Recombinant Human Growth Hormone in the Treatment of Patients With Cystic Fibrosis
CONTEXT: Recombinant human growth hormone (rhGH) improves growth in patients with growth hormone deficiency or idiopathic short stature. Its role in patients with cystic fibrosis (CF) is unclear.
OBJECTIVE: To review the effectiveness of rhGH in the treatment of patients with CF.
METHODS: Medline and the Cochrane Central Register of Controlled Trials were searched from the earliest date through April 2010. Randomized controlled trials, observational studies, systematic reviews/meta-analyses, or case reports were included if rhGH therapy was administered to patients with CF and data on prespecified harms, intermediate outcomes, or final health outcomes were reported. When applicable, end points were pooled by using a random-effects model. The overall body of evidence was graded for each outcome as insufficient, low, moderate, or high.
RESULTS: Ten unique controlled trials (n = 312) and 8 observational studies (n = 58) were included. On quantitative synthesis of controlled trials, several markers of pulmonary function, anthropometrics, and bone mineralization were significantly improved versus control. Results of single-arm observational studies for the aforementioned outcomes were generally supportive of findings in clinical trials. There is insufficient evidence to determine the effect of rhGH on intravenous antibiotic use during therapy, pulmonary exacerbations, health-related quality-of-life, bone consequences, or total mortality, but moderate evidence suggests that rhGH therapy reduces the rate of hospitalization versus control.
CONCLUSIONS: rhGH improved almost all intermediate measures of pulmonary function, height, and weight in patients with CF. Improvements in bone mineral content are also promising. However, with the exception of hospitalizations, the benefits on final health outcomes cannot be directly determined at this time.
Cystic fibrosis (CF) is a life-shortening, childhood-onset genetic disease that affects ∼30 000 people in the United States.1,2 The gene responsible for CF encodes the CF transmembrane regulator protein, which regulates sodium and chloride transport across epithelial membranes. This affects nearly all exocrine glands and produces abnormally viscous mucus and excessive secretions. The dominant clinical features are chronic lung disease and pancreatic insufficiency with poor nutrition and growth.3,4
Treatment advances in CF over the past 25 years have improved measures of nutrition, pulmonary function, and mortality. The median age of survival has improved consistently from 1955 to the most recent data in 2008.2
Growth and nutritional indices (weight for age, height for age, and percent ideal body weight [IBW]) may be predictive of future pulmonary function in children with CF. It has been suggested that improvement of linear growth in children with CF may allow more lung mass and better pulmonary function independent of improved weight gain. Poor weight and shorter height have each been shown to be independently associated with increased morbidity and mortality in patients with CF in some studies.5,–,9
Recombinant human growth hormone (rhGH) is an anabolic agent with a wide variety of actions. Some of the indications for which it is approved by the US Food and Drug Administration include the treatment of growth hormone deficiency, idiopathic short stature, Turner syndrome, Prader-Willi syndrome, and chronic renal insufficiency and for children who are small for gestational age.10 It has been investigated for the treatment of patients with CF because of their decreased growth measures and increased energy expenditures. We aimed to review the effectiveness of rhGH in patients with CF on various intermediate and final health outcomes.
We developed and followed a standard protocol for all steps of this review. A technical report that details methods, including literature search strategies and analysis plans, and includes evidence tables is available at www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productid=391.
We refined key questions on the effectiveness of rhGH in patients with CF and obtained input from a key informant panel that included a pediatric endocrinologist, pediatric pulmonologist, pediatric pharmacist, nutritionist, and a managed care organization representative (see “Acknowledgments”). The following key questions were formulated.
In patients with CF, does treatment with rhGH as an adjuvant to usual care improve intermediate outcomes including pulmonary function, growth, exercise tolerance, and bone mineralization compared with usual care alone?
In patients with CF, does treatment with rhGH as an adjuvant to usual care improve health outcomes including frequency of required intravenous antibiotic treatments, frequency of hospitalization, quality of life, bone fracture or development of osteoporosis/osteopenia, or mortality compared with usual care alone?
In patients with CF, what is the frequency of nonmalignant serious adverse effects that result from treatment with rhGH?
In patients with CF, how are efficacy, effectiveness, safety, and adverse events affected by rhGH dose, therapy duration, baseline nutritional status, and concurrent medical therapies?
In patients with CF, how do the efficacy, effectiveness, safety, and adverse events of treatment with rhGH differ between subgroups of patients?
Data Sources and Searches
Two independent investigators conducted systematic literature searches of Medline (starting from 1950), the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews from the earliest possible date through April 2010 to identify trials and studies that explicitly evaluated the impact of rhGH on outcomes in patients with CF. A manual search of references from reports of clinical trials or review articles was conducted. We contacted authors of controlled studies to obtain information on end points not reported in the published articles, and we received a response from 1 of them.
Two independent reviewers assessed studies for inclusion. Studies were included if (1) they were studies of rhGH therapy, (2) they were conducted on patients with CF, (3) data on prespecified clinical or humanistic outcomes were reported, and (4) they were reports of new discovery (specifically, randomized controlled trials, observational trials, systematic reviews/meta-analyses, or case reports).
Data Extraction and Quality Assessment
Through the use of a standardized data-abstraction tool, 2 reviewers independently collected data, and disagreement was resolved through discussion. The following information was obtained from each trial when applicable: author identification; year of publication; source of study funding; study-design characteristics and methodologic quality criteria; study population; patient baseline characteristics; comorbidities; and use of concurrent standard medical therapies. End points included pulmonary function, anthropometrics, exercise tolerance, intravenous antibiotic use, hospitalizations, health-related quality of life (HRQoL), bone mineralization, bone fracture or development of osteoporosis/osteopenia, mortality, glucose measures, and development of diabetes or malignancy.
Validity assessment was performed by using the recommendations in the Evidence-Based Practice Center Methods Guide.11 Each study was assessed for the following individual criteria: comparable study groups at baseline; detailed description of study outcomes; blinding of subjects; blinding of outcome assessors; intent-to-treat analysis; description of participant withdrawals; and potential conflict of interest. In addition, randomized controlled trials were assessed for randomization technique and allocation concealment. Observational studies were assessed for sample size, participant-selection method, exposure measurement method, potential design biases, and appropriate analyses to control for confounding. Studies were then given an overall score of good, fair, or poor. This rating system does not assess the comparative validity across different types of study design. For example, a “fair” controlled trial is not judged to have the same methodologic criteria as a “fair” single-arm observational study. Both study design and quality rating should be considered when interpreting a study.
We used the Evidence-Based Practice Center methodology for grading, which is based on the criteria and methods of GRADE (Grading of Recommendations Assessment, Development, and Evaluation) to assess the strength of evidence. This system uses 4 required domains: risk of bias; consistency; directness; and precision.11 All assessments were made by 2 investigators, and disagreements were resolved through discussion. The evidence pertaining to each key question was classified into 1 of 4 broad categories (“high,” “moderate,” “low,” or “insufficient”) that describe the degree of confidence that the evidence reflects the true effect and the potential for further research to change the confidence in the estimate of effect.11
Data Synthesis and Analysis
When sufficient data were available, outcomes were meta-analyzed. Randomized controlled trials and prospective cohort studies were pooled together when trials compared an rhGH group to a control group, henceforth described as controlled trials. Single-arm observational studies were described qualitatively in all cases.
When pooling continuous end points, a weighted mean difference was calculated by using a DerSimonian and Laird random-effects model. In cases for which mean change scores from baseline for each group were not reported, we calculated the difference between the mean baseline and mean follow-up scores for each group. SDs of the change scores were calculated by using the method proposed by Follman et al.13 In the event that there was more than 1 treatment group versus control, each treatment group was treated as a separate trial for meta-analysis by dividing the control group equally between the treatment groups. For dichotomous end points, weighted averages were reported as relative risks with associated 95% confidence intervals and pooled by using a DerSimonian and Laird random-effects model.
Statistical heterogeneity was evaluated by using the I2 statistic, which assesses the degree of inconsistency not due to chance across studies and ranges from 0% to 100%; values of 25%, 50%, and 75% represent low, medium, and high statistical heterogeneity, respectively. Visual inspection of funnel plots and Egger's weighted regression statistics were used to assess for the presence of publication bias.
Statistics were calculated by using StatsDirect 2.4.6 statistical software (StatsDirect Ltd, Cheshire, England). A P value of <.05 was considered statistically significant for all analyses.
Study Identification and Characteristics
After conducting the literature search to identify articles in which the use of rhGH in populations with CF were evaluated, we retrieved 46 unique citations, and another citation was identified from other sources (Fig 1). Eighteen articles were excluded during the title and abstract review, and 2 articles were excluded during the full-text review. A total of 26 articles matched our inclusion criteria (Tables 1 and 2).
Eighteen publications of controlled trials, which represent 10 unique trials (n = 312), met our inclusion criteria.3,14,–,38 Of the 10 trials, 8 trials compared rhGH to no treatment,14,–,17,23,–,26 1 trial used a placebo control,3 and 1 trial compared rhGH alone to either glutamine or the combination of glutamine and rhGH.20 A crossover design was used in 2 trials,16,20 whereas the others used a parallel study design.3,14,15,17,23,–,26 Only 1 trial was double-blinded.3 Four trials received funding from foundations or government,14,–,16,26 8 trials received funding from industry,3,14,15,17,20,23,25,26 and a funding source was not reported for 2 of the trials.24,30 Four of the aforementioned trials received both industry and foundation funding to conduct their studies.14,–,16,20,23
In 1 of the 10 trials patients were treated with rhGH for 4 weeks,20 whereas in the other trials patients were treated for 6 months to 1 year.3,14,–,17,23,–,26 Chronological age of the patients was up to 23 years, but 6 trials specifically evaluated prepubertal children,14,–,16,20,23,–,26 and 1 study evaluated only pubertal adolescents.24 Doses of rhGH ranged from 0.23 to 0.49 mg/kg per week, and the typical dose was 0.3 mg/kg per week.14,15,23,–,26 One trial evaluated 2 doses of rhGH compared with placebo.3 Males constituted at least half of the patients in the trials, ranging from 50% to 83% of the total number of subjects.
Single-Arm Observational Studies
Eight single-arm observational reports (n = 58) evaluated the use of rhGH in patients with CF. Three were case reports,31,37,38 of which 1 was of a patient with growth hormone deficiency and short stature,31 1 was of a patient who had previously undergone lung transplantation,37 and another was of 2 patients with CF-related liver dysfunction.38 One study was funded by a foundation grant,31 4 studies were funded by industry,32,–,34,36 and 3 did not report their sources of funding.35,37,38
The duration of treatment with rhGH ranged from 6 months to 3 years. Ages of the patients in the studies ranged from 6 months to 13 years,31,–,36,38 with the exception of 1 case report of a patient aged 18 years.37 Doses of rhGH in the studies ranged from 0.16 to 0.35 mg/kg per week,32,33,35,36,38 with the exception of 1 case report in which the dose was 2.2 mg/day.37 Two studies did not report the dose of rhGH.31,34 Baseline measures of height and weight were inconsistently reported among the observational studies, but all patients had deficient height and weight for their age.31,–,38
A summary of the results for all key questions of both qualitative and quantitative synthesis and strength of evidence is listed in Table 3. Forest plots of pooled analyses are available at www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports?pageaction=displayproduct&productid=391.
Key Question 1
Five markers of pulmonary function were evaluated in patients with CF who were receiving rhGH therapy. In controlled trials, the forced vital capacity (FVC) and percent predicted FVC significantly increased from baseline in trials that compared patients with CF who were receiving chronic rhGH therapy to control therapy. Results of single-arm observational studies support these findings. In controlled trials, the forced expiratory volume in 1 second (FEV1) significantly increased from baseline in patients with CF who received chronic rhGH therapy versus control therapy, and the percent predicted FEV1 showed no effect versus control. Results of single-arm observational studies support the FEV1 findings, but the percent predicted FEV1 findings have been mixed. In the 1 available controlled trial, no change in FEV1z score occurred in patients who received rhGH for CF versus placebo therapy, and no observational studies evaluated this parameter.
In controlled trials suitable for pooling, significant improvements in height were observed for patients with CF who received rhGH therapy versus control therapy as measured by the change in height, height velocity, and height z score. Results of observational studies or other trials not suitable for pooling support these findings. In 1 trial, the rhGH group experienced significant improvement from baseline in height percentile (baseline: 7.5 ± 1.2; 12 months: 20.0 ± 1.4; P = .032) but there were no significant changes in the control group (baseline: not reported; 12 months: 7.8 ± 1.6; P = .64).14
In controlled trials, significant improvements in weight were observed for patients with CF who received rhGH therapy versus control therapy as measured by change in weight, weight velocity, BMI, percent IBW, and lean body mass (LBM). Patients who received rhGH therapy had a trend toward a higher weight z score but did not have a higher BMI z score than those who received control therapy. In 1 trial, the rhGH group experienced a significant improvement in weight percentile (baseline: 4.0 ± 1.5; 12 months: 9.0 ± 1.3; P = .042), but there were no significant changes in the control group (baseline: not reported; 12 months: 3.5 ± 1.9; P value not reported).14 Results of observational studies in which change in weight, weight velocity, and weight z score were evaluated were generally supportive of improvements associated with rhGH therapy, although the results of 1 crossover trial not amenable for pooling did not show any improvement in LBM for patients who received rhGH compared with those who received glutamine therapy.
In controlled trials and single-arm observational studies, treating patients with rhGH therapy does not improve bone age in patients with CF. However, bone mineral content (BMC) does significantly improve with rhGH therapy in trials, and BMC z score was also improved in the 1 trial in which it was assessed. At baseline, BMC z scores were −2.1 ± 0.6 in the rhGH group compared with −1.7 ± 0.9 in the control group; at 12 months, the rhGH group had a value of −1.4 ± 0.8 vs −1.7 ± 0.8 in controls.26 The rhGH group had a statistically significant increase in BMC z score from baseline compared with controls (P = .001).
rhGH therapy in patients with CF does not seem to improve sexual maturation in boys, and the impact in girls cannot be determined at this time. Controlled trials were not amenable to pooling, and no single-arm observational data were available. In 5 controlled trials, rhGH therapy did not improve sexual maturation regardless of gender. In 1 controlled trial, mean Tanner stage regardless of gender improved, and in an analysis of 3 controlled trials, rhGH therapy significantly improved sexual maturation in girls but not in boys.
Key Question 2
There is insufficient evidence to determine the effect of rhGH on most final health outcomes. Preliminary data suggest that rhGH may have a benefit on intravenous antibiotic use. However, there is insufficient evidence to determine the effect of rhGH on pulmonary exacerbations, HRQoL, bone consequences, or mortality. There is moderate evidence to suggest that rhGH therapy reduces the rate of hospitalization.
Key Question 3
In 2 controlled trials suitable for pooling therapy with rhGH does not impact glycosylated hemoglobin A1c (A1c) in patients with CF. In patients with CF, rhGH therapy significantly increases fasting blood glucose concentrations in 3 controlled trials but does not significantly alter random, postprandial, and stimulated blood glucose concentrations. Most patients with CF who received rhGH did not develop glucose intolerance or diabetes over the duration studied (6 to 12 months) in 5 controlled trials or 3 single arm observational studies.
In patients with CF who received rhGH, injection-site reactions were a rare and insignificant adverse effect. Patients with CF on rhGH may rarely experience a transient increase in liver transaminase levels. Study withdrawals were rare in trials that evaluated rhGH in patients with CF. These endpoints could not be rated for strength of evidence given the paucity of data available.
Key Question 4
Only 1 trial provided insight into the dose-response nature of rhGH in patients with CF. In that trial, no significant differences were seen between the higher- and lower-dose groups for any evaluated parameter.
Several trials varied in the duration of rhGH therapy, allowing subgroup analysis based on therapy duration (Table 4). Trials with 1 year of rhGH therapy significantly increased percent predicted FVC, absolute FEVI, and height compared to control, while 6 months of rhGH therapy showed no effect. Trials with 1 year of rhGH therapy significantly increased fasting glucose concentrations, while trials of 6 months duration showed no effect.
rhGH has not been studied in patients with CF who have nutritional deficiencies that are not being addressed with enteral nutrition. We cannot determine the benefits of rhGH therapy in patients with unaddressed nutritional deficiencies.
The usage of concurrent medical therapies in patients enrolled in trials that evaluated rhGH therapy was sparingly reported, so the differential effect on rhGH efficacy could not be assessed.
Key Question 5
A patient's age may affect rhGH efficacy, as seen in an individual-patient data-merged analysis and subgroup analysis (Table 5). In an individual-patient data-merged analysis of trials, both prepubertal and adolescent patients had significant improvements in height, weight, LBM, and hospitalizations compared with their respective control populations. Prepubertal patients who received rhGH did not have significant increases in FEV1, and the percent predicted FEV1 was significantly lower than that in prepubertal control patients. In contrast, adolescent patients who received rhGH had significant improvements in FEV1 and percent predicted FEV1 compared with adolescent control patients. In a pooled analysis that should only be viewed as hypothesis-generating, prepubertal patients who received rhGH seemed to derive greater benefits on height than pubertal patients who received rhGH but derived lesser benefits on weight, BMI, and percent IBW. Pubertal patients who received rhGH also seemed to derive greater increases in absolute FVC, FEV1, and BMC but experienced fewer hospitalizations and smaller increases in percent predicted FVC than prepubertal patients.
Although most trials were conducted predominantly in males, the impact of gender on outcomes of rhGH therapy could be qualitatively assessed in 1 pooled analysis. The authors of the analysis did not report P values or whether the comparisons were statistically significant and did not provide patient numbers, which precluded our ability to calculate these P values. In prepubertal patients who did not receive rhGH therapy, no difference in height velocity occurred between the genders in the year before treatment allocation, but girls had greater weight velocity. In pubertal patients who did not receive rhGH therapy, girls had greater height and weight velocity than boys in the year before treatment allocation. In prepubertal patients, the first 6 months of rhGH therapy provided similar increases in height and weight velocity between genders, but in months 6 to 12 girls had greater height velocity whereas boys had greater weight velocity. In pubertal patients, the first 6 months of rhGH therapy provided similar increases in height velocity between genders, but girls had greater increases in weight velocity. In months 6 to 12, the girls had greater height and weight velocities than the boys. The occurrence of adverse effects associated with rhGH therapy in boys and girls was not individually determined.
The impact of baseline clinical status on clinical outcomes of rhGH therapy was assessed in 2 trials. In the first trial, those with a baseline height z score below −2.2 had a similar increase in height z score on rhGH therapy as those with higher baseline z scores. In the second trial, a higher baseline percent predicted FEV1 was positively correlated with the change of weight associated with rhGH therapy. The occurrence of adverse events associated with rhGH therapy in patients with different baseline clinical statuses could not be determined.
rhGH qualitatively improved almost all intermediate measures of pulmonary function, height, and weight in patients with CF. Improvements in BMC are also promising. However, with the exception of hospitalizations, the benefits on final health outcomes cannot be directly determined at this time. When relatively low-dose rhGH therapy is given to patients with CF for 6 to 12 months, it may worsen short-term markers of glucose control but has no effect on A1c.
Although rhGH is a promising therapy for the treatment of CF, there are a number of important research questions that should be answered before its role can truly be discerned. In our analysis, we found improvements in height, weight, BMC, and a few but not all measures of pulmonary function with rhGH therapy, but we do not know if this translates into significantly fewer pulmonary exacerbations or infections, deaths, or bone fractures or if therapy improves HRQoL in a meaningful way. Most of the trials compared rhGH therapy to no therapy rather than to placebo or an active control and did not rigorously assess for harms. Although study results have suggested that the risk of glucose-metabolism problems with rhGH is low (on the basis of A1c concentrations), longer durations of therapy may increase the risk of glucose intolerance more than shorter durations (on the basis of glucose concentrations).
Our systematic review and meta-analysis was limited by the available literature. To date, results of the randomized controlled trial conducted by Stalvey et al30 have not been published, and data are only available in abstract form. We opted to include these valuable data in our analysis because of the small numbers of controlled trials available. Second, we included both randomized controlled trials and observational cohort studies in the category of controlled trials because both sets of studies compared rhGH therapy to a control group. In addition, in their retrospective study report, Hardin et al24 described prospective follow-up methods similar to those seen in randomized controlled trials. In some cases, the extrapolation of numerical data from figures was necessary to report and analyze the data when numerical data were not available either in the article or by contacting the authors. Data were extracted from figures in duplicate after digitally enlarging figures and superimposing gridlines.
The data that linked improvements in pulmonary function with reductions in final health outcomes in patients with CF were most apparent with percent predicted FEV1. However, treatment with rhGH only nonsignificantly increases percent predicted FEV1. In addition, preliminary data suggest that pubertal/adolescent patients may derive more pulmonary benefits from rhGH therapy than prepubertal patients, although there are dissimilar increases in height. This suggests that improvements in pulmonary function may not be tied directly to improvements in height and that the target population for rhGH therapy needs to be refined further.
For patients with osteoporosis but without CF, therapy with bisphosphonates improves bone mineralization and reduces the risk of bone fractures.39 However, sodium fluoride treatment dramatically increases BMC but may not reduce the risk of vertebral fractures and in high doses may increase the risk of nonvertebral fractures.39 As such, it cannot be simply assumed that improvements in bone mineralization derived from rhGH therapy in patients with CF will reduce the risk of bone fractures and complications such as death.39
With the above-mentioned limitations in mind, we propose several avenues for future research. An individual-patient data meta-analysis of completed trials that evaluated rhGH therapy in patients with CF would yield important information if original trial investigators were willing to report on hospitalizations, deaths, or bone fractures. An individual-patient data meta-analysis could allow the determination of the benefits of rhGH therapy in patients with varying levels of nutritional status, pubertal status, age, and concurrent medical therapy, all of which are important unresolved issues. A large, multicenter, randomized, placebo-controlled trial should be conducted to determine the impact of rhGH therapy on hospitalizations, mortality, bone fractures, and HRQoL. Such a trial should be powered and conducted to analyze data in pubertal and prepubertal patients separately. Even if a large multicenter trial is not feasible, we suggest that smaller future trials that evaluate the impact of rhGH in patients with CF be placebo controlled and prospectively collect data on hospitalizations, mortality, bone fractures, and HRQoL and report on their results even if they are not powered to be quantitatively analyzed. Trials with treatment durations of 6 or 12 months or longer would be helpful in subsequently determining the adequate duration of therapy.
This work was funded by the Agency for Healthcare Research and Quality. The funding source provided assistance in formulating the initial study questions and provided copyright release for this article but did not participate in the literature search, data analysis, or interpretation of results.
For their input as technical expert panelists, we thank Dana S. Hardin, MD (Research Institute, Nationwide Children's Hospital, Columbus, OH), Craig D. Lapin, MD (Central Connecticut Cystic Fibrosis Center and Connecticut Children's Medical Center, Hartford, CT), Nancy R. Rodriguez, PhD, RD, CSSD (Department of Nutritional Sciences, University of Connecticut, Storrs, CT), and Jeffrey Casberg, MS, RPh (ConnectiCare, Inc & Affiliates).
- Accepted August 16, 2010.
- Address correspondence to C. Michael White, PharmD, FCP, FCCP, UCONN/Hartford Hospital EPC, 80 Seymour St, HB 13th Floor, Hartford, CT 06102-5037. E-mail:
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
- CF =
- cystic fibrosis •
- IBW =
- ideal body weight •
- rhGH =
- recombinant human growth hormone •
- HRQoL =
- health-related quality of life •
- FVC =
- forced vital capacity •
- FEV1 =
- forced expiratory volume in 1 second •
- BMC =
- bone mineral content •
- A1c =
- glycosylated hemoglobin A1c •
- LBM =
- lean body mass
- 2.↵Cystic Fibrosis Foundation. Cystic Fibrosis Foundation Patient Registry: Annual Data Report 2008. Bethesda, MD; Cystic Fibrosis Foundation: 2009
- Schnabel D,
- Grasemann C,
- Staab D,
- Wollmann H,
- Ratjen F
- Hardin DS
- Ramsey BW,
- Farrell PM,
- Pencharz P
- Stallings VA,
- Stark LJ,
- Robinson KA,
- Feranchak AP,
- Quinton H
- Hardin DS,
- Kemp SF,
- Allen DB
- 11.↵Agency for Healthcare Research and Quality. Methods guide for comparative effectiveness reviews, Rockville, MD: Agency for Healthcare Research and Quality; posted April 2009. Available at: www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productid=318
- 12.GRADE Working Group. Grading quality of evidence and strength of recommendations. BMJ. 2004;328:1490–1494
- Schibler A,
- von der Heiden R,
- Birrer P,
- Mullis PE
- von der Heiden R,
- Kraemer R,
- Birrer P,
- Waldegg G,
- Mullis PE
- Schaeffer D,
- Darmaun D,
- Punati J,
- Mauras N,
- Hayes VY
- Grasemann C,
- Ratjen F,
- Schnabel D,
- Reutershahn E,
- Vester U,
- Grasemann H
- Grasemann H,
- Grasemann C,
- Schnabel D,
- Ratjen F
- Stalvey MS,
- Geller DE,
- Anbar RD,
- Konstan MW,
- Jacobs JR,
- Bakker PJ
- Copyright © 2010 by the American Academy of Pediatrics