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BACKGROUND: Human milk is the best enteral nutrition for preterm infants. However, human milk, given at standard recommended volumes, is not adequate to meet the protein, energy, and other nutrient requirements of preterm or low birth weight infants. One strategy that may be used to address the potential nutrient deficits is to give a higher volume of enteral feeds. High volume feeds may improve nutrient accretion and growth, and in turn may improve neurodevelopmental outcomes. However, there are concerns that high volume feeds may cause feed intolerance, necrotising enterocolitis, or complications related to fluid overload such as patent ductus arteriosus and chronic lung disease. This is an update of a review published in 2017. OBJECTIVES: To assess the effect on growth and safety of high versus standard volume enteral feeds in preterm or low birth weight infants. In infants who were fed fortified human milk or preterm formula, high and standard volume feeds were defined as > 180 mL/kg/day and ≤ 180 mL/kg/day, respectively. In infants who were fed unfortified human milk or term formula, high and standard volume feeds were defined as > 200 mL/kg/day and ≤ 200 mL/kg/day, respectively. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search Cochrane Central Register of Controlled Trials (CENTRAL; 2020 Issue 6) in the Cochrane Library; Ovid MEDLINE (1946 to June 2020); Embase (1974 to June 2020); and CINAHL (inception to June 2020); Maternity & Infant Care Database (MIDIRS) (1971 to April 2020); as well as previous reviews, and trial registries. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared high versus standard volume enteral feeds for preterm or low birth weight infants. DATA COLLECTION AND ANALYSIS: Two review authors assessed trial eligibility and risk of bias and independently extracted data. We analysed treatment effects in individual trials and reported risk ratio (RR) and risk difference for dichotomous data, and mean difference (MD) for continuous data, with respective 95% confidence intervals (CIs). We used the GRADE approach to assess the certainty of evidence. The primary outcomes were weight gain, linear and head growth during hospital stay, and extrauterine growth restriction at discharge. MAIN RESULTS: We included two new RCTs (283 infants) in this update. In total, we included three trials (347 infants) in this updated review. High versus standard volume feeds with fortified human milk or preterm formula Two trials (283 infants) met the inclusion criteria for this comparison. Both were of good methodological quality, except for lack of masking. Both trials were performed in infants born at < 32 weeks' gestation. Meta‐analysis of data from both trials showed high volume feeds probably improves weight gain during hospital stay (MD 2.58 g/kg/day, 95% CI 1.41 to 3.76; participants = 271; moderate‐certainty evidence). High volume feeds may have little or no effect on linear growth (MD 0.05 cm/week, 95% CI ‐0.02 to 0.13; participants = 271; low‐certainty evidence), head growth (MD 0.02 cm/week, 95% CI ‐0.04 to 0.09; participants = 271; low‐certainty evidence), and extrauterine growth restriction at discharge (RR 0.71, 95% CI 0.50 to 1.02; participants = 271; low‐certainty evidence). We are uncertain of the effect of high volume feeds with fortified human milk or preterm formula on the risk of necrotising enterocolitis (RR 0.74, 95% CI 0.12 to 4.51; participants = 283; very‐low certainty evidence). High versus standard volume feeds with unfortified human milk or term formula One trial with 64 very low birth weight infants met the inclusion criteria for this comparison. This trial was unmasked but otherwise of good methodological quality. High volume feeds probably improves weight gain during hospital stay (MD 6.2 g/kg/day, 95% CI 2.71 to 9.69; participants = 61; moderate‐certainty evidence). The trial did not provide data on linear and head growth, and extrauterine growth restriction at discharge. We are uncertain as to the effect of high volume feeds with unfortified human milk or term formula on the risk of necrotising enterocolitis (RR 1.03, 95% CI 0.07 to 15.78; participants = 61; very low‐certainty evidence). AUTHORS' CONCLUSIONS: High volume feeds (≥ 180 mL/kg/day of fortified human milk or preterm formula, or ≥ 200 mL/kg/day of unfortified human milk or term formula) probably improves weight gain during hospital stay. The available data is inadequate to draw conclusions on the effect of high volume feeds on other growth and clinical outcomes. A large RCT is needed to provide data of sufficient quality and precision to inform policy and practice.

BACKGROUND: Uncertainty exists about the optimal point at which multi‐component fortifier should be added to human milk for promoting growth in preterm infants. The most common practice is to start fortification when the infant’s daily enteral feed volume reaches 100 mL/kg body weight. Another approach is to commence fortification earlier, in some cases as early as the first enteral feed. Early fortification of human milk could increase nutrient intake and growth rates but may increase the risk of feed intolerance and necrotising enterocolitis (NEC). OBJECTIVES: To assess effects on growth and safety of early fortification of human milk versus late fortification in preterm infants To assess whether effects vary based upon gestational age (≤ 27 weeks; 28 to 31 weeks; ≥ 32 weeks), birth weight (< 1000 g; 1000 to 1499 g; ≥ 1500 g), small or appropriate for gestational age, or type of fortifier (bovine milk‐based human milk fortifier (HMF); human milk‐based HMF; formula powder) SEARCH METHODS: We used the standard strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 8); OVID MEDLINE (R) and Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Daily and Versions (R) (1946 to 15 August 2019); MEDLINE via PubMed (1 August 2018 to 15 August 2019) for the previous year; and the Cumulative Index to Nursing and Allied Health Literatue (CINAHL) (1981 to 15 August 2019). We searched clinical trials databases and reference lists of included studies. SELECTION CRITERIA: We included randomised controlled trials that compared early versus late fortification of human milk in preterm infants. We defined early fortification as fortification started at < 100 mL/kg/d enteral feed volume or < 7 days postnatal age, and late fortification as fortification started at ≥ 100 mL/kg/d feeds or ≥ 7 days postnatal age. DATA COLLECTION AND ANALYSIS: Both review authors assessed trial eligibility and risk of bias and independently extracted data. We analysed treatment effects in individual trials, and we reported risk ratio (RR) for dichotomous data and mean difference (MD) for continuous data, with respective 95% confidence intervals (CIs). We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS: We included two trials with a total of 237 infants. All participants were very low birth weight infants (birth weight < 1500 g). Early fortification was started at 20 mL/kg/d enteral feeds in one study and 40 mL/kg/d in the other study. Late fortification was started at 100 mL/kg/d feeds in both studies. One study used bovine milk‐based fortifier, and the other used human milk‐based fortifier. Meta‐analysis showed that early fortification may have little or no effect on growth outcomes including time to regain birth weight (MD ‐0.06 days, 95% CI ‐1.32 to 1.20 days), linear growth (MD 0.10 cm/week, 95% CI ‐0.03 to 0.22 cm/week), or head growth (MD ‐0.01 cm/week, 95% CI ‐0.07 to 0.06 cm/week) during the initial hospitalisation period. Early fortification may have little or no effect on the risk of NEC (MD ‐0.01, 95% CI ‐0.07 to 0.06). The certainty of evidence was low for these outcomes due to risk of bias (lack of blinding) and imprecision (small sample size). Early fortification may have little or no effect on incidence of surgical NEC, time to reach full enteral feeds, extrauterine growth restriction at discharge, proportion of infants with feed interruption episodes, duration of total parenteral nutrition (TPN), duration of central venous line usage, or incidence of invasive infection, all‐cause mortality, and duration of hospital stay. The certainty of evidence was low for these outcomes due to risk of bias (lack of blinding) and imprecision (small sample size). We did not have data for other outcomes such as subsequent weight gain after birth weight is regained, parenteral nutrition‐associated liver disease, postdischarge growth, and neurodevelopmental outcomes. AUTHORS' CONCLUSIONS: Available evidence is insufficient to support or refute early fortification of human milk in preterm infants. Further large trials would be needed to provide data of sufficient quality and precision to inform policy and practice.

BACKGROUND: Routine monitoring of gastric residual in preterm infants on gavage feeds is a common practice that is used to guide initiation and advancement of feeds. Some literature suggests that an increase in/or an altered gastric residual may be predictive of necrotising enterocolitis. Withholding monitoring of gastric residual may take away the early indicator and thus may increase the risk of necrotising enterocolitis. However, routine monitoring of gastric residual as a guide, in the absence of uniform standards, may lead to unnecessary delay in initiation and advancement of feeds and delay in reaching full enteral feeds. This in turn may increase the duration of parenteral nutrition and central venous line usage, increasing their complications. Delay in achieving full enteral feeds increases the risk of extrauterine growth restriction and neurodevelopmental impairment. OBJECTIVES: • To assess the efficacy and safety of routine monitoring of gastric residual versus no monitoring of gastric residual in preterm infants • To assess the efficacy and safety of routine monitoring of gastric residual based on two different criteria for interrupting feeds or decreasing feed volume in preterm infants We planned to undertake subgroup analysis based on gestational age (≤ 27 weeks, 28 weeks to 31 weeks, ≥ 32 weeks), birth weight (< 1000 g, 1000 g to 1499 g, ≥ 1500 g), small for gestational age versus appropriate for gestational age infants (classified using birth weight relative to the reference population), type of feed the infant is receiving (human milk or formula milk), and frequency of monitoring of gastric residual (before every feed, before every third feed, etc.) (see "Subgroup analysis and investigation of heterogeneity"). SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 1), MEDLINE via PubMed (1966 to 19 February 2018), Embase (1980 to 19 February 2018), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to 19 February 2018). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi‐randomised trials. SELECTION CRITERIA: We selected randomised and quasi‐randomised controlled trials that compared routine monitoring of gastric residual versus no monitoring or two different criteria of gastric residual to interrupt feeds in preterm infants. DATA COLLECTION AND ANALYSIS: Two review authors assessed trial eligibility and risk of bias and independently extracted data. We analysed treatment effects in individual trials and reported the risk ratio and the risk difference for dichotomous data, and the mean difference for continuous data, with respective 95% confidence intervals. We used the GRADE approach to assess the quality of evidence. MAIN RESULTS: Two randomised controlled trials with a total of 141 preterm infants met the inclusion criteria for the comparison of routine monitoring versus no monitoring of gastric residual in preterm infants. Both trials were done in infants with birth weight < 1500 g. Routine monitoring of gastric residual may have little or no effect on the incidence of necrotising enterocolitis (risk ratio (RR) 3.07, 95% confidence interval (CI) 0.50 to 18.77; participants = 141; studies = 2; low‐quality evidence). Routine monitoring may increase the risk of feed interruption episodes (RR 2.07, 95% CI 1.39 to 3.07; participants = 141; studies = 2; low‐quality evidence); the number needed to treat for an additional harmful outcome (NNTH) was 3 (95% CI 2 to 6). Routine monitoring of gastric residual may increase time taken to establish full enteral feeds (mean difference (MD) 3.92, 95% CI 2.06 to 5.77 days; participants = 141; studies = 2; low‐quality evidence), time taken to regain birth weight (MD 1.70, 95% CI 0.01 to 3.39 days; participants = 80; studies = 1; low‐quality evidence), and number of total parenteral nutrition days (MD 3.29, 95% CI 1.66 to 4.92 days; participants = 141; studies = 2; low‐quality evidence). We are uncertain as to the effect of routine monitoring of gastric residual on other outcomes such as incidence of surgical necrotising enterocolitis, extrauterine growth restriction at discharge, parenteral nutrition‐associated liver disease, duration of central venous line (CVL) usage, incidence of invasive infection, mortality before discharge, and duration of hospital stay. We found no data for outcomes such as aspiration pneumonia, gastroesophageal reflux, growth measures following discharge, and neurodevelopmental outcome. Only one trial with 87 preterm infants met the inclusion criteria for the comparison of using two different criteria of gastric residual to interrupt feeds while monitoring gastric residual. The trial was done in infants with birth weight of 1500 to 2000 g. We are uncertain as to the effect of using two different criteria of gastric residual on outcomes such as incidence of necrotising enterocolitis or surgical necrotising enterocolitis, time to establish full enteral feeds, time to regain birth weight, number of total parenteral nutrition days, number of infants experiencing feed interruption episodes, extrauterine growth restriction at discharge, parenteral nutrition‐associated liver disease, incidence of invasive infection, and mortality before discharge (very low quality evidence). We found no data on duration of CVL usage, aspiration pneumonia, gastroesophageal reflux, duration of hospital stay, growth measures following discharge, and neurodevelopmental outcome. AUTHORS' CONCLUSIONS: Review authors found insufficient evidence as to whether routine monitoring of gastric residual reduces the incidence of necrotising enterocolitis because trial results are imprecise. Low‐quality evidence suggests that routine monitoring of gastric residual increases the risk of feed interruption episodes, increases the time taken to reach full enteral feeds and to regain birth weight, and increases the number of total parenteral nutrition (TPN) days. Available data are insufficient to comment on other major outcomes such as incidence of invasive infection, parenteral nutrition‐associated liver disease, mortality before discharge, extrauterine growth restriction at discharge, number of CVL days, and duration of hospital stay. Further randomised controlled trials are warranted to provide more precise estimates of the effects of routine monitoring of gastric residual on important outcomes, especially necrotising enterocolitis, in preterm infants.

BACKGROUND: Routine monitoring of gastric residuals in preterm infants on gavage feeds is a common practice in many neonatal intensive care units and is used to guide the initiation and advancement of feeds. No guidelines or consensus is available on whether to re‐feed or discard the aspirated gastric residuals. Although re‐feeding gastric residuals may replace partially digested milk, gastrointestinal enzymes, hormones, and trophic substances that aid in digestion and promote gastrointestinal motility and maturation, re‐feeding abnormal residuals may result in emesis, necrotising enterocolitis, or sepsis. OBJECTIVES: To assess the efficacy and safety of re‐feeding compared to discarding gastric residuals in preterm infants. The allocation should have been started in the first week of life and should have been continued at least until the baby reached full enteral feeds. The investigator could have chosen to discard the gastric residual in the re‐feeding group, if the gastric residual quality was not satisfactory. However, the criteria for discarding gastric residual should have been predefined. To conduct subgroup analysis based on gestational age (≤ 27 weeks, 28 weeks to 31 weeks, ≥ 32 weeks), birth weight (< 1000 g, 1000 g to 1499 g, ≥ 1500 g), type of milk (human milk or formula milk), quality of the gastric residual (fresh milk, curded milk, or bile‐stained gastric residual), volume of gastric residual replaced (total volume, 50% of the volume, volume of the next feed, or prespecified volume, irrespective of the volume of the aspirate, e.g. 2 mL, 3 mL), and whether the volume of gastric residual that is re‐fed is included in or excluded from the volume of the next feed (see "Subgroup analysis and investigation of heterogeneity"). SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 1), MEDLINE via PubMed (1966 to 19 February 2018), Embase (1980 to 19 February 2018), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982 to 19 February 2018). We also searched clinical trial databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi‐randomised trials. SELECTION CRITERIA: Randomised and quasi‐randomised controlled trials that compared re‐feeding versus discarding gastric residuals in preterm infants. DATA COLLECTION AND ANALYSIS: Two review authors assessed trial eligibility and risk of bias and independently extracted data. We analysed treatment effects in individual trials and reported the risk ratio and risk difference for dichotomous data, and the mean difference for continuous data, with respective 95% confidence intervals. We used the GRADE approach to assess the quality of evidence. MAIN RESULTS: We found one eligible trial that included 72 preterm infants. This trial was not blinded. We are uncertain as to the effect of re‐feeding gastric residual on efficacy outcomes such as time to regain birth weight (mean difference (MD) 0.40 days, 95% confidence interval (CI) ‐2.89 to 3.69 days; very low quality evidence), time to reach enteral feeds ≥ 120 mL/kg/d (MD ‐1.30 days, 95% CI ‐2.93 to 0.33 days; very low quality evidence), number of infants with extrauterine growth restriction at discharge (risk ratio (RR) 1.29, 95% CI 0.38 to 4.34; very low quality evidence), duration of total parenteral nutrition (MD ‐0.30 days, 95% CI ‐2.07 to 1.47 days; very low quality evidence), and length of hospital stay (MD ‐1.90 days, 95% CI ‐25.27 to 21.47 days; very low quality evidence). Similarly, we are uncertain as to the effect of re‐feeding gastric residual on safety outcomes such as incidence of stage 2 or 3 necrotising enterocolitis and/or spontaneous intestinal perforation (RR 0.71, 95% CI 0.25 to 2.04; very low quality evidence), number of episodes of feed interruption lasting ≥ 12 hours (RR 0.80, 95% CI 0.42 to 1.52; very low quality evidence), or mortality before discharge (RR 0.50, 95% CI 0.14 to 1.85; low‐quality evidence). We are uncertain as to the effect of re‐feeding gastric residual in the subgroups of human milk‐fed and formula‐fed infants. We found no data on other outcomes such as linear and head growth during hospital stay, postdischarge growth, number of infants with parenteral nutrition‐associated liver disease, and neurodevelopmental outcomes. AUTHORS' CONCLUSIONS: We found only limited data from one small unblinded trial on the efficacy and safety of re‐feeding gastric residuals in preterm infants. The quality of evidence was low to very low. Hence, available evidence is insufficient to support or refute re‐feeding of gastric residuals in preterm infants. A large, randomised controlled trial is needed to provide data of sufficient quality and precision to inform policy and practice.