High versus standard volume enteral feeds to promote growth in preterm or low birth weight infants

Thangaraj Abiramalatha; Niranjan Thomas; Sivam Thanigainathan

doi:10.1002/14651858.CD012413.pub3

Alimentación enteral a un volumen alto versus estándar para promover el crecimiento en lactantes prematuros o con bajo peso al nacer

Declaraciones de intereses de los autores

Versión publicada: 12 marzo 2021 Historial de versiones

https://doi.org/10.1002/14651858.CD012413.pub3

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Resumen

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Antecedentes

La leche materna es la mejor nutrición enteral para los lactantes prematuros. Sin embargo, la leche materna sola, proporcionada a los volúmenes estándares recomendados, no es suficiente para alcanzar los requerimientos proteicos, energéticos y de otros nutrientes de los lactantes prematuros o con bajo peso al nacer. Una estrategia que se podría utilizar para abordar los posibles déficits de nutrientes es proporcionar un mayor volumen de alimentación enteral. La alimentación a un volumen alto podría mejorar la acumulación de nutrientes y el crecimiento, y a su vez podría mejorar los desenlaces del neurodesarrollo. Sin embargo, existe la preocupación de que la alimentación a un volumen alto pueda causar intolerancia alimentaria, enterocolitis necrosante o complicaciones relacionadas con la sobrehidratación, como el conducto arterial persistente y la enfermedad pulmonar crónica.

Ésta es una actualización de una revisión publicada en 2017.

Objetivos

Evaluar el efecto sobre el crecimiento y la seguridad de la alimentación enteral a un volumen alto versus un volumen estándar en lactantes prematuros o de bajo peso al nacer. En los lactantes alimentados con leche materna enriquecida o leche maternizada para prematuros, la alimentación a un volumen alto y estándar se definió como > 180 ml/kg/día y ≤ 180 ml/kg/día, respectivamente. En los lactantes alimentados con leche materna no enriquecida o con leche maternizada para recién nacidos a término, la alimentación a un volumen alto y estándar se definió como > 200 ml/kg/día y ≤ 200 ml/kg/día, respectivamente.

Métodos de búsqueda

Se utilizó la estrategia de búsqueda estándar del Grupo Cochrane de Neonatología (Cochrane Neonatal Group) para buscar en el Registro Cochrane central de ensayos controlados (CENTRAL; 2020 número 6) en The Cochrane Library; Ovid MEDLINE (1946 a junio de 2020); Embase (1974 a junio de 2020); y CINAHL (inicio a junio de 2020); Maternity & Infant Care Database (MIDIRS) (1971 a abril de 2020); así como en revisiones anteriores y registros de ensayos.

Criterios de selección

Ensayos controlados aleatorizados (ECA) y cuasialeatorizados que compararon alimentación enteral a volumen alto versus volumen estándar en lactantes prematuros o con bajo peso al nacer.

Obtención y análisis de los datos

Dos autores de la revisión evaluaron la elegibilidad de los ensayos y el riesgo de sesgo y extrajeron los datos de forma independiente. Se analizaron los efectos del tratamiento en los ensayos individuales y se informaron las razones de riesgos (RR) y la diferencia de riesgos (DR) para los datos dicotómicos, así como la diferencia de medias para los datos continuos, con los respectivos intervalos de confianza (IC) del 95%. Se utilizó el método GRADE para evaluar la certeza de la evidencia. Los desenlaces principales fueron el aumento de peso, el crecimiento lineal y cefálico durante la estancia hospitalaria y la restricción del crecimiento extrauterino al alta.

Resultados principales

En esta actualización se incluyeron dos nuevos ECA (283 lactantes). En esta revisión actualizada se incluyeron tres ensayos (347 lactantes).

Alimentación a un volumen alto versus volumen estándar con leche materna enriquecida o leche maternizada para prematuros

Dos ensayos (283 lactantes) cumplieron los criterios de inclusión para esta comparación. Ambos fueron de buena calidad metodológica, excepto por la falta de enmascaramiento. Ambos ensayos se realizaron en lactantes con < 32 semanas de gestación. El metanálisis de los datos de ambos ensayos mostró que la alimentación a un volumen alto probablemente mejora el aumento de peso durante la estancia hospitalaria (DM 2,58 g/kg/día; IC del 95%: 1,41 a 3,76; participantes = 271; evidencia de certeza moderada). La alimentación a un volumen alto podría tener poco o ningún efecto sobre el crecimiento lineal (DM 0,05 cm/semana; IC del 95%: ‐0,02 a 0,13; participantes = 271; evidencia de certeza baja), el crecimiento cefálico (DM 0,02 cm/semana; IC del 95%: ‐0,04 a 0,09; participantes = 271; evidencia de certeza baja) y la restricción del crecimiento extrauterino al alta (RR 0,71; IC del 95%: 0,50 a 1,02; participantes = 271; evidencia de certeza baja). No existe certeza acerca del efecto de la alimentación a un volumen alto con leche materna enriquecida o leche maternizada para prematuros sobre el riesgo de enterocolitis necrosante (RR 0,74; IC del 95%: 0,12 a 4,51; participantes = 283; evidencia de certeza muy baja).

Alimentación a un volumen alto versus alimentación estándar con leche materna no enriquecida o leche maternizada para recién nacidos a término

Un ensayo con 64 lactantes con muy bajo peso cumplió los criterios de inclusión para esta comparación. Este ensayo no estaba enmascarado, pero por lo demás era de buena calidad metodológica. La alimentación a un volumen alto probablemente mejora el aumento de peso durante la estancia hospitalaria (DM 6,2 g/kg/día; IC del 95%: 2,71 a 9,69; participantes = 61; evidencia de certeza moderada). El ensayo no proporcionó datos sobre el crecimiento lineal y cefálico, ni sobre la restricción del crecimiento extrauterino al alta. No existe certeza acerca del efecto de la alimentación a un volumen alto con leche materna no enriquecida o leche maternizada para recién nacidos a término sobre el riesgo de enterocolitis necrosante (RR 1,03; IC del 95%: 0,07 a 15,78; participantes = 61; evidencia de certeza muy baja).

Conclusiones de los autores

La alimentación a un volumen alto (≥ 180 ml/kg/día de leche materna enriquecida o leche maternizada para prematuros, o ≥ 200 ml/kg/día de leche materna no enriquecida o leche maternizada para recién nacidos a término) probablemente mejora el aumento de peso durante la estancia hospitalaria. Los datos disponibles no son adecuados para establecer conclusiones sobre el efecto de la alimentación a un volumen alto sobre otros desenlaces clínicos y del crecimiento. Se necesita un ECA grande que proporcione datos de suficiente calidad y precisión para informar las políticas y la práctica.

PICO

Population

Intervention

Comparison

Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

Resumen en términos sencillos

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Alimentación a un volumen alto versus estándar para promover el crecimiento en recién nacidos prematuros o con bajo peso al nacer

Pregunta de la revisión
¿Dar a los recién nacidos prematuros (con menos de 37 semanas) o de bajo peso al nacer (menos de 2500 gramos), un volumen de alimentación mayor que el habitual promueve el crecimiento sin causar problemas de alimentación u otros efectos secundarios?

Antecedentes
Los lactantes que nacen antes de tiempo (prematuros) necesitan nutrientes adicionales para su crecimiento. Una forma de aportar una nutrición extra es dar a los recién nacidos un volumen de alimentación superior al habitual (alimentación a un volumen alto, igual o superior a 180 o 200 ml/kg/día de leche). Aunque proporcionar altos volúmenes de leche a los recién nacidos prematuros o con bajo peso al nacer podría aumentar las tasas de crecimiento, las inquietudes al respecto incluyen que estos niños no puedan tolerar altos volúmenes de alimentación y puedan presentar efectos secundarios como problemas intestinales graves. Se buscó la evidencia proveniente de ensayos clínicos que evaluara si la alimentación a un volumen alto es beneficiosa o perjudicial para los recién nacidos prematuros o con bajo peso al nacer.

Características de los estudios
La búsqueda está actualizada hasta junio de 2020. Se encontraron tres estudios que abordaron esta pregunta.

Resultados clave
La evidencia de dos estudios mostró que la alimentación a un volumen alto (≥ 180 ml/kg/día) con leche materna enriquecida (leche materna con el agregado de fortificante para leche materna) o leche maternizada para prematuros probablemente mejora el aumento de peso durante la estancia hospitalaria, cuando se compara con la alimentación a un volumen estándar. De manera similar, la evidencia de un estudio pequeño mostró que la alimentación a un volumen alto (≥ 200 ml/kg/día) con leche materna no enriquecida o leche maternizada para prematuros probablemente mejora el aumento de peso durante la estancia hospitalaria. La evidencia no es suficiente para comentar el efecto de la alimentación a un volumen alto sobre el aumento de la talla o el tamaño de la cabeza durante la estancia hospitalaria, el crecimiento y el desarrollo a largo plazo, ni el efecto sobre los problemas intestinales u otros efectos secundarios.

Conclusiones

La alimentación a un volumen alto probablemente mejora el aumento de peso durante la estancia hospitalaria. Los datos disponibles no son adecuados para establecer conclusiones sobre el efecto de la alimentación a un volumen alto sobre otros desenlaces clínicos y del crecimiento.

Authors' conclusions

Implications for practice

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 were inadequate to draw conclusions on the effect of high volume feeds on other growth outcomes such as linear and head growth during hospital stay and post‐discharge growth, or clinical outcomes such as NEC, feed interruption episodes, PDA requiring treatment, chronic lung disease, duration of hospital stay, all‐cause mortality before discharge and long‐term neurodevelopmental outcomes.

Implications for research

A large RCT is needed to assess whether high volume versus standard volume enteral feeds improve important clinical outcomes for preterm or LBW infants. Such a trial should assess weight and linear and head growth, post‐discharge growth, neurodevelopmental outcomes, and risk of potential complications of high‐volume enteral feeds. A trial of this intervention may be regarded as a research priority, since the incidence of extrauterine growth restriction in VLBW or ELBW infants has not improved much despite multi‐nutrient fortification of feeds in high‐income countries. Further, multi‐nutrient fortifiers are less frequently used in low‐ and middle‐income countries due to cost constraints, and high volume feeds may be a suitable alternative to ensure adequate nutrition in preterm or low birth weight infants in such countries.

Summary of findings

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Summary of findings 1. High compared to standard volume of fortified human milk or preterm formula in preterm or low birth weight infants

Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
High compared to standard volume of fortified human milk or preterm formula in preterm or low birth weight infants
Patient or population: preterm or low birth weight infants Setting: neonatal intensive care unit (Australia and United States) Intervention: high volume feeds with fortified human milk or preterm formula Comparison: standard volume feeds with fortified human milk or preterm formula
Outcomes	Risk with standard volumes of fortified human milk or preterm formula	Risk with High volumes of fortified human milk or preterm formula	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Weight gain during hospital stay (g/kg/day) Follow‐up: Until discharge or 35‐36 weeks PMA	The mean weight gain during hospital stay varied from 16.5 to 17.9 g/kg/day	MD 2.58 higher (1.41 higher to 3.76 higher)	‐	271 (2 RCTs)	⊕⊕⊕⊝ MODERATE ¹	Probably improves weight gain during hospital stay
Linear growth during hospital stay (cm/week) Follow‐up: Until discharge or 35‐36 weeks PMA	The mean linear growth during hospital stay varied from 0.64 to 0.89 cm/week	MD 0.05 higher (0.02 lower to 0.13 higher)	‐	271 (2 RCTs)	⊕⊕⊝⊝ LOW ^{1 2}	May or may not improve linear growth during hospital stay
Head growth during hospital stay (cm/week) Follow‐up: Until discharge or 35‐36 weeks PMA	The mean head growth during hospital stay varied from 0.59 to 0.83 cm/week	MD 0.02 higher (0.04 lower to 0.09 higher)	‐	271 (2 RCTs)	⊕⊕⊝⊝ LOW ^{1 2}	May or may not improve linear growth during hospital stay
Extrauterine growth restriction at discharge Follow‐up: Until discharge	Study population		RR 0.71 (0.50 to 1.02)	271 (2 RCTs)	⊕⊕⊝⊝ LOW ^{1 2}	May or may not reduce extrauterine growth restriction at discharge
	312 per 1,000	222 per 1,000 (156 to 318)	RR 0.71 (0.50 to 1.02)	271 (2 RCTs)	⊕⊕⊝⊝ LOW ^{1 2}
Necrotising enterocolitis Follow‐up: Until discharge	Study population		RR 0.74 (0.12 to 4.51)	283 (2 RCTs)	⊕⊝⊝⊝ VERY LOW ^{2 3}	Uncertainty regarding the effect on the risk of NEC
Necrotising enterocolitis Follow‐up: Until discharge	14 per 1,000	10 per 1,000 (2 to 62)	RR 0.74 (0.12 to 4.51)	283 (2 RCTs)	⊕⊝⊝⊝ VERY LOW ^{2 3}	Uncertainty regarding the effect on the risk of NEC
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; MD: Mean difference; PMA: Postmenstrual age; RR: Risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ Downgraded one level for serious imprecision due to small sample size ² Downgraded one level for serious risk of bias due to lack of masking ³Downgraded by two levels for very serious imprecision due to small sample size and wide confidence interval

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Summary of findings 2. High compared to standard volume of unfortified human milk or term formula in preterm or low birth weight infants

Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
High compared to standard volume of unfortified human milk or term formula in preterm or low birth weight infants
Patient or population: preterm or low birth weight infants Setting: neonatal intensive care units (India) Intervention: high volume feeds with unfortified human milk or term formula Comparison: standard volume feeds with unfortified human milk or term formula
Outcomes	Risk with standard volume of unfortified human milk or term formula	Risk with High volumes of unfortified human milk or term formula	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Weight gain during hospital stay (g/kg/day) Follow‐up: Until babies reach 1700 g weight	The mean weight gain during hospital stay was 18.7 g/kg/day	MD 6.2 higher (2.71 higher to 9.69 higher)	‐	61 (1 RCT)	⊕⊕⊕⊝ MODERATE ¹	Probably improves weight gain during hospital stay
Linear growth (cm/week)	‐	see comment	‐	(0 studies)	‐	We found no data on this outcome.
Head growth (cm/week)	‐	see comment	‐	(0 studies)	‐	We found no data on this outcome.
Extrauterine growth restriction at discharge	Study population		‐	(0 studies)	‐	We found no data on this outcome.
Extrauterine growth restriction at discharge	see comment	see comment	‐	(0 studies)	‐	We found no data on this outcome.
Necrotising enterocolitis Follow‐up: Until discharge	Study population		RR 1.03 (0.07 to 15.78)	61 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^{2 3}	Uncertainty regarding the effect on the risk of NEC
Necrotising enterocolitis Follow‐up: Until discharge	32 per 1,000	33 per 1,000 (2 to 509)	RR 1.03 (0.07 to 15.78)	61 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^{2 3}	Uncertainty regarding the effect on the risk of NEC
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; MD: Mean difference; RR: Risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: we have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ Downgraded one level for serious imprecision due to small sample size ² Downgraded one level for serious risk of bias due to lack of masking ³ Downgraded two levels for very serious imprecision due to small sample size and wide confidence intervals

Background

Description of the condition

The optimal growth rate of infants born preterm or with low birth weight (LBW) is not known (Higgins 2012). Consensus guidelines suggest that caregivers should aim to achieve a postnatal growth rate similar to the gestation‐equivalent foetal growth rate (Agostoni 2010). Many preterm or LBW infants, especially those who are very low birth weight (VLBW) or extremely low birth weight (ELBW), do not achieve these rates of growth and are growth restricted at the time of hospital discharge (Clark 2003; Cooke 2004; Ehrenkranz 1999; Horbar 2015; Lima 2014; Sakurai 2008; Shan 2009; Stevens 2016; Steward 2002;). Growth deficits can persist through childhood and adolescence and into adulthood (Brandt 2005; Dusick 2003; Euser 2008; Hack 2003; Stein 2013). Slow postnatal growth is associated with neurodevelopmental impairment and with poorer cognitive and scholastic outcomes (Brandt 2003; Franz 2009; Leppanen 2014; Neubauer 2013). Furthermore, there are concerns that nutritional deficiency and growth restriction during infancy may have adverse effects on long‐term metabolic and cardiovascular health (Embleton 2013; Higgins 2012; Lapillonne 2013).

Preterm infants have higher nutritional requirements than term infants. An energy intake of 110 to 135 Kcal/kg/day and protein intake of 3.5 to 4 g/kg/day in infants with 1000 to 1499 grams birth weight and 4 to 4.5 g/kg/day in infants with < 1000 grams birth weight are recommended to meet the higher nutrients requirement of preterm infants.

Description of the intervention

Human milk is the best enteral nutrition for newborn infants (Johnston 2012). However, human milk alone, given at volumes that meet the nutritional needs of term infants, may not meet the higher nutritional requirements of preterm or LBW infants (AAP 2004; Agostoni 2010; CPS 1995; Embleton 2007) (Table 1). The strategy most commonly employed to address these potential nutrient deficits is to supplement human milk with a multi‐component human milk fortifier (Cormack 2013; Dutta 2015; Klingenberg 2012; Uhing 2009). A Cochrane Review of randomised controlled trials provides evidence that feeding preterm infants with multi‐nutrient fortified human milk rather than unfortified human milk increases growth rates during the initial hospitalisation period (Brown 2020). However, despite fortification, the rates of extrauterine growth restriction in VLBW or ELBW infants is still high (Lee 2020; Stevens 2016). This signifies the need for further improvement in nutritional intake in these infants.

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Table 1. Typical energy and protein content of human milk or formula

Per 100 mL

Expressed breast milk

(EBM)

EBM

+ fortifier

Term formula

Preterm formula

Energy (kCal)

Protein (g)

1.5

2.0 to 2.3

1.5

2.0

The maximum volume of enteral feeds used in many centres across the world is 150 to 180 mL/kg/day (Klingenberg 2012). Fortified human milk or preterm formula (which usually gives 80 Kcal and 2 grams protein per 100 mL) given at this standard volume meets only the calorie requirement and not the protein requirement of preterm, especially ELBW infants. Increasing the volume of feeds could meet these nutrient deficits. Further, multi‐component fortifiers and nutrient‐enriched preterm formula are expensive and unaffordable in resource‐limited settings (Chawla 2008; Kler 2015). Unfortified human milk or standard term formula is still used as the sole source of enteral nutrition in such settings, where increasing the volume of feeds could be the only way to improve nutrient intake in preterm infants.

Feeding preterm or LBW infants with daily volumes of milk in excess of 180 mL/kg (high volume feeds) has been proposed as a safe and effective growth‐enhancement strategy (Klingenberg 2019; Kuschel 2000; Lewis 1984; Thomas 2012; Valman 1974; Zecca 2014). In order to provide 4 to 4.5 g/kg protein, fortified human milk or preterm formula has to be fed at a volume of 200 to 225 mL/kg/day and unfortified human milk or term formula has to be fed at a volume of 270 to 300 mL/kg/day. However, due to concerns about the risk of necrotising enterocolitis (NEC), feed intolerance and complications of fluid overload patent ductus arteriosus (PDA) and chronic lung disease (CLD), high volume enteral feeding has not become an established practice (Bertino 2009; Chawla 2008; Klingenberg 2012; Raban 2013; Sankar 2008).

How the intervention might work

Feeding preterm or LBW infants higher volumes of milk (more than 180 mL/kg/d) may promote nutrient accretion and improve growth. Higher levels of nutrient intake during this critical period may be important for optimising long‐term growth and neurodevelopment (Embleton 2013). The potential disadvantages of high volume feeds also are known. High volumes of milk may add to the physiological and metabolic stress of the immature gastrointestinal tract and its blood supply, thus increasing the risk of NEC. High volume feeds may result in or worsen gastro‐oesophageal reflux, increasing risk of apnoea or aspiration. High volume feeds may lead to fluid overload and associated complications such as peripheral or pulmonary oedema, PDA and CLD. Furthermore, enteral feeding that is ceased owing to intolerance may reduce total nutrient intake over time, thus adversely affecting growth.

Why it is important to do this review

Given the potential of high volume feeds to increase nutrient accretion and improve growth and developmental outcomes in preterm or LBW infants, as well the potential risks of this feeding strategy, we undertook a systematic review to identify and appraise data from randomised controlled trials and to provide a synthesis of evidence that could inform practice and research.

Objectives

To assess the effect on growth and safety of high versus standard volume enteral feeds in preterm or LBW 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.

To conduct subgroup analyses based on gestational age (< 28 weeks, 28 weeks to 31 weeks, ≥ 32 weeks), birth weight (< 1000 grams, 1000 grams to 1499 grams, ≥ 1500 grams), type of milk (human milk vs formula) and presence of intrauterine growth restriction (using birth weight relative to the reference population as a surrogate). (See Subgroup analysis and investigation of heterogeneity.)

Methods

Criteria for considering studies for this review

Types of studies

We included randomised controlled trials (RCTs), quasi‐ and cluster‐RCTs.

Types of participants

We included preterm (< 37 weeks' gestational age) or low birth weight (< 2500 grams birth weight) infants.

Types of interventions

Comparison 1: In infants who were fed fortified human milk or preterm formula

Intervention

High volume feeds, defined as > 180 mL/kg/day

Control

Standard volume feeds, defined as ≤ 180 mL/kg/day

Comparison 2: In infants who were fed unfortified human milk or term formula

Intervention

High volume feeds defined as > 200 mL/kg/day

Control

Standard volume feeds, defined as ≤ 200 mL/kg/day

See Differences between protocol and review.

Infants might have been randomised to the allocated intervention at any stage up to the time of achieving full enteral feeding volumes. The prescribed feeding regimen should have been followed until the infant was able to self‐regulate intake.

Types of outcome measures

Primary outcomes

Rates of weight gain (g/kg/d), linear growth (cm/week), or head growth (cm/week) during hospital stay
Proportion of infants with extrauterine growth restriction at discharge (weight less than 10th percentile for the index population)

Secondary outcomes

Number of infants with NEC (modified Bell stage 2 or 3; Walsh 1986)
Proportion of infants with feed interruption episodes (lasting ≥ 12 hours)
Time to regain birth weight (days)
Growth measures, namely weight, length and head circumference, measured at a specified postmenstrual age prior to discharge
Number of infants with PDA treated pharmacologically or surgically
Number of infants with aspiration pneumonia or pneumonitis (clinical or radiological evidence of lower respiratory tract compromise that has been attributed to covert or evident aspiration of gastric contents)
Number of infants with gastro‐oesophageal reflux diagnosed by clinical features; post‐feed (if bolus‐fed) apnoea, desaturation, irritability, or vomiting; or oesophageal pH monitoring, multiple intraluminal impedance, or endoscopy
Frequency of apnoea (no respiratory effort > 20 seconds) or bradycardia (< 100 beats per minute), or apnoea/bradycardia necessitating stimulation, oxygen administration increase, or positive‐pressure ventilation (number of episodes per day)
Frequency of episodes of spontaneous fall in oxygen saturation (SpO₂) to 85% or less (number of episodes per day)
Number of infants with CLD (requirement of oxygen supplementation at 36 weeks' postmenstrual age)
All‐cause mortality before discharge or up to 44 weeks' postmenstrual age
Duration of hospital stay (days)
Growth measures following discharge from hospital to latest follow‐up
Neurodevelopmental outcomes assessed after 12 months post‐term: neurological evaluations; developmental scores; and classifications of disability, including auditory and visual disability. We defined neurodevelopmental impairment as the presence of one or more of the following: non‐ambulant cerebral palsy; developmental quotient greater than two standard deviations below the population mean; and blindness (visual acuity < 6/60) or deafness (any hearing impairment requiring, or unimproved by, amplification)

See Differences between protocol and review.

Search methods for identification of studies

We used the standard search strategy of Cochrane Neonatal (neonatal.cochrane.org/resources-review-authors).

Electronic searches

We conducted a comprehensive search including Cochrane Central Register of Controlled Trials (CENTRAL 2020, Issue 6) in the Cochrane Library; Ovid MEDLINE(R) (1946 to 5 June 2020); Embase (1974 to 5 June 2020); CINAHL (inception to 8 June 2020); Maternity & Infant Care Database (MIDIRS), Ovid (1971 to April 2020). We have included the search strategies for each database in Appendix 1. We did not apply language restrictions.

We searched ClinicalTrials.gov for completed or ongoing trials.

This search updates the searches conducted for previous versions of the review (Abiramalatha 2017; Appendix 2).

Searching other resources

We also searched the reference lists of any articles selected for inclusion in this review in order to identify additional relevant articles.

Data collection and analysis

We used standard methods of Cochrane and Cochrane Neonatal (Higgins 2020).

Selection of studies

We screened the title and abstract of all studies identified by the above search strategy, and two review authors (TA and ST) independently assessed the full articles for all potentially relevant trials. We excluded studies that did not meet all of the inclusion criteria, and we stated the reason for exclusion. We discussed disagreements until we achieved consensus or by consulting a third author (NT).

We recorded the selection process in sufficient detail to complete a Characteristics of excluded studies table and a PRISMA flow diagram (Moher 2009).

Data extraction and management

Two review authors (TA and ST) extracted data independently using a data collection form to aid extraction of information on design, methods, participants, interventions, outcomes and treatment effects from each included study. We discussed disagreements until we achieved consensus or by consulting a third author (NT). If data from trial reports were insufficient, we contacted trialists to request further information.

Assessment of risk of bias in included studies

Two review authors (TA and ST) independently assessed the risk of bias (low, high, or unclear) of all included trials using the Cochrane ‘Risk of bias’ tool (Higgins 2011), for the following domains.

Sequence generation (selection bias)
Allocation concealment (selection bias)
Blinding of participants and personnel (performance bias)
Blinding of outcome assessment (detection bias)
Incomplete outcome data (attrition bias)
Selective reporting (reporting bias)
Any other bias

We resolved any disagreements by discussion or by consulting a third author (NT). See Appendix 3 for a more detailed description of risk of bias for each domain.

Measures of treatment effect

We analysed treatment effects in individual trials using Review Manager 5 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) (Review Manager 2020).

Unit of analysis issues

The unit of analysis was the participating infant in RCTs. We combined study results where there was little heterogeneity between study designs, and we considered interactions between effects of the intervention and the choice of randomisation unit to be unlikely.

Dealing with missing data

We requested and obtained additional data from trialists if information on important outcomes was missing or was reported unclearly.

Assessment of heterogeneity

We examined treatment effects of individual trials and heterogeneity between trial results by inspecting forest plots. We calculated the I² statistic for each RR analysis to quantify inconsistency across studies and to describe the percentage of variability in effect estimates that may be due to heterogeneity rather than to sampling error. If we detected moderate or high heterogeneity (I² ≥ 50%), we planned to explore possible causes (e.g. differences in study design, participants, interventions, or completeness of outcome assessments).

Assessment of reporting biases

As we included only two trials in the meta‐analysis, we could not examine a funnel plot for possible publication bias.

Data synthesis

We analysed all infants randomised on an intention‐to‐treat basis and treatment effects in individual trials using a fixed‐effect model to combine the data.

Certainty of evidence

We used the GRADE approach, as outlined in the GRADE Handbook (Schünemann 2013), to assess the certainty of evidence of the following (clinically relevant) outcomes: weight gain, linear and head growth during hospital stay, extrauterine growth restriction at discharge, and necrotising enterocolitis.

Two review authors (TA and ST) independently assessed the certainty of the evidence for each of the outcomes above. We considered evidence from RCTs as high certainty but downgraded the evidence one level for serious (or two levels for very serious) limitations based upon the following: design (risk of bias), consistency across studies, directness of the evidence, precision of estimates, and presence of publication bias. We used the GRADEpro GDT Guideline Development Tool to create summary of findings Table 1 and summary of findings Table 2 to report the certainty of the evidence.

The GRADE approach results in an assessment of the certainty of a body of evidence as one of four grades.

High certainty: further research is very unlikely to change our confidence in the estimate of effect.
Moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low certainty: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low certainty: we are very uncertain about the estimate.

Subgroup analysis and investigation of heterogeneity

We planned to undertake these subgroup analyses, when possible.

Based on gestational age: < 28 weeks, 28 to 31 weeks, ≥ 32 weeks
Based on birth weight: < 1000 grams, 1000 to 1499 grams, ≥ 1500 grams
Type of milk: human milk versus formula
Infants with birth weight below the 10th percentile for the reference population ('small for gestational age') versus infants with birth weight 'appropriate for gestational age

See Differences between protocol and review.

Sensitivity analysis

We planned to undertake sensitivity analyses to determine whether findings were affected when only studies using adequate methods were included (low risk of bias); adequate methods were defined as adequate randomisation and allocation concealment, blinding of intervention and measurement, and less than 10% loss to follow‐up. However, we did not conduct any sensitivity analysis, as it was not required.

Results

Description of studies

See Characteristics of included studies and Characteristics of excluded studies tables.

Results of the search

The results of the updated search are shown in Figure 1. We screened 5858 titles and abstracts that were identified via the search strategy. We carried out full‐text review of four articles. We excluded two new studies, and we reported details of the excluded studies. We identified two new eligible studies. Thus, we included a total of three studies in this review.

Figure 1

Updated study flow diagram.

Included studies

We included three RCTs with a total of 347 infants (See Characteristics of included studies table).

We included two trials for the comparison of high versus standard volume feeds with fortified human milk or preterm formula (Kuschel 2000; Travers 2020), and one trial for the comparison of high versus standard volume feeds with unfortified human milk or term formula (Thomas 2012).

Kuschel 2000, conducted in Australia, enrolled 59 infants born at less than 30 weeks' gestation. Infants in high and standard volume feeds groups received 200 and 150 mL/kd/day feeds respectively. Either fortified human milk or preterm formula was used for feeding. Fortification was continued until the baby reached 1800 to 2000 grams. The primary outcome was growth measures such as weight, length, head circumference, arm area, arm muscle are, arm fat area at 35 weeks' postmenstrual age (PMA), and mean weight gain in g/kg/day. Secondary outcomes were PMA and weight at which fortification or preterm formula was ceased, PMA when reaching full sucking feeds, PMA and weight at discharge, growth measures such as weight, length and head circumference at 12 months' corrected age, and developmental assessment using Griffiths Mental Development Scales at 12 months' corrected age.

Travers 2020, conducted in the USA, randomised 224 infants born at less than 32 weeks' gestation with a birth weight 1001 to 2500 grams to high (180 to 200 mL/kg/day) and standard volume feeds (140 to 160 mL/kd/day) groups. Either fortified human milk or preterm formula was used for feeding. The primary outcome was weight gain in g/kg/day from birth till 36 weeks' PMA. Secondary outcomes were increase in length, head circumference and mid‐arm circumference, postnatal growth failure (weight less than 10th percentile for PMA), CLD, NEC, haemodynamically significant PDA, duration of respiratory support, culture proven sepsis after study entry and mortality before hospital discharge.

Thomas 2012, conducted in India, enrolled 64 infants with birth weight < 1500 grams. Both appropriate‐ and small‐for‐gestational‐age infants were eligible to participate. Infants in the high volume group received 300 mL/kg/day, and those in the standard volume group received 200 mL/kg/day. Participants were fed with unfortified human milk plus individual micronutrient supplementation for iron, calcium, and vitamins. Multi‐nutrient fortifiers, which supplement calories and protein, were not used. The primary outcome was daily weight gain from enrolment until the infant reached 1700 grams weight. Secondary outcomes were feed intolerance, tachypnoea (respiratory rate > 60 breaths per minute), PDA (diagnosed clinically or by echocardiography), NEC (Bell stage 2A or greater), invasive infection (confirmed by blood culture) and biochemical abnormalities.

Excluded studies

We excluded four studies in total (see Characteristics of excluded studies).

We excluded two new studies (Klingenberg 2019; Zecca 2014), for the following reasons.

Klingenberg 2019 was a retrospective observational study on 99 infants born at < 30 weeks' gestation, who were fed high volume (> 180 mL/kg/day) of fortified human milk.

Zecca 2014 was an RCT. The trial compared 200 mL/kg/day versus 170 mL/kg/day of unfortified human milk, both of which were standard volume feeds. Further, the trial reported different rates of feed volume advancement in the intervention and control groups.

We excluded two studies in the original review (Abiramalatha 2017), because they were not RCTs. One was an observational study of LBW infants fed 250 mL/kg/d of milk (Lewis 1984). The other was a cohort study comparing two enteral feed volumes; 180 and 230 mL/kg/d (Valman 1974).

Risk of bias in included studies

See Figure 2.

Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for the included study.

Allocation

All three included trials used computer‐generated random numbers for sequence generation and sealed opaque envelopes for allocation concealment (Kuschel 2000; Thomas 2012; Travers 2020).

Blinding

All the three included studies were open‐label trials.

Incomplete outcome data

Trialists of all the three trials have assessed all participants for primary and secondary outcomes.

Selective reporting

The study protocol was published for Travers 2020 and all proposed outcomes were reported. The study protocol was not published for Kuschel 2000 and Thomas 2012; by personal communication with the trialists, we found that all proposed outcomes were reported.

Other potential sources of bias

We did not identify any other bias in the three included trials.

Effects of interventions

See: Summary of findings 1 High compared to standard volume of fortified human milk or preterm formula in preterm or low birth weight infants; Summary of findings 2 High compared to standard volume of unfortified human milk or term formula in preterm or low birth weight infants

High versus standard volume of fortified human milk or preterm formula (Comparison 1)

Primary outcomes

Rate of weight gain during hospital stay

(Analysis 1.1; Figure 3)

Figure 3

Forest plot of comparison: 1 High versus standard volume of fortified human milk or preterm formula, outcome: 1.1 Weight gain during hospital stay (g/kg/day).

Both trials reported this outcome (Kuschel 2000; Travers 2020). The rate of weight gain was greater in infants fed high volumes compared to those fed standard volumes of fortified milk or preterm formula (MD 2.58 g/kg/day, 95% CI 1.41 to 3.76; participants = 271). There was no evidence of heterogeneity (I² = 0%).

Linear growth during hospital stay

(Analysis 1.2)

Meta‐analysis of data from both trials (Kuschel 2000; Travers 2020), showed no difference in the outcome of linear growth during hospital stay between high and standard volume feeds groups (MD 0.05 cm/week, 95% CI ‐0.02 to 0.13; participants = 271). There was no evidence of heterogeneity (I² = 0%).

Head growth during hospital stay

(Analysis 1.3)

Meta‐analysis of data from both trials (Kuschel 2000; Travers 2020), showed no difference in head growth during hospital stay between the groups (MD 0.02 cm/week, 95% CI ‐0.04 to 0.09; participants = 271). There was no heterogeneity (I² = 10%).

Extrauterine growth restriction at discharge

(Analysis 1.4)

Both trials (Kuschel 2000; Travers 2020), reported the outcome. There was no difference in the incidence of extrauterine growth restriction (weight less than 10th percentile) at discharge between the high and standard volume feeds groups (RR 0.71, 95% CI 0.50 to 1.02; participants = 271). There was moderate heterogeneity (I² = 60%).

Secondary outcomes

NEC stage 2 or 3

(Analysis 1.5; Figure 4)

Figure 4

Forest plot of comparison: 1 High versus standard volume of fortified human milk or preterm formula, outcome: 1.5 Necrotising enterocolitis.

Both trials (Kuschel 2000; Travers 2020) reported the outcome. The meta‐analysis showed no difference in the incidence of NEC between the high and standard volume feeds groups (RR 0.74, 95% CI 0.12 to 4.51; participants = 283). There was mild heterogeneity (I² = 27%).

Feed interruption episodes

(Analysis 1.6)

One trial (Travers 2020), reported the outcome. There was no difference in the proportion of infants with feed interruption episodes ≥ 12 hours between the groups (RR 0.72, 95% CI 0.12 to 4.25; participants = 217).

Time to regain birth weight

(Analysis 1.7)

Both trials reported this outcome (Kuschel 2000; Travers 2020). The meta‐analysis showed a marginal difference, with infants given high volume feeds regaining birth weight earlier than those given standard volume feeds (MD ‐1.23 days, 95% CI ‐2.36 to ‐0.10; participants = 271). There was no evidence of heterogeneity (I² = 0%).

Weight at a specified PMA

(Analysis 1.8; Figure 5)

Figure 5

Forest plot of comparison: 1 High versus standard volume of fortified human milk or preterm formula, outcome: 1.8 Weight at a specified postmenstrual age (g).

Both trials reported the outcome. Kuschel 2000 reported the growth measures when fortification was stopped, which had a median of 34 to 35 weeks' (range 32 to 40 weeks') PMA. Travers 2020 reported growth measures at discharge or 36 weeks' PMA whichever was earlier. Meta‐analysis showed that babies who were given high volume feeds had reached greater weight at a specified PMA compared to those given standard volume feeds (MD 152.10 g, 95% CI 71.67 to 232.53; participants = 271). There was no evidence of heterogeneity (I² = 4%).

Length at a specified PMA

(Analysis 1.9)

Meta‐analysis of data from both trials (Kuschel 2000; Travers 2020) showed no difference in the length attained at a specified PMA between the two groups (MD 0.50 cm, 95% CI ‐0.04 to 1.04; participants = 271). There was no heterogeneity (I² = 0%).

Head circumference at a specified PMA

(Analysis 1.10; Figure 6)

Figure 6

Forest plot of comparison: 1 High versus standard volume of fortified human milk or preterm formula, outcome: 1.10 Head circumference at a specified postmenstrual age (cm).

Meta‐analysis of data from both trials (Kuschel 2000; Travers 2020) showed that infants in the high volume feeds group attained greater head circumference at a specified PMA than those in the standard volume feeds group (MD 0.49 cm, 95% CI 0.15 to 0.83; participants = 271). There was no evidence of heterogeneity (I² = 0%).

PDA requiring treatment

(Analysis 1.11)

Both trials (Kuschel 2000; Travers 2020), reported the outcome and there was no difference in the incidence of PDA requiring treatment (RR 0.77, 95% CI 0.28 to 2.12; participants = 271). There was no heterogeneity (I² = 0%).

Aspiration pneumonia or pneumonitis

This outcome was not reported in the trials.

Gastro‐oesophageal reflux

This outcome was not reported in the trials.

Frequency of apnoea

This outcome was not reported in the trials.

Frequency of desaturation episodes

This outcome was not reported in the trials.

Chronic lung disease

(Analysis 1.12)

Both trials (Kuschel 2000; Travers 2020), reported this outcome. There was no difference in the incidence of chronic lung disease between the groups (RR 1.01, 95% CI 0.57 to 1.81; participants = 271). There was no evidence of heterogeneity (I² = 0%).

All‐cause mortality before discharge

(Analysis 1.13)

Data was available from both the trials (Kuschel 2000; Travers 2020). Meta‐analysis showed no difference in the outcome between the high and standard volume feeds groups (RR 0.24, 95% CI 0.01 to 4.71; participants = 283). There was no evidence of heterogeneity (I² = 0%).

Duration of hospital stay

(Analysis 1.13)

Meta‐analysis of data from both the trials showed no difference in the duration of hospital stay between the groups (MD 1.00 day, 95% CI ‐3.54 to 5.54 days; participants = 271). There was no evidence of heterogeneity (I² = 0%).

Growth measures at 12 months' corrected age

(Analysis 1.15; Analysis 1.16; Analysis 1.17)

One trial (Kuschel 2000), reported growth measures at 12 months' corrected age. The trial showed no difference in the proportion of infants with weight for age less than 10th percentile (RR 0.70, 95% CI 0.23 to 2.15; participants = 47), length less than 10th percentile (RR 0.35, 95% CI 0.08 to 1.55; participants = 47) or head circumference less than 10th percentile (RR 0.35, 95% CI 0.01 to 8.11; participants = 47) at 12 months' corrected age between the high and standard volume feeds groups.

Neurodevelopmental outcomes assessed at 12 months' corrected age

(Analysis 1.18)

One trial (Kuschel 2000), reported neurodevelopmental outcomes at 12 months' corrected age. The trial showed no difference in the proportion of infants with neurodevelopmental impairment (which included cerebral palsy, severe developmental delay and/or deafness) at 12 months' corrected age between the high and standard volume feeds groups (RR 0.52, 95% CI 0.15 to 1.84; participants = 47).

High versus standard volume of unfortified milk or term formula (Comparison 2)

Primary outcomes

Rate of weight gain during hospital stay

(Analysis 2.1; Figure 7)

Figure 7

Forest plot of comparison: 2 High versus standard volume of unfortified human milk or term formula, outcome: 2.1 Weight gain during hospital stay (g/kg/day).

Thomas 2012 showed that the rate of weight gain was greater in infants fed higher volume compared to those fed standard volumes of unfortified milk or term formula (MD 6.20 g/kg/day, 95% CI 2.71 to 9.69; participants = 61).