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

Cochrane Database of Systematic Reviews

Physical activity programs for promoting bone mineralization and growth in preterm infants (Review) Schulzke SM, Kaempfen S, Trachsel D, Patole SK

Schulzke SM, Kaempfen S, Trachsel D, Patole SK. Physical activity programs for promoting bone mineralization and growth in preterm infants. Cochrane Database of Systematic Reviews 2014, Issue 4. Art. No.: CD005387. DOI: 10.1002/14651858.CD005387.pub3.

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Physical activity programs for promoting bone mineralization and growth in preterm infants (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

TABLE OF CONTENTS HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .


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[Intervention Review]

Physical activity programs for promoting bone mineralization and growth in preterm infants Sven M Schulzke1 , Siree Kaempfen1 , Daniel Trachsel2 , Sanjay K Patole3 1 Department

of Neonatology, University of Basel Children’s Hospital (UKBB), Basel, Switzerland. 2 Department of Pediatric Intensive Care/Pulmonology, University Children’s Hospital Basel, Basel, Switzerland. 3 School of Paediatrics and Child Health, School of Women’s and Infant’s Health, University of Western Australia, King Edward Memorial Hospital, Perth, Australia Contact address: Sven M Schulzke, Department of Neonatology, University of Basel Children’s Hospital (UKBB), Spitalstrasse 21, Basel, 4031, Switzerland. [email protected]. Editorial group: Cochrane Neonatal Group. Publication status and date: New search for studies and content updated (no change to conclusions), published in Issue 4, 2014. Review content assessed as up-to-date: 26 November 2009. Citation: Schulzke SM, Kaempfen S, Trachsel D, Patole SK. Physical activity programs for promoting bone mineralization and growth in preterm infants. Cochrane Database of Systematic Reviews 2014, Issue 4. Art. No.: CD005387. DOI: 10.1002/14651858.CD005387.pub3. Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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. Physical activity programs for promoting bone mineralization and growth in preterm infants (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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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 crossreferences, 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).

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 stressrelated 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.


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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.

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 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, calciumand 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.

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:


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• 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.

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: ◦ 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

◦ ◦ ◦ ◦


• Somatic growth: weight, length, head circumference: ◦ ◦ ◦ ◦


Secondary outcomes

• Complications of prematurity. 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.

◦ 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.


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◦ 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

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.

The standard methods of the CNRG were used. Assessment of heterogeneity 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.

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.


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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 singlecenter 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 xray 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.


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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. Shortterm 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


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At completion of the physical activity program Four trials (Moyer-Mileur 1995; Moyer-Mileur 2000; MoyerMileur 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).


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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/cm 2 , 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.


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Somatic growth At discharge Not reported in any of the trials. At completion of the physical activity program 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.

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).


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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

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.

Not reported in any of the trials. Subgroup analyses

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.

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


11

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 con-

cealment 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


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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.

REFERENCES

References to studies included in this review Chen 2010 {published and unpublished data} Chen HL, Lee CL, Tseng HI, Yang SN, Yang RC, Jao HC. Assisted exercise improves bone strength in very low birthweight infants by bone quantitative ultrasound. Journal of Paediatrics and Child Health 2010;46(11):653–9. Eliakim 2002 {published data only} Eliakim A, Dolfin T, Weiss E, Shainkin-Kestenbaum R, Lis M, Nemet D. The effects of exercise on body weight and circulating leptin in premature infants. Journal of Perinatology 2002;22(7):550–4. Litmanovitz 2003 {published data only} ∗ Litmanovitz I, Dolfin T, Friedland O, Arnon S, Regev R, Shainkin-Kestenbaum R, et al. Early physical activity intervention prevents decrease of bone strength in very low birth weight infants. Pediatrics 2003;112(1 Pt 1):15–9. Litmanovitz I, Friedland O, Dolfin T, Arnon S, Regev R, Eliakim A. Early physical activity intervention prevents decrease of bone strength in very low birth weight infants. Pediatric Research 2002;51:380A. Litmanovitz 2007 {published data only} Litmanovitz I, Dolfin T, Arnon S, Regev RH, Nemet D, Eliakim A. Assisted exercise and bone strength in preterm infants. Calcified Tissue International 2007;80(1):39–43. Moyer-Mileur 1995 {published data only} Moyer-Mileur L, Leutkemeier MJ, Chan GM. Physical activity enhances bone mass in very low-birth weight (VLBW) infants. Pediatric Research 1995;37:314A. ∗ Moyer-Mileur L, Luetkemeier M, Boomer L, Chan GM. Effect of physical activity on bone mineralization in premature infants. The Journal of Pediatrics 1995;127(4): 620–5. Moyer-Mileur 2000 {published data only} ∗ Moyer-Mileur LJ, Brunstetter V, McNaught TP, Gill G, Chan GM. Daily physical activity program increases bone mineralization and growth in preterm very low birth weight infants. Pediatrics 2000;106(5):1088–92. Moyer-Mileur LJ, McNaught TJ, Gurmail G, Chan GM. Physical activity and diet: key components for improved

bone mass in premature, very-low-birth weight (VLBW: 1, 500 gm) infants. Pediatric Research 1999;45:287A. Moyer-Mileur 2000a {published data only} Moyer-Mileur LJ, Bail SD, McNaught TP, Chan GM. Effect of physical activity on bone mineralization and body composition in preterm infants during the first year of life. Pediatric Research 2000;47:292A. Moyer-Mileur 2008 {published and unpublished data} Moyer-Mileur LJ, Ball SD, Brunstetter VL, Chan GM. Maternal-administered physical activity enhances bone mineral acquisition in premature very low birth weight infants. Journal of Perinatology 2008;28(6):432–7. Nemet 2002 {published data only} Nemet D, Dolfin T, Litmanowitz I, Shainkin-Kestenbaum R, Lis M, Eliakim A. Evidence for exercise-induced bone formation in premature infants. International Journal of Sports Medicine 2002;23(2):82–5. Tosun 2011 {published and unpublished data} Tosun Ö, Bayat M, Güne T, Erdem E. Daily physical activity in low-risk pre-term infants: positive impact on bone strength and mid-upper arm circumference. Annals of Human Biology 2011;38(5):635–9. Vignochi 2008 {published data only} Vignochi CM, Miura E, Canani LH. Effects of motor physical therapy on bone mineralization in premature infants: a randomized controlled study. Journal of Perinatology 2008;28(9):624–31.

References to studies excluded from this review Aly 2004 {published data only} ∗ Aly H, Moustafa MF, Hassanein SM, Massaro AN, Amer HA, Patel K. Physical activity combined with massage improves bone mineralization in premature infants: a randomized trial. Journal of Perinatology 2004;24(5):305–9. Moustafa MF, Aly HZ, Hassanein SM, Nguyen AT, Amer HA, Patel K. Can a daily program of massage and physical exercise affect bone mineralization. Pediatric Research 2003; 53:407A.


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Haley 2012 {published data only} ∗ Haley S, Beachy J, Ivaska KK, Slater H, Smith S, MoyerMileur LJ. Tactile/kinesthetic stimulation (TKS) increases tibial speed of sound and urinary osteocalcin (U-MidOC and unOC) in premature infants (29-32 weeks PMA). Bone 2012;51(4):661–6. Haley S, Slater H, Neff K, Barrett B, Evans C, Smith S, et al. Mechanical-tactile stimulation increases bone formation and tibial strength in preterm infants. Pediatric Academic Societies’ Abstract Archive 2002-2012. 2011. [: 2920.275]

Bishop 1999 Bishop NJ. Metabolic bone disease. In: Rennie JM, Roberton NRC editor(s). Textbook of Neonatology. 3rd Edition. Edinburgh: Churchill Livingstone, 1999:1002–8.

Hassanein 2002 {published data only} Hassanein SM, Moustafa MF, Amer HA. Daily physical exercise stimulates growth in premature infants: a randomized controlled trial. Pediatric Research 2002;LB 210.

Heinonen 1996 Heinonen A, Kannus P, Sievanen H, Oja P, Pasanen M, Rinne M, et al. Randomised controlled trial of effect of high-impact exercise on selected risk factors for osteoporotic fractures. Lancet 1996;348(9038):1343–7.

Massaro 2009 {published and unpublished data} Massaro AN, Hammad TA, Jazzo B, Aly H. Massage with kinesthetic stimulation improves weight gain in preterm infants. Journal of Perinatology 2009;29(5):352–7.

Juskeliene 1996 Juskeliene V, Magnus P, Bakketeig LS, Dailidiene N, Jurkuvenas V. Prevalence and risk factors for asymmetric posture in preschool children aged 6-7 years. International Journal of Epidemiology 1996;25(5):1053–9.

McDevitt 2012 {published data only} McDevitt H, White M, Ahmed SF. Randomised trial of physical activity intervention to improve bone health of preterm infants in the neonatal unit: results from the Glasgow Women & Infants’ Skeletal Health (WISH) study. Archives of Disease in Childhood 2009;94(Suppl 1):A62–4. McIntyre 1992 {published data only} McIntyre L, Hudson P, Smith L, Ho M, Specker B. Exercise increases bone mineral content in infants 1 to 15 months of age. Pediatric Research 1992;31:97A. Vignochi 2012 {published and unpublished data} Vignochi CM, Silveira RC, Miura E, Canani LH, Procianoy RS. Physical therapy reduces bone resorption and increases bone formation in preterm infants. American Journal of Perinatology 2012;29(8):573–8.

References to ongoing studies Cooper 2005 {published data only} Assisted exercise in prematurity; effects and mechanisms. ClinicalTrials.gov. Cooper 2011 {published data only} Impact of exercise on body composition in preterm infants. ClinicalTrials.gov. Litmanovitz 2010 {published data only} Litmanovitz I. The effect of physical activity on bone mineralization and immune system in very low birth weight infants. ClinicalTrials.gov.

Additional references Begg 1996 Begg C, Cho M, Eastwood S, Horton R, Moher D, Olkin I, et al. Improving the quality of reporting of randomized controlled trials. The CONSORT statement. Journal of the American Medical Association 1996;276(8):637–9.

Bonaiuti 2002 Bonaiuti D, Shea B, Iovine R, Negrini S, Robinson V, Kemper HC, et al. Exercise for preventing and treating osteoporosis in postmenopausal women. Cochrane Database of Systematic Reviews 2002, Issue 3. [DOI: 10.1002/ 14651858.CD000333]

Kerr 2001 Kerr D, Ackland T, Maslen B, Morton A, Prince R. Resistance training over 2 years increases bone mass in calcium-replete postmenopausal women. Journal of Bone and Mineral Research 2001;16(1):175–81. Koo 1988 Koo WW, Sherman R, Succop P, Oestreich AE, Tsang RC, Krug-Wispe SK, et al. Sequential bone mineral content in small preterm infants with and without fractures and rickets. Journal of Bone and Mineral Research 1988;3(2):193–7. Kuschel 2004 Kuschel CA, Harding JE. Multicomponent fortified human milk for promoting growth in preterm infants. Cochrane Database of Systematic Reviews 2004, Issue 1. [DOI: 10.1002/14651858.CD000343.pub2] Lapillonne 2004 Lapillonne A, Salle BL, Glorieux FH, Claris O. Bone mineralization and growth are enhanced in preterm infants fed an isocaloric, nutrient-enriched preterm formula through term. American Journal of Clinical Nutrition 2004; 80(6):1595–603. Larson 2000 Larson CM, Henderson RC. Bone mineral density and fractures in boys with Duchenne muscular dystrophy. Journal of Pediatric Orthopedics 2000;20(1):71–4. Lawn 2004 Lawn CJ, Chavasse RJ, Booth KA, Angeles M, Weir FJ. The neorule: a new instrument to measure linear growth in preterm infants. Archives of Disease in Childhood Fetal and Neonatal Edition 2004;89(4):F360–3. Lucas 1989 Lucas A, Brooke OG, Baker BA, Bishop N, Morley R. High alkaline phosphatase activity and growth in preterm neonates. Archives of Disease in Childhood 1989;64(7 Spec No):902–9.


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Lucas 2001 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(3):703–11. MacKelvie 2004 MacKelvie KJ, Petit MA, Khan KM, Beck TJ, McKay HA. Bone mass and structure are enhanced following a 2-year randomized controlled trial of exercise in prepubertal boys. Bone 2004;34(4):755–65. Oyemade 1981 Oyemade GA. The correction of primary knee deformities in children. International Orthopaedics 1981;5(4):241–5. Rosenberg 1992 Rosenberg SN, Verzo B, Engstrom JL, Kavanaugh K, Meier PP. Reliability of length measurements for preterm infants. Neonatal Network 1992;11(2):23–7. Salle 1992 Salle BL, Braillon P, Glorieux FH, Brunet J, Cavero E, Meunier PJ. Lumbar bone mineral content measured by dual energy X-ray absorptiometry in newborns and infants. Acta Paediatrica 1992;81(12):953–8. Slemenda 1991 Slemenda CW, Miller JZ, Hui SL, Reister TK, Johnston CC Jr. Role of physical activity in the development of skeletal mass in children. Journal of Bone and Mineral Research 1991;6(11):1227–33. Steichen 1980 Steichen JJ, Gratton TL, Tsang RC. Osteopenia of prematurity: the cause and possible treatment. The Journal of Pediatrics 1980;96(3 Pt 2):528–34.

Tubbs 2004 Tubbs RS, Webb D, Abdullatif H, Conklin M, Doyle S, Oakes WJ. Posterior cranial fossa volume in patients with rickets: insights into the increased occurrence of Chiari I malformation in metabolic bone disease. Neurosurgery 2004;55(2):380–3. Vickers 2004 Vickers A, Ohlsson A, Lacy JB, Horsley A. Massage for promoting growth and development of preterm and/or low birth-weight infants. Cochrane Database of Systematic Reviews 2004, Issue 2. [DOI: 10.1002/ 14651858.CD000390.pub2]

References to other published versions of this review

Schulzke 2007 Schulzke SM, Trachsel D, Patole SK. Physical activity programs for promoting bone mineralization and growth in preterm infants. Cochrane Database of Systematic Reviews 2007, Issue 2. [DOI: 10.1002/ 14651858.CD005387.pub2] Schulzke 2010 Schulzke SM, Trachsel D, Patole SK. Physical activity programs for promoting bone mineralization and growth in preterm infants. Cochrane Database of Systematic Reviews 2010, Issue 2. [DOI: 10.1002/ 14651858.CD005387.pub2] ∗ Indicates the major publication for the study


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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)

Participants

Eligibility 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

Interventions

Type 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)

Notes

Authors clarified methodological details when contacted in September 2012

Risk of bias Bias

Authors’ judgement

Support for judgement

Random sequence generation (selection Low risk bias)

Computer-based random method

Allocation concealment (selection bias)

Allocation not concealed

High risk

Blinding (performance bias and detection Low risk bias) All outcomes

Intervention not blinded, both protocols provided by the same trained nurse Investigator who measured tibial bone speed of sound not blinded, all other assessors blinded


16

Chen 2010

(Continued)

Incomplete outcome data (attrition bias) All outcomes

Low risk

Two dropouts in each group before the start of the intervention. No dropouts during the four-week intervention period

Selective reporting (reporting bias)

Low risk

All prespecified outcomes reported

Other bias

Unclear risk

None 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

Participants

Eligibility 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

Interventions

Types of interventions: as described in Moyer-Mileur 1995 for both intervention group (n = 10) and control group (n = 10) Duration of interventions: four weeks

Outcomes

Weight (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 Bias



Random sequence generation (selection Unclear risk bias)

Not reported


Not reported

Unclear risk


17

Eliakim 2002

(Continued)

Blinding (performance bias and detection Unclear risk bias) All outcomes

Intervention not blinded, both activity protocols provided by the same trainer Blinding of outcome assessors not reported


Low risk

No missing outcome data


Low risk


Other bias

Unclear 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

Participants

Eligibility 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

Interventions

Type of interventions: as described in Moyer-Mileur 1995 for both intervention group (n = 12) and control group (n = 12) Duration of interventions: four weeks

Outcomes

Weight (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)

Notes

This is the first trial involving infants in the first week of life

Risk of bias


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Litmanovitz 2003

(Continued)

Bias




Not reported


Not reported

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)


Low risk



Low risk


Other bias

Unclear 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)

Participants

Eligibility 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


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Litmanovitz 2007

(Continued)

Interventions

Type of interventions: as described in Moyer-Mileur 1995 for both intervention group (n = 8) and control group (n = 8) Duration of interventions: eight weeks

Outcomes

Weight (g) at beginning of the study and at completion of the protocol after eight weeks Additionally, bone ultrasound measurements and serum bone turnover markers (bonespecific alkaline phosphatase and carboxyl-terminal cross-links telopeptide of type I collagen), which are not outcomes of this review

Notes

This is the second trial involving infants in the first week of life

Risk of bias Bias




This is a quasi-randomized trial Alternating allocation made on the basis of birth order of participants


Allocation not concealed because birth order was known

High 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)


Low risk



Low risk


Other bias

Low risk

None detected


20

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

Interventions

Types 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)





Sequence based on codes retrieved from random numbers table


Sealed opaque envelopes used to conceal allocation

Low risk


21

Moyer-Mileur 1995

(Continued)


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


High risk

23/49 infants (45%) unavailable for assessment of all outcomes because of discharge/transfer before completion of the exercise protocol. Dropout rate similar between groups


Low risk


Other bias

Unclear 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


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


22

Moyer-Mileur 2000

(Continued)

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 Interventions

Types 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)







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


Low risk



Low risk


Other bias

Low risk

None detected


23

Moyer-Mileur 2000a Methods

Single-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

Participants

Eligibility criteria unclear Enrolled participants: 20 former preterm neonates, follow-up from initial hospital discharge until 12 months corrected age

Interventions

Types 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)





Follow-up study published only in abstract form


Unclear risk





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)


Unclear risk


Other bias

Unclear risk

Unable to obtain detailed information from study authors


24


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)

Notes

Study authors provided additional information about anthropometric and bone mineral data when contacted in May 2013

Risk of bias Bias







Low risk


25

Moyer-Mileur 2008

(Continued)


Intervention not blinded Blinding of outcome assessors: yes for primary outcome of pDEXA measurements, no for other 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)


Low risk


Other bias

Unclear risk

None 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

Participants

Eligibility 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

Interventions

Types of interventions: as described in Moyer-Mileur 1995 for both intervention group (n = 12) and control group (n = 12) Duration of interventions: four weeks

Outcomes

Weight (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 Physical activity programs for promoting bone mineralization and growth in preterm infants (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

26

Nemet 2002

(Continued)

Bias




Not reported


Not reported

Unclear risk


Intervention not blinded, both activity protocols provided by the same trainer Blinding of outcome assessors unclear


Low risk



Low risk


Other bias

Unclear 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


27

Tosun 2011

(Continued)

Interventions

Types 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)

Notes

This trial enrolled preterm infants within the first three days of life

Risk of bias Bias




Method 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 [...]”


Not reported

Unclear risk


Intervention not blinded, as both activity protocols were administered by the same trained occupational therapist Blinding of outcome assessors: yes


Low risk

Outcome data complete


Low risk


Other bias

Unclear risk

Quality 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


28

Vignochi 2008 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)





Not reported


Codes retrieved from “closed envelopes”

Unclear 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


29

Vignochi 2008

(Continued)


Low risk



Low risk


Other bias

Unclear 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

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.

Characteristics of excluded studies [ordered by study ID]

Study

Reason for exclusion

Aly 2004

Randomized 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 2012

Randomized 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 2002

This 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 2009

Randomized 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


30

(Continued)

authors when contacted in December 2012 McDevitt 2012

This 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 1992

This 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 2012

Randomized 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

Abbreviations: DEXA = dual-energy x-ray absorptiometry. GA = gestational age.

Characteristics of ongoing studies [ordered by study ID] Cooper 2005 Trial name or title

Assisted exercise in prematurity; effects and mechanism

Methods

Randomized, masked, controlled (parallel assignment), single-center trial

Participants

Preterm 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

Interventions

Infants receive assisted exercise or cuddle for 20 minutes Duration of interventions: four weeks

Outcomes

Primary outcomes: body composition, bone mineralization, muscle mass (muscle ultrasound, bone speed of sound, and DEXA), anthropometric measurements

Starting date

2005

Contact information

Julia K. Rich, [email protected]

Notes

ClinicalTrials.gov Identifier: NCT00580099


31

Cooper 2011 Trial name or title

Impact of exercise on body composition in premature infants

Methods


Participants

Preterm 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

Outcomes

Primary outcomes: change in lean body mass assessed by DEXA at 34 to 40 weeks GA and at 86 to 92 weeks of age

Starting date

2011

Contact information

Julia K. Rich, [email protected]

Notes


Litmanovitz 2010 Trial name or title

The effect of physical activity on bone mineralization and immune system in very low birth weight infants

Methods


Participants

Preterm 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 date

2010

Contact information

Ita Litmanovitz, [email protected]

Notes



32

DATA AND ANALYSES

Comparison 1. Physical activity program versus control

Outcome or subgroup title 1 Bone area at completion of the physical activity program 1.1 Forearm bone area at completion of the physical activity program (cm2 ) 1.2 Whole body bone area at completion of the physical activity program (cm2 ) 2 Bone mineral content at completion of the physical activity program 2.1 Radial bone mineral content (mg/cm) measured by single photon absorptiometry (SPA) 2.2 Forearm bone mineral content (mg) measured by dual-energy x-ray absorptiometry (DEXA) 2.3 Whole body bone mineral content (mg) measured by dual-energy x-ray absorptiometry (DEXA) 3 Bone mineral density at completion of the physical activity program 3.1 Radial bone mineral density (mg/cm2 ) measured by single photon absorptiometry (SPA) 3.2 Forearm bone mineral density (mg/cm2 ) measured by dual-energy x-ray absorptiometry (DEXA) 3.3 Whole body bone mineral density (mg/cm2 ) measured by dual-energy x-ray absorptiometry (DEXA) 4 Bone mineral content at 12 months corrected age (g) 5 Bone area at 12 months corrected age (cm2 )

No. of studies

No. of participants

3

Statistical method

Effect size

Mean Difference (IV, Fixed, 95% CI)

Subtotals only

2

65


1.38 [0.70, 2.07]

1

29


8.03 [4.05, 12.01]


Subtotals only

4

1

23


10.60 [1.60, 19.60]

2

65


130.91 [55.35, 206. 47]

1

29


389.1 [229.98, 548. 22]


Subtotals only

4

1

23


29.0 [-1.48, 59.48]

2

65


-0.19 [-0.39, 0.01]

1

29


10.10 [5.27, 14.93]

1

20


1

20


-17.30 [-68.95, 34. 35] -21.0 [-85.60, 43. 60]


33

6 Body weight gain during study period (g/kg/d) 7 Body length gain during study period (cm/wk) 8 Head circumference gain during study period (cm/wk) 9 Body weight at 12 months corrected age (g)

4

111


2.21 [1.23, 3.19]

4

120


0.12 [0.01, 0.24]

3

91


-0.03 [-0.14, 0.08]

1

20


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. Review:

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

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

Study or subgroup

Physical activity N

Mean Difference

Control Mean(SD)

N

Mean(SD)

Weight

IV,Fixed,95% CI

Mean Difference IV,Fixed,95% CI

1 Forearm bone area at completion of the physical activity program (cm2 ) Moyer-Mileur 2000

16

8.6 (1.3)

16

7.4 (1.4)

54.0 %

1.20 [ 0.26, 2.14 ]

Moyer-Mileur 2008

22

8.7 (1.4)

11

7.1 (1.4)

46.0 %

1.60 [ 0.59, 2.61 ]

Subtotal (95% CI)

38

100.0 %

1.38 [ 0.70, 2.07 ]

100.0 %

8.03 [ 4.05, 12.01 ]

100.0 %

8.03 [ 4.05, 12.01 ]

27

Heterogeneity: Chi2 = 0.32, df = 1 (P = 0.57); I2 =0.0% Test for overall effect: Z = 3.95 (P = 0.000080) 2 Whole body bone area at completion of the physical activity program (cm2 ) Vignochi 2008

Subtotal (95% CI)

15

15

21.13 (6.1)

14

13.1 (4.8)

14

Heterogeneity: not applicable Test for overall effect: Z = 3.95 (P = 0.000077) Test for subgroup differences: Chi2 = 10.39, df = 1 (P = 0.00), I2 =90%

-10

-5

Favours control

0

5

10

Favours exercise


34

Analysis 1.2. Comparison 1 Physical activity program versus control, Outcome 2 Bone mineral content at completion of the physical activity program. Review:


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

Study or subgroup

Treatment

Mean Difference

Control

N

Mean(SD)

N

Mean(SD)

Weight

IV,Fixed,95% CI


1 Radial bone mineral content (mg/cm) measured by single photon absorptiometry (SPA) Moyer-Mileur 1995

12

Subtotal (95% CI)

12

53.3 (12)

11

42.7 (10)

11

100.0 %

10.60 [ 1.60, 19.60 ]

100.0 %

10.60 [ 1.60, 19.60 ]

Heterogeneity: not applicable Test for overall effect: Z = 2.31 (P = 0.021) 2 Forearm bone mineral content (mg) measured by dual-energy x-ray absorptiometry (DEXA) Moyer-Mileur 2000

16

763 (145)

16

660 (185)

43.0 %

103.00 [ -12.17, 218.17 ]

Moyer-Mileur 2008

22

765 (139)

11

613 (138)

57.0 %

152.00 [ 51.88, 252.12 ]

Subtotal (95% CI)

38

100.0 %

130.91 [ 55.35, 206.47 ]

100.0 %

389.10 [ 229.98, 548.22 ]

27

Heterogeneity: Chi2 = 0.40, df = 1 (P = 0.53); I2 =0.0% Test for overall effect: Z = 3.40 (P = 0.00068) 3 Whole body bone mineral content (mg) measured by dual-energy x-ray absorptiometry (DEXA) Vignochi 2008

Subtotal (95% CI)

15

687.5 (262.3)

15

14

298.4 (167.5)

100.0 % 389.10 [ 229.98, 548.22 ]

14

Heterogeneity: not applicable Test for overall effect: Z = 4.79 (P < 0.00001) Test for subgroup differences: Chi2 = 31.08, df = 2 (P = 0.00), I2 =94%

-500

-250

Favours control

0

250

500

Favours exercise


35

Analysis 1.3. Comparison 1 Physical activity program versus control, Outcome 3 Bone mineral density at completion of the physical activity program. Review:


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

Study or subgroup

Treatment N

Mean Difference

Control Mean(SD)

N

Mean(SD)

Weight

IV,Fixed,95% CI


1 Radial bone mineral density (mg/cm2 ) measured by single photon absorptiometry (SPA) Moyer-Mileur 1995

12

Subtotal (95% CI)

12

154 (34)

11

125 (40)

11

100.0 %

29.00 [ -1.48, 59.48 ]

100.0 %

29.00 [ -1.48, 59.48 ]

Heterogeneity: not applicable Test for overall effect: Z = 1.87 (P = 0.062) 2 Forearm bone mineral density (mg/cm2 ) measured by dual-energy x-ray absorptiometry (DEXA) Moyer-Mileur 2000

16

8.8 (0.1)

16

9 (0.4)

95.4 %

-0.20 [ -0.40, 0.00 ]

Moyer-Mileur 2008

22

8.8 (1.4)

11

8.8 (1.2)

4.6 %

0.0 [ -0.92, 0.92 ]

Subtotal (95% CI)

38

100.0 %

-0.19 [ -0.39, 0.01 ]

100.0 %

10.10 [ 5.27, 14.93 ]

100.0 %

10.10 [ 5.27, 14.93 ]

27

Heterogeneity: Chi2 = 0.17, df = 1 (P = 0.68); I2 =0.0% Test for overall effect: Z = 1.90 (P = 0.058) 3 Whole body bone mineral density (mg/cm2 ) measured by dual-energy x-ray absorptiometry (DEXA) Vignochi 2008

Subtotal (95% CI)

15

32.9 (5.7)

15

14

22.8 (7.4)

14

Heterogeneity: not applicable Test for overall effect: Z = 4.10 (P = 0.000042) Test for subgroup differences: Chi2 = 20.92, df = 2 (P = 0.00), I2 =90%

-50

-25

Favours control

0

25

50

Favours exercise


36

Analysis 1.4. Comparison 1 Physical activity program versus control, Outcome 4 Bone mineral content at 12 months corrected age (g). Review:


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

Study or subgroup

Physical activity

Moyer-Mileur 2000a

Total (95% CI)

Mean Difference

Control

N

Mean(SD)

N

Mean(SD)

10

326.3 (65.9)

10

343.6 (51)

10

Weight

Mean Difference

100.0 %

-17.30 [ -68.95, 34.35 ]

IV,Fixed,95% CI

IV,Fixed,95% CI

10

100.0 % -17.30 [ -68.95, 34.35 ]

Heterogeneity: not applicable Test for overall effect: Z = 0.66 (P = 0.51) Test for subgroup differences: Not applicable

-50

-25

0

Favours control

25

50

Favours exercise

Analysis 1.5. Comparison 1 Physical activity program versus control, Outcome 5 Bone area at 12 months corrected age (cm2). Review:


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

Study or subgroup

Physical activity

Moyer-Mileur 2000a

Total (95% CI)

Mean Difference

Control

N

Mean(SD)

N

Mean(SD)

10

586 (79)

10

607 (68)

10

Weight

IV,Fixed,95% CI


100.0 %

-21.00 [ -85.60, 43.60 ]

100.0 % -21.00 [ -85.60, 43.60 ]

10


-50

-25

Favours control

0

25

50

Favours exercise


37

Analysis 1.6. Comparison 1 Physical activity program versus control, Outcome 6 Body weight gain during study period (g/kg/d). Review:


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

Study or subgroup

Physical activity

Mean Difference

Control

Weight

Mean Difference

N

Mean(SD)

N

Mean(SD)

Eliakim 2002

10

20.5 (3.48)

10

17.3 (2.21)

14.8 %

3.20 [ 0.64, 5.76 ]

Moyer-Mileur 1995

13

17.8 (2.8)

13

13.4 (2.8)

20.8 %

4.40 [ 2.25, 6.55 ]

Moyer-Mileur 2000

16

16.3 (2.6)

16

14.6 (2)

37.3 %

1.70 [ 0.09, 3.31 ]

Moyer-Mileur 2008

22

15.5 (2.8)

11

14.8 (2.5)

27.1 %

0.70 [ -1.18, 2.58 ]

100.0 %

2.21 [ 1.23, 3.19 ]

Total (95% CI)

61

IV,Fixed,95% CI

IV,Fixed,95% CI

50

Heterogeneity: Chi2 = 7.41, df = 3 (P = 0.06); I2 =59% Test for overall effect: Z = 4.42 (P = 0.000010) Test for subgroup differences: Not applicable

-4

-2

Favours control

0

2

4

Favours exercise


38

Analysis 1.7. Comparison 1 Physical activity program versus control, Outcome 7 Body length gain during study period (cm/wk). Review:


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

Study or subgroup

Physical activity

Mean Difference

Control

Weight

Mean Difference

N

Mean(SD)

N

Mean(SD)

Moyer-Mileur 1995

13

0.77 (0.24)

13

0.91 (0.18)

IV,Fixed,95% CI 49.3 %

-0.14 [ -0.30, 0.02 ]

IV,Fixed,95% CI

Moyer-Mileur 2000

16

1.4 (0.5)

16

1 (0.5)

10.9 %

0.40 [ 0.05, 0.75 ]

Moyer-Mileur 2008

22

0.8 (0.5)

11

0.8 (0.5)

10.0 %

0.0 [ -0.36, 0.36 ]

Vignochi 2008

15

1.28 (0.34)

14

0.78 (0.23)

29.7 %

0.50 [ 0.29, 0.71 ]

Total (95% CI)

66

100.0 %

0.12 [ 0.01, 0.24 ]

54

Heterogeneity: Chi2 = 25.27, df = 3 (P = 0.00001); I2 =88% Test for overall effect: Z = 2.11 (P = 0.035) Test for subgroup differences: Not applicable

-0.5

-0.25

Favours control

0

0.25

0.5

Favours exercise


39

Analysis 1.8. Comparison 1 Physical activity program versus control, Outcome 8 Head circumference gain during study period (cm/wk). Review:


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

Study or subgroup

Physical activity

Mean Difference

Control

Weight

N

Mean(SD)

N

Mean(SD)

Moyer-Mileur 1995

13

0.77 (0.18)

13

0.78 (0.15)

76.5 %

-0.01 [ -0.14, 0.12 ]

Moyer-Mileur 2000

16

1 (0.4)

16

1.1 (0.4)

16.2 %

-0.10 [ -0.38, 0.18 ]

Moyer-Mileur 2008

22

0.85 (0.5)

11

0.9 (0.6)

7.3 %

-0.05 [ -0.46, 0.36 ]

100.0 %

-0.03 [ -0.14, 0.08 ]

Total (95% CI)

51

IV,Fixed,95% CI


40

Heterogeneity: Chi2 = 0.35, df = 2 (P = 0.84); I2 =0.0% Test for overall effect: Z = 0.48 (P = 0.63) Test for subgroup differences: Not applicable

-0.2

-0.1

0

Favours control

0.1

0.2

Favours exercise

Analysis 1.9. Comparison 1 Physical activity program versus control, Outcome 9 Body weight at 12 months corrected age (g). Review:


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

Study or subgroup

Physical activity N

Moyer-Mileur 2000a

Total (95% CI)

Mean Difference

Control Mean(SD)

N

Mean(SD)

10 8700 (1400)

10

8500 (800)

10

Weight

IV,Fixed,95% CI


100.0 %

200.00 [ -799.39, 1199.39 ]

100.0 % 200.00 [ -799.39, 1199.39 ]

10


-1000

-500

Favours control

0

500

1000

Favours exercise


40

WHAT’S NEW Last assessed as up-to-date: 26 November 2009.

Date

Event

Description

19 May 2013

New search has been performed

This 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 2013

New 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

Date

Event

Description

22 August 2008

Amended

Converted to new review format.

28 December 2006

New citation required and conclusions have changed

Substantive 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.


41

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

INDEX TERMS Medical Subject Headings (MeSH) Bone Density [physiology]; Bone Diseases, Metabolic [prevention & control]; Calcification, Physiologic [∗ physiology]; Infant, Premature [growth & development; ∗ physiology]; Motor Activity [∗ physiology]; Musculoskeletal Manipulations [∗ methods]; Randomized Controlled Trials as Topic; Weight Gain [physiology]

MeSH check words Humans; Infant; Infant, Newborn


42

Bone mineralization outcomes in human milk-fed preterm infants.

Growth, bone health, and later outcomes in infants born preterm.

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Promoting Physical Activity and Nutrition in People With Stroke.

Plant growth promoting bacteria Enterobacter asburiae JAS5 and Enterobacter cloacae JAS7 in mineralization of endosulfan.

Daily physical activity in low-risk extremely low birth weight preterm infants: positive impact on bone mineral density and anthropometric measurements.

Metabolic bone disease and bone mineral density in very preterm infants.