fecal samples from infants born by cesarean delivery had lower levels of S100A8-A9 than from infants born by vaginal delivery. S100 proteins were expressed by lamina propria macrophages in intestinal tissues from infants, at higher levels than in intestinal tissues from adults. High fecal levels of S100 proteins, from 30 days to 1 year of age, were associated with higher abundance of Actinobacteria and Bifidobacteriaceae, and lower abundance of Gammaproteobacteria-particularly opportunistic Enterobacteriaceae. A low level of S100 proteins in infants' fecal samples associated with development of sepsis and obesity by age 2 years. CONCLUSION: S100A8 and S100A9 regulate development of the intestinal microbiota and immune system in neonates. Nutritional supplementation with these proteins might aide in development of preterm infants and prevent microbiota-associated disorders in later years.

Reduced fetal movements is twin pregnancies and the association with adverse neonatal outcomes.

OBJECTIVE: Reduced fetal movements (RFM) is an obstetric complaint known to be associated with adverse neonatal outcomes and should serve as an alarming sign in obstetric triage. Whether this assumption holds for twin pregnancies, is still an obstetric enigma, and this complaint is sometimes overlooked in twins. We, therefore, aimed to study neonatal outcomes in twin pregnancies complicated by RFM. We hypothesised that in twin pregnancy, maternal ability to perceive RFM will be limited, and therefore, will not be associated with adverse neonatal outcome. STUDY DESIGN: Included were all dichorionic twin pregnancies between 2009-2019 who presented to our obstetric triage at a gestational age >34 weeks with an isolated complaint of RFM and delivered during the subsequent two weeks (RFM group). The control group included patients with twin pregnancies (matched for gestational age and maternal age) who presented for routine assessment and reported regular fetal movements throughout pregnancy (no RFM group). Data regarding pregnancy, delivery, and neonatal outcomes were compared between the groups. The primary outcome was a composite of adverse neonatal outcomes, which included one or more of the following: neonatal hypoglycemia, respiratory morbidity, cerebral morbidity, phototherapy, neonatal sepsis, blood transfusions, necrotizing enterocolitis, or neonatal death. Multivariable regression analysis was used to identify independent associations with adverse neonatal outcomes. RESULTS: Maternal demographics and gestational age at delivery did not differ between the RFM group (n = 83 pregnancies and 166 neonates) and the no RFM group (n = 83 pregnancies and 166 neonates). Neonatal birthweights, as well as the rate of birthweights <10th centile, did not differ between the groups. There were 2 cases of fetal demise diagnosed at triage in the RFM group. The rate of the primary outcome, as well as NICU admissions, were significantly higher in the RFM group compared to the no RFM group (29.5 % vs. 19.2 %, p = 0.01 and 32.5 % vs. 19.2 %, p = 0.001). In multivariable analysis RFM (aOR = 1.18, 95 % CI = 1.06-2.73), and GA at delivery (aOR = 0.88, 95 % CI = 0.67-0.97) were associated with adverse neonatal outcome-independent from background confounders. CONCLUSION: Patients presented to obstetric triage with twin pregnancies and isolated RFM had higher rates of adverse neonatal outcomes and NICU admissions compared to twin pregnancies without RFM.

The effect of meconium thickness level on neonatal outcome.

BACKGROUND: Despite its prevalence and potential maternal and neonatal implications, the literature on the thickness levels of meconium stained amniotic fluid (MSAF) and its impact on neonatal outcomes is relatively outdated and relies on relatively small sample sizes. AIMS: To study if different thickness levels of MSAF correlate with adverse neonatal outcome. STUDY DESIGN: A retrospective cohort study. SUBJECTS: The medical records and neonatal charts of all women with a singleton pregnancy, who underwent a trial of labor, at 37 + 0/7 weeks or beyond, between 10/2008 and 7/2018 were reviewed. OUTCOME MEASURES: The cohort was divided according to the level of meconium reported during labor into four groups: Clear (C group), Light meconium (LM group), Intermediate meconium (IM group), and Heavy meconium (HM group). Composite neonatal outcome included at least one of the following: umbilical artery pH ≤ 7.1, sepsis, need for blood transfusion, need for phototherapy, respiratory distress syndrome, meconium aspiration syndrome, need for mechanical ventilation support, necrotizing enterocolitis, intraventricular hemorrhage, hypoxic ischemic encephalopathy, periventricular leukomalacia, seizures, hypoglycemia, hypothermia, and death. Continuous parameters were compared with Anova's test or Kruskal Wallis, and categorical variables by chi-square test or Fisher exact test, as appropriate. Multivariant logistic regression was performed in order to eliminate possible cofounders. RESULTS: Overall, 24,445 deliveries were reviewed (C-20,185, LM-1074, IM-2736, HM-450). Composite adverse neonatal outcome was more common with increasing thickness of MSAF. On multivariable analysis, IM and HM were independently associated with composite adverse neonatal outcome. CONCLUSION: The degree of meconium thickness independently correlates with composite adverse neonatal outcome.

Effects of oropharyngeal administration of colostrum on the incidence of necrotizing enterocolitis, late-onset sepsis, and death in preterm infants: a meta-analysis of RCTs.

Necrotizing enterocolitis (NEC) and late-onset sepsis (LOS) are two major contributors to death among preterm infants. Oropharyngeal administration of colostrum (OAC) has been proved as an easy, safe, and economically viable technique to help preterm neonates to build up their immunity. In this review, we assessed the effects of OAC on preterm infants. Several mainstream databases were searched including PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and a website of clinical trials. Randomized controlled trials (RCTs) comparing OAC vs. placebo or no intervention in preterm infants (gestation age <34 weeks or birth weight <1500 g) were eligible. Overall, nine RCTs (n = 689) were included in the review. Meta-analysis showed no statistical significance in terms of the incidence of NEC (RR = 0.59, 95% CI = 0.33-1.06, p = 0.08), LOS (RR = 0.78, 95% CI = 0.60-1.03, p = 0.08) and mortality rate (RR = 0.63, 95% CI = 0.38-1.05, p = 0.07). No significant difference was found in the subgroup analysis, apart from the group of the undeveloped region in NEC and mortality. In addition, time was significantly reduced in terms of achieving full enteral feeding (MD = -3.60, 95% CI = -6.55-0.64, p = 0.02) and hospital stay (MD = -10.38, 95% CI = -18.47-2.29, p = 0.01). The results show that OAC does not reduce the incidences of NEC, LOS, and death in preterm infants, but there is a trend toward a positive effect. It is therefore recommended as routine care for preterm infants in the NICU.