Leche maternizada versus leche materna para la alimentación de los lactantes prematuros o de bajo peso al nacer
Resumen
Antecedentes
Las leches artificiales se pueden manipular para que contengan mayores cantidades de macronutrientes que la leche materna, pero la leche materna confiere importantes ventajas inmunonutricionales a los lactantes prematuros o de bajo peso al nacer (BPN).
Objetivos
Determinar el efecto de la alimentación de los lactantes prematuros o de bajo peso al nacer con leche maternizada en comparación con la leche materna sobre los resultados de crecimiento y desarrollo.
Métodos de búsqueda
Se utilizó la estrategia estándar del Grupo Cochrane de Neonatología (Cochrane Neonatal Group) para realizar búsquedas en el Registro Cochrane Central de Ensayos Controlados (Cochrane Central Register of Controlled Trials) (CENTRAL 2018, número 9), y en Ovid MEDLINE, Ovid Embase, Ovid Maternity & Infant Care Database y CINAHL hasta octubre de 2018. Se realizaron búsquedas en bases de datos de ensayos clínicos, actas de congresos y en las listas de referencias de los artículos recuperados.
Criterios de selección
Ensayos controlados aleatorizados o cuasialeatorizados que compararon la alimentación de los lactantes prematuros o de bajo peso al nacer con leche maternizada versus leche materna.
Obtención y análisis de los datos
Dos autores de la revisión, de forma independiente, evaluaron la elegibilidad de los ensayos y el riesgo de sesgo y extrajeron los datos. Se planificó analizar los efectos del tratamiento según lo descrito en los ensayos individuales e informar los riesgos relativos y las diferencias de riesgos para los datos dicotómicos, y las diferencias de medias para los datos continuos, con intervalos de confianza del 95%. Se programó utilizar un modelo de efectos fijos en los metanálisis y se exploraron las posibles causas de heterogeneidad en análisis de subgrupos. Se programó utilizar los criterios GRADE para evaluar la calidad de la evidencia.
Resultados principales
No se identificaron ensayos elegibles.
Conclusiones de los autores
No hay ensayos de leche maternizada versus leche materna para la alimentación de lactantes prematuros o de bajo peso al nacer. Es poco probable que se realicen dichos ensayos debido a la dificultad de asignar una forma alternativa de nutrición a un lactante cuya madre desea alimentarle con su propia leche materna. La leche materna sigue siendo la elección predeterminada de la nutrición enteral porque los estudios observacionales y los metanálisis de los ensayos que comparan la alimentación con leche maternizada versus leche materna de donante, indican que la alimentación con leche materna tiene ventajas inmunonutricionales importantes para los lactantes prematuros o de bajo peso al nacer.
PICO
Resumen en términos sencillos
Leche maternizada versus leche materna para la alimentación de los lactantes prematuros o de bajo peso al nacer
Pregunta de la revisión
¿La alimentación de los lactantes prematuros o de bajo peso al nacer con leche maternizada en lugar de la leche materna afecta el crecimiento y el desarrollo?
Antecedentes
Las leches artificiales se pueden manipular para que contengan mayores cantidades de nutrientes importantes que la leche materna, como proteínas, pero los lactantes a menudo encuentran que la leche maternizada es difícil de digerir. Además, las leches artificiales no contienen los anticuerpos y otras sustancias presentes en la leche materna que protegen el intestino inmaduro de los lactantes prematuros o de bajo peso al nacer y reducen el riesgo de infección y de problemas intestinales graves. Si los lactantes prematuros se alimentan con leche maternizada en lugar de leche materna (lactados directamente o con leche materna extraída), podría aumentar el riesgo de estos problemas y afectar negativamente el crecimiento y el desarrollo. Debido a estas inquietudes, se revisó toda la evidencia disponible de los ensayos clínicos que compararon leche maternizada versus leche materna para la alimentación de los lactantes prematuros o de bajo peso al nacer.
Características de los estudios
En las búsquedas realizadas hasta octubre de 2018, no se encontraron ensayos controlados aleatorizados elegibles.
Resultados clave y conclusiones
No hay datos de ensayos para responder a esta pregunta. Debido a que otra revisión Cochrane mostró que la alimentación con leche maternizada comparada con la leche materna de donante aumenta el riesgo de problemas intestinales graves en los lactantes prematuros o de bajo peso al nacer, es poco probable que las familias y los médicos consideren aceptable asignar a un lactante a recibir leche maternizada como una alternativa a la leche materna cuando ésta esté disponible.
Authors' conclusions
Background
This review focuses on the comparison of feeding preterm or low birth weight (LBW) infants with artificial formula versus maternal (mother's own) breast milk. The comparison of feeding with formula versus donor breast milk is addressed in a separate review (Quigley 2018). Healthcare professional or peer‐led breastfeeding support interventions for mothers of preterm or LBW infants have been addressed in other reviews (McInnes 2008; Renfrew 2009; Ahmed 2010).
Description of the condition
Early enteral feeding strategies, including the type of milk given to infants, can affect important outcomes in preterm or LBW infants, and especially very preterm or very low birth weight (VLBW) infants who have limited nutrient reserves at birth and are subject to physiological and metabolic stresses that increase their nutrient needs (Agostoni 2010; Embleton 2017). Most very preterm or VLBW infants accumulate nutrient deficits during their initial hospital stay and many infants are growth‐restricted relative to their term‐born peers by the time they are ready to go home (Embleton 2001; Horbar 2015). Growth deficits, which can persist through childhood and adolescence, are associated with adverse neurodevelopmental, cognitive, and educational outcomes (Leppänen 2014).
Description of the intervention
Maternal breast milk is the recommended form of enteral nutrition for preterm or LBW infants (Agostoni 2010; AAP 2012; Cleminson 2015). In addition to macro‐ and micro‐nutrients that are optimised by evolution for digestion and absorption by human infants, maternal breast milk contains numerous 'immuno‐nutrients' such as secretory immunoglobulin (Ig)A, lactoferrin, cytokines, enzymes, growth factors, and leucocytes (Walsh 2019). An important benefit of maternal breast milk for preterm or LBW infants is that delivery of these immunological and growth factors to the immature intestinal mucosa promotes post‐natal physiological, neuro‐endocrinological, and metabolic adaptation (Jones 2007; Embleton 2017). Evidence from observational studies suggests that feeding with maternal breast milk rather than formula is associated with a reduced risk of serious adverse outcomes including necrotising enterocolitis and infection in very preterm and VLBW infants (Lucas 1990; Battersby 2017). A Cochrane Review of trials that compared feeding preterm or LBW infants with formula versus donor breast milk showed that formula feeding was associated with a near doubling of the risk of severe necrotising enterocolitis (Quigley 2018).
The nutritional requirements of preterm or LBW infants, and especially very preterm and VLBW infants, may not be met by enteral feeding with maternal breast milk alone (Agostoni 2010). Maternal breast milk varies in energy and protein content depending upon the stage of lactation at which it is collected, the duration of lactation, and the method of storage and delivery. Many of the processes involved in handling maternal breast milk, including refrigeration, freeze‐thawing, and pasteurisation, can reduce its macro‐nutrient and immuno‐nutrient content (Zachariassen 2013; Gidrewicz 2014). Supplementation of maternal breast milk with nutrient fortifiers (typically extracted from cow milk) is an option for increasing nutrient density (Klingenberg 2012; Tudehope 2013; Underwood 2013). Although this results in faster short‐term growth, uncertainty remains about whether fortification using bovine milk extracts increases the risk of enteral feed intolerance or necrotising enterocolitis in very preterm or VLBW infants (Brown 2016; Ellis 2019).
Intervention ‒ formula
As an alternative to breast milk, a variety of artificial formulas (usually modified cow milk) for feeding preterm or LBW infants are available commercially (Agostoni 2010; Tudehope 2012). These vary in energy, protein and micro‐nutrient content and, broadly, can be categorised as:
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standard 'term' formulas; designed for term infants, based on the composition of mature breast milk ‒ the typical energy content is between about 67 and 70 kCal/100 mL;
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nutrient‐enriched 'preterm' formulas; designed for preterm infants to provide nutrient intakes to match intra‐uterine accretion rates ‒ these are energy‐enriched (typically up to about 80 kCal/100 mL) and are variably protein‐ and mineral‐enriched.
How the intervention might work
Artificial formula, particularly nutrient‐enriched 'preterm' formula, might provide consistently higher levels of nutrients than maternal breast milk does. However, artificial formulas do not contain the same immuno‐nutritional factors that are present in maternal breast milk (Tudehope 2012; Underwood 2013). Furthermore, although bovine proteins, carbohydrates and lipids in artificial formulas are modified to improve digestibility for newborn infants, these are less likely to be tolerated than human milk macro‐nutrients, especially by the immature preterm intestine. Formula feeding might therefore delay the functional adaptation of the gastrointestinal tract and disrupt the patterns of microbial colonisation (Embleton 2017). Intestinal dysmotility and dysbiosis might exacerbate feed intolerance and delay the establishment of enteral feeding independent of parenteral nutrition (Pammi 2017). Prolonged parenteral nutrition is associated with infectious and metabolic complications that increase mortality and morbidity, prolong hospital stay, and adversely affect growth and development (Walsh 2019).
Why it is important to do this review
Given the potential for the type of enteral nutrition to affect important outcomes for preterm or LBW infants, and since uncertainty exists about the balance between the putative benefits and harms, an attempt to detect, appraise and synthesise evidence from randomised controlled trials is merited.
Objectives
To determine the effect of feeding preterm or LBW infants with formula compared with maternal breast milk on growth and developmental outcomes.
Methods
Criteria for considering studies for this review
Types of studies
Controlled trials utilizing either random or quasi‐random patient allocation.
Types of participants
Preterm (< 37 weeks' gestational age) or LBW (< 2500 g) infants.
Types of interventions
Feeding with formula milk versus maternal (mother's own) expressed milk.
Types of outcome measures
Primary outcomes
Growth
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Rates of weight gain, linear growth, head growth or skinfold thickness growth during initial hospitalisation, and z‐score at 36 weeks' or longer post‐menstrual age
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Weight, height or head circumference (or proportion of infants who remain below the 10th percentile for the index population's distribution), assessed at intervals following hospital discharge
Neurodevelopment
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Death or severe neurodevelopmental disability defined as any one or combination of the following: non‐ambulant cerebral palsy, developmental quotient more than two standard deviations below the population mean, and blindness (visual acuity < 6/60) or deafness (any hearing impairment requiring or unimproved by amplification)
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Neurodevelopmental scores in children aged at least 12 months, measured using validated assessment tools such as main domains (cognitive, motor, language) of Bayley Scales of Infant and Toddler Development, Third Edition (Bayley‐III)
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Cognitive and educational outcomes in children ≥ five years old
Necrotising enterocolitis confirmed at surgery or autopsy or diagnosed by at least two of the following clinical features (Kliegman 1987).
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Abdominal radiograph showing pneumatosis intestinalis or gas in the portal venous system or free air in the abdomen
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Abdominal distension with abdominal radiograph with gaseous distension or frothy appearance of bowel lumen (or both)
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Blood in stool
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Lethargy, hypotonia or apnoea (or combination of these)
Secondary outcomes
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Death in the neonatal period (up to 28 days) and death prior to hospital discharge
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Feed intolerance during the trial intervention period that results in cessation in enteral feeding for > 4 hours
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Time after birth to establish full enteral feeding (independently of parenteral nutrition)
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Invasive infection as determined by culture of bacteria or fungus from blood, cerebrospinal fluid, or from a normally sterile body space
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Duration of birth hospitalisation (days)
Search methods for identification of studies
We used the Cochrane Neonatal standard search strategy.
Electronic searches
We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 9) in the Cochrane Library, Ovid MEDLINE (1946 to 1 October 2018), OVID Embase (1980 to 1 October 2018), and OVID Maternity & Infant Care Database (1971 to 1 October 2018), and the Cumulative Index to Nursing and Allied Health Literature Plus (CINAHL) via Ebsco (1982 to 21 September 2018) using a combination of text words and MeSH terms described in Appendix 1. We limited the search outputs with relevant search filters for clinical trials as recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2017). We did not apply any language restrictions.
We searched ClinicalTrials.gov and the World Health Organization’s International Clinical Trials Registry Platform (www.who.int/ictrp/en) for completed or ongoing trials.
Searching other resources
We examined reference lists in previous reviews and included studies. We searched the proceedings of the annual meetings of the Pediatric Academic Societies (1993 to 2019), the European Society for Paediatric Research (1995 to 2019), the Royal College of Paediatrics and Child Health (2000 to 2019), and the Perinatal Society of Australia and New Zealand (2000 to 2019). Trials reported only as abstracts were eligible if sufficient information was available from the report, or from contact with the authors, to fulfil the inclusion criteria.
Data collection and analysis
We used the standard methods of Cochrane Neonatal (neonatal.cochrane.org).
Selection of studies
We screened the title and abstract of all studies identified by the above search strategy and two review authors (JB, VW) independently assessed the full articles for all potentially relevant trials. We excluded those studies that did not meet all of the inclusion criteria and we stated the reason for exclusion. We discussed any disagreements until consensus was achieved. We illustrated the screening and selection outcomes in a flowchart (Figure 1).
Study flow diagram: review update
Data extraction and management
Two review authors (JB, WM) planned to extract data independently using a data collection form to aid extraction of information on design, methodology, participants, interventions, outcomes and treatment effects from each included study. We planned to discuss any disagreements until we reached a consensus. If data from the trial reports were insufficient, we planned to contact the trialists for further information.
Assessment of risk of bias in included studies
Two review authors (JB and VW) planned to independently assess 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.
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Sequence generation (selection bias)
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Allocation concealment (selection bias)
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Blinding of participants and personnel (performance bias)
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Blinding of outcome assessment (detection bias)
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Incomplete outcome data (attrition bias)
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Selective reporting (reporting bias)
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Any other bias
We planned to resolve disagreements by discussion or by including a third review author (WM). See Appendix 1 for a detailed description of risk of bias for each domain.
Measures of treatment effect
We planned to calculate risk ratios and risk differences for dichotomous data and mean differences for continuous data, with respective 95% confidence intervals. If deemed appropriate to combine two or more study arms, we planned to obtain the treatment effects from the combined data using the methods described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We planned to determine the number needed to treat for an additional beneficial outcome or the number needed to treat for an additional harmful outcome for each statistically significant risk difference.
Unit of analysis issues
We specified the unit of analysis as the participating infant in individually randomised trials and the neonatal unit (or subunit) for cluster‐randomised controlled trials. For cluster trials, we planned to undertake analyses at the level of the individual while accounting for the clustering in the data using the methods recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
Dealing with missing data
Where data were missing, and could not be derived as described, we planned to approach the analysis of missing data as follows.
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Contact the original study investigators to request the missing data
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Where possible, impute missing standard deviations (SD) using the coefficient of variation or calculate the SD from other statistics including standard errors, confidence intervals, t values and P values
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If the data were likely to be missing at random, analyse the data without imputing any missing values
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If the data were not likely to be missing at random, impute the missing outcomes with replacement values, assuming all to have a poor outcome
Assessment of heterogeneity
Two review authors (JB and VW) planned to assess clinical heterogeneity, with a meta‐analysis conducted only when both agreed that study participants, interventions and outcomes were sufficiently similar.
We planned to examine the treatment effects of individual trials and heterogeneity between trial results by inspecting the forest plots. We planned to calculate the I² statistic for each analysis to quantify inconsistency across studies and 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 the possible causes (for example, differences in study design, participants, interventions or completeness of outcome assessments).
Assessment of reporting biases
If more than 10 trials were included in a meta‐analysis, we planned to examine a funnel plot for asymmetry.
Data synthesis
We planned to use a fixed‐effect model for meta‐analysis (as per Cochrane Neonatal policy). Where moderate or high heterogeneity existed, we planned to examine the potential causes in subgroup and sensitivity analyses.
Quality of evidence
We planned to use the GRADE approach, as outlined in the GRADE Handbook (Schünemann 2013), to assess the certainty of evidence for the primary outcomes (Appendix 2). We planned to use the GRADEpro GDT Guideline Development Tool to create a ‘Summary of findings’ table to report the quality of the evidence.
Subgroup analysis and investigation of heterogeneity
We planned these analyses of trials to assess subgroup differences for:
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(i) 'term' formula milk (up to 72 kCal/100 mL) or (ii) 'preterm' formula milk (> 72 kCal/100 mL) versus maternal breast milk;
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formula versus (i) unfortified or (ii) nutrient‐fortified maternal breast milk.
Results
Description of studies
We did not find any studies that fulfilled the eligibility criteria.
We excluded nine studies (Characteristics of excluded studies). Six were not randomised trials on review of the full text (Carey 1987; Greer 1988; Lucas 1990; Armand 1996; O'Connor 2003; Marseglia 2014). One was a trial of early versus later use of breast milk (Tewari 2018). Two studies were excluded because the infants were allocated to receive formula versus a mixture of maternal and donor breast milk (Narayanan 1982; Svenningsen 1982).
Risk of bias in included studies
We were unable to assess risk of bias as there were no eligible trials.
Effects of interventions
We were not able to calculate the effects of interventions as there were no eligible trials.
Discussion
Summary of main results
We did not identify any randomised controlled trials of formula versus maternal breast milk for feeding preterm or low birth weight (LBW) infants. This is likely to be due to reluctance of families, clinicians, caregivers, and researchers to assess an intervention that results in infants not receiving the immuno‐nutritional benefits of breast milk (Walsh 2019). Observational studies have found higher rates of necrotising enterocolitis in infants fed formula compared with maternal breast milk (Lucas 1990; Battersby 2017). Meta‐analysis of data from randomised controlled trials indicates that feeding with formula, compared with donor breast milk, leads to higher rates of feed intolerance and necrotising enterocolitis in preterm infants (Quigley 2018). Since maternal breast milk contains higher levels of putative immuno‐protective factors (secretory IgA, lysozyme, lactoferrin, epidermal growth factors) than donor breast milk, it is plausible that feeding with maternal breast milk will have the same or greater protective effect. Furthermore, if there is concern regarding the nutritional adequacy of maternal breast milk, infants can receive supplemental nutrition via multi‐component fortification although it is uncertain if this compromises the non‐nutritional benefits of breast milk (Brown 2016).
In resource‐poor countries, where the risk of infection in the neonatal period is much higher than in resource‐rich countries, the anti‐infective properties of maternal breast milk might confer further advantages for preterm or LBW infants. In India, a randomised trial in LBW infants "at risk of infection" found that serious infections (diarrhoea, pneumonia, septicaemia) were less common in infants allocated to receive "expressed human milk" versus formula (Narayanan 1982). "Expressed human milk" in this trial referred to a mixture of maternal and donor breast milk. As these could not be separated into subgroups, the data could not be included in the review.
Potential biases in the review process
The main concern with the review process is the possibility that we did not detect trials that are not indexed in the major bibliographic electronic databases. We attempted to minimise this threat by screening the reference lists of included trials and related reviews and searching the proceedings of the major international perinatal conferences to identify trial reports that are not published in full form in academic journals. However, we cannot be sure whether other trials have been undertaken, but not reported or indexed, and the concern remains that unpublished trials are not likely to have detected statistically significant or clinically important effects.
Agreements and disagreements with other studies or reviews
We did not identify another systematic review of randomised controlled trials of feeding preterm or VLBW infants with formula versus maternal breast milk.
Study flow diagram: review update
