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Short stature is a common concern in pediatrics. Several ambiguities and controversies persist, especially with regard to criteria, cost, medical necessity and outcomes of growth hormone (GH) therapy for idiopathic short stature (ISS). Due to these ambiguities and controversies, a series of decisions by primary care physicians (whether to refer the short child to a pediatric endocrinologist), pediatric endocrinologist (whether to recommend GH treatment), families (whether to raise concern about short stature and whether to agree to undertake treatment), and third party payers (whether to cover the costs of GH therapy) influence which individual short children will receive GH in the US. Together, these decisions determine overall GH use. Apart from child's growth characteristics, several non-physiological factors drive the critical decisions of these stakeholders. This article focuses on current ambiguities and controversies regarding GH therapy in ISS, discusses the decision-makers involved in GH therapy, and explores the factors influencing their decisions.

Objectives: Overall growth hormone (GH) use depends on decisions to both initiate treatment and continue treatment. The determinants of both are unclear. We studied how physicians decided to begin GH in idiopathic short stature and how, after an initial course of treatment, they decided to continue, intensify (increase the dose), or terminate treatment., Methods: We used a national census study of 727 pediatric endocrinologists involving a structured questionnaires with a factorial experimental design. Main outcome measures were GH recommendations for previously untreated children and those children who were treated with GH for 1 year., Results: The response rate was 90%. In previously untreated children, recommendations to initiate GH were consistent with guidelines and also influenced by family preferences and physician attitudes (P<.001). In children treated with GH, recommendations on whether to continue GH were influenced by the growth response to therapy (P<.01) but were divided regarding course of action. With identical growth responses to treatment, physician decisions diverged (intensify versus discontinue GH) and were driven by independent, nonphysiologic, and contextual factors (eg, physician attitudes, family preferences, and GH-initiation recommendation; each P<.001). Together, attitudinal and contextual factors exerted more influence on continuation decisions than did the growth response to therapy., Conclusions: Physician decisions to initiate GH are largely consistent with evidence-based medicine. However, decisions about continuing GH vary and are strongly influenced by factors other than response to treatment. With a potential market of 500 000 US children and costs exceeding $10 billion per year, changes in GH use may depend on potentially modifiable physician attitudes and family preferences as much as physiologic evidence.

GH treatment for short children is representative of many frontline issues in health care policy. In this paper, we highlight key policy issues exemplified by GH, focusing on pharmaceutical innovation, insurance coverage and pricing, and physician decisions, and we discuss their implications for endocrinology and GH use.

Background: Candidates for specialty drugs, the fastest growing and costliest pharmaceuticals, typically originate with primary care referrals. However, little is known about what drives such referrals-especially for large populations such as short, otherwise normal children (idiopathic short stature). Recent expanded approval of growth hormone (GH) makes more than 585,000 US children eligible for such treatment, potentially costing over $11 billion/y., Methods: To quantify the relative impact of patient physiological indicators, physician characteristics, and consumer preferences on referrals to endocrinologists (and potential access to GH) for short children, a national study of 1268 randomly selected US pediatricians was conducted, based on a full factorial experimental design in a structured survey., Results: While patient indicators (height, growth pattern) influenced referrals (P < 0.001), consumer drivers (family concern) and physician attitudes had almost as great an impact-especially for children with less severe growth impairment (P < 0.001). Physician belief that short stature impairs emotional well-being and physician characteristics (female, older, shorter, beliefs about drug company information) increased referrals (P < 0.03-0.001)-independent of growth parameters., Conclusions: Referral recommendations that create the pool of candidates for the specialty drug GH are heavily swayed by physician characteristics and consumer preferences, particularly in the absence of compelling physiological evidence. This makes most of children with short stature strikingly susceptible to nonphysiological influences on referrals that render them candidates for this specialty drug. Only 1 additional referral per US pediatrician would likely increase GH costs by over $100 million/y.

Background: Delivery of GH via inhalation is a potential alternative to injection. Previous studies of inhaled GH in adults have demonstrated safety and tolerability., Objective: We sought to assess safety and tolerability of inhaled GH in children and to estimate relative bioavailability and biopotency between inhaled GH and sc GH., Design/methods: This pediatric multicenter, randomized, double-blind, placebo-controlled, crossover trial had two 7-d treatment phases. Patients received inhaled GH and sc GH in the alternate phase. Placebo was administered by the route opposite from active drug. GH and IGF-I levels were measured at multiple time points. Pharmacokinetics were assessed using noncompartmental methods., Results: Twenty-two GH-deficient children aged 6-16 yr were treated. Absorption of GH appeared to be faster after inhalation with maximum serum concentrations measured at 1-4 h compared with 2-8 h for sc GH. Mean relative bioavailability for inhaled GH was 3.5% (90% confidence interval 2.7-4.4%). Mean relative biopotency, based on IGF-I response, was 5.5% (confidence interval 5.2-5.8%). Similar dose-dependent increases in mean serum GH area under the curve and IGF-I changes from baseline were seen after inhaled and sc GH doses. Inhaled GH was well tolerated and preferred to injection. No significant changes in pulmonary function tests were seen., Conclusions: In this first pediatric trial of GH delivered by inhalation, it was well tolerated and resulted in dose-dependent increases in serum GH and IGF-I levels. This study establishes that delivery of GH via the deep lung is feasible in children.

The diagnostic term, idiopathic short stature, has emerged over the past 30 years and refers to children with short stature of unknown etiology. Controversy exists regarding the scope of the diagnosis and options for its treatment. This article reviews origins of the diagnosis idiopathic short stature and current diagnostic criteria, scientific advances in delineating etiologies of idiopathic short stature, management options, and implications of management decisions for child health.

Objective: Intrauterine and neonatal growth failure of very low birth weight (VLBW; <1500 g) infants may influence adult growth attainment and have long-term implications for adult health. As part of a longitudinal study of VLBW infants, we sought to examine gender-specific changes in growth from birth to 20 years old and to identify the correlates of growth attainment at 20 years old., Design, Setting, Participants: A cohort of 103 male and 92 female VLBW infants who had a mean birth weight of 1189 g and mean gestational age of 29.8 weeks, were born from 1977 through 1979 and treated at Rainbow Babies and Children's Hospital in Cleveland, Ohio, and were free of neurosensory impairment were followed prospectively from birth and compared with a population-based sample of 101 male and 107 female normal birth weight (NBW) controls selected at 8 years old. Maternal sociodemographic status and infant birth and neonatal data did not differ significantly between male and female VLBW subjects. However, male VLBW subjects had significantly higher rates of rehospitalization during infancy than female VLBW (39% vs 21%). At 20 years, their rates of chronic illness were similar (18% vs 24%)., Main Outcome Measures: Weight and height z scores were computed at birth, 40 weeks, 8 and 20 months, and 8 and 20 years among the VLBW subjects, and at 8 and 20 years among the NBW controls. Body mass index (BMI) z scores were computed at 8 and 20 years. Among the VLBW subjects, gender-specific longitudinal growth measures were examined at birth, at the expected term date (40 weeks corrected age), and at 8 and 20 months, and 8 and 20 years of age. In addition, we compared the weight, height, and BMI of the VLBW and NBW controls at 8 and 20 years. Predictors of 20-year growth were examined via multivariate analyses., Results: Among the VLBW males, mean weight for age z scores at birth, 40 weeks, and 8 years were -0.7, -1.8, and -0.5; and height for age z scores were -1.2, -2.6, and -0.5, respectively. For VLBW females, mean weight for age z scores were -1.1, -2.0, and -0.2 and height for age z scores were -1.2, -2.4, and -0.2, respectively. At 8 years of age, VLBW males had a significantly lower mean weight, height, and BMI than NBW controls, whereas VLBW females differed significantly from their NBW controls in mean weight and BMI but not in height. Catch-up growth in weight, height, and BMI occurred between 8 and 20 years among VLBW females but not among VLBW males who remained significantly smaller than their controls at 20 years old. At 20 years mean weight of VLBW males was 69 kg versus 80 kg for controls (z score -0.4 vs +0.5); mean height was 174 cm versus 177 cm (z score -0.4 vs +0.03) and mean BMI was 23 versus 26, respectively. For VLBW females, mean weight was 65 kg versus 68 kg for controls (z score +0.3 vs +0.5), mean height was 162 versus 163 cm (z score -0.3 vs -0.1) and mean BMI was 25 versus 25, respectively. Rates of obesity (BMI >30) for VLBW males were 7% compared with 15% for controls and for VLBW females 15% compared with 18% for controls. Age of menarche was 12.4 years for VLBW females and 12.3 years for controls. Nineteen (18%) male and 20 (22%) female VLBW subjects were born small for gestational age (SGA; weight less than -2 standard deviation for gestational age). At 20 years, significantly more SGA than appropriate for gestational age VLBW males remained subnormal (less than -2 standard deviation) in weight (32% vs 6%) and height (21% vs 4%), whereas rates of subnormal growth did not differ significantly between SGA and appropriate for gestational age females (weight 5% vs 1%, height 0% vs 7%). Predictor variables included in the multivariate analyses of 20-year growth attainment were maternal education and height, race, birth weight z score (a measure of intrauterine growth failure), neonatal hospital stay (a measure of neonatal illness), and chronic illness at 20 years. Twenty-year weight was predicted by black race and chronic illness among females. Twenty-year height was predicted by maternal height and birth weight z score among both males and females and by duration of neonatal hospital stay among males only. In a separate model, when we examined the effect of being SGA at birth instead of the effect of birth weight z score, SGA birth was predictive of 20-year height among males but not among females., Conclusions: VLBW females catch up in growth by 20 years of age whereas VLBW males remain significantly shorter and lighter than controls. Since catch-up growth may be associated with metabolic and cardiovascular risk later in life, these findings may have implications for the future adult health of VLBW survivors.

Context: Use of growth hormone (GH) therapy to promote growth in children with idiopathic short stature is controversial. A fundamental issue underlying the controversy is uncertainty about the magnitude of effectiveness of GH for this condition., Objective: To determine the effect of GH on short- and long-term growth in idiopathic short stature., Study Design: Systematic review of controlled and uncontrolled studies., Data Sources: MEDLINE (1985-2000), key journals, cross-referencing of bibliographies, abstract booklets, and experts., Study Selection and Data Extraction: We performed a meta-analysis of all studies satisfying the inclusion criteria for idiopathic short stature: initial height below the 10th percentile, normal stimulated GH levels (>10 microg/L), absence of comorbid conditions, no previous GH therapy, treatment with biosynthetic GH, and inclusion of major outcome measures., Primary Outcome Measures: Growth velocity and height SD score (number of SDs from mean height for age and sex) at baseline and after 1 year to evaluate the short-term effect of GH. Adult height was analyzed to evaluate the long-term effect of GH., Data Synthesis: Ten controlled trials (434 patients) and 28 uncontrolled trials (655 patients) met the inclusion criteria. While baseline growth velocities were equivalent at baseline, 1-year growth velocity of the GH-treated group significantly exceeded that of controls by 2.86 cm/y. Similarly, in uncontrolled trials, growth velocity increased after 1 year, and height SD score increased from -2.72 at baseline to -2.19. In controlled studies, the adult height of the GH-treated group significantly exceeded controls by 0.84 SD, and in uncontrolled trials the adult height attained after GH treatment (-1.62 SDs) exceeded that predicted at baseline (-2.18 SDs). These results suggest an average gain in adult height of approximately 4 to 6 cm (range, 2.3-8.7 cm) with GH therapy. Given current treatment costs, this corresponds to more than $35 000 per inch (2.54 cm) gained in adult height in idiopathic short stature., Conclusions: Treatment with GH results in short-term increases in growth for children with idiopathic short stature, and long-term GH can increase adult height. These results are fundamental to decisions about GH use and raise questions about the goals of treatment. Use of GH for idiopathic short stature in clinical practice will depend on its efficacy in promoting growth and the value of this effect to families, physicians, and third-party payers.

This paper examines the role of parents' attitudes and preferences regarding growth hormone therapy for childhood short stature. Four main questions are addressed. First, what are the demographic characteristics of families seeking medical advice for their child's short stature? Second, what are parents' attitudes towards short stature? Third, what are parents' treatment preferences (i.e. what characteristics of growth treatments are important to parents)? Finally, how do the attitudes of parents affect physician decision making? Several studies are reviewed and data are presented to answer these questions.

Objectives: This study examines two questions that relate to patients' role in medical decision making: (1) Do patients utilize multiple attributes in evaluating different treatment options?, and (2) Do patient treatment preferences evidence heterogeneity and disparate patterns? Although research has examined these questions by using either individual- or aggregate-level approaches, the authors demonstrate an intermediate level approach (ie, relating to patient subgroups)., Methods: The authors utilize growth augmentation therapy (GAT) as a context for analyzing these questions because GAT reflects a class of nonemergency treatments that (1) are based on genetic technology, (2) aim to improve the quality (rather than quantity) of life, and (3) offer useful insights for the patient's role in medical decision making. Using conjoint analysis, a methodology especially suited for the study of patient-consumer preferences but largely unexplored in the medical field, data were obtained from 154 parents for their decision to pursue GAT for their child., Results: In all, six attributes were utilized to study GAT, including risk of long-term side effects (1:10,000 or 1:100,000), certainty of effect (50% or 100% of cases), amount of effect (1-2 inches or 4-5 inches in adult height), out-of-pocket cost ($100, $2,000, or $10,000/year) and child's attitude (likes or not likes therapy). An experimental design using conjoint analysis procedures revealed five preference patterns that reflect clear disparities in the importance that parents attach to the different attributes of growth therapy. These preference patterns are (1) child-focused (23%), (2) risk-conscious (36%), (3) balanced (23%), (4) cost-conscious (14%), and (5) ease-of-use (4%) oriented. Additional tests provided evidence for the validity of these preference patterns. Finally, this preference heterogeneity related systematically to parental characteristics (eg, demographic, psychologic)., Conclusions: The study results offer additional insights into medical decision making with the consumer as the focal point and extend previous work that has tended to emphasize either an individual- or aggregate-based analysis. Implications for researchers and health care delivery in general and growth hormone management in particular are provided.

Context: There is concern in both the medical community and the general public about mechanisms of medical decision making and the interplay of physician and insurer decisions in determining access to care., Objective: To examine the medical process influencing access to growth hormone (GH) therapy for childhood short stature by comparing coverage policies of US insurers with the treatment recommendations of US physicians., Design and Participants: Independent national representative surveys were mailed to insurers (private, Blue Cross/Blue Shield, health maintenance organizations, programs for Children with Special Health Care Needs, and Medicaid programs, n=113), primary care physicians (n=1504), and pediatric endocrinologists (n=534) with response rates of 75%, 60%, and 81%, respectively. Each survey included identical case scenarios. Primary care physicians were asked decisions about referrals to pediatric endocrinologists. Endocrinologists were asked GH treatment recommendations. Insurers were asked coverage decisions for GH therapy., Main Outcome Measures: Insurer coverage decisions for GH in specific case scenarios were compared with the recommendations of primary care physicians and pediatric endocrinologists., Results: Physician recommendations and insurance coverage decisions differed strikingly. For example, while 96% of pediatric endocrinologists recommended GH therapy for children with Turner syndrome, insurer policies covered GH therapy for only 52% of these children. Overall, referral and treatment decisions by physicians resulted in recommendations for GH therapy in 78% of children with GH deficiency, Turner syndrome, or renal failure; of those recommended for treatment, 28% were denied coverage by insurers. Similarly, GH therapy would be recommended by physicians for only 9% of children with idiopathic short stature, but insurers would not cover GH for the vast majority of these children. Furthermore, the data indicated considerable variation among insurers regarding coverage policies for GH (P<.01)., Conclusions: Access to GH therapy differs depending on the type of insurance coverage. The deep discord between physician recommendations and insurance coverage decisions, exemplified by these findings, represents a major challenge to mechanisms of health care decision making, access, and costs.

Objective: To assess the psychosocial functioning of adults who were evaluated as children for short stature and were not treated with human growth hormone., Design: Inception cohort study., Setting: Hospital-based pediatric endocrinology clinic., Participants: From 1975 to 1980, medical record review indicated that 181 of the children referred to our clinic for concerns about short stature were non-growth hormone deficient. In 1992 and 1993, we were able to recruit 35 of these patients for a follow-up study. Eligible subjects were at least 18 years of age at the time of follow-up., Main Outcome Measures: Standardized self-report questionnaires assessed various domains of psychosocial adjustment. Also, a brief test of intellectual functioning was administered and subjects underwent a semistructured in-person interview to evaluate pragmatic functioning and experiences associated with short stature., Results: Few significant differences between the study sample and standardization samples were found on measures of psychosocial and intellectual functioning. Within-group childhood height during the first evaluation appointment was not significantly associated with most adult measures of psychosocial adjustment. Shorter adult stature was significantly associated with lower educational achievement, lower self-esteem, and greater emotional distress., Conclusions: The absence of significant psychosocial distress or impairment in these subjects brings into question one basis for hormonal treatment for non-growth hormone deficient short stature; that short stature in childhood is likely to lead to psychological dysfunction in adulthood. The results, however, also suggest that shorter stature in adulthood may constitute a psychosocial stressor, increasing vulnerability across several domains.

Both pediatricians and pediatric endocrinologists are frequently required to evaluate children for possible disorders of linear growth. This article reviews the factors which influence growth as well as the etiologies of short and tall stature, and discusses the clinical and laboratory evaluation of abnormal growth. Recent developments in the evaluation of children with growth disorders are highlighted.

Pediatricians face clinical and ethical dilemmas about therapy to augment growth in short children who do not meet classic criteria for growth hormone (GH) deficiency. Biologic norms of health are unhelpful because of the uncertain relationship between stature, GH secretion, health, and disease. Instead, we suggest that GH therapy be evaluated from the perspective of cultural norms. We compare GH therapy for short normal children with currently accepted therapies for non--life-threatening pediatric conditions such as well-child care, cosmetic therapy, treatment of psychological problems, and invasive outpatient therapy for chronic conditions. Based on this analysis, we argue that the burdens of therapy, the uncertainty about long-term risks and benefits, the unclear therapeutic end point, and the implications for child health policy place routine GH therapy for children without documented deficiency of GH secretion outside current pediatric ethical norms. Such therapy is properly administered within a comprehensive clinical research protocol.