Treatment of closed femoral shaft fractures in children aged 2–10 years: a systematic review and meta-analysis

Objective To review current literature on treatment of closed femoral shaft fractures in children of 2–10 years old, with subgroup analysis of children aged 2–6 years, comparing intramedullary nailing (IMN) to conservative treatment modalities. Methods We included clinical trials and observational studies that compared traction and subsequent casting (TSC), spica casting and IMN for treatment of femur shaft fractures in children of 2–10 years of age. Subgroup analysis of children aged 2–6 years was performed. Results Compared to treatment with immediate spica casting, IMN led to significantly less coronal angulation (mean difference (MD): 2.03 degrees, confidence interval (CI) 1.15–2.90), less sagittal angulation (MD: 1.59 degrees, CI 0.82–2.35) and lower rates of LLD (Risk difference (RD): 0.07, CI 0.03–0.11). In terms of rehabilitation, IMN leaded to shorter time until walking with aids (MD: 31.53 days, CI 16.02–47.03), shorter time until independent ambulation (MD: 26.59 days, CI 22.07, 31.11) and shorter time until full weight bearing (MD: 27.05 days, CI 6.11, 47,99). Compared to TSC, IMN led to a lower rate of malunion (RD: 0.31, CI 0.05–0.56), shorter hospital stays (MD: 12.48 days, CI 11.57, 13.39), time until walking with aids (MD: 54.55, CI 40.05–69.04) and full weight bearing (MD: 27.05 days [6.11, 47,99]). Conclusion Although a lack of quality evidence, this systematic review showed a clear tendency to treatment with elastic intramedullary nails of femoral shaft fractures in children of 2–10 years of age. Level of evidence 3.


Introduction
Despite a multitude of treatment options being available, femoral shaft fractures in children continue to pose a challenge to trauma and orthopedic surgeons. These fractures are only seen in 1.4% [1] to 1.7% [2] of all pediatric fractures, and usually lead to lengthy hospitalization, prolonged periods of disability and may cause asymmetry in skeletal growth [3,4].
A multitude of treatment options have been described for these fractures. Both conservative options such as traction and spica casting and surgical options as elastic intramedullary nailing, plate fixation or a lateral femoral nail are used in daily practice. According to current consensus guidelines, treatment should differ according to age; younger children are advised to be treated with traction and/or spica cast while surgical intervention is preferred in older children [5,6]. Although the choice of treatment method in pediatric femur fractures in all age groups can be challenging, this is particularly difficult in children between 2 and 10 years of age: no consensus exists on whether conservative or surgical treatment is the best option for this particular age group.
We hypothesized that intramedullary nails (IMN) may be the superior treatment option for children aged 2-10 years. Therefore, this systematic review aims to critically appraise the current literature on treatment of femoral shaft fractures in children of 2-10 years old and to perform subgroup analysis for children of 2-6 years old.

Methods
This study was conducted by following the PRISMA guidelines. This review did not require approval from the independent ethics committee or institutional review board of the participating institutions.

Search strategy and selection criteria
To identify relevant literature on the treatment of pediatric femoral shaft fractures, we performed a systematic literature search on Pubmed, Embase and Cochrane. Databases were searched from inception to August 15th, 2020. As most common treatment modalities, we included traction with and without subsequent spica casting, immediate spica casting and intramedullary nailing. In the final search, the following keywords and their synonyms were used: "femoral shaft fractures", "pediatric", "conservative", "cast", "traction" and "intramedullary nail" A complete clinical query and search are depicted in Tables 1, 2. Our search strategy was finetuned with backward reference searching.
Three independent reviewers screened title and abstract using Rayyan QCRI. Subsequently, they screened full texts of selected articles. All articles on pediatric femoral shaft fractures comparing two or more treatments were potentially eligible. We included studies with a sample size with a mean age within 2-10 years. Randomized controlled trials (RCTs), cohort studies and observational studies were included. Reviews, case reports, comments and letters were excluded. Articles on treatment of open femur fractures were excluded. Also, articles with a follow-up of less than 3 months were excluded. Other exclusion criteria were absence of reported outcome or irrelevant outcome measures and non-English articles. Finally, articles selected for the systematic review were assessed for eligibility for the meta-analysis. Disagreements were resolved through discussion and decided on by the third reviewer.

Data extraction
Data extraction was performed independently by three reviewers with the use of a predefined data extraction form. The following characteristics were extracted from the included studies: first author, year of publication, study design, number of included patients, length of followup, included age groups and relevant outcomes. Studies

Measurement of treatment outcome
The outcomes of interest were pre-determined, decided on by the senior author. Primary treatment outcomes were divided in radiological outcome and rehabilitation. Radiological outcome was assessed in terms of malunion (rate), angulation (degrees) and leg length discrepancy or shortening (cms). Rehabilitation was assessed in terms of length of hospital stay, time until walking with aids, time until independent ambulation and time until full weight bearing. Secondary treatment outcomes were complication rate and quality of life (QoL). Before data extraction, possible complications were categorized into mild and severe complications. Mild complications were defined as those that did not require operative treatment and would not cause future disability. Major complications were defined as those that led to unscheduled operative treatment, prolonged morbidity and/ or disability. When the severity of a documented complication was unclear, it was decided upon through discussion. Regarding QoL, available literature was screened, but a lack of QoL specific outcome measures was noted. To still gain some insight in patient experience after treatment, we used patient/parent satisfaction as best available measure.

Quality assessment
Risk of bias assessment was performed at study level, using The Cochrane Risk of Bias tool (RoB) for the assessment of risk of bias of randomized controlled trials. For observational studies a modification of this tool was used, in which comparability of baseline characteristics and concurrency of cohorts were added to the assessment. We assessed quality of evidence of the RCTs using the GRADE tool.

Statistical analysis
Data were analyzed in October, 2020. As principle summary measures, mean differences (MD) were calculated for continuous outcomes and risk difference (RD) for dichotomous outcomes. When sufficient data were available confidence intervals were calculated. When SDs were missing they were calculated by use of the Cochrane SD calculator. All analyses were performed using random-effects models. We assessed statistical heterogeneity between studies by visual inspection of forest plots and I 2 tests. The significance level for treatment effects was determined by the overall-effect z test. Potential publication bias was assessed by visual assessment of funnel plots. When both RCTs and observational studies were identified, the authors performed subgroup analysis and presented both results of the pooled RCTs and total results. Moreover, subgroup analysis was performed on children of 2-6 years of age whenever a minimum of two studies investigated an outcome in this age group. For these analyses, suitable sample sizes were defined as those with a mean age of in between 3 and 5 years. Statistical analyses were performed using Review Manager (RevMan 5).

Results
A total of 2828 potentially relevant unique articles were retrieved and assessed for eligibility. Based on screening of titles and abstracts, 73 published studies were selected. No additional records were identified after backwards reference searching. The full text of the selected 73 articles was read for further selection. 52 articles were excluded, based

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on inappropriate study population, primary outcomes, study design, publication type or language. A total of 21 articles reporting on 1675 patients met all inclusion criteria and were finally included in this meta-analysis. Figure 1 presents a flow diagram depicting the stages of study selection and reasons for exclusion.

Immediate spica cast versus intramedullary nail
Our search found seven unique articles that compared immediate casting and intramedullary nails (IMN) as treatment for femoral shaft fractures (Table 3). One article was an RCT [7] one article was a quasi-prospective comparative study   [8] and five studies were retrospective comparative studies [9][10][11][12][13].

RCT and quality of evidence
In their RCT, Ruhallah et al. [7] investigated the age group of 3-12 years old and compared treatment with Rush pins with immediate spica casting. The trial was at some risk of bias (Figs. 2, 3). Quality of evidence was assessed by use of the GRADE tool. As this was the only RCT that investigated these two interventions and its low-to-moderate risk of bias, the quality of evidence based on this RCT was estimated to be 'very low'.

Observational studies
Seven observational studies were assessed for risk of bias (Figs. 2, 3). One study was at lower risk of bias [11]. The remaining articles [8-10, 12, 13] were all assessed to have a high risk of bias.

Radiological outcome
In the RCT of Ruhallah et al., radiological outcome was presented by use of Flynn's criteria [14]. In the IMN group, 88% of the fractures recovered with malalignment under 5°, compared to 20% in the cast group. Of the remaining patients treated with spica cast 38% had malalignment of 5-10° and 42% over 10°. In the intramedullary nailing group, 8% had malalignment of 5-10° and 4% over 10°. No measure of dispersion or P value was reported. Four observational studies conveyed malalignment in mean coronal and sagittal angulation, investigating a total of 611 patients. As displayed in Fig. 4 Table 4.
Three other studies reported the occurrence rate of LLD.   (Fig. 8).
In a total of 307 patients in three studies, time until independent ambulation was investigated. Ruhallah et al. found a mean difference of 28.00 days [25.49, 30.51 (Fig. 10). Subgroup analysis of children aged 2-6 years showed a mean difference of 3.35 weeks [− 1.04, 7.73]. There was no visual asymmetry in the funnel plots of reported outcomes, indicating no evidence of publication bias.

Search results
Our search yielded eight unique articles that compared traction and cast with intramedullary nails as treatment for femoral shaft fractures (Table 3). Four articles were RCTs [15][16][17][18], one was a prospective cohort study [19] and three studies were retrospective comparative studies [20][21][22] (Figs. 2, 3). The quality of evidence was assessed by use of the GRADE tool. Because of the risk of bias, the high mean age in all articles and the conflicting results of these studies, quality of evidence was assessed to be 'low'.

Observational studies
Our search yielded four non-RCT's. Because of the observational study design, all studies had a high risk of selection

Radiological outcome
Three studies compared rate of malunion in femoral   There was no visual asymmetry in the funnel plots of these results, indicating no evidence of publication bias.  s results could only be generalized in a resource-limited setting and this did not apply to our research question. Therefore, we were able to include four studies in the analysis. Shemshaki and Soleimanpour had a combined mean difference (IV, Random, 95% CI) of 12.44 days [11.52, 13.36], in favor of IMN. The pooled mean difference (IV, Random, 95% CI) was 12.48 days [11.57, 13.39] in favor of IMN (Fig. 13).
Four studies investigated days until walking with aids. Two RCT's (Shemshaki; Soleimanpour) found superior results for IMN, with a mean difference of 57.29 days [39.26, 75.32]. The pooled mean difference (IV, Random, 95% CI) of the four studies was 54.55 days [40.05, 69.04] (Fig. 14). Five studies reported days until full weight bearing after treatment. However, because Song et al. reported no measure of dispersion, we were able to include four studies in the meta-analysis. Shemshaki [6.11, 47, 99] (Fig. 15).  There was no visual asymmetry in the funnel plots of these outcomes, indicating no evidence of publication bias.

RCT and quality of evidence
Siddiqui et al. investigated the age group of 3-10 years old and compared immediate spica casting to traction with Thomas splint and subsequent casting after 3-4 weeks of soft callus formation.
We assessed the RCT of Siddiqui et al. on risk of bias by use of the Cochrane Risk of Bias tool (Figs. 2, 3). Quality of evidence was assessed by use of the GRADE tool. Reflecting this article to be the only RCT, the mean age in both groups to be higher than 2-6 years old and the moderate risk of bias, the quality of evidence based on this RCT was estimated to be 'very low'.

Observational studies
We yielded four observational studies. All studies were assessed on risk of bias (Figs. 2, 3). Curtis et al. had a relatively low risk of bias, while the other three studies were assessed to have a high risk of bias.

Radiological outcome
Siddiqui et al. published an RCT comparing these two treatments. Results were described as either satisfactory or unsatisfactory. Fractures with shortening of more than 2 cm's, coronal angulation of more than 15 degrees, sagittal angulation of more than 20 degrees or complications needing change in management, were categorized as unsatisfactory. The TSC group scored 5% unsatisfactory outcome compared to 19% in the cast group. In 3 studies, LLD was investigated in a total of 170 patients. The mean difference (IV, Random, 95% CI) was 0.  Fig. 16. There was no visual asymmetry in the funnel plots of reported outcomes, indicating no evidence of publication bias. Three studies included coronal and sagittal   angulation as outcome. In most studies, no mention of dispersion was reported.
The results are displayed in Table 5.

Complications
The major complications in the cast group were loss of reduction [13] and failure of the pin that was used for traction within the cast [25].

Quality of life: patient satisfaction
Four studies investigated patient satisfaction after treatment. Because there was no general assessment method, we were unable to pool results. All studies reported higher patient satisfaction in the IMN groups. Buechsensuetz et al. contacted patients' parents and found that 93% of the IMN group would 'definitely' choose the same treatment again, compared to only 6% of the TSC group (p < 0.001) [22]. Shemshaki et al. found that 100% of parents of IMN patients rated treatment outcome as either 'Good' or 'Excellent', compared to 74.1% of the TSC group (p = 0.003) [16]. Mehdinasab et al. reported that patients who received IMN were more satisfied without a description of assessment methods or further depiction of results [15].
In recent meta-analysis in 2018, Imam et al. compared spica casting to intramedullary nailing and reported a significant statistical difference favoring IMN in terms of duration of hospital stay, time to independent walking and patient satisfaction. Similarly, rates of malunion and angulation and duration of union significantly favored the IMN group. Therefore, they recommended the use of IMN fixation, which is, to some extent, in line with this study's conclusions. However, Imam et al. included children below 16 years old in their review. Moreover, unlike this study, they did not perform subgroup analysis and no distinction between immediate casting and casting after traction was made [29].
From the early 00's onward, significant changes in the approach of femoral shaft fractures have been presented. Particularly in school aged children (6-12 years old), surgical intervention has become the preferred treatment especially because of a short mean hospital stay and early return to daily activities [40]. Among other similar narrative reviews (Gardner [40], Flynn [41]), Heyworth et al. provided a management strategy for pediatric diaphyseal femur shaft fractures in 2012, prescribing immediate spica casting for children of 2-5 years old, and surgical intervention in children of 6-12 years old. Pavlik bandage and traction should be reserved for the youngest children, although traction is recommended as temporary option as well, until definitive treatment follows [39]. These guidelines have been roughly followed in general practice throughout the years. However, in 2019, Alluri et al. identified temporal trends in the management of femoral shaft fractures in 4-and 5-yearold children, finding that between 1997 and 2012, surgical fixation has increased with 35% for 4-year olds and 58% in 5-year olds. They, therefore, stated that the lower age limit for surgical management of these fractures was decreasing [42]. This trend was not supported by available evidence, as in 2014 Madhuri et al. conducted a systematic review comparing all treatment modalities for pediatric femoral shaft fractures. They concluded that based on their analysis, insufficient evidence existed to provide reliable recommendations on the matter [6].
Although studies investigating external fixation were not included in our analysis, there are two systematic reviews [43,44] comparing elastic intramedullary nailing to external fixation for the treatment of pediatric femoral shaft fractures. Both authors concluded that although high-quality studies are limited, IMN leads to fewer complications and is the preferred approach for femoral shaft fractures in children. As plate fixation in general is not considered a treatment modality for this age group, we decided not to include this in our study either. Nevertheless, several studies found that IMN has better outcomes than plate fixation at young age [45][46][47][48][49][50].

Limitations
In the meta-analyses comparing immediate casting and TSC to IMN, heterogeneity was high in several outcomes. Because of this, total mean differences may appear less reliable. However, in none of these outcomes there were conflicting results. Still, those results should be interpreted with caution.
Second, in studies investigating TSC, there was a variety in how long traction was continued until spica cast was applied. In one study, there was no mention of duration of traction [20], and in one study, a cast was applied in the IMN group as well [15]. This might have influenced results.
Another potential limitation is the exclusion of non-English-language studies, which might have caused bias. However, because selection was performed manually instead of by filter, the authors do not expect to have excluded relevant articles.
Cost of treatment was not included as outcome measure. Although a point of interest, the authors believed that only when all other outcomes would be equal, costs should be considered as outcome measure to determine superior treatment.
Lastly, unfortunately, we were not able to distinguish between fracture types in our analysis.
Finally, we acknowledge that a meta-analysis can only be as good as the primary studies that are included in the meta-analysis. The results of this study were limited by the limitations of the single studies. Therefore, we unfortunately were not able to distinguish between fracture types in our analysis. Also, we were unable to pool results regarding quality of life.
Still, this is the most extensive systematic review to date, and the first to compare several types of conservative treatment and surgical treatment of femoral shaft fractures in this specific age group.

Conclusion
Although several studies have been published on the treatment of femoral shaft fractures in children, choice of treatment in children of 2-10 years old can often be challenging. Especially in the age group of 2-6 years old, no consensus on treatment has been reached. This systematic review and meta-analysis revealed a lack of high-quality RCTs on the subject to fill this knowledge gap, but shows a clear tendency to treatment with elastic intramedullary nails, both in general as in 2-6-year olds. While intramedullary nailing requires subsequent implant removal which comes with additional anesthesia and surgery risks, it appears to lead to superior radiological outcomes and significantly faster rehabilitation and ambulation. While in children older than 6 years old, it has been adopted as preferred treatment modality, this review justifies the use of IMN in younger children as well. Nevertheless, to provide a definitive recommendation on future clinical practices, high-quality evidence is necessary.
Funding The authors received no specific funding for this work.

Declarations
Conflict of interest S van Cruchten, EC Warmerdam, DRJ Kempink and VA de Ridder declare that they have no conflicts of interest.
Ethical approval This is a review article. The UMC Utrecht Research Ethics Committee has confirmed that no ethical approval is required.
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