Programas de actividad física para promover la mineralización y el crecimiento de los huesos en los bebés prematuros
Resumen
Antecedentes
La falta de estimulación física puede contribuir a la enfermedad metabólica de los huesos de los lactantes prematuros, lo que da lugar a una mineralización y un crecimiento óseo deficientes. Los programas de actividad física combinados con una nutrición adecuada podrían ayudar a promover la mineralización y el crecimiento de los huesos.
Objetivos
El objetivo principal fue evaluar si los programas de actividad física en los niños prematuros mejoran la mineralización y el crecimiento de los huesos y reducen el riesgo de fracturas.
Los objetivos secundarios incluían otros posibles beneficios en cuanto a la duración de la estancia hospitalaria, las deformidades esqueléticas y los resultados del desarrollo neurológico, y los acontecimientos adversos.
Análisis de subgrupos:
‐ Dado que los lactantes más pequeños son los más vulnerables a desarrollar osteopeniaBishop 1999), se planificó un análisis de subgrupos para los lactantes con un peso al nacer < 1000 g.
‐ La ingesta de calcio y fósforo puede afectar a la capacidad de un lactante para aumentar el contenido de minerales en los huesos (KuschelKuschel 2004 Por lo tanto, se planificó un análisis adicional de subgrupos para los lactantes que reciben diferentes cantidades de calcio y fósforo, junto con alimentación enteral completa, como se indica a continuación.
∘ Por debajo de 100 mg/60 mg de calcio/fósforo o igual o superior a 100 mg/60 mg de calcio/fósforo por 100 ml de leche.
∘ Suplemento de calcio sin fósforo.
∘ Suplemento de fósforo sin calcio.
Métodos de búsqueda
Se utilizó la estrategia de búsqueda estándar del Grupo Cochrane de Neonatología (Cochrane Neonatal Review Group, CNRG). La búsqueda incluyó el Registro Cochrane Central de Ensayos Controlados (Cochrane Central Register of Controlled Trials, CENTRAL) (2012, número 9), MEDLINE, EMBASE, CINAHL (1966 a marzo de 2013), y referencias cruzadas, así como la búsqueda manual de los resúmenes de la Society for Pediatric Research y la International Journal of Sports Medicine.
Criterios de selección
Ensayos controlados aleatorizados y cuasialeatorizados que comparen programas de actividad física (extensión y flexión, ejercicios de amplitud de movimiento) versus ningún programa organizado de actividad física en niños prematuros.
Obtención y análisis de los datos
La obtención de los datos, la selección de estudios y el análisis de los datos se realizaron de acuerdo a los métodos estándar del CNRG.
Resultados principales
En esta revisión se incluyeron 11 ensayos que reclutaron a 324 lactantes prematuros (edad gestacional de 26 a 34 semanas). Todos fueron estudios pequeños (N = 16 a 50) de un solo centro que evaluaron la actividad física diaria durante tres semanas y media a ocho semanas durante la hospitalización inicial. La calidad metodológica y la notificación de los ensayos incluidos fueron variables.
Cuatro ensayos mostraron beneficios moderados a corto plazo de la actividad física para la mineralización de los huesos al completar el programa de actividad física. El único ensayo que evaluó los efectos a largo plazo sobre la mineralización ósea no mostró ningún efecto de la actividad física administrada durante la hospitalización inicial sobre la mineralización ósea a los 12 meses de edad corregida. El metanálisis de cuatro ensayos mostró un efecto positivo de la actividad física sobre el aumento de peso diario (diferencia de medias ponderada (DMP) 2,21 g/kg/d, intervalo de confianza (IC) del 95%: 1,23 a 3,19). Los datos de cuatro ensayos mostraron un efecto positivo sobre el crecimiento lineal (DMP 0,12 cm/semana, IC del 95%: 0,01 a 0,24) pero no sobre el crecimiento del perímetro craneal (DMP ‐0,03 cm/semana, IC del 95%: ‐0,14 a 0,08) durante el período de estudio. Sólo un ensayo informó sobre fracturas (este resultado no se produjo en los grupos de intervención y control) y complicaciones del parto prematuro (no hay diferencias significativas entre los grupos de intervención y control). Ninguno de los ensayos evaluó otros resultados relevantes para esta revisión.
Conclusiones de los autores
Algunas evidencias sugieren que los programas de actividad física podrían promover el aumento de peso a corto plazo y la mineralización de los huesos en los bebés prematuros. Los datos son insuficientes para permitir la evaluación de efectos perjudiciales o a largo plazo. La evidencia actual no apoya el uso sistemático de programas de actividad física en los bebés prematuros. Se necesitan más ensayos que incorporen a los lactantes con un alto riesgo inicial de osteopenia. Estos ensayos deben abordar los eventos adversos, los resultados a largo plazo y los efectos de la ingesta nutricional (calorías, proteínas, calcio, fósforo).
PICO
Resumen en términos sencillos
Programas de actividad física para promover la mineralización y el crecimiento de los huesos en los bebés prematuros
Los bebés que nacen demasiado pronto (bebés prematuros) suelen ser atendidos de manera que se minimice la actividad física para reducir el estrés y las complicaciones relacionadas con el mismo. Sin embargo, la falta de actividad física puede dar lugar a un desarrollo y crecimiento deficientes de los huesos, como se observa en los niños y adultos postrados en la cama. Se cree que los programas de actividad física (mover y presionar todas las articulaciones de todas las extremidades durante varios minutos al día) pueden promover el desarrollo y el crecimiento de los huesos en los bebés prematuros. Esta revisión encontró que la actividad física podría proporcionar un pequeño beneficio para el desarrollo y el crecimiento de los huesos a corto plazo. Los datos fueron insuficientes para permitir la evaluación de los beneficios y daños a largo plazo. Según los conocimientos actuales, los programas de actividad física no pueden ser recomendados como un procedimiento estándar para los bebés prematuros.
Authors' conclusions
Background
Description of the condition
Very low birth weight (VLBW) infants are at risk of developing osteopenia of prematurity. The major etiological factor seems to be substrate deficiency, particularly of calcium and phosphorus, in the presence of low bone mass at birth (Steichen 1980). Immobilization may also contribute to osteopenia (Bishop 1999).
Diagnostic criteria of osteopenia vary considerably. Frequently used biochemical indicators of disturbed bone metabolism are low whole blood phosphate levels, increased urinary calcium/phosphate ratios, and high plasma alkaline phosphatase levels (Bishop 1999). In neonates, peak plasma alkaline phosphatase activity greater than five times the maximum adult normal range of 130 IU/mL is associated with reduced stature at 18 months corrected age in former preterm infants (Lucas 1989).
Osteopenia in preterm infants leads to impaired bone mineralization, as measured by techniques such as single‐photon absorptiometry (SPA) or dual‐energy x‐ray absorptiometry (DEXA) (Salle 1992; Steichen 1980). As a result, growth velocity and long‐term height may be reduced (Lucas 1989). In severe cases, fractures have been reported (Koo 1988). Although reduced bone mineralization is clearly associated with multiple skeletal deformities such as bowing of the legs, scoliosis, and skull indentations (Juskeliene 1996; Oyemade 1981; Tubbs 2004), the prevalence of such deformities in former preterm infants with osteopenia has not yet been determined.
Description of the intervention
Common strategies for the prevention of osteopenia in VLBW infants include calcium and phosphorus supplementation of human milk/formula and physical activity programs. A systematic review of trials investigating the effects of fortification of human milk with multicomponent fortifiers in nursery settings found that this intervention in VLBW infants was associated with short‐term improvements in linear growth, head growth and weight gain (Kuschel 2004). In a randomized study, postdischarge multicomponent fortified formula when compared with standard formula led to enhanced linear growth at 18 months corrected age (Lucas 2001). Another randomized trial demonstrated increased bone mineral content and growth in preterm infants fed an isocaloric, calcium‐ and phosphorus‐enriched formula when compared with controls receiving a conventional preterm formula (Lapillonne 2004). In this study, increasing calcium concentration from 80 to 100 mg/100 mL and increasing phosphorus from 42.5 to 60 mg/100 mL as soon as full enteral feedings were reached was associated with higher bone mineral content and weight at term as measured by DEXA.
Mechanical strain on bones and joints stimulates bone formation and growth, and inactivity leads to bone resorption (Larson 2000; MacKelvie 2004). Physical activity programs have been shown to reduce the risk of osteoporotic fracture and bone loss in adults (Bonaiuti 2002; Heinonen 1996; Kerr 2001). Observational studies in children beyond the neonatal age also suggest that physical activity might help to promote bone mineral density (Slemenda 1991). Minimal handling is frequently a routine policy for hospitalized preterm infants to facilitate stability and to minimize stress. The resultant inactivity may lead to suboptimal stimulation of bone metabolism.
How the intervention might work
Given evidence from studies in older children and adults, regular physical activity programs (range‐of‐motion exercises) may provide a simple intervention for improving bone mineral content and skeletal growth in preterm infants. As range‐of‐motion exercises inevitably have an element of systematic holding and stroking, they may also promote general growth in preterm infants because interventions solely consisting of systematic holding and stroking (eg, massage/tactile stimulation) have been reported to promote growth (Vickers 2004). However, physical activity programs in preterm infants may have adverse effects such as fractures, or they may increase the risk or severity of complications of prematurity (eg, apnea, bradycardia) with resultant altered blood flow to vital organs such as brain and the possibility of long‐term neurodevelopmental impairment.
Why it is important to do this review
Physical activity programs are in use for promoting bone mineralization and growth in preterm neonates. These programs need to be formally assessed to provide caregivers with clinically relevant data on their efficacy and safety. The aim of this systematic review is to summarize current evidence on benefits and harms of physical activity programs in preterm infants.
Objectives
The primary objective was to assess whether physical activity programs in preterm infants improve bone mineralization and growth and reduce the risk of fracture.
The secondary objectives included other potential benefits in terms of length of hospital stay, skeletal deformities and neurodevelopmental outcomes, and adverse events.
Subgroup analysis:
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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.
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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.
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Below 100 mg/60 mg calcium/phosphorus or equal to/above 100 mg/60 mg calcium/phosphorus per 100 mL milk.
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Supplementation of calcium without phosphorus.
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Supplementation of phosphorus without calcium.
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Methods
Criteria for considering studies for this review
Types of studies
All randomized and quasi‐randomized controlled trials in which the unit of allocation was the individual infant.
Types of participants
Preterm infants born at a gestational age < 37 completed weeks who did not receive physical therapy for any indication other than osteopenia of prematurity (eg, severe contractures).
Types of interventions
Systematic physical activity programs consisting of extension and flexion, range‐of‐motion exercises of the infant's upper and lower limbs, administered for several minutes at a time several times a week for at least two weeks, compared with no organized physical activity programs. Eligible studies included those that provided physical activity for the experimental group, with or without massage and/or tactile stimulation for both experimental and control groups.
Types of outcome measures
Trials had to assess at least one of the following outcomes.
Primary outcomes
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Bone mineralization: bone mineral content, bone mineral density, and bone area as measured by absorptiometric x‐ray techniques:
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at completion of the physical activity program;
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at discharge;
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at term; and
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at 12 to 24 months corrected age.
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Fractures: proportion of infants with one or more fractures:
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at completion of the physical activity program;
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at discharge;
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at term; and
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at 12 to 24 months corrected age.
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Somatic growth: weight, length, head circumference:
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at completion of the physical activity program;
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at discharge;
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at term; and
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at 12 to 24 months corrected age.
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Secondary outcomes
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Complications of prematurity.
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Mortality at hospital discharge.
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Mean frequency of apnea during study period.
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Mean frequency of bradycardia during study period.
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Mean frequency of apnea and bradycardia during study period.
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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).
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Oxygen dependency at 28 days.
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Chronic lung disease defined as supplemental oxygen or ventilator support at 36 weeks postmenstrual age.
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Necrotizing enterocolitis.
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Retinopathy of prematurity (all stages and severe stage 3 or greater).
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Intraventricular hemorrhage (all grades and severe grade 3 or 4).
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Periventricular leukomalacia.
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Length of hospital stay (days).
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Proportion of infants with one or more secondary skeletal deformities (including skull, spine, limbs).
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Neurodevelopmental abnormalities at 18 to 24 months corrected age or later.
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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).
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Intellectual impairment (IQ greater than two standard deviations below the mean as assessed by a standardized and validated test).
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Blindness (vision less than 6/60 in both eyes).
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Sensorineural deafness requiring amplification.
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Search methods for identification of studies
The standard strategy of the Cochrane Neonatal Review Group (CNRG) was used for a literature search in September 2005 and was repeated in March 2013.
Electronic searches
The databases searched included MEDLINE, EMBASE, and CINAHL (1966 to March 2013).
The MeSH headings included Infant, Newborn, Bone Diseases, Metabolic, Motor Activity or Movement or Exercise and Exercise Therapy, and the text word "Physical activity" or "Exercise." The Cochrane Central Register of Controlled Trials (CENTRAL; 2013, Issue 4) was searched using the words "Newborn," "Physical activity," and "exercise."
Searching other resources
Previous reviews including cross‐references and references from identified studies were searched. No language restrictions were applied. Abstracts (1992 to 2012) of the Society for Pediatric Research, the European Society for Pediatric Research, and the International Journal of Sports Medicine were also searched.
Clinical trials registries were searched for ongoing or recently completed trials (clinicaltrials.gov; controlled‐trials.com; and who.int/ictrp).
Data collection and analysis
The standard methods of the CNRG were used.
Selection of studies
Two review authors (SMS and SK) independently conducted the literature search. All randomized and quasi‐randomized controlled trials fulfilling the selection criteria described in the previous section were included. Both review authors assessed the trials for eligibility for inclusion and methodological quality.
Data extraction and management
Two review authors (SMS and SK) separately extracted, assessed, and coded all data for each study. Differences were resolved by discussion. Additional information was requested from the trial authors if necessary.
Assessment of risk of bias in included studies
The standard methods of the CNRG were employed. The methodological quality of the studies was assessed using the following key criteria: allocation concealment (blinding of randomization), blinding of intervention, completeness of follow‐up, and blinding of outcome measurement/assessment. For each criterion, assessment was yes, no, cannot tell. Two review authors (SMS and SK) separately assessed each study. Disagreements were resolved by discussion. This information was added to the Characteristics of included studies table.
In addition, the following issues were evaluated and were entered into the Risk of bias in included studies table.
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Sequence generation: Was the allocation sequence adequately generated?
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Allocation concealment: Was allocation adequately concealed?
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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?
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Incomplete outcome data: Were incomplete outcome data adequately addressed?
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Selective outcome reporting: Are reports of the study free of suggestion of selective outcome reporting?
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Other sources of bias: Was the study apparently free of other problems that could put it at high risk of bias?
Measures of treatment effect
Statistical analyses were performed using Review Manager software. Categorical data were analyzed using risk ratio (RR), risk difference (RD), and the number needed to treat for an additional beneficial outcome (NNTB). Continuous data were analyzed using weighted mean difference (WMD). The 95% confidence interval (CI) was reported for all estimates.
Assessment of heterogeneity
We estimated the treatment effects of individual trials and examined heterogeneity between trials by inspecting the forest plots and quantifying the impact of heterogeneity using the I2 statistic. If we detected statistical heterogeneity, we planned to explore the possible causes (eg, differences in study quality, participants, intervention regimens, or outcome assessments) using post hoc subgroup analyses.
Data synthesis
A fixed‐effect model was used to pool data for meta‐analyses.
Subgroup analysis and investigation of heterogeneity
Subgroup analysis:
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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.
-
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Below 100 mg/60 mg calcium/phosphorus or equal to/above 100 mg/60 mg calcium/phosphorus per 100 mL milk.
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Supplementation of calcium without phosphorus.
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Supplementation of phosphorus without calcium.
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Results
Description of studies
Results of the search
Forty‐four abstracts were identified using the prespecified search strategy in March 2013. Eighteen potentially eligible studies were retrieved for detailed evaluation. Three ongoing studies were found.
Included studies
Eleven trials incorporating 324 preterm infants met inclusion criteria of this review (Chen 2010; Eliakim 2002; Litmanovitz 2003; Litmanovitz 2007; Moyer‐Mileur 1995; Moyer‐Mileur 2000; Moyer‐Mileur 2000a; Moyer‐Mileur 2008; Nemet 2002; Tosun 2011; Vignochi 2008). Abstracts with preliminary results of three studies (Litmanovitz 2003; Moyer‐Mileur 1995, Moyer‐Mileur 2000) had been reported in Pediatric Research before full publication. Seven included studies (Litmanovitz 2003; Litmanovitz 2007; Moyer‐Mileur 1995; Moyer‐Mileur 2000; Moyer‐Mileur 2008; Tosun 2011; Vignochi 2008) specified eligibility criteria for participant enrollment (see the Table, Characteristics of included studies). The following descriptions refer to enrolled rather than eligible patients. Moyer‐Mileur 1995, Moyer‐Mileur 2000, Moyer‐Mileur 2000a, and Moyer‐Mileur 2008 were single‐center studies of healthy preterm neonates (N = 49, 32, 20, and 50, respectively) conducted at the University Hospital of Utah, in Utah, USA. Moyer‐Mileur 1995 and Moyer‐Mileur 2000 enrolled two‐ to four‐week‐old preterm infants (mean gestation 28 to 30 weeks) who were fed fortified breast milk or preterm formula. The proportion of infants fed fortified breast milk was between 53% and 73% and did not differ between treatment and control groups. Infants in treatment and control groups received well‐defined interventions applied by the same trained occupational therapist, described as follows. For the exercise group, range‐of‐motion exercises with gentle compression and extension and flexion of both upper and lower extremities were provided. Each movement was done five times at each joint (wrist, elbow, shoulder, ankle, knee, and hip) five times a week. For the control group, tactile stimulation was provided, that is, a daily interactive period of holding and stroking but no range‐of‐motion activity. Both protocols were administered for three and one‐half to four weeks. Outcomes included bone mineralization as measured by absorptiometric x‐ray techniques, short‐term growth, and biochemical markers of bone metabolism. Moyer‐Mileur 2008 had a similar design, but infants were exclusively fed fortified breast milk and intervention groups received physical activity programs provided by a trained occupational therapist or by the infant's mother. Moyer‐Mileur 2000a was a follow‐up study assessing bone mineralization and postdischarge growth up to 12 months corrected age in infants who had been enrolled in a physical activity program similar to that reported in Moyer‐Mileur 2000.
Eliakim 2002, Litmanovitz 2003, Litmanovitz 2007, and Nemet 2002 were single‐center studies in preterm neonates (N = 20, 24, 16, and 24, respectively) performed at the Meir General Hospital, Sapir Medical Center, in Israel. Eliakim 2002 and Nemet 2002 enrolled four‐ to five‐week‐old preterm neonates (mean gestation 28 to 29 weeks) fed fortified breast milk or preterm formula. The proportions of infants with chronic lung disease in the study and control groups of neonates were comparable in Eliakim 2002 (40% vs 40%) and Nemet 2002 (42% vs 42%). Litmanovitz 2003 and Litmanovitz 2007 enrolled infants of similar gestational age in the first week of life, including infants receiving parenteral nutrition accompanied by fortified breast milk or preterm formula. The overall proportion of infants fed fortified breast milk was 50% in Eliakim 2002 and 46% in Litmanovitz 2003 with no significant difference between treatment and control groups noted within each trial (Eliakim 2002 five/10 vs five/10; Litmanovitz 2003 five/12 vs six/12). In Eliakim 2002, Litmanovitz 2003, and Nemet 2002, a trained person administered physical activity (treatment group) and tactile stimulation (control group) for four weeks based on the Moyer‐Mileur protocol (Moyer‐Mileur 1995; see above). Litmanovitz 2007 administered the same interventions. However, programs were applied for a total duration of eight weeks. Outcomes in this trial included short‐term growth, biochemical markers of bone and fat tissue metabolism, and bone ultrasound measurements.
Vignochi 2008 was a single‐center study in 29 preterm infants conducted at the Hospital de Clínicas de Porto Alegre in Brazil. Healthy preterm infants of 26 to 34 weeks gestational age were enrolled at three weeks postnatal age if they tolerated enteral feeds of at least 110 kcal/kg/d (fortified breast milk or preterm formula). The proportion of infants fed fortified breast milk was 21% versus 13% in the physical activity group versus the control group. Infants in the intervention group received a physical activity program based on the Moyer‐Mileur protocol. A physical therapist applied the intervention for 15 minutes daily five days a week until the participant reached a body weight of 2 kg (ie, until discharge from the hospital; mean duration of the program was 25 days). Thus, daily duration of the physical activity program in Vignochi 2008 was greater (15 minutes daily) than in Moyer‐Mileur 1995 (five minutes daily), and total duration and frequency were comparable with the original Moyer‐Mileur protocol. In contrast to the original Moyer‐Mileur protocol, infants in the control group did not receive tactile stimulation. Outcomes in Vignochi 2008 included whole body bone mineralization measured by DEXA, short‐term growth, body composition in terms of fat mass and lean mass, and biochemical markers of bone metabolism.
Chen 2010 was a single‐center study in 20 preterm infants conducted in Taiwan. Healthy preterm infants with birth weight < 1500 g were enrolled at one week postnatal age and received a physical activity program based on the Moyer‐Mileur protocol (10 minutes daily, total duration four weeks, applied by a trained nurse). Outcomes included complications of prematurity, fractures, duration of hospitalization, bone speed of sound measurements, and biochemical markers of bone metabolism.
Tosun 2011 was a single‐center study in 40 preterm infants conducted in Turkey. Preterm infants of 26 to 32 weeks gestational age were enrolled within the first three days of life and received a physical activity program identical to that used in Moyer‐Mileur 1995. Outcomes included anthropometric data and bone speed of sound measurements.
Details of included studies are shown in the Table, Characteristics of included studies.
Excluded studies
Seven randomized trials (Aly 2004; Haley 2012; Hassanein 2002; Massaro 2009; McDevitt 2012; McIntyre 1992; Vignochi 2012) were excluded from the review. One trial was excluded because the study population consisted of only term infants (McIntyre 1992). Another trial was excluded because both intervention and control groups received physical activity programs (McDevitt 2012). Three trials were excluded because the protocol prescribed physical activity programs plus additional massage (Aly 2004; Hassanein 2002) or tactile stimulation (Haley 2012) in the intervention group but no massage or tactile stimulation in the control group. The application of massage or tactile stimulation to infants only in the intervention group was considered to potentially affect the outcomes. Another trial randomly assigned infants into three study groups; one group of infants received a physical activity program plus additional massage, a second group received only massage, and the control group received neither of those measures (Massaro 2009). This trial was excluded because the duration of massage differed markedly between intervention groups. Last, one trial (Vignochi 2012) was excluded because all participants from this report are included in a previous report already incorporated in this review (Vignochi 2008).
Details of excluded studies are summarized in the Table, Characteristics of excluded studies.
Risk of bias in included studies
Overall, the methodological and reporting quality of most included trials was moderate. Only one trial explicitly stated concealment of participant allocation and method of randomization (Moyer‐Mileur 2008). Additional information received after Dr Moyer‐Mileur was contacted suggested that participant allocation was concealed in Moyer‐Mileur 1995 and Moyer‐Mileur 2000.
None of the trials attempted to blind the interventions. Short‐term follow‐up was complete (100%) in seven trials (Eliakim 2002; Litmanovitz 2003; Litmanovitz 2007; Moyer‐Mileur 2000; Nemet 2002; Tosun 2011; Vignochi 2008). Moyer‐Mileur 1995 lost 23/49 (45%) participants because of hospital discharge or transfer before completion of the four‐week study, leaving 26 (13 infants in the treatment group and the control group, respectively) in the study. Baseline data and results were available for only 26 infants completing the study. Moyer‐Mileur 2008 lost 17/50 infants (34%) because of transfer to another facility or change of feeding regimen during the four‐week study. Baseline data and results were available only for the 33 infants who completed the study. The abstract by Moyer‐Mileur 2000a from the same research group reporting on long‐term follow‐up of 20 former preterm neonates from hospital discharge to 12 months corrected age did not include baseline data of the original cohort receiving the interventions; therefore, completeness of follow‐up could not be determined. Assessors of bone mineralization in Moyer‐Mileur 1995, Moyer‐Mileur 2000, Moyer‐Mileur 2008, and Vignochi 2008 were blinded. None of the other included trials reported on blinding of assessors for outcomes relevant to this review.
Effects of interventions
Physical activity program versus control
Primary outcomes
Bone mineralization
At completion of the physical activity program
Four trials (Moyer‐Mileur 1995;Moyer‐Mileur 2000;Moyer‐Mileur 2008;Vignochi 2008) involving 117 infants reported on bone mineral content, bone mineral density, and bone area at completion of the physical activity program. Because of differences in methodologies (radial SPA vs forearm DEXA vs total body DEXA), data were not pooled for meta‐analyses.
Bone area at completion of the physical activity program (Outcome 1.1; Figure 1)
Pooled data from Moyer‐Mileur 2000 (N = 23) and Moyer‐Mileur 2008 (N = 33) suggest that physical activity versus control is associated with larger forearm bone area as measured by DEXA (WMD 1.38 cm2, 95% CI 0.70 to 2.07). Vignochi 2008 (N = 29) reported higher total body bone area in the physical activity group versus the control group (MD 8.03 cm2, 95% CI 4.05 to 12.01).
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).
Forest plot of comparison: 1 Physical activity program versus control, outcome: 1.2 Bone mineral content at completion of the physical activity program.
Bone mineral density at completion of the physical activity program (Outcome 1.3; Figure 3)
No significant effect of physical activity on radial bone mineral density was noted in Moyer‐Mileur 1995 (MD 29.0 mg/cm2, 95% CI ‐1.48 to 59.48) as measured by SPA or forearm bone mineral density in pooled data from Moyer‐Mileur 2000 and Moyer‐Mileur 2008 as measured by DEXA (WMD ‐0.19 mg/cm2, 95% CI ‐0.39 to 0.01). Vignochi 2008 reported higher total body bone mineral density in the physical activity group versus the control group (MD 10.10 mg/cm2, 95% CI 5.27 to 14.93).
Forest plot of comparison: 1 Physical activity program versus control, outcome: 1.3 Bone mineral density at completion of the physical activity program.
At discharge
Not reported in any of the trials.
At term
Not reported in any of the trials.
At 12 to 24 months corrected age
Bone mineral content and bone area at 12 months corrected age (Outcomes 1.4 and 1.5)
One trial (Moyer‐Mileur 2000a) with 20 infants who had received physical activity versus control tactile stimulation during initial hospitalization reported on whole body bone mineral content and whole body bone area at 12 months corrected age as measured by DEXA. No difference in whole body bone mineral content (MD ‐17.30 g, 95% CI ‐68.95 to 34.35) or whole body bone area (MD ‐21.00 cm2, 95% CI ‐85.60 to 43.60) was noted.
Fractures
One trial (Chen 2010) with 16 participants reported that no fractures occurred in treatment and control groups.
Somatic growth
At completion of the physical activity program
Litmanovitz 2007 (N = 16; duration of exercise eight weeks) and Tosun 2011 (N = 40; duration of exercise four weeks) did not find a significant effect of physical activity on body weight, body length, and head circumference in infants enrolled within the first week of life. Similarly, additional information from the authors of Chen 2010 (N = 16; duration of exercise four weeks) suggested no significant effect of physical activity on body weight in infants enrolled within the second week of life.
Body weight gain during study period (Outcome 1.6; Figure 4)
Six trials (Eliakim 2002; Moyer‐Mileur 1995; Moyer‐Mileur 2000; Moyer‐Mileur 2008; Nemet 2002; Vignochi 2008) with a combined total of 164 infants reported a significant effect of physical activity on weight gain during the study period. Because of lack of data, pooling of results was possible for only four trials (Eliakim 2002; Moyer‐Mileur 1995; Moyer‐Mileur 2000; Moyer‐Mileur 2008) incorporating 111 infants. Meta‐analysis showed a significant effect of physical activity on daily weight gain (WMD 2.21 g/kg/d, 95% CI 1.23 to 3.19).
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).
Forest plot of comparison: 1 Physical activity program versus control, outcome: 1.7 Body length gain during study period (cm/wk).
Forest plot of comparison: 1 Physical activity program versus control, outcome: 1.8 Head circumference gain during study period (cm/wk).
At discharge
Not reported in any of the trials.
At term
Not reported in any of the trials.
At 12 to 24 months corrected age
Body weight at 12 months corrected age (Outcome 1.9)
Only the trial by Moyer‐Mileur 2000a (N = 20; physical activity vs tactile stimulation during initial hospitalization) reported on body weight at 12 months corrected age. No significant effect of physical activity on body weight was noted at 12 months corrected age (MD 200.00 g, 95% CI ‐799.39 to 1199.39).
Secondary outcomes
Only Chen 2010 (N = 16; physical activity vs tactile stimulation for four weeks) reported typical complications of preterm birth. No difference in retinopathy of prematurity, intraventricular hemorrhage, sepsis during hospitalization, oxygen dependency at 36 weeks postmenstrual age, and duration of hospital stay between physical activity and control groups was noted. None of the included trials reported on adverse effects of the interventions, skeletal deformities, or long‐term neurodevelopmental impairment.
Subgroup analyses
Preplanned subgroup analyses based on birth weight and calcium/phosphorus supplementation could not be performed because data were inadequate or were lacking.
Discussion
Analysis of eleven small randomized trials indicates that daily physical activity programs of five to 15 minutes per day administered for three and one‐half to eight weeks during initial hospitalization might promote gains in body weight and body length, while improving bone mineralization in the short term, in healthy preterm infants (gestation 26 to 34 weeks) on full enteral feeds of fortified breast milk and/or preterm formula. The effects seem to be limited to the first few months of life and seem to be more consistent if given 15 minutes daily rather than five minutes daily. No trials have reported on adverse effects, skeletal deformities, or long‐term neurodevelopment.
Most included studies examined preterm infants of several weeks postnatal age who were not small for gestation, had no congenital abnormalities, and were medically stable and on full enteral feeds (at least 100 kcal/kg/d). All trials involved interventions based on the Moyer‐Mileur protocol (Moyer‐Mileur 1995), and several trials reported beneficial effects of physical activity versus tactile stimulation or no stimulation on short‐term growth. Additionally, some studies suggested improved short‐term bone mineralization. The effect on growth is somewhat surprising, given that all studies reporting on weight gain during the study period showed similar nutritional intake (calories, protein, calcium, phosphate) in treatment and control groups. Enhanced bone and fat free mass (Moyer‐Mileur 2000; Moyer‐Mileur 2008; Vignochi 2008), as well as changes in growth hormones leading to an anabolic situation, as evidenced by a trend toward greater insulin‐like growth factor concentrations in the physical activity group (Eliakim 2002), could explain these findings. Short‐term growth however was not improved when physical activity programs were started within the first two weeks of life (Chen 2010; Litmanovitz 2007;Tosun 2011). Four trials reported moderate short‐term benefits for bone mineralization, but none of these studies assessed long‐term effects of physical activity. Only one small trial with low statistical power assessed secondary outcomes of this review and reported no effect of physical activity on fractures, complications of preterm birth, and duration of hospital stay (Chen 2010). Statistically significant heterogeneity was noted on meta‐analysis of four trials (Moyer‐Mileur 1995; Moyer‐Mileur 2000; Moyer‐Mileur 2008;Vignochi 2008) assessing the effects of physical activity on body length (Outcome 1.7). Possible reasons for heterogeneity might be differences between studies in methodology for obtaining body length measurements and the general difficulty involved in obtaining accurate measurements of body length in preterm infants. Reproducibility of crown‐heel length measurements obtained by conventional methods (eg, tape measurement, pencil marks made on a paper barrier) is low in newborn infants (Rosenberg 1992). Hence, specific devices are required for accurate measurements in preterm infants (Lawn 2004). No other reasons for explaining this heterogeneity could be identified.
The results of this review need to be interpreted with great caution, given the considerable methodological limitations of most included trials. Although most trials were published several years after the first CONSORT statement (Begg 1996), the quality of reporting was limited. Recruitment bias cannot be excluded because most of the trials did not provide a participant flow chart or numbers of eligible patients in relation to enrolled, evaluated, and "lost to follow‐up" participants. Only one trial clearly explained concealment of participant allocation and method of randomization (Moyer‐Mileur 2008). Several trials (Eliakim 2002; Litmanovitz 2003; Moyer‐Mileur 1995; Nemet 2002) reported that infants were "matched for gestational age, birth weight, gender, corrected age, and weight at start of the study and were then randomized to either treatment or control group" without further explanation. Given the small sample size (N = 16 to 50) and the identical numbers of infants in treatment and control groups in nine of eleven trials, the quality and adequacy of randomization in most of the included trials should be questioned. However, concealment of participant allocation seems to be adequate in Moyer‐Mileur 1995, Moyer‐Mileur 2000, and Moyer‐Mileur 2008, based on comments from the study authors. None of the trials attempted blinding of the intervention. Follow‐up was incomplete in the largest studies included in this review (Moyer‐Mileur 1995, N = 49, follow‐up rate 55%; Moyer‐Mileur 2008, N = 50, follow‐up rate 66%) and was impossible to assess because of lack of data in the only study reporting on long‐term effects (Moyer‐Mileur 2000a). Apart from the evaluation of bone mineralization in Moyer‐Mileur 1995, Moyer‐Mileur 2000, Moyer‐Mileur 2008, and Vignochi 2008, assessments of outcomes relevant to this review most likely were not robustly blinded in any of the trials. Lack of statistically significant heterogeneity in most meta‐analyses in this review does not exclude heterogeneity, given the small numbers. In relation to the clinical relevance of the results, it is important to realize that the baseline risk of osteopenia in most participants was not high, given their gestation and birth weight. Thus, the validity and general applicability of these results are limited. Additionally, the clinical significance of unintentional neonatal physical activities (bathing, changing nappies, skin care) in relation to structured physical activity programs of five to 15 minutes per day remains unclear.
Forest plot of comparison: 1 Physical activity program versus control, outcome: 1.1 Bone area at completion of the physical activity program.
Forest plot of comparison: 1 Physical activity program versus control, outcome: 1.2 Bone mineral content at completion of the physical activity program.
Forest plot of comparison: 1 Physical activity program versus control, outcome: 1.3 Bone mineral density at completion of the physical activity program.
Forest plot of comparison: 1 Physical activity program versus control, outcome: 1.6 Body weight gain during study period (g/kg/d).
Forest plot of comparison: 1 Physical activity program versus control, outcome: 1.7 Body length gain during study period (cm/wk).
Forest plot of comparison: 1 Physical activity program versus control, outcome: 1.8 Head circumference gain during study period (cm/wk).
Comparison 1 Physical activity program versus control, Outcome 1 Bone area at completion of the physical activity program.
Comparison 1 Physical activity program versus control, Outcome 2 Bone mineral content at completion of the physical activity program.
Comparison 1 Physical activity program versus control, Outcome 3 Bone mineral density at completion of the physical activity program.
Comparison 1 Physical activity program versus control, Outcome 4 Bone mineral content at 12 months corrected age (g).
Comparison 1 Physical activity program versus control, Outcome 5 Bone area at 12 months corrected age (cm2).
Comparison 1 Physical activity program versus control, Outcome 6 Body weight gain during study period (g/kg/d).
Comparison 1 Physical activity program versus control, Outcome 7 Body length gain during study period (cm/wk).
Comparison 1 Physical activity program versus control, Outcome 8 Head circumference gain during study period (cm/wk).
Comparison 1 Physical activity program versus control, Outcome 9 Body weight at 12 months corrected age (g).
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Bone area at completion of the physical activity program Show forest plot | 3 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.1 Forearm bone area at completion of the physical activity program (cm2) | 2 | 65 | Mean Difference (IV, Fixed, 95% CI) | 1.38 [0.70, 2.07] |
| 1.2 Whole body bone area at completion of the physical activity program (cm2) | 1 | 29 | Mean Difference (IV, Fixed, 95% CI) | 8.03 [4.05, 12.01] |
| 2 Bone mineral content at completion of the physical activity program Show forest plot | 4 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 2.1 Radial bone mineral content (mg/cm) measured by single photon absorptiometry (SPA) | 1 | 23 | Mean Difference (IV, Fixed, 95% CI) | 10.60 [1.60, 19.60] |
| 2.2 Forearm bone mineral content (mg) measured by dual‐energy x‐ray absorptiometry (DEXA) | 2 | 65 | Mean Difference (IV, Fixed, 95% CI) | 130.91 [55.35, 206.47] |
| 2.3 Whole body bone mineral content (mg) measured by dual‐energy x‐ray absorptiometry (DEXA) | 1 | 29 | Mean Difference (IV, Fixed, 95% CI) | 389.1 [229.98, 548.22] |
| 3 Bone mineral density at completion of the physical activity program Show forest plot | 4 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 3.1 Radial bone mineral density (mg/cm2) measured by single photon absorptiometry (SPA) | 1 | 23 | Mean Difference (IV, Fixed, 95% CI) | 29.0 [‐1.48, 59.48] |
| 3.2 Forearm bone mineral density (mg/cm2) measured by dual‐energy x‐ray absorptiometry (DEXA) | 2 | 65 | Mean Difference (IV, Fixed, 95% CI) | ‐0.19 [‐0.39, 0.01] |
| 3.3 Whole body bone mineral density (mg/cm2) measured by dual‐energy x‐ray absorptiometry (DEXA) | 1 | 29 | Mean Difference (IV, Fixed, 95% CI) | 10.10 [5.27, 14.93] |
| 4 Bone mineral content at 12 months corrected age (g) Show forest plot | 1 | 20 | Mean Difference (IV, Fixed, 95% CI) | ‐17.30 [‐68.95, 34.35] |
| 5 Bone area at 12 months corrected age (cm2) Show forest plot | 1 | 20 | Mean Difference (IV, Fixed, 95% CI) | ‐21.0 [‐85.60, 43.60] |
| 6 Body weight gain during study period (g/kg/d) Show forest plot | 4 | 111 | Mean Difference (IV, Fixed, 95% CI) | 2.21 [1.23, 3.19] |
| 7 Body length gain during study period (cm/wk) Show forest plot | 4 | 120 | Mean Difference (IV, Fixed, 95% CI) | 0.12 [0.01, 0.24] |
| 8 Head circumference gain during study period (cm/wk) Show forest plot | 3 | 91 | Mean Difference (IV, Fixed, 95% CI) | ‐0.03 [‐0.14, 0.08] |
| 9 Body weight at 12 months corrected age (g) Show forest plot | 1 | 20 | Mean Difference (IV, Fixed, 95% CI) | 200.0 [‐799.39, 1199.39] |
