Background
When sufficient maternal breast milk is not available, alternative forms of enteral nutrition for preterm or low birth weight (LBW) infants are donor breast milk or artificial formula. ...Donor breast milk may retain some of the non‐nutritive benefits of maternal breast milk for preterm or LBW infants. However, feeding with artificial formula may ensure more consistent delivery of greater amounts of nutrients. Uncertainty exists about the balance of risks and benefits of feeding formula versus donor breast milk for preterm or LBW infants.
Objectives
To determine the effect of feeding with formula compared with donor breast milk on growth and development in preterm or low birth weight (LBW) infants.
Search methods
We used the Cochrane Neonatal search strategy, including electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 5), Ovid MEDLINE, Embase, and the Cumulative Index to Nursing and Allied Health Literature (3 May 2019), as well as conference proceedings, previous reviews, and clinical trials.
Selection criteria
Randomised or quasi‐randomised controlled trials (RCTs) comparing feeding with formula versus donor breast milk in preterm or LBW infants.
Data collection and analysis
Two review authors assessed trial eligibility and risk of bias and extracted data independently. We analysed treatment effects as described in the individual trials and reported risk ratios (RRs) and risk differences (RDs) for dichotomous data, and mean differences (MDs) for continuous data, with respective 95% confidence intervals (CIs). We used a fixed‐effect model in meta‐analyses and explored potential causes of heterogeneity in subgroup analyses. We assessed the certainty of evidence for the main comparison at the outcome level using GRADE methods.
Main results
Twelve trials with a total of 1879 infants fulfilled the inclusion criteria. Four trials compared standard term formula versus donor breast milk and eight compared nutrient‐enriched preterm formula versus donor breast milk. Only the five most recent trials used nutrient‐fortified donor breast milk. The trials contain various weaknesses in methodological quality, specifically concerns about allocation concealment in four trials and lack of blinding in most of the trials. Most of the included trials were funded by companies that made the study formula.
Formula‐fed infants had higher in‐hospital rates of weight gain (mean difference (MD) 2.51, 95% confidence interval (CI) 1.93 to 3.08 g/kg/day), linear growth (MD 1.21, 95% CI 0.77 to 1.65 mm/week) and head growth (MD 0.85, 95% CI 0.47 to 1.23 mm/week). These meta‐analyses contained high levels of heterogeneity. We did not find evidence of an effect on long‐term growth or neurodevelopment. Formula feeding increased the risk of necrotising enterocolitis (typical risk ratio (RR) 1.87, 95% CI 1.23 to 2.85; risk difference (RD) 0.03, 95% CI 0.01 to 0.05; number needed to treat for an additional harmful outcome (NNTH) 33, 95% CI 20 to 100; 9 studies, 1675 infants).
The GRADE certainty of evidence was moderate for rates of weight gain, linear growth, and head growth (downgraded for high levels of heterogeneity) and was moderate for neurodevelopmental disability, all‐cause mortality, and necrotising enterocolitis (downgraded for imprecision).
Authors' conclusions
In preterm and LBW infants, moderate‐certainty evidence indicates that feeding with formula compared with donor breast milk, either as a supplement to maternal expressed breast milk or as a sole diet, results in higher rates of weight gain, linear growth, and head growth and a higher risk of developing necrotising enterocolitis. The trial data do not show an effect on all‐cause mortality, or on long‐term growth or neurodevelopment.
When sufficient maternal breast milk is not available, alternative forms of enteral nutrition for preterm or low birth weight (LBW) infants are donor breast milk or artificial formula. Donor breast ...milk may retain some of the non-nutritive benefits of maternal breast milk for preterm or LBW infants. However, feeding with artificial formula may ensure more consistent delivery of greater amounts of nutrients. Uncertainty exists about the balance of risks and benefits of feeding formula versus donor breast milk for preterm or LBW infants.
To determine the effect of feeding with formula compared with donor breast milk on growth and development in preterm or low birth weight (LBW) infants.
We used the Cochrane Neonatal search strategy, including electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 6), Ovid MEDLINE, Embase, and the Cumulative Index to Nursing and Allied Health Literature (until 8 June 2017), as well as conference proceedings and previous reviews.
Randomised or quasi-randomised controlled trials (RCTs) comparing feeding with formula versus donor breast milk in preterm or LBW infants.
Two review authors assessed trial eligibility and risk of bias and extracted data independently. We analysed treatment effects as described in the individual trials and reported risk ratios (RRs) and risk differences (RDs) for dichotomous data, and mean differences (MDs) for continuous data, with respective 95% confidence intervals (CIs). We used a fixed-effect model in meta-analyses and explored potential causes of heterogeneity in subgroup analyses. We assessed the quality of evidence for the main comparison at the outcome level using "Grading of Recommendations Assessment, Development and Evaluation" (GRADE) methods.
Eleven trials, in which 1809 infants participated in total, fulfilled the inclusion criteria. Four trials compared standard term formula versus donor breast milk and seven compared nutrient-enriched preterm formula versus donor breast milk. Only the four most recent trials used nutrient-fortified donor breast milk. The trials contain various weaknesses in methodological quality, specifically concerns about allocation concealment in four trials and lack of blinding in most of the trials.Formula-fed infants had higher in-hospital rates of weight gain (mean difference (MD) 2.51, 95% confidence interval (CI) 1.93 to 3.08 g/kg/day), linear growth (MD 1.21, 95% CI 0.77 to 1.65 mm/week) and head growth (MD 0.85, 95% CI 0.47 to 1.23 mm/week). We did not find evidence of an effect on long-term growth or neurodevelopment. Formula feeding increased the risk of necrotising enterocolitis (typical risk ratio (RR) 1.87, 95% CI 1.23 to 2.85; risk difference (RD) 0.03, 95% CI 0.01 to 0.06).The GRADE quality of evidence was moderate for rates of weight gain, linear growth, and head growth (downgraded for high levels of heterogeneity) and was moderate for neurodevelopmental disability, all-cause mortality, and necrotising enterocolitis (downgraded for imprecision).
In preterm and LBW infants, feeding with formula compared with donor breast milk, either as a supplement to maternal expressed breast milk or as a sole diet, results in higher rates of weight gain, linear growth, and head growth and a higher risk of developing necrotising enterocolitis. The trial data do not show an effect on all-cause mortality, or on long-term growth or neurodevelopment.
Discriminating necrotising enterocolitis (NEC) and focal intestinal perforation (FIP) is important for clinical trials, observational cohorts, quality improvement and aetiological understanding. ...Literature suggests that timing and key features diagnose and discriminate, and that NEC subclassifications exist. We used a detailed 10-year cohort of NEC and FIP cases in preterm infants born <32 weeks' gestation from a single centre to explore antecedent factors, presentation and potential NEC subclassifications. 785 infants had 144 episodes of NEC and 38 of FIP. FIP presented earlier than NEC, but ranges overlapped, and 30% of NEC presented before day 14. Antecedent events (other than feed volumes) and outcomes did not differ between NEC and FIP. Currently used diagnostic/discriminatory features performed poorly, and subclassification identified few cases except transfusion-associated NEC. Contrary to existing literature, postnatal age at NEC presentation was not dependent on gestational age. Detailed review rather than simple definitions are required to separate NEC from FIP.
ABSTRACTThe consumption of sugars, particularly sugar-sweetened beverages (SSBs; beverages or drinks that contain added caloric sweeteners (ie, sucrose, high-fructose corn syrup, fruit juice ...concentrates), in European children and adolescents exceeds current recommendations. This is of concern because there is no nutritional requirement for free sugars, and infants have an innate preference for sweet taste, which may be modified and reinforced by pre- and postnatal exposures. Sugar-containing beverages/free sugars increase the risk for overweight/obesity and dental caries, can result in poor nutrient supply and reduced dietary diversity, and may be associated with increased risk of type 2 diabetes mellitus, cardiovascular risk, and other health effects. The term “free sugars,” includes all monosaccharides/disaccharides added to foods/beverages by the manufacturer/cook/consumer, plus sugars naturally present in honey/syrups/unsweetened fruit juices and fruit juice concentrates. Sugar naturally present in intact fruits and lactose in amounts naturally present in human milk or infant formula, cow/goat milk, and unsweetened milk products is not free sugar. Intake of free sugars should be reduced and minimised with a desirable goal of <5% energy intake in children and adolescents aged ≥2 to 18 years. Intake should probably be even lower in infants and toddlers <2 years. Healthy approaches to beverage and dietary consumption should be established in infancy, with the aim of preventing negative health effects in later childhood and adulthood. Sugar should preferably be consumed as part of a main meal and in a natural form as human milk, milk, unsweetened dairy products, and fresh fruits, rather than as SSBs, fruit juices, smoothies, and/or sweetened milk products. Free sugars in liquid form should be replaced by water or unsweetened milk drinks. National Authorities should adopt policies aimed at reducing the intake of free sugars in infants, children and adolescents. This may include education, improved labelling, restriction of advertising, introducing standards for kindergarten and school meals, and fiscal measures, depending on local circumstances.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background
Preterm infants are often growth‐restricted at hospital discharge. Feeding nutrient‐enriched formula rather than standard formula to infants after hospital discharge might facilitate ...'catch‐up' growth and might improve development.
Objectives
To compare the effects of nutrient‐enriched formula versus standard formula on growth and development of preterm infants after hospital discharge.
Search methods
We used the standard search strategy of the Cochrane Neonatal Review Group. This included searches of the Cochrane Central Register of Controlled Trials (2016, Issue 8) in the Cochrane Library, MEDLINE, Embase and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; to 8 September 2016), as well as conference proceedings and previous reviews.
Selection criteria
Randomised and quasi‐randomised controlled trials that compared the effects of feeding nutrient‐enriched formula (postdischarge formula or preterm formula) versus standard term formula to preterm infants after hospital discharge .
Data collection and analysis
Two review authors assessed trial eligibility and risk of bias and extracted data independently. We analysed treatment effects as described in the individual trials and reported risk ratios and risk differences for dichotomous data, and mean differences (MDs) for continuous data, with respective 95% confidence intervals (CIs). We used a fixed‐effect model in meta‐analyses and explored potential causes of heterogeneity by performing sensitivity analyses. We assessed quality of evidence at the outcome level using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.
Main results
We included 16 eligible trials with a total of 1251 infant participants. Trials were of variable methodological quality, with lack of allocation concealment and incomplete follow‐up identified as major potential sources of bias. Trials (N = 11) that compared feeding infants with 'postdischarge formula' (energy density about 74 kcal/100 mL) versus standard term formula (about 67 kcal/100 mL) did not find consistent evidence of effects on growth parameters up to 12 to 18 months post term. GRADE assessments indicated that evidence was of moderate quality, and that inconsistency within pooled estimates was the main quality issue.
Trials (N = 5) that compared feeding with 'preterm formula' (about 80 kcal/100 mL) versus term formula found evidence of higher rates of growth throughout infancy (weighted mean differences at 12 to 18 months post term: about 500 g in weight, 5 to 10 mm in length, 5 mm in head circumference). GRADE assessments indicated that evidence was of moderate quality, and that imprecision of estimates was the main quality issue.
Few trials assessed neurodevelopmental outcomes, and these trials did not detect differences in developmental indices at 18 months post term. Data on growth or development through later childhood have not been provided.
Authors' conclusions
Recommendations to prescribe 'postdischarge formula' for preterm infants after hospital discharge are not supported by available evidence. Limited evidence suggests that feeding 'preterm formula' (which is generally available only for in‐hospital use) to preterm infants after hospital discharge may increase growth rates up to 18 months post term.
Background
Exclusively breast milk‐fed preterm infants may accumulate nutrient deficits leading to extrauterine growth restriction. Feeding preterm infants with multi‐nutrient fortified human breast ...milk rather than unfortified breast milk may increase nutrient accretion and growth rates and may improve neurodevelopmental outcomes.
Objectives
To determine whether multi‐nutrient fortified human breast milk improves important outcomes (including growth and development) over unfortified breast milk for preterm infants without increasing the risk of adverse effects (such as feed intolerance and necrotising enterocolitis).
Search methods
We used the standard search strategy of the Cochrane Neonatal Review Group. This included electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 2), MEDLINE, EMBASE and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (until February 2016), as well as conference proceedings and previous reviews.
Selection criteria
Randomised and quasi‐randomised controlled trials that compared feeding preterm infants with multi‐nutrient (protein and energy plus minerals, vitamins or other nutrients) fortified human breast milk versus unfortified (no added protein or energy) breast milk.
Data collection and analysis
We extracted data using the standard methods of the Cochrane Neonatal Review Group. We separately evaluated trial quality, data extracted by two review authors and data synthesised using risk ratios (RRs), risk differences and mean differences (MDs). We assessed the quality of evidence at the outcome level using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.
Main results
We identified 14 trials in which a total of 1071 infants participated. The trials were generally small and weak methodologically. Meta‐analyses provided low‐quality evidence that multi‐nutrient fortification of breast milk increases in‐hospital rates of growth (MD 1.81 g/kg/d, 95% confidence interval (CI) 1.23 to 2.40); length (MD 0.12 cm/wk, 95% CI 0.07 to 0.17); and head circumference (MD 0.08 cm/wk, 95% CI 0.04 to 0.12). Only very limited data are available for growth and developmental outcomes assessed beyond infancy, and these show no effects of fortification. The data did not indicate other potential benefits or harms and provided low‐quality evidence that fortification does not increase the risk of necrotising enterocolitis in preterm infants (typical RR 1.57, 95% CI 0.76 to 3.23; 11 studies, 882 infants).
Authors' conclusions
Limited available data do not provide strong evidence that feeding preterm infants with multi‐nutrient fortified breast milk compared with unfortified breast milk affects important outcomes, except that it leads to slightly increased in‐hospital growth rates.
Infections acquired in hospital are an important cause of morbidity and mortality in very preterm infants. Several small trials have suggested that supplementing the enteral diet of very preterm ...infants with lactoferrin, an antimicrobial protein processed from cow's milk, prevents infections and associated complications. The aim of this large randomised controlled trial was to collect data to enhance the validity and applicability of the evidence from previous trials to inform practice.
In this randomised placebo-controlled trial, we recruited very preterm infants born before 32 weeks' gestation in 37 UK hospitals and younger than 72 h at randomisation. Exclusion criteria were presence of a severe congenital anomaly, anticipated enteral fasting for longer than 14 days, or no realistic prospect of survival. Eligible infants were randomly assigned (1:1) to receive either enteral bovine lactoferrin (150 mg/kg per day; maximum 300 mg/day; lactoferrin group) or sucrose (same dose; control group) once daily until 34 weeks' postmenstrual age. Web-based randomisation minimised for recruitment site, gestation (completed weeks), sex, and single versus multifetal pregnancy. Parents, caregivers, and outcome assessors were unaware of group assignment. The primary outcome was microbiologically confirmed or clinically suspected late-onset infection (occurring >72 h after birth), which was assessed in all participants for whom primary outcome data was available by calculating the relative risk ratio with 95% CI between the two groups. The trial is registered with the International Standard Randomised Controlled Trial Number 88261002.
We recruited 2203 participants between May 7, 2014, and Sept 28, 2017, of whom 1099 were assigned to the lactoferrin group and 1104 to the control group. Four infants had consent withdrawn or unconfirmed, leaving 1098 infants in the lactoferrin group and 1101 in the sucrose group. Primary outcome data for 2182 infants (1093 99·5% of 1098 in the lactoferrin group and 1089 99·0 of 1101 in the control group) were available for inclusion in the modified intention-to-treat analyses. 316 (29%) of 1093 infants in the intervention group acquired a late-onset infection versus 334 (31%) of 1089 in the control group. The risk ratio adjusted for minimisation factors was 0·95 (95% CI 0·86–1·04; p=0·233). During the trial there were 16 serious adverse events for infants in the lactoferrin group and 10 for infants in the control group. Two events in the lactoferrin group (one case of blood in stool and one death after intestinal perforation) were assessed as being possibly related to the trial intervention.
Enteral supplementation with bovine lactoferrin does not reduce the risk of late-onset infection in very preterm infants. These data do not support its routine use to prevent late-onset infection and associated morbidity or mortality in very preterm infants.
UK National Institute for Health Research Health Technology Assessment programme (10/57/49).
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Necrotising enterocolitis (NEC) is a devastating intestinal disease primarily affecting preterm infants. The underlying mechanisms are poorly understood: mother's own breast milk (MOM) is protective, ...possibly relating to human milk oligosaccharide (HMO) and infant gut microbiome interplay. We investigated the interaction between HMO profiles and infant gut microbiome development and its association with NEC.
We performed HMO profiling of MOM in a large cohort of infants with NEC (n=33) with matched controls (n=37). In a subset of 48 infants (14 with NEC), we also performed longitudinal metagenomic sequencing of infant stool (n=644).
Concentration of a single HMO, disialyllacto-N-tetraose (DSLNT), was significantly lower in MOM received by infants with NEC compared with controls. A MOM threshold level of 241 nmol/mL had a sensitivity and specificity of 0.9 for NEC. Metagenomic sequencing before NEC onset showed significantly lower relative abundance of
and higher relative abundance of
in infants with NEC. Longitudinal development of the microbiome was also impacted by low MOM DSLNT associated with reduced transition into preterm gut community types dominated by
spp and typically observed in older infants. Random forest analysis combining HMO and metagenome data before disease accurately classified 87.5% of infants as healthy or having NEC.
These results demonstrate the importance of HMOs and gut microbiome in preterm infant health and disease. The findings offer potential targets for biomarker development, disease risk stratification and novel avenues for supplements that may prevent life-threatening disease.
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