Physical activity programs for promoting bone mineralization and growth in preterm infants

  • Review
  • Intervention

Authors

  • Sven M Schulzke,

    Corresponding author
    1. University of Basel Children's Hospital (UKBB), Department of Neonatology, Basel, Switzerland
    • Sven M Schulzke, Department of Neonatology, University of Basel Children's Hospital (UKBB), Spitalstrasse 21, Basel, 4031, Switzerland. sven.schulzke@unibas.ch.

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  • Siree Kaempfen,

    1. University of Basel Children's Hospital (UKBB), Department of Neonatology, Basel, Switzerland
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  • Daniel Trachsel,

    1. University Children's Hospital Basel, Department of Pediatric Intensive Care/Pulmonology, Basel, Switzerland
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  • Sanjay K Patole

    1. King Edward Memorial Hospital, School of Paediatrics and Child Health, School of Women's and Infant's Health, University of Western Australia, Perth, Western Australia, Australia
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Abstract

Background

Lack of physical stimulation may contribute to metabolic bone disease of preterm infants, resulting in poor bone mineralization and growth. Physical activity programs combined with adequate nutrition might help to promote bone mineralization and growth.

Objectives

The primary objective was to assess whether physical activity programs in preterm infants improve bone mineralization and growth and reduce the risk of fracture.

The secondary objectives included other potential benefits in terms of length of hospital stay, skeletal deformities and neurodevelopmental outcomes, and adverse events.

Subgroup analysis:

• Given that the smallest infants are most vulnerable for developing osteopenia (Bishop 1999), a subgroup analysis was planned for infants with birth weight < 1000 g.

• Calcium and phosphorus intake may affect an infant's ability to increase bone mineral content (Kuschel 2004). Therefore, an additional subgroup analysis was planned for infants receiving different amounts of calcium and phosphorus, along with full enteral feeds as follows.

∘ Below 100 mg/60 mg calcium/phosphorus or equal to/above 100 mg/60 mg calcium/phosphorus per 100 mL milk.

∘ Supplementation of calcium without phosphorus.

∘ Supplementation of phosphorus without calcium.

Search methods

The standard search strategy of the Cochrane Neonatal Review Group (CNRG) was used. The search included the Cochrane Central Register of Controlled Trials (CENTRAL) (2012, Issue 9), MEDLINE, EMBASE, CINAHL (1966 to March 2013), and cross-references, as well as handsearching of abstracts of the Society for Pediatric Research and the International Journal of Sports Medicine.

Selection criteria

Randomized and quasi-randomized controlled trials comparing physical activity programs (extension and flexion, range-of-motion exercises) versus no organized physical activity programs in preterm infants.

Data collection and analysis

Data collection, study selection, and data analysis were performed according to the methods of the CNRG.

Main results

Eleven trials enrolling 324 preterm infants (gestational age 26 to 34 weeks) were included in this review. All were small (N = 16 to 50) single-center studies that evaluated daily physical activity for three and one-half to eight weeks during initial hospitalization. Methodological quality and reporting of included trials were variable.

Four trials demonstrated moderate short-term benefits of physical activity for bone mineralization at completion of the physical activity program. The only trial assessing long-term effects on bone mineralization showed no effect of physical activity administered during initial hospitalization on bone mineralization at 12 months corrected age. Meta-analysis from four trials demonstrated a positive effect of physical activity on daily weight gain (weighted mean difference (WMD) 2.21 g/kg/d, 95% confidence interval (CI) 1.23 to 3.19). Data from four trials showed a positive effect on linear growth (WMD 0.12 cm/wk, 95% CI 0.01 to 0.24) but not on head growth (WMD -0.03 cm/wk, 95% CI -0.14 to 0.08) during the study period. Only one trial reported on fractures (this outcome did not occur in intervention and control groups) and complications of preterm birth (no significant differences between intervention and control groups). None of the trials assessed other outcomes relevant to this review.

Authors' conclusions

Some evidence suggests that physical activity programs might promote short-term weight gain and bone mineralization in preterm infants. Data are inadequate to allow assessment of harm or long-term effects. Current evidence does not support the routine use of physical activity programs in preterm infants. Further trials incorporating infants with a high baseline risk of osteopenia are required. These trials should address adverse events, long-term outcomes, and the effects of nutritional intake (calories, protein, calcium, phosphorus).

Résumé scientifique

Programmes d'activité physique pour promouvoir la minéralisation osseuse et la croissance des nouveau-nés prématurés

Contexte

Chez les nouveau-nés prématurés, le manque de stimulation physique pourrait contribuer à une maladie osseuse métabolique nuisant à la minéralisation osseuse et à la croissance. Des programmes d'activité physique combinés à une nutrition adéquate pourraient possiblement permettre de stimuler la minéralisation osseuse et la croissance.

Objectifs

L'objectif principal était d'évaluer si les programmes d'activité physique chez les nouveau-nés prématurés améliorent la minéralisation osseuse et la croissance et réduisent le risque de fractures.

Les objectifs secondaires incluaient d'autres bénéfices potentiels en termes de durée de séjour à l'hôpital, de déformations du squelette et de résultats du développement neurologique, ainsi que les événements indésirables.

Analyse en sous-groupes :

Sachant que les nourrissons les plus petits sont les plus vulnérables au développement de l'ostéopénie (Bishop 1999), une analyse en sous-groupe a été planifiée pour les nourrissons d'un poids de naissance < 1 000 g.

Les apports en calcium et en phosphore peuvent influencer la capacité à augmenter le contenu minéral osseux chez le nourrisson (Kuschel 2004). Par conséquent, une analyse supplémentaire en sous-groupe a été planifiée pour les nourrissons recevant des quantités différentes de calcium et de phosphore, ainsi qu'une alimentation exclusivement entérale comme suit.

∘ Inférieur à 100 mg / 60 mg de calcium/phosphore ou égal/supérieur à 100 mg / 60 mg de calcium/phosphore par 100 ml de lait.

∘ Supplémentation en calcium sans phosphore.

∘ Supplémentation en phosphore sans calcium.

Stratégie de recherche documentaire

La stratégie de recherche documentaire standard du groupe de revue Cochrane sur la néonatologie (CNRG) a été utilisée. Les recherches incluaient le registre Cochrane des essais contrôlés (CENTRAL) (2012, numéro 9), MEDLINE, EMBASE, CINAHL (de 1966 à mars 2013) et les références croisées, ainsi que des recherches manuelles dans les résumés de la Society for Pediatric Research et l'International Journal of Sports Medicine.

Critères de sélection

Essais contrôlés randomisés et quasi randomisés comparant des programmes d'activité physique (extension et flexion, amplitude de mouvement) par rapport à l'absence de programmes d'activité physique organisés chez des nouveau-nés prématurés.

Recueil et analyse des données

Le recueil des données, la sélection des études et l'analyse des données ont été effectués selon les méthodes du CNRG.

Résultats principaux

Onze essais portant sur 324 nouveau-nés prématurés (d'âge gestationnel compris entre 26 et 34 semaines) ont été inclus dans cette revue. Tous étaient des études monocentriques de petite taille (N = 16 à 50) évaluant des activités physiques quotidiennes pendant trois et demie à huit semaines au cours de l'hospitalisation initiale. La qualité méthodologique et la notification des essais inclus étaient variables.

Quatre essais indiquaient que l'activité physique avait des effets bénéfiques modérés à court terme sur la minéralisation osseuse à la fin du programme d'activité physique. Le seul essai évaluant les effets à long terme sur la minéralisation osseuse ne montrait aucun effet de l'activité physique effectuée pendant l'hospitalisation initiale sur la minéralisation osseuse à 12 mois d'âge corrigé. Une méta-analyse de quatre essais a démontré un effet positif de l'activité physique sur la prise de poids quotidienne (différence moyenne pondérée (DMP) de 2,21 g/kg/j, intervalle de confiance (IC) à 95 % de 1,23 à 3,19). Les données de quatre essais montraient un effet positif sur la croissance linéaire (DMP de 0,12 cm / semaine, IC à 95 % de 0,01 à 0,24) mais pas sur la croissance de la tête (DMP de -0,03 cm / semaine, IC à 95 % de -0,14 à 0,08) au cours de la période d'étude. Un seul essai a rapporté des données sur les fractures (ce résultat n'est pas survenu dans les groupes d'intervention ou témoin) et les complications d'accouchement prématuré (aucune différence significative entre les groupes d'intervention et témoin). Aucun de ces essais n'évaluait d'autres critères de jugement pertinents pour cette revue.

Conclusions des auteurs

Certaines preuves suggèrent que les programmes d'activité physique pourraient stimuler la prise de poids et la minéralisation osseuse à court terme chez les nouveau-nés prématurés. Les données sont insuffisantes pour permettre une évaluation des effets délétères ou à long terme. Les preuves actuelles ne permettent pas de recommander l'utilisation systématique de programmes d'activité physique chez les nouveau-nés prématurés. D'autres essais recrutant des nourrissons présentant un risque élevé d'ostéopénie à l'inclusion sont nécessaires. Ces essais devraient examiner les événements indésirables, les critères de jugement à long terme et les effets de l'apport nutritionnel (calories, protéines, calcium, phosphore).

Plain language summary

Physical activity programs for promoting bone mineralization and growth in preterm infants

Babies born too early (premature babies) are often cared for in a fashion that minimizes physical activity to reduce stress and stress-related complications. However, lack of physical activity might lead to poor bone development and growth, as seen in bedridden children and adults. It is believed that physical activity programs (moving and pressing all joints on all limbs for several minutes a day) may promote bone development and growth in premature babies. This review found that physical activity might provide a small benefit for bone development and growth over a short term. Data were inadequate to allow assessment of long-term benefits and harms. Based on current knowledge, physical activity programs cannot be recommended as a standard procedure for premature babies.

Résumé simplifié

Programmes d'activité physique pour promouvoir la minéralisation osseuse et la croissance des nouveau-nés prématurés

Dans la prise en charge des bébés nés trop tôt (prématurés), l'activité physique est souvent limitée au minimum afin de réduire le stress et les complications qui y sont liées. Cependant, le manque d'activité physique pourrait nuire au développement osseux et à la croissance, comme on peut l'observer chez les enfants et les adultes alités. On pense que des programmes d'activité physique (appuyer sur les articulations de tous les membres et les mobiliser plusieurs minutes par jour) pourraient stimuler la croissance et le développement osseux des bébés prématurés. Cette revue a constaté que l'activité physique pourrait potentiellement avoir de petits effets bénéfiques sur la croissance et le développement osseux à court terme. Toutefois, les données étaient insuffisantes pour évaluer les effets bénéfiques et délétères à long terme. Sur la base des connaissances actuelles, les programmes d'activité physique ne peuvent pas être recommandés en tant que procédure standard chez les bébés prématurés.

Notes de traduction

Traduit par: French Cochrane Centre 22nd July, 2014
Traduction financée par: Financeurs pour le Canada : Instituts de Recherche en Santé du Canada, Ministère de la Santé et des Services Sociaux du Québec, Fonds de recherche du Québec-Santé et Institut National d'Excellence en Santé et en Services Sociaux; pour la France : Ministère en charge de la Santé

Streszczenie prostym językiem

Programy ćwiczeń fizycznych w promowania wzrostu i mineralizacji kości u wcześniaków

Dzieci urodzone zbyt wcześnie (wcześniaki) są często pod opieką ukierunkowaną na ograniczanie ich aktywności fizycznej w celu zmniejszenia stresu i konsekwencji związanych ze stresem. Jednakże, brak aktywności fizycznej może prowadzić do słabego rozwoju i wzrostu kości, co można zaobserwować u obłożnie chorych dzieci i dorosłych. Uważa się, że programy aktywności fizycznej (poruszanie i stosowanie nacisku we wszystkich stawach na wszystkich kończynach przez kilka minut dziennie) może promować rozwój i wzrost kości wcześniaków. W niniejszym przeglądzie wykazano, że aktywność fizyczna może skutkować niewielką korzyścią dla rozwoju i wzrostu kości w krótkim okresie czasu. Dane były niewystarczające, aby umożliwić ocenę długofalowych korzyści i szkód. Na podstawie aktualnego stanu wiedzy nie można zalecać programów aktywności fizycznej jako standardowego postępowania u wcześniaków.

Uwagi do tłumaczenia

Tłumaczenie: Joanna Zając Redakcja: Magdalena Koperny

Background

Description of the condition

Very low birth weight (VLBW) infants are at risk of developing osteopenia of prematurity. The major etiological factor seems to be substrate deficiency, particularly of calcium and phosphorus, in the presence of low bone mass at birth (Steichen 1980). Immobilization may also contribute to osteopenia (Bishop 1999).

Diagnostic criteria of osteopenia vary considerably. Frequently used biochemical indicators of disturbed bone metabolism are low whole blood phosphate levels, increased urinary calcium/phosphate ratios, and high plasma alkaline phosphatase levels (Bishop 1999). In neonates, peak plasma alkaline phosphatase activity greater than five times the maximum adult normal range of 130 IU/mL is associated with reduced stature at 18 months corrected age in former preterm infants (Lucas 1989).

Osteopenia in preterm infants leads to impaired bone mineralization, as measured by techniques such as single-photon absorptiometry (SPA) or dual-energy x-ray absorptiometry (DEXA) (Salle 1992; Steichen 1980). As a result, growth velocity and long-term height may be reduced (Lucas 1989). In severe cases, fractures have been reported (Koo 1988). Although reduced bone mineralization is clearly associated with multiple skeletal deformities such as bowing of the legs, scoliosis, and skull indentations (Juskeliene 1996; Oyemade 1981; Tubbs 2004), the prevalence of such deformities in former preterm infants with osteopenia has not yet been determined.

Description of the intervention

Common strategies for the prevention of osteopenia in VLBW infants include calcium and phosphorus supplementation of human milk/formula and physical activity programs. A systematic review of trials investigating the effects of fortification of human milk with multicomponent fortifiers in nursery settings found that this intervention in VLBW infants was associated with short-term improvements in linear growth, head growth and weight gain (Kuschel 2004). In a randomized study, postdischarge multicomponent fortified formula when compared with standard formula led to enhanced linear growth at 18 months corrected age (Lucas 2001). Another randomized trial demonstrated increased bone mineral content and growth in preterm infants fed an isocaloric, calcium- and phosphorus-enriched formula when compared with controls receiving a conventional preterm formula (Lapillonne 2004). In this study, increasing calcium concentration from 80 to 100 mg/100 mL and increasing phosphorus from 42.5 to 60 mg/100 mL as soon as full enteral feedings were reached was associated with higher bone mineral content and weight at term as measured by DEXA.

Mechanical strain on bones and joints stimulates bone formation and growth, and inactivity leads to bone resorption (Larson 2000; MacKelvie 2004). Physical activity programs have been shown to reduce the risk of osteoporotic fracture and bone loss in adults (Bonaiuti 2002; Heinonen 1996; Kerr 2001). Observational studies in children beyond the neonatal age also suggest that physical activity might help to promote bone mineral density (Slemenda 1991). Minimal handling is frequently a routine policy for hospitalized preterm infants to facilitate stability and to minimize stress. The resultant inactivity may lead to suboptimal stimulation of bone metabolism.

How the intervention might work

Given evidence from studies in older children and adults, regular physical activity programs (range-of-motion exercises) may provide a simple intervention for improving bone mineral content and skeletal growth in preterm infants. As range-of-motion exercises inevitably have an element of systematic holding and stroking, they may also promote general growth in preterm infants because interventions solely consisting of systematic holding and stroking (eg, massage/tactile stimulation) have been reported to promote growth (Vickers 2004). However, physical activity programs in preterm infants may have adverse effects such as fractures, or they may increase the risk or severity of complications of prematurity (eg, apnea, bradycardia) with resultant altered blood flow to vital organs such as brain and the possibility of long-term neurodevelopmental impairment.

Why it is important to do this review

Physical activity programs are in use for promoting bone mineralization and growth in preterm neonates. These programs need to be formally assessed to provide caregivers with clinically relevant data on their efficacy and safety. The aim of this systematic review is to summarize current evidence on benefits and harms of physical activity programs in preterm infants.

Objectives

The primary objective was to assess whether physical activity programs in preterm infants improve bone mineralization and growth and reduce the risk of fracture.

The secondary objectives included other potential benefits in terms of length of hospital stay, skeletal deformities and neurodevelopmental outcomes, and adverse events.

Subgroup analysis:

  • Given that the smallest infants are most vulnerable for developing osteopenia (Bishop 1999), a subgroup analysis was planned for infants with birth weight < 1000 g.

  • Calcium and phosphorus intake may affect an infant's ability to increase bone mineral content (Kuschel 2004). Therefore, an additional subgroup analysis was planned for infants receiving different amounts of calcium and phosphorus, along with full enteral feeds as follows.

    • Below 100 mg/60 mg calcium/phosphorus or equal to/above 100 mg/60 mg calcium/phosphorus per 100 mL milk.

    • Supplementation of calcium without phosphorus.

    • Supplementation of phosphorus without calcium.

Methods

Criteria for considering studies for this review

Types of studies

All randomized and quasi-randomized controlled trials in which the unit of allocation was the individual infant.

Types of participants

Preterm infants born at a gestational age < 37 completed weeks who did not receive physical therapy for any indication other than osteopenia of prematurity (eg, severe contractures).

Types of interventions

Systematic physical activity programs consisting of extension and flexion, range-of-motion exercises of the infant's upper and lower limbs, administered for several minutes at a time several times a week for at least two weeks, compared with no organized physical activity programs. Eligible studies included those that provided physical activity for the experimental group, with or without massage and/or tactile stimulation for both experimental and control groups.

Types of outcome measures

Trials had to assess at least one of the following outcomes.

Primary outcomes
  • Bone mineralization: bone mineral content, bone mineral density, and bone area as measured by absorptiometric x-ray techniques:

    • at completion of the physical activity program;

    • at discharge;

    • at term; and

    • at 12 to 24 months corrected age.

  • Fractures: proportion of infants with one or more fractures:

    • at completion of the physical activity program;

    • at discharge;

    • at term; and

    • at 12 to 24 months corrected age.

  • Somatic growth: weight, length, head circumference:

    • at completion of the physical activity program;

    • at discharge;

    • at term; and

    • at 12 to 24 months corrected age.

Secondary outcomes
  • Complications of prematurity.

    • Mortality at hospital discharge.

    • Mean frequency of apnea during study period.

    • Mean frequency of bradycardia during study period.

    • Mean frequency of apnea and bradycardia during study period.

    • Proportion of infants with one or more proven systemic infections diagnosed during the study period (positive culture from blood, urine, cerebrospinal fluid, or other normally sterile body fluids).

    • Oxygen dependency at 28 days.

    • Chronic lung disease defined as supplemental oxygen or ventilator support at 36 weeks postmenstrual age.

    • Necrotizing enterocolitis.

    • Retinopathy of prematurity (all stages and severe stage 3 or greater).

    • Intraventricular hemorrhage (all grades and severe grade 3 or 4).

    • Periventricular leukomalacia.

  • Length of hospital stay (days).

  • Proportion of infants with one or more secondary skeletal deformities (including skull, spine, limbs).

  • Neurodevelopmental abnormalities at 18 to 24 months corrected age or later.

    • Cerebral palsy.

    • Developmental delay (assessed by standardized and validated test, eg, Griffith or Bayley test, with abnormality defined as more than two standard deviations below the mean).

    • Intellectual impairment (IQ greater than two standard deviations below the mean as assessed by a standardized and validated test).

    • Blindness (vision less than 6/60 in both eyes).

    • Sensorineural deafness requiring amplification.

Search methods for identification of studies

The standard strategy of the Cochrane Neonatal Review Group (CNRG) was used for a literature search in September 2005 and was repeated in March 2013.

Electronic searches

The databases searched included MEDLINE, EMBASE, and CINAHL (1966 to March 2013).
The MeSH headings included Infant, Newborn, Bone Diseases, Metabolic, Motor Activity or Movement or Exercise and Exercise Therapy, and the text word "Physical activity" or "Exercise." The Cochrane Central Register of Controlled Trials (CENTRAL; 2013, Issue 4) was searched using the words "Newborn," "Physical activity," and "exercise."

Searching other resources

Previous reviews including cross-references and references from identified studies were searched. No language restrictions were applied. Abstracts (1992 to 2012) of the Society for Pediatric Research, the European Society for Pediatric Research, and the International Journal of Sports Medicine were also searched.

Clinical trials registries were searched for ongoing or recently completed trials (clinicaltrials.gov; controlled-trials.com; and who.int/ictrp).

Data collection and analysis

The standard methods of the CNRG were used.

Selection of studies

Two review authors (SMS and SK) independently conducted the literature search. All randomized and quasi-randomized controlled trials fulfilling the selection criteria described in the previous section were included. Both review authors assessed the trials for eligibility for inclusion and methodological quality.

Data extraction and management

Two review authors (SMS and SK) separately extracted, assessed, and coded all data for each study. Differences were resolved by discussion. Additional information was requested from the trial authors if necessary.

Assessment of risk of bias in included studies

The standard methods of the CNRG were employed. The methodological quality of the studies was assessed using the following key criteria: allocation concealment (blinding of randomization), blinding of intervention, completeness of follow-up, and blinding of outcome measurement/assessment. For each criterion, assessment was yes, no, cannot tell. Two review authors (SMS and SK) separately assessed each study. Disagreements were resolved by discussion. This information was added to the Characteristics of included studies table.

In addition, the following issues were evaluated and were entered into the Risk of bias in included studies table.

  • Sequence generation: Was the allocation sequence adequately generated? 

  • Allocation concealment: Was allocation adequately concealed? 

  • Blinding of participants, personnel, and outcome assessors: Was knowledge of the allocated intervention adequately prevented during the study? At study entry? At the time of outcome assessment? 

  • Incomplete outcome data: Were incomplete outcome data adequately addressed? 

  • Selective outcome reporting: Are reports of the study free of suggestion of selective outcome reporting? 

  • Other sources of bias: Was the study apparently free of other problems that could put it at high risk of bias?

Measures of treatment effect

Statistical analyses were performed using Review Manager software. Categorical data were analyzed using risk ratio (RR), risk difference (RD), and the number needed to treat for an additional beneficial outcome (NNTB). Continuous data were analyzed using weighted mean difference (WMD). The 95% confidence interval (CI) was reported for all estimates.

Assessment of heterogeneity

We estimated the treatment effects of individual trials and examined heterogeneity between trials by inspecting the forest plots and quantifying the impact of heterogeneity using the I2 statistic. If we detected statistical heterogeneity, we planned to explore the possible causes (eg, differences in study quality, participants, intervention regimens, or outcome assessments) using post hoc subgroup analyses.

Data synthesis

A fixed-effect model was used to pool data for meta-analyses.

Subgroup analysis and investigation of heterogeneity

Subgroup analysis:

  • Given that the smallest infants are most vulnerable for developing osteopenia (Bishop 1999), a subgroup analysis was planned for infants with birth weight < 1000 g.

  • Calcium and phosphorus intake may affect an infant's ability to increase bone mineral content (Kuschel 2004). Therefore, an additional subgroup analysis was planned for infants receiving different amounts of calcium and phosphorus along with full enteral feeds as follows.

    • Below 100 mg/60 mg calcium/phosphorus or equal to/above 100 mg/60 mg calcium/phosphorus per 100 mL milk.

    • Supplementation of calcium without phosphorus.

    • Supplementation of phosphorus without calcium.

Results

Description of studies

Results of the search

Forty-four abstracts were identified using the prespecified search strategy in March 2013. Eighteen potentially eligible studies were retrieved for detailed evaluation. Three ongoing studies were found.

Included studies

Eleven trials incorporating 324 preterm infants met inclusion criteria of this review (Chen 2010; Eliakim 2002; Litmanovitz 2003; Litmanovitz 2007; Moyer-Mileur 1995; Moyer-Mileur 2000; Moyer-Mileur 2000a; Moyer-Mileur 2008; Nemet 2002; Tosun 2011; Vignochi 2008). Abstracts with preliminary results of three studies (Litmanovitz 2003; Moyer-Mileur 1995, Moyer-Mileur 2000) had been reported in Pediatric Research before full publication. Seven included studies (Litmanovitz 2003; Litmanovitz 2007; Moyer-Mileur 1995; Moyer-Mileur 2000; Moyer-Mileur 2008; Tosun 2011; Vignochi 2008) specified eligibility criteria for participant enrollment (see the Table, Characteristics of included studies). The following descriptions refer to enrolled rather than eligible patients. Moyer-Mileur 1995, Moyer-Mileur 2000, Moyer-Mileur 2000a, and Moyer-Mileur 2008 were single-center studies of healthy preterm neonates (N = 49, 32, 20, and 50, respectively) conducted at the University Hospital of Utah, in Utah, USA. Moyer-Mileur 1995 and Moyer-Mileur 2000 enrolled two- to four-week-old preterm infants (mean gestation 28 to 30 weeks) who were fed fortified breast milk or preterm formula. The proportion of infants fed fortified breast milk was between 53% and 73% and did not differ between treatment and control groups. Infants in treatment and control groups received well-defined interventions applied by the same trained occupational therapist, described as follows. For the exercise group, range-of-motion exercises with gentle compression and extension and flexion of both upper and lower extremities were provided. Each movement was done five times at each joint (wrist, elbow, shoulder, ankle, knee, and hip) five times a week. For the control group, tactile stimulation was provided, that is, a daily interactive period of holding and stroking but no range-of-motion activity. Both protocols were administered for three and one-half to four weeks. Outcomes included bone mineralization as measured by absorptiometric x-ray techniques, short-term growth, and biochemical markers of bone metabolism. Moyer-Mileur 2008 had a similar design, but infants were exclusively fed fortified breast milk and intervention groups received physical activity programs provided by a trained occupational therapist or by the infant's mother. Moyer-Mileur 2000a was a follow-up study assessing bone mineralization and postdischarge growth up to 12 months corrected age in infants who had been enrolled in a physical activity program similar to that reported in Moyer-Mileur 2000.

Eliakim 2002, Litmanovitz 2003, Litmanovitz 2007, and Nemet 2002 were single-center studies in preterm neonates (N = 20, 24, 16, and 24, respectively) performed at the Meir General Hospital, Sapir Medical Center, in Israel. Eliakim 2002 and Nemet 2002 enrolled four- to five-week-old preterm neonates (mean gestation 28 to 29 weeks) fed fortified breast milk or preterm formula. The proportions of infants with chronic lung disease in the study and control groups of neonates were comparable in Eliakim 2002 (40% vs 40%) and Nemet 2002 (42% vs 42%). Litmanovitz 2003 and Litmanovitz 2007 enrolled infants of similar gestational age in the first week of life, including infants receiving parenteral nutrition accompanied by fortified breast milk or preterm formula. The overall proportion of infants fed fortified breast milk was 50% in Eliakim 2002 and 46% in Litmanovitz 2003 with no significant difference between treatment and control groups noted within each trial (Eliakim 2002 five/10 vs five/10; Litmanovitz 2003 five/12 vs six/12). In Eliakim 2002, Litmanovitz 2003, and Nemet 2002, a trained person administered physical activity (treatment group) and tactile stimulation (control group) for four weeks based on the Moyer-Mileur protocol (Moyer-Mileur 1995; see above). Litmanovitz 2007 administered the same interventions. However, programs were applied for a total duration of eight weeks. Outcomes in this trial included short-term growth, biochemical markers of bone and fat tissue metabolism, and bone ultrasound measurements.

Vignochi 2008 was a single-center study in 29 preterm infants conducted at the Hospital de Clínicas de Porto Alegre in Brazil. Healthy preterm infants of 26 to 34 weeks gestational age were enrolled at three weeks postnatal age if they tolerated enteral feeds of at least 110 kcal/kg/d (fortified breast milk or preterm formula). The proportion of infants fed fortified breast milk was 21% versus 13% in the physical activity group versus the control group. Infants in the intervention group received a physical activity program based on the Moyer-Mileur protocol. A physical therapist applied the intervention for 15 minutes daily five days a week until the participant reached a body weight of 2 kg (ie, until discharge from the hospital; mean duration of the program was 25 days). Thus, daily duration of the physical activity program in Vignochi 2008 was greater (15 minutes daily) than in Moyer-Mileur 1995 (five minutes daily), and total duration and frequency were comparable with the original Moyer-Mileur protocol. In contrast to the original Moyer-Mileur protocol, infants in the control group did not receive tactile stimulation. Outcomes in Vignochi 2008 included whole body bone mineralization measured by DEXA, short-term growth, body composition in terms of fat mass and lean mass, and biochemical markers of bone metabolism.

Chen 2010 was a single-center study in 20 preterm infants conducted in Taiwan. Healthy preterm infants with birth weight < 1500 g were enrolled at one week postnatal age and received a physical activity program based on the Moyer-Mileur protocol (10 minutes daily, total duration four weeks, applied by a trained nurse). Outcomes included complications of prematurity, fractures, duration of hospitalization, bone speed of sound measurements, and biochemical markers of bone metabolism.

Tosun 2011 was a single-center study in 40 preterm infants conducted in Turkey. Preterm infants of 26 to 32 weeks gestational age were enrolled within the first three days of life and received a physical activity program identical to that used in Moyer-Mileur 1995. Outcomes included anthropometric data and bone speed of sound measurements.

Details of included studies are shown in the Table, Characteristics of included studies.

Excluded studies

Seven randomized trials (Aly 2004; Haley 2012; Hassanein 2002; Massaro 2009; McDevitt 2012; McIntyre 1992; Vignochi 2012) were excluded from the review. One trial was excluded because the study population consisted of only term infants (McIntyre 1992). Another trial was excluded because both intervention and control groups received physical activity programs (McDevitt 2012). Three trials were excluded because the protocol prescribed physical activity programs plus additional massage (Aly 2004; Hassanein 2002) or tactile stimulation (Haley 2012) in the intervention group but no massage or tactile stimulation in the control group. The application of massage or tactile stimulation to infants only in the intervention group was considered to potentially affect the outcomes. Another trial randomly assigned infants into three study groups; one group of infants received a physical activity program plus additional massage, a second group received only massage, and the control group received neither of those measures (Massaro 2009). This trial was excluded because the duration of massage differed markedly between intervention groups. Last, one trial (Vignochi 2012) was excluded because all participants from this report are included in a previous report already incorporated in this review (Vignochi 2008).

Details of excluded studies are summarized in the Table, Characteristics of excluded studies.

Risk of bias in included studies

Overall, the methodological and reporting quality of most included trials was moderate. Only one trial explicitly stated concealment of participant allocation and method of randomization (Moyer-Mileur 2008). Additional information received after Dr Moyer-Mileur was contacted suggested that participant allocation was concealed in Moyer-Mileur 1995 and Moyer-Mileur 2000.

None of the trials attempted to blind the interventions. Short-term follow-up was complete (100%) in seven trials (Eliakim 2002; Litmanovitz 2003; Litmanovitz 2007; Moyer-Mileur 2000; Nemet 2002; Tosun 2011; Vignochi 2008). Moyer-Mileur 1995 lost 23/49 (45%) participants because of hospital discharge or transfer before completion of the four-week study, leaving 26 (13 infants in the treatment group and the control group, respectively) in the study. Baseline data and results were available for only 26 infants completing the study. Moyer-Mileur 2008 lost 17/50 infants (34%) because of transfer to another facility or change of feeding regimen during the four-week study. Baseline data and results were available only for the 33 infants who completed the study. The abstract by Moyer-Mileur 2000a from the same research group reporting on long-term follow-up of 20 former preterm neonates from hospital discharge to 12 months corrected age did not include baseline data of the original cohort receiving the interventions; therefore, completeness of follow-up could not be determined. Assessors of bone mineralization in Moyer-Mileur 1995, Moyer-Mileur 2000, Moyer-Mileur 2008, and Vignochi 2008 were blinded. None of the other included trials reported on blinding of assessors for outcomes relevant to this review.

Effects of interventions

Physical activity program versus control

Primary outcomes
Bone mineralization
At completion of the physical activity program

Four trials (Moyer-Mileur 1995; Moyer-Mileur 2000; Moyer-Mileur 2008; Vignochi 2008) involving 117 infants reported on bone mineral content, bone mineral density, and bone area at completion of the physical activity program. Because of differences in methodologies (radial SPA vs forearm DEXA vs total body DEXA), data were not pooled for meta-analyses.

Bone area at completion of the physical activity program (Outcome 1.1; Figure 1 )
Pooled data from Moyer-Mileur 2000 (N = 23) and Moyer-Mileur 2008 (N = 33) suggest that physical activity versus control is associated with larger forearm bone area as measured by DEXA (WMD 1.38 cm2, 95% CI 0.70 to 2.07). Vignochi 2008 (N = 29) reported higher total body bone area in the physical activity group versus the control group (MD 8.03 cm2, 95% CI 4.05 to 12.01).

Figure 1.

Forest plot of comparison: 1 Physical activity program versus control, outcome: 1.1 Bone area at completion of the physical activity program.

Bone mineral content at completion of the physical activity program (Outcome 1.2; Figure 2 )
Infants having physical activity in Moyer-Mileur 1995 (N = 23) had a higher mean radial bone mineral content compared with those in the control group as measured by SPA (mean difference (MD) 10.60 mg/cm, 95% CI 1.60 to 19.60). Meta-analysis of the studies Moyer-Mileur 2000 (N = 32) and Moyer-Mileur 2008 (N = 33) demonstrates higher forearm bone mineral content in the physical activity group versus the control group as measured by DEXA (WMD 130.91 mg, 95% CI 55.35 to 206.47). Vignochi 2008 (N = 29) reported higher total body bone mineral content in the physical activity group versus the control group (MD 389.10 mg, 95% CI 229.98 to 548.22).

Figure 2.

Forest plot of comparison: 1 Physical activity program versus control, outcome: 1.2 Bone mineral content at completion of the physical activity program.

Bone mineral density at completion of the physical activity program (Outcome 1.3; Figure 3 )
No significant effect of physical activity on radial bone mineral density was noted in Moyer-Mileur 1995 (MD 29.0 mg/cm2, 95% CI -1.48 to 59.48) as measured by SPA or forearm bone mineral density in pooled data from Moyer-Mileur 2000 and Moyer-Mileur 2008 as measured by DEXA (WMD -0.19 mg/cm2, 95% CI -0.39 to 0.01). Vignochi 2008 reported higher total body bone mineral density in the physical activity group versus the control group (MD 10.10 mg/cm2, 95% CI 5.27 to 14.93).

Figure 3.

Forest plot of comparison: 1 Physical activity program versus control, outcome: 1.3 Bone mineral density at completion of the physical activity program.

At discharge

Not reported in any of the trials.

At term

Not reported in any of the trials.

At 12 to 24 months corrected age

Bone mineral content and bone area at 12 months corrected age (Outcomes 1.4 and 1.5)
One trial (Moyer-Mileur 2000a) with 20 infants who had received physical activity versus control tactile stimulation during initial hospitalization reported on whole body bone mineral content and whole body bone area at 12 months corrected age as measured by DEXA. No difference in whole body bone mineral content (MD -17.30 g, 95% CI -68.95 to 34.35) or whole body bone area (MD -21.00 cm2, 95% CI -85.60 to 43.60) was noted.

Fractures

One trial (Chen 2010) with 16 participants reported that no fractures occurred in treatment and control groups.

Somatic growth
At completion of the physical activity program

Litmanovitz 2007 (N = 16; duration of exercise eight weeks) and Tosun 2011 (N = 40; duration of exercise four weeks) did not find a significant effect of physical activity on body weight, body length, and head circumference in infants enrolled within the first week of life. Similarly, additional information from the authors of Chen 2010 (N = 16; duration of exercise four weeks) suggested no significant effect of physical activity on body weight in infants enrolled within the second week of life.

Body weight gain during study period (Outcome 1.6; Figure 4 )
Six trials (Eliakim 2002; Moyer-Mileur 1995; Moyer-Mileur 2000; Moyer-Mileur 2008; Nemet 2002; Vignochi 2008) with a combined total of 164 infants reported a significant effect of physical activity on weight gain during the study period. Because of lack of data, pooling of results was possible for only four trials (Eliakim 2002; Moyer-Mileur 1995; Moyer-Mileur 2000; Moyer-Mileur 2008) incorporating 111 infants. Meta-analysis showed a significant effect of physical activity on daily weight gain (WMD 2.21 g/kg/d, 95% CI 1.23 to 3.19).

Figure 4.

Forest plot of comparison: 1 Physical activity program versus control, outcome: 1.6 Body weight gain during study period (g/kg/d).

Body length gain and head circumference gain during study period (Outcome 1.7; Figure 5, and Outcome 1.8; Figure 6 )
Five trials (Litmanovitz 2003; Moyer-Mileur 1995; Moyer-Mileur 2000; Moyer-Mileur 2008; Vignochi 2008) involving 144 infants reported on body length and head circumference gain during the study period. Only Vignochi 2008 (15 minutes of daily physical activity for four weeks compared with no intervention) reported a significant positive effect of physical activity on these outcomes. Because of lack of data, pooling of results was possible for only four trials (Moyer-Mileur 1995; Moyer-Mileur 2000; Moyer-Mileur 2008; Vignochi 2008) involving 120 infants. Meta-analyses suggest a positive effect of physical activity on gain in body length (WMD 0.12 cm/wk, 95% CI 0.01 to 0.24) but not on head circumference (WMD -0.03 cm/wk, 95% CI -0.14 to 0.08) during the study period. The I2 statistic suggested heterogeneity on the meta-analysis of gain in body length (P < 0.001, I2 = 88%). Use of a random-effects model did not reveal significant effects of physical activity on gain in body length (WMD 0.19 cm/wk, 95% CI -0.18 to 0.55).

Figure 5.

Forest plot of comparison: 1 Physical activity program versus control, outcome: 1.7 Body length gain during study period (cm/wk).

Figure 6.

Forest plot of comparison: 1 Physical activity program versus control, outcome: 1.8 Head circumference gain during study period (cm/wk).

At discharge

Not reported in any of the trials.

At term

Not reported in any of the trials.

At 12 to 24 months corrected age

Body weight at 12 months corrected age (Outcome 1.9)

Only the trial by Moyer-Mileur 2000a (N = 20; physical activity vs tactile stimulation during initial hospitalization) reported on body weight at 12 months corrected age. No significant effect of physical activity on body weight was noted at 12 months corrected age (MD 200.00 g, 95% CI -799.39 to 1199.39).

Secondary outcomes

Only Chen 2010 (N = 16; physical activity vs tactile stimulation for four weeks) reported typical complications of preterm birth. No difference in retinopathy of prematurity, intraventricular hemorrhage, sepsis during hospitalization, oxygen dependency at 36 weeks postmenstrual age, and duration of hospital stay between physical activity and control groups was noted. None of the included trials reported on adverse effects of the interventions, skeletal deformities, or long-term neurodevelopmental impairment.

Subgroup analyses

Preplanned subgroup analyses based on birth weight and calcium/phosphorus supplementation could not be performed because data were inadequate or were lacking.

Discussion

Analysis of eleven small randomized trials indicates that daily physical activity programs of five to 15 minutes per day administered for three and one-half to eight weeks during initial hospitalization might promote gains in body weight and body length, while improving bone mineralization in the short term, in healthy preterm infants (gestation 26 to 34 weeks) on full enteral feeds of fortified breast milk and/or preterm formula. The effects seem to be limited to the first few months of life and seem to be more consistent if given 15 minutes daily rather than five minutes daily. No trials have reported on adverse effects, skeletal deformities, or long-term neurodevelopment.

Most included studies examined preterm infants of several weeks postnatal age who were not small for gestation, had no congenital abnormalities, and were medically stable and on full enteral feeds (at least 100 kcal/kg/d). All trials involved interventions based on the Moyer-Mileur protocol (Moyer-Mileur 1995), and several trials reported beneficial effects of physical activity versus tactile stimulation or no stimulation on short-term growth. Additionally, some studies suggested improved short-term bone mineralization. The effect on growth is somewhat surprising, given that all studies reporting on weight gain during the study period showed similar nutritional intake (calories, protein, calcium, phosphate) in treatment and control groups. Enhanced bone and fat free mass (Moyer-Mileur 2000; Moyer-Mileur 2008; Vignochi 2008), as well as changes in growth hormones leading to an anabolic situation, as evidenced by a trend toward greater insulin-like growth factor concentrations in the physical activity group (Eliakim 2002), could explain these findings. Short-term growth however was not improved when physical activity programs were started within the first two weeks of life (Chen 2010; Litmanovitz 2007; Tosun 2011). Four trials reported moderate short-term benefits for bone mineralization, but none of these studies assessed long-term effects of physical activity. Only one small trial with low statistical power assessed secondary outcomes of this review and reported no effect of physical activity on fractures, complications of preterm birth, and duration of hospital stay (Chen 2010). Statistically significant heterogeneity was noted on meta-analysis of four trials (Moyer-Mileur 1995; Moyer-Mileur 2000; Moyer-Mileur 2008; Vignochi 2008) assessing the effects of physical activity on body length (Outcome 1.7). Possible reasons for heterogeneity might be differences between studies in methodology for obtaining body length measurements and the general difficulty involved in obtaining accurate measurements of body length in preterm infants. Reproducibility of crown-heel length measurements obtained by conventional methods (eg, tape measurement, pencil marks made on a paper barrier) is low in newborn infants (Rosenberg 1992). Hence, specific devices are required for accurate measurements in preterm infants (Lawn 2004). No other reasons for explaining this heterogeneity could be identified.

The results of this review need to be interpreted with great caution, given the considerable methodological limitations of most included trials. Although most trials were published several years after the first CONSORT statement (Begg 1996), the quality of reporting was limited. Recruitment bias cannot be excluded because most of the trials did not provide a participant flow chart or numbers of eligible patients in relation to enrolled, evaluated, and "lost to follow-up" participants. Only one trial clearly explained concealment of participant allocation and method of randomization (Moyer-Mileur 2008). Several trials (Eliakim 2002; Litmanovitz 2003; Moyer-Mileur 1995; Nemet 2002) reported that infants were "matched for gestational age, birth weight, gender, corrected age, and weight at start of the study and were then randomized to either treatment or control group" without further explanation. Given the small sample size (N = 16 to 50) and the identical numbers of infants in treatment and control groups in nine of eleven trials, the quality and adequacy of randomization in most of the included trials should be questioned. However, concealment of participant allocation seems to be adequate in Moyer-Mileur 1995, Moyer-Mileur 2000, and Moyer-Mileur 2008, based on comments from the study authors. None of the trials attempted blinding of the intervention. Follow-up was incomplete in the largest studies included in this review (Moyer-Mileur 1995, N = 49, follow-up rate 55%; Moyer-Mileur 2008, N = 50, follow-up rate 66%) and was impossible to assess because of lack of data in the only study reporting on long-term effects (Moyer-Mileur 2000a). Apart from the evaluation of bone mineralization in Moyer-Mileur 1995, Moyer-Mileur 2000, Moyer-Mileur 2008, and Vignochi 2008, assessments of outcomes relevant to this review most likely were not robustly blinded in any of the trials. Lack of statistically significant heterogeneity in most meta-analyses in this review does not exclude heterogeneity, given the small numbers. In relation to the clinical relevance of the results, it is important to realize that the baseline risk of osteopenia in most participants was not high, given their gestation and birth weight. Thus, the validity and general applicability of these results are limited. Additionally, the clinical significance of unintentional neonatal physical activities (bathing, changing nappies, skin care) in relation to structured physical activity programs of five to 15 minutes per day remains unclear.

Authors' conclusions

Implications for practice

Some evidence from eleven small randomized trials of moderate methodological and reporting quality indicates that physical activity programs might promote moderate short-term growth and bone mineralization in preterm infants. The clinical importance of these findings is questionable, given the small effect size and the low baseline risk of poor bone mineralization and growth in study participants. Available data are inadequate to permit assessment of harm or long-term effects of physical activity programs. Current evidence does not support the routine use of physical activity programs.

Implications for research

Evaluation of the benefits and harms of physical activity programs for promoting bone mineralization and growth requires further testing in well-designed randomized trials incorporating extremely low birth weight infants who are at high risk for the condition. Such trials should aim at monitoring and reporting adverse events (eg, apnea, sepsis, fractures) as well as long-term growth, bone mineralization, and neurodevelopmental outcomes, while addressing the possibility that nutritional intake (calories, protein, calcium, phosphorus) might modify the effects of physical activity.

Acknowledgements

We thank Bonny Specker, Hany Aly, An Massaro, Öznur Tosun, Hsiu-Lin Chen, and Laurie Moyer-Mileur, who clarified existing data and provided us with additional information.

The Cochrane Neonatal Review Group has been funded in part with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN267200603418C.

Data and analyses

Download statistical data

Comparison 1. Physical activity program versus control
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Bone area at completion of the physical activity program3 Mean Difference (IV, Fixed, 95% CI)Subtotals only
1.1 Forearm bone area at completion of the physical activity program (cm2)265Mean Difference (IV, Fixed, 95% CI)1.38 [0.70, 2.07]
1.2 Whole body bone area at completion of the physical activity program (cm2)129Mean Difference (IV, Fixed, 95% CI)8.03 [4.05, 12.01]
2 Bone mineral content at completion of the physical activity program4 Mean Difference (IV, Fixed, 95% CI)Subtotals only
2.1 Radial bone mineral content (mg/cm) measured by single photon absorptiometry (SPA)123Mean Difference (IV, Fixed, 95% CI)10.60 [1.60, 19.60]
2.2 Forearm bone mineral content (mg) measured by dual-energy x-ray absorptiometry (DEXA)265Mean Difference (IV, Fixed, 95% CI)130.91 [55.35, 206.47]
2.3 Whole body bone mineral content (mg) measured by dual-energy x-ray absorptiometry (DEXA)129Mean Difference (IV, Fixed, 95% CI)389.1 [229.98, 548.22]
3 Bone mineral density at completion of the physical activity program4 Mean Difference (IV, Fixed, 95% CI)Subtotals only
3.1 Radial bone mineral density (mg/cm2) measured by single photon absorptiometry (SPA)123Mean Difference (IV, Fixed, 95% CI)29.0 [-1.48, 59.48]
3.2 Forearm bone mineral density (mg/cm2) measured by dual-energy x-ray absorptiometry (DEXA)265Mean Difference (IV, Fixed, 95% CI)-0.19 [-0.39, 0.01]
3.3 Whole body bone mineral density (mg/cm2) measured by dual-energy x-ray absorptiometry (DEXA)129Mean Difference (IV, Fixed, 95% CI)10.10 [5.27, 14.93]
4 Bone mineral content at 12 months corrected age (g)120Mean Difference (IV, Fixed, 95% CI)-17.30 [-68.95, 34.35]
5 Bone area at 12 months corrected age (cm2)120Mean Difference (IV, Fixed, 95% CI)-21.0 [-85.60, 43.60]
6 Body weight gain during study period (g/kg/d)4111Mean Difference (IV, Fixed, 95% CI)2.21 [1.23, 3.19]
7 Body length gain during study period (cm/wk)4120Mean Difference (IV, Fixed, 95% CI)0.12 [0.01, 0.24]
8 Head circumference gain during study period (cm/wk)391Mean Difference (IV, Fixed, 95% CI)-0.03 [-0.14, 0.08]
9 Body weight at 12 months corrected age (g)120Mean Difference (IV, Fixed, 95% CI)200.0 [-799.39, 1199.39]
Analysis 1.1.

Comparison 1 Physical activity program versus control, Outcome 1 Bone area at completion of the physical activity program.

Analysis 1.2.

Comparison 1 Physical activity program versus control, Outcome 2 Bone mineral content at completion of the physical activity program.

Analysis 1.3.

Comparison 1 Physical activity program versus control, Outcome 3 Bone mineral density at completion of the physical activity program.

Analysis 1.4.

Comparison 1 Physical activity program versus control, Outcome 4 Bone mineral content at 12 months corrected age (g).

Analysis 1.5.

Comparison 1 Physical activity program versus control, Outcome 5 Bone area at 12 months corrected age (cm2).

Analysis 1.6.

Comparison 1 Physical activity program versus control, Outcome 6 Body weight gain during study period (g/kg/d).

Analysis 1.7.

Comparison 1 Physical activity program versus control, Outcome 7 Body length gain during study period (cm/wk).

Analysis 1.8.

Comparison 1 Physical activity program versus control, Outcome 8 Head circumference gain during study period (cm/wk).

Analysis 1.9.

Comparison 1 Physical activity program versus control, Outcome 9 Body weight at 12 months corrected age (g).

What's new

DateEventDescription
19 May 2013New search has been performedThis is an update of the review "Physical activity programs for promoting bone mineralization and growth in preterm infants," published in the Cochrane Database of Systematic Reviews, Issue 2, 2007 (Schulzke 2007) and Issue 2, 2010 (Schulzke 2010).
19 May 2013New citation required but conclusions have not changed

Updated search identified three new studies for inclusion in the review (Chen 2010; Moyer-Mileur 2008; Tosun 2011)

No changes were made to the conclusions

History

Protocol first published: Issue 3, 2006
Review first published: Issue 2, 2007

DateEventDescription
22 August 2008AmendedConverted to new review format.
28 December 2006New citation required and conclusions have changedSubstantive amendment

Contributions of authors

Sven Schulzke: design and preparation of protocol, literature search, assessment of eligibility and quality of studies, data extraction and data analysis, writing of manuscript.

Siree Kaempfen: literature search, assessment of eligibility and quality of studies, data extraction, data analysis.
Daniel Trachsel: contribution to design of protocol; literature search, assessment of eligibility and quality of studies, data extraction and data analysis, review of manuscript.
Sanjay Patole: assessment of eligibility and study quality, data extraction, guidance and supervision for planning and execution of the meta-analysis, review of manuscript.

Declarations of interest

None.

Sources of support

Internal sources

  • Department of Neonatology, University Children's Hospital, Basel, Switzerland.

  • Department of Paediatric Intensive Care, University Children's Hospital, Basel, Switzerland.

  • Department of Neonatal Paediatrics, King Edward Memorial Hospital, Perth, Australia.

External sources

  • Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, USA.

    Editorial support of the Cochrane Neonatal Review Group has been funded with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN275201100016C

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Chen 2010

Methods

Single-center randomized controlled trial

Randomization: computer-based random method

Concealment of allocation: no
Intervention not blinded, both protocols provided by the same trained nurse
Follow-up incomplete (12/16)

Outcome assessors partially blinded ("yes" for assessors of complications of preterm birth, "no" for assessors of tibial bone speed of sound measurements)

ParticipantsEligibility criteria: preterm infants with BW < 1500 g, postnatal age one week
Enrolled participants: 20 preterm neonates (four excluded before start of intervention because of severe clinical complications)
Mean birth weight approximately 1165 g, mean GA approximately 28 to 29 weeks
Exclusion criteria: patients with major congenital birth defects.
Infants received parenteral nutrition including calcium and phosphorus and were fed breast milk (fortified when intake reached 100 mL/kg/d) or preterm formula as soon as possible
InterventionsType of intervention: as described in Moyer-Mileur 1995
Duration of intervention: four weeks
Outcomes

Clinical outcomes: oxygen dependency at 36 weeks GA, retinopathy of prematurity, intraventricular hemorrhage, sepsis, length of hospital stay, fractures

Additionally, ultrasound measurements of bone speed of sound at birth and at postnatal age one, four, six, and eight weeks (not subject of this review)

Biochemical markers of bone metabolism at birth and at postnatal age two, four, and six weeks (not subject of this review)

NotesAuthors clarified methodological details when contacted in September 2012
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-based random method
Allocation concealment (selection bias)High riskAllocation not concealed
Blinding (performance bias and detection bias)
All outcomes
Low riskIntervention not blinded, both protocols provided by the same trained nurse
Investigator who measured tibial bone speed of sound not blinded, all other assessors blinded
Incomplete outcome data (attrition bias)
All outcomes
Low riskTwo dropouts in each group before the start of the intervention. No dropouts during the four-week intervention period
Selective reporting (reporting bias)Low riskAll prespecified outcomes reported
Other biasUnclear riskNone detected

Eliakim 2002

Methods

Single-center randomized controlled trial

Randomization and concealment of allocation: cannot tell
Intervention not blinded, both activity protocols provided by the same trainer
Follow-up complete (20/20)
Blinding of outcome assessors: cannot tell

ParticipantsEligibility criteria unclear
Enrolled participants: 20 preterm neonates "matched for GA, BW, gender, CA, and weight" at initiation of study
Mean birth weight approximately 1050 g, mean GA approximately 28 to 29 weeks, mean corrected age at enrollment 33 weeks GA
Most infants healthy, but inclusion of several neonates with BPD and/or diuretics
Exclusion criteria: severe IUGR, severe CNS disorders, suspected bone and/or muscular diseases or sepsis during study period
Infants had at least 100 kcal/kg/d oral intake and were fed fortified breast milk or preterm formula
InterventionsTypes of interventions: as described in Moyer-Mileur 1995 for both intervention group (n = 10) and control group (n = 10)
Duration of interventions: four weeks
OutcomesWeight (g) at beginning of the study and at completion of the protocol (28 study days)
Additionally, biochemical markers of bone and fat tissue metabolism (not subject of this review)
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding (performance bias and detection bias)
All outcomes
Unclear risk

Intervention not blinded, both activity protocols provided by the same trainer

Blinding of outcome assessors not reported

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data
Selective reporting (reporting bias)Low riskAll prespecified outcomes reported
Other biasUnclear risk

Participants in intervention and control groups "matched for gestational age, birth weight, gender, corrected age, and weight at initiation of the exercise protocol"

Quality of randomization unclear given the small sample size (N = 20) and identical numbers of participants in intervention and control groups

Litmanovitz 2003

Methods

Single-center randomized controlled trial

Randomization and concealment of allocation: cannot tell
Intervention not blinded, both activity protocols provided by the same person
Follow-up complete (24/24)
Partial blinding of outcome assessors (yes for ultrasound assessors, cannot tell for anthropometric data)
A preliminary report of this study had been published in abstract form

ParticipantsEligibility criteria: birth weight < 1500 g, body size appropriate for gestational age and birth weight, postnatal age less than one week, informed parental consent
Enrolled participants: 24 preterm neonates, mean birth weight 1135 g, mean GA approximately 28 to 29 weeks. In addition to parenteral nutrition, infants were fed fortified human breast milk or preterm formula
Exclusion criteria: intrauterine growth restriction, severe central nervous system disorder, major congenital anomalies
InterventionsType of interventions: as described in Moyer-Mileur 1995 for both intervention group (n = 12) and control group (n = 12)
Duration of interventions: four weeks
OutcomesWeight (g), length (cm), head circumference (cm) at beginning of the study and at completion of the protocol (28 study days)
Additionally, bone ultrasound measurements (not subject of this review)
NotesThis is the first trial involving infants in the first week of life
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding (performance bias and detection bias)
All outcomes
Unclear risk

Intervention not blinded, both activity protocols provided by the same person

Partial blinding of outcome assessors (yes for ultrasound assessments that are not the subject of this review, unclear for anthropometric data)

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data
Selective reporting (reporting bias)Low riskAll prespecified outcomes reported
Other biasUnclear risk

The authors state: "after matching for gestational age and birth weight, infants were randomly assigned into exercise (n=12) and control groups (n=12)"

Quality of randomization unclear, given the small sample size (N = 24) and identical numbers of participants in intervention and control groups

Litmanovitz 2007

Methods

Single-center quasi-randomized controlled trial

Randomization and concealment of allocation: no; alternating allocation was made on the basis of birth order of participants
Intervention not blinded, both activity protocols provided by the same person
Follow-up complete (16/16)
Partial blinding of outcome assessors (yes for ultrasound assessors, cannot tell for anthropometric data)

ParticipantsEligibility criteria: birth weight < 1500 g, body size appropriate for gestational age and birth weight, postnatal age less than one week, informed parental consent
Enrolled participants: 16 preterm neonates, mean birth weight 1007 g, mean GA approximately 27.3 weeks. In addition to parenteral nutrition, infants were fed fortified human breast milk or preterm formula
Exclusion criteria: intrauterine growth restriction, severe central nervous system disorder, other major congenital anomalies
InterventionsType of interventions: as described in Moyer-Mileur 1995 for both intervention group (n = 8) and control group (n = 8)
Duration of interventions: eight weeks
OutcomesWeight (g) at beginning of the study and at completion of the protocol after eight weeks
Additionally, bone ultrasound measurements and serum bone turnover markers (bone-specific alkaline phosphatase and carboxyl-terminal cross-links telopeptide of type I collagen), which are not outcomes of this review
NotesThis is the second trial involving infants in the first week of life
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk

This is a quasi-randomized trial

Alternating allocation made on the basis of birth order of participants

Allocation concealment (selection bias)High riskAllocation not concealed because birth order was known
Blinding (performance bias and detection bias)
All outcomes
Unclear risk

Intervention not blinded, both activity protocols provided by the same person

Partial blinding of outcome assessors (yes for ultrasound assessments that are not the subject of this review, unclear for anthropometric data)

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data
Selective reporting (reporting bias)Low riskAll prespecified outcomes reported
Other biasLow riskNone detected

Moyer-Mileur 1995

Methods

Single-center randomized controlled trial

Randomization was accomplished by selecting sealed envelopes containing group codes that had been generated from a random numbers table
Intervention not blinded, as both activity protocols were administered by the same trained occupational therapist
Follow-up incomplete: 23/49 infants (45%) were unavailable for assessment of all outcomes because of discharge/transfer before completion of the exercise protocol. Dropout rate was similar between groups
Blinding of outcome assessors: The technician who measured and analyzed bone density measurements was blinded to participants' group assignment

Anthropometric measurements: cannot tell
A preliminary report of this study had been published in abstract form

Participants

Eligibility criteria: 26 to 34 weeks GA, appropriate body size, able to tolerate enteral feeds of fortified breast milk or preterm formula, both 24 kcal/oz, at or above 110 kcal/kg/d

Absence of medication other than vitamin supplements, informed parental consent
Enrolled participants: 49 healthy neonates, mean birth weight approximately 1200 g, mean GA approximately 28 to 29 weeks, mean corrected age at enrollment 30 to 31 weeks GA

InterventionsTypes of interventions: exercise group (analyzed n = 13): range-of-motion exercises with gentle compression and extension and flexion of both upper and lower extremities
Each movement was done five times at each joint (wrist, elbow, shoulder, ankle, knee, and hip). The program was applied five times a week
Control group (analyzed n = 13): tactile stimulation, described as a daily interactive period of holding and stroking with no range-of-motion activity
Duration of interventions: four weeks
Outcomes

Anthropometric and bone mineral data by SPA from right distal radius at beginning of the study and at completion of the protocol (28 study days)

  • Weight (g), weight gain (g/kg/d), length (cm), length change (cm/wk), head circumference (cm), head circumference change (cm/wk)

  • Bone mineral content (mg/cm), bone mineral content change (%), bone width (mm), bone width change (%), bone mineral density (mg/cm2), bone mineral density change (%)

  • Additionally, several biochemical markers of bone metabolism (not subject of this review)

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSequence based on codes retrieved from random numbers table
Allocation concealment (selection bias)Low riskSealed opaque envelopes used to conceal allocation
Blinding (performance bias and detection bias)
All outcomes
Low risk

Intervention not blinded, as both activity protocols were administered by the same trained occupational therapist

Blinding of outcome assessors: technician who measured and analyzed bone density measurements blinded to participants' group assignment

Anthropometric measurements: blinding unclear

Incomplete outcome data (attrition bias)
All outcomes
High risk23/49 infants (45%) unavailable for assessment of all outcomes because of discharge/transfer before completion of the exercise protocol. Dropout rate similar between groups
Selective reporting (reporting bias)Low riskAll prespecified outcomes reported
Other biasUnclear risk

Bone mass data from two infants in the physical activity group and one infant in the control group omitted from data analysis by the authors of this trial because they were > two standard deviations from the mean for bone mineral content and bone width

Calculation of mean gain in occipitofrontal head circumference in the meta-analysis based on manual calculation of (head circumference at completion - head circumference at study entry) divided by four and the standard deviation reported in the paper

Moyer-Mileur 2000

Methods

Single-center randomized controlled trial

Randomization by selecting sealed envelopes containing group codes
Intervention not blinded; principal investigator and occupational therapist were aware of participants' group allocation
Follow-up complete (32/32)
Blinding of outcome assessors: yes for pDEXA measurements, no for other outcomes
A preliminary report of this study had been published in abstract form

Participants

Eligibility criteria: 26 to 32 weeks GA, birth weight 800 to 1600 g, appropriate body size, tolerating enteral feeds of fortified breast milk or preterm formula, both 24 kcal/oz, at or above 110 kcal/kg/d

Absence of medication other than vitamin supplements, informed parental consent
Enrolled participants: 32 healthy neonates, mean GA 28 to 29 weeks, mean corrected age at enrollment 32 weeks GA
Stratification: infants 800 to 1200 g and 1201 to 1500 g, infants 26 to 29 weeks GA and 30 to 32 weeks GA

InterventionsTypes of interventions: as described in Moyer-Mileur 1995 for both intervention group (n = 16) and control group (n = 16)
Duration of interventions: Both protocols were continued until a body weight of 2.0 ± 0.15 kg was reached, resulting in a mean of 27 versus 24 study days for intervention versus control group
Outcomes

Anthropometric and bone mineral data from right forearm (ulna and radius) by pDEXA at beginning of the study and at completion of the protocol (reaching body weight of 2000 g)

  • Weight (g), weight gain (g/kg/d), length (cm), length change (cm), head circumference (cm), head circumference change (cm), bone mineral content (mg), bone mineral content gain (mg), bone area (cm2), bone area gain (cm2), bone mineral density (mg/cm2), bone mineral density gain (mg/cm2)

  • Additionally, several biochemical markers of bone metabolism (not subject of this review)

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSequence based on codes retrieved from random numbers table
Allocation concealment (selection bias)Low riskSealed opaque envelopes used to conceal allocation
Blinding (performance bias and detection bias)
All outcomes
Low risk

Intervention not blinded, principal investigator and occupational therapist aware of participants' group allocation

Blinding of outcome assessors: yes for primary outcome of pDEXA measurements, no for other outcomes

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data
Selective reporting (reporting bias)Low riskAll prespecified outcomes reported
Other biasLow riskNone detected

Moyer-Mileur 2000a

MethodsSingle-center randomized controlled trial
Randomization, concealment of allocation, blinding of intervention, completeness of follow-up and blinding of outcome assessors: cannot tell
Follow-up study published in abstract form
ParticipantsEligibility criteria unclear
Enrolled participants: 20 former preterm neonates, follow-up from initial hospital discharge until 12 months corrected age
InterventionsTypes of interventions: as described in Moyer-Mileur 1995 for both intervention group (analyzed n = 10) and control group (analyzed n = 10)
Duration of interventions: unknown (physical activity stopped at hospital discharge)
Outcomes

Anthropometric measurements and bone mineral data by DEXA at hospital discharge, six months and 12 months corrected age

  • Weight (g), length (cm), total body bone mineral content (g), total body bone area (cm2), total body bone density (g/cm2)

  • Additionally, fat mass and fat free mass (not subject of this review)

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskFollow-up study published only in abstract form
Allocation concealment (selection bias)Unclear riskFollow-up study published only in abstract form
Blinding (performance bias and detection bias)
All outcomes
Unclear riskFollow-up study published only in abstract form
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk

Origin of follow-up study population and number of randomly assigned (N = ?) versus analyzed participants (N = 20) unclear

Infants in treatment and control groups did not differ in any reported outcome at discharge (first follow-up) and at 12 months (last follow-up)

Selective reporting (reporting bias)Unclear riskFollow-up study published only in abstract form
Other biasUnclear riskUnable to obtain detailed information from study authors

Moyer-Mileur 2008

Methods

Single-center randomized controlled trial

Randomization using sealed envelopes containing group assignment, generated by a random numbers table

Intervention not blinded
Follow-up incomplete, 17/50 infants (34%) unavailable for assessment of all outcomes because of transfer to another facility or change from fortified breast milk to formula before completion of the exercise protocol. Dropouts: 10/32 in intervention groups, seven/18 in control group
Blinding of outcome assessors: yes for pDEXA measurements; anthropometric measurements: cannot tell

Participants

Eligibility criteria: 26 to 31 weeks GA, appropriate body size, able to tolerate enteral feeds of fortified breast milk above 110 kcal/kg/d

Absence of medication other than vitamin supplements
Enrolled participants: 50 preterm infants, mean birth weight approximately 1200 g, mean GA 28 to 29 weeks, mean corrected age at enrollment 32 weeks GA

Stratification: infants 800 to 1200 g versus 1201 to 1500 g; 26 to 29 weeks GA versus 29 to 31 weeks GA

Interventions

Types of interventions: based on Moyer-Mileur 1995

Three groups: two intervention groups receiving daily physical activity administered by the infant's mother (n = 11) or by a trained occupational therapist (n = 11), and a control group (n = 11)

In this review, both intervention groups (n = 22) were summarized because the physical activity program was identical in both groups
Duration of interventions: protocols continued until a body weight of 2.0 ± 0.15 kg was reached

Outcomes

Anthropometric and bone mineral data from right forearm (ulna and radius) by pDEXA at beginning of the study and at completion of the protocol (reaching body weight of 2000 g)

  • Weight (g), weight gain (g/kg/d), length (cm), length change (cm/wk), head circumference (cm), head circumference change (cm/wk), bone mineral content (g), bone mineral content change (g), bone area (cm2), bone area change (cm2), bone mineral density (g/cm2), bone mineral density change (g/cm2)

  • Additionally, several biochemical markers of bone metabolism (not subject of this review)

NotesStudy authors provided additional information about anthropometric and bone mineral data when contacted in May 2013
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskSequence based on codes retrieved from random numbers table
Allocation concealment (selection bias)Low riskSealed opaque envelopes used to conceal allocation
Blinding (performance bias and detection bias)
All outcomes
Low risk

Intervention not blinded

Blinding of outcome assessors: yes for primary outcome of pDEXA measurements, no for other outcomes

Incomplete outcome data (attrition bias)
All outcomes
High risk

Fifty infants enrolled, 33 infants completed the study (11 infants in each group) and analyzed

Reasons for drop out: eleven infants transferred to another facility (intervention group: n = 6; control group: n = 5); in six infants, fortified breast milk replaced by formula milk (intervention group: n = 4, control group: n = 2)

Selective reporting (reporting bias)Low riskAll prespecified outcomes reported
Other biasUnclear riskNone detected

Nemet 2002

Methods

Single-center randomized controlled trial

Randomization and concealment of allocation: cannot tell
Intervention not blinded, both activity protocols provided by the same trainer
Follow-up complete (24/24)
Blinding of outcome assessors: cannot tell

ParticipantsEligibility criteria unclear
Enrolled participants: 24 preterm neonates "matched for GA, BW, gender, CA, and weight" at initiation of study
Mean birth weight 1050 g, mean GA 28 to 29 weeks, corrected age at enrollment 33 weeks GA
Inclusion of several neonates with BPD and/or diuretics
Exclusion criteria: severe IUGR, severe CNS disorders, suspected bone and/or muscular diseases or sepsis during study period
Infants had at least 100 kcal/kg/d oral intake and were fed fortified breast milk or preterm formula
InterventionsTypes of interventions: as described in Moyer-Mileur 1995 for both intervention group (n = 12) and control group (n = 12)
Duration of interventions: four weeks
OutcomesWeight (g) at beginning of the study and at completion of the protocol (28 study days)
Additionally, biochemical markers of bone metabolism (not subject of this review)
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding (performance bias and detection bias)
All outcomes
Unclear risk

Intervention not blinded, both activity protocols provided by the same trainer

Blinding of outcome assessors unclear

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data
Selective reporting (reporting bias)Low riskAll prespecified outcomes reported
Other biasUnclear risk

Study authors state that participants were "matched for gestational age, birth weight, gender, corrected age, and weight at initiation of the exercise protocol, and the use of medication and the prevalence of BPD. Then the subjects were randomly divided into an exercise (n=12) and a control group (n=12)"

Quality of randomization unclear, given the small sample size (N = 24) and identical numbers of participants in intervention and control groups

Tosun 2011

Methods

Single-center randomized controlled trial

Method of randomization: cannot tell

Sequence generation: cannot tell

Concealment of allocation: cannot tell
Intervention not blinded
Follow-up complete (40/40)
Blinding of outcome assessors: cannot tell

Participants

Eligibility criteria: 26 to 32 weeks GA, birth weight 800 to 1600 g, postnatal age ≤ three days, not receiving breast milk but tolerating enteral feeds with commercial formula (70 kcal/mL), resulting in caloric intake of 120 to 125 kcal/kg/d

Absence of medication other than vitamin supplements or antibiotics
Enrolled participants: forty neonates, mean GA 28 to 29 weeks, mean birth weight approximately 1100 g

InterventionsTypes of interventions: as described in Moyer-Mileur 1995 for both intervention (n = 20) and control groups (n = 20)
Duration of interventions: four weeks, resulting in a mean of 29 study days in both groups
Outcomes

Anthropometric data at beginning of the study and at completion of the protocol (29 study days)

  • Weight (g), length (cm), length change (%), head circumference (cm), weight gain (%), length change (%), head circumference change (%)

  • Additionally, tibial speed of sound (SOS), additional anthropometric indices including chest circumference, mid-upper arm circumference, tibial length (not subject of this review)

NotesThis trial enrolled preterm infants within the first three days of life
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of randomization unclear: "40 cards (20 cards for exercise group; 20 cards for control group) were put into a box. The appropriate newborns were selected accordingly [...]"
Allocation concealment (selection bias)Unclear riskNot reported
Blinding (performance bias and detection bias)
All outcomes
Unclear risk

Intervention not blinded, as both activity protocols were administered by the same trained occupational therapist

Blinding of outcome assessors: yes

Incomplete outcome data (attrition bias)
All outcomes
Low riskOutcome data complete
Selective reporting (reporting bias)Low riskAll prespecified outcomes reported
Other biasUnclear riskQuality of randomization and concealment unclear: Randomization by drawing cards out of a box as clarified by the study authors when contacted in January 2013. Unclear how sequence of cards was generated and whether cards were concealed

Vignochi 2008

  1. a

    Abbreviations:

    BPD = bronchopulmonary dysplasia.

    BW = body weight.

    CA = chronological age.

    CNS = central nervous system.

    GA = gestational age.

    IUGR = intrauterine growth retardation.

    pDEXA = peripheral dual-energy x-ray absorptiometry.

    SPA = single-photon absorptiometry.

Methods

Single-center randomized controlled trial

Randomization by selecting group codes from "closed envelopes"
Intervention not blinded. Infants in the control group received routine care without tactile stimulation
Follow-up complete (29/29)
Blinding of outcome assessors: yes for DEXA measurements, unclear for other outcomes

Participants

Eligibility criteria: 26 to 34 weeks GA and < 1600 g birth weight, appropriate body size, able to tolerate enteral feeds at or above 110 kcal/kg/d

In stable condition, not requiring supplemental oxygen or mechanical ventilation
Enrolled participants: 29 healthy preterm neonates, mean birth weight approximately 1330 g, mean GA approximately 30.8 weeks, mean corrected age at enrollment 34 weeks GA

Interventions

Types of interventions: as described in Moyer-Mileur 1995 for intervention group (n = 15) except for a longer period of daily activity (15 minutes daily in this trial vs five minutes daily in the original Moyer-Mileur protocol)

Control group did not receive physical activity program or tactile stimulation (n = 14) (control group received tactile stimulation in original Moyer-Mileur protocol)
Duration of interventions: physical activity continued until a body weight of 2.0 kg was reached (this is a criterion for discharge from hospital), resulting in a mean of 25 versus 26 study days for intervention versus control group

Outcomes

Anthropometric and total body bone mineral data by DEXA at beginning of the study and at completion of the protocol (upon reaching body weight of 2000 g)

  • Weight (g), weight gain (g/d), length (cm), length change (cm/wk), tibial length change (cm/wk), head circumference (cm), bone mineral content (mg), bone mineral content gain (mg), bone area (cm2), bone area gain (cm2), bone mineral density (mg/cm2), bone mineral density gain (mg/cm2)

  • Additionally, lean mass, fat mass, and several biochemical markers of bone metabolism (not subject of this review)

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskCodes retrieved from "closed envelopes"
Blinding (performance bias and detection bias)
All outcomes
Low risk

Intervention not blinded. Infants in the control group received routine care without tactile stimulation

Blinding of outcome assessors: yes for primary outcome of DEXA measurements, unclear for other outcomes

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data
Selective reporting (reporting bias)Low riskAll prespecified outcomes reported
Other biasUnclear risk

The study was terminated after recruitment of 29 infants because of apparent benefit of physical activity in terms of improved bone mineralization

Predetermined sample size was n = 32

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    Abbreviations:

    DEXA = dual-energy x-ray absorptiometry.

    GA = gestational age.

Aly 2004Randomized controlled trial on physical activity and massage. Neonates in the intervention group were treated with physical activity and additional massage. Neonates in the control group did not receive any of those measures. The trial was excluded because massage was provided to the intervention group only. A preliminary report of this study has been published in abstract form
Haley 2012Randomized controlled trial on physical activity and massage (ie, moderate strokes). Preterm infants in the intervention group were treated with physical activity and additional massage. Neonates in the control group did not receive any of those measures. The trial was excluded because massage was provided to the intervention group only. A preliminary report of this study has been published in abstract form
Hassanein 2002This abstract reports on a randomized controlled trial on physical activity and massage, as stated by the study authors when contacted in January 2006. Neonates in the intervention group were treated with physical activity and additional massage. Neonates in the control group did not receive any of those measures. The trial was excluded because massage was provided to the intervention group only
Massaro 2009Randomized controlled trial on physical activity and massage incorporating three arms: Preterm infants in group one received a physical activity program and additional massage; infants in group two received massage only; infants in group three did not receive any of those measures. The trial was excluded because the duration of massage in group one (physical activity plus massage) was longer than in group two (massage only), as stated by the study authors when contacted in December 2012
McDevitt 2012This abstract reports on a randomized controlled trial on physical activity in preterm infants. Neonates were randomly assigned to two groups receiving physical activity programs at different time points. The trial was excluded because physical activity was provided in both groups
McIntyre 1992This abstract reports on a randomized controlled trial in infants one to fifteen months old. The trial was excluded because no preterm infants were included in the study population, as clarified by the study authors when contacted in January 2006
Vignochi 2012Randomized controlled clinical trial on physical activity in preterm infants. Outcomes of all participants of this trial have been reported previously (Vignochi 2008), as confirmed by the study authors when contacted in November 2012. The study Vignochi 2008 is already incorporated in this review

Characteristics of ongoing studies [ordered by study ID]

Cooper 2005

Trial name or titleAssisted exercise in prematurity; effects and mechanism
MethodsRandomized, masked, controlled (parallel assignment), single-center trial
ParticipantsPreterm neonates, GA 23 to 33 weeks, GA at time of recruitment 30 to 35 weeks, on full feeds with oral intake of > 100 kcal/kg/d
InterventionsInfants receive assisted exercise or cuddle for 20 minutes
Duration of interventions: four weeks
OutcomesPrimary outcomes: body composition, bone mineralization, muscle mass (muscle ultrasound, bone speed of sound, and DEXA), anthropometric measurements
Starting date2005
Contact informationJulia K. Rich, jkrich@uci.edu
NotesClinicalTrials.gov Identifier: NCT00580099

Cooper 2011

Trial name or titleImpact of exercise on body composition in premature infants
MethodsRandomized, masked, controlled (parallel assignment), single-center trial
ParticipantsPreterm neonates GA < 29 weeks, GA at time of recruitment > 34 weeks, on full feeds
Interventions

Infants receive physical activity or no physical activity

Duration of interventions: up to one year of life

OutcomesPrimary outcomes: change in lean body mass assessed by DEXA at 34 to 40 weeks GA and at 86 to 92 weeks of age
Starting date2011
Contact informationJulia K. Rich, jkrich@uci.edu
NotesClinicalTrials.gov Identifier: NCT01386190

Litmanovitz 2010

Trial name or titleThe effect of physical activity on bone mineralization and immune system in very low birth weight infants
MethodsRandomized, masked, controlled (parallel assignment), single-center trial
ParticipantsPreterm neonates, birth weight < 1500 g, postnatal age < 14 days
Interventions

Infants receive physical activity once or twice a day versus no physical activity

Duration of interventions: eight weeks

Outcomes

Primary outcome: bone speed of sound

Secondary outcomes: anthropometric measurements

Starting date2010
Contact informationIta Litmanovitz, litmani@clalit.org.il
NotesClinicalTrials.gov Identifier: NCT01042639

Ancillary