Nutrient-enriched formula versus standard term formula for
preterm infants following hospital discharge
Henderson G, Fahey T, McGuire W
Dates
Date edited: 13/07/2007
Date of last substantive update: 25/06/2007
Date of last minor update: / /
Date next stage expected 01/08/2007
Protocol first published: Issue 2, 2004
Review first published: Issue 2, 2005
Contact reviewer
Dr William McGuire
Associate Professor of Neonatology
Department of Paediatrics and Child Health
Australian National University Medical School
Canberra Hospital Campus
Canberra
ACT 2606 AUSTRALIA
Telephone 1: +61 2 62442222
Facsimile: +61 2 62443112
E-mail: william.mcguire@act.gov.au
Contribution of reviewers
William McGuire and Tom Fahey developed the protocol for the review. Ginny Henderson and William McGuire undertook the literature search, appraised the reports (independently), extracted the data (independently), and completed the review.Internal sources of support
ANU Medical School, Canberra, AUSTRALIA
Royal College of Surgeons in Ireland, IRELAND
Griffith University, Queensland, AUSTRALIA
External sources of support
Tenovus, Scotland, UK
What's new
This is an update of the review "Calorie and protein-enriched formula versus standard term formula for improving growth and development in preterm or low birth weight infants following hospital discharge" published in The Cochrane Database of Systematic Reviews Issue 2, 2005 (Henderson 2005).Following external peer review, we have changed the description of the intervention from "calorie and protein-enriched formula" to "nutrient-enriched formula", and the population from "preterm or low birth weight infants" to "preterm infants".
We corrected a previous data entry error (weight at 12 months for two trials: Cooke 2001; Lucas 2001). This did not alter the main findings of the review.
We identified one new trial. Inclusion of this trial did not alter the main conclusions of the review.
Dates
Date review re-formatted: / /
Date new studies sought but none found: / /
Date new studies found but not yet included/excluded: / /
Date new studies found and included/excluded: / /
Date reviewers' conclusions section amended: / /
Date comment/criticism added: / /
Date response to comment/criticisms added: / /
Text of review
Synopsis
Preterm infants are often much smaller than term infants by the time that they are discharged home from hospital. This review attempted to identify evidence that feeding these infants with formula milk enriched with nutrients rather than ordinary formula designed for term infants, would increase growth rates and benefit development. Seven good quality trials were identified. These trials provided little evidence that unrestricted feeding with nutrient-enriched formula milk affects growth and development up to about 18 months of age. Long-term growth and development has not yet been assessed. Further randomised controlled trials are needed to address this question.
Abstract
Background
Preterm infants are often growth-restricted at hospital discharge. Feeding infants after hospital discharge with nutrient-enriched formula rather than standard term formula might facilitate "catch-up" growth and improve development.
Objectives
To determine the effect of feeding nutrient-enriched formula compared with standard term formula on growth and development for preterm infants following hospital discharge.
Search strategy
The standard search strategy of the Cochrane Neonatal Review Group were used. This included searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2007), MEDLINE (1966 - May 2007), EMBASE (1980 - May 2007), CINAHL (1982 - May 2007), conference proceedings, and previous reviews.
Selection criteria
Randomised or quasi-randomised controlled trials that compared the effect of feeding preterm infants following hospital discharge with nutrient-enriched formula compared with standard term formula.
Data collection & analysis
Data was extracted using the standard methods of the Cochrane Neonatal Review Group, with separate evaluation of trial quality and data extraction by two authors, and synthesis of data using weighted mean difference and a fixed effects model for meta-analysis.
Main results
Seven trials were found that were eligible for inclusion. These recruited a total of 631 infants and were generally of good methodological quality. The trials found little evidence that feeding with nutrient-enriched formula milk affected growth and development. Because of differences in the way individual trials measured and presented outcomes, data synthesis was limited. Growth data from two trials found that, at six months post-term, infants fed with nutrient-enriched formula had statistically significantly lower weights [weighted mean difference: -601 (95% confidence interval -1028, -174) grams], lengths [-18.8 (-30.0, -7.6) millimetres], and head circumferences [-10.2 ( -18.0, -2.4) millimetres], than infants fed standard term formula. At 12 to 18 months post-term, meta-analyses of data from three trials did not find any statistically significant differences in growth parameters. However, examination of these meta-analyses demonstrated statistical heterogeneity. Meta-analyses of data from two trials did not reveal a statistically significant difference in Bayley Mental Development or Psychomotor Development Indices. There are not yet any data on growth or development through later childhood.
Reviewers' conclusions
The available data do not provide strong evidence that feeding preterm infants following hospital discharge with nutrient-enriched formula compared with standard term formula affects growth rates or development up to 18 months post-term.
Background
Compared with term infants, preterm infants have very limited nutrient reserves at birth. Preterm infants are additionally subject to a variety of physiological and metabolic stresses, such as infection or respiratory distress, that increase their nutritional needs. An international consensus group has recommended nutritional requirements for preterm infants based on data from intrauterine growth and nutrient balance studies (Tsang 1993). These recommendations assume that the optimal rate of postnatal growth for preterm infants should be about the same as that of normal fetuses of an equivalent post-conceptional age. However, evidence exists that in practice these target levels of nutrient input are rarely achieved. Most preterm infants accumulate significant energy, protein, mineral, and other nutrient deficits by the time of discharge from hospital (Embleton 2001).
Preterm infants are typically discharged from hospital when they weigh between about 1.8 and 2.2 kilograms. At this stage, many preterm infants are significantly growth restricted (Lucas 1984). In a multicentre study of more than 24000 preterm infants cared for in 124 neonatal intensive care units in North America between 1997 and 2000, the prevalence of extrauterine growth restriction at hospital discharge, defined as lying below the tenth percentile of the predicted value based on intrauterine growth expectation, was 28% for weight, 34% for length, and 16% for head circumference. For each parameter, the risk of growth restriction increased with decreasing gestational age and birth weight (Clark 2003).
Following hospital discharge, demand fed preterm infants consume greater volumes of milk than term infants in order to attain some "catch up" growth (Lucas 1992a). However, nutritional and growth deficits persist throughout childhood (Morley 2000; Ford 2000). Poor postnatal growth in preterm infants, especially of the head, is associated with an increased risk of neurodevelopmental impairment in later childhood, as well as with poorer cognitive and educational outcomes (Hack 1991; Cooke 2003). Preterm infants who have accumulated deficits in calcium and phosphate by the time of hospital discharge are at increased risk of poor bone mineralisation, metabolic bone disease, and a reduced rate of skeletal growth compared to infants born at term (Rigo 2000). There has also been concern that nutritional deficiency and growth restriction both in utero and in the early neonatal period may have consequences for cardiovascular disease risk factors such as blood pressure, insulin resistance, and obesity, and for long term cardiovascular health (Barker 2002). However, whether a real causal association exists remains unclear at present (Huxley 2002).
A variety of strategies are available for improving nutrient input in preterm infants prior to hospital discharge. Several interventions including fortification of human breast milk and the use of nutrient-enriched formula milk have been assessed in other Cochrane reviews (Bell 2003; Kuschel 2003; McGuire 2003a; McGuire 2003b). There is also an increasing awareness that there is an opportunity for continued nutritional intervention during the post-hospital discharge period of early infancy (Cooke 2000; Griffin 2002). Nutritional supplementation during this period may be of particular importance for infants with ongoing additional metabolic requirements, for example due to chronic lung disease. It is important to determine whether nutritional supplementation following hospital discharge can improve important outcomes for preterm infants.
Although human breast milk is the recommended source of nutrition for young infants (54th WHA), many preterm infants, and particularly very preterm infants, receive formula milk as a major source of nutrition in the first few months following hospital discharge. A variety of formula feeds, mainly modified cow's milk, are available (Fewtrell 1999). These vary with regard to calorie, protein and mineral content and can be categorised broadly as:
1. Standard term formula; designed for term infants, based on the composition of mature breast milk. The typical energy content is 68 kcal/100 ml. The concentration of protein, approximately 1.4 to 1.5 grams/100 ml, and calcium and phosphate are not sufficient to provide the recommended nutrient needs for stable and growing preterm infants (Tsang 1993).
2. Preterm formula; energy-enriched (approximately 80 kcal/100 ml), protein-enriched (approximately 2.0 to 2.4 grams/100 ml), and variably enriched with minerals, vitamins, and trace elements to support intra-uterine nutrient accretion rates. These milks are often used for nutrition of preterm infants prior to hospital discharge.
3. Post-discharge formula; specifically designed for preterm infants post-discharge from hospital. These are less nutrient dense compared with preterm formulae, but are energy (about 72 to 74 kcal/100 ml), protein (about 1.8 grams/ 100 ml) -enriched, and variably enriched with minerals, vitamins, and trace elements compared to standard term formula milk.
The purpose of this review is to determine whether feeding preterm or low birth weight infants after hospital discharge with a nutrient-enriched formula milk versus a standard term formula improves growth and development. Whether feeding with nutrient-enriched formula milk is associated with any adverse effects is also examined. For example, feeding nutrient dense formula may reduce gastric motility and emptying (Hancock 1984; Siegel 1984). Nutrient-enriched formula milk may therefore be more poorly tolerated, so reducing nutrient delivery, and potentially removing any benefits for growth and development.
Objectives
To determine the effect of feeding preterm infants following hospital discharge with nutrient-enriched formula milk compared with standard term formula milk affects growth and development
In separate comparisons, nutrient-enriched formula milk versus standard term formula milk in babies fed formula milk exclusively, in human breast milk-fed babies fed formula as supplement, and in babies where the nutrient-enriched formula is used either as sole diet or as a supplement to breast milk were compared.
The following sub-group analyses were pre-specified:
1. Infants of very low birth weight (less than 1.5 kilograms) or who are very preterm at birth (less than 32 weeks).
2. Infants who remain small for gestational age (less than 10 th percentile for weight) at hospital discharge.
3. Infants with chronic lung disease requiring home supplemental oxygen therapy.
4. Comparisons of "preterm" formula (energy content between greater than 75 kcal/100 ml and protein content at least 2.0 grams/100 ml) versus standard term formula.
5. Comparisons of "post-discharge" formula (energy content between 72 and 75 kcal/100 ml and protein content at least 1.6 grams/100 ml, but less than 2.0 grams/100 ml) versus standard term formula.
Criteria for considering studies for this review
Types of studies
Controlled trials using random or quasi-random patient allocation. Studies published as abstracts were only eligible for inclusion if assessment of study quality was possible (either directly or after contact with the investigators) and if other criteria for inclusion were fulfilled.
Types of participants
Preterm infants (less than 37 weeks' gestation) at least partially formula milk-fed, following discharge from hospital. The intervention may have commenced up to one week prior to planned discharge from hospital. Trials that randomly assigned infants to calorie and protein-enriched formula milk versus standard term formula milk more than one week prior to hospital discharge (and then continued the intervention after hospital discharge) were not to be included in this review. These trials may be eligible for inclusion in the Cochrane review of preterm formula milk versus standard term formula milk for feeding preterm or low birth weight infants prior to hospital discharge (Bell 2003).
Types of interventions
Feeding with nutrient enriched formula milk (at least 72 kcal/100 ml, and at least 1.6 grams protein /100 ml) versus standard term formula milk (energy content less than 72 kcal/100 ml, and protein content less than 1.6 grams/100 ml). Nutrient-enriched formula milk may additionally be enriched with minerals, vitamins and trace elements. The formula milks may be fed either as sole diet or as a supplement to human milk. Infants in the trial groups should have received similar care other than the type of formula milk. For example, there should not have been any differences between groups in the prescription of target levels of volume of intake, or advice or support for demand feeding.
Types of outcome measures
Primary:
1. Growth:
(i) Rates of weight gain (grams per day, or grams per kilogram per day), linear growth (millimetres per week), head growth (millimetres per week), or skinfold thickness growth (millimetres per week) during the trial period.
(ii) Long-term growth- weight, height, or head circumference (and/or proportion of infants who remain below the tenth percentile for the index population's distribution) assessed at intervals from six months of age (corrected for preterm birth), to 18 months, and beyond.
2. Development:
(i) Neurodevelopmental outcomes at greater than, or equal to, 12 months of age (corrected for preterm birth) measured using validated assessment tools such as Bayley Scales of Infant Development
(ii) Severe neurodevelopmental disability defined as any one or combination of the following: non-ambulant cerebral palsy, developmental delay (developmental quotient less than 70), auditory and visual impairment.
(iii) Cognitive and educational outcomes at aged more than five years old: Intelligence quotient and/or indices of educational achievement measured using a validated assessment tool (including school examination results).
Secondary:
3. Measures of bone mineralisation such as serum alkaline phosphatase level, or bone mineral content assessed by dual energy x ray absorptiometry, at the end of the trial period.
4. Feed intolerance such as vomiting or diarrhoea that necessitates ceasing the study formula milk.
5. Clinical or radiological evidence of rickets on long term follow up.
6. Blood pressure and body mass index on long term follow up.
Search strategy for identification of studies
The standard search strategy of the Cochrane Neonatal Review Group was used. This consisted of searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2007), MEDLINE (1966 - May 2007), and EMBASE (1980 - May 2007), and CINAHL (1982 - May 2007). The electronic search used the following text words and MeSH terms: [Infant, Newborn OR Infant, Premature OR Infant, Low Birth Weight OR infan* OR neonat*] AND "Infant-Nutrition"/ all subheadings OR Infant Formula OR milk OR formula]. The search outputs were limited with the relevant search filters for clinical trials. No language restriction was applied. References in previous reviews and studies were examined. Abstracts presented at the Society for Pediatric Research, European Society for Pediatric Research, the North American Society of Pediatric Gastroenterology and Nutrition, and the European Society of Paediatric Gastroenterology, Hepatology and Nutrition between 1990 and 2006/7 were searched. 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. The UK National Research Register (http://www.nrr.nhs.uk), and Current Controlled Trials (http://www.controlled-trials.com) websites were searched for completed or ongoing trials.
Methods of the review
1. William McGuire (WM) and Ginny Henderson (GH) screened the title and abstract of all studies identified by the above search strategy and obtained the full articles for all potentially relevant trials. WM and GH re-assessed independently the full text of these reports using an eligibility form based on the pre-specified inclusion criteria. Those studies that did not meet all of the inclusion criteria were excluded. Any disagreements were resolved by discussion until consensus was achieved.
2. WM and GH used the criteria and standard methods of the Cochrane Neonatal Review Group to assess independently the methodological quality of the included trials in terms of allocation concealment, blinding of parents or caregivers and assessors to intervention, and completeness of assessment in all randomised individuals. Where necessary, additional information was requested from trial authors to clarify methodology and results.
3. WM and GH used a data collection form to aid extraction of relevant information and data from each included study. Each reviewer extracted the data separately, compared data, and resolved differences by discussion until consensus was achieved. If data from the trial reports were insufficient, the authors were contacted for further information.
4. Outcomes for continuous data are presented using the weighted mean difference with 95% confidence interval. No categorical data are presented.
5. The treatment effects of individual trials and heterogeneity between trial results were examined by inspecting the forest plots and quantifying the impact of heterogeneity in any meta-analysis using a measure of the degree of inconsistency in the studies' results (I2 statistic). If statistical heterogeneity was detected, the possible causes (for example, differences in study quality, participants, intervention regimens, or outcome assessments) were explored using post hoc sub group analyses. A fixed effects model was used for meta-analysis.
Description of studies
Seven trials were identified that fulfilled the eligibility criteria (Carver 2001; Cooke 2001; De Curtis 2002; Koo 2006; Litmanovitz 2004; Lucas 1992; Lucas 2001). These trials are described in the table, Characteristics of Included Studies. Six studies were excluded (Agosti 2003; Bhatia 1991; Brunton 1998; Chan 1994; Cooper 1985; Wheeler 1996). The reasons for exclusion are listed in the table, Characteristics of Excluded Studies. Three further reports of potentially eligible trials were identified (Atkinson 1999; Atkinson 2004; Picaud 2005). These have only been reported in abstract form. Further clarification of a number of issues is needed to determine if these may be included in an update of this review.
All of the included studies were undertaken since the late 1980s by investigators attached to perinatal centres in Europe, Israel, or North America. 631infants in total participated in the trials. Participating infants were of birth weight less than 1500 grams in one study (Litmanovitz 2004), 1750 grams in three studies (Cooke 2001; De Curtis 2002; Lucas 2001), 1800 grams in one study (Carver 2001), and 1850 grams in one study (Lucas 1992).
In six trials (Carver 2001; De Curtis 2002; Koo 2006; Litmanovitz 2004; Lucas 1992; Lucas 2001), the energy content of the nutrient-enriched formula milks ranged from 72 to 74 kcal/100ml and the protein content from 1.8 to 1.9 grams/100ml ("post-discharge formula"). In the other trial (Cooke 2001), the intervention milk contained 80 kcal/100ml and 2.2 grams of protein per 100ml ("preterm formula"). The standard term formula in all of the trials contained 66 to 68 kcal/100ml and 1.4 to 1.5 grams of protein per 100ml. All of the participating infants were exclusively formula-fed ad libitum. These feeds were intended to be the principal source of milk for two months post-term (De Curtis 2002), six months post-term (Cooke 2001; Litmanovitz 2004), up to nine months post-term (Lucas 1992; Lucas 2001), or up to 12 months post-term (Carver 2001; Koo 2006).
The main outcomes assessed were growth parameters (weight, length, and occipito-frontal head circumference), feed tolerance, and measures of bone mineralisation. Two trials assessed neuro-developmental outcomes beyond infancy using Bayley Scales of Infant Development II (Cooke 2001; Lucas 2001).
Methodological quality of included studies
In general, the methodological quality of the included studies was good, although only one trial report explicitly explained the method of randomisation (Lucas 2001). In the other trials, it is not clear whether allocation concealment was adequate. One trial was reported in abstract form only (Litmanovitz 2004). All of the trials blinded investigators and caregivers to the type of milk that the infant received. Five of the trials achieved complete or near-complete follow-up (Cooke 2001; De Curtis 2002; Koo 2006; Litmanovitz 2004; Lucas 1992; Lucas 2001). There was substantial loss to follow-up in one trial (Carver 2001).
Results
NUTRIENT-ENRICHED FORMULA VS. STANDARD TERM FORMULA
PRIMARY OUTCOMES:
Growth (Outcomes 01.01- 01.04)
Carver 2001 reported higher rates of growth during the trial period in nutrient-enriched formula milk group. There was substantial loss to follow-up during the trial. The published report does not state how many infants were assessed at the various time points. The data could not be used to calculate mean differences. Cooke 2001 did not find a statistically significant difference in rate of weight gain during the trial period. These data were presented in graphs only and were not able to be extracted to allow calculation of the mean difference. At 18 months post-term, the nutrient-enriched formula group was statistically significantly heavier than the control group [mean difference: 500 (95% confidence interval 25, 974) grams], but there were not any statistically significant differences in length or head circumference. De Curtis 2002 did not find any statistically significant differences in the rate of gain of weight, length, or head circumference during the two months trial period. Koo 2006 reported that the mean weight, head circumference, and length was lower in the nutrient-enriched formula group at six, nine, and twelve months after hospital discharge. Lucas 1992 reported statistically significantly higher rates of weight gain and linear growth in infants who received nutrient-enriched formula milk during the nine months trial period. There was no statistically significant difference in the rate of head growth. These data were presented graphically. Relevant data could not be extracted in order to calculate mean differences. Lucas 2001 reported that at completion of the intervention period (nine months post-term), weight and length were statistically significantly greater in infants who received nutrient-enriched formula milk but that there was not a statistically significant difference in head circumference. At 18 months, there were not any statistically significant differences in weight or head circumference. The group of infants who received nutrient-enriched formula milk remained statistically significantly longer on average than the control group [mean difference 9.0 (95% confidence interval 0.3 to 17.7) millimetres]. Litmanovitz 2004 did not find any statistically significant difference in the weight, length, or head circumference at six months post-term.
Meta-analyses of growth data from two trials (Koo 2006; Litmanovitz 2004) found that, at six months post-term, infants fed with nutrient-enriched formula had statistically significantly lower weights [weighted mean difference: -601 (95% confidence interval -1028, -174) grams], lengths [weighted mean difference: -18.8 (95% confidence interval -30.0, -7.6) millimetres], and head circumferences [weighted mean difference: -10.2 (95% confidence interval -18.0, -2.4) millimetres], than infants fed standard term formula. At nine months post-term, meta-analyses of data from two trials (Koo 2006; Lucas 2001) did not find any statistically significant differences in growth parameters. At 12 - 18 months post-term, meta-analyses of data from three trials (Cooke 2001; Koo 2006; Lucas 2001) did not find any statistically significant differences in growth parameters. However, these meta-analyses demonstrated statistical heterogeneity.
Subgroup analyses of only the two trials that used "post-discharge" formula milk (Koo 2006; Lucas 2001), rather than "preterm" formula (Cooke 2001), did not find a statistically significant difference in weight or length at 12 - 18 months post-term. The head circumference in the enriched-formula group was statistically significantly lower than in the standard term formula group [weighted mean difference: -4.5 (95% confidence interval -9.1, -0.04) millimetres]. This meta-analysis did not demonstrate statistical heterogeneity.
Subgroup analyses of only the trial that used "preterm" formula (Cooke 2001), did not find a statistically significant difference in length or head circumference at 12 - 18 months post-term. Infants in the enriched-formula group were statistically significantly heavier than infants in the standard term formula group [mean difference: 500 (95% confidence interval 25, 974) grams].
Development (Outcome 01.05)
Neither Cooke 2001 nor Lucas 2001, nor a meta-analysis of data from both trials detected a statistically significant difference in the Bayley Scales Mental Development Index [weighted mean difference 0.23 (95% confidence interval -2.99 to 3.45)] or Psychomotor Development Index [weighted mean difference 0.55 (95% confidence interval -1.95 to 3.05)]. Lucas 2001 reported no statistically significant difference in the "number of infants considered to have either a possible or definite neurological deficit" (not defined further) at 18 months post-term. None of the included trials assessed cognitive and educational outcomes.
SECONDARY OUTCOMES:
Bone mineralisation (Outcome 01.06)
Cooke 2001 assessed body composition with dual energy x-ray absorptiometry at six months and again at 12 months post-term. There were not any statistically significant differences in the bone area, bone mineral mass, or bone mineral density measurements between the groups. In the published report, all of these data were presented in graphs and could not be extracted for estimation of mean differences. The investigators also reported that there were not any statistically significant differences in the serum phosphorus, calcium and alkaline phosphatase levels measured at intervals during the study period (up to six months post-term). These data were presented mainly in graphs and could not be extracted for estimation of mean differences. De Curtis 2002 did not find any statistically significant differences in the bone mineral content or the bone area at the end of the two months study period. Koo 2006 reported that at the end of the 12 months study period the infants who received nutrient-enriched formula had statistically significantly lower bone mass (measured using dual-energy X-ray adsorptiometry). The data were presented in graphs and could not be extracted for calculation of mean differences. Lucas 1992 assessed bone width and bone mineral content of the radius at nine months post-term. The bone width was not statistically significantly different between the groups. The bone mineral content was statistically significantly higher in the group of infants who received the nutrient-enriched formula milk: Mean difference 20.6 (95% confidence interval 7.8 to 33.4) milligrams/centimetre. Lucas 2001did not assess any measures of bone mineralisation. Litmanovitz 2004 did not find any statistically significant differences in bone strength assessed as "bone speed of sound" measured with ultrasound or in serum levels of bone specific alkaline phosphatase at six months post-term.
Feed intolerance
Only Lucas 1992 assessed this outcome. There were no statistically significant differences in the mean numbers of vomits or possets per day. None of the participating infants ceased taking a study formula because of feed intolerance. None of the three trials that reported the time of introduction of weaning foods found a statistically significant difference (Cooke 2001; Lucas 1992; Lucas 2001).
None of the trials assessed the effect of the intervention on clinical or radiological evidence of rickets, or on body mass index or blood pressure on long-term follow-up.
Sub-group analyses:
1. infants of very low birth weight (less than 1.5 kilograms) or who are very preterm at birth (less than 32 weeks): Only one trial recruited exclusively very low birth weight infants (Litmanovitz 2004). As detailed above, the investigators did not find any statistically significant difference in the weight, length, or head circumference, or in measures of bone mineralisation at six months post-term.
2. infants who remain small for gestational age (less than 10th percentile for weight) at hospital discharge: No subgroup data available.
3. infants with chronic lung disease requiring home supplemental oxygen therapy: No subgroup data available.
4. infants fed standard term formula versus infants fed "preterm" formula: One trial (Cooke 2001)- see above.
5. infants fed standard term formula versus infants fed "post-discharge" formula: Six trials (Carver 2001; De Curtis 2002; Koo 2006; Litmanovitz 2004; Lucas 1992; Lucas 2001)- see above.
Discussion
No evidence was found demonstrating that post-hospital discharge growth of preterm infants is higher in infants who receive nutrient-enriched formula milk compared to standard term formula. In fact, meta-analyses of data from two trials suggests that infants who are fed with nutrient-enriched formula have statistically significantly lower weights, lengths, and head circumferences at six months post-discharge. The clinical significance of these findings is unclear. Meta-analyses of trials that undertook longer follow-up (12 to 18 months) did not reveal any statistically significant differences in these growth parameters. Data from one trial indicated that preterm infants fed with formula milk with 80 kcal/100ml and 2.2 grams of protein/100ml ("preterm formula") weighed about 500 grams heavier at 18 months post-term. It is not yet known whether this difference persists through later childhood. The effect of this intervention on long term development is also unclear. The available data do not provide any evidence that feeding with nutrient-enriched formula milk improves neurodevelopmental outcomes when assessed at 18 months post-term. There are not yet any data on longer-term cognitive and educational outcomes.
The infants who participated in the included trials were fed ad libitum. Nutrient intake was measured in four of the trials (Carver 2001; Cooke 2001; De Curtis 2002; Lucas 1992). De Curtis 2002 and Lucas 1992 found that the volume of milk consumed during the study period was not statistically significantly different between the comparison groups. However, Carver 2001 and Cooke 2001 found that the infants fed with standard term milk consumed more milk than those fed with nutrient-enriched formula. As a consequence of this adjustment of intake, infants in the comparison groups in these trials received similar levels of calories suggesting that the primary regulation of volume of intake is determined by the energy content of the milk. The infants fed with nutrient-enriched formula milk still received more protein and minerals than infants who received standard term formula. Protein and mineral supplements are necessary to promote the accumulation of lean body and bone mass. However, it is interesting to note the findings of those trials could not be included in this review because the nutrient-enriched formula milk differed only in protein and mineral content (but not energy) from standard term formula. One trial found evidence that feeding with protein- and mineral-enriched milk was associated with higher rates of growth (Wheeler 1996), but the other two studies found no evidence of effect (Chan 1994; Cooper 1985).
Reviewers' conclusions
Implications for practice
There is no evidence that feeding preterm infants after hospital discharge with a nutrient-enriched formula milk (compared to a standard term formula) leads to a higher rates of growth or affects neurodevelopment.
Implications for research
Follow-up of infants who participated in the trials identified in this review might provide further data on the effect of this intervention on growth through later childhood, specifically whether final height is affected, and on later neurodevelopmental outcomes. Further large randomised controlled trials are needed to evaluate the effects of feeding preterm infants with nutrient-enriched formula milks following hospital discharge. It may be appropriate to focus research efforts on the subgroup of preterm infants who are not able to feed ad libitum following hospital discharge, and who have extra metabolic demands, for example because of growth restriction or chronic lung disease. Trials should aim to assess long-term clinically important outcomes, principally final height and body composition and neurodevelopment (including cognitive and educational outcomes).
Acknowledgements
We thanks Dr Litmanovitz for clarification of aspects of Litmanovitz 2004.
Potential conflict of interest
None.
Characteristics of included studies
| Study | Methods | Participants | Interventions | Outcomes | Notes | Allocation concealment |
| Carver 2001 | Blinding of randomisation: can't tell
Blinding of intervention: yes
Complete follow-up: no
Blinding of outcome measurement: yes | 125 preterm infants (birth weight less than 1800 grams or gestation less than 37 weeks). Infants with severe bronchopulmonary dysplasia, cardiac, respiratory, gastrointestinal ir other systemic diseases at time of discharge were not eligible to participate. | Nutrient-enriched formula (energy content 74 kcal/100ml, protein content 1.9 grams/100ml, and calcium and phosphorus content 78 mg/100ml and 46 mg/100ml respectively) (N= 67) or standard term formula (energy content 68 kcal/100ml, protein content 1.5 grams/100ml) (N= 56). The intention was for the allocated formula to be the main milk source from hospital discharge until twelve months post-term. | Growth parameters at intervals until the end of the 12 months study period. | Setting: Multi-centre, six perinatal centres in North America.
Loss to follow up (study exit). Infants exited the study early (and did not have growth parameters measured) for a variety of reasons including study non-compliance (not defined or described), gastro-intestinal upset, and "illness unrelated to the study feedings" (not defined or described). 31 of 67 in post-discharge formula group, and 26 of 56 in standard term formula group left the study early (plus two other infants who were randomised but did not take part in the study). The total loss of follow up is 59 of 125 (47%) but not clear at which time points these infants left the trial. | B |
| Cooke 2001 | Blinding of randomisation: can't tell
Blinding of intervention: yes
Complete follow-up: yes
Blinding of outcome measurement: yes | 103 preterm infants (birth weight less than 1750 grams or gestation less than 35 weeks). Only infants who were "growing normally" (rate of weight gain more than 25 grams/kg/day) at time of discharge were eligible to participate. | Nutrient-enriched formula (energy content 80 kcal/100ml, protein content 2.2 grams/100ml, and calcium and phosphorus content 108 mg/100ml and 54 mg/100ml respectively) (N= 49) or a standard term formula (energy content 66 kcal/100ml, protein content 1.4 grams/100ml) (N= 54) from hospital discharge until six months post term. | Anthropometric and developmental parameters (including Bayley Scales of Infant Development II) and measures of bone mineralisation. | Setting: Royal Victoria Hospital, Newcastle upon Tyne, UK.
This trial included a third randomised group of infants (N= 26) allocated to receive "preterm" formula from the time of hospital discharge until they reach "term", and then standard term formula from that point until six months post-term.
Cooke 2001 reported growth data for boys and girls separately. We combined the data for inclusion in this review. | B |
| De Curtis 2002 | Blinding of randomisation: can't tell
Blinding of intervention: yes
Complete follow-up: yes
Blinding of outcome measurement: yes | 33 formula milk-fed preterm infants (birth weight less than 1750 grams or gestation less than 35 weeks). | Nutrient-enriched formula (energy content 74 kcal/100ml, protein content 1.8 grams/100ml, and calcium and phosphorus content 80 mg/100ml and 40 mg/100ml respectively) (N= 16) or standard term formula (energy content 66 kcal/100ml, protein content 1.4 grams/100ml) (N= 17) from hospital discharge until two months post-term. | Growth parameters and bone mineralisation measured using dual energy x-ray absorptiometry at the end of the 2 months study period. | Setting: Department of Pediatrics, University of Liege, Belgium. | B |
| Koo 2006 | Blinding of randomisation: no
Blinding of intervention: yes
Complete follow-up: no
Blinding of outcome measurement: yes | 89 preterm infants ready for hospital discharge (gestational age at birth less than 35 weeks). Infants with major congenital malformation, previous gastrointestinal surgery, or abnormal suck and swallow actions were not eligible to participate. | Nutrient-enriched formula (energy content 74 kcal/100ml, protein content 1.9 grams/100ml, and calcium and phosphorus content 78 mg/100ml and 46 mg/100ml respectively) (N= 44) or standard term formula (energy content 67 kcal/100ml, protein content 1.5 grams/100ml) (N= 45). The intention was for the allocated formula to be fed ad libitum until twelve months efter discharge. | Growth parameters and bone mineral content at intervals until the end of the 12 months study period. | Setting: Department of Pediatrics, Wayne State University and Hutzel Hospital, Detroit, USA. | D |
| Litmanovitz 2004 | Blinding of randomisation: can't tell
Blinding of intervention: can't tell
Complete follow-up: yes
Blinding of outcome measurement: can't tell | 20 healthy very low birth weight infants at hospital discharge. | Nutrient-enriched formula (energy content 74 kcal/100ml, protein content 1.9 grams/100ml (N= 10) or a standard term formula (energy content 67 kcal/100ml, protein content 1.5 grams/100ml) (N= 10) following hospital discharge. The formulas were intended to provide the sole milk intake up to a post-term age of six months. | Weight, length, head circumference, and measures of bone mineralisation at term and at six months post-term. | Setting: Meir General Hospital, Kfar-saba, Israel. | B |
| Lucas 1992 | Blinding of randomisation: can't tell
Blinding of intervention: yes
Complete follow-up: yes
Blinding of outcome measurement: can't tell | 32 exclusively bottle-fed preterm infants, birth weight less than 1850 grams, and weight less than 3000 grams at hospital discharge. | Nutrient-enriched formula (energy content 72 kcal/100ml, protein content 1.85 grams/100ml, and calcium and phosphorus content 70 mg/100ml and 35 mg/100ml respectively) (N= 16)or a standard term formula (energy content 68 kcal/100ml, protein content 1.4 grams/100ml) (N=15) following hospital discharge. The formulas were intended to provide the sole milk intake up to a post-term age of nine months. | Measures of growth (weight, crown-heel length and head circumference), feed tolerance, and bone mineralisation during the trial period. | Setting: Department of Paediatrics, Rosie Maternity Hospital, Cambridge.
One infant who was randomised to the standard term formula group was transferred to another hospital prior to the planned hospital discharge and could not be included in any follow up assessments. | B |
| Lucas 2001 | Blinding of randomisation: yes (sealed opaque envelopes)
Blinding of intervention: yes
Complete follow-up: yes
Blinding of outcome measurement: yes | 229 formula milk-fed preterm infants, birth weight less than 1750 grams, and weight less than 3000 grams at hospital discharge.
| Nutrient-enriched formula (energy content 72 kcal/100ml, protein content 1.85 grams/100ml, and calcium and phosphorus content 70 mg/100ml and 35 mg/100ml respectively) (N= 113) or standard term formula (energy content 68 kcal/100ml, protein content 1.5 grams/100ml) (N= 116) from hospital-discharge until nine months post-term.
| Growth parameters up to 18 months post-term, and neuro-development (Bayley Scales) at 18 months post-term.
| Setting: Five neonatal centres in the UK. 1993-5.
Growth outcomes assessed for all participating infants, developmental assessments available for 184 (of 229) recruited infants. | A |
Characteristics of excluded studies
| Study | Reason for exclusion |
| Agosti 2003 | The "control" formula milk was protein-enriched (1.7 grams/ 100ml). |
| Bhatia 1991 | Both of the formula milks had protein concentrations of less than 1.6 grams/ 100ml. |
| Brunton 1998 | Both of the formula milks were calorie-enriched. |
| Chan 1994 | Neither of the formula milks were calorie-enriched. |
| Cooper 1985 | Neither of the formula milks were calorie-enriched. |
| Wheeler 1996 | Neither of the formula milks were calorie-enriched. |
References to studies
References to included studies
Carver 2001 {published data only}Carver JD, Wu PY, Hall RT, Ziegler EE, Sosa R, Jacobs J et al. Growth of preterm infants fed nutrient-enriched or term formula after hospital discharge. Pediatrics 2001;107:683-9.
Cooke 2001 {published data only}
* Cooke RJ, Embleton ND, Griffin IJ, Wells JC, McCormick KP. Feeding preterm infants after hospital discharge: growth and development at 18 months of age. Pediatric Research 2001;49:719-22.
Cooke RJ, Griffin IJ, McCormick K, Wells JC, Smith JS, Robinson SJ, Leighton M. Feeding preterm infants after hospital discharge: effect of dietary manipulation on nutrient intake and growth. Pediatric Research 1998;43:355-60.
Cooke RJ, McCormick K, Griffin IJ, Embleton N, Faulkner K, Wells JC, Rawlings DC. Feeding preterm infants after hospital discharge: effect of diet on body composition. Pediatric Research 1999;46:461-4.
De Curtis 2002 {published data only}
De Curtis M, Pieltain C, Rigo J. Body composition in preterm infants fed standard term or enriched formula after hospital discharge. European Journal of Nutrition 2002;41:177-82.
Koo 2006 {published data only}
Koo WW, Hockman EM. Posthospital discharge feeding for preterm infants: effects of standard compared with enriched milk formula on growth, bone mass, and body composition. American Journal of Clinical Nutrition 2006;84:1357-64.
Litmanovitz 2004 {published data only}
Litmanovitz I, Dolfin T, Arnon S, Bauer S, Regev R, Shainkin-Kestenbaum R, Lis M, Eliakim A. Bone strength and growth of preterm infants fed nutrient-enriched or term formula after hospital discharge. Pediatric Research 2004;55:274A.
Lucas 1992 {published data only}
Bishop NJ, King FJ, Lucas A. Increased bone mineral content of preterm infants fed with a nutrient enriched formula after discharge from hospital. Archives of Disease in Childhood 1993;68:573-8.
* Lucas A, Bishop NJ, King FJ, Cole TJ. Randomised trial of nutrition for preterm infants after discharge. Archives of Disease in Childhood 1992;67:324-7.
Lucas 2001 {published data only}
Lucas A, Fewtrell MS, Morley R, Singhal A, Abbott RA, Isaacs E et al. Randomized trial of nutrient-enriched formula versus standard formula for postdischarge preterm infants. Pediatrics 2001;108:703-11.
References to excluded studies
Agosti 2003 {published data only}Agosti M, Vegni C, Calciolari G, Marini A; GAMMA Study Group. Post-discharge nutrition of the very low-birthweight infant: interim results of the multicentric GAMMA study. Acta Paediatrica Supplement 2003;91:39-43.
Bhatia 1991 {published data only}
Bhatia J, Rassin DK. Feeding the premature infant after hospital discharge: growth and biochemical responses. Journal of Pediatrics 1991;118:515-9.
Brunton 1998 {published data only}
Brunton JA, Saigal S, Atkinson SA. Growth and body composition in infants with bronchopulmonary dysplasia up to 3 months corrected age: a randomized trial of a high-energy nutrient-enriched formula fed after hospital discharge. Journal of Pediatrics 1988;133:340-5.
Chan 1994 {published data only}
* Chan GM, Borschel MW, Jacobs JR. Effects of human milk or formula feeding on the growth, behavior, and protein status of preterm infants discharged from the newborn intensive care unit. American Journal of Clinical Nutrition 1994;60:710-6.
Chan GM. Growth and bone mineral status of discharged very low birth weight infants fed different formulas or human milk. Journal of Pediatrics 1993;123:439-43.
Cooper 1985 {published data only}
Cooper PA, Rothberg AD. Feeding of very-low-birth-weight infants with special formula--continued use beyond 2000 g and effects on growth to 1 year. South African Medical Journal 1985;67:716-8.
Wheeler 1996 {published data only}
Wheeler RE, Hall RT. Feeding of premature infant formula after hospital discharge of infants weighing less than 1800 grams at birth. Journal of Perinatology 1996;16:111-6.
References to studies awaiting assessment
Atkinson 1999 {published data only}Atkinson SA, Randall-Simpson J, Chang M, Paes B. Randomised trial of feeding nutrient-enriched versus standard formula to premature infants during the first year of life. Pediatric Research 1999;45:276A.
Atkinson 2004 {published data only}
Atkinson SA, Paes B, Saigal S, Hussey T, Lee D. Nutrient-enriched discharge formula compared to standard term formula does not benefit growth, bone mineral accretion or trace element status in preterm small for gestational age (SGA) infants to one year corrected age: A RCT. Pediatric Research 2004;55:383A.
Picaud 2005 {published data only}
Picaud JC, Plan O, Pidoux O, et al. Effect of post-discharge nutrition on growth and whole body mineralization in very low birth weight (VLBW) infants. In: PAS2005:57:1326.
* indicates the primary reference for the study
Other references
Additional references
54th WHAThe World Health Organization. In: 54th World Health Assembly. Vol. 54.2. 2001.
Barker 2002
Barker DJ. Fetal programming of coronary heart disease. Trends in Endocrinology and Metabolism 2002;13:364-8.
Bell 2003
Bell JC, Askie LM, Simmer K. Preterm formula milk versus term formula milk for feeding preterm or low birth weight infants. In: Cochrane Database of Systematic Reviews, Issue 4, 2003. John Wiley & Sons, Ltd.
Clark 2003
Clark RH, Thomas P, Peabody J. Extrauterine growth restriction remains a serious problem in prematurely born neonates. Pediatrics 2003;111:986-90.
Cooke 2000
Cooke RJ, Embleton ND. Feeding issues in preterm infants. Archives of Disease in Childhood 2000;83:F215-8.
Cooke 2003
Cooke RWI, Foulder-Hughes L. Growth impairment in the very preterm and cognitive and motor performance at 7 years. Archives of Disease in Childhood 2003;88:482-7.
Embleton 2001
Embleton NE, Pang N, Cooke RJ. Postnatal malnutrition and growth retardation: an inevitable consequence of current recommendations in preterm infants? Pediatrics 2001;107:270-3.
Fewtrell 1999
Fewtrell M, Lucas A. Nutritional physiology: dietary requirements of term and preterm infants. In: Rennie JM, Roberton NRC, editor(s). Textbook of Neonatology. 3rd edition. Edinburgh: Churchill Livingstone, 1999:305-25.
Ford 2000
Ford GW, Doyle LW, Davis NM, Callanan C. Very low birth weight and growth into adolescence. Archives of Pediatrics and Adolescent Medicine 2000;154:778-84.
Griffin 2002
Griffin IJ. Post discharge nutrition for high risk neonates. Clinics in Perinatology 2002;29:327-44.
Hack 1991
Hack M, Breslau N, Weissman B, Aram D, Klein N, Borawski E. Effect of very low birthweight and subnormal head size on cognitive abilities at school age. New England Journal of Medicine 1991;325:231–7.
Hancock 1984
Hancock PJ, Bancalari E. Gastric motility in premature infants fed two different formulas. Journal of Pediatric Gastroenterology and Nutrition 1984;3:696-9.
Huxley 2002
Huxley R, Neil A, Collins R. Unravelling the fetal origins hypothesis: is there really an inverse association between birthweight and subsequent blood pressure? Lancet 2002;360:659-65.
Kuschel 2003
Kuschel CA, Harding JE. Multicomponent fortified human milk for promoting growth in preterm infants. In: Cochrane Database of Systematic Reviews, Issue 4, 2003. John Wiley & Sons, Ltd.
Lucas 1984
Lucas A, Gore SM, Cole TJ, Bamford MF, Dossetor JF, Barr I et al. Multicentre trial on feeding low birthweight infants: effects of diet on early growth. Archives of Disease in Childhood 1984;59:722-30.
Lucas 1992a
Lucas A, King F, Bishop NB. Postdischarge formula consumption in infants born preterm. Archives of Disease in Childhood 1992;67:691-2.
McGuire 2003a
McGuire W, Anthony MY. Formula milk versus term human milk for feeding preterm or low birth weight infants. In: Cochrane Database of Systematic Reviews, Issue 4, 2003. John Wiley & Sons, Ltd.
McGuire 2003b
McGuire W, Anthony MY. Formula milk versus preterm human milk for feeding preterm or low birth weight infants. In: Cochrane Database of Systematic Reviews, Issue 4, 2003. John Wiley & Sons, Ltd.
Morley 2000
Morley R, Lucas A. Randomized diet in the neonatal period and growth performance until 7.5-8 y of age in preterm children. American Journal of Clinical Nutrition 2000;71:822-8.
Rigo 2000
Rigo J, De Curtis M, Pieltain C, Picaud JC, Salle BL, Senterre J. Bone mineral metabolism in the micropremie. Clinics in Perinatology 2000;27:147-70.
Siegel 1984
Siegel M, Lebenthal E, Krantz B. Effect of caloric density on gastric emptying in premature infants. Journal of Pediatrics 1984;104:118-22.
Tsang 1993
Tsang RC, Lucas A, Uauy R, Zlotkin S. Nutritional needs of the preterm infant. Scientific basis and practical guidelines. New York: Williams and Wilkins, 1993.
Other published versions of this review
McGuire 2005Henderson G, Fahey T, McGuire W. Calorie and protein-enriched formula versus standard term formula for improving growth and development in preterm or low birth weight infants following hospital discharge. In: Cochrane Database of Systematic Reviews, Issue 2, 2005. Chichester, UK: John Wiley & Sons, Ltd.
Comparisons and data
| Comparison or outcome |
Studies |
Participants |
Statistical method |
Effect size |
| 01 Nutrient-enriched formula versus standard
term formula |
| 01 Growth rates during trial period |
|
|
WMD (fixed), 95% CI |
Subtotals only |
| 02 Growth parameters at 6 months post -term |
|
|
WMD (fixed), 95% CI |
Subtotals only |
| 03 Growth parameters at 9 months post -term |
|
|
WMD (fixed), 95% CI |
Subtotals only |
| 04 Growth parameters at 12-18 months post -term |
|
|
WMD (fixed), 95% CI |
Subtotals only |
| 05 Development |
|
|
WMD (fixed), 95% CI |
Subtotals only |
| 06 Bone mineralisation |
|
|
WMD (fixed), 95% CI |
Subtotals only |
| 02 "Post-discharge" nutrient-enriched formula
versus standard term formula |
| 01 Growth parameters at 12-18 months post -term |
|
|
WMD (fixed), 95% CI |
Subtotals only |
| 02 Development |
|
|
WMD (fixed), 95% CI |
Subtotals only |
| 03 "Preterm" nutrient-enriched formula versus
standard term formula |
| 01 Growth parameters at 12-18 months post -term |
|
|
WMD (fixed), 95% CI |
Subtotals only |
| 02 Development |
|
|
WMD (fixed), 95% CI |
Subtotals only |
01 Nutrient-enriched formula versus standard term formula
01.01 Growth rates during trial period
01.01.01 Weight gain (grams/kilogram/day)
01.01.02 Linear growth (millimetres/week)
01.01.03 Head circumference (millimetres/week)
01.02 Growth parameters at 6 months post -term
01.02.01 Weight at 6 months post-term (grams)
01.02.02 Crown-heel length at 6 months post-term (millimetres)
01.02.03 Head circumference at 6 months post-term (millimetres)
01.03 Growth parameters at 9 months post -term
01.03.01 Weight at 9 months post term (grams)
01.03.02 Crown-heel length at 9 months post-term (millimetres)
01.03.03 Head circumference at 9 months post-term (millimetres)
01.04 Growth parameters at 12-18 months post
-term
01.04.01 Weight at 12-18 months post term (grams)
01.04.02 Crown-heel length at 12-18 months post-term (millimetres)
01.04.03 Head circumference at 12-18 months post-term (millimetres)
1.05 Development
01.05.01 Bayley Scales of Infant Development II: Mental Development Index
01.05.02 Bayley Scales of Infant Development II: Psychomotor Development Index
01.06 Bone mineralisation
01.06.01 Bone area at 2 months post-term (centimetres squared)
01.06.02 Bone mineral content at 2 months post-term (grams)
01.06.03 Bone "speed of sound" assessed with ultrasound at 6 months post-term (millimetres/second)
01.06.04 Bone specific serum alkaline phosphatase at six months post-term (units/litre)
01.06.05 Bone width at 9 months post-term (centimetres)
01.06.06 Bone mineral content at 9 months post-term (milligrams/centimetre)
02 "Post-discharge" nutrient-enriched formula versus standard term formula
02.01 Growth parameters at 12-18 months post
-term
02.01.01 Weight at 12-18 months post term (grams)
02.01.02 Crown-heel length at 12-18 months post-term (millimetres)
02.01.03 Head circumference at 12-18 months post-term (millimetres)
02.02 Development
02.02.01 Bayley Scales of Infant Development II: Mental Development Index
02.02.02 Bayley Scales of Infant Development II: Psychomotor Development Index
03 "Preterm" nutrient-enriched formula versus standard term formula
03.01 Growth parameters at 12-18 months post
-term
03.01.01 Weight at 12-18 months post term (grams)
03.01.02 Crown-heel length at 12-18 months post-term (millimetres)
03.01.03 Head circumference at 12-18 months post-term (millimetres)
03.02 Development
03.02.01 Bayley Scales of Infant Development II: Mental Development Index
03.02.02 Bayley Scales of Infant Development II: Psychomotor Development Index
Contact details for co-reviewers
Prof Tom Fahey
Professor of General Practice
Department of Family Medicine and General Practice
Royal College of Surgeons in Ireland Medical School
Mercer's Medical Centre
Lower Stephen Street
Dublin
IRELAND
2
Telephone 1: +353 1 4022 305
Facsimile: +353 1 4022 455
E-mail: t.fahey@cochraneprimarycare.org
URL: http://www.dundee.ac.uk/generalpractice
Mrs Ginny Henderson, RN BN MSc
Associate Lecturer
School of Nursing and Midwifery
Griffith University
Nathan Campus
226 Grey St, PO Box 3370
South Brisbane
Queensland AUSTRALIA
4104
Telephone 1: 61 7 3735 5317 extension: 55317
Facsimile: 61 7 3735 7984
E-mail: G.Henderson@griffith.edu.au
| This review is published as a Cochrane review in The Cochrane Library,
Issue 1, 2008 (see http://www.thecochranelibrary.com
for information). Cochrane reviews are regularly updated as new evidence
emerges and in response to feedback. The Cochrane Library should be consulted
for the most recent version of the review. |
